34
C H A P T E R
Drugs Used in Disorders
of Coagulation
James L. Zehnder, MD
C ASE STUDY
A 25-year-old woman presents to the emergency depart-
ment complaining of acute onset of shortness of breath and
pleuritic pain. She had been in her usual state of health until
2 days prior when she noted that her left leg was swollen and
red. Her only medication was oral contraceptives. Family
history was significant for a history of “blood clots” in mul-
tiple members of the maternal side of her family. Physical
examination demonstrates an anxious woman with stable
vital signs. The left lower extremity demonstrates erythema
Hemostasis refers to the finely regulated dynamic process of main-
taining fluidity of the blood, repairing vascular injury, and limit-
ing blood loss while avoiding vessel occlusion (thrombosis) and
inadequate perfusion of vital organs. Either extreme—excessive
bleeding or thrombosis—represents a breakdown of the hemo-
static mechanism. Common causes of dysregulated hemostasis
include hereditary or acquired defects in the clotting mechanism
and secondary effects of infection or cancer. Atrial fibrillation is
associated with stasis of blood in the atria, formation of clots, and
increased risk of occlusive stroke. Because of the high prevalence
of chronic atrial fibrillation, especially in the older population,
use of anticoagulants is common. Guidelines for the use of oral
anticoagulants (CHA2DS2-VASC score, see January C et al refer-
ence) are based on various risk factors (congestive heart failure,
hypertension, age, diabetes, history of stroke, vascular disease,
and sex). The drugs used to inhibit thrombosis and to limit abnor-
mal bleeding are the subjects of this chapter.
608
and edema and is tender to touch. Oxygen saturation by
fingertip pulse oximeter while breathing room air is 87%
(normal > 90%). Ultrasound reveals a deep vein thrombosis
in the left lower extremity; chest computed tomography scan
confirms the presence of pulmonary emboli. Laboratory
blood tests indicate elevated d-dimer levels. What therapy
is indicated acutely? What are the long-term therapy
options? How long should she be treated? Should this indi-
vidual use oral contraceptives?
MECHANISMS OF BLOOD
COAGULATION
The vascular endothelial cell layer lining blood vessels has an
anticoagulant phenotype, and circulating blood platelets and
clotting factors do not normally adhere to it to an appreciable
extent. In the setting of vascular injury, the endothelial cell layer
rapidly undergoes a series of changes resulting in a more proco-
agulant phenotype. Injury exposes reactive subendothelial matrix
proteins such as collagen and von Willebrand factor, which
results in platelet adherence and activation, and secretion and
synthesis of vasoconstrictors and platelet-recruiting and activating
molecules. Thus, thromboxane A2 (TXA2) is synthesized from
arachidonic acid within platelets and is a platelet activator and
potent vasoconstrictor. Products secreted from platelet granules
include adenosine diphosphate (ADP), a powerful inducer of
platelet aggregation, and serotonin (5-HT), which stimulates
 CHAPTER 34  Drugs Used in Disorders of Coagulation     609

Wall defect

C vWF EC

GP Ib
Ia
ADP GP
PGI2
TXA2
5-HT –
GP Intrinsic Extrinsic
IIb/IIIa

Platelets Xa
Degranulation
+ GP + +
+ IIb/IIIa Activation
+
GP +
IIb/IIIa
Fibrin
Thrombin Prothrombin
+

Fibrinogen

FIGURE 34–1  Thrombus formation at the site of the damaged vascular wall (EC, endothelial cell) and the role of platelets and clotting fac-
tors. Platelet membrane receptors include the glycoprotein (GP) Ia receptor, binding to collagen (C); GP Ib receptor, binding von Willebrand fac-
tor (vWF); and GP IIb/IIIa, which binds fibrinogen and other macromolecules. Antiplatelet prostacyclin (PGI2) is released from the endothelium.
Aggregating substances released from the degranulating platelet include adenosine diphosphate (ADP), thromboxane A2 (TXA2), and serotonin
(5-HT). Production of factor Xa by intrinsic and extrinsic pathways is detailed in Figure 34–2. (Redrawn and reproduced, with permission, from Simoons ML,
Decker JW: New directions in anticoagulant and antiplatelet treatment. [Editorial.] Br Heart J 1995;74:337.)

aggregation and vasoconstriction. Activation of platelets results in
a conformational change in the αIIbβIII integrin (IIb/IIIa) recep-
tor, enabling it to bind fibrinogen, which cross-links adjacent
platelets, resulting in aggregation and formation of a platelet plug
(Figure 34–1). Simultaneously, the coagulation system cascade
is activated, resulting in thrombin generation and a fibrin clot,
which stabilizes the platelet plug (see below). Knowledge of the
hemostatic mechanism is important for diagnosis of bleeding
disorders. Patients with defects in the formation of the primary
platelet plug (defects in primary hemostasis, eg, platelet function
defects, von Willebrand disease) typically bleed from surface sites
(gingiva, skin, heavy menses) with injury. In contrast, patients
with defects in the clotting mechanism (secondary hemostasis,
eg, hemophilia A) tend to bleed into deep tissues (joints, muscle,
retroperitoneum), often with no apparent inciting event, and
bleeding may recur unpredictably.
The platelet is central to normal hemostasis and thromboem-
bolic disease, and is the target of many therapies discussed in this
chapter. Platelet-rich thrombi (white thrombi) form in the high
flow rate and high shear force environment of arteries. Occlusive
arterial thrombi cause serious disease by producing downstream
ischemia of extremities or vital organs, and they can result in limb
amputation or organ failure. Venous clots tend to be more fibrin-
rich, contain large numbers of trapped red blood cells, and are
recognized pathologically as red thrombi. Deep venous thrombi
(DVT) can cause severe swelling and pain of the affected extremity,
but the most feared consequence is pulmonary embolism (PE).
This occurs when part or all of the clot breaks off from its location
in the deep venous system and travels as an embolus through the
right side of the heart and into the pulmonary arterial circulation.
Occlusion of a large pulmonary artery by an embolic clot can pre-
cipitate acute right heart failure and sudden death. In addition lung
ischemia or infarction will occur distal to the occluded pulmonary
arterial segment. Such emboli usually arise from the deep venous
system of the proximal lower extremities or pelvis. Although all
thrombi are mixed, the platelet nidus dominates the arterial throm-
bus and the fibrin tail dominates the venous thrombus.
BLOOD COAGULATION CASCADE
Blood coagulates due to the transformation of soluble fibrinogen
into insoluble fibrin by the enzyme thrombin. Several circulat-
ing proteins interact in a cascading series of limited proteolytic
reactions (Figure 34–2). At each step, a clotting factor zymogen
undergoes limited proteolysis and becomes an active protease
(eg, factor VII is converted to factor VIIa). Each protease factor
activates the next clotting factor in the sequence, culminating in
the formation of thrombin (factor IIa). Several of these factors are
targets for drug therapy (Table 34–1).
Thrombin has a central role in hemostasis and has many func-
tions. In clotting, thrombin proteolytically cleaves small peptides
610    SECTION VI  Drugs Used to Treat Diseases of the Blood, Inflammation, & Gout

Clotting in the Lab TABLE 34–1  Blood clotting factors and drugs that
1
affect them.
Contact
factors Component Target for the
or Factor Common Synonym Action of:

XIa I Fibrinogen
Tissue
II Prothrombin Heparin, dabigatran (IIa);
factor,
warfarin (synthesis)
IXa VIIa
Intrinsic VIIIa Extrinsic III Tissue thromboplastin
pathway pathway
(PT) IV Calcium
(PTT) Xa
V Proaccelerin
Va
VII Proconvertin Warfarin (synthesis)
II IIa
VIII Antihemophilic factor
(AHF)
fibrinogen fibrin IX Christmas factor, Warfarin (synthesis)
clot plasma thromboplas-
tin component (PTC)
X Stuart-Prower factor Heparin, rivaroxiban,
Clotting in Vivo apixaban, edoxaban (Xa);
warfarin (synthesis)
Wound
XI Plasma thromboplas-
Natural Anticoagulant Systems tin antecedent (PTA)
Antithrombin III/heparin XII Hageman factor
TF/VIIa
IXa Protein C/Protein S XIII Fibrin-stabilizing factor

Tissue factor pathway Proteins C Warfarin (synthesis)

inhibitor and S
XIa VIIIa Xa
Plasminogen Thrombolytic enzymes,
Va aminocaproic acid
1
Thrombin See Figure 34–2 and text for additional details.

ensures that under normal circumstances, repair of vascular injury

Fibrin
FIGURE 34–2  A model of blood coagulation. With tissue factor
(TF), factor VII forms an activated complex (VIIa-TF) that catalyzes the
activation of factor IX to factor IXa. Activated factor XIa also catalyzes
this reaction. Tissue factor pathway inhibitor inhibits the catalytic
action of the VIIa-TF complex. The cascade proceeds as shown, result-
ing ultimately in the conversion of fibrinogen to fibrin, an essential
component of a functional clot. The two major anticoagulant drugs,
heparin and warfarin, have very different actions. Heparin, acting
in the blood, directly activates anticlotting factors, specifically anti-
thrombin, which inactivates the factors enclosed in rectangles. War-
farin, acting in the liver, inhibits the synthesis of the factors enclosed
in circles. Proteins C and S exert anticlotting effects by inactivating
activated factors Va and VIIIa.
from fibrinogen, allowing fibrinogen to polymerize and form
a fibrin clot. Thrombin also activates many upstream clotting
factors, leading to more thrombin generation, and activates fac-
tor XIII, a transaminase that cross-links the fibrin polymer and
stabilizes the clot. Thrombin is a potent platelet activator and
mitogen. Thrombin also exerts anticoagulant effects by activating
the protein C pathway, which attenuates the clotting response
(Figure 34–2). It should therefore be apparent that the response to
vascular injury is a complex and precisely modulated process that
occurs without thrombosis and downstream ischemia—that is,
the response is proportionate and reversible. Eventually vascular
remodeling and repair occur with reversion to the quiescent rest-
ing anticoagulant endothelial cell phenotype.
Initiation of Clotting: The Tissue
Factor-VIIa Complex
The main initiator of blood coagulation in vivo is the tissue factor
(TF)–factor VIIa pathway (Figure 34–2). Tissue factor is a trans-
membrane protein ubiquitously expressed outside the vasculature
but not normally expressed in an active form within vessels. The
exposure of TF on damaged endothelium or to blood that has
extravasated into tissue binds TF to factor VIIa. This complex,
in turn, activates factors X and IX. Factor Xa along with factor
Va forms the prothrombinase complex on activated cell surfaces,
which catalyzes the conversion of prothrombin (factor II) to
thrombin (factor IIa). Thrombin, in turn, activates upstream clot-
ting factors, primarily factors V, VIII, and XI, resulting in ampli-
fication of thrombin generation. The TF-factor VIIa-catalyzed
activation of factor Xa is regulated by tissue factor pathway
inhibitor (TFPI). Thus after initial activation of factor X to Xa
by TF-VIIa, further propagation of the clot occurs by feedback
amplification of thrombin through the intrinsic pathway factors
 CHAPTER 34  Drugs Used in Disorders of Coagulation     611

VIII and IX. (This provides an explanation for why patients with
deficiency of factor VIII or IX—hemophilia A and hemophilia B, Plasminogen
respectively—have a severe bleeding disorder.) Activation Inhibition
It is also important to note that the coagulation mechanism Various stimuli
in vivo does not occur in solution, but is localized to activated
+
cell surfaces expressing anionic phospholipids such as phosphati-
dylserine, and is mediated by Ca2+ bridging between the anionic Blood Blood + − Antiactivators
phospholipids and γ-carboxyglutamic acid residues of the clotting proactivator activator

factors. This is the basis for using calcium chelators such as eth- t-PA, urokinase + − Aminocaproic
ylenediamine tetraacetic acid (EDTA) or citrate to prevent blood acid
Streptokinase
from clotting in a test tube.
Antithrombin (AT) is an endogenous anticoagulant and a Activator +
member of the serine protease inhibitor (serpin) family; it inacti-
Proactivator
vates the serine proteases IIa, IXa, Xa, XIa, and XIIa. The endog- Plasmin
enous anticoagulants protein C and protein S attenuate the blood Anistreplase
clotting cascade by proteolysis of the two cofactors Va and VIIIa. + +
From an evolutionary perspective, it is of interest that factors V
Thrombin Fibrin
and VIII have an identical overall domain structure and consider- Fibrinogen
Fibrinogen Fibrin clot degradation
degradation
able homology, consistent with a common ancestor gene; likewise products
products,
Factor XIII D-dimer
the serine proteases are descendants of a trypsin-like common
ancestor. Thus, the TF-VIIa initiating complex, serine proteases,
and cofactors each have their own lineage-specific attenuation FIGURE 34–3  Schematic representation of the fibrinolytic
mechanism (Figure 34–2). Defects in natural anticoagulants system. Plasmin is the active fibrinolytic enzyme. Several clinically
result in an increased risk of venous thrombosis. The most com- useful activators are shown on the left in bold. Anistreplase is a
mon defect in the natural anticoagulant system is a mutation in combination of streptokinase and the proactivator plasminogen.
factor V (factor V Leiden), which results in resistance to inactiva- Aminocaproic acid (right) inhibits the activation of plasminogen to
plasmin and is useful in some bleeding disorders. t-PA, tissue plas-
tion by the protein C/protein S mechanism.
minogen activator.

Fibrinolysis follow massive tissue injury, advanced cancers, obstetric emergen-

Fibrinolysis refers to the process of fibrin digestion by the fibrin-
specific protease, plasmin. The fibrinolytic system is similar to
the coagulation system in that the precursor form of the serine
protease plasmin circulates in an inactive form as plasminogen.
In response to injury, endothelial cells synthesize and release tis-
sue plasminogen activator (t-PA), which converts plasminogen
to plasmin (Figure 34–3). Plasmin remodels the thrombus and
limits its extension by proteolytic digestion of fibrin.
Both plasminogen and plasmin have specialized protein
domains (kringles) that bind to exposed lysines on the fibrin clot
and impart clot specificity to the fibrinolytic process. It should be
noted that this clot specificity is only observed at physiologic levels
of t-PA. At the pharmacologic levels of t-PA used in thrombolytic
therapy, clot specificity is lost and a systemic lytic state is created,
with attendant increase in bleeding risk. As in the coagulation
cascade, there are negative regulators of fibrinolysis: endothelial
cells synthesize and release plasminogen activator inhibitor (PAI),
which inhibits t-PA; in addition α2 antiplasmin circulates in the
blood at high concentrations and under physiologic conditions
will rapidly inactivate any plasmin that is not clot-bound. How-
ever, this regulatory system is overwhelmed by therapeutic doses
of plasminogen activators.
If the coagulation and fibrinolytic systems are pathologically
activated, the hemostatic system may careen out of control, lead-
ing to generalized intravascular clotting and bleeding. This process
is called disseminated intravascular coagulation (DIC) and may
cies such as abruptio placentae or retained products of conception,
or bacterial sepsis. The treatment of DIC is to control the underly-
ing disease process; if this is not possible, DIC is often fatal.
Regulation of the fibrinolytic system is useful in therapeutics.
Increased fibrinolysis is effective therapy for thrombotic disease.
Tissue plasminogen activator, urokinase, and streptokinase
all activate the fibrinolytic system (Figure 34–3). Conversely,
decreased fibrinolysis protects clots from lysis and reduces the
bleeding of hemostatic failure. Aminocaproic acid is a clinically
useful inhibitor of fibrinolysis. Heparin and the oral anticoagulant
drugs do not affect the fibrinolytic mechanism.
■■ BASIC PHARMACOLOGY OF
THE ANTICOAGULANT DRUGS
The ideal anticoagulant drug would prevent pathologic throm-
bosis and limit reperfusion injury yet allow a normal response
to vascular injury and limit bleeding. Theoretically this could
be accomplished by preservation of the TF-VIIa initiation phase
of the clotting mechanism with attenuation of the secondary
intrinsic pathway propagation phase of clot development. At
this time such a drug does not exist; all anticoagulants and fibri-
nolytic drugs have an increased bleeding risk as their principle
toxicity.
612    SECTION VI  Drugs Used to Treat Diseases of the Blood, Inflammation, & Gout

INDIRECT THROMBIN INHIBITORS composed of d-glucosamine-l-iduronic acid and d-glucosamine-

The indirect thrombin inhibitors are so-named because their
antithrombotic effect is exerted by their interaction with a
separate protein, antithrombin. Unfractionated heparin (UFH),
also known as high-molecular-weight (HMW) heparin, low-
molecular-weight (LMW) heparin, and the synthetic pentasac-
charide fondaparinux bind to antithrombin and enhance its
inactivation of factor Xa (Figure 34–4). Unfractionated heparin
and to a lesser extent LMW heparin also enhance antithrombin’s
inactivation of thrombin.
HEPARIN
Chemistry & Mechanism of Action
Heparin is a heterogeneous mixture of sulfated mucopolysaccha-
rides. It binds to endothelial cell surfaces and a variety of plasma
proteins. Its biologic activity is dependent upon the endogenous
anticoagulant antithrombin. Antithrombin inhibits clotting
factor proteases, especially thrombin (IIa), IXa, and Xa, by form-
ing equimolar stable complexes with them. In the absence of
heparin, these reactions are slow; in the presence of heparin, they
are accelerated 1000-fold. Only about a third of the molecules
in commercial heparin preparations have an accelerating effect
because the remainder lack the unique pentasaccharide sequence
needed for high-affinity binding to antithrombin. The active
heparin molecules bind tightly to antithrombin and cause a con-
formational change in this inhibitor. The conformational change
of antithrombin exposes its active site for more rapid interaction
with the proteases (the activated clotting factors). Heparin func-
tions as a cofactor for the antithrombin-protease reaction without
being consumed. Once the antithrombin-protease complex is
formed, heparin is released intact for renewed binding to more
antithrombin.
The antithrombin binding region of commercial unfraction-
ated heparin consists of repeating sulfated disaccharide units
d-glucuronic acid. High-molecular-weight fractions of heparin
with high affinity for antithrombin markedly inhibit blood
coagulation by inhibiting all three factors, especially thrombin and
factor Xa. Unfractionated heparin has a molecular weight range of
5000–30,000 Da. In contrast, the shorter-chain, low-molecular-
weight fractions of heparin inhibit activated factor X but have
less effect on thrombin than the HMW species. Nevertheless,
numerous studies have demonstrated that LMW heparins such
as enoxaparin, dalteparin, and tinzaparin are effective in several
thromboembolic conditions. In fact, these LMW heparins—in
comparison with UFH—have equal efficacy, increased bioavail-
ability from the subcutaneous site of injection, and less frequent
dosing requirements (once or twice daily is sufficient).
USP heparin is harmonized to the World Health Organization
International Standard (IS) unit dose. Enoxaparin is obtained
from the same sources as regular UFH, but doses are specified in
milligrams. Fondaparinux also is specified in milligrams. Daltepa-
rin, tinzaparin, and danaparoid (an LMW heparinoid containing
heparan sulfate, dermatan sulfate, and chondroitin sulfate), on the
other hand, are specified in anti-factor Xa units.
Monitoring of Heparin Effect
Close monitoring of the activated partial thromboplastin time
(aPTT or PTT) is necessary in patients receiving UFH. Levels of
UFH may also be determined by protamine titration (therapeu-
tic levels 0.2–0.4 unit/mL) or anti-Xa units (therapeutic levels
0.3–0.7 unit/mL). Weight-based dosing of the LMW heparins
results in predictable pharmacokinetics and plasma levels in
patients with normal renal function. Therefore, LMW heparin
levels are not generally measured except in the setting of renal
insufficiency, obesity, and pregnancy. LMW heparin levels can be
determined by anti-Xa units. For enoxaparin, peak therapeutic
levels should be 0.5–1 unit/mL for twice-daily dosing, determined
4 hours after administration, and approximately 1.5 units/mL for
once-daily dosing.

Antithrombin III
(inactive)

Thrombin
Antithrombin III Antithrombin III Factor
Thrombin
(active) (active) Xa
Factor
Factor IXa
Unfractionated Heparin XIa
LMW Heparin

FIGURE 34–4  Differences between low-molecular-weight (LMW) heparins and high-molecular-weight heparin (unfractionated heparin).
Fondaparinux is a small pentasaccharide fragment of heparin. Activated antithrombin III (AT III) degrades thrombin, factor X, and several other
factors. Binding of these drugs to AT III can increase the catalytic action of AT III 1000-fold. The combination of AT III with unfractionated heparin
increases degradation of both factor Xa and thrombin. Combination with fondaparinux or LMW heparin more selectively increases degradation
of Xa.
 CHAPTER 34  Drugs Used in Disorders of Coagulation     613

Toxicity Administration & Dosage

A. Bleeding and Miscellaneous Effects The indications for the use of heparin are described in the section
The major adverse effect of heparin is bleeding. This risk can on clinical pharmacology. A plasma concentration of heparin of
be decreased by scrupulous patient selection, careful control of 0.2–0.4 unit/mL (by protamine titration) or 0.3–0.7 unit/mL
dosage, and close monitoring. Elderly women and patients with (anti-Xa units) is considered to be the therapeutic range for
renal failure are more prone to hemorrhage. Heparin is of animal treatment of venous thromboembolic disease. This concentra-
origin and should be used cautiously in patients with allergy. tion generally corresponds to a PTT of 1.5–2.5 times baseline.
Increased loss of hair and reversible alopecia have been reported. However, the use of the PTT for heparin monitoring is problem-
Long-term heparin therapy is associated with osteoporosis and atic. There is no standardization scheme for the PTT as there is
spontaneous fractures. Heparin accelerates the clearing of post- for the prothrombin time (PT) and its international normalized
prandial lipemia by causing the release of lipoprotein lipase from ratio (INR) in warfarin monitoring. The PTT in seconds for a
tissues, and long-term use is associated with mineralocorticoid given heparin concentration varies between different reagent/
deficiency. instrument systems. Thus, if the PTT is used for monitoring, the
laboratory should determine the clotting time that corresponds to
B. Heparin-Induced Thrombocytopenia the therapeutic range by protamine titration or anti-Xa activity,
as listed above.
Heparin-induced thrombocytopenia (HIT) is a systemic hyper-
In addition, some patients have a prolonged baseline PTT due
coagulable state that occurs in 1–4% of individuals treated with
to factor deficiency or inhibitors (which could increase bleeding
UFH. Surgical patients are at greatest risk. The reported incidence
risk) or lupus anticoagulant (which is not associated with bleeding
of HIT is lower in pediatric populations outside the critical care
risk but may be associated with thrombosis risk). Using the PTT
setting; it is relatively rare in pregnant women. The risk of HIT
to assess heparin effect in such patients is problematic. An alter-
may be higher in individuals treated with UFH of bovine origin
native is to use anti-Xa activity to assess heparin concentration, a
compared with porcine heparin and is lower in those treated
test now widely available on automated coagulation instruments.
exclusively with LMW heparin.
This approach measures heparin concentration; however, it does
Morbidity and mortality in HIT are related to thrombotic
not provide the global assessment of intrinsic pathway integrity
events. Venous thrombosis occurs most commonly, but occlusion
of the PTT.
of peripheral or central arteries is not infrequent. If an indwell-
The following strategy is recommended: prior to initiating
ing catheter is present, the risk of thrombosis is increased in that
anticoagulant therapy of any type, the integrity of the patient’s
extremity. Skin necrosis has been described, particularly in indi-
hemostatic system should be assessed by a careful history of
viduals treated with warfarin in the absence of a direct thrombin
prior bleeding events, as well as baseline PT and PTT. If there
inhibitor, presumably due to acute depletion of the vitamin K–
is a prolonged clotting time, the cause of this (deficiency or
dependent anticoagulant protein C occurring in the presence of
inhibitor) should be determined prior to initiating therapy, and
high levels of procoagulant proteins and an active hypercoagulable
treatment goals stratified to a risk-benefit assessment. In high-
state.
risk patients measuring both the PTT and anti-Xa activity may
The following points should be considered in all patients
be useful. When intermittent heparin administration is used,
receiving heparin: Platelet counts should be performed frequently;
the aPTT or anti-Xa activity should be measured 6 hours after
thrombocytopenia appearing in a time frame consistent with an
the administered dose to maintain prolongation of the aPTT to
immune response to heparin should be considered suspicious for
2–2.5 times that of the control value. However, LMW heparin
HIT; and any new thrombus occurring in a patient receiving hep-
therapy is the preferred option in this case, as no monitoring is
arin therapy should raise suspicion of HIT. Patients who develop
required in most patients.
HIT are treated by discontinuance of heparin and administration
Continuous intravenous administration of heparin is accom-
of the direct thrombin inhibitor argatroban.
plished via an infusion pump. After an initial bolus injection of
80–100 units/kg, a continuous infusion of about 15–22 units/kg
Contraindications per hour is required to maintain the anti-Xa activity in the
range of 0.3–0.7 units/mL. Low-dose prophylaxis is achieved
Heparin is contraindicated in patients with HIT, hypersensitivity
with subcutaneous administration of heparin, 5000 units
to the drug, active bleeding, hemophilia, significant thrombocy-
every 8–12 hours. Because of the danger of hematoma forma-
topenia, purpura, severe hypertension, intracranial hemorrhage,
tion at the injection site, heparin must never be administered
infective endocarditis, active tuberculosis, ulcerative lesions of the
intramuscularly.
gastrointestinal tract, threatened abortion, visceral carcinoma, or
Prophylactic enoxaparin is given subcutaneously in a dosage
advanced hepatic or renal disease. Heparin should be avoided in
of 30 mg twice daily or 40 mg once daily. Full-dose enoxaparin
patients who have recently had surgery of the brain, spinal cord,
therapy is 1 mg/kg subcutaneously every 12 hours. This cor-
or eye; and in patients who are undergoing lumbar puncture or
responds to a therapeutic anti-factor Xa level of 0.5–1 unit/mL.
regional anesthetic block. Despite the apparent lack of placental
Selected patients may be treated with enoxaparin 1.5 mg/kg
transfer, heparin should be used in pregnant women only when
once a day, with a target anti-Xa level of 1.5 units/mL.
clearly indicated.
614    SECTION VI  Drugs Used to Treat Diseases of the Blood, Inflammation, & Gout
The prophylactic dosage of dalteparin is 5000 units subcuta-
neously once a day; therapeutic dosing is 200 units/kg once a
day for venous disease or 120 units/kg every 12 hours for acute
coronary syndrome. LMW heparin should be used with caution
in patients with renal insufficiency or body weight greater than
150 kg. Measurement of the anti-Xa level is useful to guide dos-
ing in these individuals.
The synthetic pentasaccharide molecule fondaparinux
avidly binds antithrombin with high specific activity, result-
ing in efficient inactivation of factor Xa. Fondaparinux has a
long half-life of 15 hours, allowing for once-daily dosing by
subcutaneous administration. Fondaparinux is effective in the
prevention and treatment of venous thromboembolism and
does not appear to cross-react with pathologic HIT antibodies
in most individuals.
Reversal of Heparin Action
Excessive anticoagulant action of heparin is treated by discon-
tinuance of the drug. If bleeding occurs, administration of a
specific antagonist such as protamine sulfate is indicated. Prot-
amine is a highly basic, positively charged peptide that combines
with negatively charged heparin as an ion pair to form a stable
complex devoid of anticoagulant activity. For every 100 units
of heparin remaining in the patient, 1 mg of protamine sulfate
is given intravenously; the rate of infusion should not exceed
50 mg in any 10-minute period. Excess protamine must be
avoided; it also has an anticoagulant effect. Neutralization of
LMW heparin by protamine is incomplete. Limited experience
suggests that 1 mg of protamine sulfate may be used to partially
neutralize 1 mg of enoxaparin. Protamine will not reverse the
activity of fondaparinux. Excess danaparoid can be removed by
plasmapheresis.
OH OH
CH2
O O O O O
Dicumarol
O
O
Phenindione
FIGURE 34–5  Structural formulas of several oral anticoagulant drugs and of vitamin K. The carbon atom of warfarin shown at the asterisk
is an asymmetric center.
WARFARIN & OTHER COUMARIN
ANTICOAGULANTS
Chemistry & Pharmacokinetics
The clinical use of the coumarin anticoagulants began with the
discovery of an anticoagulant substance formed in spoiled sweet
clover silage, which caused hemorrhagic disease in cattle. At the
behest of local farmers, a chemist at the University of Wisconsin
identified the toxic agent as bishydroxycoumarin. Dicumarol, a
synthesized derivative, and its congeners, most notably warfarin
(Wisconsin Alumni Research Foundation, with “-arin” from cou-
marin added; Figure 34–5), were initially used as rodenticides.
In the 1950s, warfarin (under the brand name Coumadin) was
introduced as an antithrombotic agent in humans. Warfarin is one
of the most commonly prescribed drugs.
Warfarin is generally administered as the sodium salt and has
100% oral bioavailability. Over 99% of racemic warfarin is bound
to plasma albumin, which may contribute to its small volume
of distribution (the albumin space), its long half-life in plasma
(36 hours), and the lack of urinary excretion of unchanged drug.
Warfarin used clinically is a racemic mixture composed of equal
amounts of two enantiomorphs. The levorotatory S-warfarin is
four times more potent than the dextrorotatory R-warfarin. This
observation is useful in understanding the stereoselective nature of
several drug interactions involving warfarin.
Mechanism of Action
Coumarin anticoagulants block the γ-carboxylation of several glu-
tamate residues in prothrombin and factors VII, IX, and X as well
as the endogenous anticoagulant proteins C and S (Figure 34–2,
Table 34–1). The blockade results in incomplete coagulation
CH2 CO CH3
ONa
CH
*
O
Warfarin sodium
O
CH3
CH3
CH2 CH C C16H33
O
Phytonadione (vitamin K1)

factor molecules that are biologically inactive. The protein car-
boxylation reaction is coupled to the oxidation of vitamin K. The
vitamin must then be reduced to reactivate it. Warfarin prevents
reductive metabolism of the inactive vitamin K epoxide back to
its active hydroquinone form (Figure 34–6). Mutational change
of the gene for the responsible enzyme, vitamin K epoxide reduc-
tase (VKORC1), can give rise to genetic resistance to warfarin in
humans and rodents.
There is an 8- to 12-hour delay in the action of warfarin.
Its anticoagulant effect results from a balance between partially
inhibited synthesis and unaltered degradation of the four vita-
min K–dependent clotting factors. The resulting inhibition
of coagulation is dependent on their degradation half-lives in
the circulation. These half-lives are 6, 24, 40, and 60 hours for
factors VII, IX, X, and II, respectively. Importantly, protein C
has a short half-life similar to factor VIIa. Thus the immediate
effect of warfarin is to deplete the procoagulant factor VII and
anticoagulant protein C, which can paradoxically create a tran-
sient hypercoagulable state due to residual activity of the longer
half-life procoagulants in the face of protein C depletion (see
below). For this reason in patients with active hypercoagulable
states, such as acute DVT or PE, UFH or LMW heparin is
always used to achieve immediate anticoagulation until adequate
warfarin-induced depletion of the procoagulant clotting factors
is achieved. The duration of this overlapping therapy is generally
5–7 days.
COO– –
OOC COO–
CH2 CH
CH2 CH2
Descarboxy- Prothrombin
prothrombin
CO2
Carboxylase
OH O2 O
CH3 CH3
O give the same INR results for a given sample. For most reagent
R R
OH O
KH2 KO
Warfarin
FIGURE 34–6  Vitamin K cycle–metabolic interconversions of
vitamin K associated with the synthesis of vitamin K–dependent clot-
ting factors. Vitamin K1 or K2 is activated by reduction to the hydro-
quinone form (KH2). Stepwise oxidation to vitamin K epoxide (KO) is
coupled to prothrombin carboxylation by the enzyme carboxylase.
The reactivation of vitamin K epoxide is the warfarin-sensitive step
(warfarin). The R on the vitamin K molecule represents a 20-carbon
phytyl side chain in vitamin K1 and a 30- to 65-carbon polyprenyl side
chain in vitamin K2.
CHAPTER 34  Drugs Used in Disorders of Coagulation     615
Toxicity
Warfarin crosses the placenta readily and can cause a hemor-
rhagic disorder in the fetus. Furthermore, fetal proteins with
γ-carboxyglutamate residues found in bone and blood may be
affected by warfarin; the drug can cause a serious birth defect
characterized by abnormal bone formation. Thus, warfarin should
never be administered during pregnancy. Cutaneous necrosis
with reduced activity of protein C sometimes occurs during the
first weeks of therapy in patients who have inherited deficiency
of protein C. Rarely, the same process causes frank infarction of
the breast, fatty tissues, intestine, and extremities. The pathologic
lesion associated with the hemorrhagic infarction is venous throm-
bosis, consistent with a hypercoagulable state due to warfarin-
induced depletion of protein C.
Administration & Dosage
Treatment with warfarin should be initiated with standard doses
of 5–10 mg. The initial adjustment of the prothrombin time takes
about 1 week, which usually results in a maintenance dosage of
5–7 mg/d. The prothrombin time (PT) should be increased to
a level representing a reduction of prothrombin activity to 25%
of normal and maintained there for long-term therapy. When the
activity is less than 20%, the warfarin dosage should be reduced
or omitted until the activity rises above 20%. Inherited poly-
morphisms in 2CYP2C9 and VKORC1 have significant effects
on warfarin dosing; however, algorithms incorporating genomic
information to predict initial warfarin dosing were no better than
standard clinical algorithms in two of three large randomized trials
examining this issue (see Chapter 5).
The therapeutic range for oral anticoagulant therapy is defined
in terms of an international normalized ratio (INR). The INR
is the prothrombin time ratio (patient prothrombin time/mean
of normal prothrombin time for lab)ISI, where the ISI exponent
refers to the International Sensitivity Index and is dependent on
the specific reagents and instruments used for the determination.
The ISI serves to relate measured prothrombin times to a World
Health Organization reference standard thromboplastin; thus the
prothrombin times performed on different properly calibrated
instruments with a variety of thromboplastin reagents should
and instrument combinations in current use, the ISI is close to
1, making the INR roughly the ratio of the patient prothrombin
time to the mean normal prothrombin time. The recommended
INR for prophylaxis and treatment of thrombotic disease is 2–3.
Patients with some types of artificial heart valves (eg, tilting disk)
or other medical conditions increasing thrombotic risk have a
recommended range of 2.5–3.5. While a prolonged INR is widely
used as an indication of integrity of the coagulation system in liver
disease and other disorders, it has been validated only in patients
in steady state on chronic warfarin therapy.
Occasionally patients exhibit warfarin resistance, defined as
progression or recurrence of a thrombotic event while in the
therapeutic range. These individuals may have their INR target
raised (which is accompanied by an increase in bleeding risk) or
616    SECTION VI  Drugs Used to Treat Diseases of the Blood, Inflammation, & Gout

be changed to an alternative form of anticoagulation (eg, daily for their hypoprothrombinemic interaction are a stereoselective
injections of LMW heparin or one of the newer oral anticoagu- inhibition of oxidative metabolic transformation of S-warfarin
lants). Warfarin resistance is most commonly seen in patients with (the more potent isomer) and displacement of albumin-bound
advanced cancers, typically of gastrointestinal origin (Trousseau’s warfarin, increasing the free fraction. For this and other reasons,
syndrome). LMW heparin is superior to warfarin in preventing neither phenylbutazone nor sulfinpyrazone is in common use in
recurrent venous thromboembolism in patients with cancer. the United States. Metronidazole, fluconazole, and trimethoprim-
sulfamethoxazole also stereoselectively inhibit the metabolic
Drug Interactions transformation of S-warfarin, whereas amiodarone, disulfiram,
and cimetidine inhibit metabolism of both enantiomorphs of
The coumarin anticoagulants often interact with other drugs and warfarin (see Chapter 4). Aspirin, hepatic disease, and hyper-
with disease states. These interactions can be broadly divided into thyroidism augment warfarin’s effects—aspirin by its effect on
pharmacokinetic and pharmacodynamic effects (Table 34–2). platelet function and the latter two by increasing the turnover rate
Pharmacokinetic mechanisms for drug interaction with warfarin of clotting factors. The third-generation cephalosporins eliminate
mainly involve cytochrome P450 CYP2C9 enzyme induction, the bacteria in the intestinal tract that produce vitamin K and, like
enzyme inhibition, and reduced plasma protein binding. Phar- warfarin, also directly inhibit vitamin K epoxide reductase.
macodynamic mechanisms for interactions with warfarin are Barbiturates and rifampin cause a marked decrease of the
synergism (impaired hemostasis, reduced clotting factor synthesis, anticoagulant effect by induction of the hepatic enzymes that
as in hepatic disease), competitive antagonism (vitamin K), and transform racemic warfarin. Cholestyramine binds warfarin in the
an altered physiologic control loop for vitamin K (hereditary intestine and reduces its absorption and bioavailability.
resistance to oral anticoagulants). Pharmacodynamic reductions of anticoagulant effect occur
The most serious interactions with warfarin are those that with increased vitamin K intake (increased synthesis of clotting
increase the anticoagulant effect and the risk of bleeding. The factors), the diuretics chlorthalidone and spironolactone (clotting
most dangerous of these interactions are the pharmacokinetic factor concentration), hereditary resistance (mutation of vitamin
interactions with the mostly obsolete pyrazolones phenylbu- K reactivation cycle molecules), and hypothyroidism (decreased
tazone and sulfinpyrazone. These drugs not only augment the turnover rate of clotting factors).
hypoprothrombinemia but also inhibit platelet function and may Drugs with no significant effect on anticoagulant therapy
induce peptic ulcer disease (see Chapter 36). The mechanisms include ethanol, phenothiazines, benzodiazepines, acetamino-
phen, opioids, indomethacin, and most antibiotics.
TABLE 34–2  Pharmacokinetic and
pharmacodynamic drug and body Reversal of Warfarin Action
interactions with oral anticoagulants.
Excessive anticoagulant effect and bleeding from warfarin can be
Increased Prothrombin Time Decreased Prothrombin Time reversed by stopping the drug and administering oral or parenteral
vitamin K1 (phytonadione), fresh-frozen plasma, prothrombin
Pharmacokinetic Pharmacokinetic
complex concentrates, and recombinant factor VIIa (rFVIIa). A
Amiodarone Barbiturates four-factor concentrate containing factors II, VII, IX, and X (Pro-
Cimetidine Cholestyramine thrombin Complex Concentrate, [Human]; Kcentra) (4F PCC)
Disulfiram Rifampin is available. The disappearance of excessive effect is not correlated
Fluconazole 1 with plasma warfarin concentrations but rather with reestablish-
ment of normal activity of the clotting factors. A modest excess of
Metronidazole1
anticoagulant effect without bleeding may require no more than
Phenylbutazone1 cessation of the drug. The warfarin effect can be rapidly reversed
Sulfinpyrazone1 in the setting of severe bleeding with the administration of pro-
Trimethoprim-sulfamethoxazole thrombin complex or rFVIIa coupled with intravenous vitamin K.
Pharmacodynamic Pharmacodynamic
It is important to note that due to the long half-life of warfarin, a
single dose of vitamin K or rFVIIa may not be sufficient.
Drugs Drugs
Aspirin (high doses) Diuretics
Cephalosporins, third-generation Vitamin K
ORAL DIRECT FACTOR Xa
Heparin, argatroban, dabigatran, INHIBITORS
rivaroxaban, apixaban
Oral Xa inhibitors, including rivaroxaban, apixaban, and edoxa-
Body factors Body factors ban represent a new class of oral anticoagulant drugs that require
Hepatic disease Hereditary resistance no monitoring. Along with oral direct thrombin inhibitors
Hyperthyroidism Hypothyroidism (discussed below) this new class of direct oral anticoagulant
1
Stereoselectively inhibits the oxidative metabolism of the S-warfarin enantiomorph
(DOAC) drugs is having a major impact on antithrombotic
of racemic warfarin. pharmacotherapy.

Pharmacology
Rivaroxaban, apixaban, and edoxaban inhibit factor Xa, in the
final common pathway of clotting (see Figure 34–2). These drugs
are given as fixed doses and do not require monitoring. They have
a rapid onset of action and shorter half-lives than warfarin.
Rivaroxaban has high oral bioavailability when taken with
food. Following an oral dose, the peak plasma level is achieved
within 2–4 hours; the drug is extensively protein-bound. It is a
substrate for the cytochrome P450 system and the P-glycoprotein
transporter. Drugs inhibiting both CYP3A4 and P-glycoprotein
(eg, ketoconazole) result in increased rivaroxaban effect. One third
of the drug is excreted unchanged in the urine and the remainder
is metabolized and excreted in the urine and feces. The drug half-
life is 5–9 hours in patients age 20–45 years and is increased in
the elderly and in those with impaired renal or hepatic function.
Apixaban has an oral bioavailability of 50% and prolonged
absorption, resulting in a half-life of 12 hours with repeat dos-
ing. The drug is a substrate of the cytochrome P450 system and
P-glycoprotein and is excreted in the urine and feces. As with riva-
roxaban, drugs inhibiting both CYP3A4 and P-glycoprotein, as
well as impairment of renal or hepatic function, result in increased
drug effect.
Edoxaban is a once-daily Xa inhibitor with a 62% oral bio-
availability. Peak drug concentrations occur 1–2 hours after dosage
and are not affected by food. The drug half-life is 10–14 hours.
Edoxaban does not induce CYP450 enzymes. No dose reduc-
tion is required with concurrent use of P-glycoprotein inhibitors.
Edoxaban is primarily excreted unchanged in the urine.
Administration & Dosage
Rivaroxaban is approved for prevention of embolic stroke in
patients with atrial fibrillation without valvular heart disease,
prevention of venous thromboembolism following hip or knee
surgery, and treatment of venous thromboembolic disease (VTE).
The prophylactic dosage is 10 mg orally per day for 35 days for
hip replacement or 12 days for knee replacement. For treatment
of DVT/PE the dosage is 15 mg twice daily for 3 weeks followed
by 20 mg/d. Depending on clinical presentation and risk factors,
patients with VTE are treated for 3–6 months; rivaroxaban is also
approved for prolonged therapy in selected patients to reduce
recurrence risk at the treatment dose. Apixaban is approved for
prevention of stroke in nonvalvular atrial fibrillation, for preven-
tion of VTE following hip or knee surgery, and for treatment and
long-term prevention of VTE. The dosage for atrial fibrillation is
5 mg twice daily; the dose for VTE is 10 mg twice a day for the
first week, followed by 5 mg twice a day. The prophylactic dose
for prevention of VTE following hip or knee surgery or long-term
prevention of VTE following initial therapy is 2.5 mg twice a day.
The recommended duration of therapy in hip and knee replace-
ment is the same as for rivaroxaban. Edoxaban is approved for
prevention of stroke in nonvalvular atrial fibrillation, and to treat
VTE following treatment with heparin or LMWH for 5–10 days.
The dose for atrial fibrillation and VTE treatment is 60 mg once
daily. For patients with creatinine clearance of 15–50 mL/min or
those taking concomitant P-glycoprotein inhibitors, the dose is
CHAPTER 34  Drugs Used in Disorders of Coagulation     617
30 mg once daily. Edoxaban is contraindicated in patients with
atrial fibrillation and creatinine clearance >95 mL/min, due to
the increased rate of ischemic stroke in this group compared with
patients taking warfarin.
Assessment of and Reversal of Anti-Xa
Drug Effect
Measurement of anti-Xa drug effect is not needed in most situa-
tions but can be accomplished by anti-Xa assays calibrated for the
drug in question. Andexanet alfa is a factor Xa “decoy” molecule
without procoagulant activity that competes for binding to anti-
Xa drugs. In clinical trials involving apixaban and rivaroxaban,
andexanet given by IV infusion resulted in rapid decrease in anti-
Xa effect. Non-neutralizing antibodies occurred in 17% of those
treated; the effect of these antibodies with drug re-exposure is
not known. Based on the available data, andexanet is likely to be
the first antidote approved for use in patients treated with anti-
Xa agents who require rapid reversal for surgery or uncontrolled
bleeding.
DIRECT THROMBIN INHIBITORS
The direct thrombin inhibitors (DTIs) exert their anticoagulant
effect by directly binding to the active site of thrombin, thereby
inhibiting thrombin’s downstream effects. This is in contrast to
indirect thrombin inhibitors such as heparin and LMW hepa-
rin (see above), which act through antithrombin. Hirudin and
bivalirudin are large, bivalent DTIs that bind at the catalytic or
active site of thrombin as well as at a substrate recognition site.
Argatroban and melagatran are small molecules that bind only
at the thrombin active site.
PARENTERAL DIRECT THROMBIN
INHIBITORS
Leeches have been used for bloodletting since the age of Hip-
pocrates. More recently, surgeons have used medicinal leeches
(Hirudo medicinalis) to prevent thrombosis in the fine vessels
of reattached digits. Hirudin is a specific, irreversible throm-
bin inhibitor from leech saliva that for a time was available in
recombinant form as lepirudin. Its action is independent of anti-
thrombin, which means it can reach and inactivate fibrin-bound
thrombin in thrombi. Lepirudin has little effect on platelets or the
bleeding time. Like heparin, it must be administered parenterally
and is monitored by aPTT. Lepirudin was approved by the U.S.
Food and Drug Administration (FDA) for use in patients with
thrombosis related to heparin-induced thrombocytopenia (HIT).
Lepirudin is excreted by the kidney and should be used with great
caution in patients with renal insufficiency as no antidote exists.
Up to 40% of patients who receive long-term infusions develop
an antibody directed against the thrombin-lepirudin complex.
These antigen-antibody complexes are not cleared by the kidney
and may result in an enhanced anticoagulant effect. Some patients
re-exposed to the drug developed life-threatening anaphylactic
618    SECTION VI  Drugs Used to Treat Diseases of the Blood, Inflammation, & Gout
reactions. Lepirudin production was discontinued by the manu-
facturer in 2012.
Bivalirudin, another bivalent inhibitor of thrombin, is admin-
istered intravenously, with a rapid onset and offset of action. The
drug has a short half-life with clearance that is 20% renal and the
remainder metabolic. Bivalirudin also inhibits platelet activation
and has been FDA-approved for use in percutaneous coronary
angioplasty.
Argatroban is a small molecule thrombin inhibitor that is
FDA-approved for use in patients with HIT with or without
thrombosis and coronary angioplasty in patients with HIT. It,
too, has a short half-life, is given by continuous intravenous infu-
sion, and is monitored by aPTT. Its clearance is not affected by
renal disease but is dependent on liver function; dose reduction is
required in patients with liver disease. Patients on argatroban will
demonstrate elevated INRs, rendering the transition to warfarin
difficult (ie, the INR will reflect contributions from both warfarin
and argatroban). (INR is discussed in detail in the section on
warfarin administration.) A nomogram is supplied by the manu-
facturer to assist in this transition.
ORAL DIRECT THROMBIN INHIBITOR
Advantages of oral direct thrombin inhibition include predictable
pharmacokinetics and bioavailability, which allow for fixed dosing
and predictable anticoagulant response and make routine coagu-
lation monitoring unnecessary. Similar to the direct oral anti-Xa
drugs described above, the rapid onset and offset of action of these
agents allow for immediate anticoagulation.
Dabigatran etexilate mesylate is the only oral direct thrombin
inhibitor approved by the FDA. Dabigatran is approved for reduc-
tion in risk of stroke and systemic embolism with nonvalvular
atrial fibrillation, treatment of VTE following 5–7 days of initial
heparin or LMWH therapy, reduction of the risk of recurrent
VTE, and VTE prophylaxis following hip or knee replacement
surgery.
Pharmacology
Dabigatran and its metabolites are direct thrombin inhibitors.
Following oral administration, dabigatran etexilate mesylate is
converted to dabigatran. The oral bioavailability is 3–7% in
normal volunteers. The drug is a substrate for the P-glycoprotein
efflux pump; P-glycoprotein inhibitors such as ketoconazole
should be avoided in patients with impaired renal function. The
half-life of the drug in normal volunteers is 12–17 hours. Renal
impairment results in prolonged drug clearance.
Administration & Dosage
For prevention of stroke and systemic embolism in nonvalvular
atrial fibrillation, the dosage is 150 mg twice daily for patients
with creatinine clearance greater than 30 mL/min. For decreased
creatinine clearance of 15–30 mL/min, the dosage is 75 mg twice
daily. No monitoring is required.
Assessment of and Reversal of
Antithrombin Drug Effect
As with any anticoagulant drug, the primary toxicity of dabigatran
is bleeding. Dabigatran will prolong the PTT, thrombin time, and
ecarin clotting time, which can be used to estimate drug effect
if necessary. The ecarin clotting time [ECT] is another clotting
test based on the use of a protein isolated from viper venom.
Idarucizumab is a humanized monoclonal antibody Fab fragment
that binds to dabigatran and reverses the anticoagulant effect. The
drug is approved for use in situations requiring emergent surgery
or for life-threatening bleeding. The recommended dose is 5 g
given intravenously. If bleeding re-occurs a second dose may be
given. The drug is primarily excreted by the kidneys. The half-life
in patients with normal renal function is approximately 1 hour.
Summary of the Direct Oral Anticoagulant
Drugs
The direct oral anticoagulant drugs have consistently shown
equivalent antithrombotic efficacy and lower bleeding rates when
compared with traditional warfarin therapy. In addition, these
drugs offer the advantages of rapid therapeutic effect, no monitor-
ing requirement, and fewer drug interactions in comparison with
warfarin, which has a narrow therapeutic window, is affected by
diet and many drugs, and requires monitoring for dosage optimi-
zation. However, the short half-life of the newer anticoagulants
has the important consequence that patient noncompliance will
quickly lead to loss of anticoagulant effect and risk of thromboem-
bolism. Given the convenience of once- or twice-daily oral dosing,
lack of a monitoring requirement, and fewer drug and dietary
interactions documented thus far, the new direct oral anticoagu-
lants represent a significant advance in the prevention and therapy
of thrombotic disease.
■■ BASIC PHARMACOLOGY OF
THE FIBRINOLYTIC DRUGS
Fibrinolytic drugs rapidly lyse thrombi by catalyzing the forma-
tion of the serine protease plasmin from its precursor zymogen,
plasminogen (Figure 34–3). These drugs create a generalized lytic
state when administered intravenously. Thus, both protective
hemostatic thrombi and target thromboemboli are broken down.
The Box: Thrombolytic Drugs for Acute Myocardial Infarction
describes the use of these drugs in one major application.
Pharmacology
Streptokinase is a protein (but not an enzyme in itself ) syn-
thesized by streptococci that combines with the proactivator
plasminogen. This enzymatic complex catalyzes the conversion
of inactive plasminogen to active plasmin. Urokinase is a human
enzyme synthesized by the kidney that directly converts plas-
minogen to active plasmin. Plasmin itself cannot be used because
naturally occurring inhibitors (antiplasmins) in plasma prevent its

Thrombolytic Drugs For Acute Myocardial Infarction
The paradigm shift in 1980 on the causation of acute myo-
cardial infarction to acute coronary occlusion by a thrombus
created the rationale for thrombolytic therapy of this com-
mon lethal disease. At that time—and for the first time—
intravenous thrombolytic therapy for acute myocardial
infarction in the European Cooperative Study Group trial
was found to reduce mortality. Later studies, with thousands
of patients in each trial, provided enough statistical power
for the 20% reduction in mortality to be considered statisti-
cally significant. Although the standard of care in areas with
adequate facilities and experience in percutaneous coronary
intervention (PCI) now favors catheterization and placement
effects. However, the absence of inhibitors for urokinase and the
streptokinase-proactivator complex permits their use clinically.
Plasmin formed inside a thrombus by these activators is protected
from plasma antiplasmins; this allows it to lyse the thrombus from
within.
Plasminogen can also be activated endogenously by tissue
plasminogen activators (t-PAs). These activators preferentially
activate plasminogen that is bound to fibrin, which (in theory)
confines fibrinolysis to the formed thrombus and avoids sys-
temic activation. Recombinant human t-PA is manufactured
as alteplase. Reteplase is another recombinant human t-PA
from which several amino acid sequences have been deleted.
Tenecteplase is a mutant form of t-PA that has a longer half-
life, and it can be given as an intravenous bolus. Reteplase and
tenecteplase are as effective as alteplase and have simpler dosing
schemes because of their longer half-lives.
Indications & Dosage
Administration of fibrinolytic drugs by the intravenous route is
indicated in cases of pulmonary embolism with hemodynamic
instability, severe deep venous thrombosis such as the superior
vena caval syndrome, and ascending thrombophlebitis of the
iliofemoral vein with severe lower extremity edema. These drugs are
also given intra-arterially, especially for peripheral vascular disease.
Thrombolytic therapy in the management of acute myocardial
infarction requires careful patient selection, the use of a specific
thrombolytic agent, and the benefit of adjuvant therapy. Strepto-
kinase is administered by intravenous infusion of a loading dose
of 250,000 units, followed by 100,000 units/h for 24–72 hours.
Patients with antistreptococcal antibodies can develop fever,
allergic reactions, and therapeutic resistance. Urokinase requires
a loading dose of 300,000 units given over 10 minutes and a
maintenance dose of 300,000 units/h for 12 hours. Alteplase
(t-PA) is given as a 15-mg bolus followed by 0.75 mg/kg (up to
50 mg) over 30 minutes and then 0.5 mg/kg (up to 35 mg) over
60 minutes. Reteplase is given as two 10-unit bolus injections,
the second administered 30 minutes after the first injection.
CHAPTER 34  Drugs Used in Disorders of Coagulation     619
of a stent, thrombolytic therapy is still very important where
PCI is not readily available.
The proper selection of patients for thrombolytic therapy
is critical. The diagnosis of acute myocardial infarction is made
clinically and is confirmed by electrocardiography. Patients with
ST-segment elevation and bundle branch block on electrocardi-
ography have the best outcomes. All trials to date show the great-
est benefit for thrombolytic therapy when it is given early, within
6 hours after symptomatic onset of acute myocardial infarction.
Thrombolytic drugs reduce the mortality of acute myocardial
infarction. The early and appropriate use of any thrombolytic drug
probably transcends possible advantages of a particular drug.
Tenecteplase is given as a single intravenous bolus ranging from
30 to 50 mg depending on body weight. Recombinant t-PA has
also been approved for use in acute ischemic stroke within 3 hours
of symptom onset. In patients without hemorrhagic infarct or
other contraindications, this therapy has been demonstrated to
provide better outcomes in several randomized clinical trials. The
recommended dose is 0.9 mg/kg, not to exceed 90 mg, with 10%
given as a bolus and the remainder during a 1-hour infusion.
Streptokinase has been associated with increased bleeding risk in
acute ischemic stroke when given at a dose of 1.5 million units,
and its use is not recommended in this setting.
■■ BASIC PHARMACOLOGY OF
ANTIPLATELET AGENTS
Platelet function is regulated by three categories of substances. The
first group consists of agents generated outside the platelet that
interact with platelet membrane receptors, eg, catecholamines,
collagen, thrombin, and prostacyclin. The second category con-
tains agents generated within the platelet that interact with mem-
brane receptors, eg, ADP, prostaglandin D2, prostaglandin E2,
and serotonin. A third group comprises agents generated within
the platelet that act within the platelet, eg, prostaglandin endo-
peroxides and thromboxane A2, the cyclic nucleotides cAMP and
cGMP, and calcium ion. From this list of agents, several targets
for platelet inhibitory drugs have been identified (Figure 34–1):
inhibition of prostaglandin synthesis (aspirin), inhibition of ADP-
induced platelet aggregation (clopidogrel, prasugrel, ticlopidine),
and blockade of glycoprotein IIb/IIIa (GP IIb/IIIa) receptors on
platelets (abciximab, tirofiban, and eptifibatide). Dipyridamole
and cilostazol are additional antiplatelet drugs.
ASPIRIN
The prostaglandin thromboxane A2 is an arachidonate product
that causes platelets to change shape, release their granules, and
620    SECTION VI  Drugs Used to Treat Diseases of the Blood, Inflammation, & Gout
aggregate (see Chapter 18). Drugs that antagonize this pathway
interfere with platelet aggregation in vitro and prolong the bleed-
ing time in vivo. Aspirin is the prototype of this class of drugs.
As described in Chapter 18, aspirin inhibits the synthesis of
thromboxane A2 by irreversible acetylation of the enzyme cyclo-
oxygenase. Other salicylates and nonsteroidal anti-inflammatory
drugs also inhibit cyclooxygenase but have a shorter duration of
inhibitory action because they cannot acetylate cyclooxygenase;
that is, their action is reversible.
In 2014, following a review of the available data, the FDA
reversed course and concluded that aspirin for primary prophylaxis
(patients without a history of myocardial infarction or stroke)
was not supported by the available data but did carry significant
bleeding risk. In contrast, meta-analysis of many published trials
of aspirin and other antiplatelet agents have demonstrated the util-
ity of aspirin in the secondary prevention of vascular events among
patients with a history of vascular events.
THIENOPYRIDINES: TICLOPIDINE,
CLOPIDOGREL, & PRASUGREL
Ticlopidine, clopidogrel, and prasugrel reduce platelet aggregation
by inhibiting the ADP pathway of platelets. These drugs irrevers-
ibly block the ADP P2Y12 receptor on platelets. Unlike aspirin,
these drugs have no effect on prostaglandin metabolism. Use of
ticlopidine, clopidogrel, or prasugrel to prevent thrombosis is now
considered standard practice in patients undergoing placement of
a coronary stent. As the indications and adverse effects of these
drugs are different, they will be considered individually.
Ticlopidine is approved for prevention of stroke in patients with
a history of a transient ischemic attack (TIA) or thrombotic stroke,
and in combination with aspirin for prevention of coronary stent
thrombosis. Adverse effects of ticlopidine include nausea, dyspepsia,
and diarrhea in up to 20% of patients, hemorrhage in 5%, and,
most seriously, leukopenia in 1%. The leukopenia is detected by
regular monitoring of the white blood cell count during the first
3 months of treatment. Development of thrombotic thrombo-
cytopenic purpura has also been associated with the ingestion of
ticlopidine. The dosage of ticlopidine is 250 mg twice daily orally.
Because of the significant side effect profile, the use of ticlopidine
for stroke prevention should be restricted to those who are intoler-
ant of or have failed aspirin therapy. Dosages of ticlopidine less than
500 mg/d may be efficacious with fewer adverse effects.
Clopidogrel is approved for patients with unstable angina or
non-ST-elevation acute myocardial infarction (NSTEMI) in com-
bination with aspirin; for patients with ST-elevation myocardial
infarction (STEMI); or recent myocardial infarction, stroke, or
established peripheral arterial disease. For NSTEMI, the dosage
is a 300-mg loading dose orally followed by 75 mg daily of clopi-
dogrel, with a daily aspirin dosage of 75–325 mg. For patients
with STEMI, the dosage is 75 mg daily of clopidogrel orally, in
association with aspirin as above; and for recent myocardial infarc-
tion, stroke, or peripheral vascular disease, the dosage is 75 mg/d.
Clopidogrel has fewer adverse effects than ticlopidine and is
rarely associated with neutropenia. Thrombotic thrombocytopenic
purpura has been reported. Because of its superior adverse effect
profile and dosing requirements, clopidogrel is frequently preferred
over ticlopidine. The antithrombotic effects of clopidogrel are dose-
dependent; within 5 hours after an oral loading dose of 300 mg,
80% of platelet activity will be inhibited. The maintenance dosage
of clopidogrel is 75 mg/d, which achieves maximum platelet inhibi-
tion. The duration of the antiplatelet effect is 7–10 days. Clopido-
grel is a prodrug that requires activation via the cytochrome P450
enzyme isoform CYP2C19. Depending on the single nucleotide
polymorphism (SNP) inheritance pattern in CYP2C19, individuals
may be poor metabolizers of clopidogrel, and these patients may
be at increased risk of cardiovascular events due to inadequate
drug effect. The FDA has recommended CYP2C19 genotyping to
identify such patients and advises prescribers to consider alterna-
tive therapies in poor metabolizers (see Chapter 5). However, more
recent studies have questioned the impact of CYP2C19 metabolizer
status on outcomes. Drugs that impair CYP2C19 function, such as
omeprazole, should be used with caution.
Prasugrel, similar to clopidogrel, is approved for patients with
acute coronary syndromes. The drug is given orally as a 60-mg
loading dose and then 10 mg/d in combination with aspirin
as outlined for clopidogrel. The Trial to assess Improvement in
Therapeutic Outcomes by Optimizing Platelet Inhibition with
Prasugrel (TRITON-TIMI38) compared prasugrel with clopi-
dogrel in a randomized, double-blind trial with aspirin and other
standard therapies managed with percutaneous coronary inter-
ventions. This trial showed a reduction in the primary composite
cardiovascular endpoint (cardiovascular death, nonfatal stroke, or
nonfatal myocardial infarction) for prasugrel in comparison with
clopidogrel. However, the major and minor bleeding risk was
increased with prasugrel. Prasugrel is contraindicated in patients
with history of TIA or stroke because of increased bleeding risk.
In contrast to clopidogrel, cytochrome P450 genotype status is not
an important factor in prasugrel pharmacology.
Ticagrelor is a newer type of ADP inhibitor (cyclopentyl triazo-
lopyrimidine) and is also approved for oral use in combination with
aspirin in patients with acute coronary syndromes. Cangrelor is a
parenteral P2Y12 inhibitor approved for IV use in coronary interven-
tions in patients without previous ADP P2Y12 inhibitor therapy.
Aspirin & Clopidogrel Resistance
The reported incidence of resistance to these drugs varies greatly,
from less than 5% to 75%. In part this variation reflects the
definition of resistance (recurrent thrombosis while on antiplatelet
therapy versus in vitro testing), methods by which drug response
is measured, and patient compliance. Several methods for testing
aspirin and clopidogrel resistance in vitro are now FDA-approved.
However, the measures of drug resistance vary considerably by
testing method. These tests may be useful in selected patients to
assess compliance or identify patients at increased risk of recur-
rent thrombotic events. However, their utility in routine clinical
decision-making outside of clinical trials remains controversial.
A recent randomized prospective trial found no benefit over
standard therapy when information obtained from monitoring
antiplatelet drug effect was used to alter therapy.

BLOCKADE OF PLATELET
GLYCOPROTEIN IIb/IIIa RECEPTORS
The platelet GP IIb/IIIa (integrin αIIbβ3) receptor functions
as a receptor mainly for fibrinogen and vitronectin but also for
fibronectin and von Willebrand factor. Activation of this receptor
complex is the final common pathway for platelet aggregation.
Ligands for GP IIb/IIIa contain an Arg-Gly-Asp (RGD) sequence
motif important for ligand binding, and thus RGD constitutes a
therapeutic target. There are approximately 50,000 copies of this
complex on the surface of each platelet. Persons lacking this recep-
tor have a bleeding disorder, Glanzmann’s thrombasthenia.
The GP IIb/IIIa antagonists are used in patients with acute
coronary syndromes. These drugs target the platelet GP IIb/IIIa
receptor complex shown in Figure 34–1. Abciximab, a chime-
ric monoclonal antibody directed against the IIb/IIIa complex
including the vitronectin receptor, was the first agent approved
in this class of drugs. It has been approved for use in percutane-
ous coronary intervention and in acute coronary syndromes.
Eptifibatide is a cyclic peptide derived from rattlesnake venom
that contains a variation of the RGD motif (KGD). Tirofiban
is a peptidomimetic inhibitor with the RGD sequence motif.
Eptifibatide and tirofiban inhibit ligand binding to the IIb/IIIa
receptor by their occupancy of the receptor but do not block the
vitronectin receptor. Because of their short half-lives, they must be
given by continuous infusion. Oral formulations of GP IIb/IIIa
antagonists are in various stages of development.
ADDITIONAL ANTIPLATELET-DIRECTED
DRUGS
Dipyridamole is a vasodilator that also inhibits platelet function
by inhibiting adenosine uptake and cGMP phosphodiesterase
activity. Dipyridamole by itself has little or no beneficial effect.
Therefore, therapeutic use of this agent is primarily in combina-
tion with aspirin to prevent cerebrovascular ischemia. It may also
be used in combination with warfarin for primary prophylaxis of
thromboemboli in patients with prosthetic heart valves. A combi-
nation of dipyridamole complexed with 25 mg of aspirin is now
available for secondary prophylaxis of cerebrovascular disease.
Cilostazol is a phosphodiesterase inhibitor that promotes vaso-
dilation and inhibition of platelet aggregation. Cilostazol is used
primarily to treat intermittent claudication.
■■ DRUGS USED IN BLEEDING
DISORDERS
VITAMIN K
Vitamin K confers biologic activity upon prothrombin and factors
VII, IX, and X by participating in their postribosomal modifica-
tion. Vitamin K is a fat-soluble substance found primarily in
leafy green vegetables. The dietary requirement is low because
CHAPTER 34  Drugs Used in Disorders of Coagulation     621
the vitamin is additionally synthesized by bacteria that colonize
the human intestine. Two natural forms exist: vitamins K1 and
K2. Vitamin K1 (phytonadione; Figure 34–5) is found in food.
Vitamin K2 (menaquinone) is found in human tissues and is syn-
thesized by intestinal bacteria.
Vitamins K1 and K2 require bile salts for absorption from the
intestinal tract. Vitamin K1 is available clinically in oral and par-
enteral forms. Onset of effect is delayed for 6 hours but the effect
is complete by 24 hours when treating depression of prothrombin
activity caused by excess warfarin or vitamin K deficiency. Intra-
venous administration of vitamin K1 should be slow, as rapid
infusion can produce dyspnea, chest and back pain, and even
death. Vitamin K repletion is best achieved with intravenous or
oral administration because its bioavailability after subcutaneous
administration is erratic. Vitamin K1 is currently administered
to all newborns to prevent the hemorrhagic disease of vitamin K
deficiency, which is especially common in premature infants.
The water-soluble salt of vitamin K3 (menadione) should never be
used in therapeutics. It is particularly ineffective in the treatment
of warfarin overdosage. Vitamin K deficiency frequently occurs in
hospitalized patients in intensive care units because of poor diet,
parenteral nutrition, recent surgery, multiple antibiotic therapy, and
uremia. Severe hepatic failure results in diminished protein synthesis
and a hemorrhagic diathesis that is unresponsive to vitamin K.
PLASMA FRACTIONS
Sources & Preparations
Deficiencies in plasma coagulation factors can cause bleeding
(Table 34–3). Spontaneous bleeding occurs when factor activ-
ity is less than 5–10% of normal. Factor VIII deficiency (clas-
sic hemophilia, or hemophilia A) and factor IX deficiency
(Christmas disease, or hemophilia B) account for most of the
heritable coagulation defects. Concentrated plasma fractions and
recombinant protein preparations are available for the treatment
of these deficiencies. Administration of plasma-derived, heat- or
detergent-treated factor concentrates and recombinant factor con-
centrates are the standard treatments for prevention and treatment
of bleeding associated with hemophilia. Lyophilized factor VIII
concentrates are prepared from large pools of plasma. Transmis-
sion of viral diseases such as hepatitis B and C and HIV is reduced
or eliminated by pasteurization and by extraction of plasma with
solvents and detergents. However, this treatment does not remove
other potential causes of transmissible diseases such as prions. For
this reason, recombinant clotting factor preparations are recom-
mended whenever possible for factor replacement. The best use
of these therapeutic materials requires diagnostic specificity of the
deficient factor and quantitation of its activity in plasma. Recently,
several longer-acting factor VIII and IX preparations have been
developed. Eloctate is a factor VIII-Fc domain conjugate that
prolongs the factor VIII half-life and allows twice-weekly dosing
in many cases. Idelvion is a factor IX-albumin conjugate with a
half-life of 100 hours (native factor IX has a half-life of 16 hours)
and is FDA-approved for prophylaxis or treatment of bleeding
in hemophilia B patients, offering the possibility of once-weekly
622    SECTION VI  Drugs Used to Treat Diseases of the Blood, Inflammation, & Gout

TABLE 34–3  Therapeutic products for the treatment of coagulation disorders.1

Half-Life of
Factor Deficiency State Hemostatic Levels Infused Factor Replacement Source

I Hypofibrinogenemia 1 g/dL 4 days Cryoprecipitate, FFP

II Prothrombin deficiency 30–40% 3 days Prothrombin complex concentrates (intermediate purity factor
IX concentrates)
V Factor V deficiency 20% 1 day FFP
VII Factor VII deficiency 30% 4–6 hours FFP
Prothrombin complex concentrates (intermediate purity factor
IX concentrates) Recombinant factor VIIa
VIII Hemophilia A 30–50% 12 hours Recombinant factor VIII products
100% for major Plasma-derived high purity concentrates
bleeding or trauma
Cryoprecipitate2
Some patients with mild deficiency will respond to DDAVP
IX Hemophilia B 30–50% 24 hours Recombinant factor IX products
Christmas disease 100% for major Plasma-derived high purity concentrates
bleeding or trauma
X Stuart-Prower defect 25% 36 hours FFP
Prothrombin complex concentrates
XI Hemophilia C 30–50% 3 days FFP
XII Hageman defect Not required Treatment not necessary
von von Willebrand disease 30% Approximately Intermediate purity factor VIII concentrates that contain
Willebrand 10 hours von Willebrand factor
Type I patients respond to DDAVP
Cryoprecipitate2
XIII Factor XIII deficiency 5% 6 days FFP
Cryoprecipitate
FFP, fresh frozen plasma; DDAVP, 1-deamino-8-d-arginine vasopressin.
1
For warfarin overdose or coumarin rodenticide poisoning, a four-factor concentrate (II, VII, IX, X) is available. Antithrombin concentrates are available for patients with thrombosis
in the setting of antithrombin deficiency. Activated protein C concentrates were approved for treatment of sepsis but withdrawn from the market in 2011 following publication
of a study demonstrating no benefit in sepsis and increased bleeding risk.
2
Cryoprecipitate should be used to treat bleeding in the setting of factor VIII deficiency and von Willebrand disease only in an emergency in which pathogen-inactivated products
are not available.

dosing in the case of Idelvion. Intermediate purity factor VIII con-
centrates (as opposed to recombinant or high purity concentrates)
contain significant amounts of von Willebrand factor. Humate-P
is a factor VIII concentrate that is approved by the FDA for the
treatment of bleeding associated with von Willebrand disease.
Vonicog alfa is a recombinant von Willebrand factor product
approved for treatment and control of bleeding in adults with von
Willebrand disease. Fresh frozen plasma is used for factor deficien-
cies for which no recombinant form of the protein is available. A
four-factor plasma replacement preparation containing vitamin
K–dependent factors II VII, IX, and X (4F PCC, Kcentra) is avail-
able for rapid reversal of warfarin in bleeding patients.
Clinical Uses
Hemophilia A and B patients are given factor VIII and IX replace-
ment, respectively, as prophylaxis to prevent bleeding, and in
higher doses to treat bleeding events or to prepare for surgery.
Desmopressin acetate increases the factor VIII activity of
patients with mild hemophilia A or von Willebrand disease. It can
be used in preparation for minor surgery such as tooth extraction
without any requirement for infusion of clotting factors if the
patient has a documented adequate response. High-dose intrana-
sal desmopressin (see Chapter 17) is available and has been shown
to be efficacious and well tolerated by patients.
Freeze-dried concentrates of plasma containing prothrombin,
factors IX and X, and varied amounts of factor VII (Proplex,
etc) are commercially available for treating deficiencies of these
factors (Table 34–3). Each unit of factor IX per kilogram of
body weight raises its activity in plasma 1.5%. Heparin is often
added to inhibit coagulation factors activated by the manufactur-
ing process. However, addition of heparin does not eliminate all
thromboembolic risk.
Some preparations of factor IX concentrate contain activated
clotting factors, which has led to their use in treating patients
with inhibitors or antibodies to factor VIII or factor IX.

Two products are available expressly for this purpose: Autoplex
(with factor VIII correctional activity) and FEIBA (Factor
Eight Inhibitor Bypass Activity). These products are not uni-
formly successful in arresting hemorrhage, and the factor IX
inhibitor titers often rise after treatment with them. Acquired
inhibitors of coagulation factors may also be treated with
porcine factor VIII (for factor VIII inhibitors) and recombi-
nant activated factor VII. Recombinant activated factor VII
(NovoSeven) increasingly is being used to treat coagulopathy
associated with liver disease and major blood loss in trauma
and surgery. These recombinant and plasma-derived factor
concentrates are very expensive, and the indications for them
are very precise. Therefore, close consultation with a hematolo-
gist knowledgeable in this area is essential.
Cryoprecipitate is a plasma protein fraction obtainable from
whole blood. It is used to treat deficiencies or qualitative abnor-
malities of fibrinogen, such as that which occurs with dissemi-
nated intravascular coagulation and liver disease. A single unit of
cryoprecipitate contains 300 mg of fibrinogen.
Cryoprecipitate may also be used for patients with factor VIII
deficiency and von Willebrand disease if desmopressin is not
indicated and a pathogen-inactivated, recombinant, or plasma-
derived product is not available. The concentration of factor VIII
and von Willebrand factor in cryoprecipitate is not as great as that
found in the concentrated plasma fractions. Moreover, cryopre-
cipitate is not treated in any manner to decrease the risk of viral
exposure. For infusion, the frozen cryoprecipitate unit is thawed
and dissolved in a small volume of sterile citrate-saline solution
and pooled with other units. Rh-negative women with potential
for childbearing should receive only Rh-negative cryoprecipitate
because of possible contamination of the product with Rh-positive
blood cells.
RECOMBINANT FACTOR VIIa
Recombinant factor VIIa is approved for treatment of inherited
or acquired hemophilia A or B with inhibitors, treatment of
bleeding associated with invasive procedures in congenital or
acquired hemophilia, or factor VII deficiency. In the European
Union, the drug is also approved for treatment of Glanzmann’s
thrombasthenia.
Factor VIIa initiates activation of the clotting pathway by
activating factor IX and factor X in association with tissue factor
(see Figure 34–2). The drug is given by bolus injection. For
hemophilia A or B with inhibitors and bleeding, the dosage is
90 mg/kg every 2 hours until hemostasis is achieved, and then
continued at 3- to 6-hour intervals until stable. For congenital
factor VII deficiency, the recommended dosage is 15–30 mg/kg
every 4–6 hours until hemostasis is achieved.
Factor VIIa has been widely used for off-label indications,
including bleeding with trauma, surgery, intracerebral hemor-
rhage, and warfarin toxicity. A major concern of off-label use has
been the possibility that thrombotic events may be increased.
A recent study examined rates of thromboembolic events in
35 placebo-controlled trials where factor VIIa was administered
CHAPTER 34  Drugs Used in Disorders of Coagulation     623
for nonapproved indications. This study found an increase in
arterial, but not venous, thrombotic events, particularly among
elderly individuals.
ORPHAN DRUGS FOR TREATMENT OF
RARE HEREDITARY COAGULATION
DISORDERS
Orphan drug status is a designation given by the FDA to promote
development of therapies for rare disorders (see Chapter 1).
Factor XIII is a transaminase that crosslinks fibrin within a
clot, thereby stabilizing it. Congenital factor XIII deficiency is a
rare bleeding disorder. Recombinant factor XIII A-subunit is
FDA-approved for prevention of bleeding in patients with factor
XIII deficiency.
Factor X concentrate is a plasma-derived factor X preparation
that is FDA-approved for control of bleeding in patients with
factor X deficiency and for perioperative management of patients
with mild factor X deficiency.
Protein C concentrate is a plasma-derived protein C prepara-
tion approved for treatment of life-threatening thrombosis or pur-
pura fulminans, a life-threatening disorder involving thrombosis
in skin and systemic circulation.
Recombinant antithrombin is FDA-approved for preven-
tion of perioperative and peripartum thromboembolic events in
patients with hereditary antithrombin deficiency.
FIBRINOLYTIC INHIBITORS:
AMINOCAPROIC ACID
Aminocaproic acid (EACA), which is chemically similar to the
amino acid lysine, is a synthetic inhibitor of fibrinolysis. It com-
petitively inhibits plasminogen activation (Figure 34–3). It is
rapidly absorbed orally and is cleared from the body by the kidney.
The usual oral dosage of EACA is 6 g four times a day. When the
drug is administered intravenously, a 5-g loading dose should be
infused over 30 minutes to avoid hypotension. Tranexamic acid
is an analog of aminocaproic acid and has the same properties. It
is administered orally with a 15-mg/kg loading dose followed by
30 mg/kg every 6 hours.
Clinical uses of EACA are as adjunctive therapy in hemo-
philia, as therapy for bleeding from fibrinolytic therapy, and as
prophylaxis for rebleeding from intracranial aneurysms. Treat-
ment success has also been reported in patients with postsurgical
gastrointestinal bleeding and postprostatectomy bleeding and
bladder hemorrhage secondary to radiation- and drug-induced
cystitis. Adverse effects of the drug include intravascular throm-
bosis from inhibition of plasminogen activator, hypotension,
myopathy, abdominal discomfort, diarrhea, and nasal stuffiness.
The drug should not be used in patients with disseminated
intravascular coagulation or genitourinary bleeding of the upper
tract, eg, kidney and ureters, because of the potential for exces-
sive clotting.
624    SECTION VI  Drugs Used to Treat Diseases of the Blood, Inflammation, & Gout

DRUGS REMOVED FROM MARKET
FOR LACK OF EFFICACY OR SAFETY:
APROTININ AND ACTIVATED PROTEIN C
Aprotinin is a serine protease inhibitor (serpin) that inhibits
fibrinolysis by free plasmin and may have other antihemor-
rhagic effects as well. It also inhibits the plasmin-streptokinase
complex in patients who have received that thrombolytic
agent. Aprotinin was shown to reduce bleeding—by as much
as 50%—from many types of surgery, especially that involving
extracorporeal circulation for open-heart procedures and liver
transplantation. However, clinical trials and internal data from
the manufacturer suggested that use of the drug was associated
with an increased risk of renal failure, heart attack, and stroke.
A prospective trial was initiated in Canada but halted early
because of concerns that use of the drug was associated with
increased mortality. The drug was removed from the market
in 2007.
Drotrecogin alfa is a recombinant form of activated protein
C that was initially approved by the FDA in 2001 for reduction
of mortality in adults with sepsis associated with acute organ dys-
function and high mortality. The drug was voluntarily withdrawn
from the market in 2011 after a follow-up study showed no sur-
vival benefit in sepsis.

P R E P A R A T I O N S A V A I L A B L E

GENERIC NAME AVAILABLE AS GENERIC NAME AVAILABLE AS

Abciximab ReoPro Eptifibatide Integrilin
Alteplase recombinant [t-PA] Activase Factor VIIa: see Coagulation  
Aminocaproic acid Generic, Amicar factor VIIa recombinant
Anisindione Miradon (outside the USA) Factor VIII: see  
Antihemophilic factor
Antihemophilic factor Alphanate, Bioclate, Helixate, Hemofil
[factor VIII, AHF] M, Koate-HP, Kogenate, Monoclate, Factor IX complex, human AlphaNine SD, Bebulin VH, BeneFix,
Recombinate, others Konyne 80, Mononine, Profilnine SD,
Proplex T, Proplex SX-T
Anti-inhibitor coagulant Autoplex T, Feiba VH Immuno
complex 4F PCC Kcentra
Antithrombin III Thrombate III, ATryn Fondaparinux Generic, Arixtra
Apixaban Eliquis Heparin sodium Generic, Liquaemin
Argatroban Generic Prasugrel Effient
Bivalirudin Generic, Angiomax Protamine Generic
Cilostazol Generic, Pletal Reteplase Retavase
Clopidogrel Generic, Plavix Rivaroxaban Xarelto
Coagulation factor VIIa NovoSeven Streptokinase Streptase
recombinant Tenecteplase TNKase
Dabigatran Pradaxa Ticlopidine Generic, Ticlid
Dalteparin Fragmin Tinzaparin Innohep
Danaparoid Orgaran Tirofiban Aggrastat
Desirudin Iprivask Tranexamic acid Generic, Cyklokapron, Lysteda
Dipyridamole Generic, Persantine Urokinase Abbokinase, Kinlytic
Enoxaparin (low-molecular- Generic, Lovenox Vitamin K Generic, various
weight heparin) Warfarin Generic, Coumadin

REFERENCES Mannucci PM, Levi M: Prevention and treatment of major blood loss. N Engl J
Med 2007;356:2301.
Direct Oral Anticoagulants
January C et al: 2014 AHA/ACC/HRS Guideline for the Management of Patients Drugs Used in Thrombotic Disorders
With Atrial Fibrillation: A Report of the American College of Cardiology/
American Heart Association Task Force on Practice Guidelines and the Furie B: Do pharmacogenetics have a role in the dosing of vitamin K antagonists?
Heart Rhythm Society. J Am Coll Cardiol 2014;64:e1. N Engl J Med 2013;369:2345.
Li A, Lopes RD, Garcia DA: Use of direct oral anticoagulants in special popula- Kearon C et al: Antithrombotic therapy for VTE disease: Chest guideline and
tions. Hematol Oncol Clin North Am 2016;30:1053. expert panel report. Chest 2016;149:315.
Samuelson BT, Cuker A: Measurement and reversal of the direct oral anticoagu-
lants. Blood Rev 2016;31:77.

Blood Coagulation & Bleeding Disorders

Dahlback B: Advances in understanding pathogenic mechanisms of thrombophilic
disorders. Blood 2008;112:19.

C ASE STUDY ANSWER
This patient has pulmonary embolism secondary to a
deep venous thrombosis (DVT). Options for treating this
patient include unfractionated heparin or low-molecular-
weight heparin followed by warfarin, with INR goal of
2–3; parenteral anticoagulation for 5–7 days followed by
edoxaban; or rivaroxaban, apixaban, or dabigatran alone
CHAPTER 34  Drugs Used in Disorders of Coagulation     625
without monitoring. As this situation can be considered a
provoked event given the history of oral contraceptive use,
the recommended duration of therapy would be 3–6 months
depending on individual risk factors and preferences. The
patient should be counseled to use an alternative form of
contraception.
 35
C H A P T E R
Agents Used in
Dyslipidemia
Mary J. Malloy, MD, & John P. Kane, MD, PhD
C ASE STUDY
A 42-year-old woman has heterozygous familial hyper-
cholesterolemia (HeFH) but is otherwise well and has no
symptoms of coronary or peripheral vascular disease. A
carotid ultrasound was normal. Her mother had a myo-
cardial infarction at age 51 and had no known risk factors
other than her presumed HeFH. The patient also has ele-
vated lipoprotein (a) at 2.5 times normal and low HDL-C
(43 mg/dL). She developed muscle symptoms with each
of 3 statins (atorvastatin, rosuvastatin, and simvastatin)
Plasma lipids are transported in complexes called lipoproteins.
Metabolic disorders that involve elevations in any lipoprotein
species are termed hyperlipoproteinemias or hyperlipidemias.
Hyperlipemia denotes increased levels of triglycerides.
The major clinical sequelae of hyperlipidemias are acute
pancreatitis and atherosclerosis. The former occurs in patients
with marked hyperlipemia. Control of triglycerides can prevent
recurrent attacks of this life-threatening disease.
Atherosclerosis is the leading cause of death for both genders in
the USA and other Western countries. Lipoproteins that contain
apolipoprotein (apo) B-100 convey lipids into the artery wall.
These are low-density (LDL), intermediate-density (IDL),
very-low-density (VLDL), and lipoprotein(a) (Lp[a]). Remnant
lipoproteins formed during the catabolism of chylomicrons that
contain the B-48 protein (apo B-48) can also enter the artery wall,
contributing to atherosclerosis.
Cellular components in atherosclerotic plaques (atheromas)
include foam cells, which are transformed macrophages, and
smooth muscle cells filled with cholesteryl esters. These cellular
alterations result from endocytosis of modified lipoproteins via at
least four species of scavenger receptors. Chemical modification
626
so they were discontinued although she did not develop
elevated levels of creatine kinase. Her untreated LDL-C is
235 mg/dL and triglycerides 125 mg/dL. Her LDL-C goal
for primary prevention of arteriosclerotic vascular disease
is in the 70-mg/dL range because of her multiple lipopro-
tein risk factors and her mother’s history of premature
coronary artery disease. She has no other risk factors and
her diet and exercise habits are excellent. How would you
manage this patient?
of lipoproteins by free radicals creates ligands for these receptors.
The atheroma grows with the accumulation of foam cells,
collagen, fibrin, and frequently calcium. Whereas such lesions
can slowly occlude coronary vessels, clinical symptoms are more
frequently precipitated by rupture of unstable atheromatous
plaques, leading to activation of platelets and formation of occlu-
sive thrombi.
Although treatment of hyperlipidemia can cause slow physical
regression of plaques, the well-documented reduction in acute
coronary events that follows vigorous lipid-lowering treatment
is attributable chiefly to mitigation of the inflammatory activity
of macrophages and is evident within 2–3 months after starting
therapy.
High-density lipoproteins (HDL) exert several antiathero-
genic effects. They participate in retrieval of cholesterol from the
artery wall and inhibit the oxidation of atherogenic lipoproteins.
Low levels of HDL (hypoalphalipoproteinemia) are an indepen-
dent risk factor for atherosclerotic disease and thus are a potential
target for intervention.
Cigarette smoking is a major risk factor for coronary disease. It
is associated with reduced levels of HDL, impairment of cholesterol
 CHAPTER 35  Agents Used in Dyslipidemia    627

retrieval, cytotoxic effects on the endothelium, increased oxidation
of lipoproteins, and stimulation of thrombogenesis. Diabetes, also
a major risk factor, is another source of oxidative stress.
Normal coronary arteries can dilate in response to ischemia,
increasing delivery of oxygen to the myocardium. This process
is mediated by nitric oxide, acting on smooth muscle cells of
the arterial media. The release of nitric oxide from the vascular
endothelium is impaired by atherogenic lipoproteins, thus aggra-
vating ischemia. Reducing levels of atherogenic lipoproteins and
inhibiting their oxidation restores endothelial function.
Because atherogenesis is multifactorial, therapy should be
directed toward all modifiable risk factors. Atherogenesis is a
dynamic process. Quantitative angiographic trials have demon-
strated net regression of plaques during aggressive lipid-lowering
therapy. Primary and secondary prevention trials have shown
significant reduction in mortality from new coronary events and
in all-cause mortality.
■■ PATHOPHYSIOLOGY OF
HYPERLIPOPROTEINEMIA
NORMAL LIPOPROTEIN
METABOLISM
Structure
Lipoproteins have hydrophobic core regions containing cholesteryl
esters and triglycerides surrounded by unesterified cholesterol,
phospholipids, and apoproteins. Certain lipoproteins contain
very high-molecular-weight B proteins that exist in two forms:
B-48, formed in the intestine and found in chylomicrons and
their remnants; and B-100, synthesized in liver and found in
VLDL, VLDL remnants (IDL), LDL (formed from VLDL), and
Lp(a) lipoproteins. HDL consist of at least 20 discrete molecular
species containing apolipoprotein A-I (apo A-I). About 100 other
proteins are known to be distributed variously among the HDL
species.
Synthesis & Catabolism
A. Chylomicrons
Chylomicrons are formed in the intestine and carry triglycerides
of dietary origin, unesterified cholesterol, and cholesteryl esters.
They transit the thoracic duct to the bloodstream.
Triglycerides are removed from the chylomicrons in extrahe-
patic tissues through a pathway shared with VLDL that involves
hydrolysis by the lipoprotein lipase (LPL) system. Decrease
in particle diameter occurs as triglycerides are depleted. Surface
lipids and small apoproteins are transferred to HDL. The resultant
chylomicron remnants are taken up by receptor-mediated endocy-
tosis into hepatocytes.
B. Very-Low-Density Lipoproteins
VLDL are secreted by liver and export triglycerides to peripheral
tissues (Figure 35–1). VLDL triglycerides are hydrolyzed by
LPL, yielding free fatty acids for storage in adipose tissue and for
oxidation in tissues such as cardiac and skeletal muscle. Deple-
tion of triglycerides produces remnants (IDL), some of which
undergo endocytosis directly into hepatocytes. The remainder are
converted to LDL by further removal of triglycerides mediated by
hepatic lipase. This process explains the “beta shift” phenomenon,
the increase of LDL (beta-lipoprotein) in serum as hypertriglyc-
eridemia subsides. Increased levels of LDL can also result from
increased secretion of VLDL and from decreased LDL catabolism.
C. Low-Density Lipoproteins
LDL are catabolized chiefly in hepatocytes and other cells after
receptor-mediated endocytosis. Cholesteryl esters from LDL
are hydrolyzed, yielding free cholesterol for the synthesis of cell
membranes. Cells also obtain cholesterol by synthesis via a path-
way involving the formation of mevalonic acid by HMG-CoA
reductase. Production of this enzyme and of LDL receptors is
transcriptionally regulated by the content of cholesterol in the
cell. Normally, about 70% of LDL is removed from plasma by
hepatocytes. Even more cholesterol is delivered to the liver via IDL
and chylomicrons. Unlike other cells, hepatocytes can eliminate
cholesterol by secretion in bile and by conversion to bile acids.

ACRONYMS D. Lp(a) Lipoprotein

Apo Apolipoprotein Lp(a) lipoprotein is formed from LDL and the (a) protein, linked
CETP Cholesteryl ester transfer protein
by a disulfide bridge. The (a) protein is highly homologous with
plasminogen but is not activated by tissue plasminogen activator.
CK Creatine kinase
It occurs in a number of isoforms of different molecular weights.
HDL High-density lipoproteins Levels of Lp(a) vary from nil to over 2000 nM/L and are deter-
HMG-CoA 3-Hydroxy-3-methylglutaryl-coenzyme A mined chiefly by genetic factors. Lp(a) is found in atherosclerotic
IDL Intermediate-density lipoproteins plaques and contributes to coronary disease by inhibiting throm-
LCAT Lecithin:cholesterol acyltransferase bolysis. It is also associated with aortic stenosis. Levels are elevated
LDL Low-density lipoproteins
in certain inflammatory states. The risk of coronary disease is
strongly related to the level of Lp(a). A common variant (I4399M)
Lp(a) Lipoprotein(a)
in the coding region is associated with elevated levels.
LPL Lipoprotein lipase
PCSK9 Proprotein convertase subtilisin/kexin type 9 E. High-Density Lipoproteins
PPAR Peroxisome proliferator-activated receptor The apoproteins of HDL are secreted largely by the liver and
VLDL Very-low-density lipoproteins intestine. Much of the lipid comes from the surface monolayers of
628    SECTION VI  Drugs Used to Treat Diseases of the Blood, Inflammation, & Gout

Hepatocyte Blood Capillary

ApoE endothelium
Golgi
vesicle B-100

RER ApoC
HDL
Lipoprotein
lipase
ApoB, VLDL
ApoE,
ApoC

VLDL
Cholesterol LDL receptor remnant
Lysosome

FFA
*
*

Mevalonic HDL
acid HMG-CoA LDL
reductase

Peripheral cell
Acetyl-
CoA

Cholesterol biosynthetic Cholesterol

pathway Lysosome Cholesteryl
esters

FIGURE 35–1  Metabolism of lipoproteins of hepatic origin. The heavy arrows show the primary pathways. Nascent VLDL are secreted via
the Golgi apparatus. They acquire additional apo C lipoproteins and apo E from HDL. Very-low-density lipoproteins (VLDL) are converted to
VLDL remnants (IDL) by lipolysis via lipoprotein lipase in the vessels of peripheral tissues. In the process, C apolipoproteins and a portion of the
apo E are given back to high-density lipoproteins (HDL). Some of the VLDL remnants are converted to LDL by further loss of triglycerides and
loss of apo E. A major pathway for LDL degradation involves the endocytosis of LDL by LDL receptors in the liver and the peripheral tissues,
for which apo B-100 is the ligand. Dark color denotes cholesteryl esters; light color denotes triglycerides; the asterisk denotes a functional
ligand for LDL receptors; triangles indicate apo E; circles and squares represent C apolipoproteins. FFA, free fatty acid; RER, rough endoplasmic
reticulum. (Adapted, with permission, from Kane J, Malloy M: Disorders of lipoproteins. In: Rosenberg RN et al [editors]: The Molecular and Genetic Basis of Neurological
Disease. 2nd ed. Butterworth-Heinemann, 1997.)

chylomicrons and VLDL during lipolysis. HDL also acquires cho-
lesterol from peripheral tissues, protecting the cholesterol homeo-
stasis of cells. Free cholesterol is chiefly exported from the cell
membrane by a transporter, ABCA1, acquired by a small particle
termed prebeta-1 HDL, and then esterified by lecithin:cholesterol
acyltransferase (LCAT), leading to the formation of larger HDL
species. Cholesterol is also exported by the ABCG1 transporter
and the scavenger receptor, SR-BI, to large HDL particles. The
cholesteryl esters are transferred to VLDL, IDL, LDL, and
chylomicron remnants with the aid of cholesteryl ester transfer
protein (CETP). Much of the cholesteryl ester thus transferred
is ultimately delivered to the liver by endocytosis of the acceptor
lipoproteins. HDL can also deliver cholesteryl esters directly to the
liver via SR-BI that does not cause endocytosis of the lipoproteins.
At the population level, HDL cholesterol (HDL-C) levels relate
inversely to atherosclerosis risk. Among individuals, the capacity
to accept exported cholesterol can vary widely at identical levels
of HDL-C. The ability of peripheral tissues to export cholesterol
via the transporter mechanism and the acceptor capacity of HDL
are emerging as major determinants of coronary atherosclerosis.
LIPOPROTEIN DISORDERS
Lipoprotein disorders are detected by measuring lipids in serum
after a 10-hour fast. Risk of heart disease increases with concentra-
tions of the atherogenic lipoproteins, is inversely related to levels
of HDL-C, and is modified by other risk factors. Evidence from
clinical trials suggests that an LDL cholesterol (LDL-C) level of
50-60 mg/dL is optimal for patients with coronary disease. Ideally,
triglycerides should be below 120 mg/dL. Although LDL-C is
still the primary target of treatment, reducing the levels of VLDL
and IDL also is important. Calculation of non-HDL cholesterol
provides a means of assessing levels of all the lipoproteins in the
VLDL to LDL cascade. Differentiation of the disorders requires
identification of the lipoproteins involved (Table 35–1). Diag-
nosis of a primary disorder usually requires further clinical and
 CHAPTER 35  Agents Used in Dyslipidemia    629

TABLE 35–1  The primary hyperlipoproteinemias and their treatment.

Disorder Manifestations Diet + Single Drug1 Drug Combination

Primary chylomicronemia
(familial lipoprotein lipase,
cofactor deficiency; others)
Familial hypertriglyceridemia
Familial combined
hyperlipoproteinemia
 
 
Familial dysbetalipoproteinemia
Familial hypercholesterolemia
 Heterozygous
 Homozygous
Familial ligand-defective
apo B-100
Lp(a) hyperlipoproteinemia
1
Single-drug therapy with marine omega-3 dietary supplement should be evaluated before drug combinations are used.
2
Select pharmacologically compatible reductase inhibitor (see text).
Chylomicrons, VLDL increased
VLDL increased; chylomicrons
may be increased
VLDL predominantly increased
LDL predominantly increased
VLDL, LDL increased
VLDL remnants, chylomicron
remnants increased
LDL increased
LDL increased
LDL increased
Lp(a) increased
Dietary management; Omega-3 fatty Fibrate plus niacin
acids, fibrate, or niacin
(Apo C-III antisense)
Dietary management; Omega-3 fatty Fibrate plus niacin
acids, fibrate, or niacin
Reductase inhibitor, Omega-3 fatty acids, Two or three of the single
fibrate, niacin agents2
Reductase inhibitor, ezetimibe, or niacin Two or three of the single
agents
Reductase inhibitor, Omega-3 fatty acids, Niacin or fibrate plus reductase
or niacin inhibitor2
Fibrate, reductase inhibitor, niacin, Omega Reductase inhibitor plus fibrate
3 fatty acids or niacin
Reductase inhibitor, resin, niacin, or Two or three of the individual
ezetimibe drugs
Atorvastatin, rosuvastatin, ezetimibe, Combinations of some of the
mipomersen, lomitapide or PCSK9 MAB single agents
Reductase inhibitor, niacin, or ezetimibe Two or three of the single
agents
Niacin  

genetic data as well as ruling out secondary hyperlipidemias

(Table 35–2).
THE PRIMARY
Phenotypes of abnormal lipoprotein distribution are described HYPERTRIGLYCERIDEMIAS
in this section. Drugs mentioned for use in these conditions Hypertriglyceridemia is associated with increased risk of coronary
are described in the following section on basic and clinical disease. Chylomicrons, VLDL, and IDL are found in atheroscle-
pharmacology. rotic plaques. These patients tend to have cholesterol-rich VLDL
of small particle diameter and small, dense LDL. Hypertriglyceri-
TABLE 35–2  Secondary causes of hyperlipoproteinemia. demic patients with coronary disease or risk equivalents should be
treated aggressively. Patients with triglycerides above 700 mg/dL
Hypertriglyceridemia Hypercholesterolemia
should be treated to prevent acute pancreatitis because the LPL
Diabetes mellitus Hypothyroidism clearance mechanism is saturated at about this level.
Alcohol ingestion Early nephrosis Hypertriglyceridemia is an important component of the
Severe nephrosis Resolving lipemia metabolic syndrome, which also includes insulin resistance,
Estrogens Immunoglobulin-lipoprotein
hypertension, and abdominal obesity. Reduced levels of HDL-C
complex disorders are usually observed due to transfer of cholesteryl esters to the
Uremia Anorexia nervosa
triglyceride-rich lipoprotein particles. Hyperuricemia is frequently
present. Insulin resistance appears to be central to this disorder.
HIV infection Cholestasis
Management of these patients frequently requires, in addition
Myxedema Hypopituitarism to a fibrate, the use of metformin, another antidiabetic agent, or
Glycogen storage disease Corticosteroid excess both (see Chapter 41). The severity of hypertriglyceridemia of any
Hypopituitarism Androgen overdose cause is increased in the presence of the metabolic syndrome or
Acromegaly   type 2 diabetes.
Immunoglobulin-lipoprotein  
complex disorders Primary Chylomicronemia
Lipodystrophy   Chylomicrons are not present in the serum of normal individu-
Protease inhibitors, tacrolimus,   als who have fasted 10 hours. The recessive traits of deficiency
sirolimus, other drugs of LPL, its cofactor apo C-II, the LMF1 or GPIHBP1 proteins,
630    SECTION VI  Drugs Used to Treat Diseases of the Blood, Inflammation, & Gout
or ANGPTL4 and Apo A-V, are usually associated with severe
lipemia (2000 mg/dL of triglycerides or higher when the patient
is consuming a typical American diet). These disorders might not
be diagnosed until an attack of acute pancreatitis occurs. Patients
may have eruptive xanthomas, hepatosplenomegaly, hypersplen-
ism, and lipid-laden foam cells in bone marrow, liver, and spleen.
The lipemia is aggravated by estrogens because they stimulate
VLDL production, and pregnancy may cause marked increases
in triglycerides despite strict dietary control. Although these
patients have a predominant chylomicronemia, they may also
have moderately elevated VLDL, presenting with a pattern called
mixed lipemia (fasting chylomicronemia and elevated VLDL).
Deficiency of lipolytic activity can be diagnosed after intravenous
injection of heparin. A presumptive diagnosis is made by dem-
onstrating a pronounced decrease in triglycerides 72 hours after
elimination of daily dietary fat. Marked restriction of total dietary
fat and abstention from alcohol are the basis of effective long-term
treatment. Niacin, a fibrate, or marine omega-3 fatty acids may be
of some benefit if VLDL levels are increased. Apo C-III antisense
is a potential adjunct to therapy.
Familial Hypertriglyceridemia
The primary hypertriglyceridemias probably reflect a variety of
genetic determinants. Many patients have centripetal obesity with
insulin resistance. Other factors, including alcohol and estrogens, that
increase secretion of VLDL aggravate the lipemia. Impaired removal
of triglyceride-rich lipoproteins with overproduction of VLDL
can result in mixed lipemia. Eruptive xanthomas, lipemia retinalis,
epigastric pain, and pancreatitis are variably present depending on the
severity of the lipemia. Treatment is primarily dietary, with restriction
of total fat, avoidance of alcohol and exogenous estrogens, weight
reduction, exercise, and supplementation with marine omega-3 fatty
acids. Most patients also require treatment with a fibrate. If insulin
resistance is not present, niacin may be useful.
Familial Combined Hyperlipoproteinemia
(FCH)
In this common disorder, which is associated with an increased
incidence of coronary disease, individuals may have elevated levels
of VLDL, LDL, or both, and the pattern may change with time.
Familial combined hyperlipoproteinemia involves an approximate
doubling in VLDL secretion and appears to be transmitted as a
dominant trait. Triglycerides can be increased by the factors noted
above. Elevations of cholesterol and triglycerides are generally mod-
erate, and xanthomas are absent. Diet alone does not normalize
lipid levels. A reductase inhibitor alone, or in combination with nia-
cin or fenofibrate, is usually required to treat these patients. When
fenofibrate is combined with a reductase inhibitor, either pravas-
tatin or rosuvastatin is recommended because neither is metabolized
via CYP3A4. Marine omega-3 fatty acids may be useful.
Familial Dysbetalipoproteinemia
In this disorder, remnants of chylomicrons and VLDL accumu-
late and levels of LDL are decreased. Because remnants are rich in
cholesteryl esters, the level of total cholesterol may be as high as that of
triglycerides. Diagnosis is confirmed by the absence of the ε3 and ε4
alleles of apo E, the ε2/ε2 genotype. Other apo E isoforms that lack
receptor ligand properties can also be associated with this disorder.
Patients often develop tuberous or tuberoeruptive xanthomas, or
characteristic planar xanthomas of the palmar creases. They tend to
be obese, and some have impaired glucose tolerance. These factors,
as well as hypothyroidism, can aggravate the lipemia. Coronary and
peripheral atherosclerosis occurs with increased frequency. Weight
loss, together with decreased fat, cholesterol, and alcohol consump-
tion, may be sufficient, but a fibrate or niacin is usually needed to
control the condition. These agents can be given together in more
resistant cases. Reductase inhibitors are also effective because they
increase hepatic LDL receptors that participate in remnant removal.
THE PRIMARY
HYPERCHOLESTEROLEMIAS
LDL Receptor Deficient Familial
Hypercholesterolemia (FH)
This is an autosomal dominant trait. Although levels of LDL tend
to increase throughout childhood, the diagnosis can often be made
on the basis of elevated umbilical cord blood cholesterol. In most
heterozygotes, cholesterol levels range from 260 to 500 mg/dL.
Triglycerides are usually normal. Tendon xanthomas are often
present. Arcus corneae and xanthelasma may appear in the
third decade. Coronary disease tends to occur prematurely. In
homozygous familial hypercholesterolemia, which can lead to
coronary disease in childhood, levels of cholesterol often exceed
1000 mg/dL and early tuberous and tendinous xanthomas occur.
These patients may also develop elevated plaque-like xanthomas
of the aortic valve, digital webs, buttocks, and extremities.
Some individuals have combined heterozygosity for alleles
producing nonfunctional and kinetically impaired receptors. In
heterozygous patients, LDL can be normalized with reductase
inhibitors or combined drug regimens (Figure 35–2). Homozy-
gotes and those with combined heterozygosity whose receptors
retain even minimal function may partially respond to niacin,
ezetimibe, and reductase inhibitors. Emerging therapies for these
patients include mipomersen, employing an antisense strategy
targeted at apo B-100, and lomitapide, a small molecule inhibitor
of microsomal triglyceride transfer protein (MTP), and monoclo-
nal antibodies directed at PCSK9. LDL apheresis is effective in
medication-refractory patients.
Familial Ligand-Defective Apolipoprotein
B-100
Defects in the domain of apo B-100 that binds to the LDL
receptor impair the endocytosis of LDL, leading to hypercho-
lesterolemia of moderate severity. Tendon xanthomas may occur.
Response to reductase inhibitors is variable. Upregulation of LDL
receptors in liver increases endocytosis of LDL precursors but does
not increase uptake of ligand-defective LDL particles. Fibrates or
niacin may have beneficial effects by reducing VLDL production.
 CHAPTER 35  Agents Used in Dyslipidemia    631

LDL-C, low levels of HDL-C, and often modest hypertriglyceri-

demia. Rarely, a totally ablative form, Wolman disease, occurs in
infancy. A recombinant replacement enzyme therapy, sebelipase
Blood Hepatocyte Gut alfa, effectively restores the hydrolysis of cholesteryl esters in liver,
normalizing plasma lipoprotein levels.
Acetyl-CoA

Other Disorders
HMG-CoA
Deficiency of cholesterol 7α-hydroxylase can increase LDL in
B-100

LDL R HMG-CoA
reductase
inhibitors
Ezetimibe
Cholesterol
VLDL
B-100 Niacin
Bile acids
Resins
FIGURE 35–2  Sites of action of HMG-CoA reductase inhibitors,
niacin, ezetimibe, and resins used in treating hyperlipidemias. Low-
density lipoprotein (LDL) receptors are increased by treatment with
resins and HMG-CoA reductase inhibitors. VLDL, very-low-density
lipoproteins; R, LDL receptor.
Familial Combined Hyperlipoproteinemia
(FCH)
Some persons with familial combined hyperlipoproteinemia have
only an elevation in LDL. Serum cholesterol is often less than
350 mg/dL. Dietary and drug treatment, usually with a reduc-
tase inhibitor, is indicated. It may be necessary to add niacin or
ezetimibe to normalize LDL.
Lp(a) Hyperlipoproteinemia
This familial disorder, which is associated with increased athero-
genesis and arterial thrombus formation, is determined chiefly by
alleles that dictate increased production of the (a) protein moiety.
Lp(a) can be secondarily elevated in patients with severe nephro-
sis and certain other inflammatory states. Niacin reduces levels
of Lp(a) in many patients. Reduction of levels of LDL-C below
100 mg/dL decreases the risk attributable to Lp(a), as does the
administration of low-dose aspirin. PCSK9 monoclonal antibod-
ies also reduce levels of Lp(a) by about 25%.
Cholesteryl Ester Storage Disease
Individuals lacking activity of lysosomal acid lipase (LAL) accu-
mulate cholesteryl esters in liver and certain other cell types lead-
ing to hepatomegaly with subsequent fibrosis, elevated levels of
the heterozygous state. Homozygotes also can have elevated
triglycerides, resistance to reductase inhibitors as a single agent,
and increased risk of gallstones and coronary disease. A combi-
nation of niacin with a reductase inhibitor appears to be effec-
tive. Autosomal recessive hypercholesterolemia (ARH) is due to
mutations in a protein that normally assists in endocytosis of
LDL. High-dose reductase inhibitor plus ezetimibe is effective.
The receptor chaperone PCSK9 normally conducts the receptor
to the lysosome for degradation. Gain-of-function mutations
in PCSK9 are associated with elevated levels of LDL-C and
could be managed with a PCSK9 antibody. The ABCG5 and
ABCG8 half-transporters act together in enterocytes and hepa-
tocytes to export phytosterols into the intestinal lumen and bile,
respectively. Homozygous or combined heterozygous ablative
mutations in either transporter result in elevated levels of LDL
enriched in phytosterols, tendon and tuberous xanthomas, and
accelerated atherosclerosis. Ezetimibe is a specific therapeutic for
this disorder.
HDL Deficiency
Rare genetic disorders, including Tangier disease and LCAT
(lecithin:cholesterol acyltransferase) deficiency, are associated
with extremely low levels of HDL. Familial hypoalphalipo-
proteinemia is a more common disorder with levels of HDL
cholesterol usually below 35 mg/dL in men and 45 mg/dL in
women. These patients tend to have premature atherosclerosis,
and the low HDL may be the only identified risk factor. Man-
agement should include special attention to avoidance or treat-
ment of other risk factors. Niacin increases HDL in many of
these patients but the effect on outcome is unknown. Reductase
inhibitors and fibric acid derivatives exert lesser effects. Aggres-
sive LDL reduction is indicated.
In the presence of hypertriglyceridemia, HDL cholesterol is
low because of exchange of cholesteryl esters from HDL into
triglyceride-rich lipoproteins. Treatment of the hypertriglyceride-
mia increases the HDL-C level.
SECONDARY
HYPERLIPOPROTEINEMIA
Before primary disorders can be diagnosed, secondary causes of
the phenotype must be considered. The more common conditions
are summarized in Table 35–2. The lipoprotein abnormality usu-
ally resolves if the underlying disorder can be treated successfully.
These secondary disorders can also aggravate a primary genetic
disorder.
632    SECTION VI  Drugs Used to Treat Diseases of the Blood, Inflammation, & Gout
■■ DIETARY MANAGEMENT OF
HYPERLIPOPROTEINEMIA
Dietary measures are initiated first—unless the patient has
evident coronary or peripheral vascular disease—and may
obviate the need for drugs. Patients with the familial hypercho-
lesterolemias always require drug therapy in addition to diet.
Cholesterol and saturated and trans-fats are the principal factors
that increase LDL.
Total fat, sucrose, and especially fructose increase VLDL.
Alcohol can cause significant hypertriglyceridemia by increasing
hepatic secretion of VLDL. Synthesis and secretion of VLDL
are increased by excess calories. During weight loss, LDL and
VLDL levels may be much lower than can be maintained dur-
ing neutral caloric balance. The conclusion that diet suffices for
management can be made only after weight has stabilized for at
least 1 month.
General recommendations include limiting total calories from
fat to 20–25% of daily intake, saturated fats to less than 7%, and
cholesterol to less than 200 mg/d. Reductions in serum cholesterol
range from 10% to 20% on this regimen. Use of complex carbo-
hydrates and fiber is recommended, and cis-monounsaturated fats
should predominate. Weight reduction, caloric restriction, and
avoidance of alcohol are especially important for patients with
elevated triglycerides.
The effect of dietary fats on hypertriglyceridemia is depen-
dent on the disposition of double bonds in the fatty acids.
Omega-3 fatty acids found in fish oils, but not those from plant
sources, activate peroxisome proliferator-activated receptor-alpha
(PPAR-α) and can induce profound reduction of triglycerides
in some patients. They also have anti-inflammatory and antiar-
rhythmic activities. Omega-3 fatty acids are available over the
counter as triglycerides from marine sources or as a prescription
medication containing ethyl esters of omega-3 fatty acids. It is
necessary to determine the content of docosahexaenoic acid and
eicosapentaenoic acid in over-the-counter preparations. Appro-
priate amounts should be taken to provide up to 3–4 g of these
fatty acids (combined) daily. It is important to select preparations
free of mercury and other contaminants. The omega-6 fatty acids
present in vegetable oils may cause triglycerides to increase.
Patients with primary chylomicronemia and some with mixed
lipemia must consume a diet severely restricted in total fat
(10–20 g/d, of which 5 g should be vegetable oils rich in essential
fatty acids), and fat-soluble vitamins should be given.
Homocysteine, which initiates proatherogenic changes in
endothelium, can be reduced in many patients by restriction of
total protein intake to the amount required for amino acid replace-
ment. Supplementation with folic acid plus other B vitamins, and
administration of betaine, a methyl donor, is indicated in severe
homocysteinemia. Reduction of high levels of homocysteine is
especially important in individuals with elevated levels of Lp(a).
Consumption of red meat should be minimized to reduce the
production by the intestinal biome of tetramethyl amine oxide, a
compound injurious to arteries.
■■ BASIC & CLINICAL
PHARMACOLOGY OF DRUGS
USED IN HYPERLIPIDEMIA
The decision to use drug therapy for hyperlipidemia is based
on the specific metabolic defect and its potential for causing
atherosclerosis or pancreatitis. Suggested regimens for the princi-
pal lipoprotein disorders are presented in Table 35–1. Diet should
be continued to achieve the full potential of the drug regimen.
These drugs should be avoided in pregnant and lactating women
and those likely to become pregnant. All drugs that alter plasma
lipoprotein concentrations potentially require adjustment of doses
of anticoagulants. Children with heterozygous familial hypercho-
lesterolemia may be treated with a resin or reductase inhibitor,
usually after 7 or 8 years of age, when myelination of the central
nervous system is essentially complete. The decision to treat a
child should be based on the level of LDL, other risk factors, the
family history, and the child’s age. Drugs are usually not indicated
before age 16 in the absence of multiple risk factors or compound
genetic dyslipidemias.
COMPETITIVE INHIBITORS OF
HMG-COA REDUCTASE (REDUCTASE
INHIBITORS: “STATINS”)
These compounds are structural analogs of HMG-CoA (3-hydroxy-
3-methylglutaryl-coenzyme A, Figure 35–3). Lovastatin,
atorvastatin, fluvastatin, pravastatin, simvastatin, rosuvastatin,
and pitavastatin belong to this class. They are most effective in
reducing LDL. Other effects include decreased oxidative stress and
vascular inflammation with increased stability of atherosclerotic
lesions. It has become standard practice to initiate reductase inhibi-
tor therapy immediately after acute coronary syndromes, regardless
of lipid levels.
Chemistry & Pharmacokinetics
Lovastatin and simvastatin are inactive lactone prodrugs that are
hydrolyzed in the gastrointestinal tract to the active β-hydroxyl
derivatives, whereas pravastatin has an open, active lactone ring.
Atorvastatin, fluvastatin, and rosuvastatin are fluorine-containing
congeners that are active as given. Absorption of the ingested doses
of the reductase inhibitors varies from 40% to 75% with the excep-
tion of fluvastatin, which is almost completely absorbed. All have
high first-pass extraction by the liver. Most of the absorbed dose is
excreted in the bile; 5–20% is excreted in the urine. Plasma half-
lives of these drugs range from 1 to 3 hours except for atorvastatin
(14 hours), pitavastatin (12 hours), and rosuvastatin (19 hours).
Mechanism of Action
HMG-CoA reductase mediates the first committed step in sterol
biosynthesis. The active forms of the reductase inhibitors are
structural analogs of the HMG-CoA intermediate (Figure 35–3)
 CHAPTER 35  Agents Used in Dyslipidemia    633

CH3 CH3
HO HO
–
COO COO–
OH OH

CoA

HMG-CoA reduced Mevalonate

intermediate

HO O HO
–
COO
O OH

O O

H3C O O
H3C
CH3 CH3
CH3 CH3

H3C H3C
Lovastatin Lovastatin (active form)

FIGURE 35–3  Inhibition of HMG-CoA reductase. Top: The HMG-CoA intermediate that is the immediate precursor of mevalonate, a
critical compound in the synthesis of cholesterol. Bottom: The structure of lovastatin and its active form, showing the similarity to the normal
HMG-CoA intermediate (shaded areas).

that is formed by HMG-CoA reductase in the synthesis of meva-
lonate. These analogs cause partial inhibition of the enzyme and
thus may impair the synthesis of isoprenoids such as ubiquinone
and dolichol and the prenylation of proteins. It is not known
whether this has biologic significance. However, the reductase
inhibitors clearly induce an increase in high-affinity LDL recep-
tors. This effect increases both the fractional catabolic rate
of LDL and the liver’s extraction of LDL precursors (VLDL
remnants) from the blood, thus reducing LDL (Figure 35–2).
Because of marked first-pass hepatic extraction, the major effect
is on the liver. Preferential activity in liver of some congeners
appears to be attributable to tissue-specific differences in uptake.
Modest decreases in plasma triglycerides and small increases in
HDL also occur.
Clinical trials involving many of the statins have dem-
onstrated significant reduction of new coronary events and
atherothrombotic stroke. Mechanisms other than reduction of
lipoprotein levels appear to be involved. The availability of iso-
prenyl groups from the HMG-CoA pathway for prenylation of
proteins is reduced by statins, resulting in reduced prenylation
of Rho and Rab proteins. Prenylated Rho activates Rho kinase,
which mediates a number of mechanisms in vascular biology.
The observation that reduction in new coronary events occurs
more rapidly than changes in morphology of arterial plaques
suggests that these pleiotropic effects may be important. Like-
wise, decreased prenylation of Rab reduces the accumulation of
Aβ protein in neurons, possibly mitigating the manifestations of
Alzheimer’s disease.
Therapeutic Uses & Dosage
Reductase inhibitors are useful alone or with resins, niacin, or
ezetimibe in reducing levels of LDL. Women with hyperlipidemia
who are pregnant, lactating, or likely to become pregnant should
not be given these agents. Use in children is restricted to selected
patients with familial hypercholesterolemias.
Because cholesterol synthesis occurs predominantly at night,
reductase inhibitors—except atorvastatin, rosuvastatin, and
pitavastatin—should be given in the evening. Absorption
generally (with the exception of pravastatin and pitavastatin)
is enhanced by food. Daily doses of lovastatin vary from
10 to 80 mg. Pravastatin is nearly as potent on a mass basis
as lovastatin with a maximum recommended daily dose of
80 mg. Simvastatin is twice as potent and is given in doses of
5–80 mg daily. Because of increased risk of myopathy with the
80-mg/d dose, the U.S. Food and Drug Administration (FDA)
issued labeling for scaled dosing of simvastatin and combined
ezetimibe/simvastatin in 2011. Pitavastatin is given in doses of
1–4 mg daily. Fluvastatin appears to be about half as potent as
lovastatin on a mass basis and is given in doses of 10–80 mg
daily. Atorvastatin is given in doses of 10–80 mg/d, and rosuvas-
tatin at 5–40 mg/d. The dose-response curves of pravastatin and
634    SECTION VI  Drugs Used to Treat Diseases of the Blood, Inflammation, & Gout
especially of fluvastatin tend to level off in the upper part of the
dosage range in patients with moderate to severe hypercholester-
olemia. Those of other statins are somewhat more linear.
Toxicity
Elevations of serum aminotransferase activity (up to three times
normal) occur in some patients. This is often intermittent and
usually not associated with other evidence of hepatic toxicity.
Therapy may be continued in such patients in the absence of
symptoms if aminotransferase levels are monitored and stable. In
some patients, who may have underlying liver disease or a his-
tory of alcohol abuse, levels may exceed three times normal. This
finding portends more severe hepatic toxicity. These patients may
present with malaise, anorexia, and precipitous decreases in LDL.
Medication should be discontinued immediately in these patients
and in asymptomatic patients whose aminotransferase activity is
persistently elevated to more than three times the upper limit of
normal. These agents should be used with caution and in reduced
dosage in patients with hepatic parenchymal disease, north
Asians, and the elderly. Severe hepatic disease may preclude their
use. In general, aminotransferase activity should be measured at
baseline, at 1–2 months, and then every 6–12 months (if stable).
Monitoring of liver enzymes should be more frequent if the
patient is taking other drugs that have potential interactions with
the statin. Excess intake of alcohol tends to aggravate hepatotoxic
effects of statins. Fasting plasma glucose levels tend to increase
5–7 mg/dL with statin treatment. Long-term studies have shown a
small but significant increase in the incidence of type 2 diabetes in
statin-treated patients, most of whom had findings of prediabetes
before treatment.
Minor increases in creatine kinase (CK) activity in plasma
are observed in some patients receiving reductase inhibitors, fre-
quently associated with heavy physical activity. Rarely, patients
may have marked elevations in CK activity, often accompanied
by generalized discomfort or weakness in skeletal muscles. If the
drug is not discontinued, myoglobinuria can occur, leading to
renal injury. Myopathy may occur with monotherapy, but there
is an increased incidence in patients also receiving certain other
drugs. Genetic variation in an anion transporter (OATP1B1) is
associated with severe myopathy and rhabdomyolysis induced by
statins. Variants in the gene (SLCO1B1) coding for this protein
can now be assessed (see Chapter 5).
The catabolism of lovastatin, simvastatin, and atorvastatin
proceeds chiefly through CYP3A4, whereas that of fluvastatin
and rosuvastatin, and to a lesser extent pitavastatin, is medi-
ated by CYP2C9. Pravastatin is catabolized through other
pathways, including sulfation. The 3A4-dependent reductase
inhibitors tend to accumulate in plasma in the presence of
drugs that inhibit or compete for the 3A4 cytochrome. These
include the macrolide antibiotics, cyclosporine, ketoconazole
and its congeners, some HIV protease inhibitors, tacrolimus,
nefazodone, fibrates, paroxetine, venlafaxine, and others (see
Chapters 4 and 66). Concomitant use of reductase inhibitors
with amiodarone or verapamil also causes an increased risk of
myopathy.
Conversely, drugs such as phenytoin, griseofulvin, barbiturates,
rifampin, and thiazolidinediones increase expression of CYP3A4
and can reduce the plasma concentrations of the 3A4-dependent
reductase inhibitors. Inhibitors of CYP2C9 such as ketoconazole
and its congeners, metronidazole, sulfinpyrazone, amiodarone,
and cimetidine may increase plasma levels of fluvastatin and
rosuvastatin. Pravastatin and rosuvastatin appear to be the statins
of choice for use with verapamil, the ketoconazole group of
antifungal agents, macrolides, and cyclosporine. Doses should
be kept low and the patient monitored frequently. Plasma levels
of lovastatin, simvastatin, and atorvastatin may be elevated in
patients ingesting more than 1 liter of grapefruit juice daily. All
statins undergo glycosylation, thus creating an interaction with
gemfibrozil.
Creatine kinase activity should be measured in patients
receiving potentially interacting drug combinations. In all
patients, CK should be measured at baseline. If muscle pain,
tenderness, or weakness appears, CK should be measured
immediately and the drug discontinued if activity is elevated sig-
nificantly over baseline. The myopathy usually reverses promptly
upon cessation of therapy. If the association is unclear, the
patient can be rechallenged under close surveillance. Myopathy
in the absence of elevated CK can occur. Rarely, hypersensitivity
syndromes have been reported that include a lupus-like disor-
der, dermatomyositis, peripheral neuropathy, and autoimmune
myopathy. The latter presents as severe pain and weakness in
proximal muscles that does not remit when the statin is discon-
tinued. It is HMG-CoA reductase antibody positive and requires
immunosuppressive treatment.
Reductase inhibitors may be temporarily discontinued in the
event of serious illness, trauma, or major surgery to minimize the
potential for liver and muscle toxicity.
Use of red yeast rice, a fermentation product that contains
statin activity, is not recommended because the statin content
is highly variable and some preparations contain a nephrotoxin,
citrinin. The long-term safety of these preparations, which often
contain a large number of poorly studied organic compounds, has
not been established.
FIBRIC ACID DERIVATIVES
(FIBRATES)
Gemfibrozil and fenofibrate decrease levels of VLDL and, in
some patients, LDL as well. Another fibrate, bezafibrate, is not
yet available in the USA.
Chemistry & Pharmacokinetics
Gemfibrozil is absorbed quantitatively from the intestine and
is tightly bound to plasma proteins. It undergoes enterohepatic
circulation and readily passes the placenta. The plasma half-life
is 1.5 hours. Seventy percent is eliminated through the kidneys,
mostly unmodified. The liver modifies some of the drug to
hydroxymethyl, carboxyl, or quinol derivatives. Fenofibrate is
an isopropyl ester that is hydrolyzed completely in the intestine.
 CHAPTER 35  Agents Used in Dyslipidemia    635

Its plasma half-life is 20 hours. Sixty percent is excreted in the in reduction in the exchange of triglycerides into HDL in place
urine as the glucuronide, and about 25% in feces. of cholesteryl esters.
CH3
CH3 Therapeutic Uses & Dosage
O CH2 CH2 CH2 C COOH Fibrates are useful drugs in hypertriglyceridemias in which
CH3
VLDL predominate and in dysbetalipoproteinemia. They also
CH3 may be of benefit in treating the hypertriglyceridemia that
Gemfibrozil results from treatment with antiviral protease inhibitors. The
usual dose of gemfibrozil is 600 mg orally once or twice daily.
The dosage of fenofibrate as Tricor is one to three 48-mg tablets
CH3 (or a single 145-mg tablet) daily. Dosages of other preparations
Cl C O C C O CH(CH3)2 vary. Absorption of gemfibrozil is improved when the drug is
O CH3 O
taken with food.
Fenofibrate
Toxicity
Rare adverse effects of fibrates include rashes, gastrointestinal
Mechanism of Action symptoms, myopathy, arrhythmias, hypokalemia, and high blood
Fibrates function primarily as ligands for the nuclear transcription levels of aminotransferases or alkaline phosphatase. A few patients
receptor PPAR-α. They transcriptionally upregulate LPL, apo A-I, show decreases in white blood count or hematocrit. Both agents
and apo A-II, and they downregulate apo C-III, an inhibitor of may potentiate the action of anticoagulants, and doses of these
lipolysis. A major effect is an increase in oxidation of fatty acids in agents should be adjusted. Rhabdomyolysis has occurred rarely.
liver and striated muscle (Figure 35–4). They increase lipolysis of Risk of myopathy increases when fibrates are given with reductase
lipoprotein triglyceride via LPL. Intracellular lipolysis in adipose inhibitors. Fenofibrate is the fibrate of choice for use in combi-
tissue is decreased. Levels of VLDL decrease, in part as a result of nation with a statin. Fibrates should be avoided in patients with
decreased secretion by the liver. Only modest reductions of LDL hepatic or renal dysfunction. There appears to be a modest increase
occur in most patients. In others, especially those with combined in the risk of cholesterol gallstones, reflecting an increase in the
hyperlipidemia, LDL often increases as triglycerides are reduced. cholesterol content of bile. Therefore, fibrates should be used with
HDL cholesterol increases moderately. Part of this apparent caution in patients with biliary tract disease or in those at higher
increase is a consequence of lower triglyceride in plasma, resulting risk such as women, obese patients, and Native Americans.

Skeletal muscle Fatty acid oxidation

Endothelium Fatty acids

Blood Lipoprotein lipase Transcription of LPL

vessels
Hydrolysis of VLDL
and chylomicron
VLDL, triglycerides
Chylomicron

Liver Triglycerides
Secretion
Apo Clll synthesis
Synthesis
Apo Al and Apo AII synthesis Fatty acids
Oxidation

Oxidation products

FIGURE 35–4  Hepatic and peripheral effects of fibrates. These effects are mediated by activation of peroxisome proliferator-activated receptor-α,
which decreases the secretion of VLDL and increases its peripheral metabolism. LPL, lipoprotein lipase; VLDL, very-low-density lipoproteins.
636    SECTION VI  Drugs Used to Treat Diseases of the Blood, Inflammation, & Gout
NIACIN (NICOTINIC ACID)
Niacin (but not niacinamide) decreases triglycerides and LDL
levels, and Lp(a) in most patients. It often increases HDL levels
significantly. Historically, combination therapy including niacin
has been associated with regression of atherosclerotic coronary
lesions in three angiographic trials and with extension of lifespan
in one large trial in which patients received niacin alone.
Chemistry & Pharmacokinetics
In its role as a vitamin, niacin (vitamin B3) is converted in the
body to the amide, which is incorporated into niacinamide
adenine dinucleotide (NAD), which in turn has a critical role
in energy metabolism. In pharmacologic doses, it has impor-
tant effects on lipid metabolism that are poorly understood. It
is excreted in the urine unmodified and as several metabolites.
One, N-methyl nicotinamide, creates a draft on methyl groups
that can occasionally result in erythrocyte macrocytosis, similar to
deficiency of folate or vitamin B12.
Mechanism of Action
Niacin inhibits VLDL secretion, in turn decreasing production
of LDL (Figure 35–2). Increased clearance of VLDL via the LPL
pathway contributes to reduction of triglycerides. Excretion of
neutral sterols in the stool is increased acutely as cholesterol is
mobilized from tissue pools and a new steady state is reached.
The catabolic rate for HDL is decreased. Fibrinogen levels are
reduced, and levels of tissue plasminogen activator appear to
increase. Niacin inhibits the intracellular lipase of adipose tissue
via receptor-mediated signaling, possibly reducing VLDL produc-
tion by decreasing the flux of free fatty acids to the liver. Sustained
inhibition of lipolysis has not been established, however.
Therapeutic Uses & Dosage
In combination with a resin or reductase inhibitor, niacin nor-
malizes LDL in most patients with heterozygous familial hyper-
cholesterolemia and other forms of hypercholesterolemia. These
combinations are also indicated in some cases of nephrosis. In
severe mixed lipemia that is incompletely responsive to diet,
niacin often produces marked reduction of triglycerides, an effect
enhanced by marine omega-3 fatty acids. It is useful in patients
with combined hyperlipidemia and in those with dysbetalipopro-
teinemia. Niacin is clearly the most effective agent for increasing
HDL and reduces Lp(a) in most patients.
For treatment of heterozygous familial hypercholesterolemia,
2–6 g of niacin daily is usually required; more than this should not
be given. For other types of hypercholesterolemia and for hypertri-
glyceridemia, 1.5–3.5 g daily is often sufficient. Crystalline niacin
should be given in divided doses with meals, starting with 100 mg
two or three times daily and increasing gradually.
Toxicity
Most persons experience a harmless cutaneous vasodilation and
sensation of warmth after each dose when niacin is started or
the dose increased. Taking 81–325 mg of aspirin 30 minutes
beforehand blunts this prostaglandin-mediated effect. Naproxen,
220 mg once daily, also mitigates the flush. Tachyphylaxis to
flushing usually occurs within a few days at doses above 1.5–3 g
daily. Patients should be warned to expect the flush and under-
stand that it is a harmless side effect. Pruritus, rashes, dry skin or
mucous membranes, and acanthosis nigricans have been reported.
The latter requires the discontinuance of niacin because of its
association with insulin resistance. Some patients experience nau-
sea and abdominal discomfort. Many can continue the drug at
reduced dosage, with inhibitors of gastric acid secretion or with
antacids not containing aluminum. Niacin should be avoided in
patients with significant peptic disease.
Reversible elevations in aminotransferases up to twice normal
may occur, usually not associated with liver toxicity. However,
liver function should be monitored at baseline and at appropri-
ate intervals. Rarely, true hepatotoxicity may occur, and the
drug should be discontinued. The association of severe hepatic
dysfunction, including acute necrosis, with the use of over-the-
counter sustained-release preparations of niacin has been reported.
This effect has not been noted to date with an extended-release
preparation, Niaspan, given at bedtime in doses of 2 g or less.
Carbohydrate tolerance may be moderately impaired, especially in
obese patients. Niacin may be given to diabetics who are receiv-
ing insulin and to some receiving oral agents but it may increase
insulin resistance. This can be addressed by increasing the dose of
insulin or the oral agents. Hyperuricemia occurs in some patients
and occasionally precipitates gout. Allopurinol can be given with
niacin if needed. Red cell macrocytosis can occur and is not
an indication for discontinuing treatment. Significant platelet
deficiency can occur rarely and is reversible on cessation of treat-
ment. Rarely, niacin is associated with arrhythmias, mostly atrial,
and with macular edema, both requiring cessation of treatment.
Patients should be instructed to report blurring of distance vision.
Niacin may potentiate the action of antihypertensive agents,
requiring adjustment of their dosages. Birth defects have been
reported in offspring of animals given very high doses.
BILE ACID–BINDING RESINS
Colestipol, cholestyramine, and colesevelam are useful only for
isolated increases in LDL. In patients who also have hypertriglyc-
eridemia, VLDL levels may be further increased during treatment
with resins.
Chemistry & Pharmacokinetics
The bile acid-binding agents are large polymeric cationic exchange
resins that are insoluble in water. They bind bile acids in the
intestinal lumen and prevent their reabsorption. The resin itself
is not absorbed.
Mechanism of Action
Bile acids, metabolites of cholesterol, are normally efficiently
reabsorbed in the jejunum and ileum (Figure 35–2). Excretion
is increased up to tenfold when resins are given, resulting in

enhanced conversion of cholesterol to bile acids in liver via
7α-hydroxylation, which is normally controlled by negative
feedback by bile acids. Decreased activation of the FXR receptor
by bile acids may result in a modest increase in plasma triglycer-
ides but can also improve glucose metabolism in patients with
diabetes. The latter effect is due to increased secretion of the
incretin glucagon-like peptide-1 from the intestine, thus increas-
ing insulin secretion. Increased uptake of LDL and IDL from
plasma results from upregulation of LDL receptors, particularly
in liver. Therefore, the resins are without effect in patients with
homozygous familial hypercholesterolemia who have no function-
ing receptors but may be useful in those with some residual recep-
tor function and in patients with receptor-defective combined
heterozygous states.
Therapeutic Uses & Dosage
The resins are used in treatment of patients with primary hyper-
cholesterolemia, producing approximately 20% reduction in LDL
cholesterol in maximal dosage. If resins are used to treat LDL ele-
vations in persons with combined hyperlipidemia, they may cause
an increase in VLDL, requiring the addition of a second agent
such as a fibrate or niacin. Resins are also used in combination
with other drugs to achieve further hypocholesterolemic effect
(see below). They may be helpful in relieving pruritus in patients
who have cholestasis and bile salt accumulation. Because the resins
bind digitalis glycosides, they may be useful in digitalis toxicity.
Colestipol and cholestyramine are available as granular prepa-
rations. A gradual increase of dosage of granules from 4 or 5 g/d
to 20 g/d is recommended. Total dosages of 30–32 g/d may
be needed for maximum effect. The usual dosage for a child is
10–20 g/d. Granular resins are mixed with juice or water and
allowed to hydrate for 1 minute. Colestipol is also available in
1-g tablets that must be swallowed whole, with a maximum dose
of 16 g daily. Colesevelam is available in 625-mg tablets and as a
suspension (1875-mg or 3750-mg packets). The maximum dose is
six tablets or 3750 mg as suspension, daily. Resins should be taken
in two or three doses with meals.
Toxicity
Common complaints are constipation and bloating, usually
relieved by increasing dietary fiber. Resins should be avoided in
patients with diverticulitis. Heartburn and diarrhea are occasion-
ally reported. In patients who have preexisting bowel disease or
cholestasis, steatorrhea may occur. Malabsorption of vitamin K
occurs rarely, leading to hypoprothrombinemia. Prothrombin
time should be measured frequently in patients who are taking
resins and anticoagulants. Malabsorption of folic acid has been
reported rarely. Increased formation of gallstones, particularly
in obese persons, was an anticipated adverse effect but has rarely
occurred in practice.
Absorption of certain drugs, including those with neutral or
cationic charge as well as anions, may be impaired by the resins.
These include digitalis glycosides, thiazides, warfarin, tetracycline,
thyroxine, iron salts, pravastatin, fluvastatin, ezetimibe, folic
acid, phenylbutazone, aspirin, and ascorbic acid, among others.
CHAPTER 35  Agents Used in Dyslipidemia    637
In general, additional medication (except niacin) should be given
1 hour before or at least 2 hours after the resin to ensure adequate
absorption. Colesevelam does not bind digoxin, warfarin, or
reductase inhibitors.
INHIBITORS OF INTESTINAL STEROL
ABSORPTION
Ezetimibe inhibits intestinal absorption of phytosterols and cho-
lesterol. Added to statin therapy, it provides an additional effect,
decreasing LDL levels and further reducing the dimensions of
atherosclerotic plaques.
Chemistry & Pharmacokinetics
Ezetimibe is readily absorbed and conjugated in the intestine to an
active glucuronide, reaching peak blood levels in 12–14 hours. It
undergoes enterohepatic circulation, and its half-life is 22 hours.
Approximately 80% of the drug is excreted in feces. Plasma con-
centrations are substantially increased when it is administered
with fibrates and reduced when it is given with cholestyramine.
Other resins may also decrease its absorption. There are no signifi-
cant interactions with warfarin or digoxin.
OH
OH
N F
O
F
Ezetimibe
Mechanism of Action
Ezetimibe selectively inhibits intestinal absorption of cholesterol
and phytosterols. A transport protein, NPC1L1, is the target of the
drug. It is effective in the absence of dietary cholesterol because it
also inhibits reabsorption of cholesterol excreted in the bile.
Therapeutic Uses & Dosage
The effect of ezetimibe on cholesterol absorption is constant over
the dosage range of 5–20 mg/d. Therefore, a daily dose of 10 mg
is used. Average reduction in LDL cholesterol with ezetimibe alone
in patients with primary hypercholesterolemia is about 18%, with
minimal increases in HDL cholesterol. It is also effective in patients
with phytosterolemia. Ezetimibe is synergistic with reductase inhib-
itors, producing decrements as great as 25% in LDL cholesterol
beyond that achieved with the reductase inhibitor alone.
Toxicity
Ezetimibe does not appear to be a substrate for cytochrome P450
enzymes. Experience to date reveals a low incidence of reversible
impaired hepatic function with a small increase in incidence when
given with a reductase inhibitor. Myositis has been reported rarely.
638    SECTION VI  Drugs Used to Treat Diseases of the Blood, Inflammation, & Gout
INHIBITION OF MICROSOMAL
TRIGLYCERIDE TRANSFER PROTEIN
Microsomal triglyceride transfer protein (MTP) plays an
essential role in the addition of triglycerides to nascent VLDL
in liver, and to chylomicrons in the intestine. Its inhibition
decreases VLDL secretion and consequently the accumulation
of LDL in plasma. An MTP inhibitor, lomitapide, is available
but is currently restricted to patients with homozygous familial
hypercholesterolemia. It causes accumulation of triglycerides in
the liver in some individuals. Elevations in transaminases can
occur. Patients must maintain a low fat diet to avoid steator-
rhea and should take steps to minimize deficiency of essential
fat-soluble nutrients. Lomitapide is given orally in gradually
increasing doses of 5- to 60-mg capsules once daily 2 hours
after the evening meal. It is available only through a restricted
(REMS) program for patients with homozygous familial
hypercholesterolemia.
ANTISENSE INHIBITION OF APO
B-100 SYNTHESIS
Mipomersen is an antisense oligonucleotide that targets apo
B-100, mainly in the liver. It is important to note that the apo
B-100 gene is also transcribed in the retina and in cardiomyo-
cytes. Subcutaneous injections of mipomersen reduce levels of
LDL and Lp(a). Mild to moderate injection site reactions and
flu-like symptoms can occur. The drug is available only for use
in homozygous familial hypercholesterolemia through a restricted
(REMS) program.
PCSK9 INHIBITION
Development of inhibitors of proprotein convertase subtilisin/
kexin type 9 (PCSK9) followed on the observation that loss
of function mutations result in very low levels of LDL and no
apparent morbidity. Therapeutic agents currently available in
this class are humanized antibodies to PCSK9 (evolocumab,
alirocumab). LDL reductions of up to 70% at the highest
doses have been achieved with these agents when administered
subcutaneously every two weeks. (Evolocumab can also be
given monthly at a higher dose). Triglycerides and apo B-100
are reduced, and Lp(a) levels decrease by about 25%. Rarely,
hypersensitivity reactions have occurred. Local reactions at the
injection site, upper respiratory and flu-like symptoms have
been observed more frequently. Use of these agents is restricted
to patients who have familial hypercholesterolemia or clinical
atherosclerotic cardiovascular disease who require additional
reduction of LDL. They are given with diet and maximal toler-
ated statin and/or ezetimibe. Development of small molecules
and antisense oligonucleotides to inhibit PCSK9 is underway.
Studies of PCSK9 inhibition should be approached with cau-
tion because of its established role in normal cell biology. These
agents are very expensive.
AGENTS UNDER DEVELOPMENT
CETP INHIBITION
Cholesteryl ester transfer protein (CETP) transfers cholesteryl
esters from mature, large diameter HDL particles to triglyceride-
rich lipoproteins that ultimately deliver the esters to liver whence
both cholesterol and bile acids can be eliminated into the intes-
tine. Inhibition of CETP leads to accumulation of mature HDL
particles and diminution of the transport of cholesteryl esters to
liver. The accumulation of large HDL particles does not have the
cardioprotective effect anticipated on the basis of epidemiologic
studies. Some reduction of LDL-C can be achieved and choles-
terol efflux capacity enhanced. Thus far no drug (eg, torcetrapib,
anacetrapib) in this class has been approved.
AMP KINASE ACTIVATION
AMP-activated protein kinase acts as a sensor of energy status in
cells. When increased ATP availability is required, AMP kinase
increases fatty acid oxidation and insulin sensitivity, and inhibits
cholesterol and triglyceride biosynthesis. Although the trials to
date have been directed at decreasing LDL-C levels, AMP kinase
activation may have merit for management of the metabolic syn-
drome and diabetes. An agent combining AMP kinase activation
and ATP citrate lyase inhibition is in clinical trials.
CYCLODEXTRINS
These are circular sugar polymers that can solubilize hydrophobic
drugs for delivery and are approved for this purpose. They can
also solubilize cholesterol from tissue sites such as arteriosclerotic
plaque. Early stage animal studies on this potential therapeutic
activity are in progress.
TREATMENT WITH DRUG
COMBINATIONS
Combined drug therapy is useful (1) when VLDL levels are signif-
icantly increased during treatment of hypercholesterolemia with a
resin; (2) when LDL and VLDL levels are both elevated initially;
(3) when LDL or VLDL levels are not normalized with a single
agent, or (4) when an elevated level of Lp(a) or an HDL deficiency
coexists with other hyperlipidemias. The lowest effective doses
should be used in combination therapy and the patient should be
monitored more closely for evidence of toxicity. In combinations
that include resins, the other agent (with the exception of niacin)
should be separated temporally to ensure absorption.
FIBRIC ACID DERIVATIVES & BILE
ACID-BINDING RESINS
This combination is sometimes useful in treating patients with
familial combined hyperlipidemia who are intolerant of niacin or
statins. However, it may increase the risk of cholelithiasis.
 CHAPTER 35  Agents Used in Dyslipidemia    639

HMG-CoA REDUCTASE INHIBITORS & REDUCTASE INHIBITORS &

BILE ACID-BINDING RESINS
This synergistic combination is useful in the treatment of familial
hypercholesterolemia but may not control levels of VLDL in some
patients with familial combined hyperlipoproteinemia.
NIACIN & BILE ACID-BINDING RESINS
This combination effectively controls VLDL levels during resin
therapy of familial combined hyperlipoproteinemia or other
disorders involving both increased VLDL and LDL levels. When
VLDL and LDL levels are both initially increased, doses of niacin
as low as 1–3 g/d may be sufficient in combination with a resin.
The niacin-resin combination is effective for treating heterozygous
familial hypercholesterolemia.
NIACIN & REDUCTASE INHIBITORS
If the maximum tolerated statin dose fails to achieve the LDL
cholesterol goal in a patient with hypercholesterolemia, niacin
may be helpful. This combination may be useful in the treatment
of familial combined hyperlipoproteinemia.
REDUCTASE INHIBITORS & EZETIMIBE
This combination is synergistic in treating primary hypercho-
lesterolemia and may be of use in the treatment of patients
with homozygous familial hypercholesterolemia who have some
receptor function.
FENOFIBRATE
Fenofibrate appears to be complementary with most statins in
the treatment of familial combined hyperlipoproteinemia and
other conditions involving elevations of both LDL and VLDL.
The combination of fenofibrate with rosuvastatin appears to
be especially well tolerated. Some other statins may interact
unfavorably owing to effects on cytochrome P450 metabolism.
In any case, particular vigilance for liver and muscle toxicity is
indicated.
COMBINATIONS OF RESINS, EZETIMIBE,
NIACIN, & REDUCTASE INHIBITORS
These agents act in a complementary fashion to normalize cho-
lesterol in patients with severe disorders involving elevated LDL.
The effects are sustained, and little compound toxicity has been
observed. Effective doses of the individual drugs may be lower
than when each is used alone; for example, as little as 1–2 g of
niacin may substantially increase the effects of the other agents.
COMBINATIONS OF PCSK9 ANTIBODY
WITH STATIN AND EZETIMIBE
These agents can be used together to achieve maximal reduction of
LDL. Because of the need for parenteral administration of PCSK9
antibody and its expense, this therapy is reserved for patients with
familial hypercholesterolemia or atherosclerotic vascular disease
who do not respond adequately to other regimens.

SUMMARY Drugs Used in Dyslipidemia

Subclass, Pharmacokinetics, Toxicities,
Drug Mechanism of Action Effects Clinical Applications Interactions

STATINS        
•  Atorvastatin, Inhibit HMG-CoA reductase Reduce cholesterol synthesis and Atherosclerotic vascular Oral • duration 12–24 h • Toxicity: Myopathy,
simvastatin, upregulate low-density disease (primary and hepatic dysfunction • Interactions:
rosuvastatin, lipoprotein (LDL) receptors on secondary prevention) CYP-dependent metabolism (3A4, 2C9)
pitavastatin hepatocytes • modest reduction • acute coronary interacts with CYP inhibitors/competitors
in triglycerides syndromes

•  Fluvastatin, pravastatin, lovastatin: Similar but somewhat less efficacious

FIBRATES        
•  Fenofibrate, Peroxisome proliferator- Decrease secretion of Hypertriglyceridemia, Oral • duration 3–24 h • Toxicity: Myopathy,
gemfibrozil activated receptor-alpha very-low-density lipoproteins low HDL hepatic dysfunction
(PPAR-α) agonists (VLDL) • increase lipoprotein
lipase activity • increase
high-density lipoproteins (HDL)

(continued)
640    SECTION VI  Drugs Used to Treat Diseases of the Blood, Inflammation, & Gout

Subclass, Pharmacokinetics, Toxicities,

Drug Mechanism of Action Effects Clinical Applications Interactions

BILE ACID SEQUESTRANTS

•  Colestipol Binds bile acids in gut
• prevents reabsorption
• increases cholesterol
catabolism • upregulates LDL
receptors
Decreases LDL Elevated LDL, digitalis Oral • taken with meals • not absorbed
toxicity, pruritus • Toxicity: Constipation, bloating • interferes
with absorption of some drugs and vitamins

•  Cholestyramine, colesevelam: Similar to colestipol

STEROL ABSORPTION INHIBITOR

•  Ezetimibe Blocks sterol transporter Inhibits reabsorption of Elevated LDL, Oral • duration 24 h • Toxicity: Low incidence
NPC1L1 in intestine brush cholesterol excreted in bile phytosterolemia of hepatic dysfunction, myositis
border • decreases LDL and phytosterols

NIACIN
  Decreases catabolism of
apo AI • reduces VLDL
secretion from liver
Increases HDL • decreases Low HDL • elevated VLDL, Oral • large doses • Toxicity: Gastric irritation,
lipoprotein(a) [Lp(a)], LDL Lp(a); elevated LDL in flushing, low incidence of hepatic toxicity
statin-unresponsive or • may reduce glucose tolerance
intolerant patients

•  Extended-release niacin: Similar to regular niacin

•  Sustained-release niacin (not the same as extended-release product): Should be avoided

PCSK9 HUMANIZED MONOCLONAL ANTIBODIES

Evolocumab Complexes PCSK9 Inhibits catabolism of LDL Familial Parenteral • Cost ~ $14,000/year • Toxicity:
receptor hypercholesterolemia not injection site reactions, nasopharyngitis,
responsive to oral therapy flu-like symptoms, rarely myalgia,
neurocognitive and ophthalmologic events

•  Alirocumab Similar to evolucumab

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Curr Opin Lipidol 2017;28:170.
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Alirocumab Praluent kinase in patients with hypercholesterolemia: Results of a multicenter, ran-
domized, double-blind, placebo-controlled, parallel-group trial. J Am Coll
Atorvastatin Generic, Lipitor
Cardiol 2013;62:1154.
Cholestyramine Generic, Questran, Prevalite Boekholdt SM et al: Levels and changes of HDL cholesterol and apolipoprotein
Colesevelam Welchol A-I in relation to risk of cardiovascular events among statin-treated patients:
Colestipol Generic, Colestid A meta-analysis. Circulation 2013;128:1504.
Evolocumab Repatha Bonow RO, Yancy CW: High-intensity statins for secondary prevention. JAMA
Cardiol 2017;2:55.
Ezetimibe Generic, Zetia
Cannon CP et al: Ezetimibe added to statin therapy after acute coronary
Fenofibrate Generic, Tricor, Antara, Lofibra syndrome. N Engl J Med 2015;372:2387.
Fluvastatin Generic, Lescol, Lescol XL Chou R et al: Statins for prevention of cardiovascular disease in adults: Evidence
Gemfibrozil Generic, Lopid report and systematic review for the US Preventive Services Task Force.
JAMA 2016;316:2008.
Lomitapide Juxtapid
Dron JS, Hegele RA: Complexity of mechanisms among human proprotein
Mipomersen Kynamro convertase subtilisin-kexin type 9 variants. Curr Opin Lipidol 2017;28:161.
Lovastatin Generic, Mevacor, Altoprev Elam M, Lovato E, Ginsberg H: The role of fibrates in cardiovascular disease
Niacin, nicotinic acid, vitamin B3 Generic only prevention, The ACCORD–lipid perspective. Curr Opin Lipidol 2011;22:55.
Omega-3 fatty acids–marine Lovaza Gaudet D et al: Antisense inhibition of apolipoprotein C-III in patients with
hypertriglyceridemia. N Engl J Med 2015;373:438.
Pitavastatin Livalo
Gouni-Berthold I et al: Systematic review of published phase 3 data on anti-
Pravastatin Generic, Pravachol PCSK9 monoclonal antibodies in patients with hypercholesterolaemia. Br J
Rosuvastatin Generic, Crestor Clin Pharmacol 2016;82:1412.
Simvastatin Generic, Zocor International Atherosclerosis Society: IAS Position Paper: Global Recommenda-
tions for the Management of Dyslipidemia. Available at: www.athero.org/
COMBINATION TABLETS
IASPositionPaper.asp.
Ezetimibe/simvastatin Vytorin Jacobson TA et al: On behalf of the NLA Expert Panel. National Lipid Association
Niacin/lovastatin extended-release Advicor recommendations for patient-centered management of dyslipidemia: Part 2.
Niacin/simvastatin extended-release Simcor J Clin Lipidol 2015;9:S1.

LaRosa JC et al: Safety and effect of very low levels of low density lipoprotein
cholesterol on cardiovascular events. Am J Cardiol 2013;111:1221.
Mampuya WM et al: Treatment strategies in patients with statin intolerance: The
Cleveland Clinic experience. Am Heart J 2013;166:597.
Nduka C et al: Impact of antiretroviral therapy on serum lipoprotein levels
and dyslipidemias: a systematic review and meta-analysis. Int J Cardiol
2015;199:307.
Perry CM: Lomitapide: A review of its use in adults with homozygous familial
hypercholesterolemia. Am J Cardiovasc Drugs 2013;13:265.
Raal FJ, Stein EA: The effects of mipomersen on inhibiting hepatic VLDL
apolipoprotein B 100 and propensity for hepatic steatosis. Clin Chem
2016;62:1052.
Reith C, Armitage J: Management of residual risk after statin therapy. Atheroscle-
rosis 2016;245;161.
Rodriguez F: Association between intensity of statin therapy and mortality
in patients with atherosclerotic cardiovascular disease. JAMA Cardiol
2016;2:47.
C ASE STUDY ANSWER
The patient’s history of muscle symptoms should be care-
fully evaluated. The genotype at the SLCO1B1 locus might be
obtained to determine whether myositis is due to impaired
metabolism of statins. If you agree that her muscle symptoms
were clearly associated with statin use but were not particu-
larly severe and not associated with creatine kinase elevations
significantly greater than normal, you could prescribe any
one the agents she tried in the past or select a different statin.
The starting dose should be low and the drug given on alter-
nate days, increasing the dose and frequency to achieve the
CHAPTER 35  Agents Used in Dyslipidemia    641
Silverman MG et al: Association between lowering LDL-C and cardiovascular risk
reduction among different therapeutic interventions: A systematic review
and meta-analysis. JAMA Cardiol 2016;316:1289.
Stone NJ et al: 2013 ACC/AHA guidelines on the treatment of blood choles-
terol to reduce atherosclerotic cardiovascular risk in adults. A report of the
American College of Cardiology/American Heart Association task force on
practice guidelines. Circulation 2014; 129 (25 Suppl 2):S1. Erratum: Cir-
culation 2015;132:e396.
Swiger JK et al: Statins and cognition: A systematic review and meta-analysis of
short and long term cognitive effects. Mayo Clin Proceed 2013;88:1213.
Tsujita K et al: Impact of dual-lipid lowering with ezetimibe and atorvastatin on
coronary plaque regression in patients with percutaneous coronary interven-
tion. The randomized controlled PRECISE-IVUS trial. J Am Coll Cardiol
2015;66:495.
Yahya R et al: Lomitapide effects HDL composition and function. Atherosclerosis
2016;251:15.
Zimmer S et al: Cyclodextrin promotes atherosclerosis regression via macrophage
reprogramming. Sci Transl Med 2016;8:333ra50.
LDL-C goal. If this is not tolerated or the goal is not reached,
alternate drugs can be used, including a bile acid binding resin,
intestinal sterol absorption inhibitor, or niacin (monitoring
uric acid, glucose, and liver enzymes). These can be used in
combinations with each other or with a low dose statin. If all
else fails, use of a PCSK9 monoclonal antibody should be con-
sidered. Her homocysteine level should be measured because
of the synergy between that amino acid and Lp(a) with respect
to thrombotic risk. Also, because of her elevated Lp(a), she
should be evaluated for aortic stenosis.
656    SECTION VI  Drugs Used to Treat Diseases of the Blood, Inflammation, & Gout
infections) is increased, although it remains very low. Activation
of latent tuberculosis is lower with etanercept than with other
TNF-α–blocking agents. Nevertheless, all patients should be
screened for latent or active tuberculosis before starting TNF-α–
blocking agents. The use of TNF-α–blocking agents is also associ-
ated with increased risk of HBV reactivation; screening for HBV
is important before starting the treatment.
TNF-α–blocking agents increase the risk of skin cancers—
including melanoma—which necessitates periodic skin examina-
tion, especially in high-risk patients. On the other hand, there is no
clear evidence of increased risk of solid malignancies or lymphomas
with TNF-α–blocking agents, and their incidence may not be
different compared with other bDMARDs or active RA itself.
A low incidence of newly formed dsDNA antibodies and
antinuclear antibodies (ANAs) has been documented when using
TNF-α–blocking agents, but clinical lupus is extremely rare and
the presence of ANA and dsDNA antibodies per se does not
contraindicate the use of TNF-α–blocking agents. In patients
with borderline or overt heart failure (HF), TNF-α–blocking
agents can exacerbate HF. TNF-α–blocking agents can induce the
immune system to develop antidrug antibodies in about 17% of
cases. These antibodies may interfere with drug efficacy and cor-
relate with infusion site reactions. Injection site reactions occur in
20–40% of patients, although they rarely result in discontinuation
of therapy. Cases of alopecia areata, hypertrichosis, and erosive
lichen planus have been reported. Cutaneous pseudo-lymphomas
are reported rarely with TNF-α–blocking agents, especially inflix-
imab. TNF-α–blocking agents may increase the risk of gastroin-
testinal ulcers and large bowel perforation including diverticular
and appendiceal perforation.
Nonspecific interstitial pneumonia, psoriasis, and sarcoidosis-
like syndrome are among the rare reported toxicities associated
with TNF-α blockers. Rare cases of leukopenia, neutropenia,
thrombocytopenia, and pancytopenia have also been reported.
The precipitating drug should be discontinued in such cases.
USTEKINUMAB
1. Mechanism of Action: Ustekinumab is an IL-12 and IL-23
antagonist. It is a fully human IgG monoclonal antibody to the
p40 protein subunit, which is part of both IL-12 and IL-23.
These two cytokines are important contributors to the chronic
inflammation in psoriasis plaques, PsA, and Crohn’s disease.
Ustekinumab prevents the binding of the p40 subunit of both
IL-12 and IL-23 to the IL-12 receptor b1 found on the surface
of CD4 T cells and NK cells. This interruption interferes with
IL-12 and IL-23 signal transduction and suppresses the forma-
tion of proinflammatory TH1 and TH17 cells.
2. Pharmacokinetics: Ustekinumab is available as a 45- and
90-mg SC injection for PsA and plaque psoriasis. Its bioavail-
ability is 57% following SC injection; time to peak plasma
concentration is 7–13.5 days and elimination half-life is
10–126 days. For adults with PsA, a loading dose at 0 and
4 weeks is followed by maintenance doses once every 12 weeks.
IV infusion as a 130 mg dose is available for Crohn’s disease.
3. Indications: Ustekinumab is indicated for treatment of adult
patients with PsA. It can be used as monotherapy or in combi-
nation with methotrexate. Other indications include plaque
psoriasis and Crohn’s disease.
4. Adverse Effects: Upper respiratory tract infection is the most
common side effect, but rare severe infection, malignancy,
and reversible posterior leukoencephalopathy syndrome have
been reported. Ustekinumab should be discontinued at least
15 weeks before live vaccines are administered and can be
resumed at least 2 weeks after.
SECUKINUMAB
1. Mechanism of Action: Secukinumab is a human IgG1 mono-
clonal antibody that selectively binds to the IL-17A cytokine,
inhibiting its interaction with the IL-17A receptor. IL-17A is
involved in normal inflammatory and immune responses.
Elevated concentrations of IL-17A are found in psoriatic
plaques and PsA.
2. Pharmakokinetics: Secukinumab is available as a SC injection
or lyophilized powder for injection. Its peak plasma concentra-
tion is 13.7 mcg/mL (150 mg dose) and 27.3 mcg/mL (300 mg
dose); elimination half-life is 22–31 days.
3. Indications and Dosage: Secukinumab is indicated for moder-
ate to severe plaque psoriasis in patients who are candidates for
systemic therapy or phototherapy. Initial loading dose is 300
mg SC at weeks 0, 1, 2, 3, and 4, followed by monthly main-
tenance (300 mg SC or 150 mg SC monthly). For adults with
active PsA and moderate to severe plaque psoriasis, the same
recommendations are followed. For patients with psoriatic
arthritis as well as AS, administer with or without a loading
dosage by SC injection; 150 mg SC every 4 weeks with or
without MTX is recommended.
4. Adverse Effects: As for any of these biologics, infection is
a common side effect (28.7%). Nasopharyngitis occurs in
about 12%. TB status should be evaluated prior to therapy.
Secukinumab may exacerbate Crohn’s disease.
TOFACITINIB
1. Mechanism of Action: Tofacitinib is a targeted synthetic small
molecule (tsDMARD) that selectively inhibits all members of
the Janus kinase (JAK; see Chapter 2) family to varying
degrees. At therapeutic doses, tofacitinib exerts its effect mainly
by inhibiting JAK3, and to a lesser extent JAK1, hence inter-
rupting the JAK-STAT signaling pathway. This pathway plays
a major role in the pathogenesis of autoimmune diseases
including RA. The JAK3/JAK1 complex is responsible for
signal transduction from the common γ-chain receptor (IL-
2RG) for IL-2, -4, -7, -9, -15, and -21, which subsequently
influences transcription of several genes that are crucial for the
differentiation, proliferation, and function of NK cells and T
and B lymphocytes. In addition, JAK1 (in combination with
 SECTION VII  ENDOCRINE DRUGS
Hypothalamic & Pituitary
Hormones
Roger K. Long, MD, & Hakan Cakmak, MD
C ASE STUDY
A 4-year-old boy (height 90 cm, –3 standard deviations
[SD]; weight 14.5 kg, approximately 15th percentile)
presents with short stature. Review of the past history
and growth chart demonstrates normal birth weight and
birth length, but a progressive decrease in height per-
centiles relative to age-matched normal ranges starting
at 6 months of age, and orthostasis with febrile illnesses.
Physical examination demonstrates short stature and
mild generalized obesity. Genital examination reveals
descended but small testes and a phallic length of –2 SD.
The control of metabolism, growth, and reproduction is medi-
ated by a combination of neural and endocrine systems located
in the hypothalamus and pituitary gland. The pituitary weighs
about 0.6 g and rests at the base of the brain in the bony sella
turcica near the optic chiasm and the cavernous sinuses. The
pituitary consists of an anterior lobe (adenohypophysis) and a
posterior lobe (neurohypophysis) (Figure 37–1). It is connected
to the overlying hypothalamus by a stalk of neurosecretory fibers
37
C H A P T E R
Laboratory evaluations demonstrate growth hormone
(GH) deficiency and a delayed bone age of 18 months.
The patient is started on replacement with recombinant
human GH at a dose of 40 mcg/kg per day subcutaneously.
After 1 year of treatment, his height velocity has increased
from 5 cm/y to 11 cm/y. How does GH stimulate growth
in children? What other hormone deficiencies are sug-
gested by the patient’s history and physical examination?
What other hormone replacements is this patient likely
to require?
and blood vessels, including a portal venous system that drains
the hypothalamus and perfuses the anterior pituitary. The portal
venous system carries small regulatory hormones (Figure 37–1,
Table 37–1) from the hypothalamus to the anterior pituitary.
The posterior lobe hormones are synthesized in the hypothala-
mus and transported via the neurosecretory fibers in the stalk of
the pituitary to the posterior lobe; from there they are released
into the circulation.
667
668    SECTION VII  Endocrine Drugs

GHRH
Hypothalamus
■■ ANTERIOR PITUITARY
TRH
CRH
DA
SST HORMONES & THEIR
GnRH HYPOTHALAMIC REGULATORS
–
All the hormones produced by the anterior pituitary except
+ prolactin are key participants in hormonal systems in which they
regulate the production of hormones and autocrine-paracrine
factors by endocrine glands and other peripheral tissues. In these
Portal venous systems, the secretion of the pituitary hormone is under the
system control of one or more hypothalamic hormones. Each hypotha-
Anterior
Posterior lamic-pituitary-endocrine gland system or axis provides multiple
pituitary opportunities for complex neuroendocrine regulation of growth
pituitary
and development, metabolism, and reproductive function.

ANTERIOR PITUITARY &

HYPOTHALAMIC HORMONE
GH
TSH
RECEPTORS
ACTH The anterior pituitary hormones can be classified according to
PRL Oxytocin
LH
hormone structure and the types of receptors that they activate.
FSH
Growth hormone (GH) and prolactin (PRL), single-chain pro-
ADH
tein hormones with significant homology, form one group. Both
hormones activate receptors of the JAK/STAT superfamily (see
Chapter 2). Three pituitary hormones—thyroid-stimulating
Endocrine hormone (TSH, thyrotropin), follicle-stimulating hormone
glands, liver, bone, (FSH), and luteinizing hormone (LH)— are dimeric pro-
& other tissues teins that activate G protein-coupled receptors (see Chapter 2).
TSH, FSH, and LH share a common α subunit. Their β sub-
units, though somewhat similar to each other, differ enough to
confer receptor specificity. Finally, adrenocorticotropic hor-
mone (ACTH), a peptide cleaved from a larger precursor, pro-
Target tissues
opiomelanocortin (POMC) represents a third category. POMC
can be cleaved into various other biologically active peptides like
FIGURE 37–1  The hypothalamic-pituitary endocrine α-melanocyte-stimulating hormone (MSH) and β-endorphin
system. Hormones released from the anterior pituitary stimulate
the production of hormones by a peripheral endocrine gland,
the liver, or other tissues, or act directly on target tissues. ACRONYMS
Prolactin and the hormones released from the posterior pituitary
ACTH Adrenocorticotropic hormone (corticotropin)
(vasopressin and oxytocin) act directly on target tissues. Hypotha-
lamic factors regulate the release of anterior pituitary hormones. CRH Corticotropin-releasing hormone
ACTH, adrenocorticotropin; ADH, antidiuretic hormone [vasopres- FSH Follicle-stimulating hormone
sin]; CRH, corticotropin-releasing hormone; DA, dopamine; FSH, GH Growth hormone
follicle-stimulating hormone; GH, growth hormone; GHRH, growth
GHRH Growth hormone–releasing hormone
hormone-releasing hormone; GnRH, gonadotropin-releasing hor-
mone; LH, luteinizing hormone; PRL, prolactin; SST, somatostatin; GnRH Gonadotropin-releasing hormone
TRH, thyrotropin-releasing hormone; TSH, thyroid-stimulating hCG Human chorionic gonadotropin
hormone. hMG Human menopausal gonadotropin
IGF Insulin-like growth factor
LH Luteinizing hormone
Drugs that mimic or block the effects of hypothalamic and PRL Prolactin
pituitary hormones have pharmacologic applications in three
rhGH Recombinant human growth hormone
primary areas: (1) as replacement therapy for hormone deficiency
states; (2) as antagonists for diseases caused by excess production SST Somatostatin
of pituitary hormones; and (3) as diagnostic tools for identifying TRH Thyrotropin-releasing hormone
several endocrine abnormalities. TSH Thyroid-stimulating hormone (thyrotropin)
 CHAPTER 37  Hypothalamic & Pituitary Hormones    669

TABLE 37–1  Links between hypothalamic, anterior pituitary, and target organ hormone or mediator.1
Primary Target Organ Hormone
Anterior Pituitary Hormone Hypothalamic Hormone Target Organ or Mediator

Growth hormone (GH, Growth hormone-releasing hormone Liver, bone, muscle, Insulin-like growth factor-I (IGF-I)
somatotropin) (GHRH) (+), Somatostatin (−) kidney, and others
Thyroid-stimulating hormone (TSH) Thyrotropin-releasing hormone (TRH) (+) Thyroid Thyroxine, triiodothyronine
Adrenocorticotropin (ACTH) Corticotropin-releasing hormone (CRH) (+) Adrenal cortex Cortisol
Follicle-stimulating hormone (FSH) Gonadotropin-releasing hormone Gonads Estrogen, progesterone,
Luteinizing hormone (LH) (GnRH) (+)2 testosterone
Prolactin (PRL) Dopamine (−) Breast —
1
All of these hormones act through G protein-coupled receptors except GH and PRL, which act through JAK/STAT receptors.
2
Endogenous GnRH, which is released in pulses, stimulates LH and FSH release. When administered continuously as a drug, GnRH and its analogs inhibit LH and FSH release
through down-regulation of GnRH receptors.
(+), stimulant; (−), inhibitor.

(see Chapter 31). Like TSH, LH, and FSH, ACTH acts through Whereas all the pituitary and hypothalamic hormones described
a G protein–coupled receptor. A unique feature of the ACTH previously are available for use in humans, only a few are of major
receptor (also known as the melanocortin 2 receptor) is that a clinical importance. Because of the greater ease of administration
transmembrane protein, melanocortin 2 receptor accessory protein, of target endocrine gland hormones or their synthetic analogs,
is essential for normal ACTH receptor trafficking and signaling. the related hypothalamic and pituitary hormones are used infre-
TSH, FSH, LH, and ACTH share similarities in the regulation quently as treatments. However, many of them (TRH, TSH,
of their release from the pituitary. Each is under the control of CRH, ACTH, GnRH, GHRH) are used for specialized diagnostic
a distinctive hypothalamic peptide that stimulates their produc- testing. These agents are described in Tables 37–2 and 37–3 and
tion by acting on G protein-coupled receptors (Table 37–1). are not discussed further in this chapter. In contrast, GH, SST,
TSH release is regulated by thyrotropin-releasing hormone
(TRH), whereas the release of LH and FSH (known collectively
as gonadotropins) is stimulated by pulses of gonadotropin-
releasing hormone (GnRH). ACTH release is stimulated by
TABLE 37–2  Clinical uses of hypothalamic hormones
and their analogs.
corticotropin-releasing hormone (CRH). An important regula-
tory feature shared by these four structurally related hormones is Hypothalamic
that they and their hypothalamic releasing factors are subject to Hormone Clinical Uses
feedback inhibitory regulation by the hormones whose produc- Growth hormone- Used rarely as a diagnostic test for GH and
tion they control. TSH and TRH production are inhibited by the releasing hormone GHRH sufficiency
two key thyroid hormones, thyroxine and triiodothyronine (see (GHRH)
Chapter 38). Gonadotropin and GnRH production is inhibited in Thyrotropin- May be used to diagnose TRH or TSH
women by estrogen and progesterone, and in men by testosterone releasing- hormone deficiencies; not currently available for
(TRH, protirelin) clinical use in United States
and other androgens. ACTH and CRH production are inhibited
by cortisol. Feedback regulation is critical to the physiologic con- Corticotropin-releasing Used rarely to distinguish Cushing’s disease
hormone (CRH) from ectopic ACTH secretion
trol of thyroid, adrenal cortical, and gonadal function and is also
important in pharmacologic treatments that affect these systems. Gonadotropin- May be used in a single dose to assess
releasing hormone initiation of puberty (pubertal gonadotropin
The hypothalamic hormonal control of GH and prolac- (GnRH) response)
tin differs from the regulatory systems for TSH, FSH, LH,
May be used in pulses to treat infertility
and ACTH. The hypothalamus secretes two hormones that
caused by GnRH deficiency
regulate GH; growth hormone-releasing hormone (GHRH)
  Analogs used in long-acting formulations
stimulates GH production, whereas the peptide somatostatin to inhibit gonadal function in children with
(SST) inhibits GH production. GH and its primary peripheral precocious puberty, in some transgender/
mediator, insulin-like growth factor-I (IGF-I), also pro- gender variant early pubertal adolescents
vide feedback to inhibit GH release. Prolactin production is (to block endogenous puberty), in men
with prostate cancer and women under-
inhibited by the catecholamine dopamine acting through the going assisted reproductive technology
D2 subtype of dopamine receptors. The hypothalamus does (ART) or women who require ovarian
not produce a hormone that specifically stimulates prolactin suppression for a gynecologic disorder
secretion, although TRH can stimulate prolactin release, par- Dopamine Dopamine agonists (eg, bromocriptine,
ticularly when TRH concentrations are high in the setting of cabergoline) used for treatment of
primary hypothyroidism. hyperprolactinemia
670    SECTION VII  Endocrine Drugs
LH, FSH, GnRH, and dopamine or analogs of these hormones
are commonly used and are described in the following text.
GROWTH HORMONE (SOMATOTROPIN)
Growth hormone, an anterior pituitary hormone, is required dur-
ing childhood and adolescence for attainment of normal adult size
and has important effects throughout postnatal life on lipid and
carbohydrate metabolism, and on lean body mass and bone den-
sity. Its growth-promoting effects are primarily mediated via IGF-I
(also known as somatomedin C). Individuals with congenital or
acquired deficiency of GH during childhood or adolescence fail to
reach their midparental target adult height and have disproportion-
ately increased body fat and decreased muscle mass. Adults with
GH deficiency also have disproportionately low lean body mass.
Chemistry & Pharmacokinetics
A. Structure
Growth hormone is a 191-amino-acid peptide with two sulfhydryl
bridges. Its structure closely resembles that of prolactin. In the
past, medicinal GH was isolated from the pituitaries of human
cadavers. However, this form of GH was found to be contami-
nated with prions that could cause Creutzfeldt-Jakob disease. For
this reason, it is no longer used. Somatropin, the recombinant
form of GH, has a 191-amino-acid sequence that is identical with
the predominant native form of human GH.
B. Absorption, Metabolism, and Excretion
Circulating endogenous GH has a half-life of approximately
20 minutes and is predominantly cleared by the liver. Recom-
binant human GH (rhGH) is administered subcutaneously
6–7 times per week. Peak levels occur in 2–4 hours, and active
blood levels persist for approximately 36 hours.
Pharmacodynamics
Growth hormone mediates its effects via cell surface receptors of
the JAK/STAT cytokine receptor superfamily. The hormone has
two distinct GH receptor binding sites. Dimerization of two GH
receptors is stimulated by a single GH molecule and activates
TABLE 37–3  Diagnostic uses of thyroid-stimulating
hormone and adrenocorticotropin.
Hormone Diagnostic Use
Thyroid-stimulating- In patients who have been treated surgically
hormone (TSH; for thyroid carcinoma, to test for cancer recur-
thyrotropin) rence by assessing TSH-stimulated radioac-
tive iodine uptake and serum thyroglobulin
level (see Chapter 38)
Adrenocorticotropin In patients suspected of adrenal insufficiency,
(ACTH) either central (CRH/ACTH deficiency)
or peripheral (cortisol deficiency), in
particular in suspected cases of congenital
adrenal hyperplasia. (See Figure 39–1 and
Chapter 39.)
signaling cascades mediated by receptor-associated JAK tyrosine
kinases and STATs (see Chapter 2). The hormone has complex
effects on growth, body composition, and carbohydrate, protein,
and lipid metabolism. The growth-promoting effects are mediated
principally, but not solely, through an increase in the production
of IGF-I. Much of the circulating IGF-I is produced by the liver.
Growth hormone also stimulates production of IGF-I in bone,
cartilage, muscle, kidney, and other tissues, where it has autocrine
or paracrine roles. It stimulates longitudinal bone growth until the
epiphyseal plates fuse—near the end of puberty. In both children
and adults, GH has anabolic effects in muscle and catabolic effects
in adipose cells that shift the balance of body mass to an increase
in muscle mass and a reduction in adiposity. The direct and indi-
rect effects of GH on carbohydrate metabolism are mixed, in part
because GH and IGF-I have opposite effects on insulin sensitiv-
ity. Growth hormone reduces insulin sensitivity, which results in
mild hyperinsulinemia and increased blood glucose levels, whereas
IGF-I has insulin-like effects on glucose transport. In patients who
are unable to respond to growth hormone because of severe resistance
(caused by GH receptor mutations, post-receptor signaling muta-
tions, or GH antibodies), the administration of recombinant human
IGF-I may cause hypoglycemia because of its insulin-like effects.
Clinical Pharmacology
A. Growth Hormone Deficiency
Growth hormone deficiency can have a genetic basis, be associated
with midline developmental defect syndromes (eg, septo-optic
dysplasia), or be acquired as a result of damage to the pituitary
or hypothalamus by a traumatic event (including breech or
traumatic delivery), intracranial tumors, infection, infiltrative
or hemorrhagic processes, or irradiation. Neonates with isolated
GH deficiency are typically of normal size at birth because pre-
natal growth is not GH-dependent. In contrast, IGF-I is essen-
tial for normal prenatal and postnatal growth. Through poorly
understood mechanisms, IGF-I expression and postnatal growth
become GH-dependent during the first year of life. In childhood,
GH deficiency typically presents as short stature, often with mild
adiposity. Another early sign of GH deficiency is hypoglycemia
due to the loss of a counter-regulatory hormonal response of GH
to hypoglycemia; young children are at risk for this condition due
to high sensitivity to insulin. Criteria for diagnosis of GH defi-
ciency usually include (1) a subnormal height velocity for age and
(2) a subnormal serum GH response following provocative testing
with at least two GH secretagogues. Clonidine (α2-adrenergic
agonist), levodopa (dopaminergic agonist), and exercise are factors
that increase GHRH levels. Arginine and insulin-induced hypo-
glycemia cause diminished SST, which increases GH release. The
prevalence of GH deficiency is approximately 1:5000. If therapy
with rhGH is initiated at an early age, many children with short
stature due to GH deficiency will achieve an adult height within
their midparental target height range.
In the past, it was believed that adults with GH deficiency do
not exhibit a significant syndrome. However, more detailed stud-
ies suggest that adults with GH deficiency often have generalized
obesity, reduced muscle mass, asthenia, diminished bone mineral

density, dyslipidemia, and reduced cardiac output. Growth hor-
mone-deficient adults who have been treated with GH experience
reversal of many of these manifestations.
B. Growth Hormone Treatment of Pediatric Patients
with Short Stature
Although the greatest improvement in growth occurs in
patients with GH deficiency, exogenous GH has some effect
on height in children with short stature caused by condi-
tions other than GH deficiency. Growth hormone has been
approved for several conditions (Table 37–4) and has been
used experimentally or off-label in many others. Prader-Willi
syndrome is an autosomal dominant genetic disease associated
with growth failure, obesity, and carbohydrate intolerance. In
children with Prader-Willi syndrome and growth failure, GH
treatment decreases body fat and increases lean body mass,
linear growth, and energy expenditure.
Growth hormone treatment has also been shown to have
a strong beneficial effect on final height of girls with Turner
syndrome (45 X karyotype and variants). In clinical trials, GH
treatment has been shown to increase final height in girls with
Turner syndrome by 10–15 cm (4–6 inches). Because girls with
Turner syndrome also have either absent or rudimentary ovaries,
GH must be judiciously combined with gonadal steroids to
achieve maximal height. Other conditions of pediatric growth
failure for which GH treatment is approved include chronic renal
insufficiency pre-transplant and small-for-gestational-age at birth
TABLE 37–4  Clinical uses of recombinant human
growth hormone.
Primary Therapeutic
Objective Clinical Condition
Growth Growth failure in pediatric patients
associated with:
    Growth hormone deficiency
    Chronic renal insufficiency pre-transplant
    Noonan syndrome
    Prader-Willi syndrome
   Short stature homeobox-containing gene
(SHOX) deficiency
    Turner syndrome
   Small-for-gestational-age with failure to
catch up by age 2 years
    Idiopathic short stature
Improved metabolic Growth hormone deficiency in adults
state, increased lean
body mass, sense of
well-being
Increased lean body Wasting in patients with HIV infection
mass, weight, and
physical endurance
Improved gastrointes- Short bowel syndrome in patients who
tinal function are also receiving specialized nutritional
support
CHAPTER 37  Hypothalamic & Pituitary Hormones    671
in which the child’s height remains more than 2 standard devia-
tions below normal at 2 years of age.
A controversial but approved use of GH is for children with
idiopathic short stature (ISS). This is a heterogeneous popula-
tion that has in common no identifiable cause of the short stature.
Some have arbitrarily defined ISS clinically as having a height at
least 2.25 standard deviations below normal for children of the
same age and a predicted adult height that is less than 2.25 stan-
dard deviations below normal. In this group of children, many
years of GH therapy result in an average increase in adult height of
4–7 cm (1.57–2.76 inches) at a cost of $5000–$40,000 per year.
The complex issues involved in the cost-risk-benefit relationship
of this use of GH are important because an estimated 400,000
children in the United States fit the diagnostic criteria for ISS.
Treatment of children with short stature should be carried out
by specialists experienced in GH administration. Dose requirements
vary with the condition being treated, with GH-deficient children
typically being most responsive. Children must be observed closely
for slowing of growth velocity, which could indicate a need to
increase the dosage or the possibility of epiphyseal plate fusion or
intercurrent problems such as hypothyroidism or malnutrition.
Other Uses of Growth Hormone
Growth hormone affects many organ systems and also has a net
anabolic effect. It has been tested in a number of conditions that
are associated with a severe catabolic state and is approved for the
treatment of wasting in patients with AIDS. In 2004, GH was
approved for treatment of patients with short bowel syndrome who
are dependent on total parenteral nutrition (TPN). After intestinal
resection or bypass, the remaining functional intestine in many
patients undergoes extensive adaptation that allows it to adequately
absorb nutrients. However, other patients fail to adequately adapt
and develop a malabsorption syndrome. Growth hormone has been
shown to increase intestinal growth and improve its function in
experimental animals. Benefits of GH treatment for patients with
short bowel syndrome and dependence on TPN have mostly been
short-lived in the clinical studies that have been published to date.
Growth hormone is administered with glutamine, which also has
trophic effects on the intestinal mucosa.
Growth hormone is a popular component of “anti-aging”
programs. Serum levels of GH normally decline with aging; anti-
aging programs claim that injection of GH or administration of
drugs purported to increase GH release are effective anti-aging
remedies. These claims are largely unsubstantiated. In contrast,
studies in mice and the nematode Caenorhabditis elegans have
clearly demonstrated that analogs of human GH and IGF-I con-
sistently shorten life span and that loss-of-function mutations in
the signaling pathways for the GH and IGF-I analogs lengthen life
span. Another use of GH is by athletes for a purported increase
in muscle mass and athletic performance. Growth hormone is one
of the drugs banned by the International Olympic Committee.
In 1993, the FDA approved the use of recombinant bovine
growth hormone (rbGH) in dairy cattle to increase milk produc-
tion. Although milk and meat from rbGH-treated cows appear
to be safe, these cows have a higher incidence of mastitis, which
672    SECTION VII  Endocrine Drugs
could increase antibiotic use and result in greater antibiotic
residues in milk and meat.
Toxicity & Contraindications
Children generally tolerate growth hormone treatment well.
Adverse events are relatively rare and include pseudotumor cere-
bri, slipped capital femoral epiphysis, progression of scoliosis,
edema, hyperglycemia, and increased risk of asphyxiation in
severely obese patients with Prader-Willi syndrome and upper
airway obstruction or sleep apnea. Patients with Turner syndrome
have an increased risk of otitis media while taking GH. In chil-
dren with GH deficiency, periodic evaluation of the other anterior
pituitary hormones may reveal concurrent deficiencies, which
also require treatment (ie, with hydrocortisone, levothyroxine, or
gonadal hormones). Pancreatitis, gynecomastia, and nevus growth
have occurred in patients receiving GH. Adults tend to have more
adverse effects from GH therapy. Peripheral edema, myalgias,
and arthralgias (especially in the hands and wrists) occur com-
monly but remit with dosage reduction. Carpal tunnel syndrome
can occur. Growth hormone treatment increases the activity of
cytochrome P450 isoforms, which may reduce the serum levels of
drugs metabolized by that enzyme system (see Chapter 4). There
has been no increased incidence of malignancy among patients
receiving GH therapy, but such treatment is contraindicated in
a patient with a known active malignancy. Proliferative retinopa-
thy may rarely occur. Growth hormone treatment of critically ill
patients appears to increase mortality. The long-term health effects
of GH treatment in childhood are unknown. The results from the
Safety and Appropriateness of GH in Europe (SAGHE) study are
variable. A higher all-cause mortality (mostly due to cardiovascu-
lar disease) was found in the GH treatment group in the French
arm of the study, but no long-term risks of GH treatment were
observed in the study arm from another region of Europe.
MECASERMIN
A small number of children with growth failure have severe
IGF-I deficiency that is not responsive to exogenous GH.
Causes include mutations in the GH receptor and in the GH
receptor signaling pathway, neutralizing antibodies to GH, and
IGF-I gene defects. In 2005, the FDA approved two forms of
recombinant human IGF-I (rhIGF-I) for treatment of severe
IGF-I deficiency that is not responsive to GH: mecasermin
and mecasermin rinfabate. Mecasermin is rhIGF-I alone, while
mecasermin rinfabate is a complex of rhIGF-I and recom-
binant human insulin-like growth factor–binding protein-3
(rhIGFBP-3). This binding protein significantly increases the
circulating half-life of rhIGF-I. Normally, the great majority
of the circulating IGF-I is bound to IGFBP-3, which is pro-
duced principally by the liver under the control of GH. Due to
a patent settlement, mecasermin rinfabate is not available for
short stature-related indications. Mecasermin is administered
subcutaneously twice daily at a recommended starting dosage
of 0.04–0.08 mg/kg per dose and increased weekly up to a
maximum twice-daily dosage of 0.12 mg/kg per dose.
The most important adverse effect observed with mecaser-
min is hypoglycemia. To avoid hypoglycemia, the prescribing
instructions require consumption of a carbohydrate-containing
meal or snack 20 minutes before or after mecasermin administra-
tion. Several patients have experienced intracranial hypertension,
adenotonsillar hypertrophy, and asymptomatic elevation of liver
enzymes.
GROWTH HORMONE ANTAGONISTS
Antagonists of GH are used to reverse the effects of GH-
producing cells (somatotrophs) in the anterior pituitary that tend
to form GH-secreting tumors. Hormone-secreting pituitary ade-
nomas occur most commonly in adults. In adults, GH-secreting
adenomas cause acromegaly, which is characterized by abnormal
growth of cartilage and bone tissue, and many organs including
skin, muscle, heart, liver, and the gastrointestinal tract. When a
GH-secreting adenoma occurs before the long bone epiphyses
close, it leads to a rare condition, gigantism. Larger pituitary ade-
nomas produce greater amounts of GH and also can impair visual
and central nervous system function by encroaching on nearby
brain structures. The initial therapy of choice for GH-secreting
adenomas is endoscopic transsphenoidal surgery. Medical therapy
with GH antagonists is introduced if GH hypersecretion persists
after surgery. These agents include somatostatin analogs and dopa-
mine receptor agonists, which reduce the production of GH, and
the novel GH receptor antagonist pegvisomant, which prevents
GH from activating GH signaling pathways. Radiation therapy
is reserved for patients with inadequate response to surgical and
medical therapies.
Somatostatin Analogs
Somatostatin, a 14-amino-acid peptide (Figure 37–2), is found in
the hypothalamus, other parts of the central nervous system, the
pancreas, and other sites in the gastrointestinal tract. It functions
primarily as an inhibitory paracrine factor and inhibits the release
of GH, TSH, glucagon, insulin, and gastrin. Somatostatin is rap-
idly cleared from the circulation, with a half-life of 1–3 minutes.
S S
Somatostatin
Ala Cys
Gly Ser
1
Cys Lys
Asn Phe Phe Trp Lys Thr
Phe Thr 14
13
2
3 11 12
4 5 6 7 8 9 10
S S
Octreotide
D-Phe Cys Thr-ol Acetate
Cys Phe D-Trp Lys Thr
FIGURE 37–2  Above: Amino acid sequence of somatostatin.
Below: Sequence of the synthetic analog, octreotide.

The kidney appears to play an important role in its metabolism
and excretion.
Somatostatin has limited therapeutic usefulness because of
its short duration of action and multiple effects in many secre-
tory systems. A series of longer-acting somatostatin analogs that
retain biologic activity have been developed. Octreotide, the most
widely used somatostatin analog (Figure 37–2), is 45 times more
potent than somatostatin in inhibiting GH release but only twice
as potent in reducing insulin secretion. Because of this relatively
reduced effect on pancreatic beta cells, hyperglycemia rarely occurs
during treatment. The plasma elimination half-life of octreotide is
about 80 minutes, 30 times longer than that of somatostatin.
Octreotide, 50–200 mcg given subcutaneously every 8 hours,
reduces symptoms caused by a variety of hormone-secreting
tumors: acromegaly, carcinoid syndrome, gastrinoma, gluca-
gonoma, insulinoma, VIPoma, and ACTH-secreting tumor. Other
therapeutic use indications include diarrhea—secretory, HIV asso-
ciated, diabetic, chemotherapy, or radiation induced—and portal
hypertension. Somatostatin receptor scintigraphy, using radiola-
beled octreotide, is useful in localizing neuroendocrine tumors
having somatostatin receptors and helps predict the response to
octreotide therapy. Octreotide is also useful for the acute control
of bleeding from esophageal varices.
Octreotide acetate injectable long-acting suspension is a slow-
release microsphere formulation. It may be instituted after a brief
course of shorter-acting octreotide has been demonstrated to be
effective and tolerated. Injections into alternate gluteal muscles are
repeated at 4-week intervals in doses of 10–40 mg.
Adverse effects of octreotide therapy include nausea, vomit-
ing, abdominal cramps, flatulence, and steatorrhea with bulky
bowel movements. Biliary sludge and gallstones may occur after
6 months of use in 20–30% of patients. However, the yearly
incidence of symptomatic gallstones is about 1%. Cardiac effects
include sinus bradycardia (25%) and conduction disturbances
(10%). Pain at the site of injection is common, especially with the
long-acting octreotide suspension. Vitamin B12 deficiency may
occur with long-term use of octreotide.
A long-acting formulation of lanreotide, another octapeptide
somatostatin analog, is approved for treatment of acromegaly.
Lanreotide appears to have effects comparable to those of octreo-
tide in reducing GH levels and normalizing IGF-I concentrations.
Pegvisomant
Pegvisomant is a GH receptor antagonist used to treat acromegaly.
It is the polyethylene glycol (PEG) derivative of a mutant GH,
B2036. Pegylation reduces its clearance and improves its overall
clinical effectiveness. Like native GH, pegvisomant has two GH
receptor binding sites. However, one of its GH receptor binding
sites has increased affinity for the GH receptor, whereas its second
GH receptor binding site has reduced affinity. This differential
receptor affinity allows the initial step (GH receptor dimeriza-
tion) but blocks the conformational changes required for signal
transduction. In clinical trials, pegvisomant was administered
subcutaneously to patients with acromegaly; daily treatment for
12 months or more reduced serum levels of IGF-I into the normal
CHAPTER 37  Hypothalamic & Pituitary Hormones    673
range in 97%. Pegvisomant does not inhibit GH secretion and
may lead to increased GH levels and possible adenoma growth.
No serious problems have been observed; however, increases in
liver enzymes without liver failure have been reported.
THE GONADOTROPINS
(FOLLICLE-STIMULATING HORMONE
& LUTEINIZING HORMONE) & HUMAN
CHORIONIC GONADOTROPIN
The gonadotropins are produced by gonadotroph cells, which
comprise 7–15% of the cells in the pituitary. These hormones
serve complementary functions in the reproductive process.
In women, the principal function of FSH is to stimulate ovar-
ian follicle development. Both FSH and LH are needed for
ovarian steroidogenesis. In the ovary, LH stimulates androgen
production by theca cells in the follicular stage of the menstrual
cycle, whereas FSH stimulates the conversion of androgens to
estrogens by granulosa cells. In the luteal phase of the menstrual
cycle, estrogen and progesterone production is primarily under the
control first of LH and then, if pregnancy occurs, under the con-
trol of human chorionic gonadotropin (hCG). Human chorionic
gonadotropin is a placental glycoprotein nearly identical with LH;
its actions are mediated through LH receptors.
In men, FSH is the primary regulator of spermatogenesis,
whereas LH is the main stimulus for testosterone synthesis in
Leydig cells. FSH helps maintain high local androgen concen-
trations in the vicinity of developing sperm by stimulating the
production of androgen-binding protein in Sertoli cells. FSH
also stimulates the conversion by Sertoli cells of testosterone to
estrogen that is also required for spermatogenesis.
FSH, LH, and hCG are available in several pharmaceutical
forms. They are used in states of infertility to stimulate spermato-
genesis in men and to induce follicle development and ovulation
in women. Their most common clinical use is for the controlled
ovarian stimulation that is the cornerstone of assisted reproductive
technologies such as in vitro fertilization (IVF, see below).
Chemistry & Pharmacokinetics
All three hormones—FSH, LH, and hCG—are heterodimers that
share an identical α subunit in addition to a distinct β subunit
that confers receptor specificity. The β subunits of hCG and
LH are nearly identical, and these two hormones are used inter-
changeably. All the gonadotropin preparations are administered
by subcutaneous or intramuscular injection, usually on a daily
basis. Half-lives vary by preparation and route of injection from
10 to 40 hours.
A. Menotropins
The first commercial gonadotropin product containing both FSH
and LH was extracted from the urine of postmenopausal women.
This purified extract of FSH and LH is known as menotropins,
or human menopausal gonadotropins (hMG). From the early
1960s, these preparations were used for the stimulation of follicle
674    SECTION VII  Endocrine Drugs
development in women. The early extraction techniques were very
crude, requiring around 30 L of urine to manufacture enough
hMG needed for a single treatment cycle. These initial prepara-
tions were also contaminated with other proteins; less than 5% of
the proteins present were bioactive. The FSH-to-LH bioactivity
ratio of these early preparations was 1:1. As purity improved,
it was necessary to add hCG in order to maintain this ratio of
bioactivity.
B. Follicle-Stimulating Hormone
Three forms of purified FSH are available. Urofollitropin, also
known as uFSH, is a purified preparation of human FSH extracted
from the urine of postmenopausal women. Virtually all the LH
activity has been removed through a form of immuno-affinity
chromatography that uses anti-hCG antibodies. Urofollitropin
was withdrawn from the US market in 2015. Two recombinant
forms of FSH (rFSH) are also available: follitropin alfa and
follitropin beta. The amino acid sequences of these two products
are identical to that of human FSH. They differ from each other
and urofollitropin in the composition of carbohydrate side chains.
The rFSH preparations have a shorter half-life than preparations
derived from human urine but stimulate estrogen secretion at least
as efficiently and, in some studies, more efficiently. Compared
with urine derived gonadotropins, rFSH preparations have little
protein contamination, much less batch-to-batch variability, and
may cause less local tissue reaction. The rFSH preparations are
considerably more expensive.
C. Luteinizing Hormone
Lutropin alfa, the first and only recombinant form of human
LH, was introduced in the United States in 2004 but withdrawn
in 2012. When given by subcutaneous injection, it has a half-life
of about 10 hours. Lutropin has only been approved for use in
combination with follitropin alfa for stimulation of follicular
development in infertile hypogonadotropic hypogonadal women
with profound LH deficiency (<1.2 IU/L). Lutropin alfa with
follitropin alfa may also be of benefit in certain subgroups of nor-
mogonadotropic women (eg, those with an inadequate response
to prior follitropin alfa monotherapy). It has not been approved
for use with the other preparations of FSH or for induction of
ovulation.
D. Human Chorionic Gonadotropin
Human chorionic gonadotropin is produced by the human
placenta and excreted into the urine, whence it can be extracted
and purified. It is a glycoprotein consisting of a 92-amino-acid
α subunit virtually identical to that of FSH, LH, and TSH, and
a β subunit of 145 amino acids that resembles that of LH except
for the presence of a carboxyl terminal sequence of 30 amino acids
not present in LH. Choriogonadotropin alfa (rhCG) is a recom-
binant form of hCG. Because of its greater consistency in biologic
activity, rhCG is packaged and dosed on the basis of weight rather
than units of activity. All of the other gonadotropins, including
rFSH, are packaged and dosed on the basis of units of activity.
Both the hCG preparation that is purified from human urine
and rhCG can be administered by subcutaneous or intramuscular
injection.
Pharmacodynamics
The gonadotropins and hCG exert their effects through
G protein-coupled receptors. LH and FSH have complex effects
on reproductive tissues in both sexes. In women, these effects
change over the time course of a menstrual cycle as a result of
a complex interplay among concentration-dependent effects of
the gonadotropins, cross-talk of LH, FSH, and gonadal steroids,
and the influence of other ovarian hormones. A coordinated
pattern of FSH and LH secretion during the menstrual cycle
(see Figure 40–1) is required for normal follicle development,
ovulation, and pregnancy.
During the first 8 weeks of pregnancy, the progesterone and
estrogen required to maintain pregnancy are produced by the
ovarian corpus luteum. For the first few days after ovulation, the
corpus luteum is maintained by maternal LH. However, as mater-
nal LH concentration falls owing to increasing concentrations of
progesterone and estrogen, the corpus luteum will continue to
function only if the role of maternal LH is taken over by hCG
produced by syncytiotrophoblast cells in the placenta.
Clinical Pharmacology
A. Ovulation Induction
The gonadotropins are used to induce follicle development and
ovulation in women with anovulation that is secondary to hypo-
gonadotropic hypogonadism, polycystic ovary syndrome, and
other causes. Because of the high cost of gonadotropins and the
need for close monitoring during their administration, they are
generally reserved for anovulatory women who fail to respond
to other less complicated forms of treatment (eg, clomiphene;
see Chapter 40). Gonadotropins are also used for controlled ovar-
ian stimulation in assisted reproductive technology procedures.
Currently, a number of different protocols use gonadotropins in
ovulation induction and controlled ovulation stimulation, and
new protocols are continually being developed to improve the
rates of success and to decrease the two primary risks of ovulation
induction: multiple pregnancies and the ovarian hyperstimula-
tion syndrome (OHSS; see below).
Although the details differ, all of these protocols are based
on the complex physiology that underlies a normal menstrual
cycle. Like a menstrual cycle, controlled ovulation stimulation
is discussed in relation to a cycle that begins on the first day of
a menstrual bleed (Figure 37–3). Shortly after the first day (usu-
ally on day 2), daily injections with one of the FSH preparations
(hMG, urofollitropin, or rFSH) are begun and continued for
approximately 8–12 days. In women with hypogonadotropic
hypogonadism, follicle development requires treatment with
a combination of FSH and LH because these women do not
produce the basal level of LH that is required for normal follicle
development. The dose and duration of gonadotropin treatment
are based on the response as measured by the serum estradiol
concentration and by ultrasound evaluation of ovarian follicle
 CHAPTER 37  Hypothalamic & Pituitary Hormones    675

Oocyte
retrieval & Embryo
fertilization transfer

hCG

Gonadotropin
Progesterone
Time (days) Menses

GnRH agonist
or
GnRH
antagonist

Luteal phase Follicular phase Luteal phase

FIGURE 37–3  Controlled ovarian stimulation in preparation for an assisted reproductive technology such as in vitro fertilization. Follicular
phase: Follicle development is stimulated with gonadotropin injections that begin about 2 days after menses begin. When the follicles are
ready, as assessed by ultrasound measurement of follicle size, final oocyte maturation is induced by an injection of hCG. Luteal phase: Shortly
thereafter oocytes are retrieved and fertilized in vitro. The recipient’s luteal phase is supported with injections of progesterone. To prevent
a premature luteinizing-hormone surge, endogenous LH secretion is inhibited with either a GnRH agonist or a GnRH antagonist. In most
protocols, the GnRH agonist is started midway through the preceding luteal cycle.

development. When exogenous gonadotropins are used to stimu-
late follicle development, there is risk of a premature endogenous
surge in LH owing to the rapidly increasing serum estradiol levels.
To prevent this, gonadotropins are almost always administered
in conjunction with a drug that blocks the effects of endogenous
GnRH—either continuous administration of a GnRH agonist,
which downregulates GnRH receptors, or a GnRH receptor
antagonist (see below and Figure 37–3).
When appropriate follicular maturation has occurred, the
gonadotropin and the GnRH agonist or GnRH antagonist injec-
tions are discontinued and hCG (3300–10,000 IU) is adminis-
tered subcutaneously to induce final follicular maturation and, in
ovulation induction protocols, ovulation. The hCG administra-
tion is followed by timed intercourse or intrauterine insemination
in ovulation induction and by oocyte retrieval in assisted repro-
ductive technology procedures. Because use of GnRH agonists
or antagonists during the follicular phase of ovulation induction
suppresses endogenous LH production, it is important to provide
exogenous hormonal support of the luteal phase. In clinical trials,
exogenous progesterone, hCG, or a combination of the two have
been effective at providing adequate luteal support. However,
progesterone is preferred for luteal support because hCG carries a
higher risk of OHSS in patients with high follicular response to
gonadotropins.
B. Male Infertility
Most of the signs and symptoms of hypogonadism in males
(eg, delayed puberty, retention of prepubertal secondary sex
characteristics after puberty) can be adequately treated with
exogenous androgen; however, treatment of infertility in hypogo-
nadal men requires the activity of both LH and FSH. For many
years, conventional therapy has consisted of initial treatment
for 8–12 weeks with injections of 1000–2500 IU hCG several
times per week. After the initial phase, hMG is injected at a dose
of 75–150 units three times per week. In men with hypogo-
nadal hypogonadism, it takes an average of 4–6 months of such
treatment for sperm to appear in the ejaculate in up to 90% of
patients, but often not at normal levels. Even if pregnancy does
not occur spontaneously, the number of sperm is often sufficient
that pregnancy can be achieved by insemination with the patient’s
semen (intrauterine insemination) or with the help of an assisted
reproductive technique such as in vitro fertilization with or with-
out intracytoplasmic sperm injection (ICSI), in which a single
sperm is injected directly into a mature oocyte that has been
retrieved after controlled ovarian stimulation of a female partner.
With the advent of ICSI, the minimum threshold of spermato-
genesis required for pregnancy is greatly lowered.
C. Outdated Uses
Chorionic gonadotropin is approved for the treatment of prepu-
bertal cryptorchidism. Prepubertal boys were treated with intra-
muscular injections of hCG for 2–6 weeks. However, this clinical
use is no longer supported because the long-term efficacy of hor-
monal treatment of cryptorchidism (~20%) is much lower than
the long-term efficacy of surgical treatment (>95%), and because
of concerns that early childhood treatment with hCG treatment
has a negative impact on germ cells in addition to increasing the
risk of precocious puberty.
In the United States, chorionic gonadotropin has a black-
box warning against its use for weight loss. The use of hCG
plus severe calorie restriction for weight loss was popularized
by a publication in the 1950s claiming that the hCG selectively
676    SECTION VII  Endocrine Drugs
mobilizes body fat stores. This practice continues today, despite
a preponderance of subsequent scientific evidence from placebo-
controlled trials that hCG does not provide any weight loss
benefit beyond the weight loss associated with severe calorie
restriction alone.
Toxicity & Contraindications
In women treated with gonadotropins and hCG, the two most
serious complications are OHSS and multiple pregnancies.
Stimulation of the ovary during ovulation induction often leads
to uncomplicated ovarian enlargement that usually resolves
spontaneously. However, OHSS may occur and can be associ-
ated with ovarian enlargement, intravascular depletion, ascites,
liver dysfunction, pulmonary edema, electrolyte imbalance, and
thromboembolic events. Although OHSS is often self-limited,
with spontaneous resolution within a few days, severe disease
may require hospitalization and intensive care. Triggering the
final oocyte maturation with hCG carries the risk of inducing
OHSS. GnRH agonists also induce this final oocyte maturation
by promoting the release of endogenous gonadotropin stores from
the hypophysis and can be used as an alternative to hCG. Use of
the GnRH agonist trigger dramatically reduces the risk of OHSS,
owing to the short half-life of the GnRH agonist–induced endog-
enous LH surge.
The probability of multiple pregnancies is greatly increased
when ovulation induction and assisted reproductive technologies
are used. In ovulation induction, the risk of a multiple pregnancy
is estimated to be 5–10%, whereas the percentage of multiple
pregnancies in the general population is closer to 1%. Multiple
pregnancies carry an increased risk of complications, such as
gestational diabetes, preeclampsia, and preterm labor. For in
vitro fertilization procedures, the risk of a multiple pregnancy is
determined primarily by the number of embryos transferred to
the recipient. A strong trend in recent years has been to transfer
single embryos.
Other reported adverse effects of gonadotropin treatment are
headache, depression, edema, precocious puberty, and (rarely)
production of antibodies to hCG. In men treated with gonadotro-
pins, the risk of gynecomastia is directly correlated with the level
of testosterone produced in response to treatment.
GONADOTROPIN-RELEASING
HORMONE & ITS ANALOGS
Gonadotropin-releasing hormone is secreted by neurons in the
hypothalamus. It travels through the hypothalamic-pituitary
venous portal plexus to the anterior pituitary, where it binds to G
protein-coupled receptors on the plasma membranes of gonado-
trophs. Pulsatile GnRH secretion is required to stimulate the
gonadotrophs to produce and release LH and FSH.
Sustained nonpulsatile administration of GnRH or GnRH
analogs inhibits the release of FSH and LH by the pituitary in
both women and men, resulting in hypogonadotropic hypogo-
nadism. GnRH agonists are used to induce gonadal suppression
in men with prostate cancer or children with central precocious
puberty. They are also used in women who are undergoing assisted
reproductive technology procedures or who have a gynecologic
problem that is benefited by ovarian suppression.
Chemistry & Pharmacokinetics
A. Structure
GnRH is a decapeptide found in all mammals. Gonadorelin is
an acetate salt of synthetic human GnRH. Substitution of amino
acids at the 6 position or replacement of the C-terminal glycine-
amide produces synthetic agonists. Both modifications make
them more potent and longer-lasting than native GnRH and
gonadorelin. Such analogs of GnRH include goserelin, buserelin,
histrelin, leuprolide, nafarelin, and triptorelin.
B. Pharmacokinetics
Gonadorelin can be administered intravenously or subcutane-
ously. Other GnRH agonists can be administered subcutaneously,
intramuscularly, via nasal spray (nafarelin), or as a subcutaneous
implant. The half-life of intravenous gonadorelin is 4 minutes,
and the half-lives of subcutaneous and intranasal GnRH analogs
are approximately 3 hours. The duration of clinical uses of GnRH
agonists varies from a few days for controlled ovarian stimulation
to a number of years for treatment of metastatic prostate cancer.
Therefore, preparations have been developed with a range of dura-
tions of action from several hours (for daily administration) to 1,
4, 6, or 12 months (depot forms).
Pharmacodynamics
The physiologic actions of GnRH exhibit complex dose-response
relationships that change dramatically from the fetal period
through the end of puberty. This is not surprising in view of the
complex role that GnRH plays in normal reproduction, particu-
larly in female reproduction. Pulsatile GnRH release occurs and
is responsible for stimulating LH and FSH production during the
fetal and neonatal period. Subsequently, from the age of 2 years
until the onset of puberty, GnRH secretion falls off and the
pituitary simultaneously exhibits very low sensitivity to GnRH.
Just before puberty, an increase in the frequency and amplitude
of GnRH release occurs and then, in early puberty, pituitary sen-
sitivity to GnRH increases, which is due in part to the effect of
increasing concentrations of gonadal steroids. In females, it usu-
ally takes several months to a year after the onset of puberty for
the hypothalamic-pituitary system to produce an LH surge and
ovulation. By the end of puberty, the system is well established
so that menstrual cycles proceed at relatively constant intervals.
The amplitude and frequency of GnRH pulses vary in a regular
pattern through the menstrual cycle with the highest amplitudes
occurring during the luteal phase and the highest frequency occur-
ring late in the follicular phase. Lower pulse frequencies favor FSH
secretion, whereas higher pulse frequencies favor LH secretion.
Gonadal steroids as well as the peptide hormones activin, inhibin,
and follistatin have complex modulatory effects on the gonadotro-
pin response to GnRH.

In the pharmacologic use of GnRH and its analogs, pulsa-
tile intravenous administration of gonadorelin every 1–4 hours
stimulates FSH and LH secretion. Continuous administration
of gonadorelin or its longer-acting analogs produces a biphasic
response. During the first 7–10 days, an agonist effect results
in increased concentrations of gonadal hormones in males and
females; this initial phase is referred to as a flare. After this period,
the continued presence of GnRH results in an inhibitory action
that manifests as a drop in the concentration of gonadotropins and
gonadal steroids (ie, hypogonadotropic hypogonadal state). The
inhibitory action is due to a combination of receptor downregula-
tion and changes in the signaling pathways activated by GnRH.
Clinical Pharmacology
The GnRH agonists are occasionally used for stimulation of
gonadotropin production. They are used far more commonly for
suppression of gonadotropin release.
A. Stimulation
1. Female infertility—In the current era of widespread avail-
ability of gonadotropins and assisted reproductive technology, the
use of pulsatile GnRH administration to treat infertility is uncom-
mon. Although pulsatile GnRH is less likely than gonadotropins
to cause multiple pregnancies and OHSS, the inconvenience and
cost associated with continuous use of an intravenous pump and
difficulties obtaining native GnRH (gonadorelin) are barriers to
pulsatile GnRH. When this approach is used, a portable battery-
powered programmable pump and intravenous tubing deliver
pulses of gonadorelin every 90 minutes.
Gonadorelin or a GnRH agonist analog can be used to initi-
ate an LH surge and ovulation in women with infertility who are
undergoing ovulation induction with gonadotropins. Tradition-
ally, hCG has been used to initiate ovulation in this situation.
However, there is some evidence that gonadorelin or a GnRH
agonist is less likely than hCG to cause OHSS.
2. Male infertility—It is possible to use pulsatile gonadorelin for
infertility in men with hypothalamic hypogonadotropic hypogo-
nadism. A portable pump infuses gonadorelin intravenously every
90 minutes. Serum testosterone levels and semen analyses must
be done regularly. At least 3–6 months of pulsatile infusions are
required before significant numbers of sperm are seen. As described
above, treatment of hypogonadotropic hypogonadism is more com-
monly done with hCG and hMG or their recombinant equivalents.
3. Diagnosis of LH responsiveness—GnRH may be useful
in determining whether delayed puberty in a hypogonadotropic
adolescent is due to constitutional delay or to hypogonadotropic
hypogonadism. The LH response (but not the FSH response)
to a single dose of GnRH may distinguish between these two
conditions; however, there can be significant individual overlap
in the LH response between the two groups. Serum LH levels are
measured before and at several times after an intravenous or sub-
cutaneous bolus of GnRH. An increase in serum LH with a peak
that is greater than 5–8 mIU/mL suggests early pubertal status.
CHAPTER 37  Hypothalamic & Pituitary Hormones    677
An impaired LH response suggests hypogonadotropic hypogonad-
ism due to either pituitary or hypothalamic disease, but does not
rule out constitutional delay of puberty.
B. Suppression of Gonadotropin Production
1. Controlled ovarian stimulation—In the controlled ovar-
ian stimulation that provides multiple mature oocytes for assisted
reproductive technologies such as in vitro fertilization, it is criti-
cal to suppress an endogenous LH surge that could prematurely
trigger ovulation. This suppression is most commonly achieved by
daily subcutaneous injections of leuprolide or daily nasal applica-
tions of nafarelin. For leuprolide, treatment is commonly initiated
with 1 mg daily for about 10 days until menstrual bleeding occurs.
At that point, the dose is reduced to 0.5 mg daily until hCG is
administered (Figure 37–3). For nafarelin, the beginning dosage
is generally 400 mcg twice a day, which is decreased to 200 mcg
when menstrual bleeding occurs.
2. Endometriosis—Endometriosis is defined as the presence of
estrogen-sensitive endometrium outside the uterus that results in
cyclical abdominal pain in premenopausal women. The pain of
endometriosis is often reduced by abolishing exposure to the cycli-
cal changes in the concentrations of estrogen and progesterone that
are a normal part of the menstrual cycle. The ovarian suppression
induced by continuous treatment with a GnRH agonist greatly
reduces estrogen and progesterone concentrations and prevents
cyclical changes. The preferred duration of treatment with a GnRH
agonist is limited to 6 months because ovarian suppression beyond
this period can result in decreased bone mineral density. When relief
of pain from treatment with a GnRH agonist supports continued
therapy for more than 6 months, the addition of add-back therapy
(estrogen or progestins) reduces or eliminates GnRH agonist-
induced bone mineral loss and provides symptomatic relief without
reducing the efficacy of pain relief. Leuprolide and goserelin are
administered as depot preparations that provide 1 or 3 months of
continuous GnRH agonist activity. Nafarelin is administered twice
daily as a nasal spray at a dose of 0.2 mg per spray.
3. Uterine leiomyomata (uterine fibroids)—Uterine leio-
myomata are benign, estrogen-sensitive, smooth muscle tumors
in the uterus that can cause menorrhagia, with associated anemia
and pelvic pain. Treatment for 3–6 months with a GnRH agonist
reduces fibroid size and, when combined with supplemental iron,
improves anemia. The effects of GnRH agonists are temporary,
with gradual recurrent growth of leiomyomas to previous size
within several months after cessation of treatment. GnRH ago-
nists have been used widely for preoperative treatment of uterine
leiomyomas, both for myomectomy and hysterectomy. GnRH
agonists have been shown to improve hematologic parameters,
shorten hospital stay, and decrease blood loss, operating time, and
postoperative pain when given for 3 months preoperatively.
4. Prostate cancer—Androgen deprivation therapy is the
primary medical therapy for prostate cancer. Combined antian-
drogen therapy with continuous GnRH agonist and an andro-
gen receptor antagonist is as effective as surgical castration in
678    SECTION VII  Endocrine Drugs
reducing serum testosterone concentrations and effects. Leupro-
lide, goserelin, histrelin, buserelin, and triptorelin are approved
for this indication. The preferred formulation is one of the
long-acting depot forms that provide 1, 3, 4, 6, or 12 months of
active drug therapy. During the first 7–10 days of GnRH analog
therapy, serum testosterone levels increase because of the agonist
action of the drug; this can precipitate pain in patients with
bone metastases, and tumor growth and neurologic symptoms in
patients with vertebral metastases. It can also temporarily worsen
symptoms of urinary obstruction. Such tumor flares can usually
be avoided with the concomitant administration of an androgen
receptor antagonist (flutamide, bicalutamide, or nilutamide) (see
Chapter 40). Within about 2 weeks, serum testosterone levels fall
to the hypogonadal range.
5. Central precocious puberty—Continuous administration
of a GnRH agonist is indicated for treatment of central precocious
puberty (onset of secondary sex characteristics before 7–8 years
in girls or 9 years in boys). Before embarking on treatment with
a GnRH agonist, one must confirm central precocious puberty
by demonstrating a pubertal gonadotropin response to GnRH or
a “test dose” of a GnRH analog. Treatment is typically indicated
in a child whose final height would be otherwise significantly
compromised (as evidenced by a significantly advanced bone age)
or in whom the early development of pubertal secondary sexual
characteristics or menses causes significant emotional distress.
While central precocious puberty is most often idiopathic, it is
important to rule out central nervous system pathology with MRI
imaging of the hypothalamic-pituitary area.
Treatment is most commonly carried out with either every
month or every three months intramuscular depot injection of
leuprolide acetate or with a once-yearly implant of histrelin acetate.
Daily subcutaneous regimens and multiple daily nasal spray regi-
mens of GnRH agonists also are available but are not recommended
due to poor adherence. Treatment with a GnRH agonist is generally
continued long enough to optimize adult height and allow pubertal
development that is concurrent with peers. Typically treatment is
continued until age 11 in females and age 12 in males.
6. Other—The gonadal suppression provided by continuous
GnRH agonist treatment is used in the management of advanced
breast and ovarian cancer. In addition, recently published clini-
cal practice guidelines recommend the use of continuous GnRH
agonist administration in early pubertal transgender adolescents
to block endogenous puberty prior to subsequent treatment with
cross-gender gonadal hormones.
Toxicity
Gonadorelin can cause headache, light-headedness, nausea, and
flushing. Local swelling often occurs at subcutaneous injection
sites. Generalized hypersensitivity dermatitis has occurred after
long-term subcutaneous administration. Rare acute hypersensi-
tivity reactions include bronchospasm and anaphylaxis. Sudden
pituitary apoplexy and blindness have been reported following
administration of GnRH to a patient with a gonadotropin-
secreting pituitary tumor.
Continuous treatment of women with a GnRH analog
(leuprolide, nafarelin, goserelin) causes the typical symptoms of
menopause, which include hot flushes, sweats, and headaches.
Depression, diminished libido, generalized pain, vaginal dryness,
and breast atrophy may also occur. Ovarian cysts may develop
within the first month of therapy due to its flare effect on gonado-
tropin secretion and generally resolve after an additional 6 weeks.
Reduced bone mineral density and osteoporosis may occur with
prolonged use, so patients should be monitored with bone den-
sitometry before repeated treatment courses. Depending on the
condition being treated with the GnRH agonist, it may be pos-
sible to ameliorate the signs and symptoms of the hypoestrogenic
state without losing clinical efficacy by adding back a small dose
of a progestin alone or in combination with a low dose of an estro-
gen. Contraindications to the use of GnRH agonists in women
include pregnancy and breast-feeding.
In men treated with continuous GnRH agonist administration,
adverse effects include hot flushes and sweats, edema, gynecomas-
tia, decreased libido, decreased hematocrit, reduced bone density,
asthenia, and injection site reactions. GnRH analog treatment of
children is generally well tolerated. However, temporary exacerba-
tion of precocious puberty may occur during the first few weeks
of therapy. Nafarelin nasal spray may cause or aggravate sinusitis.
GnRH RECEPTOR ANTAGONISTS
Four synthetic decapeptides that function as competitive antago-
nists of GnRH receptors are available for clinical use. Ganirelix,
cetrorelix, abarelix, and degarelix inhibit the secretion of FSH
and LH in a dose-dependent manner. Ganirelix and cetrorelix
are approved for use in controlled ovarian stimulation proce-
dures, whereas degarelix and abarelix are approved for men with
advanced prostate cancer.
Pharmacokinetics
Ganirelix and cetrorelix are absorbed rapidly after subcutaneous
injection. Administration of 0.25 mg daily maintains GnRH antag-
onism. Alternatively, a single 3.0-mg dose of cetrorelix suppresses
LH secretion for 96 hours. Degarelix therapy is initiated with 240
mg administered as two subcutaneous injections. Maintenance dos-
ing is with an 80-mg subcutaneous injection every 28 days.
Clinical Pharmacology
A. Suppression of Gonadotropin Production
GnRH antagonists are approved for preventing the LH surge
during controlled ovarian stimulation. They offer several advan-
tages over continuous treatment with a GnRH agonist. Because
GnRH antagonists produce an immediate antagonist effect, their
use can be delayed until day 6–8 of the in vitro fertilization cycle
(Figure 37–3), and thus the duration of administration is shorter.
They also appear to have a less suppressive effect on the ovarian
response to gonadotropin stimulation, which permits a decrease in
the total duration and dose of gonadotropin. On the other hand,
because their antagonist effects reverse more quickly after their

discontinuation, adherence to the treatment regimen is critical.
The antagonists produce a more complete suppression of LH
secretion than agonists. The suppression of LH may impair fol-
licular development when recombinant or the purified form of
FSH is used during an in vitro fertilization cycle. Clinical trials
have shown a slightly lower rate of pregnancy in in vitro fertiliza-
tion cycles that used GnRH antagonist treatment compared with
cycles that used GnRH agonist treatment.
B. Advanced Prostate Cancer
Degarelix and abarelix are approved for the treatment of symp-
tomatic advanced prostate cancer. These GnRH antagonists
reduce concentrations of gonadotropins and androgens more
rapidly than GnRH agonists and avoid the testosterone surge seen
with GnRH agonist therapy.
Toxicity
When used for controlled ovarian stimulation, ganirelix and
cetrorelix are well tolerated. The most common adverse effects are
nausea and headache. During the treatment of men with prostate
cancer, degarelix caused injection-site reactions and increases in
liver enzymes. Like continuous treatment with a GnRH agonist,
degarelix and abarelix lead to signs and symptoms of androgen
deprivation, including hot flushes and weight gain.
PROLACTIN
Prolactin is a 198-amino-acid peptide hormone produced in the
anterior pituitary. Its structure resembles that of GH. Prolactin is
the principal hormone responsible for lactation. Milk production
is stimulated by prolactin when appropriate circulating levels of
estrogens, progestins, corticosteroids, and insulin are present. A
deficiency of prolactin—which can occur in rare states of pituitary
deficiency—is manifested by failure to lactate. No preparation of
prolactin is available for use in prolactin-deficient patients.
In pituitary stalk section from surgery or head trauma, stalk
compression due to a sellar mass, or rare cases of hypothalamic
destruction, prolactin levels may be elevated as a result of
impaired transport of dopamine (prolactin-inhibiting hormone)
to the pituitary. Much more commonly, prolactin is elevated as
a result of prolactin-secreting adenomas. In addition, a number
of drugs elevate prolactin levels. These include antipsychotic and
gastrointestinal motility drugs that are known dopamine receptor
antagonists, estrogens, and opiates. Hyperprolactinemia causes
hypogonadism, which manifests with infertility, oligomenorrhea
or amenorrhea, and galactorrhea in premenopausal women, and
with loss of libido, erectile dysfunction, and infertility in men.
In the case of large tumors (macroadenomas), it can be associ-
ated with symptoms of a pituitary mass, including visual changes
due to compression of the optic nerves. The hypogonadism and
infertility associated with hyperprolactinemia result from inhibi-
tion of GnRH release. For patients with symptomatic hyperpro-
lactinemia, inhibition of prolactin secretion can be achieved with
dopamine agonists, which act in the pituitary to inhibit prolactin
release.
CHAPTER 37  Hypothalamic & Pituitary Hormones    679
DOPAMINE AGONISTS
Adenomas that secrete excess prolactin usually retain the sensitiv-
ity to inhibition by dopamine exhibited by normal pituitary lacto-
trophs, prolactin secreting cells. Bromocriptine and cabergoline
are ergot derivatives (see Chapters 16 and 28) with a high affinity
for dopamine D2 receptors. Quinagolide, a drug approved in
Europe, is a nonergot agent with similarly high D2 receptor affin-
ity. The chemical structure and pharmacokinetic features of ergot
alkaloids are presented in Chapter 16.
Dopamine agonists suppress prolactin release very effectively
in patients with hyperprolactinemia and GH release is reduced in
patients with acromegaly, although not as effectively. Bromocriptine
has also been used in Parkinson’s disease to improve motor func-
tion and reduce levodopa requirements (see Chapter 28). Newer,
nonergot D2 agonists used in Parkinson’s disease (pramipexole and
ropinirole; see Chapter 28) have been reported to interfere with
lactation, but they are not approved for use in hyperprolactinemia.
Pharmacokinetics
All available dopamine agonists are active as oral preparations, and
all are eliminated by metabolism. They can also be absorbed sys-
temically after vaginal insertion of tablets to avoid nausea due to
oral administration. Cabergoline, with a half-life of approximately
65 hours, has the longest duration of action. Quinagolide has a
half-life of about 20 hours, whereas the half-life of bromocriptine
is about 7 hours. After vaginal administration, serum levels peak
more slowly.
Clinical Pharmacology
A. Hyperprolactinemia
A dopamine agonist is the standard first-line treatment for hyper-
prolactinemia. These drugs shrink pituitary prolactin-secreting
tumors, lower circulating prolactin levels, and restore ovulation
in approximately 70% of women with microadenomas and 30%
of women with macroadenomas (Figure 37–4). Cabergoline is
initiated at 0.25 mg twice weekly orally or vaginally. It can be
increased gradually, according to serum prolactin determina-
tions, up to a maximum of 1 mg twice weekly. Bromocriptine is
generally taken daily after the evening meal at the initial dose of
1.25 mg; the dose is then increased as tolerated. Most patients
require 2.5–7.5 mg daily. Long-acting oral bromocriptine formu-
lations (Parlodel SRO) and intramuscular formulations (Parlodel
LAR) are available outside the United States.
B. Physiologic Lactation
Dopamine agonists were used in the past to prevent breast
engorgement when breast-feeding was not desired. Their use for
this purpose has been discouraged because of toxicity (see Toxicity
& Contraindications).
C. Acromegaly
A dopamine agonist alone or in combination with pituitary sur-
gery, radiation therapy, or octreotide administration can be used
680    SECTION VII  Endocrine Drugs

A Dopamine agonist therapy during the early weeks of pregnancy

120 has not been associated with an increased risk of spontaneous
Serum prolactin (mcg/liter)

100 abortion or congenital malformations. Although there has been

a longer experience with the safety of bromocriptine during early
80
pregnancy, there is growing evidence that cabergoline is also safe
60 in women with macroadenomas who must continue a dopamine
40 agonist during pregnancy. In patients with small pituitary adeno-
mas, dopamine agonist therapy is discontinued upon conception
20
because growth of microadenomas during pregnancy is rare.
0 Patients with very large adenomas require vigilance for tumor
0 2 4 6 8 10 12 14 16 18 20 22 24
progression and often require a dopamine agonist throughout
Weeks of cabergoline therapy
pregnancy. There have been rare reports of stroke or coronary
B
thrombosis in postpartum women taking bromocriptine to
100
suppress postpartum lactation.
80
% of patients

60
40
20
0 are synthesized in neuronal cell bodies in the hypothalamus and
Complete Partial
success success
FIGURE 37–4  Results from a clinical trial of cabergoline in
women with hyperprolactinemia and anovulation. A: The dashed line
indicates the upper limit of normal serum prolactin concentrations.
B: Complete success was defined as pregnancy or at least two
consecutive menses with evidence of ovulation at least once. Partial
success was two menstrual cycles without evidence of ovulation or
just one ovulatory cycle. The most common reasons for withdrawal
from the trial were nausea, headache, dizziness, abdominal pain,
and fatigue. (Adapted from Webster J et al: A comparison of cabergoline and
bromocriptine in the treatment of hyperprolactinemic amenorrhea. N Engl J Med
1994;331:904.)
to treat acromegaly. The doses required are higher than those
used to treat hyperprolactinemia. For example, patients with
acromegaly require 20–30 mg/d of bromocriptine and seldom
respond adequately to bromocriptine alone unless the pituitary
tumor secretes prolactin as well as GH.
Toxicity & Contraindications
Dopamine agonists can cause nausea, headache, light-headedness,
orthostatic hypotension, and fatigue. Psychiatric manifestations
occasionally occur, even at lower doses, and may take months
to resolve. Erythromelalgia occurs rarely. High dosages of ergot-
derived preparations can cause cold-induced peripheral digital
vasospasm. Pulmonary infiltrates have occurred with chronic
high-dosage therapy. Cabergoline treatment at high doses for
Parkinson’s disease is associated with higher risk of valvular heart
disease, but probably not at the lower dose used for hyperpro-
lactinemia. Cabergoline appears to cause nausea less often than
bromocriptine. Vaginal administration can reduce nausea, but
may cause local irritation.
■■ POSTERIOR PITUITARY
HORMONES
The two posterior pituitary hormones—vasopressin and oxytocin—
Failure
transported via their axons to the posterior pituitary, where they are
stored and then released into the circulation. Each has limited but
important clinical uses.
OXYTOCIN
Oxytocin is a peptide hormone secreted by the posterior pituitary.
Oxytocin stimulates muscular contractions in the uterus and
myoepithelial contractions in the breast. Thus, it is involved in
parturition and the letdown of milk. During the second half of
pregnancy, uterine smooth muscle shows an increase in the expres-
sion of oxytocin receptors and becomes increasingly sensitive to
the stimulant action of endogenous oxytocin.
Chemistry & Pharmacokinetics
A. Structure
Oxytocin is a 9-amino-acid peptide with an intrapeptide disulfide
cross-link (Figure 37–5). Its amino acid sequence differs from that
of vasopressin at positions 3 and 8.
B. Absorption, Metabolism, and Excretion
Oxytocin is administered intravenously for initiation and aug-
mentation of labor. It also can be administered intramuscularly for
control of postpartum bleeding. Oxytocin is not bound to plasma
proteins and is rapidly eliminated by the kidneys and liver, with a
circulating half-life of 5 minutes.
Pharmacodynamics
Oxytocin acts through G protein–coupled receptors and the
phosphoinositide-calcium second-messenger system to contract
uterine smooth muscle. Oxytocin also stimulates the release of

S S
Cys - Tyr - IIe - Gln - Asn - Cys - Pro - Leu - Gly - NH2
1 2 3 4 5 6 7 8 9
Oxytocin
S S
Cys - Tyr - Phe - Gln - Asn - Cys - Pro - Arg - Gly - NH2
1 2 3 4 5 6 7 8 9 of standard fetal monitoring. High concentrations of oxytocin
Arginine vasopressin
S S
O
CH2CH2C - Tyr - Phe - Gln - Asn - Cys - Pro - D-Arg - Gly - NH2
1 2 3 4 5 6 7 8 9
Desmopressin
FIGURE 37–5  Posterior pituitary hormones and desmopressin.
(Adapted, with permission, from Ganong WF: Review of Medical Physiology, 21st ed.
McGraw-Hill, 2003. Copyright © The McGraw-Hill Companies, Inc.)
prostaglandins and leukotrienes that augment uterine contraction.
In small doses oxytocin increases both the frequency and the force
of uterine contractions. At higher doses, it produces sustained
contraction.
Oxytocin also causes contraction of myoepithelial cells sur-
rounding mammary alveoli, which leads to milk letdown. Without
oxytocin-induced contraction, normal lactation cannot occur. At
high concentrations, oxytocin has weak antidiuretic and pressor
activity due to activation of vasopressin receptors.
Clinical Pharmacology
Oxytocin is used to induce labor for conditions requiring
expedited vaginal delivery such as uncontrolled maternal diabe-
tes, worsening preeclampsia, intrauterine infection, or ruptured
membranes after 34 gestational weeks. It is also used to augment
protracted labor. Oxytocin can also be used in the immediate
postpartum period to stop vaginal bleeding due to uterine atony.
Before delivery, oxytocin is usually administered intrave-
nously via an infusion pump with appropriate fetal and maternal
monitoring. For induction of labor, an initial infusion rate of
0.5–2 mU/min is increased every 30–60 minutes until a physi-
ologic contraction pattern is established. The maximum infusion
rate is 20 mU/min. For postpartum uterine bleeding, 10–40 units
are added to 1 L of 5% dextrose, and the infusion rate is titrated
to control uterine atony. Alternatively, 10 units of oxytocin can be
administered by intramuscular injection.
During the antepartum period, oxytocin induces uterine con-
tractions that transiently reduce placental blood flow to the fetus.
The oxytocin challenge test measures the fetal heart rate response
to a standardized oxytocin infusion and provides information
about placental circulatory reserve. An abnormal response, seen as
late decelerations in the fetal heart rate, indicates fetal hypoxia and
may warrant immediate cesarean delivery.
CHAPTER 37  Hypothalamic & Pituitary Hormones    681
Toxicity & Contraindications
When oxytocin is used judiciously, serious toxicity is rare. The
toxicity that does occur is due either to excessive stimulation of
uterine contractions or to inadvertent activation of vasopressin
receptors. Excessive stimulation of uterine contractions before
delivery can cause fetal distress, placental abruption, or uterine
rupture. These complications can be detected early by means
with activation of vasopressin receptors can cause excessive fluid
retention, or water intoxication, leading to hyponatremia, heart
failure, seizures, and death. Bolus injections of oxytocin can cause
hypotension. To avoid hypotension, oxytocin is administered
intravenously as dilute solutions at a controlled rate.
Contraindications to oxytocin include fetal distress, fetal mal-
presentation, placental abruption, and other predispositions for
uterine rupture, including previous extensive uterine surgery.
OXYTOCIN ANTAGONIST
Atosiban is an antagonist of the oxytocin receptor that has been
approved outside the United States as a treatment (tocolysis) for
preterm labor. Atosiban is a modified form of oxytocin that is
administered by intravenous infusion for 2–48 hours. In a small
number of published clinical trials, atosiban appears to be as effec-
tive as β-adrenoceptor-agonist tocolytics and to produce fewer
adverse effects. In 1998, however, the FDA decided not to approve
atosiban based on concerns about efficacy and safety.
VASOPRESSIN (ANTIDIURETIC
HORMONE, ADH)
Vasopressin is a peptide hormone released by the posterior pituitary
in response to rising plasma tonicity or falling blood pressure. It pos-
sesses antidiuretic and vasopressor properties. A deficiency of this
hormone results in diabetes insipidus (see also Chapters 15 and 17).
Chemistry & Pharmacokinetics
A. Structure
Vasopressin is a nonapeptide with a 6-amino-acid ring and a
3-amino-acid side chain. The residue at position 8 is arginine in
humans and in most other mammals except pigs and related spe-
cies, whose vasopressin contains lysine at position 8 (Figure 37–5).
Desmopressin acetate (DDAVP, 1-desamino-8-d-arginine vaso-
pressin) is a long-acting synthetic analog of vasopressin with mini-
mal pressor activity and an antidiuretic-to-pressor ratio 4000 times
that of vasopressin. Desmopressin is modified at position 1 and
contains a d-amino acid at position 8. Like vasopressin and oxytocin,
desmopressin has a disulfide linkage between positions 1 and 6.
B. Absorption, Metabolism, and Excretion
Vasopressin is administered by intravenous or intramuscular
injection. The half-life of circulating vasopressin is approximately
682    SECTION VII  Endocrine Drugs

15 minutes, with renal and hepatic metabolism via reduction of
the disulfide bond and peptide cleavage.
Desmopressin can be administered intravenously, subcutane-
ously, intranasally, or orally. The half-life of circulating desmo-
pressin is 1.5–2.5 hours. Nasal desmopressin is available as a unit
dose spray that delivers 10 mcg per spray; it is also available with
a calibrated nasal tube that can be used to deliver a more precise
dose. Nasal bioavailability of desmopressin is 3–4%, whereas oral
bioavailability is less than 1%.
Pharmacodynamics
Vasopressin activates two subtypes of G protein–coupled recep-
tors (see Chapter 17). V1 receptors are found on vascular smooth
muscle cells and mediate vasoconstriction via the coupling protein
Gq and phospholipase C. V2 receptors are found on renal tubule
cells and reduce diuresis through increased water permeability
and water resorption in the collecting tubules via Gs and adenylyl
cyclase. Extrarenal V2-like receptors regulate the release of coagu-
lation factor VIII and von Willebrand factor, which increases
platelet aggregation.
Clinical Pharmacology
Vasopressin and desmopressin are treatments of choice for
pituitary diabetes insipidus. The dosage of desmopressin is
10–40 mcg (0.1–0.4 mL) in two to three divided doses as a
nasal spray or, as an oral tablet, 0.1–0.2 mg two to three times
daily. The dosage by injection is 1–4 mcg (0.25–1 mL) every
12–24 hours as needed for polyuria, polydipsia, or hypernatre-
mia. Bedtime desmopressin therapy, by intranasal or oral admin-
istration, ameliorates nocturnal enuresis by decreasing nocturnal
urine production. Vasopressin infusion is effective in some
cases of esophageal variceal bleeding and colonic diverticular
bleeding. High-dose vasopressin as a 40-unit intravenous bolus
injection may be given to replace epinephrine in the Advanced
Cardiovascular Life Support (ACLS) resuscitation protocol for
pulseless arrest.
Desmopressin is also used for the treatment of coagulopathy in
hemophilia A and von Willebrand disease (see Chapter 34).
Toxicity & Contraindications
Headache, nausea, abdominal cramps, agitation, and allergic reac-
tions occur rarely. Overdosage can result in hyponatremia and
seizures.
Vasopressin (but not desmopressin) can cause vasoconstriction
and should be used cautiously in patients with coronary artery
disease. Nasal insufflation of desmopressin may be less effective
when nasal congestion is present.
VASOPRESSIN ANTAGONISTS
A group of nonpeptide antagonists of vasopressin receptors has
been investigated for use in patients with hyponatremia or acute
heart failure, which is often associated with elevated concentrations
of vasopressin. Conivaptan has high affinity for both V1a and V2
receptors. Tolvaptan has a 30-fold higher affinity for V2 than for
V1 receptors. In several clinical trials, both agents promoted the
excretion of free water, relieved symptoms, and reduced objective
signs of hyponatremia and heart failure. Conivaptan, administered
intravenously, and tolvaptan, given orally, are approved by the
FDA for treatment of hyponatremia. Tolvaptan treatment dura-
tion is limited to 30 days due to risk of hepatotoxicity, including
life-threatening liver failure. Several other nonselective nonpeptide
vasopressin receptor antagonists are being investigated for these
conditions (see Chapter 15).

SUMMARY Hypothalamic & Pituitary Hormones1

Mechanism of Pharmacokinetics,
Subclass, Drug Action Effects Clinical Applications Toxicities, Interactions

GROWTH HORMONE (GH)

  •  Somatropin Recombinant form of Restores normal growth and
human GH • acts metabolic GH effects in
through GH receptors GH-deficient individuals
to increase production • increases final adult height
of IGF-I in some children with short
stature not due to GH
deficiency
Replacement in GH deficiency
• increased final adult height in
children with certain conditions
associated with short stature (see
Table 37–4) • wasting in HIV
infection • short bowel syndrome
SC injection • Toxicity: Pseudotumor
cerebri, slipped capital femoral
epiphysis, edema, hyperglycemia,
progression of scoliosis, risk of
asphyxia in severely obese patients
with Prader-Willi syndrome and upper
airway obstruction or sleep apnea

IGF-I AGONIST
  •  Mecasermin Recombinant form of Improves growth and Replacement in IGF-I deficiency that SC injection • Toxicity: Hypoglycemia,
IGF-I that stimulates metabolic IGF-I effects in is not responsive to exogenous GH intracranial hypertension, increased
IGF-I receptors individuals with IGF-I liver enzymes
deficiency due to severe GH
resistance

(continued)
 CHAPTER 37  Hypothalamic & Pituitary Hormones    683

Mechanism of Pharmacokinetics,
Subclass, Drug Action Effects Clinical Applications Toxicities, Interactions

SOMATOSTATIN ANALOGS
  •  Octreotide Agonist at somatostatin Inhibits production of GH Acromegaly and several other SC or IV injection • long-acting
receptors and, to a lesser extent, of TSH, hormone-secreting tumors • acute formulation injected IM monthly
glucagon, insulin, and gastrin control of bleeding from esophageal • Toxicity: Gastrointestinal
varices disturbances, gallstones, bradycardia,
cardiac conduction problems

  •  Lanreotide: Similar to octreotide; available as a long-acting formulation for acromegaly

GH RECEPTOR ANTAGONIST
  •  Pegvisomant Blocks GH receptors Ameliorates effects of excess Acromegaly SC injection • Toxicity: Increased liver
GH production enzymes

GONADOTROPINS: FOLLICLE-STIMULATING HORMONE (FSH) ANALOGS

  •  Follitropin alfa Activates FSH receptors Mimics effects of Controlled ovarian stimulation
endogenous FSH • infertility due to hypogonadotropic
hypogonadism in men
SC injection • Toxicity: Ovarian
hyperstimulation syndrome and
multiple pregnancies in women
• gynecomastia in men • headache,
depression, edema in both sexes

  •  Follitropin beta: A recombinant product with the same peptide sequence as follitropin alfa but differs in its carbohydrate side chains
  •  Urofollitropin: Human FSH purified from the urine of postmenopausal women
  •  Menotropins (hMG): Extract of the urine of postmenopausal women; contains both FSH and LH activity

GONADOTROPINS: LUTEINIZING HORMONE (LH) ANALOGS

  • Human chorionic Agonist at LH Mimics effects of Initiation of final oocyte maturation IM or SC injection • Toxicity: Ovarian
gonadotropin receptors endogenous LH and ovulation during controlled hyperstimulation syndrome
(hCG) ovarian stimulation • male • headache, depression, edema in
hypogonadotropic hypogonadism both sexes

  •  Choriogonadotropin alfa: Recombinant form of hCG

  •  Lutropin: Recombinant form of human LH
  •  Menotropins (hMG): Extract of the urine of postmenopausal women that contains both FSH and LH activity

GONADOTROPIN-RELEASING HORMONE (GnRH) ANALOGS

  •  Leuprolide Agonist at GnRH
receptors
Increased LH and FSH Ovarian suppression • controlled
secretion with intermittent ovarian stimulation • central
administration • reduced LH precocious puberty • block of
and FSH secretion with endogenous puberty in some
prolonged continuous transgender/gender variant early
administration pubertal adolescents • advanced
prostate cancer
Administered IV, SC, IM, or intranasally
• depot formulations are available
• Toxicity: Headache, light-headedness,
nausea, injection site reactions
• symptoms of hypogonadism with
continuous treatment

  •  Gonadorelin: Synthetic human GnRH

  •  Other GnRH analogs: Goserelin, buserelin, histrelin, nafarelin, and triptorelin

GONADOTROPIN-RELEASING HORMONE (GnRH) RECEPTOR ANTAGONISTS

  •  Ganirelix Blocks GnRH receptors Reduces endogenous Prevention of premature LH surge SC injection • Toxicity: Nausea,
production of LH and FSH during controlled ovarian headache
stimulation

  •  Cetrorelix: Similar to ganirelix, approved for controlled ovarian stimulation

  •  Degarelix and abarelix: Approved for advanced prostate cancer

(continued)
684    SECTION VII  Endocrine Drugs

Mechanism of Pharmacokinetics,
Subclass, Drug Action Effects Clinical Applications Toxicities, Interactions

DOPAMINE AGONISTS
  •  Bromocriptine Activates dopamine Suppresses pituitary
D2 receptors secretion of prolactin and,
less effectively, GH
• dopaminergic effects on
CNS motor control and
behavior
Treatment of hyperprolactinemia
• acromegaly • Parkinson’s disease
(see Chapter 28)
Administered orally or, for
hyperprolactinemia, vaginally
• Toxicity: Gastrointestinal
disturbances, orthostatic hypotension,
headache, psychiatric disturbances,
vasospasm and pulmonary infiltrates
in high doses

  •  Cabergoline: Another ergot derivative with similar effects

OXYTOCIN Activates oxytocin Increased uterine Induction and augmentation of IV infusion or IM injection • Toxicity:
receptors contractions labor • control of uterine Fetal distress, placental abruption,
hemorrhage after delivery uterine rupture, fluid retention,
hypotension

OXYTOCIN RECEPTOR ANTAGONIST

  •  Atosiban Blocks oxytocin Decreased uterine Tocolysis for preterm labor IV infusion • Toxicity: Concern about
receptors contractions (not available in the USA) increased rates of infant death; not
FDA approved

VASOPRESSIN RECEPTOR AGONISTS

  •  Desmopressin Relatively selective Acts in the kidney collecting
vasopressin V2 receptor duct cells to decrease the
agonist excretion of water • acts on
extrarenal V2 receptors to
increase factor VIII and von
Willebrand factor
Pituitary diabetes insipidus Oral, IV, SC, or intranasal • Toxicity:
• pediatric primary nocturnal Gastrointestinal disturbances,
enuresis • hemophilia A and von headache, hyponatremia, allergic
Willebrand disease reactions

  •  Vasopressin: Available for treatment of diabetes insipidus and sometimes used to control bleeding from esophageal varices

VASOPRESSIN RECEPTOR ANTAGONIST

  •  Conivaptan Antagonist of Reduced renal excretion of Hyponatremia in hospitalized IV infusion • Toxicity: Infusion site
vasopressin V1a and water in conditions patients reactions
V2 receptors associated with increased
vasopressin

  •  Tolvaptan: Similar but more selective for vasopressin V2 receptors; oral administration; treatment course limited to 30 days due to risk of hepatotoxicity
1
See Tables 37–2 and 37–3 for summaries of the clinical uses of the rarely used hypothalamic and pituitary hormones not described in this table.
 CHAPTER 37  Hypothalamic & Pituitary Hormones    685

P R E P A R A T I O N S A V A I L A B L E
GENERIC NAME AVAILABLE AS GENERIC NAME AVAILABLE AS
GROWTH FACTOR AGONISTS & ANTAGONISTS Leuprolide acetate Generic, Eligard, Lupron
Lanreotide acetate Somatuline Depot Lutropin alfa (rLH) Luveris*
Mecasermin Increlex Menotropins (hMG) Menopur, Repronex
Octreotide acetate Generic, Sandostatin, Sandostatin LAR Nafarelin acetate Synarel
Depot Triptorelin pamoate Trelstar, Trelstar LA, Trelstar Depot
Pegvisomant Somavert Urofollitropin Bravelle*, Fertinex*
Somatropin Genotropin, Humatrope, Norditropin, PROLACTIN ANTAGONISTS (DOPAMINE AGONISTS)
Nutropin, Omnitrope, Saizen,
Bromocriptine mesylate Generic, Parlodel, Cycloset
Serostim, Tev-tropin, Zorbtive
Cabergoline Generic, Dostinex
GONADOTROPIN AGONISTS & ANTAGONISTS
OXYTOCIN
Abarelix Plenaxis*
Oxytocin Generic, Pitocin
Cetrorelix acetate Cetrotide
Choriogonadotropin alfa Ovidrel VASOPRESSIN AGONISTS AND ANTAGONISTS
(rhCG) Conivaptan HCl Vaprisol
Chorionic gonadotropin (hCG) Generic, Profasi, Pregnyl Desmopressin acetate Generic, Minirin, Stimate
Degarelix Firmagon (DDAVP)
Follitropin alfa (rFSH) Gonal-f Tolvaptan Samsca
Follitropin beta (rFSH) Follistim Vasopressin Generic, Pitressin
Ganirelix acetate Antagon OTHER
Gonadorelin hydrochloride Factrel Corticorelin ovine triflutate Acthrel
(GnRH) Corticotropin H.P. Acthar Gel
Goserelin acetate Zoladex Cosyntropin Generic, Cortrosyn, Cosyntropin
Histrelin acetate Supprelin LA, Vantas Thyrotropin alfa Thyrogen
*
Withdrawn from the USA.

REFERENCES Katznelson L et al: American Association of Clinical Endocrinologists medical guide-

Abramovici A, Cantu J, Jenkins SM: Tocolytic therapy for acute preterm labor.
Obstet Gynecol Clin North Am 2012;39:77.
Al-Inany HG et al: Gonadotrophin-releasing hormone antagonists for assisted
reproductive technology. Cochrane Database Syst Rev 2011;(5):CD001750.
Beall SA, DeCherney A: History and challenges surrounding ovarian stimulation
in the treatment of infertility. Fertil Steril 2012;97:795.
Caldwell PH, Deshpande AV, Von Gontard A: Management of nocturnal enuresis.
BMJ 2013;347:f6259.
Carel JC et al: Consensus statement on the use of gonadotropin-releasing hormone
analogs in children. Pediatrics 2009;123:752.
Carel JC et al: Long-term mortality after recombinant growth hormone treat-
ment for isolated growth hormone deficiency or childhood short stature:
Preliminary report of the French SAGhE study. J Clin Endocrinol Metab
2012;97:416.
Collett-Solberg PF et al: The role of recombinant human insulin-like growth
factor-I in treating children with short stature. J Clin Endocrinol Metab
2008;93:10.
Dong Q, Rosenthal SM: Endocrine disorders of the hypothalamus and pituitary.
In: Swaiman KF, Ashwal S, Ferriero DM (editors): Pediatric Neurology,
5th ed. Mosby, Inc. (Elsevier, Inc.), 2011.
Dreicer R et al: New data, new paradigms for treating prostate cancer patients—
VI: Novel hormonal therapy approaches. Urology 2011;78(5 Suppl):S494.
Gabe SG et al: Obstetrics: Normal and Problem Pregnancies, 6th ed. Churchill
Livingstone, 2012.
Han TS, Bouloux PM: What is the optimal therapy for young males with hypogo-
nadotropic hypogonadism? Clin Endocrinol 2010;72:731.
Hodson EM, Willis NS, Craig JC: Growth hormone for children with chronic
kidney disease. Cochrane Database Syst Rev 2012;(2):CD003264.
lines for clinical practice for the diagnosis and treatment of acromegaly—2011
update. Endo Pract 2011;s4:1.
Lanning NJ, Carter-Su C: Recent advances in growth hormone signaling. Rev
Endocr Metab Disord 2006;7:225.
Melmed S et al (editors): Williams Textbook of Endocrinology, 13th ed. Elsevier,
2016.
Papatsonis DN et al: Maintenance therapy with oxytocin antagonists for inhibiting
preterm birth after threatened preterm labour. Cochrane Database Syst Rev
2013;(10):CD005938.
Penson D et al: Effectiveness of hormonal and surgical therapies for cryptorchi-
dism: A systematic review. Pediatrics 2013;131:e1897.
Richmond E, Rogol AD: Current indications for growth hormone therapy for
children and adolescents. Endocr Dev 2010;18:92.
Rosenfeld RG, Hwa V: The growth hormone cascade and its role in mammalian
growth. Horm Res 2009;71(Suppl 2):36.
Sävendahl L et al: Long-term mortality and causes of death in isolated GHD,
ISS, and SGA patients treated with recombinant growth hormone during
childhood in Belgium, The Netherlands, and Sweden: Preliminary report of
3 countries participating in the EU SAGhE study. J Clin Endocrinol Metab
2012;97:E213.
Snyder PJ: Treatment of hyperprolactinemia due to lactotroph adenoma and other
causes. Available online at: www.uptodate.com.
Speroff L, Fritz MA: Clinical Gynecologic Endocrinology and Infertility, 8th ed.
Lippincott Williams & Wilkins, 2010.
Strauss JF, Barbieri RL: Yen & Jaffe’s Reproductive Endocrinology, 6th ed. Elsevier,
2009.
Surrey ES: Gonadotropin-releasing hormone agonist and add-back therapy: What
do the data show? Curr Opin Obstet Gynecol 2010;22:283.
686    SECTION VII  Endocrine Drugs
Taylor BE, Buchman TG: Is there a role for growth hormone therapy in refractory
critical illness? Curr Opin Crit Care Med 2008;14:438.
Tena-Sempere M: Deciphering puberty: Novel partners, novel mechanisms. Eur J
Endocrinol 2012;167:733.
Wales PW et al: Human growth hormone and glutamine for patients with short
bowel syndrome. Cochrane Database Syst Rev 2010;(16):CD006321.
Webster J et al: A comparison of cabergoline and bromocriptine in the treatment of
hyperprolactinemic amenorrhea. N Engl J Med 1994;331:904.
C ASE STUDY ANSWER
While growth hormone (GH) may have some direct
growth-promoting effects, it is thought to mediate skeletal
growth principally through production of insulin-like
growth factor-I (IGF-I) at the epiphyseal plate, which acts
mainly in an autocrine/paracrine manner. IGF-I may also
promote statural growth through endocrine mechanisms.
The findings of small testes and a microphallus in this
patient suggest a diagnosis of hypogonadism, likely as a
consequence of gonadotropin deficiency. This patient is
Westhoff G, Cotter AM, Tolosa JE: Prophylactic oxytocin for the third stage of
labour to prevent postpartum haemorrhage. Cochrane Database Syst Rev
2013;(10):CD001808.
Wit JM et al: Idiopathic short stature: Definition, epidemiology, and diagnostic
evaluation. Growth Horm IGF Res 2008;18:89.
Youssef MA et al: Gonadotropin-releasing hormone agonist versus HCG for
oocyte triggering in antagonist assisted reproductive technology cycles.
Cochrane Database Syst Rev 2011;(1):CD008046.
at risk for multiple hypothalamic/pituitary deficiencies.
He may already have or may subsequently develop ACTH/
cortisol and TSH/thyroid hormone deficiencies and thus
may require supplementation with hydrocortisone and
levothyroxine, in addition to supplementation with GH
and testosterone. He should also be evaluated for the pres-
ence of central diabetes insipidus and, if present, treated
with desmopressin, a V2 vasopressin receptor–selective
analog.

Thyroid & Antithyroid
*
Drugs
Betty J. Dong, PharmD, FASHP, FCCP, FAPHA
C ASE STUDY
JP is a 33-year-old woman who presents with complaints of
fatigue requiring daytime naps, weight gain, cold intoler-
ance, and muscle weakness for the last few months. These
complaints are new since she used to always feel “hot,” noted
difficulty sleeping, and could eat anything that she wanted
without gaining weight. She also would like to become preg-
nant in the near future. Because of poor medication adherence
to methimazole and propranolol, she received radioactive
iodine (RAI) therapy, developed hypothyroidism, and was
started on levothyroxine 100 mcg daily. Other medications
include calcium carbonate three times daily to “protect her
THYROID PHYSIOLOGY
The normal thyroid gland secretes sufficient amounts of the thyroid
hormones—triiodothyronine (T3) and tetraiodothyronine (T4,
thyroxine)—to normalize growth and development, body tem-
perature, and energy levels. These hormones contain 59% and
65% (respectively) of iodine as an essential part of the molecule.
Calcitonin, the second type of thyroid hormone, is important in the
regulation of calcium metabolism and is discussed in Chapter 42.
Iodide Metabolism
The recommended daily adult iodide (I−)† intake is 150 mcg (200 mcg
during pregnancy and lactation and up to 250 mcg for children).
*
This chapter is dedicated to Dr. Francis S. Greenspan, co-author,
mentor, colleague, and friend who will be sorely missed by his many
colleagues and by his patients for his kindness, generosity, and
expert care as chief of the Thyroid Clinic at UCSF.
†
In this chapter, the term “iodine” denotes all forms of the element; the
term “iodide” denotes only the ionic form, I−
38
C H A P T E R
bones” and omeprazole for “heartburn.” On physical exami-
nation, her blood pressure is 130/89 mm Hg with a pulse of
50 bpm. Her weight is 136 lb (61.8 kg), an increase of 10 lb
(4.5 kg) in the last year. Her thyroid gland is not palpable
and her reflexes are delayed. Laboratory findings include a
thyroid-stimulating hormone (TSH) level of 24.9 μIU/mL
(normal 0.45–4.12 μIU/mL) and a free thyroxine level of
8 pmol/L (normal 10–18 pmol/L). Evaluate the management
of her past history of hyperthyroidism and assess her current
thyroid status. Identify your treatment recommendations to
maximize control of her current thyroid status.
Iodide, ingested from food, water, or medication, is rapidly
absorbed and enters an extracellular fluid pool. The thyroid gland
removes about 75 mcg a day from this pool for hormone synthesis,
and the balance is excreted in the urine. If iodide intake is increased,
the fractional iodine uptake by the thyroid is diminished.
Biosynthesis of Thyroid Hormones
Once taken up by the thyroid gland, iodide undergoes a series
of enzymatic reactions that incorporate it into active thyroid
hormone (Figure 38–1). The first step is the transport of iodide
into the thyroid gland by an intrinsic follicle cell basement mem-
brane protein called the sodium/iodide symporter (NIS). This can
be inhibited by large doses of iodides as well as anions (eg, thiocya-
nate (SCN−), pertechnetate (TcO4 ), and perchlorate (CIO4 ). At
− −
−
the apical cell membrane a second I transport enzyme called pen-
drin controls the flow of iodide across the membrane. Pendrin is
also found in the cochlea of the inner ear. If pendrin is deficient or
absent (SLC26A4 mutation), a hereditary syndrome of goiter and
deafness, called Pendred syndrome (PDS), ensues. At the apical
687
688    SECTION VII  Endocrine Drugs

Thyroid gland

Transport Thyroglobulin
Peroxidase Organification
− −
I I I° MIT-DIT- T3-T4
Iodides
–
–
– Proteolysis
Iodides,
thioamides
SCN–, ClO4 –

T4, T3
Peripheral Blood
tissues
T4, T3
Radiocontrast
media,
–
β-blockers,
corticosteroids,
amiodarone
T3

FIGURE 38–1  Biosynthesis of thyroid hormones. The sites of action of various drugs that interfere with thyroid hormone biosynthesis are shown.

cell membrane, iodide is oxidized by thyroidal peroxidase (TPO)
to iodine, in which form it rapidly iodinates tyrosine residues
within the thyroglobulin molecule to form monoiodotyrosine
(MIT) and diiodotyrosine (DIT). This process is called iodide
organification. Thyroidal peroxidase is transiently blocked by
high levels of intrathyroidal iodide and blocked more persistently
by thioamide drugs. Gene expression of TPO is stimulated by
thyroid-stimulating hormone (TSH).
Two molecules of DIT combine within the thyroglobulin
molecule to form l-thyroxine (T4). One molecule of MIT and
one molecule of DIT combine to form T3. In addition to thyro-
globulin, other proteins within the gland may be iodinated, but
these iodoproteins do not have hormonal activity. Thyroxine, T3,
MIT, and DIT are released from thyroglobulin by exocytosis and
proteolysis of thyroglobulin at the apical colloid border. The MIT
and DIT are then deiodinated within the gland, and the iodine is
reutilized. This process of proteolysis is also blocked by high levels
of intrathyroidal iodide. The ratio of T4 to T3 within thyroglobu-
lin is approximately 5:1, so that most of the hormone released is
thyroxine. Eighty percent of T3 circulating in the blood is derived
from peripheral metabolism of thyroxine and the rest from direct
thyroid secretion (see below, Figure 38–2).
Transport of Thyroid Hormones
Thyroxine and T3 in plasma are reversibly bound to protein, pri-
marily thyroxine-binding globulin (TBG). Only about 0.04% of
total T4 and 0.4% of T3 exist in the free form (as FT4 and FT3).
Many physiologic and pathologic states and drugs affect T4, T3,
and thyroid transport. However, the actual levels of free hormone
generally remain normal, reflecting feedback control.
Peripheral Metabolism of Thyroid Hormones
The primary pathway for the peripheral metabolism of thyroxine
is deiodination by three 5′deiodinase enzymes (D1, D2, D3).
Deiodination of T4 may occur by monodeiodination of the outer
ring, producing 3,5,3′-triiodothyronine (T3), which is three to
four times more potent than T4. The D1 enzyme is responsible
for about 24% of the circulating T3 while 64% of peripheral T3
is generated by D2, which also regulates T3 levels in the brain
and pituitary. D3 deiodination produces metabolically inactive
3,3′,5′-triiodothyronine (reverse T3 [rT3]), (Figure 38–2). The
low serum levels of T3 and rT3 in normal individuals are due to
the high metabolic clearances of these two compounds.
Drugs such as amiodarone, iodinated contrast media, β block-
ers, and corticosteroids, as well as severe illness or starvation,
inhibit the 5′-deiodinase necessary for the conversion of T4 to T3,
resulting in low T3 and high rT3 levels in the serum. A polymor-
phism in the D2 gene can reduce T3 activation and impair thyroid
hormone response. The pharmacokinetics of thyroid hormones
are listed in Table 38–1.
Evaluation of Thyroid Function
The tests used to evaluate thyroid function are listed in Table 38–2.
 CHAPTER 38  Thyroid & Antithyroid Drugs    689

I I INACTIVATION
NH2
Deamination
HO O CH2 CH Decarboxylation
Conjugation
COOH (glucuronide or
I I sulfate)
Thyroxine

Deiodination
Activation Inactivation

I I
NH2 NH2

HO O CH2 CH HO O CH2 CH

COOH COOH
I I I I
3,5,3′-Triiodothyronine 3,3′,5′-Triiodothyronine
(T3) (reverse T3)

FIGURE 38–2  Peripheral metabolism of thyroxine. (Adapted, with permission, from Gardner DG, Shoback D [editors]: Greenspan’s Basic & Clinical Endocrinology,
8th ed. McGraw-Hill, 2007. Copyright © The McGraw-Hill Companies, Inc.)

A. Thyroid-Pituitary Relationships inhibit the synthesis and secretion of TRH. Other hormones or
Control of thyroid function via thyroid-pituitary feedback is also drugs may also affect the release of TRH or TSH.
discussed in Chapter 37. Hypothalamic cells secrete thyrotropin-
releasing hormone (TRH) (Figure 38–3). TRH is secreted into B. Autoregulation of the Thyroid Gland
capillaries of the pituitary portal venous system, and in the pitu- The thyroid gland also regulates its uptake of iodide and thyroid
itary gland, TRH stimulates the synthesis and release of thyrotro- hormone synthesis by intrathyroidal mechanisms that are inde-
pin (thyroid-stimulating hormone, TSH). TSH in turn stimulates pendent of TSH. These mechanisms are primarily related to the
an adenylyl cyclase–mediated mechanism in the thyroid cell to level of iodine in the blood. Large doses of iodine inhibit iodide
increase the synthesis and release of T4 and T3. T3, the more active organification (Wolff-Chaikoff block; see Figure 38–1). In certain
of the two hormones, acts in a negative feedback fashion in the disease states (eg, Hashimoto’s thyroiditis), this can inhibit thyroid
pituitary to block the action of TSH and in the hypothalamus to hormone synthesis and result in hypothyroidism. Hyperthyroid-
ism can result from the loss of the Wolff-Chaikoff block in suscep-
tible individuals (eg, multinodular goiter).
TABLE 38–1  Summary of thyroid hormone kinetics. C. Abnormal Thyroid Stimulators
Variable T4 T3 In Graves’ disease (see below), lymphocytes secrete a TSH
receptor–stimulating antibody (TSH-R Ab [stim]), also known as
Volume of distribution 10 L 40 L
thyroid-stimulating immunoglobulin (TSI). This immunoglobu-
Extrathyroidal pool 800 mcg 54 mcg lin binds to the TSH receptor and stimulates the gland in the same
Daily production 75 mcg 25 mcg fashion as TSH itself. The duration of its effect, however, is much
Fractional turnover 10% 60% longer than that of TSH. TSH receptors are also found in orbital
per day fibrocytes, which may be stimulated by high levels of TSH-R
Metabolic clearance 1.1 L 24 L Ab [stim] and can cause ophthalmopathy.
per day
Half-life (biologic) 7 days 1 day
Serum levels
■■ BASIC PHARMACOLOGY OF
 Total 4.8–10.4 mcg/dL 60–181 ng/dL THYROID & ANTITHYROID DRUGS
(62–134 nmol/L) (0.92–2.79 nmol/L)
 Free 0.8–2.7 ng/dL 230–420 pg/dL
THYROID HORMONES
(10.3–34.7 pmol/L) (3.5–6.47 pmol/L)
Chemistry
Amount bound 99.96% 99.6%
The structural formulas of thyroxine and triiodothyronine as
Biologic potency 1 4
well as reverse triiodothyronine (rT3) are shown in Figure 38–2.
Oral absorption 70% 95%
All of these naturally occurring molecules are levo (l) isomers.
690    SECTION VII  Endocrine Drugs

TABLE 38–2  Typical adult values for thyroid function tests.

Name of Test Normal Value1 Results in Hypothyroidism Results in Hyperthyroidism

Total thyroxine (T4) 4.8–10.4 mcg/dL (62–134 nmol/L) Low High

Total triiodothyronine (T3) 59–156 ng/dL Normal or low High
  (0.9–2.4 nmol/L)    
Free T4 (FT4) 0.8–1.4 ng/dL (10–18 pmol/L) Low High
Free T3 (FT3) 169–371 ng/dL (2.6–5.7 pmol/L) Low High
Thyrotropic hormone (TSH) 0.45–4.12 μIU/mL High2 Low
  (0.45–4.12 mIU/L)    
123
I uptake at 24 hours 5–35% Low High
Antithyroglobulin antibodies (Tg-Ab) <200 IU/mL Often present Usually present
Thyroperoxidase antibodies (ATPO) ≤100 WHO units Often present Usually present
123 99m
Isotope scan with I or TcO4 Normal pattern Test not indicated Diffusely enlarged gland
Fine-needle aspiration (FNA) biopsy Normal pattern Test not indicated Test not indicated
Serum thyroglobulin Women: 1.5–38.5 mcg/L Test not indicated Test not indicated
Men: 1.4–29.2 mcg/L
TSH receptor-stimulating antibody or Negative <140% of baseline Test not indicated Elevated in Graves’ disease
thyroid-stimulating immunoglobulin (TSI)
1
Results may vary with different laboratories.
2
Exception is central hypothyroidism.

The synthetic dextro (d) isomer of thyroxine, dextrothyroxine, is restored. Thus, the concentration of total and bound hormone
has approximately 4% of the biologic activity of the l-isomer as will increase, but the concentration of free hormone and the
evidenced by its lesser ability to suppress TSH secretion and cor- steady-state elimination will remain normal. The reverse occurs
rect hypothyroidism. when thyroid binding sites are decreased.

Pharmacokinetics Mechanism of Action

Thyroxine is absorbed best in the duodenum and ileum; absorp-
tion is modified by intraluminal factors such as food, drugs,
gastric acidity, and intestinal flora. Oral bioavailability of current
preparations of l-thyroxine averages 70 to 80% (Table 38–1).
In contrast, T3 is almost completely absorbed (95%). T4 and T3
absorption appears not to be affected by mild hypothyroidism but
may be impaired in severe myxedema with ileus. These factors are
important in switching from oral to parenteral therapy. For par-
enteral use, the intravenous route is preferred for both hormones.
In patients with hyperthyroidism, the metabolic clearances of
T4 and T3 are increased and the half-lives decreased; the opposite
is true in patients with hypothyroidism. Drugs that induce hepatic
microsomal enzymes (eg, rifampin, phenobarbital, carbamaze-
pine, phenytoin, tyrosine kinase inhibitors, HIV protease inhibi-
tors) increase the metabolism of both T4 and T3 (Table 38–3).
Despite this change in clearance, the normal hormone concentra-
tion is maintained in the majority of euthyroid patients as a result
of compensatory hyperfunction of the thyroid. However, patients
dependent on T4 replacement medication may require increased
dosages to maintain clinical effectiveness. A similar compensation
occurs if binding sites are altered. If TBG sites are increased by
pregnancy, estrogens, or oral contraceptives, there is an initial shift
of hormone from the free to the bound state and a decrease in its
rate of elimination until the normal free hormone concentration
A model of thyroid hormone action is depicted in Figure 38–4,
which shows the free forms of thyroid hormones, T4 and T3,
dissociated from thyroid-binding proteins, entering the cell
by the active transporters (eg, monocarboxylate transporter
8 [MCT8], MCT10, and organic anion transporting polypep-
tide [OATP1C1]). Transporter mutations can result in a clinical
syndrome of mental retardation, myopathy, and low serum T4
levels (Allan-Herndon-Dudley syndrome). Within the cell, T4 is
converted to T3 by 5′-deiodinase, and the T3 enters the nucleus,
where T3 binds to a specific T3 thyroid receptor protein, a member
of the c-erb oncogene family. (This family also includes the steroid
hormone receptors and receptors for vitamins A and D.) The T3
receptor exists in two forms, α and β. Mutations in both α and
β genes have been associated with generalized thyroid hormone
resistance. Cigarette smoking and environmental agents (eg, poly-
chlorinated biphenyls) also may interfere with receptor action.
Differing concentrations of receptor forms in different tissues may
account for variations in T3 effect on these tissues.
Most of the effects of thyroid on metabolic processes appear
to be mediated by activation of nuclear receptors that lead to
increased formation of RNA and subsequent protein synthesis, eg,
increased formation of Na+/K+-ATPase. This is consistent with
the observation that the action of thyroid is manifested in vivo
with a time lag of hours or days after its administration.

Acute Circadian and
psychosis pulsatile rhythms
+ + Severe
Cold stress
+ –
H
Hypothalamus
Somato-
+ – statin Corticoids
– or
TRH
dopamine
– Many of the manifestations of thyroid hyperactivity resemble
AP
T4,T3
–
TSH +
+ retraction, tremor, excessive sweating, anxiety, and nervousness.
Thyroid
– I–
FIGURE 38–3  The hypothalamic-pituitary-thyroid axis. Acute
psychosis or prolonged exposure to cold may activate the axis.
Hypothalamic thyroid-releasing hormone (TRH) stimulates pituitary
thyroid-stimulating hormone (TSH) release, while somatostatin and
dopamine inhibit it. TSH stimulates T4 and T3 synthesis and release
from the thyroid, and they in turn inhibit both TRH and TSH synthesis
and release. Small amounts of iodide are necessary for hormone
production, but large amounts inhibit T3 and T4 production and
release. Solid arrows, stimulatory influence; dashed arrows,
inhibitory influence. H, hypothalamus; AP, anterior pituitary.
Large numbers of thyroid hormone receptors are found in the
most hormone-responsive tissues (pituitary, liver, kidney, heart,
skeletal muscle, lung, and intestine), while few receptor sites occur
in hormone-unresponsive tissues (spleen, testes). The brain, which
lacks an anabolic response to T3, contains an intermediate number
of receptors. In congruence with their biologic potencies, the affin-
ity of the receptor site for T4 is about ten times lower than that for
T3. Under some conditions, the number of nuclear receptors may
be altered to preserve body homeostasis. For example, starvation
lowers both circulating T3 hormone and cellular T3 receptors.
Effects of Thyroid Hormones
The thyroid hormones are responsible for optimal growth, devel-
opment, function, and maintenance of all body tissues. Excess or
inadequate amounts result in the signs and symptoms of hyper-
thyroidism or hypothyroidism, respectively (Table 38–4). Since
T3 and T4 are qualitatively similar, they may be considered as one
hormone in the discussion that follows.
CHAPTER 38  Thyroid & Antithyroid Drugs    691
Thyroid hormone is critical for the development and func-
tioning of nervous, skeletal, and reproductive tissues. Its effects
depend on protein synthesis as well as potentiation of the secretion
and action of growth hormone. Thyroid deprivation in early life
results in irreversible mental retardation and dwarfism—typical of
congenital cretinism.
Effects on growth and calorigenesis are accompanied by a per-
vasive influence on metabolism of drugs as well as carbohydrates,
fats, proteins, and vitamins. Many of these changes are dependent
upon or modified by activity of other hormones. Conversely, the
secretion and degradation rates of virtually all other hormones,
including catecholamines, cortisol, estrogens, testosterone, and
insulin, are affected by thyroid status.
sympathetic nervous system overactivity (especially in the cardio-
vascular system), although catecholamine levels are not increased.
Changes in catecholamine-stimulated adenylyl cyclase activity
as measured by cAMP are found with changes in thyroid activ-
ity. Thyroid hormone increases the numbers of β receptors and
enhances amplification of the β-receptor signal. Other clinical
symptoms reminiscent of excessive epinephrine activity (and par-
tially alleviated by adrenoceptor antagonists) include lid lag and
The opposite constellation of effects is seen in hypothyroidism
(Table 38–4).
Thyroid Preparations
See the Preparations Available section at the end of this chapter
for a list of available preparations. These preparations may be
synthetic (levothyroxine, liothyronine, liotrix) or of animal origin
(desiccated thyroid).
Thyroid hormones are not effective and can be detrimental in
the management of obesity, abnormal vaginal bleeding, or depres-
sion if thyroid hormone levels are normal. Recent meta-analysis of
T3 co-administered with antidepressants showed some depression
benefits, but the results were inconclusive and further confirma-
tion for its optimal use is required.
Synthetic levothyroxine is the preparation of choice for thyroid
replacement and suppression therapy because of its stability,
content uniformity, low cost, lack of allergenic foreign protein,
easy laboratory measurement of serum levels, and long half-life
(7 days), which permits once-daily to weekly administration.
In addition, T4 is converted to T3 intracellularly; thus, admin-
istration of T4 produces both hormones and T3 administra-
tion is unnecessary. Generic levothyroxine preparations provide
comparable efficacy and are more cost-effective than branded
preparations, It is preferable that patients remain on a consistent
levothyroxine preparation between refills to avoid changes in bio-
availability. A branded soft gel capsule (Tirosint) had faster, more
complete dissolution and was less affected by gastric pH or coffee
than a tablet formulation.
Although liothyronine (T3) is three to four times more potent
than levothyroxine, it is not recommended for routine replace-
ment therapy because of its shorter half-life (24 hours), requiring
multiple daily doses, and difficulty in monitoring its adequacy of
692    SECTION VII  Endocrine Drugs

TABLE 38–3  Drug effects and thyroid function.

Drug Effect Drugs

Change in thyroid hormone synthesis

 Inhibition of TRH or TSH secretion without induction of Bexarotene, dopamine, bromocriptine, cabergoline, levodopa, corticosteroids,
hypothyroidism or hyperthyroidism somatostatin, octreotide, metformin, interleukin-6, heroin
 Inhibition of thyroid hormone synthesis or release Iodides (including amiodarone), lithium, aminoglutethimide, thioamides, ethionamide,
with the induction of hypothyroidism (or occasionally tyrosine kinase inhibitors (eg, sunitinib, sorafenib, imatinib), HIV protease inhibitors
hyperthyroidism)
Alteration of thyroid hormone transport and serum total T3 and T4 levels, but usually no modification of FT4 or TSH
  Increased TBG Estrogens, tamoxifen, raloxifene, heroin, methadone, mitotane, 5-fluorouracil,
perphenazine
  Decreased TBG Androgens, anabolic steroids, glucocorticoids, danazol, l-asparaginase, nicotinic acid
 Displacement of T3 and T4 from TBG with transient Salicylates, fenclofenac, mefenamic acid, intravenous furosemide, heparin
hyperthyroxinemia
Alteration of T4 and T3 metabolism with modified serum T3 and T4 levels but not TSH levels (unless receiving thyroxine replacement therapy)
 Increased hepatic metabolism, enhanced degradation Nicardipine, phenytoin, carbamazepine, primidone, phenobarbital, rifampin, rifabutin,
of thyroid hormone tyrosine kinase inhibitors (eg, sunitinib, sorafenib, imatinib), sertraline, quetiapine
 Inhibition of 5′-deiodinase with decreased T3, Iopanoic acid, ipodate, amiodarone, β blockers, corticosteroids, propylthiouracil,
increased rT3 flavonoids, interleukin-6
Other interactions
  Interference with T4 absorption from the gut Oral bisphosphonates, cholestyramine, colesevelam, colestipol, chromium picolinate,
charcoal, ciprofloxacin, proton pump inhibitors, sucralfate, Kayexalate, raloxifene,
sevelamer hydrochloride, aluminum hydroxide, ferrous sulfate, calcium carbonate,
bran/fiber, soy, coffee, orlistat
 Induction of autoimmune thyroid disease with Interferon-α, interleukin-2, interferon-β, lithium, amiodarone, tyrosine kinase inhibitors
hypothyroidism or hyperthyroidism (eg, sunitinib, sorafenib, imatinib)
Effect of thyroid function on drug effects
 Anticoagulation Lower doses of warfarin required in hyperthyroidism, higher doses in hypothyroidism
  Glucose control Increased hepatic glucose production and glucose intolerance in hyperthyroidism;
impaired insulin action and glucose disposal in hypothyroidism
  Cardiac drugs Higher doses of digoxin required in hyperthyroidism; lower doses in hypothyroidism
  Sedatives; analgesics Increased sedative and respiratory depressant effects from sedatives and opioids in
hypothyroidism; converse in hyperthyroidism

replacement by conventional laboratory tests. T3 should also be
avoided in patients with cardiac disease due to significant eleva-
tions in peak levels and a greater risk of cardiotoxicity. Using the
more expensive thyroxine and liothyronine fixed-dose combina-
tion (liotrix) and desiccated thyroid has not been shown to be
more effective than T4 administration alone. T3 is best reserved
for short-term TSH suppression. Research is ongoing to clarify
whether T3 might be more appropriate in patients with a poly-
morphism in the D2 gene or in those who continue to report
fatigue, weight gain, and mental impairment while on T4 alone.
The use of desiccated thyroid rather than synthetic prepara-
tions is never justified, since the disadvantages of protein antige-
nicity, product instability, variable hormone concentrations, and
difficulty in laboratory monitoring far outweigh the advantage
of lower cost. Significant amounts of T3 found in some thyroid
extracts may produce significant elevations in T3 levels and
toxicity. Exact equi-effective doses have not been determined.
Approximate equivalence of desiccated thyroid 60 mg (1 gr) to
80 to 100 mcg of levothyroxine, and approximately 37.5 mcg of
liothyronine has been reported. Any dosage conversions should be
re-titrated based on laboratory and clinical response.
The shelf life of synthetic hormone preparations is about
2 years, particularly if they are stored in dark bottles to minimize
spontaneous deiodination. The shelf life of desiccated thyroid is
not known with certainty, but its potency is better preserved if it
is kept dry.
ANTITHYROID AGENTS
Reduction of thyroid activity and hormone effects can be
accomplished by agents that interfere with the production of
thyroid hormones, by agents that modify the tissue response to
thyroid hormones, or by glandular destruction with radiation
or surgery. Goitrogens are agents that suppress secretion of T3
and T4 to subnormal levels and thereby increase TSH, which in
turn produces glandular enlargement (goiter). The antithyroid
compounds used clinically include the thioamides, iodides, and
radioactive iodine.
 CHAPTER 38  Thyroid & Antithyroid Drugs    693

Nucleus

Coactivator
Corepressor

TR-LBD TR-LBD

TR-DBD TR-DBD

TRE

Cytoplasm
TBPs

T4 T3

B
Corepressor T4 T3

Coactivator T4

TR-LBD 5'Dl
RXR-LBD
TR-LBD T3

TR-DBD RXR-DBD TR-DBD

Transcription T3

TRE

FIGURE 38–4  Model of the interaction of T3 with the T3 receptor. A: Inactive phase—the unliganded T3 receptor dimer bound to the
thyroid hormone response element (TRE) along with corepressors acts as a suppressor of gene transcription. B: Active phase—T3 and T4
circulate bound to thyroid-binding proteins (TBPs). The free hormones are transported into the cell by a specific transport system. Within
the cytoplasm, T4 is converted to T3 by 5′-deiodinase (5′DI); T3 then moves into the nucleus. There it binds to the ligand-binding domain of
the thyroid receptor (TR) monomer. This promotes disruption of the TR homodimer and heterodimerization with retinoid X receptor (RXR)
on the TRE, displacement of corepressors, and binding of coactivators. The TR-coactivator complex activates gene transcription, which leads
to alteration in protein synthesis and cellular phenotype. TR-LBD, T3 receptor ligand-binding domain; TR-DBD, T3 receptor DNA-binding
domain; RXR-LBD, retinoid X receptor ligand-binding domain; RXR-DBD, retinoid X receptor DNA-binding domain; T3, triiodothyronine; T4,
tetraiodothyronine, l-thyroxine. (Adapted, with permission, from Gardner DG, Shoback D [editors]: Greenspan’s Basic & Clinical Endocrinology, 8th ed. McGraw-Hill,
2007. Copyright © The McGraw-Hill Companies, Inc.)

THIOAMIDES methimazole (other than agranulocytosis or hepatitis). The chemical

The thioamides methimazole and propylthiouracil are major
drugs for treatment of thyrotoxicosis. In the United Kingdom,
carbimazole, which is converted to methimazole in vivo, is widely
used. Methimazole is about ten times more potent than propyl-
thiouracil and is the drug of choice in adults and children. Due
to a black box warning about severe hepatitis, propylthiouracil
should be reserved for use during the first trimester of pregnancy,
in thyroid storm, and in those experiencing adverse reactions to
structures of these compounds are shown in Figure 38–5. The
thiocarbamide group is essential for antithyroid activity.
Pharmacokinetics
Methimazole is completely absorbed but at variable rates. It is readily
accumulated by the thyroid gland and has a volume of distribution
similar to that of propylthiouracil. Excretion is slower than with pro-
pylthiouracil; 65–70% of a dose is recovered in the urine in 48 hours.
694    SECTION VII  Endocrine Drugs

TABLE 38–4  Manifestations of thyrotoxicosis and hypothyroidism.

System Thyrotoxicosis Hypothyroidism

Skin and appendages
Eyes, face
Cardiovascular system
Respiratory system
Gastrointestinal system
Central nervous system
Musculoskeletal system
Renal system
Hematopoietic system
Reproductive system
Metabolic system
1
The anemia of hyperthyroidism is usually normochromic and caused by increased red blood cell turnover. The anemia of hypothyroidism may be normochromic, hyperchromic,
or hypochromic and may be due to decreased production rate, decreased iron absorption, decreased folic acid absorption, or to autoimmune pernicious anemia. LDH, lactic
dehydrogenase; AST, aspartate aminotransferase.
Warm, moist skin; sweating; heat intolerance; fine,
thin hair; Plummer’s nails; pretibial dermopathy
(Graves’ disease)
Retraction of upper lid with wide stare; periorbital
edema; exophthalmos; diplopia (Graves’ disease)
Decreased peripheral vascular resistance; increased
heart rate, stroke volume, cardiac output, pulse pres-
sure; high-output heart failure; increased inotropic
and chronotropic effects; arrhythmias; angina
Dyspnea; hypoventilation; decreased vital capacity
Increased appetite; increased frequency of bowel
movements; hypoproteinemia
Nervousness; hyperkinesia; emotional lability,
agitation
Weakness and muscle fatigue; increased deep tendon
reflexes; tremors; hypercalcemia; osteoporosis
Mild polyuria; increased renal blood flow; increased
glomerular filtration rate
Increased erythropoiesis; anemia1
Menstrual irregularities; amenorrhea; infertility;
increased gonadal steroid metabolism
Increased basal metabolic rate; negative nitrogen
balance; hyperglycemia; increased free fatty acids;
decreased total cholesterol and triglycerides;
increased hormone degradation; increased require-
ments for fat- and water-soluble vitamins; increased
drug metabolism; decreased warfarin requirement
Pale, cool, puffy, yellowish skin, face, and hands; dry and
brittle hair; brittle nails
Drooping of eyelids; periorbital edema; loss of temporal
aspects of eyebrows; puffy, nonpitting facies; large tongue,
hoarseness
Increased peripheral vascular resistance; decreased heart
rate, stroke volume, cardiac output, pulse pressure; low-
output heart failure; ECG: bradycardia, prolonged PR interval,
flat T wave, low voltage; pericardial effusion
Pleural effusions; hypoventilation and CO2 retention; sleep
apnea
Decreased appetite; decreased frequency of bowel
movements, constipation; ascites
Lethargy/fatigue; general slowing of mental processes;
neuropathies; weakness and muscle cramps
Stiffness and muscle fatigue; carpal tunnel syndrome;
decreased deep tendon reflexes; increased alkaline
phosphatase, LDH, AST
Impaired water excretion; decreased renal blood flow;
decreased glomerular filtration rate
Decreased erythropoiesis; anemia1
Menorrhagia; infertility; decreased libido; impotence;
oligospermia; decreased gonadal steroid metabolism
Decreased basal metabolic rate; slight positive nitrogen
balance; delayed degradation of insulin with increased
sensitivity; increased total cholesterol and triglycerides;
hyponatremia; decreased hormone degradation; decreased
requirements for fat- and water-soluble vitamins; decreased
drug metabolism; increased warfarin requirement

In contrast, propylthiouracil is rapidly absorbed, reaching peak

serum levels after 1 hour. The bioavailability of 50–80% may be
H O H
N N due to incomplete absorption or a large first-pass effect in the liver.
The volume of distribution approximates total body water with
S S accumulation in the thyroid gland. Most of an ingested dose of
N N propylthiouracil is excreted by the kidney as the inactive glucuro-
H C3H7 nide within 24 hours.
CH3 The short plasma half-life of these agents (1.5 hours for pro-
Propylthiouracil Methimazole pylthiouracil and 6 hours for methimazole) has little influence
O on the duration of the antithyroid action or the dosing interval
C O C2H5 because both agents are accumulated by the thyroid gland. For
propylthiouracil, giving the drug every 6–8 hours is reasonable
N
since a single 100 mg dose can inhibit iodine organification by
S 60% for 7 hours. Since a single 30 mg dose of methimazole exerts
an antithyroid effect for longer than 24 hours, a single daily dose
N
is effective in the management of mild to severe hyperthyroidism.
CH3 Both thioamides cross the placental barrier and are concen-
Carbimazole trated by the fetal thyroid, so that caution must be employed
when using these drugs in pregnancy. Because of the risk of fetal
FIGURE 38–5  Structure of thioamides. The thiocarbamide hypothyroidism, both thioamides are classified as FDA pregnancy
moiety is shaded in color. category D (evidence of human fetal risk based on adverse reaction

data from investigational or marketing experience, see Chapter 59).
Of the two, propylthiouracil is preferable during the first trimester
of pregnancy because it is more strongly protein-bound and, there-
fore, crosses the placenta less readily. In addition, methimazole has
been, albeit rarely, associated with congenital malformations. Both
thioamides are secreted in low concentrations in breast milk but
are considered safe for the nursing infant.
Pharmacodynamics
The thioamides act by multiple mechanisms. The major action
is to prevent hormone synthesis by inhibiting the thyroid
peroxidase-catalyzed reactions and blocking iodine organifica-
tion. In addition, they block coupling of the iodotyrosines. They
do not block uptake of iodide by the gland. Propylthiouracil but
not methimazole also inhibits the peripheral deiodination of T4
and T3 (Figure 38–1). Since the synthesis rather than the release
of hormones is affected, the onset of these agents is slow, often
requiring 3–4 weeks before stores of T4 are depleted.
Toxicity
Adverse reactions to the thioamides occur in 3–12% of treated
patients. Most reactions occur early, especially nausea and gas-
trointestinal distress. An altered sense of taste or smell may
occur with methimazole. The most common adverse effect is
a maculopapular pruritic rash (4–6%), at times accompanied
by systemic signs such as fever. Rare adverse effects include an
urticarial rash, vasculitis, a lupus-like reaction, lymphadenopathy,
hypoprothrombinemia, exfoliative dermatitis, polyserositis, and
acute arthralgia. An increased risk of severe hepatitis, sometimes
resulting in death, has been reported with propylthiouracil (black
box warning), so it should be avoided in children and adults
unless no other options are available. Cholestatic jaundice is more
common with methimazole than propylthiouracil. Asymptomatic
elevations in transaminase levels can also occur.
The most dangerous complication is agranulocytosis (granulo-
cyte count < 500 cells/mm3), an infrequent but potentially fatal
adverse reaction. It occurs in 0.1–0.5% of patients taking thio-
amides, but the risk may be increased in older patients and usually
within the first 90 days in those receiving more than 40 mg/d
of methimazole. The reaction is usually rapidly reversible when
the drug is discontinued, but broad-spectrum antibiotic therapy
may be necessary for complicating infections. Colony-stimulating
factors (eg, G-CSF; see Chapter 33) may hasten recovery of the
granulocytes. The cross-sensitivity between propylthiouracil and
methimazole is about 50%; therefore, switching drugs in patients
with severe reactions is not recommended.
ANION INHIBITORS
−
Monovalent anions such as perchlorate (ClO4 ), pertechnetate
(TcO4 ), and thiocyanate (SCN−) can block uptake of iodide by
−
the gland through competitive inhibition of the iodide transport
mechanism. Since these effects can be overcome by large doses of
iodides, their effectiveness is somewhat unpredictable.
CHAPTER 38  Thyroid & Antithyroid Drugs    695
The major clinical use for potassium perchlorate is to block
thyroidal reuptake of I− in patients with iodide-induced hyper-
thyroidism (eg, amiodarone-induced hyperthyroidism). How-
ever, potassium perchlorate is rarely used clinically because it is
associated with aplastic anemia.
IODIDES
Prior to the introduction of the thioamides in the 1940s, iodides
were the major antithyroid agents; today they are rarely used as
sole therapy.
Pharmacodynamics
Iodides have several actions on the thyroid. They inhibit organifi-
cation and hormone release and decrease the size and vascularity
of the hyperplastic gland. In susceptible individuals, iodides can
induce hyperthyroidism (Jod-Basedow phenomenon) or precipi-
tate hypothyroidism.
In pharmacologic doses (>6 mg/d), the major action of iodides
is to inhibit hormone release, possibly through inhibition of
thyroglobulin proteolysis. Improvement in thyrotoxic symptoms
occurs rapidly—within 2–7 days—hence the value of iodide
therapy in thyroid storm. In addition, iodides decrease the vascu-
larity, size, and fragility of a hyperplastic gland, making the drugs
valuable as preoperative preparation for surgery.
Clinical Use of Iodide
Disadvantages of iodide therapy include an increase in intraglandu-
lar stores of iodine, which may delay onset of thioamide therapy or
prevent use of radioactive iodine therapy for several weeks. Thus,
iodides should be initiated after onset of thioamide therapy and
avoided if treatment with radioactive iodine seems likely. Iodide
should not be used alone, because the gland will escape from the
iodide block in 2–8 weeks, and its withdrawal may produce severe
exacerbation of thyrotoxicosis in an iodine-enriched gland. Chronic
use of iodides in pregnancy should be avoided, since they cross
the placenta and can cause fetal goiter. In radiation emergencies
involving release of radioactive iodine isotopes, the thyroid-blocking
effects of potassium iodide can protect the gland from subsequent
damage if administered before radiation exposure.
Toxicity
Adverse reactions to iodine (iodism) are uncommon and in most
cases reversible upon discontinuance. They include acneiform rash
(similar to that of bromism), swollen salivary glands, mucous mem-
brane ulcerations, conjunctivitis, rhinorrhea, drug fever, metallic
taste, bleeding disorders, and rarely, anaphylactoid reactions.
RADIOACTIVE IODINE
131
I is the only isotope used for treatment of thyrotoxicosis.
(Others are used in diagnosis.) Administered orally in solution as
sodium 131I, it is rapidly absorbed, concentrated by the thyroid,
696    SECTION VII  Endocrine Drugs
and incorporated into storage follicles. Its therapeutic effect
depends on emission of β rays with an effective half-life of 5 days
and a penetration range of 400–2000 μm. Within a few weeks
after administration, destruction of the thyroid parenchyma is
evidenced by epithelial swelling and necrosis, follicular disrup-
tion, edema, and leukocyte infiltration. Advantages of radioio-
dine include easy administration, effectiveness, low expense, and
absence of pain. Fears of radiation-induced genetic damage, leuke-
mia, and neoplasia have not been realized after more than 50 years
of clinical experience with radioiodine therapy for hyperthyroid-
ism. Radioactive iodine should not be administered to pregnant
women or nursing mothers, since it crosses the placenta to destroy
the fetal thyroid gland and it is excreted in breast milk.
ADRENOCEPTOR-BLOCKING AGENTS
Beta blockers without intrinsic sympathomimetic activity (eg,
metoprolol, propranolol, atenolol) are effective therapeutic
adjuncts in the management of thyrotoxicosis since many of these
symptoms mimic those associated with sympathetic stimulation.
Propranolol has been the β blocker most widely studied and
used in the therapy of thyrotoxicosis. Beta blockers cause clinical
improvement of hyperthyroid symptoms but do not typically
alter thyroid hormone levels. Propranolol at doses greater than
160 mg/d may also reduce T3 levels approximately 20% by
inhibiting the peripheral conversion of T4 to T3.
■■ CLINICAL PHARMACOLOGY OF
THYROID & ANTITHYROID DRUGS
HYPOTHYROIDISM
Hypothyroidism is a syndrome resulting from deficiency of thy-
roid hormones and is manifested largely by a reversible slowing
down of all body functions (Table 38–4). In infants and children,
there is striking retardation of growth and development that
results in dwarfism and irreversible mental retardation.
TABLE 38–5  Etiology and pathogenesis of hypothyroidism.
Cause Pathogenesis
Hashimoto’s thyroiditis Autoimmune destruction of thyroid
1 2
Drug-induced Blocked hormone formation
Dyshormonogenesis Impaired synthesis of T4 due to enzyme
deficiency
131
Radiation, I, X-ray, Destruction or removal of gland
thyroidectomy
Congenital (cretinism) Athyreosis or ectopic thyroid, iodine defi-
ciency; TSH receptor-blocking antibodies
Secondary (TSH deficit) Pituitary or hypothalamic disease
1
Iodides, lithium, fluoride, thioamides, aminosalicylic acid, phenylbutazone, amiodarone, perchlorate, ethionamide, thiocyanate, cytokines (interferons, interleukins), bexarotene,
tyrosine kinase inhibitors, etc. See Table 38–3.
2
See Table 38–3 for specific pathogenesis.
The etiology and pathogenesis of hypothyroidism are outlined
in Table 38–5. Hypothyroidism can occur with or without thy-
roid enlargement (goiter). The laboratory diagnosis of hypothy-
roidism in the adult is easily made by the combination of low free
thyroxine and elevated serum TSH levels (Table 38–2).
The most common cause of hypothyroidism in the United
States at this time is probably Hashimoto’s thyroiditis, an immu-
nologic disorder in genetically predisposed individuals. In this
condition, there is evidence of humoral immunity in the presence
of antithyroid antibodies and lymphocyte sensitization to thyroid
antigens. Genetic mutations as discussed previously and certain
medications also can cause hypothyroidism (Table 38–5).
MANAGEMENT OF HYPOTHYROIDISM
Except for hypothyroidism caused by drugs, which can be
treated in some cases by simply removing the depressant agent,
the general strategy of replacement therapy is appropriate. The
most satisfactory preparation is levothyroxine, administered as
either a branded or generic preparation. Multiple trials have
documented that combination levothyroxine plus liothyronine
is not superior to levothyroxine alone although some patients
remain unwell on thyroxine alone. Genetic variations in deio-
dinases or hormone transporters may account for some of this
lack of efficacy.
There is some variability in the absorption of thyroxine;
dosage will also vary depending on age and weight. Infants and
children require more T4 per kilogram of body weight than
adults. The average dosage for an infant 1–6 months of age is
10–15 mcg/kg per day, whereas the average dosage for an adult
is about 1.7 mcg/kg per day (0.8 mcg/lb per day ) or 125 mcg/d.
Older adults (>65 years of age) may require less thyroxine
(1.6 mcg/kg per day or 0.7 mcg/lb per day ) for replacement as
body mass declines. In patients requiring suppression therapy
post-thyroidectomy for thyroid cancer, the average daily dosage of
T4 is 2.2 mcg/kg or 1 mcg/lb. Higher thyroxine requirements have
also been reported in patients with celiac disease and Helicobacter
pylori gastritis; thyroxine doses may be lower following treatment.
Goiter Degree of Hypothyroidism
Present early, absent later Mild to severe
Present Mild to moderate
Present Mild to severe
Absent Severe
Absent or present Severe
Absent Mild

Since interactions with certain foods (eg, bran, soy, coffee) and
drugs (Table 38–3) can impair its absorption, thyroxine should be
administered on an empty stomach (eg, 60 minutes before meals,
4 hours after meals, or at bedtime) to maintain TSH within an
optimal range of 0.5–2.5 mIU/L. Its long half-life of 7 days per-
mits once-daily dosing. Children should be monitored for normal
growth and development. Serum TSH and free thyroxine should
always be measured before a change in dosage to avoid transient
serum alterations. It takes 6–8 weeks after starting a given dose of
thyroxine to reach steady-state levels in the bloodstream. Thus,
dosage changes should be made slowly.
In younger patients or those with very mild disease, full
replacement therapy may be started immediately. In older patients
(>50 years) without cardiac disease, levothyroxine can be started
at a dosage of 50 mcg/d. In long-standing hypothyroidism and in
older patients with underlying cardiac disease, it is imperative to
start with reduced dosages of levothyroxine, 12.5–25 mcg/d for
2 weeks, before increasing by 12.5–25 mcg/d every 2 weeks until
euthyroidism or drug toxicity is observed. In cardiac patients, the
heart is very sensitive to the level of circulating thyroxine, and if
angina pectoris or cardiac arrhythmia develops, it is essential to
stop or reduce the thyroxine dosage immediately.
Thyroxine toxicity is directly related to the hormone level. In
children, restlessness, insomnia, and accelerated bone maturation
and growth may be signs of thyroxine toxicity. In adults, increased
nervousness, heat intolerance, episodes of palpitation and tachycar-
dia, or unexplained weight loss may be the presenting symptoms.
If these symptoms are present, it is important to monitor serum
TSH and FT4 levels (Table 38–2), which will determine whether
the symptoms are due to excess thyroxine blood levels. Chronic
overtreatment with T4, particularly in elderly patients, can increase
the risk of atrial fibrillation and accelerated osteoporosis.
Special Problems in Management of
Hypothyroidism
A. Myxedema and Coronary Artery Disease
Since myxedema frequently occurs in older persons, it is often
associated with underlying coronary artery disease. In this situa-
tion, the low levels of circulating thyroid hormone actually protect
the heart against increasing demands that could result in angina
pectoris, atrial fibrillation, or myocardial infarction. Correction
of myxedema must be done cautiously to avoid provoking these
cardiac events. If coronary artery surgery is indicated, it should
be done first, prior to correction of the myxedema by thyroxine
administration.
B. Myxedema Coma
Myxedema coma is an end state of untreated hypothyroidism.
It is associated with progressive weakness, stupor, hypothermia,
hypoventilation, hypoglycemia, hyponatremia, water intoxication,
shock, and death.
Myxedema coma is a medical emergency. The patient should
be treated in the intensive care unit, since tracheal intubation and
mechanical ventilation may be required. Associated illnesses such
as infection or heart failure must be treated by appropriate therapy.
CHAPTER 38  Thyroid & Antithyroid Drugs    697
It is important to give all preparations intravenously, because
patients with myxedema coma absorb drugs poorly from other
routes. Intravenous fluids should be administered with caution
to avoid excessive water intake. These patients have large pools of
empty T3 and T4 binding sites that must be filled before there is
adequate free thyroxine to affect tissue metabolism. Accordingly,
the treatment of choice in myxedema coma is to give a loading
dose of levothyroxine intravenously—usually 300–400 mcg ini-
tially, followed by 50–100 mcg daily. Intravenous T3 5–20 mcg
initially, followed by 2.5–10 mcg every 8 hours also can be added
but may be more cardiotoxic and more difficult to monitor. Lower
T4 and T3 doses should be considered for smaller or older patients,
or those with concomitant cardiac disease or arrhythmias. Intra-
venous hydrocortisone is indicated if the patient has associated
adrenal or pituitary insufficiency but is probably not necessary
in most patients with primary myxedema. Opioids and sedatives
must be used with extreme caution.
C. Hypothyroidism and Pregnancy
Hypothyroid women frequently have anovulatory cycles and are
therefore relatively infertile until restoration of the euthyroid state.
This has led to the widespread use of thyroid hormone for infer-
tility, although there is no evidence for its usefulness in infertile
euthyroid patients. In a pregnant hypothyroid patient receiving
thyroxine, it is extremely important that the daily dose of thy-
roxine be adequate because early development of the fetal brain
depends on maternal thyroxine. In many hypothyroid patients,
an increase in the thyroxine dose (about 25–30%) is required to
normalize the serum TSH level during pregnancy. It is reason-
able to counsel women to take one extra dose of their current
thyroxine tablet twice a week separated by several days as soon as
they are pregnant. Thyroxine should also be administered apart
from prenatal vitamins and calcium by at least 4 hours. Because
of the elevated maternal TBG levels and, therefore, elevated total
T4 levels, adequate maternal thyroxine dosages warrant mainte-
nance of TSH between 0.1 and 3.0 mIU/L (eg, first trimester,
0.1–2.5 mIU/L; second trimester, 0.2–3.0 mIU/L; third trimester,
0.3–3.0 mIU/L) and the total T4 at or above the upper range of
normal.
D. Subclinical Hypothyroidism
Subclinical hypothyroidism, defined as an elevated TSH level and
normal thyroid hormone levels, occurs in 4–10% of the general
population and increases to 20% in women older than age 50.
Levothyroxine should be individualized based on the risks and
benefits of treatment. The consensus of expert thyroid organiza-
tions concluded that thyroid hormone therapy should be consid-
ered for patients with TSH levels greater than 10 mIU/L while
close TSH monitoring is appropriate for those with lower TSH
elevations.
E. Drug-Induced Hypothyroidism
Drug-induced hypothyroidism (Table 38–3) can be satisfactorily
managed with levothyroxine therapy if the offending agent cannot
be stopped. In the case of amiodarone-induced hypothyroidism,
698    SECTION VII  Endocrine Drugs
levothyroxine therapy may be necessary even after discontinuance
because of amiodarone’s very long half-life.
HYPERTHYROIDISM
Hyperthyroidism (thyrotoxicosis) is the clinical syndrome that
results when tissues are exposed to high levels of thyroid hormone
(Table 38–4).
GRAVES’ DISEASE
The most common form of hyperthyroidism is Graves’ disease, or
diffuse toxic goiter. The presenting signs and symptoms of Graves’
disease are set forth in Table 38–4.
Pathophysiology
Graves’ disease is considered to be an autoimmune disorder in
which a defect in suppressor T lymphocytes stimulates B lym-
phocytes to synthesize antibodies (TSH-R Ab [stim]) to thyroidal
antigens. The TSH-R Ab [stim] is directed against the TSH
receptor in the thyroid cell membrane and stimulates growth and
biosynthetic activity of the thyroid cell. Genetics, the postpartum
state, cigarette smoking, and physical and emotional stress increase
TSH-R Ab [stim] development. A genetic predisposition is shown
by a high frequency of HLA-B8 and HLA-DR3 in Caucasians,
HLA-Bw46 and HLA-B5 in Chinese, and HLA-B17 in African
Americans. Spontaneous remission occurs but some patients
require years of antithyroid therapy.
Laboratory Diagnosis
In most patients with hyperthyroidism, T3, T4, FT4, and FT3 are
elevated and TSH is suppressed (Table 38–2). Radioiodine uptake
is usually markedly elevated as well. Antithyroglobulin, thyroid
peroxidase, and TSH-R Ab [stim] antibodies are usually present.
Management of Graves’ Disease
The three primary methods for controlling hyperthyroidism are
antithyroid drug therapy, destruction of the gland with radioactive
iodine, and surgical thyroidectomy. None of these methods alters
the underlying pathogenesis of the disease.
A. Antithyroid Drug Therapy
Drug therapy is most useful in young patients with small glands
and mild disease. Methimazole (preferred) or propylthiouracil
is administered until the disease undergoes spontaneous remis-
sion. This is the only therapy that leaves an intact thyroid gland,
but it does require a long period of treatment and observation
(12–18 months), and there is a 50–60% incidence of relapse.
Methimazole is preferable to propylthiouracil (except in preg-
nancy and thyroid storm) because it has a lower risk of serious liver
injury and can be administered once daily, which may improve
adherence. Antithyroid drug therapy is usually begun with divided
doses, shifting to maintenance therapy with single daily doses
when the patient becomes clinically euthyroid. However, mild
to moderately severe thyrotoxicosis can often be controlled with
methimazole given in a single morning dose of 20–40 mg initially
for 4–8 weeks to normalize hormone levels. Maintenance therapy
requires 5–15 mg once daily. Alternatively, therapy is started
with propylthiouracil, 100–150 mg every 6 or 8 hours until the
patient is euthyroid, followed by gradual reduction of the dose to
the maintenance level of 50–150 mg once daily. In addition to
inhibiting iodine organification, propylthiouracil also inhibits the
conversion of T4 to T3, so it brings the level of activated thyroid
hormone down more quickly than does methimazole. The best
clinical guide to remission is reduction in the size of the goiter.
Laboratory tests most useful in monitoring the course of therapy
are serum FT3, FT4, and TSH levels.
Reactions to antithyroid drugs have been described above.
A minor rash can often be controlled by antihistamine therapy.
Because the more severe reaction of agranulocytosis is often her-
alded by sore throat or high fever, patients receiving antithyroid
drugs must be instructed to discontinue the drug and seek imme-
diate medical attention if these symptoms develop. White cell and
differential counts and a throat culture are indicated in such cases,
followed by appropriate antibiotic therapy. Treatment should also
be stopped if significant elevations in transaminases (two to three
times the upper limit of normal) occur.
B. Thyroidectomy
A near-total thyroidectomy is the treatment of choice for patients
with very large glands or multinodular goiters. Patients are treated
with antithyroid drugs until euthyroid (about 6 weeks). In addi-
tion, for 10–14 days prior to surgery, they receive saturated
solution of potassium iodide, 5 drops twice daily, to diminish
vascularity of the gland and simplify surgery. About 80–90% of
patients will require thyroid supplementation following near-total
thyroidectomy.
C. Radioactive Iodine
Radioiodine therapy (RAI) utilizing 131I is the preferred treat-
ment for most patients over 21 years of age. In patients without
heart disease, the therapeutic dose may be given immediately in
a range of 80–120 μCi/g of estimated thyroid weight corrected
for uptake. In patients with underlying heart disease or severe
thyrotoxicosis and in elderly patients, it is desirable to treat with
antithyroid drugs (preferably methimazole) until the patient is
euthyroid. The medication is stopped for 2 to 3 days before RAI
is administered so as not to interfere with RAI retention but
can be restarted 3–5 days later, and then gradually tapered over
4–6 weeks as thyroid function normalizes. Iodides should be
avoided to ensure maximal 131I uptake. Six to 12 weeks following
the administration of RAI, the gland will shrink in size and the
patient will usually become euthyroid or hypothyroid. A second
dose may be required if there is minimal response 3 months post-
RAI. Hypothyroidism occurs in about 80% of patients following
RAI. Serum FT4 and TSH levels should be monitored regularly.
When hypothyroidism develops, prompt replacement with oral
levothyroxine, 50–150 mcg daily, should be instituted.

D. Adjuncts to Antithyroid Therapy
During the acute phase of thyrotoxicosis, β-adrenoceptor–blocking
agents without intrinsic sympathomimetic activity are appropriate
in symptomatic patients aged 60 years or more, in those with heart
rates greater than 90 beats/min, and in those with cardiovascular
disease. Propranolol, 20–40 mg orally every 6 hours, or metopro-
lol, 25–50 mg orally every 6–8 hours, will control tachycardia,
hypertension, and atrial fibrillation. Beta-adrenoceptor–blocking
agents are gradually withdrawn as serum thyroxine levels return
to normal. Diltiazem, 90–120 mg three or four times daily, can
be used to control tachycardia in patients in whom β blockers are
contraindicated, eg, those with asthma. Dihydropyridine calcium
channel blockers may not be as effective as diltiazem or vera-
pamil. Adequate nutrition and vitamin supplements are essential.
Barbiturates accelerate T4 breakdown (by hepatic enzyme induc-
tion) and may be helpful both as sedatives and to lower T4 levels.
Bile acid sequestrants (eg, cholestyramine) can also rapidly lower
T4 levels by increasing the fecal excretion of T4.
TOXIC UNINODULAR GOITER & TOXIC
MULTINODULAR GOITER
These forms of hyperthyroidism occur often in older women
with nodular goiters. Free thyroxine is moderately elevated or
occasionally normal, but FT3 or T3 is strikingly elevated. Single
toxic adenomas can be managed with either surgical excision of
the adenoma or with radioiodine therapy. Toxic multinodular
goiter is usually associated with a large goiter and is best treated
by preparation with methimazole (preferable) or propylthiouracil
followed by subtotal thyroidectomy.
SUBACUTE THYROIDITIS
During the acute phase of a viral infection of the thyroid
gland, there is destruction of thyroid parenchyma with transient
release of stored thyroid hormones. A similar state may occur in
patients with Hashimoto’s thyroiditis. These episodes of transient
thyrotoxicosis have been termed spontaneously resolving hyperthy-
roidism. Supportive therapy is usually all that is necessary, such
as β-adrenoceptor–blocking agents without intrinsic sympatho-
mimetic activity (eg, propranolol) for tachycardia and aspirin or
nonsteroidal anti-inflammatory drugs to control local pain and
fever. Corticosteroids may be necessary in severe cases to control
the inflammation.
SPECIAL PROBLEMS
Thyroid Storm
Thyroid storm, or thyrotoxic crisis, is sudden acute exacerba-
tion of all of the symptoms of thyrotoxicosis, presenting as a
life-threatening syndrome. Vigorous management is mandatory.
Propranolol, 60–80 mg orally every 4 hours, or intravenous pro-
pranolol, 1–2 mg slowly every 5–10 minutes to a total of 10 mg,
CHAPTER 38  Thyroid & Antithyroid Drugs    699
or esmolol, 50–100 mg/kg per min, is helpful to control the severe
cardiovascular manifestations. If β blockers are contraindicated by
the presence of severe heart failure or asthma, hypertension and
tachycardia may be controlled with diltiazem, 90–120 mg orally
three or four times daily or 5–10 mg/h by intravenous infusion
(asthmatic patients only). Release of thyroid hormones from the
gland is retarded by the administration of saturated solution of
potassium iodide, 5 drops orally every 6 hours starting 1 hour
after giving thioamides. Hormone synthesis is blocked by the
administration of propylthiouracil, 500–1000 mg as a loading
dose, followed by 250 mg orally every 4 hours. If the patient is
*
unable to take propylthiouracil by mouth, a rectal formulation
can be prepared and administered in a dosage of 400 mg every
6 hours as a retention enema. Methimazole may also be pre-
pared for rectal administration in a dose of 60–80 mg daily.
Hydrocortisone, 50 mg intravenously every 6 hours, will pro-
tect the patient against shock and will block the conversion of
T4 to T3, rapidly reducing the level of thyroactive material in
the blood.
Supportive therapy is essential to control fever, heart failure,
and any underlying disease process that may have precipitated the
acute storm. In rare situations, where the above methods are not
adequate to control the problem, oral bile acid sequestrants (eg,
cholestyramine), plasmapheresis, or peritoneal dialysis has been
used to lower the levels of circulating thyroxine.
Ophthalmopathy
Although severe ophthalmopathy is rare, it is difficult to treat. A
15–20% risk of aggravating severe eye disease may occur follow-
ing RAI, especially in those who smoke. Management requires
effective treatment of the thyroid disease, usually by total surgical
excision or 131I ablation of the gland plus oral prednisone therapy
(see below). In addition, local therapy may be necessary, eg,
elevation of the head to diminish periorbital edema and artificial
tears to relieve corneal drying due to exophthalmos. Smoking
cessation should be advised to prevent progression of the ophthal-
mopathy. For the severe, acute inflammatory reaction, prednisone,
60–100 mg orally daily for about a week and then 60–100 mg
every other day, tapering the dose over 6–12 weeks, may be effec-
tive. If steroid therapy fails or is contraindicated, irradiation
of the posterior orbit, using well-collimated high-energy X-ray
therapy, will frequently result in marked improvement of the
acute process. Threatened loss of vision is an indication for sur-
gical decompression of the orbit. Eyelid or eye muscle surgery
may be necessary to correct residual problems after the acute
process has subsided.
Dermopathy
Dermopathy or pretibial myxedema will often respond to topical
corticosteroids applied to the involved area and covered with an
occlusive dressing.
*
To prepare a water suspension propylthiouracil enema, grind eight
50-mg tablets and suspend the powder in 90 mL of sterile water.
700    SECTION VII  Endocrine Drugs
Thyrotoxicosis During Pregnancy
Ideally, women in the childbearing period with severe dis-
ease should have definitive therapy with 131I or subtotal thyroid-
ectomy prior to pregnancy in order to avoid an acute exacerbation
of the disease during pregnancy or following delivery. If thyro-
toxicosis does develop during pregnancy, RAI is contraindicated
because it crosses the placenta and may injure the fetal thyroid.
Propylthiouracil (fewer teratogenic risks than methimazole) can
be given in the first trimester, and then methimazole can be given
for the remainder of the pregnancy in order to avoid potential liver
damage. The dosage of propylthiouracil must be kept to the mini-
mum necessary for control of the disease (ie, <300 mg/d), because
it may affect the function of the fetal thyroid gland. Alternatively,
a subtotal thyroidectomy can be safely performed during the mid
trimester. It is essential to give the patient a thyroid supplement
during the balance of the pregnancy.
Neonatal Graves’ Disease
Graves’ disease may occur in the newborn infant, due either to pas-
sage of maternal TSH-R Ab [stim] through the placenta, stimulat-
ing the thyroid gland of the neonate, or to genetic transmission of
the trait to the fetus. Laboratory studies reveal an elevated free T4,
a markedly elevated T3, and a low TSH—in contrast to the normal
infant, in whom TSH is elevated at birth. TSH-R Ab [stim] is
usually found in the serum of both the child and the mother.
If caused by maternal TSH-R Ab [stim], the disease is usually
self-limited and subsides over a period of 4–12 weeks, coincid-
ing with the fall in the infant’s TSH-R Ab [stim] level. However,
treatment is necessary because of the severe metabolic stress the
infant experiences. Therapy includes propylthiouracil at a dosage
of 5–10 mg/kg daily in divided doses at 8-hour intervals; Lugol’s
solution (8 mg of iodide per drop), 1 drop every 8 hours; and
propranolol, 2 mg/kg daily in divided doses. Careful supportive
therapy is essential. If the infant is very ill, oral prednisone, 2 mg/
kg daily in divided doses, will help block conversion of T4 to T3.
These medications are gradually reduced as the clinical picture
improves and can be discontinued by 6–12 weeks.
SUBCLINICAL HYPERTHYROIDISM
Subclinical hyperthyroidism is defined as a suppressed TSH level
(below the normal range) in conjunction with normal thyroid
hormone levels. Cardiac toxicity (eg, atrial fibrillation), especially
in older persons and those with underlying cardiac disease, is of
greatest concern. The consensus of thyroid experts concluded
that hyperthyroidism treatment is appropriate in those with TSH
less than 0.1 mIU/L, while close monitoring of the TSH level is
appropriate for those with less TSH suppression.
Amiodarone-Induced Thyrotoxicosis
In addition to those patients who develop hypothyroidism caused
by amiodarone, approximately 3% of patients receiving this drug
will develop hyperthyroidism instead. Two types of amiodarone-
induced thyrotoxicosis have been reported: iodine-induced (type I),
which often occurs in persons with underlying thyroid disease (eg,
multinodular goiter, Graves’ disease); and an inflammatory thyroid-
itis (type II) that occurs in patients without thyroid disease due to
leakage of thyroid hormone into the circulation. Treatment of type I
requires therapy with thioamides, while type II responds best to glu-
cocorticoids. Since it is not always possible to differentiate between
the two types, thioamides and glucocorticoids are often admin-
istered together. If possible, amiodarone should be discontinued;
however, rapid improvement does not occur due to its long half-life.
NONTOXIC GOITER
Nontoxic goiter is a syndrome of thyroid enlargement without
excessive thyroid hormone production. Enlargement of the
thyroid gland is often due to TSH stimulation from inadequate
thyroid hormone synthesis. The most common cause of nontoxic
goiter worldwide is iodide deficiency, but in the United States,
it is Hashimoto’s thyroiditis. Other causes include germ-line
or acquired mutations in genes involved in hormone synthesis,
dietary goitrogens, and neoplasms (see below).
Goiter due to iodide deficiency is best managed by prophy-
lactic administration of iodide. The optimal daily iodide intake
is 150–200 mcg. Iodized salt and iodate used as preservatives in
flour and bread are excellent sources of iodine in the diet. In areas
where it is difficult to introduce iodized salt or iodate preserva-
tives, a solution of iodized poppy-seed oil has been administered
intramuscularly to provide a long-term source of inorganic iodine.
Goiter due to ingestion of goitrogens in the diet is managed by
elimination of the goitrogen or by adding sufficient thyroxine to
shut off TSH stimulation. Similarly, in Hashimoto’s thyroiditis and
dyshormonogenesis, adequate thyroxine therapy—150–200 mcg/d
orally—will suppress pituitary TSH and result in slow regression of
the goiter as well as correction of hypothyroidism.
THYROID NEOPLASMS
Neoplasms of the thyroid gland may be benign (adenomas) or
malignant. The primary diagnostic test is a fine needle aspira-
tion biopsy and cytologic examination. Benign lesions may be
monitored for growth or symptoms of local obstruction, which
would mandate surgical excision. Levothyroxine therapy is not
recommended for the suppression of benign nodules, especially
in iodine sufficient areas. Management of thyroid carcinoma
requires a total thyroidectomy, postoperative radioiodine therapy
in selected instances, and lifetime replacement with levothyroxine.
The evaluation for recurrence of some thyroid malignancies often
involves withdrawal of thyroxine replacement for 4–6 weeks—
accompanied by the development of hypothyroidism. Tumor
recurrence is likely if there is a rise in serum thyroglobulin (ie, a
tumor marker) or a positive 131I scan when TSH is elevated. Alter-
natively, administration of recombinant human TSH (Thyrogen)
can produce comparable TSH elevations without discontinuing
thyroxine and avoiding hypothyroidism. Recombinant human
TSH is administered intramuscularly once daily for 2 days. A
rise in serum thyroglobulin or a positive 131I scan will indicate a
recurrence of the thyroid cancer.
 CHAPTER 38  Thyroid & Antithyroid Drugs    701

SUMMARY Drugs Used in the Management of Thyroid Disease

Mechanism of Action Pharmacokinetics, Toxicities,
Subclass, Drug and Effects Indications Interactions

THYROID PREPARATIONS      
•  Levothyroxine (T4) Activation of nuclear receptors Hypothyroidism See Table 38–1 • maximum effect seen
•  Liothyronine (T3) results in gene expression with RNA after 6–8 weeks of therapy • Toxicity: See
formation and protein synthesis Table 38–4 for symptoms of thyroid excess

ANTITHYROID AGENTS      
THIOAMIDES      
•  Methimazole Inhibit thyroid peroxidase reactions Hyperthyroidism Oral • duration of action: 24 h
•  Propylthiouracil (PTU) • block iodine organification • inhibit (methimazole), 6–8 h (PTU) • delayed onset
peripheral deiodination of T4 and T3 of action • Toxicity: Nausea, gastrointestinal
(primarily PTU) distress, rash, agranulocytosis, hepatitis
(PTU black box), hypothyroidism

IODIDES
•  Lugol’s solution Inhibit organification and hormone Preparation for surgical thyroidectomy Oral • acute onset within 2–7 days • Toxicity:
•  Potassium iodide release • reduce the size and Rare (see text)
vascularity of the gland

BETA BLOCKERS
•  Propranolol, other β blockers Inhibition of β adrenoreceptors Hyperthyroidism, especially thyroid Onset within hours • duration of 4–6 h (oral
lacking partial agonist activity • inhibit T4 to T3 conversion (only storm • adjunct to control tachycardia, propranolol) • Toxicity: Asthma, AV
propranolol) hypertension, and atrial fibrillation blockade, hypotension, bradycardia

RADIOACTIVE IODINE 131I (RAI)      

  Radiation destruction of thyroid Hyperthyroidism • patients should be Oral • half-life 5 days • onset in 6–12 weeks
parenchyma euthyroid or on β blockers before • maximum effect in 3–6 months • Toxicity:
RAI • avoid in pregnancy and in Sore throat, sialitis, hypothyroidism
nursing mothers

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The initial methimazole treatment was appropriate and
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are reasonable and effective strategies for definitive treat-
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pregnant to avoid an acute hyperthyroid exacerbation
during pregnancy or following delivery. Her hypothy-
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day or 100 mcg daily. Because she is young and has no
cardiac disease, full replacement doses were appropriate
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Zimmermann MB, Boelaert K: Iodine deficiency and thyroid disorders. Lancet
Diabetes Endocrinol 2015;3:286.
to start. However, her elevated TSH level indicates inad-
equate levothyroxine replacement which may be related
to nonadherence, or concomitant calcium and omeprazole
co-administration. For optimal absorption, levothyroxine
should be taken orally 60 minutes before meals on an
empty stomach or at bedtime, and separated by 4 hours
from her calcium administration. Lower thyroxine doses
may also be sufficient if her omeprazole is stopped. Once
weekly thyroxine injections may be effective in those with
ongoing nonadherence. Thyroid function tests should be
monitored after 6–8 weeks of therapy, obtained before
thyroxine administration to avoid transient hormone alter-
ations, and the dosage adjusted to achieve a normal TSH
level and resolution of hypothyroid symptoms.

Adrenocorticosteroids
& Adrenocortical
Antagonists
George P. Chrousos, MD
C ASE STUDY
A 19-year-old man complains of anorexia, fatigue, dizziness,
and weight loss of 8 months’ duration. The examining
physician discovers postural hypotension and moderate
vitiligo (depigmented areas of skin) and obtains routine blood
tests. She finds hyponatremia, hyperkalemia, and acidosis and
suspects Addison’s disease. She performs a standard ACTH
The natural adrenocortical hormones are steroid molecules
produced and released by the adrenal cortex. Deficiency of
the adrenocortical hormones results in the signs and symp-
toms of Addison’s disease. Excess production causes Cushing’s
syndrome. Both natural and synthetic corticosteroids are used for
the diagnosis and treatment of disorders of adrenal function. They
are also used—more often and in much larger doses—for treat-
ment of a variety of inflammatory and immunologic disorders.
Secretion of adrenocortical steroids, especially the glucocor-
ticoids, is controlled by the pituitary release of corticotropin
(ACTH) (see Chapter 37). Corticotropin is derived from a larger
protein synthesized in the pituitary, pro-opiomelanocortin
(POMC). Secretion of the salt-retaining hormone aldosterone
is primarily under the influence of circulating angiotensin and
potassium. Corticotropin has some actions that do not depend on
its effect on adrenocortical secretion. However, its pharmacologic
value as an anti-inflammatory agent and its use in testing adre-
nal function depend on its secretory action. Its pharmacology is
reviewed only briefly here.
Inhibitors of the synthesis or antagonists of the action of the
adrenocortical steroids are important in the treatment of several
conditions. These agents are described at the end of this chapter.
39
C H A P T E R
1–24 stimulation test, which reveals an insufficient plasma
cortisol response compatible with primary adrenal insuf-
ficiency. The diagnosis of autoimmune Addison’s disease is
made, and the patient must start replacement of the hormones
he cannot produce himself. How should this patient be
treated? What precautions should he take?
■■ ADRENOCORTICOSTEROIDS
The adrenal cortex releases a large number of steroids into the
circulation. Some have minimal biologic activity and func-
tion primarily as precursors, and there are some for which no
function has been established. The hormonal steroids may be
classified as those having important effects on intermediary
metabolism and immune function (glucocorticoids), those
having principally salt-retaining activity (mineralocorticoids),
and those having androgenic or estrogenic activity (see
Chapter 40). In humans, the major glucocorticoid is cortisol
and the most important mineralocorticoid is aldosterone.
Quantitatively, dehydroepiandrosterone (DHEA) in its sulfated
form (DHEAS) is the major adrenal androgen. However,
DHEA and two other adrenal androgens, androstenedione
and androstenediol, are weak androgens and androstenediol is
a potent estrogen. Androstenedione can be converted to tes-
tosterone and estradiol in extra-adrenal tissues (Figure 39–1).
Adrenal androgens constitute the major endogenous precursors
of estrogen in women after menopause and in younger patients
in whom ovarian function is deficient or absent.
703
704    SECTION VII  Endocrine Drugs

17α-Hydroxylase 17, 20-Lyase

CH3 (P450c17) CH3
Acetate
C O C O O
Cholesterol OH
(ACTH?)
NADPH
O2

Pregnenolone 17-Hydroxy- Dehydroepi-

pregnenolone androsterone
HO HO HO
CH3 CH3
3β-Dehydrogenase
∆5,∆4-Isomerase C O C O O
NAD+ OH

Progesterone 17-Hydroxy- ∆4-Androstene-

progesterone 3,17-dione
O O O
CH2OH CH2OH
21α-Hydroxylase
C O C O
(P450c21)
OH

Testosterone

11-Deoxy-
11β-Deoxycortisol
corticosterone
O O
CH2OH CH2OH

11β-Hydroxylase C O C O Estradiol
(P450c11)
HO HO OH

CH2OH

C O Corticosterone Cortisol
CHO O O
HO

Aldosterone
O

Mineralocorticoid Glucocorticoid Androgen and

pathway pathway estrogen pathway

FIGURE 39–1  Outline of major pathways in adrenocortical hormone biosynthesis. The major secretory products are underlined. Pregneno-
lone is the major precursor of corticosterone and aldosterone, and 17-hydroxypregnenolone is the major precursor of cortisol. The enzymes and
cofactors for the reactions progressing down each column are shown on the left and across columns at the top of the figure. When a particular
enzyme is deficient, hormone production is blocked at the points indicated by the shaded bars. (Reproduced, with permission, from Ganong WF: Review
of Medical Physiology, 22nd ed. McGraw-Hill, 2005. Copyright © The McGraw-Hill Companies, Inc.)

THE NATURALLY OCCURRING system, which is very sensitive to negative feedback by the circu-
lating cortisol and exogenous (synthetic) glucocorticoids. Cortisol
GLUCOCORTICOIDS; CORTISOL is synthesized from cholesterol (as shown in Figure 39–1). The
(HYDROCORTISONE) mechanisms controlling its secretion are discussed in Chapter 37.
The rate of secretion follows a circadian rhythm (Figure 39–2)
Pharmacokinetics governed by pulses of ACTH that peak in the early morning hours
Cortisol (also called hydrocortisone, compound F) exerts a wide and after meals. In plasma, cortisol is bound to circulating pro-
range of physiologic effects, including regulation of intermediary teins. Corticosteroid-binding globulin (CBG), an α2 globulin
metabolism, cardiovascular function, growth, and immunity. Its synthesized by the liver, binds about 90% of the circulating hor-
synthesis and secretion are tightly regulated by the central nervous mone under normal circumstances. The remainder is free (about

24 Hour Sampling
Normal
Serum Cortisol
8 am 8 pm Dark
Circadian Tissue Glucocorticoid Sensitivity/Gr Acetylation
Glucocorticoid Sensitivity
GR Acetylation
Target Tissue
Target Tissue
Glucocorticoid Sensitivity
8 am 8 pm Dark
FIGURE 39–2  Circadian variation in plasma cortisol throughout
the 24-hour day (upper panel). The sensitivity of tissues to gluco-
corticoids is also circadian but inverse to that of cortisol, with low
sensitivity in the late morning and high sensitivity in the evening and
early night (lower panel). The sensitivity of tissues to glucocorticoids
is inversely related to that of glucocorticoid receptor (GR) acetylation
by the transcription factor CLOCK; the acetylated receptor has
decreased transcriptional activity. (Adapted, with permission, from Nader N,
Chrousos GP, Kino T: Interactions of the circadian CLOCK system and the HPA axis.
Trends Endocrinol Metab 2010;21:277. Copyright Elsevier.)
5–10%) or loosely bound to albumin (about 5%) and is available
to exert its effect on target cells. When plasma cortisol levels
exceed 20–30 mcg/dL, CBG is saturated, and the concentration
of free cortisol rises rapidly. CBG is increased in pregnancy, with
estrogen administration, and in hyperthyroidism. It is decreased
by hypothyroidism, genetic defects in synthesis, and protein
deficiency states. Albumin has a large capacity but low affinity for
cortisol, and for practical purposes albumin-bound cortisol should
be considered free. Synthetic corticosteroids such as dexametha-
sone are largely bound to albumin rather than CBG.
The half-life of cortisol in the circulation is normally about
60–90 minutes; it may be increased when hydrocortisone (the phar-
maceutical preparation of cortisol) is administered in large amounts
or when stress, hypothyroidism, or liver disease is present. Only 1%
of cortisol is excreted unchanged in the urine as free cortisol; about
20% of cortisol is converted to cortisone by 11-hydroxysteroid
dehydrogenase in the kidney and other tissues with mineralocorti-
coid receptors (see below) before reaching the liver. Most cortisol is
metabolized in the liver. About one-third of the cortisol produced
daily is excreted in the urine as dihydroxy ketone metabolites and is
measured as 17-hydroxysteroids (see Figure 39–3 for carbon num-
bering). Many cortisol metabolites are conjugated with glucuronic
acid or sulfate at the C3 and C21 hydroxyls, respectively, in the liver;
they are then excreted in the urine.
CHAPTER 39  Adrenocorticosteroids & Adrenocortical Antagonists    705
In some species (eg, the rat), corticosterone is the major gluco-
corticoid. It is less firmly bound to protein and therefore metabo-
lized more rapidly. The pathways of its degradation are similar to
those of cortisol.
Pharmacodynamics
A. Mechanism of Action
Most of the known effects of the glucocorticoids are mediated by
8 am
widely distributed intracellular glucocorticoid receptors. These
proteins are members of the superfamily of nuclear receptors,
which includes steroid, sterol (vitamin D), thyroid, retinoic
acid, and many other receptors with unknown or nonexistent
GR Acetylation at
ligands (orphan receptors). All these receptors interact with the
Target Tissues
promoters of—and regulate the transcription of—target genes
(Figure 39–4). In the absence of the hormonal ligand, glucocorti-
coid receptors are primarily cytoplasmic, in oligomeric complexes
with chaperone heat-shock proteins (hsp). The most important
of these are two molecules of hsp90, although other proteins (eg,
8 am hsp40, hsp70, FKBP5) are also involved. Free hormone from
the plasma and interstitial fluid enters the cell and binds to the
receptor, inducing conformational changes that allow it to dis-
sociate from the heat shock proteins and dimerize. The dimeric
ligand-bound receptor complex then is actively transported into
the nucleus, where it interacts with DNA and nuclear proteins.
As a homodimer, it binds to glucocorticoid receptor elements
(GREs) in the promoters of responsive genes. The GRE is com-
posed of two palindromic sequences that bind to the hormone
receptor dimer.
In addition to binding to GREs, the ligand-bound receptor
also forms complexes with and influences the function of other
transcription factors, such as AP1 and nuclear factor kappa-B
(NF-κB), which act on non-GRE-containing promoters, to con-
tribute to the regulation of transcription of their responsive genes.
These transcription factors have broad actions on the regulation
of growth factors, proinflammatory cytokines, etc, and to a great
extent mediate the anti-growth, anti-inflammatory, and immuno-
suppressive effects of glucocorticoids.
Two genes for the corticoid receptor have been identified: one
encoding the classic glucocorticoid receptor (GR) and the other
encoding the mineralocorticoid receptor (MR). Alternative splic-
ing of human glucocorticoid receptor pre-mRNA generates two
highly homologous isoforms, termed hGRα and hGRβ. Human
GRα is the classic ligand-activated glucocorticoid receptor,
which, in the hormone-bound state, modulates the expression
of glucocorticoid-responsive genes. In contrast, hGRβ does not
bind glucocorticoids and is transcriptionally inactive. However,
hGRβ is able to inhibit the effects of hormone-activated hGRα
on glucocorticoid-responsive genes, playing the role of a physi-
ologically relevant endogenous inhibitor of glucocorticoid action.
It was recently shown that the two hGR alternative transcripts
have eight distinct translation initiation sites—ie, in a human cell
there may be up to 16 GRα and GRβ isoforms, which may form
up to 256 homodimers and heterodimers with different transcrip-
tional and possibly nontranscriptional activities. This variability
suggests that this important class of steroid receptors has complex
706    SECTION VII  Endocrine Drugs

21 21
CH2OH CH2OH
20 20
C O C O
18 18
H3C OH H3C OH
HO 12 17 HO 12 17
11 13 11 13 16
19 16 19
H3C 14 H3C H 14 15
1 9 8 15 1 8
9
2 10 10
2
H H
3 5 7 3 5 7
4
O 6 O 4 6

Cortisol (hydrocortisone) Prednisolone

21 21
CH2OH CH2OH
20 20
C O O CH3
C O
18 18
H3C OH H3C
HO HO 12
C
12 17 17
11 13 11 13
19 16 CH3 19 16 O CH3
H3C 14 H3C 14
1 9 8 15 1 9 8 15
2 10 2 10
F F
3 5 7 3 5 7
O 4 6 O 4 6

Betamethasone Triamcinolone (acetonide moiety shaded)

FIGURE 39–3  Chemical structures of several glucocorticoids. The acetonide-substituted derivatives (eg, triamcinolone acetonide) have
increased surface activity and are useful in dermatology. Dexamethasone is identical to betamethasone except for the configuration of the
methyl group at C16: in betamethasone it is beta (projecting up from the plane of the rings); in dexamethasone it is alpha.

stochastic activities. In addition, rare mutations in hGR may
result in partial glucocorticoid resistance. Affected individuals
have increased ACTH secretion because of reduced pituitary feed-
back and additional endocrine abnormalities (see below).
The prototype GR isoform is composed of about 800 amino acids
and can be divided into three functional domains (see Figure 2–6).
The glucocorticoid-binding domain is located at the carboxyl
terminal of the molecule. The DNA-binding domain is located in the
middle of the protein and contains nine cysteine residues. This region
folds into a “two-finger” structure stabilized by zinc ions connected to
cysteines to form two tetrahedrons. This part of the molecule binds
to the GREs that regulate glucocorticoid action on glucocorticoid-
regulated genes. The zinc fingers represent the basic structure by
which the DNA-binding domain recognizes specific nucleic acid
sequences. The amino-terminal domain is involved in the transactiva-
tion activity of the receptor and increases its specificity.
The interaction of glucocorticoid receptors with GREs or
other transcription factors is facilitated or inhibited by several
families of proteins called steroid receptor coregulators, divided
into coactivators and corepressors. The coregulators do this by serv-
ing as bridges between the receptors and other nuclear proteins
and by expressing enzymatic activities such as histone acetylase or
deacetylase, which alter the conformation of nucleosomes and the
transcribability of genes.
Between 10% and 20% of expressed genes in a cell are regu-
lated by glucocorticoids. The number and affinity of receptors
for the hormone, the complement of transcription factors and
coregulators, and post-transcription events determine the relative
specificity of these hormones’ actions in various cells. The effects
of glucocorticoids are mainly due to proteins synthesized from
mRNA transcribed from their target genes.
Some of the effects of glucocorticoids can be attributed to
their binding to mineralocorticoid receptors. Indeed, MRs bind
aldosterone and cortisol with similar affinity. A mineralocor-
ticoid effect of the higher levels of cortisol is avoided in some
tissues (eg, kidney, colon, salivary glands) by expression of
11β-hydroxysteroid dehydrogenase type 2, the enzyme responsible
for biotransformation to its 11-keto derivative (cortisone), which
has minimal action on aldosterone receptors.
The GR also interacts with other regulators of cell function.
One such molecule is CLOCK/BMAL-1, a transcription factor
dimer expressed in all tissues and generating the circadian rhythm
of cortisol secretion (Figure 39–2) at the suprachiasmatic nucleus
of the hypothalamus. CLOCK is an acetyltransferase that acety-
lates the hinge region of the GR, neutralizing its transcriptional
activity and thus rendering target tissues resistant to glucocorti-
coids. As shown in Figure 39–2, lower panel, the glucocorticoid
target tissue sensitivity rhythm generated is in reverse phase to that
of circulating cortisol concentrations, explaining the increased
sensitivity of the organism to evening administration of glucocor-
ticoids. The GR also interacts with NF-κB, a regulator of produc-
tion of cytokines and other molecules involved in inflammation.
 CHAPTER 39  Adrenocorticosteroids & Adrenocortical Antagonists    707

R hsp90
hsp90 x
(Unstable)
S
R

S S
S S Steroid-receptor
R* R* dimer (activated)

DNA
S
Response
CBG S R*
GRE
S R*

Protein

Transcription
mRNA pre- machinery
(Editing) mRNA (RNA poly-
merase, etc)

Cytoplasm Nucleus

FIGURE 39–4  A model of the interaction of a steroid, S (eg, cortisol), and its receptor, R, and the subsequent events in a target cell. The
steroid is present in the blood in bound form on the corticosteroid-binding globulin (CBG) but enters the cell as the free molecule. The intracel-
lular receptor is bound to stabilizing proteins, including two molecules of heat-shock protein 90 (hsp90) and several others including FKBP5,
denoted as “X” in the figure. This receptor complex is incapable of activating transcription. When the complex binds a molecule of cortisol,
an unstable complex is created and the hsp90 and associated molecules are released. The steroid-receptor complex is now able to dimerize,
enter the nucleus, bind to a glucocorticoid response element (GRE) on the regulatory region of the gene, and regulate transcription by RNA
polymerase II and associated transcription factors. A variety of regulatory factors (not shown) may participate in facilitating (coactivators) or
inhibiting (corepressors) the steroid response. The resulting mRNA is edited and exported to the cytoplasm for the production of protein that
brings about the final hormone response. An alternative to the steroid-receptor complex interaction with a GRE is an interaction with and
altering the function of other transcription factors, such as NF-κB in the nucleus of cells.

Prompt effects such as initial feedback suppression of pituitary
ACTH occur in minutes and are too rapid to be explained on the
basis of gene transcription and protein synthesis. It is not known
how these effects are mediated. Among the proposed mechanisms are
direct effects on cell membrane receptors for the hormone or nonge-
nomic effects of the classic hormone-bound glucocorticoid receptor.
The putative membrane receptors might be entirely different from
the known intracellular receptors. For example, recent studies impli-
cate G protein–coupled membrane receptors in the response of glu-
tamatergic neurons to glucocorticoids in rats. Furthermore, all steroid
receptors (except the MRs) have been shown to have palmitoylation
motifs that allow enzymatic addition of palmitate and increased local-
ization of the receptors in the vicinity of plasma membranes. Such
receptors are available for direct interactions with and effects on vari-
ous membrane-associated or cytoplasmic proteins without the need
for entry into the nucleus and induction of transcriptional actions.
B. Physiologic Effects
The glucocorticoids have widespread effects because they influ-
ence the function of most cells in the body. The major metabolic
consequences of glucocorticoid secretion or administration are due to
direct actions of these hormones in the cell. However, some impor-
tant effects are the result of homeostatic responses by insulin and
glucagon. Although many of the effects of glucocorticoids are dose-
related and become magnified when large amounts are administered
for therapeutic purposes, there are also other effects—called permissive
effects—without which many normal functions become deficient.
For example, the response of vascular and bronchial smooth muscle to
catecholamines is diminished in the absence of cortisol and restored
by physiologic amounts of this glucocorticoid. Similarly, the lipolytic
responses of fat cells to catecholamines, ACTH, and growth hormone
are attenuated in the absence of glucocorticoids.
C. Metabolic Effects
The glucocorticoids have important dose-related effects on car-
bohydrate, protein, and fat metabolism. The same effects are
responsible for some of the serious adverse effects associated with
their use in therapeutic doses. Glucocorticoids stimulate and are
required for gluconeogenesis and glycogen synthesis in the fast-
ing state. They stimulate phosphoenolpyruvate carboxykinase,
708    SECTION VII  Endocrine Drugs
glucose-6-phosphatase, and glycogen synthase and the release of
amino acids in the course of muscle catabolism.
Glucocorticoids increase serum glucose levels and thus stimu-
late insulin release but inhibit the uptake of glucose by muscle
cells, while they stimulate hormone-sensitive lipase and thus
lipolysis. The increased insulin secretion stimulates lipogenesis
and to a lesser degree inhibits lipolysis, leading to a net increase in
fat deposition combined with increased release of fatty acids and
glycerol into the circulation.
The net results of these actions are most apparent in the fasting
state, when the supply of glucose from gluconeogenesis, the release
of amino acids from muscle catabolism, the inhibition of periph-
eral glucose uptake, and the stimulation of lipolysis all contribute
to maintenance of an adequate glucose supply to the brain.
D. Catabolic and Antianabolic Effects
Although glucocorticoids stimulate RNA and protein synthesis in the
liver, they have catabolic and antianabolic effects in lymphoid and
connective tissue, muscle, peripheral fat, and skin. Supraphysiologic
amounts of glucocorticoids lead to decreased muscle mass and weak-
ness and thinning of the skin. Catabolic and antianabolic effects on
bone are the cause of osteoporosis in Cushing’s syndrome and impose
a major limitation in the long-term therapeutic use of glucocorticoids.
In children, glucocorticoids reduce growth. This effect may be par-
tially prevented by administration of growth hormone in high doses,
but this use of growth hormone is not recommended.
E. Anti-Inflammatory and Immunosuppressive Effects
Glucocorticoids dramatically reduce the manifestations of inflam-
mation. This is due to their profound effects on the concentration,
distribution, and function of peripheral leukocytes and to their
suppressive effects on inflammatory cytokines and chemokines and
on other mediators of inflammation. Inflammation, regardless of
its cause, is characterized by the extravasation and infiltration of
leukocytes into the affected tissue. These events are mediated by a
complex series of interactions of white cell adhesion molecules with
those on endothelial cells and are inhibited by glucocorticoids. After
a single dose of a short-acting glucocorticoid, the concentration
of neutrophils in the circulation increases while the lymphocytes
(T and B cells), monocytes, eosinophils, and basophils decrease.
The changes are maximal at 6 hours and are dissipated in 24 hours.
The increase in neutrophils is due both to increased influx into
the blood from the bone marrow and to decreased migration
from the blood vessels, leading to a reduction in the number
of cells at the site of inflammation. The reduction in circulating
lymphocytes, monocytes, eosinophils, and basophils is primarily the
result of their movement from the vascular bed to lymphoid tissue.
Glucocorticoids also inhibit the functions of tissue macro-
phages and other antigen-presenting cells. The ability of these
cells to respond to antigens and mitogens is reduced. The effect
on macrophages is particularly marked and limits their ability
to phagocytose and kill microorganisms and to produce tumor
necrosis factor α, interleukin 1, metalloproteinases, and plasmino-
gen activator. Both macrophages and lymphocytes produce less
interleukin 12 and interferon-γ, important inducers of Th1 cell
activity, and cellular immunity.
In addition to their effects on leukocyte function, gluco-
corticoids influence the inflammatory response by inhibiting
phospholipase A2 and thus reduce the synthesis of arachidonic
acid, the precursor of prostaglandins and leukotrienes, and of
platelet-activating factor. Finally, glucocorticoids reduce expres-
sion of cyclooxygenase 2, the inducible form of this enzyme, in
inflammatory cells, thus reducing the amount of enzyme available
to produce prostaglandins (see Chapters 18 and 36).
Glucocorticoids cause vasoconstriction when applied directly
to the skin, possibly by suppressing mast cell degranulation. They
also decrease capillary permeability by reducing the amount of
histamine released by basophils and mast cells.
The anti-inflammatory and immunosuppressive effects of
glucocorticoids are largely due to the actions described above. In
humans, complement activation is unaltered, but its effects are
inhibited. Antibody production can be reduced by large doses of
steroids, although it is unaffected by moderate doses (eg, 20 mg/d
of prednisone).
The anti-inflammatory and immunosuppressive effects of these
agents are widely useful therapeutically but are also responsible for
some of their most serious adverse effects (see text that follows).
F. Other Effects
Glucocorticoids have important effects on the nervous system.
Adrenal insufficiency causes marked slowing of the alpha rhythm
of the electroencephalogram and is associated with depression.
Increased amounts of glucocorticoids often produce behavioral
disturbances in humans: initially insomnia and euphoria and sub-
sequently depression. Large doses of glucocorticoids may increase
intracranial pressure (pseudotumor cerebri).
Glucocorticoids given chronically suppress the pituitary release
of ACTH, growth hormone, thyroid-stimulating hormone, and
luteinizing hormone.
Large doses of glucocorticoids have been associated with the devel-
opment of peptic ulcer, possibly by suppressing the local immune
response against Helicobacter pylori. They also promote fat redistribu-
tion in the body, with increase of visceral, facial, nuchal, and supracla-
vicular fat, and they appear to antagonize the effect of vitamin D on
calcium absorption. The glucocorticoids also have important effects on
the hematopoietic system. In addition to their effects on leukocytes,
they increase the number of platelets and red blood cells.
Cortisol deficiency results in impaired renal function (particu-
larly glomerular filtration), augmented vasopressin secretion, and
diminished ability to excrete a water load.
Glucocorticoids have important effects on the development
of the fetal lungs. Indeed, the structural and functional changes
in the lungs near term, including the production of pulmonary
surface-active material required for air breathing (surfactant), are
stimulated by glucocorticoids.
Recently, glucocorticoids were found to have direct effects
on the epigenetic regulation of specific target genes by altering
the activities of DNA methyltransferases and other enzymes par-
ticipating in epigenesis. This is of particular importance in the
prenatal treatment of pregnant mothers or treatment of young
infants and children, when the effects of glucocorticoids may be
long-term or even permanent. These effects may predispose these
 CHAPTER 39  Adrenocorticosteroids & Adrenocortical Antagonists    709

patients to behavioral or somatic disorders, such as depression or
obesity and metabolic syndrome.
SYNTHETIC CORTICOSTEROIDS
Glucocorticoids have become important agents for use in the treat-
ment of many inflammatory, immunologic, hematologic, and other
disorders. This has stimulated the development of many synthetic
steroids with anti-inflammatory and immunosuppressive activity.
Pharmacokinetics
Pharmaceutical steroids are usually synthesized from cholic acid
obtained from cattle or steroid sapogenins found in plants. Fur-
ther modifications of these steroids have led to the marketing of
a large group of synthetic steroids with special characteristics that
are pharmacologically and therapeutically important (Table 39–1;
Figure 39–3).
The metabolism of the naturally occurring adrenal steroids has
been discussed above. The synthetic corticosteroids (Table 39–1) are
in most cases rapidly and completely absorbed when given by mouth.
Although they are transported and metabolized in a fashion similar to
that of the endogenous steroids, important differences exist.
Alterations in the glucocorticoid molecule influence its affinity
for glucocorticoid and mineralocorticoid receptors as well as its
protein-binding affinity, side chain stability, rate of elimination,
and metabolic products. Halogenation at the 9 position, unsatu-
ration of the Δ1–2 bond of the A ring, and methylation at the
2 or 16 position prolong the half-life by more than 50%. The Δ1
compounds are excreted in the free form. In some cases, the agent
given is a prodrug; for example, prednisone is rapidly converted to
the active product prednisolone in the body.
Pharmacodynamics
The actions of the synthetic steroids are similar to those of cor-
tisol (see above). They bind to the specific intracellular receptor
proteins and produce the same effects but have different ratios of
glucocorticoid to mineralocorticoid potency (Table 39–1).
CLINICAL PHARMACOLOGY
A. Diagnosis and Treatment of Disturbed Adrenal
Function
1. Adrenocortical insufficiency
a. Chronic (Addison’s disease)—Chronic adrenocortical insuf-
ficiency is characterized by weakness, fatigue, weight loss, hypo-
tension, hyperpigmentation, and inability to maintain the blood
glucose level during fasting. In such individuals, minor noxious,

TABLE 39–1  Some commonly used natural and synthetic corticosteroids for general use. See Table 61–2 for
dermatologic corticosteroids.

Activity1
Equivalent Oral
Agent  Anti-Inflammatory Topical Salt-Retaining Dose (mg)  Forms Available 

Short- to medium-acting glucocorticoids

  Hydrocortisone (cortisol) 1 1 1 20 Oral, injectable, topical
 Cortisone 0.8 0 0.8 25 Oral
 Prednisone 4 0 0.3 5 Oral
 Prednisolone 5 4 0.3 5 Oral, injectable
 Methylprednisolone 5 5 0.25 4 Oral, injectable
2
 Meprednisone 5   0 4 Oral, injectable
Intermediate-acting glucocorticoids
 Triamcinolone 5 53 0 4 Oral, injectable, topical
2
 Paramethasone 10   0 2 Oral, injectable
2
 Fluprednisolone 15 7 0 1.5 Oral
Long-acting glucocorticoids
 Betamethasone 25–40 10 0 0.6 Oral, injectable, topical
 Dexamethasone 30 10 0 0.75 Oral, injectable, topical
Mineralocorticoids
 Fludrocortisone 10 0 250 2 Oral
 Desoxycorticosterone 0 0 20   Injectable, pellets
acetate2
1
Potency relative to hydrocortisone.
2
Outside United States.
3
Triamcinolone acetonide: Up to 100.
710    SECTION VII  Endocrine Drugs
traumatic, or infectious stimuli may produce acute adrenal insuf-
ficiency with circulatory shock and even death.
In primary adrenal insufficiency, about 20–30 mg of hydrocor-
tisone must be given daily, with increased amounts during periods
of stress. Although hydrocortisone has some mineralocorticoid
activity, this must be supplemented by an appropriate amount of
a salt-retaining hormone such as fludrocortisone. Synthetic gluco-
corticoids that are long-acting and devoid of salt-retaining activity
should not be administered to these patients.
b. Acute—When acute adrenocortical insufficiency is suspected,
treatment must be instituted immediately. Therapy consists of
large amounts of parenteral hydrocortisone in addition to cor-
rection of fluid and electrolyte abnormalities and treatment of
precipitating factors.
Hydrocortisone sodium succinate or phosphate in doses of
100 mg intravenously is given every 8 hours until the patient is
stable. The dose is then gradually reduced, achieving maintenance
dosage within 5 days.
The administration of salt-retaining hormone is resumed when
the total hydrocortisone dosage has been reduced to 50 mg/d.
2. Adrenocortical hypo- and hyperfunction
a. Congenital adrenal hyperplasia—This group of disorders
is characterized by specific defects in the synthesis of cortisol. In
pregnancies at high risk for congenital adrenal hyperplasia, fetuses
can be protected from genital abnormalities by administration of
dexamethasone to the mother.
The most common defect is a decrease in or lack of P450c21
(21α-hydroxylase) activity.* As can be seen in Figure 39–1, this
would lead to a reduction in cortisol synthesis and thus produce a
compensatory increase in ACTH release. The adrenal becomes hyper-
plastic and produces abnormally large amounts of precursors such as
17-hydroxyprogesterone that can be diverted to the androgen path-
way, which leads to virilization and can result in ambiguous genitalia
in the female fetus. Metabolism of this compound in the liver leads to
pregnanetriol, which is characteristically excreted into the urine in
large amounts in this disorder and can be used to make the diagnosis
and to monitor efficacy of glucocorticoid substitution. However, the
most reliable method of detecting this disorder is the increased
response of plasma 17-hydroxyprogesterone to ACTH stimulation.
If the defect is in 11-hydroxylation, large amounts of deoxy-
corticosterone are produced, and because this steroid has miner-
alocorticoid activity, hypertension with or without hypokalemic
alkalosis ensues. When 17-hydroxylation is defective in the adre-
nals and gonads, hypogonadism is also present. However, increased
amounts of 11-deoxycorticosterone are formed, and the signs and
symptoms associated with mineralocorticoid excess—such as
hypertension and hypokalemia— also are observed.
When first seen, the infant with congenital adrenal hyperplasia
may be in acute adrenal crisis and should be treated as described
above, using appropriate electrolyte solutions and an intravenous
preparation of hydrocortisone in stress doses. Once the patient
* However, it may also result from abnormal secretion by hyper-
Names for the adrenal steroid synthetic enzymes include the follow-
ing: P450c11 (11β-hydroxylase), P450c17 (17α-hydroxylase), P450c21
(21α-hydroxylase).
is stabilized, oral hydrocortisone, 12–18 mg/m2 per day in two
unequally divided doses (two thirds in the morning, one third in
late afternoon) is begun. The dosage is adjusted to allow normal
growth and bone maturation and to prevent androgen excess.
Alternate-day therapy with prednisone has also been used to
achieve greater ACTH suppression without increasing growth
inhibition. Fludrocortisone, 0.05–0.2 mg/d, should also be
administered by mouth, with added salt to maintain normal blood
pressure, plasma renin activity, and electrolytes.
b. Cushing’s syndrome—Cushing’s syndrome is usually the
result of bilateral adrenal hyperplasia secondary to an ACTH-
secreting pituitary adenoma (Cushing’s disease) but occasionally
is due to tumors or nodular hyperplasia of the adrenal gland or
ectopic production of ACTH by other tumors. The manifesta-
tions are those associated with the chronic presence of excessive
glucocorticoids. When glucocorticoid hypersecretion is marked and
prolonged, a rounded, plethoric face and trunk obesity are striking
in appearance. Protein loss may be significant and includes muscle
wasting; thinning, purple striae, and easy bruising of the skin;
poor wound healing; and osteoporosis. Other serious disturbances
include mental disorders, hypertension, and diabetes. This disorder
is treated by surgical removal of the tumor producing ACTH or
cortisol, irradiation of the pituitary tumor, or resection of one or
both adrenals. These patients must receive large doses of cortisol
during and after the surgical procedure. Doses of up to 300 mg of
soluble hydrocortisone may be given as a continuous intravenous
infusion on the day of surgery. The dose must be reduced slowly
to normal replacement levels, since rapid reduction in dose may
produce withdrawal symptoms, including fever and joint pain. If
adrenalectomy has been performed, long-term maintenance is simi-
lar to that outlined above for adrenal insufficiency.
c. Primary generalized glucocorticoid resistance
(Chrousos syndrome)—This rare sporadic or familial genetic
condition is usually due to inactivating mutations of the glucocor-
ticoid receptor gene. The hypothalamic-pituitary-adrenal (HPA)
axis hyperfunctions in an attempt to compensate for the defect,
and the increased production of ACTH leads to high circulating
levels of cortisol and cortisol precursors such as corticosterone
and 11-deoxycorticosterone with mineralocorticoid activity, as
well as of adrenal androgens. These increased levels may result in
hypertension with or without hypokalemic alkalosis and hyper-
androgenism expressed as virilization and precocious puberty in
children and acne, hirsutism, male pattern baldness, and men-
strual irregularities (mostly oligo-amenorrhea and hypofertility) in
women. The therapy of this syndrome is high doses of synthetic
glucocorticoids such as dexamethasone with no inherent min-
eralocorticoid activity. These doses are titrated to normalize the
production of cortisol, cortisol precursors, and adrenal androgens.
d. Aldosteronism—Primary aldosteronism usually results from
the excessive production of aldosterone by an adrenal adenoma.
plastic glands or from a malignant tumor. The clinical findings of
hypertension, weakness, and tetany are related to the continued
 CHAPTER 39  Adrenocorticosteroids & Adrenocortical Antagonists    711
renal loss of potassium, which leads to hypokalemia, alkalosis,
and elevation of serum sodium concentrations. This syndrome
can also be produced in disorders of adrenal steroid biosynthesis
by excessive secretion of deoxycorticosterone, corticosterone, or
18-hydroxycorticosterone—all compounds with inherent miner-
alocorticoid activity.
In contrast to patients with secondary aldosteronism (see text that
follows), these patients have low (suppressed) levels of plasma renin
activity and angiotensin II. When treated with fludrocortisone (0.2
mg twice daily orally for 3 days) or deoxycorticosterone acetate (20
mg/d intramuscularly for 3 days—but not available in the United
States), patients fail to retain sodium and the secretion of aldosterone
is not significantly reduced. When the disorder is mild, it may escape
detection if serum potassium levels are used for screening. However,
it may be detected by an increased ratio of plasma aldosterone to
renin. Patients generally improve when treated with spironolactone,
an aldosterone receptor-blocking agent, and the response to this agent
is of diagnostic and therapeutic value.
3. Use of glucocorticoids for diagnostic purposes—It is
sometimes necessary to suppress the production of ACTH to
identify the source of a particular hormone or to establish whether
its production is influenced by the secretion of ACTH. In these
circumstances, it is advantageous to use a very potent substance
such as dexamethasone because the use of small quantities reduces
the possibility of confusion in the interpretation of hormone
assays in blood or urine. For example, if complete suppression is
achieved by the use of 50 mg of cortisol, the urinary 17-hydroxy-
corticosteroids will be 15–18 mg/24 h, since one-third of the dose
given will be recovered in urine as 17-hydroxycorticosteroid. If an
equivalent dose of 1.5 mg of dexamethasone is used, the urinary
excretion will be only 0.5 mg/24 h and blood levels will be low.
The dexamethasone suppression test is used for the diagnosis of
Cushing’s syndrome and has also been used in the differential diag-
nosis of depressive psychiatric states. As a screening test, 1 mg dexa-
methasone is given orally at 11 pm, and a plasma sample is obtained
the following morning. In normal individuals, the morning cortisol
concentration is usually <3 mcg/dL, whereas in Cushing’s syndrome
the level is usually >5 mcg/dL. The results are not reliable in the
patient with depression, anxiety, concurrent illness, and other stress-
ful conditions or in the patient who is receiving a medication that
enhances the catabolism of dexamethasone in the liver. To distinguish
between hypercortisolism due to anxiety, depression, and alcoholism
(pseudo-Cushing syndrome) and bona fide Cushing’s syndrome, a
combined test is carried out, consisting of dexamethasone (0.5 mg
orally every 6 hours for 2 days) followed by a standard corticotropin-
releasing hormone (CRH) test (1 mg/kg given as a bolus intravenous
infusion 2 hours after the last dose of dexamethasone).
In patients in whom the diagnosis of Cushing’s syndrome has
been established clinically and confirmed by a finding of elevated
free cortisol in the urine, suppression with large doses of dexa-
methasone will help to distinguish patients with Cushing’s disease
from those with steroid-producing tumors of the adrenal cortex
or with the ectopic ACTH syndrome. Dexamethasone is given in
a dosage of 0.5 mg orally every 6 hours for 2 days, followed by
2 mg orally every 6 hours for 2 days, and the urine is then assayed
for cortisol or its metabolites (Liddle’s test); or dexamethasone is
given as a single dose of 8 mg at 11 pm, and the plasma cortisol
is measured at 8 am the following day. In patients with Cushing’s
disease, the suppressant effect of dexamethasone usually produces
a 50% reduction in hormone levels. In patients in whom suppres-
sion does not occur, the ACTH level will be low in the presence of
a cortisol-producing adrenal tumor and elevated in patients with
an ectopic ACTH-producing tumor.
B. Corticosteroids and Stimulation of Lung Maturation
in the Fetus
Lung maturation in the fetus is regulated by the fetal secretion of
cortisol. Treatment of the mother with large doses of glucocorticoid
reduces the incidence of respiratory distress syndrome in infants
delivered prematurely. When delivery is anticipated before 34 weeks
of gestation, intramuscular betamethasone, 12 mg, followed by an
additional dose of 12 mg 18–24 hours later, is commonly used. Beta-
methasone is chosen because maternal protein binding and placental
metabolism of this corticosteroid is less than that of cortisol, allowing
increased transfer across the placenta to the fetus. A study of more
than 10,000 infants born at 23–25 weeks of gestation indicated that
exposure to exogenous corticosteroids before birth reduced the death
rate and evidence of neurodevelopmental impairment.
C. Corticosteroids and Nonadrenal Disorders
The synthetic analogs of cortisol are useful in the treatment of
a diverse group of diseases unrelated to any known disturbance
of adrenal function (Table 39–2). The usefulness of corticoste-
roids in these disorders is a function of their ability to suppress
inflammatory and immune responses and to alter leukocyte
function, as previously described (see also Chapter 55). These
agents are useful in disorders in which host response is the cause
of the major manifestations of the disease. In instances in which
the inflammatory or immune response is important in control-
ling the pathologic process, therapy with corticosteroids may be
dangerous but justified to prevent irreparable damage from an
inflammatory response—if used in conjunction with specific
therapy for the disease process.
Since corticosteroids are not usually curative, the pathologic
process may progress while clinical manifestations are suppressed.
Therefore, chronic therapy with these drugs should be undertaken
with great care and only when the seriousness of the disorder
warrants their use and when less hazardous measures have been
exhausted.
In general, attempts should be made to bring the disease pro-
cess under control using medium- to intermediate-acting gluco-
corticoids such as prednisone and prednisolone (Table 39–1), as
well as all ancillary measures possible to keep the dose low. Where
possible, alternate-day therapy should be used (see the following
text). Therapy should not be decreased or stopped abruptly. When
prolonged therapy is anticipated, it is helpful to obtain chest
x-rays and a tuberculin test, since glucocorticoid therapy can reac-
tivate dormant tuberculosis. The presence of diabetes, peptic ulcer,
osteoporosis, and psychological disturbances should be taken into
consideration, and cardiovascular function should be assessed.
712    SECTION VII  Endocrine Drugs

TABLE 39–2  Some therapeutic indications for the use of glucocorticoids in nonadrenal disorders.
Disorder Examples

Allergic reactions Angioneurotic edema, asthma, bee stings, contact dermatitis, drug reactions, allergic rhinitis, serum sickness, urticaria
Collagen-vascular Giant cell arteritis, lupus erythematosus, mixed connective tissue syndromes, polymyositis, polymyalgia rheumatica,
disorders rheumatoid arthritis, temporal arteritis
Eye diseases Acute uveitis, allergic conjunctivitis, choroiditis, optic neuritis
Gastrointestinal diseases Inflammatory bowel disease, nontropical sprue, subacute hepatic necrosis
Hematologic disorders Acquired hemolytic anemia, acute allergic purpura, leukemia, lymphoma, autoimmune hemolytic anemia, idiopathic
thrombocytopenic purpura, multiple myeloma
Systemic inflammation Acute respiratory distress syndrome (sustained therapy with moderate dosage accelerates recovery and decreases
mortality)
Infections Acute respiratory distress syndrome, sepsis
Inflammatory conditions Arthritis, bursitis, tenosynovitis
of bones and joints
Nausea and vomiting A large dose of dexamethasone reduces emetic effects of chemotherapy and general anesthesia
Neurologic disorders Cerebral edema (large doses of dexamethasone are given to patients following brain surgery to minimize cerebral
edema in the postoperative period), multiple sclerosis
Organ transplants Prevention and treatment of rejection (immunosuppression)
Pulmonary diseases Aspiration pneumonia, bronchial asthma, prenatal prevention of infant respiratory distress syndrome, sarcoidosis
Renal disorders Nephrotic syndrome
Skin diseases Atopic dermatitis, dermatoses, lichen simplex chronicus (localized neurodermatitis), mycosis fungoides, pemphigus,
psoriasis, seborrheic dermatitis, xerosis
Thyroid diseases Malignant exophthalmos, subacute thyroiditis
Miscellaneous Hypercalcemia, mountain sickness

Treatment for transplant rejection is a very important applica-
tion of glucocorticoids. The efficacy of these agents is based on
their ability to reduce antigen expression from the grafted tissue,
delay revascularization, and interfere with the sensitization of
cytotoxic T lymphocytes and the generation of primary antibody-
forming cells.
Toxicity
The benefits obtained from glucocorticoids vary considerably.
Use of these drugs must be carefully weighed in each patient
against their widespread effects. The major undesirable effects of
glucocorticoids are the result of their hormonal actions, which
lead to the clinical picture of iatrogenic Cushing’s syndrome (see
later in text).
When glucocorticoids are used for short periods (<2 weeks), it
is unusual to see serious adverse effects even with moderately large
doses. However, insomnia, behavioral changes (primarily hypo-
mania), and acute peptic ulcers are occasionally observed even
after only a few days of treatment. Acute pancreatitis is a rare but
serious acute adverse effect of high-dose glucocorticoids.
is a function of the dosage and the genetic background of the
patient. In the face, rounding, puffiness, fat deposition, and
plethora usually appear (moon facies). Similarly, fat tends to be
redistributed from the extremities to the trunk, the back of the
neck, and the supraclavicular fossae. There is an increased growth
of fine hair over the face, thighs and trunk. Steroid-induced punc-
tate acne may appear, and insomnia and increased appetite are
noted. In the treatment of dangerous or disabling disorders, these
changes may not require cessation of therapy. However, the under-
lying metabolic changes accompanying them can be very serious
by the time they become obvious. The continuing breakdown
of protein and diversion of amino acids to glucose production
increase the need for insulin and over time result in weight gain;
visceral fat deposition; myopathy and muscle wasting; thinning of
the skin, with striae and bruising; hyperglycemia; and eventually
osteoporosis, diabetes, and aseptic necrosis of the hip. Wound
healing is also impaired under these circumstances. When diabetes
occurs, it is treated with diet and insulin. These patients are often
resistant to insulin but rarely develop ketoacidosis. In general,
patients treated with corticosteroids should be on high-protein
and potassium-enriched diets.

A. Metabolic Effects B. Other Complications

Most patients who are given daily doses of 100 mg of hydrocorti- Other serious adverse effects of glucocorticoids include peptic
sone or more (or the equivalent amount of synthetic steroid) for ulcers and their consequences. The clinical findings associated
longer than 2 weeks undergo a series of changes that have been with certain disorders, particularly bacterial and mycotic infec-
termed iatrogenic Cushing’s syndrome. The rate of development tions, may be masked by the corticosteroids, and patients must
 CHAPTER 39  Adrenocorticosteroids & Adrenocortical Antagonists    713
be carefully monitored to avoid serious mishap when large doses
are used. Severe myopathy is more frequent in patients treated
with long-acting glucocorticoids. The administration of such
compounds has been associated with nausea, dizziness, and weight
loss in some patients. These effects are treated by changing drugs,
reducing dosage, and increasing potassium and protein intake.
Hypomania or acute psychosis may occur, particularly in patients
receiving very large doses of corticosteroids. Long-term therapy with
intermediate- and long-acting steroids is associated with depression
and the development of posterior subcapsular cataracts. Psychiatric
follow-up and periodic slit-lamp examination are indicated in such
patients. Increased intraocular pressure is common, and glaucoma
may be induced. Benign intracranial hypertension also occurs. In dos-
ages of 45 mg/m2 per day or more of hydrocortisone or its equivalent,
growth retardation occurs in children. Medium-, intermediate-, and
long-acting glucocorticoids have greater growth-suppressing potency
than the natural steroid at equivalent doses.
When given in larger than physiologic amounts, steroids such
as cortisone and hydrocortisone, which have mineralocorticoid
effects in addition to glucocorticoid effects, cause some sodium
and fluid retention and loss of potassium. In patients with normal
cardiovascular and renal function, this leads to a hypokalemic,
hypochloremic alkalosis and eventually to a rise in blood pressure.
In patients with hypoproteinemia, renal disease, or liver disease,
edema may also occur. In patients with heart disease, even small
degrees of sodium retention may lead to heart failure. These
effects can be minimized by using synthetic non-salt-retaining
steroids, sodium restriction, and judicious amounts of potassium
supplements.
C. Adrenal Suppression
When corticosteroids are administered for more than 2 weeks,
adrenal suppression may occur. If treatment extends over weeks
to months, the patient should be given appropriate supplemen-
tary therapy at times of minor stress (twofold dosage increases
for 24–48 hours) or severe stress (up to tenfold dosage increases
for 48–72 hours) such as accidental trauma or major surgery.
If corticosteroid dosage is to be reduced, it should be tapered
slowly. If therapy is to be stopped, the reduction process should
be quite slow when the dose reaches replacement levels. It may
take 2–12 months for the hypothalamic-pituitary-adrenal axis to
function acceptably, and cortisol levels may not return to normal
for another 6–9 months. The glucocorticoid-induced suppression
is not a pituitary problem, and treatment with ACTH does not
reduce the time required for the return of normal function.
If the dosage is reduced too rapidly in patients receiving glu-
cocorticoids for a certain disorder, the symptoms of the disorder
may reappear or increase in intensity. However, patients without
an underlying disorder (eg, patients cured surgically of Cushing’s
disease) also develop symptoms with rapid reductions in cortico-
steroid levels. These symptoms include anorexia, nausea or vomit-
ing, weight loss, lethargy, headache, fever, joint or muscle pain,
and postural hypotension. Although many of these symptoms
may reflect true glucocorticoid deficiency, they may also occur
in the presence of normal or even elevated plasma cortisol levels,
suggesting glucocorticoid dependence.
Contraindications & Cautions
A. Special Precautions
Patients receiving glucocorticoids must be monitored carefully for
the development of hyperglycemia, glycosuria, sodium retention
with edema or hypertension, hypokalemia, peptic ulcer, osteopo-
rosis, and hidden infections.
The dosage should be kept as low as possible, and intermittent
administration (eg, alternate-day) should be used when satisfactory
therapeutic results can be obtained on this schedule. Even patients
maintained on relatively low doses of corticosteroids may require
supplementary therapy at times of stress, such as when surgical
procedures are performed or intercurrent illness or accidents occur.
B. Contraindications
Glucocorticoids must be used with great caution in patients with
peptic ulcer, heart disease or hypertension with heart failure,
certain infectious illnesses such as varicella and tuberculosis,
psychoses, diabetes, osteoporosis, or glaucoma.
Selection of Drug & Dosage Schedule
Glucocorticoid preparations differ with respect to relative anti-
inflammatory and mineralocorticoid effect, duration of action,
cost, and dosage forms available (Table 39–1), and these factors
should be taken into account in selecting the drug to be used.
A. ACTH versus Adrenocortical Steroids
In patients with normal adrenals, ACTH was used in the past to
induce the endogenous production of cortisol to obtain similar
effects. However, except when an increase in androgens is desir-
able, the use of ACTH as a therapeutic agent has been abandoned.
Instances in which ACTH was claimed to be more effective than
glucocorticoids were probably due to the administration of smaller
amounts of corticosteroids than were produced by the dosage of
ACTH.
B. Dosage
In determining the dosage regimen to be used, the physician must
consider the seriousness of the disease, the amount of drug likely
to be required to obtain the desired effect, and the duration of
therapy. In some diseases, the amount required for maintenance of
the desired therapeutic effect is less than the dose needed to obtain
the initial effect, and the lowest possible dosage for the needed
effect should be determined by gradually lowering the dose until
a small increase in signs or symptoms is noted.
When it is necessary to maintain continuously elevated plasma
corticosteroid levels to suppress ACTH, a slowly absorbed par-
enteral preparation or small oral doses at frequent intervals are
required. The opposite situation exists with respect to the use
of corticosteroids in the treatment of inflammatory and allergic
disorders. The same total quantity given in a few doses may be
more effective than that given in many smaller doses or in a slowly
absorbed parenteral form.
Severe autoimmune conditions involving vital organs must
be treated aggressively, and undertreatment is as dangerous
714    SECTION VII  Endocrine Drugs
as overtreatment. To minimize the deposition of immune com-
plexes and the influx of leukocytes and macrophages, 1 mg/kg
per day of prednisone in divided doses is required initially. This
dosage is maintained until the serious manifestations respond. The
dosage can then be gradually reduced.
When large doses are required for prolonged periods of time,
alternate-day administration of the compound may be tried.
When used in this manner, very large amounts (eg, 100 mg of
prednisone) can sometimes be administered with less marked
adverse effects because there is a recovery period between each
dose. The transition to an alternate-day schedule can be made
after the disease process is under control. It should be done
gradually and with additional supportive measures between doses.
When selecting a drug for use in large doses, a medium- or
intermediate-acting synthetic steroid with little mineralocorti-
coid effect is advisable. If possible, it should be given as a single
morning dose.
C. Special Dosage Forms
Local therapy, such as topical preparations for skin disease, oph-
thalmic forms for eye disease, intra-articular injections for joint
disease, inhaled steroids for asthma, and hydrocortisone enemas
for ulcerative colitis, provides a means of delivering large amounts
of steroid to the diseased tissue with reduced systemic effects.
Beclomethasone dipropionate, and several other
glucocorticoids—primarily budesonide, flunisolide, and mometa-
sone furoate, administered as aerosols—have been found to be
extremely useful in the treatment of asthma (see Chapter 20).
Beclomethasone dipropionate, triamcinolone acetonide,
budesonide, flunisolide, fluticasone, and others are available as
nasal sprays for the topical treatment of allergic rhinitis. They
are effective at doses (one or two sprays one, two, or three times
daily) that in most patients result in plasma levels that are too low
to influence adrenal function or have any other systemic effects.
Corticosteroids incorporated in ointments, creams, lotions,
and sprays are used extensively in dermatology. These preparations
are discussed in more detail in Chapter 61.
Recently, new timed-release hydrocortisone tablets were devel-
oped for the replacement treatment of Addisonian and congenital
adrenal hyperplasia patients. These tablets produce plasma cortisol
levels that are similar to those secreted normally in a circadian
fashion.
MINERALOCORTICOIDS (ALDOSTERONE,
DEOXYCORTICOSTERONE,
FLUDROCORTISONE)
The most important mineralocorticoid in humans is aldosterone.
However, small amounts of deoxycorticosterone (DOC) are also
formed and released. Although the amount is normally insignifi-
cant, DOC was of some importance therapeutically in the past. Its
actions, effects, and metabolism are qualitatively similar to those
described below for aldosterone. Fludrocortisone, a synthetic
corticosteroid, is the most commonly prescribed salt-retaining
hormone.
Aldosterone
Aldosterone is synthesized mainly in the zona glomerulosa of
the adrenal cortex. Its structure and synthesis are illustrated in
Figure 39–1. The rate of aldosterone secretion is subject to several
influences. ACTH produces a moderate stimulation of its release,
but this effect is not sustained for more than a few days in the
normal individual. Although aldosterone is no less than one third
as effective as cortisol in suppressing ACTH, the quantities of
aldosterone produced by the adrenal cortex and its plasma concen-
trations are insufficient to participate in any significant feedback
control of ACTH secretion.
Without ACTH, aldosterone secretion falls to about half
the normal rate, indicating that other factors, eg, angiotensin,
are able to maintain and perhaps regulate its secretion (see
Chapter 17). Independent variations between cortisol and
aldosterone secretion can also be demonstrated by means of
lesions in the nervous system such as decerebration, which
decreases the secretion of cortisol while increasing the secretion
of aldosterone.
A. Physiologic and Pharmacologic Effects
Aldosterone and other steroids with mineralocorticoid proper-
ties promote the reabsorption of sodium from the distal part of
the distal convoluted renal tubule and from the cortical collect-
ing tubules, loosely coupled to the excretion of potassium and
hydrogen ion. Sodium reabsorption in the sweat and salivary
glands, gastrointestinal mucosa, and across cell membranes in
general is also increased. Excessive levels of aldosterone produced
by tumors or overdosage with synthetic mineralocorticoids lead to
hypokalemia, metabolic alkalosis, increased plasma volume, and
hypertension.
Mineralocorticoids act by binding to the mineralocorticoid
receptor in the cytoplasm of target cells, especially principal cells
of the distal convoluted and collecting tubules of the kidney.
The drug-receptor complex activates a series of events similar to
those described above for the glucocorticoids and illustrated in
Figure 39–4. It is of interest that this receptor has the same affin-
ity for cortisol, which is present in much higher concentrations in
the extracellular fluid. The specificity for mineralocorticoids in the
kidney appears to be conferred, at least in part, by the presence—
in the kidney—of the enzyme 11β-hydroxysteroid dehydrogenase
type 2, which converts cortisol to cortisone. The latter has low
affinity for the receptor and is inactive as a mineralocorticoid or
glucocorticoid in the kidney. The major effect of activation of the
aldosterone receptor is increased expression of Na+/K+-ATPase and
the epithelial sodium channel (ENaC).
B. Metabolism
Aldosterone is secreted at the rate of 100–200 mcg/d in normal
individuals with a moderate dietary salt intake. The plasma level
in men (resting supine) is about 0.007 mcg/dL. The half-life of
aldosterone injected in tracer quantities is 15–20 minutes, and it
does not appear to be firmly bound to serum proteins.
The metabolism of aldosterone is similar to that of cortisol,
about 50 mcg/24 h appearing in the urine as conjugated
 CHAPTER 39  Adrenocorticosteroids & Adrenocortical Antagonists    715
tetrahydroaldosterone. Approximately 5–15 mcg/24 h is excreted
free or as the 3-oxo glucuronide.
Deoxycorticosterone (DOC)
DOC, which also serves as a precursor of aldosterone (Figure 39–1),
is normally secreted in amounts of about 200 mcg/d. Its half-life
when injected into the human circulation is about 70 minutes.
Preliminary estimates of its concentration in plasma are approxi-
mately 0.03 mcg/dL. The control of its secretion differs from that
of aldosterone in that the secretion of DOC is primarily under the
control of ACTH. Although the response to ACTH is enhanced
by dietary sodium restriction, due to adaptations, a low-salt diet
does not increase DOC secretion. The secretion of DOC may be
markedly increased in abnormal conditions such as adrenocorti-
cal carcinoma and congenital adrenal hyperplasia with reduced
P450c11 or P450c17 activity.
Fludrocortisone
This compound, a potent steroid with both glucocorticoid and
mineralocorticoid activity, is the most widely used mineralocorti-
coid. Oral doses of 0.1 mg two to seven times weekly have potent
salt-retaining activity and are used in the treatment of adrenocor-
tical insufficiency associated with mineralocorticoid deficiency.
These dosages are too small to have important anti-inflammatory
or antigrowth effects.
ADRENAL ANDROGENS
The adrenal cortex secretes large amounts of DHEA and smaller
amounts of androstenedione and testosterone. Although these
androgens are thought to contribute to the normal maturation
process, they do not stimulate or support major androgen-
dependent pubertal changes in humans. Studies suggest that
DHEA and its sulfate may have other important physiologic
actions. If that is correct, these results are probably due to the
peripheral conversion of DHEA to more potent androgens or to
estrogens and interaction with androgen and estrogen receptors,
respectively. Additional effects may be exerted through an inter-
action with the GABAA and glutamate receptors in the brain or
with a nuclear receptor in several central and peripheral sites. The
therapeutic use of DHEA in humans has been explored, but the
substance has already been adopted with uncritical enthusiasm
by members of the sports drug culture and the vitamin and food
supplement culture.
The results of a placebo-controlled trial of DHEA in patients
with systemic lupus erythematosus have been reported as well as
those of a study of DHEA replacement in women with adrenal
insufficiency. In both studies a small beneficial effect was seen,
with significant improvement of the disease in the former and
a clearly added sense of well-being in the latter. The androgenic
or estrogenic actions of DHEA could explain the effects of the
compound in both situations. In contrast, there is no evidence
to support DHEA use to increase muscle strength or improve
memory.
■■ ANTAGONISTS OF
ADRENOCORTICAL AGENTS
SYNTHESIS INHIBITORS &
GLUCOCORTICOID ANTAGONISTS
Inhibitors of steroid synthesis act at several different steps and one
glucocorticoid antagonist acts at the receptor level.
Aminoglutethimide
Aminoglutethimide (Figure 39–5) blocks the conversion of
cholesterol to pregnenolone (see Figure 39–1) and causes a
reduction in the synthesis of all hormonally active steroids. It has
been used in conjunction with dexamethasone or hydrocortisone
to reduce or eliminate estrogen production in patients with
carcinoma of the breast. In a dosage of 1 g/d it was well toler-
ated; however, with higher dosages, lethargy and skin rash were
common effects. The use of aminoglutethimide in breast cancer
patients has now been supplanted by tamoxifen or by another
class of drugs, the aromatase inhibitors (see Chapters 40 and 54).
Aminoglutethimide can be used in conjunction with metyra-
pone or ketoconazole to reduce steroid secretion in patients with
Cushing’s syndrome due to adrenocortical cancer who do not
respond to mitotane.
Aminoglutethimide also apparently increases the clearance of
some steroids. It has been shown to enhance the metabolism of
dexamethasone, reducing its half-life from 4–5 hours to 2 hours.
Ketoconazole
Ketoconazole, an antifungal imidazole derivative (see Chapter 48),
is a potent and rather nonselective inhibitor of adrenal and
gonadal steroid synthesis. This compound inhibits the cholesterol
side-chain cleavage, P450c17, C17,20-lyase, 3β-hydroxysteroid
dehydrogenase, and P450c11 enzymes required for steroid hor-
mone synthesis. The sensitivity of the P450 enzymes to this
compound in mammalian tissues is much lower than that needed
to treat fungal infections, so that its inhibitory effects on steroid
biosynthesis are seen only at high doses.
Ketoconazole has been used in the treatment of patients
with Cushing’s syndrome due to several causes. Dosages of
200–1200 mg/d have caused a reduction in hormone levels
and clinical improvement in some patients. This drug has some
hepatotoxicity and should be started at 200 mg/d and slowly
increased by 200 mg/d every 2–3 days up to a total daily dose
of 1000 mg.
Etomidate
Etomidate [R-1-(1-ethylphenyl)imidazole-5-ethyl ester] is used
for induction of general anesthesia and sedation. At subhypnotic
doses of 0.1 mg/kg per hour this drug inhibits adrenal steroido-
genesis at the level of 11β-hydroxylase and has been used as the
only parenteral medication available in the treatment of severe
Cushing’s syndrome.
716    SECTION VII  Endocrine Drugs

CI CI CI N O CH3 N
CH C C
CI C CH3
H
Mitotane Metyrapone

C2H5

NH2

O O
N

H N
Aminoglutethimide
N CI

O CH2
O CI

CH3C N N OCH2 O
H

Ketoconazole

FIGURE 39–5  Some adrenocortical blockers. Because of their toxicity, some of these compounds are no longer available in the United States.

Metyrapone In patients with Cushing’s syndrome, a normal response to

Metyrapone (Figure 39–5) is a relatively selective inhibitor of
steroid 11-hydroxylation, interfering with cortisol and corticoste-
rone synthesis. In the presence of a normal pituitary gland, there
is a compensatory increase in pituitary ACTH release and adrenal
11-deoxycortisol secretion. This response is a measure of the
capacity of the anterior pituitary to produce ACTH and has been
adapted for clinical use as a diagnostic test. Although the toxicity
of metyrapone is much lower than that of mitotane (see text that
follows), the drug may produce transient dizziness and gastroin-
testinal disturbances. This agent has not been widely used in the
treatment of Cushing’s syndrome. However, in doses of 0.25 g
twice daily to 1 g four times daily, metyrapone can reduce cortisol
production to normal levels in some patients with endogenous
Cushing’s syndrome. Thus, it may be useful in the management
of severe manifestations of cortisol excess while the cause of this
condition is being determined or in conjunction with radiation
or surgical treatment. Metyrapone is the only adrenal-inhibiting
medication that can be administered to pregnant women with
Cushing’s syndrome. The major adverse effects observed are salt
and water retention and hirsutism resulting from diversion of the
11-deoxycortisol precursor to DOC and androgen synthesis.
Metyrapone is commonly used in tests of adrenal function.
The blood levels of 11-deoxycortisol and the urinary excretion of
17-hydroxycorticoids are measured before and after administra-
tion of the compound. Normally, there is a twofold or greater
increase in the urinary 17-hydroxycorticoid excretion. A dosage of
300–500 mg every 4 hours for six doses is often used, and urine
collections are made on the day before and the day after treatment.
metyrapone indicates that the cortisol excess is not the result of a
cortisol-secreting adrenal carcinoma or adenoma, since secretion
by such tumors produces suppression of ACTH and atrophy of
normal adrenal cortex.
Pituitary function may also be tested by administering metyra-
pone, 2–3 g orally at midnight and by measuring the level of ACTH
or 11-deoxycortisol in blood drawn at 8 am or by comparing
the excretion of 17-hydroxycorticosteroids in the urine during the
24-hour periods preceding and following administration of the
drug. In patients with suspected or known lesions of the pituitary,
this procedure is a means of estimating the ability of the gland to
produce ACTH. Metyrapone has been withdrawn from the market
in the United States but is available on a compassionate basis.
Trilostane
Trilostane is a 3β-17 hydroxysteroid dehydrogenase inhibitor that
interferes with the synthesis of adrenal and gonadal hormones and
is comparable to aminoglutethimide. Trilostane’s adverse effects
are predominantly gastrointestinal; adverse effects occur in about
50% of patients with both trilostane and aminoglutethimide.
There is no cross-resistance or crossover of side effects between
these compounds. Trilostane is not available in the United States.
Abiraterone
Abiraterone is the newest of the steroid synthesis inhibitors to be
approved. It blocks 17α-hydroxylase (P450c17) and 17,20-lyase
(Figure 39–1), and predictably reduces synthesis of cortisol in
 CHAPTER 39  Adrenocorticosteroids & Adrenocortical Antagonists    717
the adrenal and gonadal steroids in the gonads. A compensatory
increase occurs in ACTH and aldosterone synthesis, but this can
be prevented by concomitant administration of dexamethasone.
Abiraterone is an orally active steroid prodrug and is approved for
the treatment of refractory prostate cancer.
Mifepristone (RU-486)
The search for a glucocorticoid receptor antagonist finally
succeeded in the early 1980s with the development of the
11β-aminophenyl-substituted 19-norsteroid called RU-486, later
named mifepristone. Unlike the enzyme inhibitors previously
discussed, mifepristone is a pharmacologic antagonist at the
steroid receptor. This compound has strong antiprogestin activity
and initially was proposed as a contraceptive-contragestive agent.
High doses of mifepristone exert antiglucocorticoid activity by
blocking the glucocorticoid receptor, since mifepristone binds
to it with high affinity, causing (1) some stabilization of the hsp-
glucocorticoid receptor complex and inhibition of the dissocia-
tion of the RU-486–bound glucocorticoid receptor from the hsp
chaperone proteins; and (2) alteration of the interaction of the
glucocorticoid receptor with coregulators, favoring the formation
of a transcriptionally inactive complex in the cell nucleus. The
result is inhibition of glucocorticoid receptor activation.
The mean half-life of mifepristone is 20 hours. This is longer
than that of many natural and synthetic glucocorticoid agonists
(dexamethasone has a half-life of 4–5 hours). Less than 1% of
the daily dose is excreted in the urine, suggesting a minor role of
kidneys in the clearance of the compound. The long plasma half-
life of mifepristone results from extensive and strong binding to
plasma proteins. Less than 5% of the compound is found in the
free form when plasma is analyzed by equilibrium dialysis. Mife-
pristone can bind to albumin and α1-acid glycoprotein, but it has
no affinity for corticosteroid-binding globulin.
In humans, mifepristone causes generalized glucocorticoid
resistance. Given orally to several patients with Cushing’s syn-
drome due to ectopic ACTH production or adrenal carcinoma,
it was able to reverse the cushingoid phenotype, eliminate car-
bohydrate intolerance, normalize blood pressure, correct thyroid
and gonadal hormone suppression, and to ameliorate the psycho-
logical sequelae of hypercortisolism in these patients. At present,
this use of mifepristone can only be recommended for inoperable
patients with ectopic ACTH secretion or adrenal carcinoma who
have failed to respond to other therapeutic manipulations. Its
pharmacology and use in women as a progesterone antagonist are
discussed in Chapter 40.
Mitotane
Mitotane (Figure 39–5), a drug related to the DDT class of insec-
ticides, has a nonselective cytotoxic action on the adrenal cortex
in dogs and to a lesser extent in humans. This drug is adminis-
tered orally in divided doses up to 12 g daily. About one-third
of patients with adrenal carcinoma show a reduction in tumor
mass. In 80% of patients, the toxic effects are sufficiently severe
to require dose reduction. These include diarrhea, nausea, vomit-
ing, depression, somnolence, and skin rashes. The drug has been
withdrawn from the market in the United States but is available
on a compassionate basis.
MINERALOCORTICOID ANTAGONISTS
In addition to agents that interfere with aldosterone synthesis (see
above), there are steroids that compete with aldosterone for its
receptor and decrease its effect peripherally. Progesterone is mildly
active in this respect.
Spironolactone is a 7α-acetylthiospirolactone. Its onset of action
is slow, and the effects last for 2–3 days after the drug is discontin-
ued. It is used in the treatment of primary aldosteronism in dosages
of 50–100 mg/d. This agent reverses many of the manifestations
of aldosteronism. It has been useful in establishing the diagnosis in
some patients and in ameliorating the signs and symptoms when
surgical removal of an adenoma is delayed. When used diagnosti-
cally for the detection of aldosteronism in hypokalemic patients
with hypertension, dosages of 400–500 mg/d for 4–8 days—with an
adequate intake of sodium and potassium—restore potassium levels
to or toward normal. Spironolactone is also useful in preparing these
patients for surgery. Dosages of 300–400 mg/d for 2 weeks are used
for this purpose and may reduce the incidence of cardiac arrhythmias.
O
O
H3C
H3C
O
O
S C CH3
Spironolactone
Spironolactone is also an androgen antagonist and as such is
sometimes used in the treatment of hirsutism and acne in women.
Dosages of 50–200 mg/d cause a reduction in the density, diameter,
and rate of growth of facial hair in patients with idiopathic hirsut-
ism or hirsutism secondary to androgen excess. The effect can usu-
ally be seen in 2 months and becomes maximal in about 6 months.
Spironolactone as a diuretic is discussed in Chapter 15. The
drug has benefits in heart failure greater than those predicted from
its diuretic effects alone (see Chapter 13). Adverse effects reported
for spironolactone include hyperkalemia, cardiac arrhythmia,
menstrual abnormalities, gynecomastia, sedation, headache,
gastrointestinal disturbances, and skin rashes.
Eplerenone, another aldosterone antagonist, is approved for
the treatment of hypertension and heart failure (see Chapters 11,
13, and 15). Like spironolactone, eplerenone has also been found
to reduce mortality in heart failure. This aldosterone receptor
antagonist is somewhat more selective than spironolactone and
has no reported effects on androgen receptors. The standard dos-
age in hypertension is 50–100 mg/d. The most common toxicity
is hyperkalemia, but this is usually mild.
Drospirenone, a progestin, is an oral contraceptive (see
Chapter 40), and also antagonizes the effects of aldosterone.
718    SECTION VII  Endocrine Drugs

P R E P A R A T I O N S Chrousos GP: Stress and disorders of the stress system. Nat Rev Endocrinol
2009;5:374.
A V A I L A B L E Chrousos GP, Kino T: Glucocorticoid signaling in the cell: Expanding clinical
implications to complex human behavioral and somatic disorders. In:
Glucocorticoids and mood: Clinical manifestations, risk factors, and molec-
GENERIC NAME AVAILABLE AS ular mechanisms. Proc NY Acad Sci 2009;1179:153.
*
GLUCOCORTICOIDS FOR ORAL & PARENTERAL USE Cutolo M, Chrousos GP, Pincus T: Special issue on glucocorticoid therapy in
Betamethasone Celestone rheumatic diseases. Neuroimmunomodulation. 2015;22:3.
Betamethasone sodium phosphate Generic, Celestone Phosphate Elenkov IJ, Chrousos GP: Stress hormones, TH1/TH2 patterns, pro/anti-inflammatory
cytokines and susceptibility to disease. Trends Endocrinol Metab 1999;10:359.
Budesonide Generic, Entocort EC
Elenkov IJ et al: Cytokine dysregulation, inflammation, and wellbeing. Neuroim-
Cortisone Generic munomodulation 2005;12:255.
Dexamethasone Generic, Decadron Franchimont D et al: Glucocorticoids and inflammation revisited: The state of the
Dexamethasone sodium phosphate Generic art. Neuroimmunomodulation 2002–2003;10:247.
Hydrocortisone (cortisol) Generic, Cortef Graber AL et al: Natural history of pituitary-adrenal recovery following long-term
suppression with corticosteroids. J Clin Endocrinol Metab 1965;25:11.
Hydrocortisone acetate Generic
Hochberg Z, Pacak K, Chrousos GP: Endocrine withdrawal syndromes. Endocr
Hydrocortisone sodium phosphate Hydrocortone Rev 2003;24:523.
Hydrocortisone sodium succinate Generic, Solu-Cortef, others Kalantaridou S, Chrousos GP: Clinical review 148: Monogenic disorders of
Methylprednisolone Generic, Medrol puberty. J Clin Endocrinol Metab 2002;87:2481.
Methylprednisolone acetate Generic, Depo-Medrol Kino T, Charmandari E, Chrousos G (editors): Glucocorticoid action: Basic and
clinical implications. Ann NY Acad Sci 2004;1024.
Methylprednisolone sodium Generic, Solu-Medrol, others
Kino T et al: The GTP-binding (G) protein β interacts with the activated gluco-
succinate
corticoid receptor and suppresses its transcriptional activity in the nucleus.
Prednisolone Generic, Prelone, others J Cell Biol 2005;20:885.
Prednisolone acetate Generic, Flo-Pred Koch CA, Chrousos GP (editors): Endocrine hypertension: Underlying mecha-
Prednisolone sodium phosphate Generic, Hydeltrasol nisms and therapy. In: Contemporary Endocrinology, vol XIII. Springer, 2013.
Prednisone Generic, Deltasone, Prednicot Koch CA, Pacak K, Chrousos GP: The molecular pathogenesis of hereditary and
sporadic adrenocortical and adrenomedullary tumors. J Clin Endocrinol
Triamcinolone acetonide Generic, Kenalog, Azmacort Metab 2002;87:5367.
Triamcinolone hexacetonide Aristospan Mao J, Regelson W, Kalimi M: Molecular mechanism of RU 486 action: A review.
MINERALOCORTICOIDS Mol Cellular Biochem 1992;109:1.
Fludrocortisone acetate Generic, Florinef Acetate, Marik PE et al: Clinical practice guidelines for the diagnosis and management of
Cortineff Acetate corticosteroid insufficiency in critical illness: Recommendations of an inter-
national task force. Crit Care Med 2008;36:1937.
ADRENAL STEROID INHIBITORS
Markou A et al: Stress-induced aldosterone hyper-secretion in a substantial
Abiraterone Zytiga subset of patients with essential hypertension. J Clin Endocrinol Metab.
Ketoconazole Generic, Nizoral 2015;100:2857.
Etomidate Amidate Meduri GU et al: Activation and regulation of systemic inflammation in ARDS:
Rationale for prolonged glucocorticoid therapy. Chest 2009;136:1631.
Mifepristone Mifeprex, Korlym
Meduri GU et al: Steroid treatment in ARDS: A critical appraisal of the ARDS
Mitotane Lysodren network trial and the recent literature. Intens Care Med 2008;34:61.
Glucocorticoids for respiratory use: See Chapter 20. Glucocorticoids for dermatologic Merke DP et al: Future directions in the study and management of congenital
use: See Chapter 61. Glucocorticoids for gastrointestinal use: See Chapter 62. adrenal hyperplasia due to 21-hydroxylase deficiency. Ann Intern Med
2002;136:320.
Nader N, Chrousos GP, Kino T: Interactions of the circadian CLOCK system and
the HPA axis. Trends Endocrinol Metab 2010;21:277.
REFERENCES Papanastasiou L et al: Primary aldosteronism in hypertensive patients: Clinical
Alesci S et al: Glucocorticoid-induced osteoporosis: From basic mechanisms to implications and target therapy. Eur J Clin Invest. 2014;44:697.
clinical aspects. Neuroimmunomodulation 2005;12:1. Pervanidou P, Kanaka-Gantenbein C, Chrousos GP: Assessment of metabolic
Bamberger CM, Schulte HM, Chrousos GP: Molecular determinants of gluco- profile in a clinical setting. Curr Opin Clin Nutr Metab Care 2006;9:589.
corticoid receptor function and tissue sensitivity to glucocorticoids. Endocr Preda VA et al: Etomidate in the management of hypercortisolaemia in Cushing’s
Rev 1996;17:245. syndrome: A review. Eur J Endocrinol 2012;167:137.
Charmandari E et al: Peripheral CLOCK regulates target-tissue glucocorticoid Tsigos C, Chrousos GP: Differential diagnosis and management of Cushing’s
receptor transcriptional activity in a circadian fashion in man. PLoS One syndrome. Annu Rev Med 1996;47:443.
2011;6:e25612.
Whitaker MJ et al: An oral multiparticulate, modified-release, hydrocortisone
Charmandari E, Kino T: Chrousos syndrome: A seminal report, a phylogenetic replacement therapy that provides physiological cortisol exposure. Clin
enigma and the clinical implications of glucocorticoid signaling changes. Eur Endocrinol (Oxf ) 2014;80:554.
J Clin Invest 2010;40:932.
Zannas AS, Chrousos GP. Glucocorticoid signaling drives epigenetic and tran-
Charmandari E, Nicolaides NC, Chrousos GP: Adrenal insufficiency. Lancet. scription factors to induce key regulators of human parturition. Sci Signal
2014;383:2152. 2015;8:fs19.
Charmandari E, Tsigos C, Chrousos GP: Neuroendocrinology of stress. Ann Rev
Physiol 2005;67:259.
 CHAPTER 39  Adrenocorticosteroids & Adrenocortical Antagonists    719

C ASE STUDY ANSWER

The patient should be placed on replacement oral hydrocor- for increased treatment at 2 times standard glucocorticoid
tisone at 10 mg/m2 per day and fludrocortisone at 75 mcg/d. dosage for 24 hours for minor stress and 10 times replace-
He should be given a MedicAlert bracelet and instructions ment of hydrocortisone for major stress over 48 hours.
 40
C H A P T E R
The Gonadal Hormones
& Inhibitors
George P. Chrousos, MD
C ASE STUDY
A 25-year-old woman with menarche at 13 years and
menstrual periods until about 1 year ago complains of hot
flushes, skin and vaginal dryness, weakness, poor sleep, and
scanty and infrequent menstrual periods of a year’s dura-
tion. She visits her gynecologist, who obtains plasma levels
of follicle-stimulating hormone and luteinizing hormone,
both of which are moderately elevated. She is diagnosed
■■ THE OVARY (ESTROGENS,
PROGESTINS, OTHER
OVARIAN HORMONES, ORAL
CONTRACEPTIVES, INHIBITORS
& ANTAGONISTS, & OVULATION-
INDUCING AGENTS)
The ovary has important gametogenic functions that are inte-
grated with its hormonal activity. In the human female, the
gonad is relatively quiescent during childhood, the period of
rapid growth and maturation. At puberty, the ovary begins a
30- to 40-year period of cyclic function called the menstrual
cycle because of the regular episodes of bleeding that are its most
obvious manifestation. It then fails to respond to gonadotropins
secreted by the anterior pituitary gland, and the cessation of cyclic
bleeding that occurs is called menopause.
The mechanism responsible for the onset of ovarian func-
tion at the time of puberty is thought to be neural in origin,
because the immature gonad can be stimulated by gonadotro-
pins already present in the pituitary and because the pituitary is
responsive to exogenous hypothalamic gonadotropin-releasing
720
with premature ovarian failure, and estrogen and pro-
gesterone replacement therapy is recommended. A dual-
energy absorptiometry scan (DEXA) reveals a bone density
t-score of <2.5 SD, ie, frank osteoporosis. How should the
ovarian hormones she lacks be replaced? What extra mea-
sures should she take for her osteoporosis while receiving
treatment?
hormone (GnRH). Despite extensive research in the field, the
mechanism of puberty initiation still remains an enigma. Pulsatile
pituitary gonadotropin secretion under the guidance of GnRH
definitely constitutes a sine qua non for pubertal onset. However,
the secretion of GnRH in the human hypothalamus is regulated
by kisspeptin and its receptor, as well as by permissive or opposing
signals mediated by neurokinin B and dynorphin acting on their
respective receptors. These three supra-GnRH regulators com-
pose the Kisspeptin, Neurokinin B, and Dynorphin neuron
(KNDy) system, a key player in pubertal onset and progression.
Recently, makorin ring finger protein 3 (MKRN3) was also
implicated in pubertal onset by contributing to the regulation
of the KNDy system. However, the inhibitory (gamma-amino
butyric acid, neuropeptide Y, and RFamide-related peptide-3)
and stimulatory (glutamate) signals acting upstream of KNDy call
into question the primary role of MKRN3 as the gatekeeper of
puberty. Recently, epigenetic mechanisms involving derepression
of genes, such as that of kisspeptin, have been implicated in puber-
tal onset. Ultimately, withdrawal of a childhood-related inhibitory
effect upon hypothalamic arcuate nucleus neurons allows these
neurons to produce GnRH in pulses with the appropriate ampli-
tude, which stimulate the release of follicle-stimulating hormone
(FSH) and luteinizing hormone (LH) (see Chapter 37). At first,
 CHAPTER 40  The Gonadal Hormones & Inhibitors     721

ACRONYMS a corpus albicans. The endometrium, which proliferated during

the follicular phase and developed its glandular function during
CBG Corticosteroid-binding globulin (transcortin)
the luteal phase, is shed in the process of menstruation. These
DHEA Dehydroepiandrosterone events are summarized in Figure 40–1.
DHEAS Dehydroepiandrosterone sulfate The ovary normally ceases its gametogenic and endocrine
ERE Estrogen response element function with time. This change is accompanied by a cessation
FSH Follicle-stimulating hormone in uterine bleeding (menopause) and occurs at a mean age of
52 years in the United States. Although the ovary ceases to secrete
GnRH Gonadotropin-releasing hormone
estrogen, significant levels of estrogen persist in many women as a
HDL High-density lipoprotein
result of conversion of adrenal and ovarian steroids such as andro-
HRT Hormone replacement therapy (also called HT) stenedione to estrone and estradiol in adipose and possibly other
LDL Low-density lipoprotein nonendocrine tissues.
LH Luteinizing hormone
PRE Progesterone response element A. Disturbances in Ovarian Function
SERM Selective estrogen receptor modulator Disturbances of cyclic function are common even during the peak
years of reproduction. A minority of these result from inflam-
SHBG Sex hormone-binding globulin
matory or neoplastic processes that influence the functions of
TBG Thyroxine-binding globulin
the uterus, ovaries, or pituitary. Many of the minor disturbances
leading to periods of amenorrhea or anovulatory cycles are

small amounts of the latter two hormones are released during the
night, and the limited quantities of ovarian estrogen secreted in Follicular development
response start to cause breast development. Subsequently, FSH
and LH are secreted throughout the day and night, causing secre-
tion of higher amounts of estrogen and leading to further breast
enlargement, alterations in fat distribution, and a growth spurt
that culminates in epiphyseal closure in the long bones. The
change of ovarian function at puberty is called gonadarche. Endometrium
A year or so after gonadarche, sufficient estrogen is produced
to induce endometrial changes and periodic bleeding (menarche).
After the first few irregular cycles, which may be anovulatory,
normal cyclic function is established. 0 7 14 21 28
At the beginning of each cycle, a variable number of follicles Days
(vesicular follicles), each containing an ovum, begin to enlarge 80
in response to FSH. After 5 or 6 days, one follicle, called the Gonadotropins
dominant follicle, begins to develop more rapidly. The outer 60
theca and inner granulosa cells of this follicle multiply and,
mIU/mL

under the influence of LH, synthesize and release estrogens at 40

an increasing rate. The estrogens appear to inhibit FSH release
LH FSH
and may lead to regression of the smaller, less mature follicles.
20
The mature dominant ovarian follicle consists of an ovum sur-
rounded by a fluid-filled antrum lined by granulosa and theca
0
cells. The estrogen secretion reaches a peak just before midcycle,
400
and the granulosa cells begin to secrete progesterone. These
Estradiol
changes stimulate the brief surge in LH and FSH release that
pg/mL

precedes and causes ovulation. When the follicle ruptures, the 200
ovum is released into the abdominal cavity near the opening of
0
the uterine tube.
Following the above events, the cavity of the ruptured fol- 20
licle fills with blood (corpus hemorrhagicum), and the lutein- Progesterone
ng/mL

ized theca and granulosa cells proliferate and replace the blood
to form the corpus luteum. The cells of this structure produce
estrogens and progesterone for the remainder of the cycle, or 0
1 7 14 21 28
longer if pregnancy occurs.
If pregnancy does not occur, the corpus luteum begins to FIGURE 40–1  The menstrual cycle, showing plasma levels of
degenerate and ceases hormone production, eventually becoming pituitary and ovarian hormones and histologic changes.
722    SECTION VII  Endocrine Drugs

self-limited. They are often associated with emotional or physical
stress and reflect temporary alterations in the stress centers in the
brain that control the secretion of GnRH. Anovulatory cycles are
also associated with eating disorders (bulimia, anorexia nervosa)
and with severe exercise such as distance running and swimming.
Among the more common organic causes of persistent ovulatory
disturbances are pituitary prolactinomas and syndromes and
tumors characterized by excessive ovarian or adrenal androgen
production. Normal ovarian function can be modified by andro-
gens produced by the adrenal cortex or tumors arising from it.
The ovary also gives rise to androgen-producing neoplasms such
as arrhenoblastomas, as well as to estrogen-producing granulosa
cell tumors.
THE ESTROGENS
Estrogenic activity is shared by a large number of chemical sub-
stances. In addition to the variety of steroidal estrogens derived
from animal sources, numerous nonsteroidal estrogens have
been synthesized. Many phenols are estrogenic, and estrogenic
activity has been identified in diverse forms of life including
those found in ocean sediments. Estrogen-mimetic compounds
(flavonoids) are found in many plants, including saw palmetto,
and soybeans and other foods. A diet rich in these plant prod-
ucts may cause slight estrogenic effects. Additionally, some
compounds used in the manufacture of plastics (bisphenols,
alkylphenols, phthalate phenols) have been found to be estro-
genic. It has been proposed that these agents are associated
with an increased breast cancer incidence in both women and
men in the industrialized world.
Natural Estrogens
The major estrogens produced by women are estradiol (estradiol-
17β, E2), estrone (E1), and estriol (E3) (Figure 40–2). Estradiol
is the major secretory product of the ovary. Although some
estrone is produced in the ovary, most estrone and estriol are
formed in the liver from estradiol or in peripheral tissues from
androstenedione and other androgens (see Figure 39–1). As
noted above, during the first part of the menstrual cycle estro-
gens are produced in the ovarian follicle by the theca and granu-
losa cells. After ovulation, the estrogens as well as progesterone

Follicular phase Luteal phase

Pregnenolone Pregnenolone

17α-Hydroxypregnenolone Progesterone

Dehydroepiandrosterone 17α-Hydroxyprogesterone

18 O OH
H3C H3C
12 17
19 11 13 16
H3C 14 15 H3C
1 9
2 10 8
3 5 7
4 6
O O
Androstenedione Testosterone

Aromatase

OH O O OH
H3C H3C H3C H3C
OH OH
C D

A B
HO HO HO HO
Estriol 16α-Hydroxyestrone Estrone 17β-Estradiol

2-Hydroxyestrone 2-Hydroxyestradiol
and other metabolites and other metabolites

FIGURE 40–2  Biosynthesis and metabolism of estrogens and testosterone.

 CHAPTER 40  The Gonadal Hormones & Inhibitors     723

are synthesized by the luteinized granulosa and theca cells of
the corpus luteum, and the pathways of biosynthesis are slightly
different.
During pregnancy, a large amount of estrogen is synthesized
by the fetoplacental unit—consisting of the fetal adrenal zone,
secreting androgen precursor, and the placenta, which aromatizes
it into estrogen. The estriol synthesized by the fetoplacental unit is
released into the maternal circulation and excreted into the urine.
Repeated assay of maternal urinary estriol excretion has been used
in the assessment of fetal well-being.
One of the most prolific natural sources of estrogenic sub-
stances is the stallion, which liberates more of these hormones than
the pregnant mare or pregnant woman. The equine estrogens—
equilenin and equilin—and their congeners are unsaturated in
the B as well as the A ring and are excreted in large quantities in
urine, from which they can be recovered and used for medicinal
purposes.
In normal women, estradiol is produced at a rate that varies
during the menstrual cycle, resulting in plasma levels as low as
50 pg/mL in the early follicular phase to as high as 350–850 pg/mL
at the time of the preovulatory peak (Figure 40–1).
Synthetic Estrogens
A variety of chemical alterations have been applied to the natural
estrogens. The most important effect of these alterations has been
to increase their oral effectiveness. Some structures are shown in
Figure 40–3. Those with therapeutic use are listed in Table 40–1.
In addition to the steroidal estrogens, a variety of nonsteroidal
compounds with estrogenic activity have been synthesized and
used clinically. These include dienestrol, diethylstilbestrol, benzes-
trol, hexestrol, methestrol, methallenestril, and chlorotrianisene.
Pharmacokinetics
When released into the circulation, estradiol binds strongly to an
α2 globulin (sex hormone–binding globulin [SHBG]) and with
lower affinity to albumin. Bound estrogen is relatively unavailable
for diffusion into cells, and it is the free fraction that is physiologi-
cally active. Estradiol is converted by the liver and other tissues
to estrone and estriol (Figure 40–2) and their 2-hydroxylated
derivatives and conjugated metabolites (which are too insoluble
in lipid to cross the cell membrane readily) and excreted in the
bile. Estrone and estriol have low affinity for the estrogen receptor.

Steroidal,
natural
OH O OH
H3C H3C H3C
OH

HO HO HO
Estradiol Estrone Estriol

Steroidal,
synthetic
OH OH OH
H3C 20 21 H3C H3C
C CH C CH C CH

HO H3C O O

Ethinyl estradiol Mestranol Quinestrol

Nonsteroidal,
synthetic

CH3 Cl

CH2 H3C O C C O CH3 C2H5 CH3

HO C C OH CH C COOH

CH2 H3C O CH3

CH3 O CH3

Diethylstilbestrol Chlorotrianisene Methallenestril

FIGURE 40–3  Compounds with estrogenic activity.

724    SECTION VII  Endocrine Drugs
TABLE 40–1  Commonly used estrogens.
Preparation Average Replacement Dosage
Ethinyl estradiol 0.005–0.02 mg/d
Micronized estradiol 1–2 mg/d
Estradiol cypionate 2–5 mg every 3–4 weeks
Estradiol valerate 2–20 mg every other week
Estropipate 1.25–2.5 mg/d
Conjugated, esterified, or mixed estrogenic substances:
 Oral 0.3–1.25 mg/d
 Injectable 0.2–2 mg/d
 Transdermal Patch
Quinestrol 0.1–0.2 mg/week
Chlorotrianisene 12–25 mg/d
Methallenestril 3–9 mg/d
However, the conjugates may be hydrolyzed in the intestine to
active, reabsorbable compounds. Estrogens are also excreted in
small amounts in the breast milk of nursing mothers.
Because significant amounts of estrogens and their active
metabolites are excreted in the bile and reabsorbed from the
intestine, the resulting enterohepatic circulation ensures that
orally administered estrogens will have a high ratio of hepatic to
peripheral effects. As noted below, the hepatic effects are thought
to be responsible for some undesirable actions such as synthesis of
increased clotting factors and plasma renin substrate. The hepatic
effects of estrogen can be minimized by routes that avoid first-pass
liver exposure, ie, vaginal, transdermal, or by injection.
Physiologic Effects
A. Mechanism
Estrogens in the blood and interstitial fluid are bound to SHBG,
from which they dissociate to cross the cell membrane, enter
the nucleus, and bind to their receptor. Two genes code for two
estrogen receptor isoforms, α and β, which are members of the
superfamily of steroid, sterol, retinoic acid, and thyroid receptors.
Unlike glucocorticoid receptors, estrogen receptors are found pre-
dominantly in the nucleus, where they are bound to heat shock
proteins that stabilize them (see Figure 39–4).
Binding of the hormone to its receptor alters the recep-
tor’s conformation and releases it from the stabilizing proteins
(predominantly Hsp90). The receptor-hormone complex forms
dimers (usually ERα-ERα, ERβ-ERβ, or ERα-ERβ) that bind
to a specific sequence of nucleotides, called estrogen response
elements (EREs), in the regulatory regions of various genes
and regulate their transcription. The ERE is composed of two
half-sites arranged as a palindrome separated by a small group of
nucleotides called the spacer. The interaction of a receptor dimer
with the ERE also involves a number of nuclear proteins, the
coregulators, as well as components of the transcription machin-
ery. Complex interactions with various coregulators appear to be
responsible for some of the tissue-specific effects that govern the
actions of selective estrogen receptor modulators (SERMs, see
below). The receptor may also bind to other transcription factors
to influence the effects of these factors on their responsive genes.
Interestingly, although ERβ has its own separate actions from
ERα, it also acts as a dominant negative inhibitor of ERα. Thus,
while ERα has many growth-promoting properties, ERβ has anti-
growth effects. Many phytoestrogens act via the ERβ protecting
cells from the pro-growth effects of ERα.
The relative concentrations and types of receptors, receptor
coregulators, and transcription factors confer the cell specificity
of the hormone’s actions. The genomic effects of estrogens are
mainly due to proteins synthesized by translation of RNA tran-
scribed from a responsive gene. Some of the effects of estrogens
are indirect, mediated by the autocrine and paracrine actions of
autacoids such as growth factors, lipids, glycolipids, and cytokines
produced by the target cells in response to estrogen.
2+
Rapid estrogen-induced effects such as granulosa cell Ca
uptake and increased uterine blood flow do not require gene
activation. These appear to be mediated by nongenomic effects of
the classic estrogen receptor-estrogen complex, influencing several
intracellular signaling pathways.
Recently, all steroid receptors except the mineralocorticoid
receptors were shown to have palmitoylation motifs that allow
enzymatic addition of palmitate and increased localization of the
receptors in the vicinity of plasma membranes. Such receptors
are available for direct interactions with, and effects on, various
membrane-associated or cytoplasmic proteins without the need
for entry into the nucleus and induction of transcriptional actions.
B. Female Maturation
Estrogens are required for the normal sexual maturation and
growth of the female. They stimulate the development of the
vagina, uterus, and uterine tubes as well as the secondary sex
characteristics. They stimulate stromal development and ductal
growth in the breast and are responsible for the accelerated growth
phase and the closing of the epiphyses of the long bones that
occur at puberty. They contribute to the growth of axillary and
pubic hair and alter the distribution of body fat to produce typical
female body contours. Larger quantities also stimulate develop-
ment of pigmentation in the skin, most prominent in the region
of the nipples and areolae and in the genital region.
C. Endometrial Effects
In addition to its growth effects on uterine muscle, estrogen plays
an important role in the development of the endometrial lin-
ing. When estrogen production is properly coordinated with the
production of progesterone during the normal human menstrual
cycle, regular periodic bleeding and shedding of the endometrial
lining occur. Continuous exposure to estrogens for prolonged
periods leads to hyperplasia of the endometrium that is usually
associated with abnormal bleeding patterns.
D. Metabolic and Cardiovascular Effects
Estrogens have a number of important metabolic and cardiovascu-
lar effects. They seem to be partially responsible for maintenance

of the normal structure and function of the skin and blood vessels
in women. Estrogens also decrease the rate of resorption of bone
by promoting the apoptosis of osteoclasts and by antagonizing
the osteoclastogenic and pro-osteoclastic effects of parathyroid
hormone and interleukin 6. Estrogens also stimulate adipose tis-
sue production of leptin and are in part responsible for the higher
levels of this hormone in women than in men.
In addition to stimulating the synthesis of enzymes and growth
factors leading to uterine and breast growth and differentiation,
estrogens alter the production and activity of many other proteins
in the body. Metabolic alterations in the liver are especially impor-
tant, so that there is a higher circulating level of proteins such as
transcortin (corticosteroid-binding globulin [CBG]), thyroxine-
binding globulin (TBG), SHBG, transferrin, renin substrate, and
fibrinogen. This leads to increased circulating levels of thyroxine,
estrogen, testosterone, iron, copper, and other substances.
Alterations in the composition of the plasma lipids caused by
estrogens are characterized by an increase in the high-density lipo-
proteins (HDL), a slight reduction in the low-density lipoproteins
(LDL), and a reduction in total plasma cholesterol levels. Plasma
triglyceride levels are increased. Estrogens decrease hepatic oxida-
tion of adipose tissue lipid to ketones and increase synthesis of
triglycerides.
E. Effects on Blood Coagulation
Estrogens enhance the coagulability of blood. Many changes
in factors influencing coagulation have been reported, includ-
ing increased circulating levels of factors II, VII, IX, and X
and decreased antithrombin III, partially as a result of the
hepatic effects mentioned above. Increased plasminogen levels
and decreased platelet adhesiveness have also been found (see
Hormonal Contraception, below).
F. Other Effects
Estrogens induce the synthesis of progesterone receptors. They
are responsible for estrous behavior in animals and may influ-
ence behavior and libido in humans. Administration of estrogens
stimulates central components of the stress system, including the
production of corticotropin-releasing hormone and the activity
of the sympathetic system, and promotes a sense of well-being
when given to women who are estrogen-deficient. They also
facilitate the loss of intravascular fluid into the extracellular space,
producing edema. The resulting decrease in plasma volume causes
a compensatory retention of sodium and water by the kidney.
Estrogens also modulate sympathetic nervous system control of
smooth muscle function.
Clinical Uses*
A. Primary Hypogonadism
Estrogens have been used extensively for replacement therapy
in estrogen-deficient patients. The estrogen deficiency may be
due to primary failure of development of the ovaries, premature
menopause, castration, or menopause.
*
The use of estrogens in contraception is discussed later in this chapter.
CHAPTER 40  The Gonadal Hormones & Inhibitors     725
Treatment of primary hypogonadism is usually begun at
11–13 years of age in order to stimulate the development of
secondary sex characteristics and menses, to stimulate optimal
growth, to prevent osteoporosis, and to avoid the psychologi-
cal consequences of delayed puberty and estrogen deficiency.
Treatment attempts to mimic the physiology of puberty. It is ini-
tiated with small doses of estrogen (0.3 mg conjugated estrogens
or 5–10 mcg ethinyl estradiol) on days 1–21 each month and
is slowly increased to adult doses and then maintained until the
age of menopause (approximately 51 years of age). A progestin is
added after the first uterine bleeding. When growth is completed,
chronic therapy consists mainly of the administration of adult
doses of both estrogens and progestins, as described below.
B. Postmenopausal Hormonal Therapy
In addition to the signs and symptoms that follow closely
upon the cessation of normal ovarian function—such as loss of
menstrual periods, vasomotor symptoms, sleep disturbances, and
genital atrophy—there are longer-lasting changes that influence
the health and well-being of postmenopausal women. These
include an acceleration of bone loss, which in susceptible women
may lead to vertebral, hip, and wrist fractures; and lipid changes,
which may contribute to the acceleration of atherosclerotic cardio-
vascular disease noted in postmenopausal women. The effects of
estrogens on bone have been extensively studied, and the effects
of hormone withdrawal have been well-characterized. However,
the role of estrogens and progestins in the cause and prevention
of cardiovascular disease, which is responsible for 350,000 deaths
per year, and breast cancer, which causes 35,000 deaths per year,
is less well understood.
When normal ovulatory function ceases and the estrogen
levels fall after menopause, oophorectomy, or premature ovarian
failure, there is an accelerated rise in plasma cholesterol and LDL
concentrations, while LDL receptors decline. HDL is not much
affected, and levels remain higher than in men. Very-low-density
lipoprotein and triglyceride levels are also relatively unaffected.
Since cardiovascular disorders account for most deaths in this age
group, the risk for these disorders constitutes a major consider-
ation in deciding whether hormonal “replacement” therapy (HRT,
also correctly called HT) is indicated and influences the selection
of hormones to be administered. Estrogen replacement therapy
has a beneficial effect on circulating lipids and lipoproteins, and
this was earlier thought to be accompanied by a reduction in myo-
cardial infarction by about 50% and of fatal strokes by as much as
40%. These findings, however, have been disputed by the results
of a large study from the Women’s Health Initiative (WHI) project
showing no cardiovascular benefit from estrogen plus progestin
replacement therapy in perimenopausal or older postmenopausal
patients. In fact, there may be a small increase in cardiovascular
problems as well as breast cancer in women who received the
replacement therapy. Interestingly, a small protective effect against
colon cancer was observed. Although current clinical guidelines
do not recommend routine hormone therapy in postmenopausal
women, the validity of the WHI report has been questioned. In
any case, there is no increased risk for breast cancer if therapy is
given immediately after menopause and for the first 7 years, while
726    SECTION VII  Endocrine Drugs
the cardiovascular risk depends on the degree of atherosclerosis
at the onset of therapy. Transdermal or vaginal administration
of estrogen may be associated with decreased cardiovascular risk
because it bypasses the liver circulation. Women with premature
menopause should definitely receive hormone therapy.
In some studies, a protective effect of estrogen replacement
therapy against Alzheimer’s disease was observed. However, several
other studies have not supported these results.
Progestins antagonize estrogen’s effects on LDL and HDL to
a variable extent. However, one large study has shown that the
addition of a progestin to estrogen replacement therapy does not
influence the cardiovascular risk.
Optimal management of the postmenopausal patient requires
careful assessment of her symptoms as well as consideration of her
age and the presence of (or risks for) cardiovascular disease, osteo-
porosis, breast cancer, and endometrial cancer. Bearing in mind
the effects of the gonadal hormones on each of these disorders,
the goals of therapy can then be defined and the risks of therapy
assessed and discussed with the patient.
If the main indication for therapy is hot flushes and sleep distur-
bances, therapy with the lowest dose of estrogen required for symp-
tomatic relief is recommended. Treatment may be required for only
a limited period of time and the possible increased risk for breast
cancer avoided. In women who have undergone hysterectomy,
estrogens alone can be given 5 days per week or continuously, since
progestins are not required to reduce the risk for endometrial hyper-
plasia and cancer. Hot flushes, sweating, insomnia, and atrophic
vaginitis are generally relieved by estrogens; many patients experi-
ence some increased sense of well-being; and climacteric depression
and other psychopathologic states are improved.
The role of estrogens in the prevention and treatment of osteo-
porosis has been carefully studied (see Chapter 42). The amount
of bone present in the body is maximal in the young active adult
in the third decade of life and begins to decline more rapidly in
middle age in both men and women. The development of osteo-
porosis also depends on the amount of bone present at the start of
this process, on vitamin D and calcium intake, and on the degree
of physical activity. The risk of osteoporosis is highest in smokers
who are thin, Caucasian, and inactive and have a low calcium
intake and a strong family history of osteoporosis. Depression also
is a major risk factor for development of osteoporosis in women.
Estrogens should be used in the smallest dosage consistent
with relief of symptoms. In women who have not undergone hys-
terectomy, it is most convenient to prescribe estrogen on the first
21–25 days of each month. The recommended dosages of estro-
gen are 0.3–1.25 mg/d of conjugated estrogen or 0.01–0.02 mg/d
of ethinyl estradiol. Dosages in the middle of these ranges have
been shown to be maximally effective in preventing the decrease
in bone density occurring at menopause. From this point of view,
it is important to begin therapy as soon as possible after the meno-
pause for maximum effect. In these patients and others not taking
estrogen, calcium supplements that bring the total daily calcium
intake up to 1500 mg are useful.
Patients at low risk of developing osteoporosis who mani-
fest only mild atrophic vaginitis can be treated with topical
preparations. The vaginal route of application is also useful in the
treatment of urinary tract symptoms in these patients. It is impor-
tant to realize, however, that although locally administered estro-
gens escape the first-pass effect (so that some undesirable hepatic
effects are reduced), they are almost completely absorbed into the
circulation, and these preparations should be given cyclically.
As noted below, the administration of estrogen is associated
with an increased risk of endometrial carcinoma. The administra-
tion of a progestational agent with the estrogen prevents endo-
metrial hyperplasia and markedly reduces the risk of this cancer.
When estrogen is given for the first 25 days of the month and the
progestin medroxyprogesterone (10 mg/d) is added during the last
10–14 days, the risk is only half of that in women not receiving
hormone replacement therapy. On this regimen, some women will
experience a return of symptoms during the period off estrogen
administration. In these patients, the estrogen can be given con-
tinuously. If the progestin produces sedation or other undesirable
effects, its dose can be reduced to 2.5–5 mg for the last 10 days of
the cycle with a slight increase in the risk for endometrial hyper-
plasia. These regimens are usually accompanied by bleeding at the
end of each cycle. Some women experience migraine headaches
during the last few days of the cycle. The use of a continuous
estrogen regimen will often prevent their occurrence. Women who
object to the cyclic bleeding associated with sequential therapy can
also consider continuous therapy. Daily therapy with 0.625 mg of
conjugated equine estrogens and 2.5–5 mg of medroxyprogester-
one will eliminate cyclic bleeding, control vasomotor symptoms,
prevent genital atrophy, maintain bone density, and show a favor-
able lipid profile with a small decrease in LDL and an increase in
HDL concentrations. These women have endometrial atrophy
on biopsy. About half of these patients experience breakthrough
bleeding during the first few months of therapy. About 70–80%
become amenorrheic after the first 4 months, and most remain
so. The main disadvantage of continuous therapy is the need for
uterine biopsy if bleeding occurs after the first few months.
As noted above, estrogens may also be administered vaginally
or transdermally. When estrogens are given by these routes, the
liver is bypassed on the first circulation, and the ratio of the liver
effects to peripheral effects is reduced.
In patients in whom estrogen replacement therapy is contra-
indicated, such as those with estrogen-sensitive tumors, relief of
vasomotor symptoms may be obtained by the use of clonidine.
C. Other Uses
Estrogens combined with progestins can be used to suppress
ovulation in patients with intractable dysmenorrhea or when sup-
pression of ovarian function is used in the treatment of hirsutism
and amenorrhea due to excessive secretion of androgens by the
ovary. Under these circumstances, greater suppression may be
needed, and oral contraceptives containing 50 mcg of estrogen
or a combination of a low-estrogen pill with GnRH suppression
may be required.
Adverse Effects
Adverse effects of variable severity have been reported with the
therapeutic use of estrogens. Many other effects reported in

conjunction with hormonal contraceptives may be related to their
estrogen content. These are discussed below.
A. Uterine Bleeding
Estrogen therapy is a major cause of postmenopausal uterine
bleeding. Unfortunately, vaginal bleeding at this time of life may
also be due to carcinoma of the endometrium. To avoid confusion,
patients should be treated with the smallest amount of estrogen
possible. It should be given cyclically so that bleeding, if it occurs,
will be more likely to occur during the withdrawal period. As
noted above, endometrial hyperplasia can be prevented by admin-
istration of a progestational agent with estrogen in each cycle.
B. Cancer
The relation of estrogen therapy to cancer continues to be the
subject of active investigation. Although no adverse effect of short-
term estrogen therapy on the incidence of breast cancer has been
demonstrated, a small increase in the incidence of this tumor may
occur with prolonged therapy. Although the risk factor is small
(1.25), the impact may be great since this tumor occurs in 10% of
women, and addition of progesterone does not confer a protective
effect. Studies indicate that following unilateral excision of breast
cancer, women receiving tamoxifen (an estrogen partial agonist,
see below) show a 35% decrease in contralateral breast cancer
compared with controls. These studies also demonstrate that
tamoxifen is well tolerated by most patients, produces estrogen-
like alterations in plasma lipid levels, and stabilizes bone mineral
loss. Studies bearing on the possible efficacy of tamoxifen and
raloxifene in postmenopausal women at high risk for breast cancer
show decreases of risk for at least 5 years, but of unknown further
duration. Another study showed that postmenopausal hormone
replacement therapy with estrogens plus progestins was associated
with greater breast epithelial cell proliferation and breast epithe-
lial cell density than estrogens alone or no replacement therapy.
Furthermore, with estrogens plus progestins, breast proliferation
was localized to the terminal duct-lobular unit of the breast, which
is the main site of development of breast cancer. Thus, further
studies are needed to conclusively assess the possible association
between progestins and breast cancer risk.
Many studies show an increased risk of endometrial carcinoma
in patients taking estrogens alone. The risk seems to vary with the
dose and duration of treatment: 15 times greater in patients taking
large doses of estrogen for 5 or more years, in contrast with two to
four times greater in patients receiving lower doses for short peri-
ods. However, as noted above, the concomitant use of a progestin
prevents this increased risk and may in fact reduce the incidence
of endometrial cancer to less than that in the general population.
There have been a number of reports of adenocarcinoma of the
vagina in young women whose mothers were treated with large
doses of diethylstilbestrol early in pregnancy. These cancers are most
common in young women (ages 14–44). The incidence is less than
1 per 1000 women exposed—too low to establish a cause-and-
effect relationship with certainty. However, the risks for infertility,
ectopic pregnancy, and premature delivery also are increased. It is
now recognized that there is no indication for the use of dieth-
ylstilbestrol during pregnancy, and it should be avoided. It is not
CHAPTER 40  The Gonadal Hormones & Inhibitors     727
known whether other estrogens have a similar effect or whether the
observed phenomena are peculiar to diethylstilbestrol. This agent
should be used only in the treatment of cancer (eg, of the prostate)
or as a “morning after” contraceptive (see page 736).
C. Other Effects
Nausea and breast tenderness are common and can be minimized
by using the smallest effective dose of estrogen. Hyperpigmenta-
tion also occurs. Estrogen therapy is associated with an increase in
frequency of migraine headaches as well as cholestasis, gallbladder
disease, and hypertension.
Contraindications
Estrogens should not be used in patients with estrogen-dependent
neoplasms such as carcinoma of the endometrium or in those
with—or at high risk for—carcinoma of the breast. They
should be avoided in patients with undiagnosed genital bleeding,
liver disease, or a history of thromboembolic disorder. In addition,
the use of estrogens should be avoided by heavy smokers.
Preparations & Dosages
The dosages of commonly used natural and synthetic preparations
are listed in Table 40–1. Although all of the estrogens produce
almost the same hormonal effects, their potencies vary both
between agents and depending on the route of administration. As
noted above, estradiol is the most active endogenous estrogen, and
it has the highest affinity for the estrogen receptor. However, its
metabolites estrone and estriol have weak uterine effects.
For a given level of gonadotropin suppression, oral estrogen prepa-
rations have more effect on the circulating levels of CBG, SHBG,
and a host of other liver proteins, including angiotensinogen, than
do transdermal preparations. The oral route of administration allows
greater concentrations of hormone to reach the liver, thus increas-
ing the synthesis of these proteins. Transdermal preparations were
developed to avoid this effect. When administered transdermally,
50–100 mcg of estradiol has effects similar to those of 0.625–1.25 mg
of conjugated oral estrogens on gonadotropin concentrations, endo-
metrium, and vaginal epithelium. Furthermore, the transdermal
estrogen preparations do not significantly increase the concentrations
of renin substrate, CBG, and TBG and do not produce the character-
istic changes in serum lipids. Combined oral preparations containing
0.625 mg of conjugated estrogens and 2.5 mg of medroxyprogester-
one acetate are available for menopausal replacement therapy. Tablets
containing 0.625 mg of conjugated estrogens and 5 mg of medroxy-
progesterone acetate are available to be used in conjunction with con-
jugated estrogens in a sequential fashion. Estrogens alone are taken on
days 1–14 and the combination on days 15–28.
THE PROGESTINS
Natural Progestins: Progesterone
Progesterone is the most important progestin in humans. In addi-
tion to having important hormonal effects, it serves as a precur-
sor to the estrogens, androgens, and adrenocortical steroids. It is
728    SECTION VII  Endocrine Drugs

TABLE 40–2  Properties of some progestational agents.

Activities1

   Route  Duration of Action  Estrogenic Androgenic Antiestrogenic Antiandrogenic Anabolic

Progesterone and derivatives

 Progesterone IM 1 day − − + − −
 Hydroxyprogesterone IM 8–14 days sl sl − − −
caproate
 Medroxyprogesterone IM, PO Tabs: 1–3 days; − + + − −
acetate injection: 4–12 weeks
  Megestrol acetate PO 1–3 days − + − + −
17-Ethinyl testosterone derivatives
 Dimethisterone PO 1–3 days − − sl − −
19-Nortestosterone derivatives
 Desogestrel PO 1–3 days − − − − −
 Norethynodrel PO 1–3 days + − − − −
 Lynestrenol2 PO 1–3 days + + − − +
 Norethindrone PO 1–3 days sl + + − +
  Norethindrone acetate PO 1–3 days sl + + − +
  Ethynodiol diacetate PO 1–3 days sl + + − −
2
  l-Norgestrel PO 1–3 days − + + − +
1
Interpretation: + = active; – = inactive; sl = slightly active. Activities have been reported in various species using various end points and may not apply to humans.
2
Not available in USA.

synthesized in the ovary, testis, and adrenal cortex from circulating
cholesterol. Large amounts are also synthesized and released by the
placenta during pregnancy.
In the ovary, progesterone is produced primarily by the corpus
luteum. Normal males appear to secrete 1–5 mg of progesterone
daily, resulting in plasma levels of about 0.03 mcg/dL. The level
is only slightly higher in the female during the follicular phase
of the cycle, when only a few milligrams per day of progesterone
are secreted. During the luteal phase, plasma levels range from
0.5 mcg/dL to more than 2 mcg/dL (Figure 40–1). Plasma levels
of progesterone are further elevated and reach their peak levels in
the third trimester of pregnancy.
Synthetic Progestins
A variety of progestational compounds have been synthesized.
Some are active when given by mouth. They are not a uniform
group of compounds, and all of them differ from progesterone in
one or more respects. Table 40–2 lists some of these compounds
and their effects. In general, the 21-carbon compounds (hydroxy-
progesterone, medroxyprogesterone, megestrol, and dimethis-
terone) are the most closely related, pharmacologically as well
as chemically, to progesterone. A new group of third-generation
synthetic progestins has been introduced, principally as compo-
nents of oral contraceptives. These “19-nor, 13-ethyl” steroid
compounds include desogestrel (Figure 40–4), gestodene, and
norgestimate. They are claimed to have lower androgenic activity
than older synthetic progestins.
Pharmacokinetics
Progesterone is rapidly absorbed following administration by any
route. Its half-life in the plasma is approximately 5 minutes, and
small amounts are stored temporarily in body fat. It is almost
completely metabolized in one passage through the liver, and for
that reason it is quite ineffective when the usual formulation is
administered orally. However, high-dose oral micronized proges-
terone preparations have been developed that provide adequate
progestational effect.
In the liver, progesterone is metabolized to pregnanediol and
conjugated with glucuronic acid. It is excreted into the urine
as pregnanediol glucuronide. The amount of pregnanediol in
the urine has been used as an index of progesterone secretion.
This measure has been very useful despite the fact that the pro-
portion of secreted progesterone converted to this compound
varies from day to day and from individual to individual. In
addition to progesterone, 20α- and 20β-hydroxyprogesterone
(20α- and 20β-hydroxy-4-pregnene-3-one) also are found.
These compounds have about one-fifth the progestational
activity of progesterone in humans and other species. Little is
known of their physiologic role, but 20α-hydroxyprogesterone
is produced in large amounts in some species and may be of
some importance biologically.
The usual routes of administration and durations of action of
the synthetic progestins are listed in Table 40–2. Most of these
agents are extensively metabolized to inactive products that are
excreted mainly in the urine.

21
CH3
20
C O
18
17
11 13
19
O O
Progesterone Hydroxyprogesterone
C C CH3
OH
O
CH3 O
Dimethisterone Norethindrone
FIGURE 40–4  Progesterone and some progestational agents in clinical use.
Physiologic Effects
A. Mechanism
The mechanism of action of progesterone—described in more
detail above—is similar to that of other steroid hormones.
Progestins enter the cell and bind to progesterone receptors that
are distributed in the nucleus and the cytoplasm. The ligand-
receptor complex binds to a progesterone response element
(PRE) to activate gene transcription. The response element for
progesterone appears to be similar to the corticosteroid response
element, and the specificity of the response depends upon which
receptor is present in the cell as well as upon other cell-specific
receptor coregulators and interacting transcription factors. The
progesterone-receptor complex forms a dimer before binding to
DNA. Like the estrogen receptor, it can form heterodimers as well
as homodimers between two isoforms, A and B. These isoforms
are produced by alternative splicing of the same gene.
B. Effects of Progesterone
Progesterone has little effect on protein metabolism. It stimulates
lipoprotein lipase activity and seems to favor fat deposition. The
effects on carbohydrate metabolism are more marked. Proges-
terone increases basal insulin levels and the insulin response to
glucose. There is usually no manifest change in carbohydrate
tolerance. In the liver, progesterone promotes glycogen storage,
possibly by facilitating the effect of insulin. Progesterone also
promotes ketogenesis.
Progesterone can compete with aldosterone for the mineralo-
corticoid receptor of the renal tubule, causing a decrease in Na+
reabsorption. This leads to an increased secretion of aldosterone
by the adrenal cortex (eg, in pregnancy). Progesterone increases
body temperature in humans. The mechanism of this effect is not
CHAPTER 40  The Gonadal Hormones & Inhibitors     729
CH3
CH3 C O
C O OH
OH
CH3
Medroxyprogesterone
C CH CH3 C CH
CH2
OH CH2 OH
Desogestrel
known, but an alteration of the temperature-regulating centers in
the hypothalamus has been suggested. Progesterone also alters the
function of the respiratory centers. The ventilatory response to CO2
is increased by progesterone but synthetic progestins with an ethinyl
group do not have respiratory effects. This leads to a measurable
reduction in arterial and alveolar Pco2 during pregnancy and in the
luteal phase of the menstrual cycle. Progesterone and related steroids
also have depressant and hypnotic effects on the brain.
Progesterone is responsible for the alveolobular development
of the secretory apparatus in the breast. It also participates in the
preovulatory LH surge and causes the maturation and secretory
changes in the endometrium that are seen following ovulation
(Figure 40–1).
Progesterone decreases the plasma levels of many amino acids
and leads to increased urinary nitrogen excretion. It induces
changes in the structure and function of smooth endoplasmic
reticulum in experimental animals.
Other effects of progesterone and its analogs are noted below
in the section, Hormonal Contraception.
C. Synthetic Progestins
The 21-carbon progesterone analogs antagonize aldosterone-
induced sodium retention (see above). The remaining compounds
(“19-nortestosterone” third-generation agents) produce a decidual
change in the endometrial stroma, do not support pregnancy
in test animals, are more effective gonadotropin inhibitors, and
may have minimal estrogenic and androgenic or anabolic activ-
ity (Table 40–2; Figure 40–4). They are sometimes referred to
as “impeded androgens.” Progestins without androgenic activity
include desogestrel, norgestimate, and gestodene. The first two
of these compounds are dispensed in combination with ethinyl
estradiol for oral contraception (Table 40–3) in the United States.
730    SECTION VII  Endocrine Drugs

TABLE 40–3  Some oral and implantable contraceptive agents in use.1

  Estrogen (mg) Progestin (mg)

Monophasic Combination Tablets

  Aviane, Falmina, Lessina, Lutera, Orsythia, Sronyx Ethinyl estradiol 0.02 l-Norgestrel 0.1
  Beyaz, Gianvi, Loryna, Yaz, Vestura Ethinyl estradiol 0.02 Drospirone 3
  Gildess 1/20, Junel, Loestrin, Microgestin, Minastrin Ethinyl estradiol 0.02 Norethindrone 1
  Apri, Desogen, Ortho-Cept, Reclipsen, Solia Ethinyl estradiol 0.03 Desonorgestrel 0.15
  Altavera, Chateal, Introvate, Jolessa, Kurvelo, Levora, Marlissa, Portia Ethinyl estradiol 0.03 l-Norgestrel 0.15
  Cryselle, Elinest, Low-Ogestrel Ethinyl estradiol 0.03 Norgestrel 0.30
  Ocella, Safyral, Syeda, Yasmin, Zarah Ethinyl estradiol 0.03 Drospirenone 3
  Gildess, Junel, Loestrin, Microgestin Ethinyl estradiol 0.03 Norethindrone 1.5
  Cyclafem 1/35, Necon 1/35, Norinyl 1/35 Ethinyl estradiol 0.035 Norethindrone 1
  Estarylla, MonoNessa, Ortho-Cyclen, Previfem, Sprintec Ethinyl estradiol 0.035 Norgestimate 0.25
 Alyacen 1/35; Cyclafem 1/35, Dasetta 1/35, Necon 1/35, Norinyl 1+35, Ethinyl estradiol 0.035 Norethindrone 1
Nortrel 1/35, Ortho-Novum 1/35, Pirmella 1/35
  Brevicon, Modicon, Necon 0.5/35, Nortrel 0.5/35, Wera Ethinyl estradiol 0.035 Norethindrone 0.5
  Ovcon-35, Femcon Fe, Balziva, Briellyn, Gildagia, others Ethinyl estradiol 0.035 Norethindrone 0.4
  Ogestrel 0.5/50 Ethinyl estradiol 0.05 d,l-Norgestrel 0.5
  Norinyl 1+50, Necon 1/50 Mestranol 0.05 Norethindrone 1
Biphasic Combination Tablets
  Azurette, Kariva, Mircette, Viorele
  Days 1–21 Ethinyl estradiol 0.02 Desogestrel 0.15
  Days 22–27 Ethinyl estradiol 0.01 None  
  Necon 10/11
  Days 1–10 Ethinyl estradiol 0.035 Norethindrone 0.5
  Days 11–21 Ethinyl estradiol 0.035 Norethindrone 1.0
Triphasic Combination Tablets
  Enpresse, Levonest, Myzilra, Triphasil, Tri-Levlen, Trivora
  Days 1–6 Ethinyl estradiol 0.03 l-Norgestrel 0.05
  Days 7–11 Ethinyl estradiol 0.04 l-Norgestrel 0.075
  Days 12–21 Ethinyl estradiol 0.03 l-Norgestrel 0.125
  Casiant, Cyclessa, Cesia, Velivet
  Days 1–6 Ethinyl estradiol 0.025 Desogestrel 0.1
  Days 7–14 Ethinyl estradiol 0.025 Desogestrel 0.125
  Days 15–21 Ethinyl estradiol 0.025 Desogestrel 0.15
  Alyacen 7/7/7, Cyclafem 7/7/7, Dasetta 7/7/7, Ortho-Novum 7/7/7, Necon 7/7/7, Nortrel 7/7/7, Pirmella 7/7/7
  Days 1–7 Ethinyl estradiol 0.035 Norethindrone 0.5
  Days 8–14 Ethinyl estradiol 0.035 Norethindrone 0.75
  Days 15–21 Ethinyl estradiol 0.035 Norethindrone 1.0
 Ortho-Tri-Cyclen
  Days 1–7 Ethinyl estradiol 0.035 Norgestimate 0.18
  Days 8–14 Ethinyl estradiol 0.035 Norgestimate 0.215
  Days 15–21 Ethinyl estradiol 0.035 Norgestimate 0.25
(continued)
 CHAPTER 40  The Gonadal Hormones & Inhibitors     731

TABLE 40–3  Some oral and implantable contraceptive agents in use.1  (Continued)
  Estrogen (mg) Progestin (mg)

4-Phasic Combination Tablet

 Natazia
  Days 1–2 Estradiol valerate 3 None —
  Days 3–8 Estradiol valerate 2 Dienogest 2
  Days 9–25 Estradiol valerate 2 Dienogest 3
  Day 26–27 Estradiol valerate 1 None —
Daily Progestin Tablets
 Camila, Errin, Heather, Jencycla, Jolivette, Lyza, Nora-BE, Nor-QD, Ortho None — Norethindrone 0.35
Micronor
Contraceptive Transdermal Patch (Apply 1 Patch per Week)
  Ortho Evra Ethinyl estradiol 0.02/24 h Norgestromin 0.150/24 h
Implantable Progestin Preparation
  Implanon, Nexplanon None Etonogestrel (one tube of 68 mg)
1
The estrogen-containing compounds are arranged in order of increasing content of estrogen. Other preparations are available. (Ethinyl estradiol and mestranol have similar
potencies.)

Oral contraceptives containing the progestin cyproterone acetate
(also an antiandrogen) in combination with ethinyl estradiol are
investigational in the United States.
Clinical Uses
A. Therapeutic Applications
The major uses of progestational hormones are for hormone
replacement therapy (see above) and hormonal contraception
(see below). In addition, they are useful in producing long-term
ovarian suppression for other purposes. When used alone in large
doses parenterally (eg, medroxyprogesterone acetate, 150 mg
intramuscularly every 90 days), prolonged anovulation and amen-
orrhea result. This therapy has been employed in the treatment
of dysmenorrhea, endometriosis, and bleeding disorders when
estrogens are contraindicated, and for contraception. The major
problem with this regimen is the prolonged time required in
some patients for ovulatory function to return after cessation of
therapy. It should not be used for patients planning a pregnancy
in the near future. Similar regimens will relieve hot flushes in
some menopausal women and can be used if estrogen therapy is
contraindicated.
Medroxyprogesterone acetate, 10–20 mg orally twice weekly—
or intramuscularly in doses of 100 mg/m2 every 1–2 weeks—will
prevent menstruation, but it will not arrest accelerated bone
maturation in children with precocious puberty.
Progestins do not appear to have any place in the therapy of
threatened or habitual abortion. Early reports of the usefulness of
these agents resulted from the unwarranted assumption that after
several abortions the likelihood of repeated abortions was over
90%. When progestational agents were administered to patients
with previous abortions, a salvage rate of 80% was achieved. It is
now recognized that similar patients abort only 20% of the time
even when untreated. On the other hand, progesterone was given
experimentally to delay premature labor with encouraging results.
Progesterone and medroxyprogesterone have been used in the
treatment of women who have difficulty in conceiving and who
demonstrate a slow rise in basal body temperature. There is no
convincing evidence that this treatment is effective.
Preparations of progesterone and medroxyprogesterone have
been used to treat premenstrual syndrome. Controlled studies
have not confirmed the effectiveness of such therapy except when
doses sufficient to suppress ovulation have been used.
B. Diagnostic Uses
Progesterone can be used as a test of estrogen secretion. The
administration of progesterone, 150 mg/d, or medroxyprogester-
one, 10 mg/d, for 5–7 days, is followed by withdrawal bleeding
in amenorrheic patients only when the endometrium has been
stimulated by estrogens. A combination of estrogen and progestin
can be given to test the responsiveness of the endometrium in
patients with amenorrhea.
Contraindications, Cautions, & Adverse
Effects
Studies of progestational compounds alone and with combination
oral contraceptives indicate that the progestin in these agents may
increase blood pressure in some patients. The more androgenic pro-
gestins also reduce plasma HDL levels in women. (See Hormonal
Contraception, below.) Two recent studies suggest that combined
progestin plus estrogen replacement therapy in postmenopausal
women may increase breast cancer risk significantly compared with
the risk in women taking estrogen alone. These findings require
careful examination and if confirmed will lead to important changes
in postmenopausal hormone replacement practice.
732    SECTION VII  Endocrine Drugs
OTHER OVARIAN HORMONES
The normal ovary produces small amounts of androgens,
including testosterone, androstenedione, and dehydroepian-
drosterone. Of these, only testosterone has a significant amount
of biologic activity, although androstenedione can be converted
to testosterone or estrone in peripheral tissues. The normal
woman produces less than 200 mcg of testosterone in 24 hours,
and about one-third of this is probably formed in the ovary
directly. The physiologic significance of these small amounts of
androgens is not established, but they may be partly responsible
for normal hair growth at puberty, for stimulation of female
libido, and, possibly, for metabolic effects. Androgen produc-
tion by the ovary may be markedly increased in some abnormal
states, usually in association with hirsutism and amenorrhea as
noted above.
The ovary also produces inhibin and activin. These pep-
tides consist of several combinations of α and β subunits and
are described in greater detail later. The αβ dimer (inhibin)
inhibits FSH secretion while the ββ dimer (activin) increases
FSH secretion. Studies in primates indicate that inhibin has
no direct effect on ovarian steroidogenesis but that activin
modulates the response to LH and FSH. For example, simul-
taneous treatment with activin and human FSH enhances
FSH stimulation of progesterone synthesis and aromatase
activity in granulosa cells. When combined with LH, activin
suppressed the LH-induced progesterone response by 50%
but markedly enhanced basal and LH-stimulated aromatase
activity. Activin may also act as a growth factor in other tis-
sues. The physiologic roles of these modulators are not fully
understood.
Relaxin is another peptide that can be extracted from the
ovary. The three-dimensional structure of relaxin is related to that
of growth-promoting peptides and is similar to that of insulin.
Although the amino acid sequence differs from that of insulin, this
hormone, like insulin, consists of two chains linked by disulfide
bonds, cleaved from a prohormone. It is found in the ovary, pla-
centa, uterus, and blood. Relaxin synthesis has been demonstrated
in luteinized granulosa cells of the corpus luteum. It has been
shown to increase glycogen synthesis and water uptake by the
myometrium and to decrease uterine contractility. In some spe-
cies, it changes the mechanical properties of the cervix and pubic
ligaments, facilitating delivery.
In women, relaxin has been measured by immunoassay.
Levels were highest immediately after the LH surge and during
menstruation. A physiologic role for this peptide has not been
established.
Clinical trials with relaxin have been conducted in patients
with dysmenorrhea. Relaxin has also been administered to patients
in premature labor and during prolonged labor. When applied to
the cervix of a woman at term, it facilitates dilation and shortens
labor.
Several other nonsteroidal substances such as corticotropin-
releasing hormone, follistatin, and prostaglandins are produced
by the ovary. These probably have paracrine effects within the
ovary.
■■ HORMONAL CONTRACEPTION
(ORAL, PARENTERAL, &
IMPLANTED CONTRACEPTIVES)
A large number of oral contraceptives containing estrogens or pro-
gestins (or both) are now available for clinical use (Table 40–3).
These preparations vary chemically and pharmacologically and
have many properties in common as well as definite differences
important for the correct selection of the optimum agent.
Two types of preparations are used for oral contraception:
(1) combinations of estrogens and progestins and (2) continuous
progestin therapy without concomitant administration of estrogens.
The combination agents are further divided into monophasic
forms (constant dosage of both components during the cycle) and
biphasic or triphasic forms (dosage of one or both components
is changed once or twice during the cycle). The preparations for
oral use are all adequately absorbed, and in combination prepara-
tions the pharmacokinetics of neither drug is significantly altered
by the other.
Only one implantable contraceptive preparation is available
at present in the USA. Etonogestrel, also used in some oral con-
traceptives, is available in the subcutaneous implant form listed
in Table 40–3. Several hormonal contraceptives are available as
vaginal rings or intrauterine devices. Intramuscular injection of
large doses of medroxyprogesterone also provides contraception
of long duration.
Pharmacologic Effects
A. Mechanism of Action
The combinations of estrogens and progestins exert their con-
traceptive effect largely through selective inhibition of pituitary
function that results in inhibition of ovulation. The combination
agents also produce a change in the cervical mucus, in the uterine
endometrium, and in motility and secretion in the uterine tubes,
all of which decrease the likelihood of conception and implanta-
tion. The continuous use of progestins alone does not always
inhibit ovulation. The other factors mentioned, therefore, play a
major role in the prevention of pregnancy when these agents are
used.
B. Effects on the Ovary
Chronic use of combination agents depresses ovarian function.
Follicular development is minimal, and corpora lutea, larger fol-
licles, stromal edema, and other morphologic features normally
seen in ovulating women are absent. The ovaries usually become
smaller even if enlarged before therapy.
The great majority of patients return to normal menstrual
patterns when these drugs are discontinued. About 75% will
ovulate in the first posttreatment cycle and 97% by the third
posttreatment cycle. About 2% of patients remain amenor-
rheic for periods of up to several years after administration is
stopped.
The cytologic findings on vaginal smears vary depending on
the preparation used. However, with almost all of the combined

drugs, a low maturation index is found because of the presence of
progestational agents.
C. Effects on the Uterus
After prolonged use, the cervix may show some hypertrophy and
polyp formation. There are also important effects on the cervical
mucus, making it more like postovulation mucus, ie, thicker and
less copious.
Agents containing both estrogens and progestins produce
further morphologic and biochemical changes of the endometrial
stroma under the influence of the progestin, which also stimulates
glandular secretion throughout the luteal phase. The agents con-
taining “19-nor” progestins—particularly those with the smaller
amounts of estrogen—tend to produce more glandular atrophy
and usually less bleeding.
D. Effects on the Breast
Stimulation of the breasts occurs in most patients receiving
estrogen-containing agents. Some enlargement is generally noted.
The administration of estrogens and combinations of estrogens
and progestins tends to suppress lactation, but when the doses are
small, the effects on breast-feeding are not appreciable. Studies of
the transport of the oral contraceptives into breast milk suggest
that only small amounts of these compounds cross into the milk,
and they have not been considered to be of importance.
E. Other Effects of Oral Contraceptives
1. Effects on the central nervous system—The central
nervous system effects of the oral contraceptives have not been
well studied in humans. A variety of effects of estrogen and pro-
gesterone have been noted in animals. Estrogens tend to increase
excitability in the brain, whereas progesterone tends to decrease it.
The thermogenic action of progesterone and some of the synthetic
progestins is also thought to occur in the central nervous system.
It is very difficult to evaluate any behavioral or emotional effects
of these compounds in humans. Although the incidence of pro-
nounced changes in mood, affect, and behavior appears to be low,
milder changes are commonly reported, and estrogens are being
successfully employed in the therapy of premenstrual tension syn-
drome, postpartum depression, and climacteric depression.
2. Effects on endocrine function—The inhibition of pituitary
gonadotropin secretion has been mentioned. Estrogens also alter
adrenal structure and function. Estrogens given orally or at high
doses increase the plasma concentration of the α2 globulin that
binds cortisol (corticosteroid-binding globulin). Plasma concen-
trations may be more than double the levels found in untreated
individuals, and urinary excretion of free cortisol is elevated.
These preparations cause alterations in the renin-angiotensin-
aldosterone system. Plasma renin activity has been found to
increase, and there is an increase in aldosterone secretion.
Thyroxine-binding globulin is increased. As a result, total
plasma thyroxine (T4) levels are increased to those commonly seen
during pregnancy. Since more of the thyroxine is bound, the free
thyroxine level in these patients is normal. Estrogens also increase
the plasma level of SHBG and decrease plasma levels of free
CHAPTER 40  The Gonadal Hormones & Inhibitors     733
androgens by increasing their binding; large amounts of estrogen
may decrease androgens by gonadotropin suppression.
3. Effects on blood—Serious thromboembolic phenomena
occurring in women taking oral contraceptives gave rise to a great
many studies of the effects of these compounds on blood coagula-
tion. A clear picture of such effects has not yet emerged. The oral
contraceptives do not consistently alter bleeding or clotting times.
The changes that have been observed are similar to those reported
in pregnancy. There is an increase in factors VII, VIII, IX, and X
and a decrease in antithrombin III. Increased amounts of couma-
rin anticoagulants may be required to prolong prothrombin time
in patients taking oral contraceptives.
There is an increase in serum iron and total iron-binding
capacity similar to that reported in patients with hepatitis.
Significant alterations in the cellular components of blood have
not been reported with any consistency. A number of patients
have been reported to develop folic acid deficiency anemias.
4. Effects on the liver—These hormones also have profound
effects on the function of the liver. Some of these effects are del-
eterious and will be considered below in the section on adverse
effects. The effects on serum proteins result from the effects of the
estrogens on the synthesis of the various α2 globulins and fibrino-
gen. Serum haptoglobins produced in the liver are depressed
rather than increased by estrogen. Some of the effects on carbohy-
drate and lipid metabolism are probably influenced by changes in
liver metabolism (see below).
Important alterations in hepatic drug excretion and metab-
olism also occur. Estrogens in the amounts seen during
pregnancy or used in oral contraceptive agents delay the clear-
ance of sulfobromophthalein and reduce the flow of bile. The
proportion of cholic acid in bile acids is increased while the pro-
portion of chenodeoxycholic acid is decreased. These changes may
be responsible for the observed increase in cholelithiasis associated
with the use of these agents.
5. Effects on lipid metabolism—As noted above, estrogens
increase serum triglycerides and free and esterified cholesterol.
Phospholipids are also increased, as are HDL; levels of LDL usu-
ally decrease. Although the effects are marked with doses of 100
mcg of mestranol or ethinyl estradiol, doses of 50 mcg or less have
minimal effects. The progestins (particularly the “19-nortestos-
terone” derivatives) tend to antagonize these effects of estrogen.
Preparations containing small amounts of estrogen and a proges-
tin may slightly decrease triglycerides and HDL.
6. Effects on carbohydrate metabolism—The administra-
tion of oral contraceptives produces alterations in carbohydrate
metabolism similar to those observed in pregnancy. There is a
reduction in the rate of absorption of carbohydrates from the
gastrointestinal tract. Progesterone increases the basal insulin
level and the rise in insulin induced by carbohydrate ingestion.
Preparations with more potent progestins such as norgestrel may
cause progressive decreases in carbohydrate tolerance over several
years. However, the changes in glucose tolerance are reversible on
discontinuing medication.
734    SECTION VII  Endocrine Drugs
7. Effects on the cardiovascular system—These agents cause
small increases in cardiac output associated with higher systolic
and diastolic blood pressure and heart rate. The pressure returns
to pretreatment levels when treatment is terminated. Although the
magnitude of the pressure change is small in most patients, it is
marked in a few. It is important that blood pressure be followed
in each patient. An increase in blood pressure has been reported to
occur in a few postmenopausal women treated with estrogens alone.
8. Effects on the skin—The oral contraceptives have been noted
to increase pigmentation of the skin (chloasma). This effect seems
to be enhanced in women with dark complexions and by exposure
to ultraviolet light. Some of the androgen-like progestins might
increase the production of sebum, causing acne in some patients.
However, since ovarian androgen is suppressed, many patients
note decreased sebum production, acne, and terminal hair growth.
The sequential oral contraceptive preparations as well as estrogens
alone often decrease sebum production.
Clinical Uses
The most important use of combined estrogens and progestins is
for oral contraception. A large number of preparations are available
for this specific purpose, some of which are listed in Table 40–3.
They are specially packaged for ease of administration. In general,
they are very effective; when these agents are taken according to
directions, the risk of conception is extremely small. The pregnancy
rate with combination agents is estimated to be about 5–12 per
100 woman-years at risk. (Under conditions of perfect adherence,
the pregnancy rate would be 0.5–1 per 100 woman-years.) Con-
traceptive failure has been observed in some patients when one or
more doses are missed, if phenytoin is also being used (which may
increase catabolism of the compounds), or if antibiotics are taken
that alter enterohepatic cycling of metabolites.
Progestins and estrogens are also useful in the treatment of
endometriosis. When severe dysmenorrhea is the major symptom,
the suppression of ovulation with estrogen alone may be followed
by painless periods. However, in most patients this approach is
inadequate. The long-term administration of large doses of pro-
gestins or combinations of progestins and estrogens prevents the
periodic breakdown of the endometrial tissue and in some cases
will lead to endometrial fibrosis and prevent the reactivation of
implants for prolonged periods.
As is true with most hormonal preparations, many of the
undesired effects are physiologic or pharmacologic actions that
are objectionable only because they are not pertinent to the
situation for which they are being used. Therefore, the product
containing the smallest effective amounts of hormones should
be selected for use.
Adverse Effects
The incidence of serious known toxicities associated with the use
of these drugs is low—far lower than the risks associated with
pregnancy. There are a number of reversible changes in intermedi-
ary metabolism. Minor adverse effects are frequent, but most are
mild and many are transient. Continuing problems may respond
to simple changes in pill formulation. Although it is not often
necessary to discontinue medication for these reasons, as many as
one third of all patients started on oral contraception discontinue
use for reasons other than a desire to become pregnant.
A. Mild Adverse Effects
1. Nausea, mastalgia, breakthrough bleeding, and edema are
related to the amount of estrogen in the preparation. These
effects can often be alleviated by a shift to a preparation con-
taining smaller amounts of estrogen or to agents containing
progestins with more androgenic effects.
2. Changes in serum proteins and other effects on endocrine
function (see above) must be taken into account when thyroid,
adrenal, or pituitary function is being evaluated. Increases in
sedimentation rate are thought to be due to increased levels of
fibrinogen.
3. Headache is mild and often transient. However, migraine is
often made worse and has been reported to be associated with
an increased frequency of cerebrovascular accidents. When this
occurs or when migraine has its onset during therapy with these
agents, treatment should be discontinued.
4. Withdrawal bleeding sometimes fails to occur—most often
with combination preparations—and may cause confusion
with regard to pregnancy. If this is disturbing to the patient, a
different preparation may be tried or other methods of contra-
ception used.
B. Moderate Adverse Effects
Any of the following may require discontinuance of oral
contraceptives:
1. Breakthrough bleeding is the most common problem in using
progestational agents alone for contraception. It occurs in as
many as 25% of patients. It is more frequently encountered in
patients taking low-dose preparations than in those taking
combination pills with higher levels of progestin and estrogen.
The biphasic and triphasic oral contraceptives (Table 40–3)
decrease breakthrough bleeding without increasing the total
hormone content.
2. Weight gain is more common with the combination agents
containing androgen-like progestins. It can usually be con-
trolled by shifting to preparations with less progestin effect or
by dieting.
3. Increased skin pigmentation may occur, especially in dark-
skinned women. It tends to increase with time, the incidence
being about 5% at the end of the first year and about 40% after
8 years. It is thought to be exacerbated by vitamin B deficiency.
It is often reversible upon discontinuance of medication but
may disappear very slowly.
4. Acne may be exacerbated by agents containing androgen-like
progestins (Table 40–2), whereas agents containing large
amounts of estrogen usually cause marked improvement in acne.
5. Hirsutism may also be aggravated by the “19-nortestosterone”
derivatives, and combinations containing nonandrogenic
progestins are preferred in these patients.

6. Ureteral dilation similar to that observed in pregnancy has been
reported, and bacteriuria is more frequent.
7. Vaginal infections are more common and more difficult to treat
in patients who are using oral contraceptives.
8. Amenorrhea occurs in some patients. Following cessation of
administration of oral contraceptives, 95% of patients with
normal menstrual histories resume normal periods and all but
a few resume normal cycles during the next few months. How-
ever, some patients remain amenorrheic for several years. Many
of these patients also have galactorrhea. Patients who have had
menstrual irregularities before taking oral contraceptives are
particularly susceptible to prolonged amenorrhea when the
agents are discontinued. Prolactin levels should be measured in
these patients, since many have prolactinomas.
C. Severe Adverse Effects
1. Vascular disorders—Thromboembolism was one of the
earliest of the serious unanticipated effects to be reported and has
been the most thoroughly studied.
a. Venous thromboembolic disease—Superficial or deep
thromboembolic disease in women not taking oral contraceptives
occurs in about 1 patient per 1000 woman years. The overall inci-
dence of these disorders in patients taking low-dose oral contracep-
tives is about threefold higher. The risk for this disorder is increased
during the first month of contraceptive use and remains constant
for several years or more. The risk returns to normal within a
month when use is discontinued. The risk of venous thrombosis or
pulmonary embolism is increased among women with predisposing
conditions such as stasis, altered clotting factors such as antithrom-
bin III, increased levels of homocysteine, or injury. Genetic disor-
ders, including mutations in the genes governing the production
of protein C (factor V Leiden), protein S, hepatic cofactor II, and
others, markedly increase the risk of venous thromboembolism. The
incidence of these disorders is too low for cost-effective screening
by current methods, but prior episodes or a family history may be
helpful in identifying patients with increased risk.
The incidence of venous thromboembolism appears to be
related to the estrogen but not the progestin content of oral
contraceptives and is not related to age, parity, mild obesity, or
cigarette smoking. Decreased venous blood flow, endothelial
proliferation in veins and arteries, and increased coagulability of
blood resulting from changes in platelet functions and fibrinolytic
systems contribute to the increased incidence of thrombosis. The
major plasma inhibitor of thrombin, antithrombin III, is substan-
tially decreased during oral contraceptive use. This change occurs
in the first month of treatment and lasts as long as treatment
persists, reversing within a month thereafter.
b. Myocardial infarction—The use of oral contraceptives is asso-
ciated with a slightly higher risk of myocardial infarction in women
who are obese, have a history of preeclampsia or hypertension, or
have hyperlipoproteinemia or diabetes. There is a much higher risk
in women who smoke. The risk attributable to oral contraceptives
in women 30–40 years of age who do not smoke is about 4 cases
per 100,000 users per year, as compared with 185 cases per 100,000
CHAPTER 40  The Gonadal Hormones & Inhibitors     735
among women 40–44 who smoke heavily. The association with
myocardial infarction is thought to involve acceleration of athero-
genesis because of decreased glucose tolerance, decreased levels of
HDL, increased levels of LDL, and increased platelet aggregation.
In addition, facilitation of coronary arterial spasm may play a role
in some of these patients. The progestational component of oral
contraceptives decreases HDL cholesterol levels, in proportion to
the androgenic activity of the progestin. The net effect, therefore,
will depend on the specific composition of the pill used and the
patient’s susceptibility to the particular effects. Recent studies sug-
gest that risk of infarction is not increased in past users who have
discontinued oral contraceptives.
c. Cerebrovascular disease—The risk of stroke is concen-
trated in women over age 35. It is increased in current users of
oral contraceptives but not in past users. However, subarachnoid
hemorrhages have been found to be increased among both current
and past users and may increase with time. The risk of thrombotic
or hemorrhagic stroke attributable to oral contraceptives (based
on older, higher-dose preparations) has been estimated at about
37 cases per 100,000 users per year.
In summary, available data indicate that oral contraceptives
increase the risk of various cardiovascular disorders at all ages and
among both smokers and nonsmokers. However, this risk appears
to be concentrated in women 35 years of age or older who are
heavy smokers. It is clear that these risk factors must be considered
in each individual patient for whom oral contraceptives are being
considered. Some experts have suggested that screening for coagu-
lopathy should be performed before starting oral contraception.
2. Gastrointestinal disorders—Many cases of cholestatic jaun-
dice have been reported in patients taking progestin-containing
drugs. The differences in incidence of these disorders from one
population to another suggest that genetic factors may be involved.
The jaundice caused by these agents is similar to that produced by
other 17-alkyl-substituted steroids. It is most often observed in the
first three cycles and is particularly common in women with a his-
tory of cholestatic jaundice during pregnancy. Jaundice and pruritus
disappear 1–8 weeks after the drug is discontinued.
These agents have also been found to increase the incidence of
symptomatic gallbladder disease, including cholecystitis and chol-
angitis. This is probably the result of the alterations responsible for
jaundice and bile acid changes described above.
It also appears that the incidence of hepatic adenomas is
increased in women taking oral contraceptives. Ischemic bowel
disease secondary to thrombosis of the celiac and superior and
inferior mesenteric arteries and veins has also been reported in
women using these drugs.
3. Depression—Depression of sufficient degree to require cessa-
tion of therapy occurs in about 6% of patients treated with some
preparations.
4. Cancer—The occurrence of malignant tumors in patients tak-
ing oral contraceptives has been studied extensively. It is now clear
that these compounds reduce the risk of endometrial and ovarian
cancer. The lifetime risk of breast cancer in the population as
736    SECTION VII  Endocrine Drugs
a whole does not seem to be affected by oral contraceptive use.
Some studies have shown an increased risk in younger women,
and it is possible that tumors that develop in younger women
become clinically apparent sooner. The relation of risk of cervical
cancer to oral contraceptive use is still controversial. It should be
noted that a number of recent studies associate the use of oral
contraceptives by women who are infected with human papillo-
mavirus with an increased risk of cervical cancer.
5. Other—In addition to the above effects, a number of other
adverse reactions have been reported for which a causal relation
has not been established. These include alopecia, erythema multi-
forme, erythema nodosum, and other skin disorders.
Contraindications & Cautions
These drugs are contraindicated in patients with thrombophlebitis,
thromboembolic phenomena, and cardiovascular and cerebrovas-
cular disorders or a past history of these conditions. They should
not be used to treat vaginal bleeding when the cause is unknown.
They should be avoided in patients with known or suspected
tumors of the breast or other estrogen-dependent neoplasms. Since
these preparations have caused aggravation of preexisting disorders,
they should be avoided or used with caution in patients with liver
disease, asthma, eczema, migraine, diabetes, hypertension, optic
neuritis, retrobulbar neuritis, or convulsive disorders.
The oral contraceptives may produce edema, and for that
reason they should be used with great caution in patients in heart
failure or in whom edema is otherwise undesirable or dangerous.
Estrogens may increase the rate of growth of fibroids. There-
fore, for women with these tumors, agents with the smallest
amounts of estrogen and the most androgenic progestins should
be selected. The use of progestational agents alone for contracep-
tion might be especially useful in such patients (see below).
These agents are contraindicated in adolescents in whom
epiphyseal closure has not yet been completed.
Women using oral contraceptives must be made aware of
an important interaction that occurs with antimicrobial drugs.
Because the normal gastrointestinal flora increase the entero-
hepatic cycling (and bioavailability) of estrogens, antimicrobial
drugs that interfere with these organisms may reduce the efficacy
of oral contraceptives. Additionally, coadministration with potent
inducers of the hepatic microsomal metabolizing enzymes, such as
rifampin, may increase liver catabolism of estrogens or progestins
and diminish the efficacy of oral contraceptives.
Contraception with Progestins Alone
Small doses of progestins administered orally or by implantation
under the skin can be used for contraception. They are particu-
larly suited for use in patients for whom estrogen administration
is undesirable. They are about as effective as intrauterine devices
or combination pills containing 20–30 mcg of ethinyl estradiol.
There is a high incidence of abnormal bleeding.
Effective contraception can also be achieved by injecting
150 mg of depot medroxyprogesterone acetate (DMPA) every
3 months. After a 150-mg dose, ovulation is inhibited for at least
14 weeks. Almost all users experience episodes of unpredictable
spotting and bleeding, particularly during the first year of use.
Spotting and bleeding decrease with time, and amenorrhea is
common. This preparation is not desirable for women planning
a pregnancy soon after cessation of therapy because ovulation
suppression can sometimes persist for as long as 18 months after
the last injection. Long-term DMPA use reduces menstrual blood
loss and is associated with a decreased risk of endometrial cancer.
Suppression of endogenous estrogen secretion may be associated
with a reversible reduction in bone density, and changes in plasma
lipids are associated with an increased risk of atherosclerosis.
The progestin implant method utilizes the subcutaneous implan-
tation of capsules containing etonogestrel. These capsules release
one-fifth to one-third as much steroid as oral agents, are extremely
effective, and last for 2–4 years. The low levels of hormone have
little effect on lipoprotein and carbohydrate metabolism or blood
pressure. The disadvantages include the need for surgical insertion
and removal of capsules and some irregular bleeding rather than
predictable menses. An association of intracranial hypertension
with an earlier type of implant utilizing norgestrel was observed in
a small number of women. Patients experiencing headache or visual
disturbances should be checked for papilledema.
Contraception with progestins is useful in patients with
hepatic disease, hypertension, psychosis or mental retardation,
or prior thromboembolism. The side effects include headache,
dizziness, bloating and weight gain of 1–2 kg, and a reversible
reduction of glucose tolerance.
A. Postcoital Contraceptives
Pregnancy can be prevented following coitus by the adminis-
tration of estrogens alone, progestin alone, or in combination
(“morning after” contraception). When treatment is begun
within 72 hours, it is effective 99% of the time. Some effective
schedules are shown in Table 40–4. The hormones are often
administered with antiemetics, since 40% of patients have nausea
or vomiting. Other adverse effects include headache, dizziness,
breast tenderness, and abdominal and leg cramps. Considerable
controversy has accompanied the proposal to make these agents
available without a prescription in the United States.
Mifepristone, an antagonist at progesterone and glucocorticoid
receptors, has a luteolytic effect and is effective as a postcoital
TABLE 40–4  Schedules for use of postcoital
contraceptives.
Conjugated estrogens: 10 mg three times daily for 5 days
Ethinyl estradiol: 2.5 mg twice daily for 5 days
Diethylstilbestrol: 50 mg daily for 5 days
Mifepristone: 600 mg once with misoprostol, 400 mcg once1
l-Norgestrel: 1.5 mg once (Plan B One-Step2)
l-Norgestrel: 0.75 mg twice daily for 1 day (eg, Plan B2)
Norgestrel, 0.5 mg, with ethinyl estradiol, 0.05 mg (eg, Ovral, Preven2):
Two tablets and then two in 12 hours
1
Mifepristone given on day 1, misoprostol on day 3.
2
Sold as emergency contraceptive kits.
 CHAPTER 40  The Gonadal Hormones & Inhibitors     737

contraceptive. When combined with a prostaglandin it is also an of patients, and many other minor adverse effects are observed.
effective abortifacient. Studies of patients treated with tamoxifen as adjuvant therapy for
early breast cancer have shown a 35% decrease in contralateral
Beneficial Effects of Oral Contraceptives breast cancer. However, adjuvant therapy extended beyond 5 years
in patients with breast cancer has shown no further improvement
It has become apparent that reduction in the dose of the constitu-
in outcome. In fact, resistant lines of tumor cells may recognize
ents of oral contraceptives has markedly reduced mild and severe
tamoxifen as an agonist rather than an antagonist, perhaps due to
adverse effects, providing a relatively safe and convenient method
changes in the coregulators that interact with the estrogen recep-
of contraception for many young women. Treatment with oral
tor. Toremifene is a structurally similar compound with very
contraceptives has also been shown to be associated with many
similar properties, indications, and toxicities.
benefits unrelated to contraception. These include a reduced
risk of ovarian cysts, ovarian and endometrial cancer, and benign
breast disease. There is a lower incidence of ectopic pregnancy.
Iron deficiency and rheumatoid arthritis are less common, and Hypothalamus
premenstrual symptoms, dysmenorrhea, endometriosis, acne, and
hirsutism may be ameliorated with their use.

■■ ESTROGEN & PROGESTERONE

INHIBITORS & ANTAGONISTS – GnRH antagonists
GnRH
+/– GnRH agonists
TAMOXIFEN & RELATED PARTIAL
AGONIST ESTROGENS
+ Clomiphene
Anterior –
Tamoxifen, a competitive partial agonist inhibitor of estradiol pituitary
Oral
contraceptives,
at the estrogen receptor (Figure 40–5), was the first selective danazol
estrogen receptor modulator (SERM) to be introduced. The
mechanism of its mixed agonist/antagonist relations to the
FSH, LH
estrogen receptor has been intensively studied but is still not
completely understood. Proposals include recruitment of differ-
ent coregulators to the estrogen receptor when it binds tamoxi-
fen rather than estrogen, differential activation of heterodimers Ovary
(ERα-ERβ) versus homodimers, competition of ERα by ERβ Progesterone
and others. Tamoxifen is extensively used in the palliative treat- (Luteal phase)
ment of breast cancer in postmenopausal women and is approved – Ketoconazole,
for chemoprevention of breast cancer in high-risk women (see danazol
Chapter 54). It is a nonsteroidal agent (see structure below) that
is given orally. Peak plasma levels are reached in a few hours. Testosterone
Tamoxifen has an initial half-life of 7–14 hours in the circulation
Androstenedione
and is predominantly excreted by the liver. One of its metabolites
via CYP2D6 is 4-hydroxytamoxifen (endoxifen), a more potent – Anastrozole,
SERM. Therefore, strong inhibitors of 2D6 should be avoided others
in patients receiving tamoxifen. It is used in doses of 10–20 mg
twice daily. Hot flushes and nausea and vomiting occur in 25% Estradiol Estrone Estriol
– Fulvestrant
CH3 +/– SERMs
OCH2CH2N
CH3
Estrogen
response
element

C C
Expression in estrogen-responsive cells
CH2CH3
FIGURE 40–5  Control of ovarian secretion and the actions of its
hormones. In the follicular phase the ovary produces mainly estro-
gens; in the luteal phase it produces estrogens and progesterone.
Tamoxifen SERMs, selective estrogen receptor modulators. See text.
738    SECTION VII  Endocrine Drugs
Prevention of the expected loss of lumbar spine bone density
and plasma lipid changes consistent with a reduction in the risk
for atherosclerosis have also been reported in tamoxifen-treated
patients following spontaneous or surgical menopause. However,
this agonist activity also affects the uterus and may increase the
risk of endometrial cancer.
Raloxifene is another partial estrogen agonist-antagonist at
some but not all target tissues. It has estrogenic effects on lipids
and bone but appears not to stimulate the endometrium or breast.
Although subject to a high first-pass effect, raloxifene has a very
large volume of distribution and a long half-life (>24 hours), so
it can be taken once a day. Raloxifene has been approved in the
United States for the prevention of postmenopausal osteoporosis
and prophylaxis of breast cancer in women with risk factors.
Newer SERMs have been developed and one, bazedoxifene, in
combination with conjugated estrogens, is approved for treatment
of menopausal symptoms and prophylaxis of postmenopausal
osteoporosis.
Clomiphene is an older partial agonist, a weak estrogen that
also acts as a competitive inhibitor of endogenous estrogens
(Figure 40–5). It has found use as an ovulation-inducing agent
(see below).
MIFEPRISTONE (RU-486)
Mifepristone is a “19-norsteroid” that binds strongly to the pro-
gesterone and glucocorticoid receptors and inhibits the activity of
progesterone and that of glucocorticoids (see Chapter 39). The
drug has luteolytic properties in 80% of women when given in the
midluteal period. The mechanism of this effect is unknown, but
it may provide the basis for using mifepristone as a contraceptive
(as opposed to an abortifacient). However, because the compound
has a long half-life of 20–40 hours, large doses may prolong the
follicular phase of the subsequent cycle and so make it difficult
to use continuously for this purpose. A single dose of 600 mg is
an effective emergency postcoital contraceptive, though it may
result in delayed ovulation in the following cycle. As noted in
Chapter 39, the drug also binds to and acts as an antagonist at
the glucocorticoid receptor. Limited clinical studies suggest that
mifepristone or other analogs with similar properties may be use-
ful in the treatment of endometriosis, Cushing’s syndrome, breast
cancer, and possibly other neoplasms such as meningiomas that
contain glucocorticoid or progesterone receptors.
H3C CH3
N of danazol, has both progestational and mild androgenic effects.
OH
H3C C CCH3
O in 2 months. About 85% of patients show marked improvement
Mifepristone
Mifepristone’s major use thus far has been to terminate early
pregnancies. Doses of 400–600 mg/d for 4 days or 800 mg/d for
2 days successfully terminated pregnancy in >85% of the women
studied. The major adverse effect was prolonged bleeding that
on most occasions did not require treatment. The combination
of a single oral dose of 600 mg of mifepristone and a vaginal
pessary containing 1 mg of prostaglandin E1 or oral misoprostol
has been found to effectively terminate pregnancy in over 95%
of patients treated during the first 7 weeks after conception. The
adverse effects of the medications included vomiting, diarrhea,
and abdominal or pelvic pain. As many as 5% of patients have
vaginal bleeding requiring intervention. Because of these adverse
effects, mifepristone is administered only by physicians at family
planning centers. Note: In a very small number of cases, use of a
vaginal tablet for the prostaglandin dose has been associated with
sepsis, so it is recommended that both drugs be given by mouth
in all patients.
ZK 98734 (lilopristone) is a potent experimental progester-
one inhibitor and abortifacient in doses of 25 mg twice daily.
Like mifepristone, it also appears to have antiglucocorticoid
activity.
DANAZOL
Danazol, an isoxazole derivative of ethisterone (17α-ethinyl-
testosterone) with weak progestational, androgenic, and gluco-
corticoid activities, is used to suppress ovarian function. Danazol
inhibits the midcycle surge of LH and FSH and can prevent
the compensatory increase in LH and FSH following castration
in animals, but it does not significantly lower or suppress basal
LH or FSH levels in normal women (Figure 40–5). Danazol
binds to androgen, progesterone, and glucocorticoid receptors
and can translocate the androgen receptor into the nucleus to
initiate androgen-specific RNA synthesis. It does not bind to
intracellular estrogen receptors, but it does bind to sex hormone–
binding and corticosteroid-binding globulins. It inhibits P450scc
(the cholesterol side chain–cleaving enzyme), 3β-hydroxysteroid
dehydrogenase, 17α-hydroxysteroid dehydrogenase, P450c17
(17α-hydroxylase), P450c11 (11β-hydroxylase), and P450c21
(21β-hydroxylase). However, it does not inhibit aromatase, the
enzyme required for estrogen synthesis. It increases the mean
clearance of progesterone, probably by competing with the
hormone for binding proteins, and may have similar effects on
other active steroid hormones. Ethisterone, a major metabolite
Danazol is slowly metabolized in humans, having a half-life of
>15 hours. This results in stable circulating levels when the drug
is administered twice daily. It is highly concentrated in the liver,
adrenals, and kidneys and is excreted in both feces and urine.
Danazol has been employed as an inhibitor of gonadal function
and has found its major use in the treatment of endometriosis.
For this purpose, it can be given in a dosage of 600 mg/d. The
dosage is reduced to 400 mg/d after 1 month and to 200 mg/d
in 3–12 months.

Danazol has also been used in the treatment of fibrocystic
disease of the breast and hematologic or allergic disorders, includ-
ing hemophilia, Christmas disease, idiopathic thrombocytopenic
purpura, and angioneurotic edema.
The major adverse effects are weight gain, edema, decreased
breast size, acne and oily skin, increased hair growth, deepening
of the voice, headache, hot flushes, changes in libido, and muscle
cramps. Although mild adverse effects are very common, it is
seldom necessary to discontinue the drug because of them. Occa-
sionally, because of its inherent glucocorticoid activity, danazol
may cause adrenal suppression.
Danazol should be used with great caution in patients with
hepatic dysfunction, since it has been reported to produce mild
to moderate hepatocellular damage in some patients, as evidenced
by enzyme changes. It is also contraindicated during pregnancy
and breast-feeding, as it may produce urogenital abnormalities in
the offspring.
OTHER INHIBITORS
Anastrozole, a selective nonsteroidal inhibitor of aromatase (the
enzyme required for estrogen synthesis, Figures 40–2 and 40–5),
is effective in some women whose breast tumors have become
resistant to tamoxifen (see Chapter 54). Letrozole is similar.
Exemestane, a steroid molecule, is an irreversible inhibitor of
aromatase. Like anastrozole and letrozole, it is approved for use in
women with advanced breast cancer (see Chapter 54).
Several other aromatase inhibitors are undergoing clinical trials
in patients with breast cancer. Fadrozole is an oral nonsteroidal
(triazole) inhibitor of aromatase activity. These compounds appear to
be as effective as tamoxifen. In addition to their use in breast cancer,
aromatase inhibitors have been successfully employed as adjuncts to
androgen antagonists in the treatment of precocious puberty and as
primary treatment in the excessive aromatase syndrome.
Fulvestrant is a pure estrogen receptor antagonist that has
been somewhat more effective than those with partial agonist
effects in some patients who have become resistant to tamoxifen.
Fulvestrant is approved for use in breast cancer patients who have
become resistant to tamoxifen. ICI 164,384 is a newer antagonist;
it inhibits dimerization of the occupied estrogen receptor and
interferes with its binding to DNA.
GnRH and its analogs (nafarelin, buserelin, etc) have become
important in both stimulating and inhibiting ovarian function.
They are discussed in Chapter 37.
OVULATION-INDUCING AGENTS
CLOMIPHENE
Clomiphene citrate, a partial estrogen agonist, is closely related
to the estrogen chlorotrianisene (Figure 40–3). This compound
is well absorbed when taken orally. It has a half-life of 5–7 days
and is excreted primarily in the urine. It exhibits significant pro-
tein binding and enterohepatic circulation and is distributed to
adipose tissues.
CHAPTER 40  The Gonadal Hormones & Inhibitors     739
Pharmacologic Effects
A. Mechanisms of Action
Clomiphene is a partial agonist at estrogen receptors. The
estrogenic agonist effects are best demonstrated in animals with
marked gonadal deficiency. Clomiphene has also been shown to
effectively inhibit the action of stronger estrogens. In humans
it leads to an increase in the secretion of gonadotropins and
estrogens by inhibiting estradiol’s negative feedback effect on the
release of gonadotropins (Figure 40–5).
B. Effects
The pharmacologic importance of clomiphene rests on its ability
to stimulate ovulation in women with oligomenorrhea or amen-
orrhea and ovulatory dysfunction. The majority of patients suffer
from polycystic ovary syndrome, a common disorder affecting
about 7% of women of reproductive age. The syndrome is char-
acterized by gonadotropin-dependent ovarian hyperandrogenism
associated with anovulation and infertility. The disorder is fre-
quently accompanied by adrenal hyperandrogenism. Clomiphene
probably blocks the feedback inhibitory influence of estrogens on
the hypothalamus, causing a surge of gonadotropins, which leads
to ovulation.
Clinical Use
Clomiphene is used in the treatment of disorders of ovulation in
patients who wish to become pregnant. Usually, a single ovulation
is induced by a single course of therapy, and the patient must be
treated repeatedly until pregnancy is achieved, since normal cyclic
ovulatory function does not usually resume. The compound is of
no value in patients with ovarian or pituitary failure.
When clomiphene is administered in a dosage of 100 mg/d for
5 days, a rise in plasma LH and FSH is observed after several days.
In patients who ovulate, the initial rise is followed by a second rise
of gonadotropin levels just prior to ovulation.
Adverse Effects
The most common adverse effects in patients treated with this
drug are hot flushes, which resemble those experienced by meno-
pausal patients. They tend to be mild, and disappear when the
drug is discontinued. There have been occasional reports of eye
symptoms due to intensification and prolongation of afterimages.
These are generally of short duration. Headache, constipation,
allergic skin reactions, and reversible hair loss have been reported
occasionally.
The effective use of clomiphene is associated with some stimu-
lation of the ovaries and usually with ovarian enlargement. The
degree of enlargement tends to be greater and its incidence higher
in patients who have enlarged ovaries at the beginning of therapy.
A variety of other symptoms such as nausea and vomiting,
increased nervous tension, depression, fatigue, breast soreness,
weight gain, urinary frequency, and heavy menses have also been
reported. However, these appear to result from the hormonal
changes associated with an ovulatory menstrual cycle rather than
from the medication. The incidence of multiple pregnancy is
740    SECTION VII  Endocrine Drugs
approximately 10%. Clomiphene has not been shown to have an
adverse effect when inadvertently given to women who are already
pregnant.
Contraindications & Cautions
Special precautions should be observed in patients with enlarged
ovaries. These women are thought to be more sensitive to this
drug and should receive small doses. Any patient who complains
of abdominal symptoms should be examined carefully. Maxi-
mum ovarian enlargement occurs after the 5-day course has been
completed, and many patients can be shown to have a palpable
increase in ovarian size by the seventh to tenth days. Treatment
with clomiphene for more than a year may be associated with an
increased risk of low-grade ovarian cancer; however, the evidence
for this effect is not conclusive.
Special precautions must also be taken in patients who have
visual symptoms associated with clomiphene therapy, since these
symptoms may make activities such as driving more hazardous.
OTHER DRUGS USED IN
OVULATORY DISORDERS
In addition to clomiphene, a variety of other hormonal and non-
hormonal agents are used in treating anovulatory disorders. They
are discussed in Chapter 37.
■■ THE TESTIS (ANDROGENS
& ANABOLIC STEROIDS,
ANTIANDROGENS, & MALE
CONTRACEPTION)
The testis, like the ovary, has both gametogenic and endocrine
functions. The onset of gametogenic function of the testes is
controlled largely by the secretion of FSH by the pituitary. High
concentrations of testosterone locally are also required for con-
tinuing sperm production in the seminiferous tubules. The Sertoli
cells in the seminiferous tubules may be the source of the estra-
diol produced in the testes via aromatization of locally produced
testosterone. With LH stimulation, testosterone is produced by
the interstitial or Leydig cells found in the spaces between the
seminiferous tubules.
The Sertoli cells in the testis synthesize and secrete a variety
of active proteins, including müllerian duct inhibitory factor,
inhibin, and activin. As in the ovary, inhibin and activin appear to
be the product of three genes that produce a common α subunit
and two β subunits, A and B. Activin is composed of the two β
subunits (βAβB). There are two inhibins (A and B), which con-
tain the α subunit and one of the β subunits. Activin stimulates
pituitary FSH release and is structurally similar to transforming
growth factor-β, which also increases FSH. The inhibins in con-
junction with testosterone and dihydrotestosterone are responsible
for the feedback inhibition of pituitary FSH secretion.
ANDROGENS & ANABOLIC
STEROIDS
In humans, the most important androgen secreted by the testis is
testosterone. The pathways of synthesis of testosterone in the tes-
tes are similar to those previously described for the adrenal gland
and ovary (Figures 39–1 and 40–2).
In men, approximately 8 mg of testosterone is produced daily.
About 95% is produced by the Leydig cells and only 5% by the
adrenals. The testis also secretes small amounts of another potent
androgen, dihydrotestosterone, as well as androstenedione and
dehydroepiandrosterone, which are weak androgens. Pregneno-
lone and progesterone and their 17-hydroxylated derivatives are
also released in small amounts. Plasma levels of testosterone in
males are about 0.6 mcg/dL after puberty and appear to decline
after age 50. Testosterone is also present in the plasma of women
in concentrations of approximately 0.03 mcg/dL and is derived in
approximately equal parts from the ovaries and adrenals and by
the peripheral conversion of other hormones.
About 65% of circulating testosterone is bound to sex hor-
mone-binding globulin. SHBG is increased in plasma by estrogen,
by thyroid hormone, and in patients with cirrhosis of the liver. It
is decreased by androgen and growth hormone and is lower in
obese individuals. Most of the remaining testosterone is bound to
albumin. Approximately 2% remains free and available to enter
cells and bind to intracellular receptors.
Metabolism
In many target tissues, testosterone is converted to dihydrotestos-
terone by 5α-reductase. In these tissues, dihydrotestosterone is the
major active androgen. The conversion of testosterone to estradiol
by P450 aromatase also occurs in some tissues, including adipose
tissue, liver, and the hypothalamus, where it may be of importance
in regulating gonadal function.
The major pathway for the degradation of testosterone in
humans occurs in the liver, with the reduction of the double bond
and ketone in the A ring, as is seen in other steroids with a Δ4-
ketone configuration in the A ring. This leads to the production of
inactive substances such as androsterone and etiocholanolone that
are then conjugated and excreted in the urine.
Androstenedione, dehydroepiandrosterone (DHEA), and
dehydroepiandrosterone sulfate (DHEAS) are also produced in
significant amounts in humans, although largely in the adrenal
gland rather than in the testes. They contribute slightly to the
normal maturation process supporting other androgen-dependent
pubertal changes in the human, primarily development of pubic
and axillary hair and bone maturation. As noted in Chapter 39,
some studies suggest that DHEA and DHEAS may have other
central nervous system and metabolic effects and may prolong
life in rabbits. In men they may improve the sense of well-
being and inhibit atherosclerosis. In a placebo-controlled clini-
cal trial in patients with systemic lupus erythematosus, DHEA
demonstrated some beneficial effects (see Adrenal Androgens,
Chapter 39). Adrenal androgens are to a large extent metabo-
lized in the same fashion as testosterone. Both steroids—but

particularly androstenedione—can be converted by peripheral
tissues to estrone in very small amounts (1–5%). The P450 aro-
matase enzyme responsible for this conversion is also found in the
brain and is thought to play an important role in development.
Physiologic Effects
In the normal male, testosterone or its active metabolite
5α-dihydrotestosterone is responsible for the many changes that
occur in puberty. In addition to the general growth-promoting
properties of androgens on body tissues, these hormones are
responsible for penile and scrotal growth. Changes in the skin
include the appearance of pubic, axillary, and beard hair. The
sebaceous glands become more active, and the skin tends to
become thicker and oilier. The larynx grows and the vocal cords
become thicker, leading to a lower-pitched voice. Skeletal growth
is stimulated and epiphyseal closure accelerated. Other effects
include growth of the prostate and seminal vesicles, darkening
of the skin, and increased skin circulation. Androgens play an
important role in stimulating and maintaining sexual function
in men. Androgens increase lean body mass and stimulate body
hair growth and sebum secretion. Metabolic effects include the
reduction of hormone binding and other carrier proteins and
increased liver synthesis of clotting factors, triglyceride lipase, α1-
antitrypsin, haptoglobin, and sialic acid. They also stimulate renal
erythropoietin secretion and decrease HDL levels.
Synthetic Steroids with Androgenic &
Anabolic Action
Testosterone, when administered by mouth, is rapidly absorbed.
However, it is largely converted to inactive metabolites, and only
about one sixth of the dose administered is available in active form.
Testosterone can be administered parenterally, but it has a more
prolonged absorption time and greater activity in the propionate,
enanthate, undecanoate, or cypionate ester forms. These derivatives
are hydrolyzed to release free testosterone at the site of injection.
Testosterone derivatives alkylated at the 17 position, eg, methyltes-
tosterone and fluoxymesterone, are active when given by mouth.
Testosterone and its derivatives have been used for their ana-
bolic effects as well as in the treatment of testosterone deficiency.
Although testosterone and other known active steroids can be iso-
lated in pure form and measured by weight, biologic assays are still
used in the investigation of new compounds. In some of these stud-
ies in animals, the anabolic effects of the compound as measured
by trophic effects on muscles or the reduction of nitrogen excretion
may be dissociated from the other androgenic effects. This has led
to the marketing of compounds claimed to have anabolic activity
associated with only weak androgenic effects. Unfortunately, this
dissociation is less marked in humans than in the animals used for
testing (Table 40–5), and all are potent androgens.
Pharmacologic Effects
A. Mechanism of Action
Like other steroids, testosterone acts intracellularly in target cells.
In skin, prostate, seminal vesicles, and epididymis, it is converted
CHAPTER 40  The Gonadal Hormones & Inhibitors     741
TABLE 40–5  Androgens: Preparations available and
relative androgenic:anabolic activity in
animals.
Drug Androgenic:Anabolic Activity
Testosterone 1:1
Testosterone cypionate 1:1
Testosterone enanthate 1:1
Methyltestosterone 1:1
Fluoxymesterone 1:2
Oxymetholone 1:3
Oxandrolone 1:3–1:13
Nandrolone decanoate 1:2.5–1:4
to 5α-dihydrotestosterone by 5α-reductase. In these tissues, dihy-
drotestosterone is the dominant androgen. The distribution of this
enzyme in the fetus is different and has important developmental
implications.
Testosterone and dihydrotestosterone bind to the intracellular
androgen receptor, initiating a series of events similar to those
described above for estradiol and progesterone, leading to growth,
differentiation, and synthesis of a variety of enzymes and other
functional proteins.
B. Effects
In the male at puberty, androgens cause development of the
secondary sex characteristics (see above). In the adult male, large
doses of testosterone—when given alone—or its derivatives sup-
press the secretion of gonadotropins and result in some atrophy
of the interstitial tissue and the tubules of the testes. Since fairly
large doses of androgens are required to suppress gonadotropin
secretion, it has been postulated that inhibin, in combination with
androgens, is responsible for the feedback control of secretion. In
women, androgens are capable of producing changes similar to
those observed in the prepubertal male. These include growth of
facial and body hair, deepening of the voice, enlargement of the
clitoris, frontal baldness, and prominent musculature. The natural
androgens stimulate erythrocyte production.
The administration of androgens reduces the excretion of nitro-
gen into the urine, indicating an increase in protein synthesis or a
decrease in protein breakdown within the body. This effect is much
more pronounced in women and children than in normal men.
Clinical Uses
A. Androgen Replacement Therapy in Men
Androgens are used to replace or augment endogenous androgen
secretion in hypogonadal men (Table 40–6). Even in the presence
of pituitary deficiency, androgens are used rather than gonadotropin
except when normal spermatogenesis is to be achieved. In patients
with hypopituitarism, androgens are not added to the treatment
regimen until puberty, at which time they are instituted in gradually
increasing doses to achieve the growth spurt and the development
of secondary sex characteristics. In these patients, therapy should
742    SECTION VII  Endocrine Drugs
TABLE 40–6  Androgen preparations for replacement
therapy.
Route of
Drug Administration Dosage
Methyltestosterone Oral 25–50 mg/d
  Sublingual (buccal) 5–10 mg/d
Fluoxymesterone Oral 2–10 mg/d
Testosterone enanthate Intramuscular See text
Testosterone cypionate Intramuscular See text
Testosterone Transdermal 2.5–10 mg/d
  Topical gel (1%) 5–10 g/d
be started with long-acting agents such as testosterone enanthate or
cypionate in doses of 50 mg intramuscularly, initially every 4, then
every 3, and finally every 2 weeks, with each change taking place
at 3-month intervals. The dose is then doubled to 100 mg every
2 weeks until maturation is complete. Finally, it is changed to the
adult replacement dose of 200 mg at 2-week intervals.
Testosterone propionate, though potent, has a short duration
of action and is not practical for long-term use. Testosterone
undecanoate can be given orally, administering large amounts
of the steroid twice daily (eg, 40 mg/d); however, this is not
recommended because oral testosterone administration has been
associated with liver tumors. Testosterone can also be administered
transdermally; skin patches or gels are available for scrotal or other
skin area application. Two applications daily are usually required
for replacement therapy. Implanted pellets and other longer-acting
preparations are under study. The development of polycythemia
or hypertension may require some reduction in dose.
B. Gynecologic Disorders
Androgens are used occasionally in the treatment of certain
gynecologic disorders, but the undesirable effects in women are
such that they must be used with great caution. Androgens have
been used to reduce breast engorgement during the postpartum
period, usually in conjunction with estrogens. The weak androgen
danazol is used in the treatment of endometriosis (see above).
Androgens are sometimes given in combination with estro-
gens for replacement therapy in the postmenopausal period in an
attempt to eliminate the endometrial bleeding that may occur when
only estrogens are used and to enhance libido. They have been used
for chemotherapy of breast tumors in premenopausal women.
C. Use as Protein Anabolic Agents
Androgens and anabolic steroids have been used in conjunction
with dietary measures and exercises in an attempt to reverse pro-
tein loss after trauma, surgery, or prolonged immobilization and
in patients with debilitating diseases. Evidence to support this use
of androgens is poor except when hypogonadism is also present.
D. Anemia
In the past, large doses of androgens were employed in the treatment
of refractory anemias such as aplastic anemia, Fanconi’s anemia, sickle
cell anemia, myelofibrosis, and hemolytic anemias. Recombinant
erythropoietin has largely replaced androgens for this purpose.
E. Osteoporosis
Androgens and anabolic agents have been used in the treatment of
osteoporosis, either alone or in conjunction with estrogens. With
the exception of substitution therapy in hypogonadism, bisphos-
phonates have largely replaced androgen use for this purpose.
F. Use as Growth Stimulators
These agents have been used to stimulate growth in boys with
delayed puberty. If the drugs are used carefully, these children will
probably achieve their expected adult height. If treatment is too
vigorous, the patient may grow rapidly at first but will not achieve
full predicted final stature because epiphyseal closure is acceler-
ated. It is difficult to control this type of therapy adequately even
with frequent x-ray examination of the epiphyses, since the action
of the hormones on epiphyseal centers may continue for many
months after therapy is discontinued.
G. Anabolic Steroid and Androgen Abuse in Sports
The use of anabolic steroids by athletes has received worldwide
attention. Many athletes and their coaches believe that anabolic
steroids—in doses 10–200 times larger than the daily normal
physiologic production—increase strength and aggressiveness,
thereby improving competitive performance. Such effects have
been unequivocally demonstrated only in women. Furthermore,
the adverse effects of these drugs clearly make their use inad-
visable. As a result, most sports organizations have developed
extremely sensitive assays, conduct random testing, and apply
strong penalties if drugs are detected.
H. Aging
Androgen production falls with age in men and may contribute to
the decline in muscle mass, strength, and libido. Preliminary studies
of androgen replacement in aging males with low androgen levels
show an increase in lean body mass and hematocrit and a decrease
in bone turnover. However, many factors other than deficient
androgen production contribute to these effects of aging. Longer
studies will be required to assess the usefulness of this therapy.
Adverse Effects
The adverse effects of these compounds are due largely to their
masculinizing actions and are most noticeable in women and
prepubertal children. In women, the administration of more than
200–300 mg of testosterone per month is usually associated with
hirsutism, acne, amenorrhea, clitoral enlargement, and deepening
of the voice. These effects may occur with even smaller doses in
some women. Some of the androgenic steroids exert progestational
activity, leading to endometrial bleeding upon discontinuation.
These hormones also alter serum lipids and could conceivably
increase susceptibility to atherosclerotic disease in women.
Except under the most unusual circumstances, androgens
should not be used in infants. Recent studies in animals suggest
that administration of androgens in early life may have profound

effects on maturation of central nervous system centers governing
sexual development, particularly in the female. Administration of
these drugs to pregnant women may lead to masculinization or
undermasculinization of the external genitalia in the female and
male fetus, respectively. Although the above-mentioned effects
may be less marked with the anabolic agents, they do occur.
Sodium retention and edema are not common but must be
carefully watched for in patients with heart and kidney disease.
Most of the synthetic androgens and anabolic agents are
17-alkyl-substituted steroids. Administration of drugs with this
structure is often associated with evidence of hepatic dysfunction.
Hepatic dysfunction usually occurs early in the course of treat-
ment, and the degree is proportionate to the dose. Bilirubin levels
may increase until clinical jaundice is apparent. The cholestatic
jaundice is reversible upon cessation of therapy, and permanent
changes do not occur. In older males, prostatic hyperplasia may
develop, causing urinary retention.
Replacement therapy in men may cause acne, sleep apnea,
erythrocytosis, gynecomastia, and azoospermia. Supraphysiologic
doses of androgens produce azoospermia and decrease in testicular
size, both of which may take months to recover after cessation of
therapy. The alkylated androgens in high doses can produce pelio-
sis hepatica, cholestasis, and hepatic failure. They lower plasma
HDL and may increase LDL. Hepatic adenomas and carcinomas
have also been reported. Behavioral effects include psychological
dependence, increased aggressiveness, and psychotic symptoms.
Contraindications & Cautions
The use of androgenic steroids is contraindicated in pregnant women
or women who may become pregnant during the course of therapy.
Androgens should not be administered to male patients with
carcinoma of the prostate or breast. Until more is known about the
effects of these hormones on the central nervous system in develop-
ing children, they should be avoided in infants and young children.
Special caution is required in giving these drugs to children to
produce a growth spurt. In most patients, the use of somatotropin
is more appropriate (see Chapter 37).
Care should be exercised in the administration of these drugs to
patients with renal or cardiac disease predisposed to edema. If sodium
and water retention occurs, it will respond to diuretic therapy.
Methyltestosterone therapy is associated with creatinuria, but
the significance of this finding is not known.
Caution: Several cases of hepatocellular carcinoma have been
reported in patients with aplastic anemia treated with androgen
anabolic therapy. Erythropoietin and colony-stimulating factors
(see Chapter 33) should be used instead.
ANDROGEN SUPPRESSION &
ANTIANDROGENS
ANDROGEN SUPPRESSION
In contrast to the lack of strong indications for the use of androgen
supplementation (except in the case of hypogonadism), the use of
inhibitors of androgen synthesis and of androgen antagonists has
CHAPTER 40  The Gonadal Hormones & Inhibitors     743
several well-documented applications. The treatment of advanced
prostatic carcinoma often requires orchiectomy or large doses of estro-
gens to reduce available endogenous androgen. The psychological
effects of the former and gynecomastia produced by the latter make
these approaches undesirable. As noted in Chapter 37, the GnRH
analogs, such as goserelin, nafarelin, buserelin, and leuprolide acetate,
produce effective gonadal suppression when blood levels are continu-
ous rather than pulsatile (see Chapter 37 and Figure 40–6).
ANTIANDROGENS
The potential usefulness of antiandrogens in the treatment of
patients producing excessive amounts of testosterone has led to the
search for effective drugs that can be used for this purpose. Several
approaches to the problem, especially inhibition of synthesis and
receptor antagonism, have met with some success.
Steroid Synthesis Inhibitors
Ketoconazole, used primarily in the treatment of fungal dis-
ease, is an inhibitor of adrenal and gonadal steroid synthesis, as
described in Chapter 39. It does not affect ovarian aromatase, but
it reduces human placental aromatase activity. It displaces estra-
diol and dihydrotestosterone from sex hormone-binding protein
in vitro and increases the estradiol:testosterone ratio in plasma in
vivo by a different mechanism. However, it does not appear to be
clinically useful in women with increased androgen levels because
of the toxicity associated with prolonged use of the 400–800 mg/d
required. The drug has also been used experimentally to treat pros-
tatic carcinoma, but the results have not been encouraging. Men
treated with ketoconazole often develop reversible gynecomastia
during therapy; this may be due to the demonstrated increase in
the estradiol:testosterone ratio.
Inhibition of Conversion of Steroid
Precursors to Androgens
Several compounds have been developed that inhibit the
17-hydroxylation of progesterone or pregnenolone, thereby
preventing the action of the side chain-splitting enzyme and
the further transformation of these steroid precursors to active
androgens. A few of these compounds have been tested clini-
cally but have been too toxic for prolonged use. As noted in
Chapter 39, abiraterone, a newer 17α-hydroxylase inhibitor,
has been approved for use in metastatic prostate cancer.
Since dihydrotestosterone—not testosterone—appears to be
the essential androgen in the prostate, androgen effects in this
and similar dihydrotestosterone-dependent tissues can be reduced
by an inhibitor of 5α-reductase (Figure 40–6). Finasteride, a
steroid-like inhibitor of this enzyme, is orally active and causes a
reduction in dihydrotestosterone levels that begins within 8 hours
after administration and lasts for about 24 hours. The half-life is
about 8 hours (longer in elderly individuals). About 40–50% of
the dose is metabolized; more than half is excreted in the feces.
Finasteride has been reported to be moderately effective in reduc-
ing prostate size in men with benign prostatic hyperplasia and is
744    SECTION VII  Endocrine Drugs

Hypothalamus O

C NHC(CH3)3
CH3

CH3

GnRH
O
N H
– GnRH antagonists (1) H
Finasteride
+/– GnRH agonists (2)

Receptor Inhibitors
Pituitary Flutamide, a substituted anilide, is a potent antiandrogen that has
gonadotrophs
been used in the treatment of prostatic carcinoma. Although not
a steroid, it behaves like a competitive antagonist at the androgen
receptor. It is rapidly metabolized in humans. It frequently causes
LH
mild gynecomastia (probably by increasing testicular estrogen
production) and occasionally causes mild reversible hepatic toxic-
ity. Administration of this compound causes some improvement
Testis
in most patients with prostatic carcinoma who have not had prior
endocrine therapy. Preliminary studies indicate that flutamide
– Ketoconazole, (3)
spironolactone is also useful in the management of excess androgen effect in
women.
Testosterone
F3C
5α- – Finasteride O
Reductase (4)
O2N NH C CH CH3
Dihydrotestosterone
CH3
Flutamide,
cyproterone, (5) Flutamide
– –
spironolactone

Androgen-receptor complex Bicalutamide, nilutamide, and enzalutamide are potent

Androgen
response
element
Expression of appropriate
genes in androgen-responsive cells
FIGURE 40–6  Control of androgen secretion and activity and
some sites of action of antiandrogens: (1) competitive inhibition of
GnRH receptors; (2) stimulation (+, pulsatile administration) or inhibi-
tion via desensitization of GnRH receptors (–, continuous administra-
tion); (3) decreased synthesis of testosterone in the testis; (4) decreased
synthesis of dihydrotestosterone by inhibition of 5α-reductase;
(5) competition for binding to cytosol androgen receptors.
approved for this use in the United States. The dosage is 5 mg/d.
Dutasteride is a similar orally active steroid derivative with a slow
onset of action and a much longer half-life than finasteride. It is
approved for treatment of benign prostatic hyperplasia at a dosage
of 0.5 mg daily. These drugs are not approved for use in women
or children, although finasteride has been used successfully in the
treatment of hirsutism in women and is approved for treatment of
early male pattern baldness in men (1 mg/d).
orally active antiandrogens that can be administered as a single
daily dose and are used in patients with metastatic carcinoma of
the prostate. Studies in patients with carcinoma of the prostate
indicate that these agents are well tolerated. Bicalutamide is rec-
ommended (to reduce tumor flare) for use in combination with
a GnRH analog and may have fewer gastrointestinal side effects
than flutamide. A dosage of 150–200 mg/d (when used alone)
is required to reduce prostate-specific antigen levels to those
achieved by castration, but, in combination with a GnRH analog,
50 mg/d may be adequate. Nilutamide is administered in a dosage
of 300 mg/d for 30 days followed by 150 mg/d. The dosage of
enzalutamide is 160 mg/d orally.
Cyproterone and cyproterone acetate are effective anti-
androgens that inhibit the action of androgens at the target
organ. The acetate form has a marked progestational effect that
suppresses the feedback enhancement of LH and FSH, leading
to a more effective antiandrogen effect. These compounds have
been used in women to treat hirsutism and in men to decrease
excessive sexual drive and are being studied in other conditions
in which the reduction of androgenic effects would be useful.
Cyproterone acetate in a dosage of 2 mg/d administered con-
currently with an estrogen is used in the treatment of hirsutism
in women, doubling as a contraceptive pill; it has orphan drug
status in the United States.
 CHAPTER 40  The Gonadal Hormones & Inhibitors     745

Spironolactone, a competitive inhibitor of aldosterone (see P R E P A R A T I *O N S

Chapter 15), also competes with dihydrotestosterone for the andro- A V A I L A B L E
gen receptors in target tissues. It also reduces 17α-hydroxylase
activity, lowering plasma levels of testosterone and androstene-
GENERIC NAME AVAILABLE AS
dione. It is used in dosages of 50–200 mg/d in the treatment of
ESTROGENS
hirsutism in women and appears to be as effective as finasteride,
Conjugated estrogens (equine) Premarin
flutamide, or cyproterone in this condition.
Diethylstilbestrol† Generic, DES, Stilphostrol
Esterified estrogens Cenestin, Enjuvia, Menest

CHEMICAL CONTRACEPTION Estradiol

Estradiol cypionate in oil
Generic, Estrace, others
Depo-Estradiol, others
IN MEN Estradiol transdermal Generic, Estraderm, Estrasorb,
Estrogel, others
Although many studies have been conducted, an effective and Estradiol valerate in oil Generic, Delestrogen
nontoxic oral contraceptive for men has not yet been found. For Estropipate Generic, Ogen
example, various androgens, including testosterone and testos- PROGESTINS
terone enanthate, in a dosage of 400 mg per month, produced Levonorgestrel Generic, Plan B, others
azoospermia in less than half the men treated. Minor adverse Medroxyprogesterone acetate Generic, Provera
reactions, including gynecomastia and acne, were encountered. Megestrol acetate Generic, Megace
Testosterone in combination with danazol was well tolerated but Norethindrone acetate Generic, Aygestin
no more effective than testosterone alone. Androgens in combina- Progesterone Generic, Prometrium, others
tion with a progestin such as medroxyprogesterone acetate were ANDROGENS & ANABOLIC STEROIDS
no more effective. However, preliminary studies indicate that the Fluoxymesterone Androxy
intramuscular administration of 100 mg of testosterone enanthate Methyltestosterone Android, others
weekly together with 500 mg of levonorgestrel daily orally can Nandrolone decanoate Generic, Deca Durabolin, others
produce azoospermia in 94% of men. Retinoic acid is important Oxandrolone Generic, Oxandrin
in the maturation of sperm and the testis contains a unique iso- Oxymetholone Androl-50
form of the alcohol dehydrogenase enzyme that converts retinol Testosterone Generic
to retinoic acid but no nontoxic inhibitor of this enzyme has been Testosterone cypionate in oil Generic, Depo-testosterone
found to date. Testosterone enanthate in oil Generic, Delatestryl
Cyproterone acetate, a very potent progestin and antian- Testosterone transdermal system Androderm, AndroGel
drogen, also produces oligospermia; however, it does not cause Testosterone pellets Testopel
reliable contraception. ANTAGONISTS & INHIBITORS
At present, pituitary hormones—and potent antagonist analogs (See also Chapter 37)  
of GnRH—are receiving increased attention. A GnRH antagonist Abiraterone Zytiga
in combination with testosterone has been shown to produce Anastrozole Generic, Arimidex
reversible azoospermia in nonhuman primates. Bazedoxifene (in combination with Duavee
conjugated equine estrogens)
Bicalutamide Generic, Casodex
GOSSYPOL Clomiphene Generic, Clomid, Serophene,
Milophene
Extensive trials of this cottonseed derivative have been conducted Danazol Generic, Danocrine
in China. This compound destroys elements of the seminiferous Dutasteride Avodart
epithelium but does not significantly alter the endocrine function Enzalutamide Xtandi
of the testis. Exemestane Generic, Aromasin
In Chinese studies, large numbers of men were treated with Finasteride Generic, Propecia, Proscar
20 mg/d of gossypol or gossypol acetic acid for 2 months, Flutamide Generic, Eulexin
followed by a maintenance dosage of 60 mg/week. On Fulvestrant Faslodex
this regimen, 99% of men developed sperm counts below Letrozole Generic, Femara
4 million/mL. Preliminary data indicate that recovery (return Mifepristone Mifeprex, Korlym
of normal sperm count) following discontinuance of gossypol Nilutamide Nilandron
administration is more apt to occur in men whose counts do not Raloxifene Evista
fall to extremely low levels and when administration is not con- Tamoxifen Generic, Nolvadex
tinued for more than 2 years. Hypokalemia is the major adverse Toremifene Fareston
effect and may lead to transient paralysis. Because of low effi- *
Oral contraceptives are listed in Table 40–3.
cacy and significant toxicity, gossypol has been abandoned as a †
Withdrawn in the United States.
candidate male contraceptive.
746    SECTION VII  Endocrine Drugs

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C ASE STUDY ANSWER

The patient should be advised to start daily transdermal and normal monthly uterine bleeding resume. She should
estradiol therapy (100 mcg/d) along with oral natural pro- also be advised to get adequate exercise and increase
gesterone (200 mg/d) for the last 12 days of each 28-day her calcium and vitamin D intake as treatment for her
cycle. On this regimen, her symptoms should disappear osteoporosis.

Pancreatic Hormones &
Antidiabetic Drugs
Martha S. Nolte Kennedy, MD, &
Umesh Masharani, MBBS, MRCP (UK)
C ASE STUDY
A 66-year-old obese Caucasian man presented to an
academic Diabetes Center for advice regarding his diabetes
treatment. His diabetes was diagnosed 10 years previously
on routine testing. He was initially given metformin but
when his control deteriorated, the metformin was stopped
and insulin treatment initiated. The patient was taking
50 units of insulin glargine and an average of 25 units of
insulin aspartate pre-meals. He had never seen a diabetes
educator or a dietitian. He was checking his glucose levels
■■ THE ENDOCRINE PANCREAS
The endocrine pancreas in the adult human consists of approxi-
mately 1 million islets of Langerhans interspersed throughout
the pancreatic gland. Within the islets, at least five hormone-
producing cells are present (Table 41–1). Their hormone products
include insulin, the storage and anabolic hormone of the body;
islet amyloid polypeptide (IAPP, or amylin), which modulates
appetite, gastric emptying, and glucagon and insulin secretion;
glucagon, the hyperglycemic factor that mobilizes glycogen
stores; somatostatin, a universal inhibitor of secretory cells; pan-
creatic peptide, a small protein that facilitates digestive processes
by a mechanism not yet clarified; and ghrelin, a peptide known
to increase pituitary growth hormone release.
41
C H A P T E R
4 times a day. He was smoking half a pack of cigarettes a day.
On examination, his weight was 132 kg (BMI 39.5); blood
pressure 145/71; and signs of mild peripheral neuropathy
were present. Laboratory tests noted an HbA1c value of
8.1%, urine albumin 3007 mg/g creatinine (normal <30),
serum creatinine 0.86 mg/dL (0.61–1.24), total choles-
terol 128 mg/dL, triglycerides 86 mg/dL, HDL cholesterol
38 mg/dL, and LDL cholesterol 73 mg/dL (on atorvastatin
40 mg daily). How would you treat this patient?
■■ INSULIN
Chemistry
Insulin is a small protein with a molecular weight in humans of
5808. It contains 51 amino acids arranged in two chains (A and
B) linked by disulfide bridges; there are species differences in the
amino acids of both chains. Proinsulin, a long single-chain protein
molecule, is processed within the Golgi apparatus of beta cells and
packaged into granules, where it is hydrolyzed into insulin and a
residual connecting segment called C-peptide by removal of four
amino acids (Figure 41–1).
Insulin and C-peptide are secreted in equimolar amounts
in response to all insulin secretagogues; a small quantity of
747
748    SECTION VII  Endocrine Drugs

TABLE 41–1  Pancreatic islet cells and their secretory somatostatin, and leptin; α-adrenergic sympathetic activity;
products. chronically elevated glucose; and low concentrations of fatty
acids. Inhibitory drugs include diazoxide, phenytoin, vinblas-
Approximate tine, and colchicine.
Cell Types1 Percent of Islet Mass Secretory Products
One mechanism of stimulated insulin release is diagrammed
Alpha (A) cell 20 Glucagon, proglucagon in Figure 41–2. As shown in the figure, hyperglycemia results in
Beta (B) cell 75 Insulin, C-peptide, increased intracellular ATP levels, which close ATP-dependent
proinsulin, amylin potassium channels. Decreased outward potassium efflux results
Delta (D) cell 3–5 Somatostatin in depolarization of the beta cell and opening of voltage-gated
Epsilon cell <1 Ghrelin calcium channels. The resulting increased intracellular calcium
1 triggers secretion of the hormone. The insulin secretagogue drug
Within pancreatic polypeptide-rich lobules of adult islets, located only in the poste-
rior portion of the head of the human pancreas, glucagon cells are scarce (<0.5%) and group (sulfonylureas, meglitinides, and d-phenylalanine) exploits
F cells make up as much as 80% of the cells. parts of this mechanism.

unprocessed or partially hydrolyzed proinsulin is released as well. Insulin Degradation

Although proinsulin may have some mild hypoglycemic action,
C-peptide has no known physiologic function. Granules within
the beta cells store the insulin in the form of crystals consisting of
two atoms of zinc and six molecules of insulin. The entire human
pancreas contains up to 8 mg of insulin, representing approxi-
mately 200 biologic units. Originally, the unit was defined on
the basis of the hypoglycemic activity of insulin in rabbits. With
improved purification techniques, the unit is presently defined on
the basis of weight, and present insulin standards used for assay
purposes contain 28 units per milligram.
The liver and kidney are the two main organs that remove insu-
lin from the circulation. The liver normally clears the blood of
approximately 60% of the insulin released from the pancreas by
virtue of its location as the terminal site of portal vein blood flow,
with the kidney removing 35–40% of the endogenous hormone.
However, in insulin-treated diabetics receiving subcutaneous
insulin injections, this ratio is reversed, with as much as 60%
of exogenous insulin being cleared by the kidney and the liver
removing no more than 30–40%. The half-life of circulating
insulin is 3–5 minutes.

Insulin Secretion Circulating Insulin

Insulin is released from pancreatic beta cells at a low basal rate
and at a much higher stimulated rate in response to a variety of
stimuli, especially glucose. Other stimulants such as other sugars
(eg, mannose), amino acids (especially gluconeogenic amino
acids, eg, leucine, arginine), hormones such as glucagon-like
polypeptide 1 (GLP-1), glucose-dependent insulinotropic poly-
peptide (GIP), glucagon, cholecystokinin, high concentrations
of fatty acids, and β-adrenergic sympathetic activity are recog-
nized. Stimulatory drugs include sulfonylureas, meglitinide and
nateglinide, isoproterenol, and acetylcholine. Inhibitory signals
are hormones including insulin itself, islet amyloid polypeptide,
Basal serum insulin values of 5–15 μU/mL (30–90 pmol/L) are
found in normal humans, with a peak rise to 60–90 μU/mL
(360–540 pmol/L) during meals.
The Insulin Receptor
After insulin has entered the circulation, it diffuses into tissues,
where it is bound by specialized receptors that are found on the
membranes of most tissues. The biologic responses promoted by
these insulin-receptor complexes have been identified in the pri-
mary target tissues regulating energy metabolism, ie, liver, muscle,

C-peptide

A chain S S

1 10 21
S S

S S 32
B chain
31

1 3 10 20 28 29 30

FIGURE 41–1  Structure of human proinsulin (C-peptide plus A and B chains) and insulin. Insulin is shown as the shaded (orange color)
peptide chains, A and B. Differences in the A and B chains and amino acid modifications for the rapid-acting insulin analogs (aspart, lispro,
and glulisine) and long-acting insulin analogs (glargine and detemir) are discussed in the text. (Adapted, with permission, from Gardner DG, Shoback D
[editors]: Greenspan’s Basic & Clinical Endocrinology, 9th ed. McGraw-Hill, 2011. Copyright © The McGraw-Hill Companies, Inc.)
 CHAPTER 41  Pancreatic Hormones & Antidiabetic Drugs     749

K+ channel
Sulfonylurea drugs
–
(block, depolarize)

(Closes channel, K+
depolarizes cell)

Glucose
transporter ATP
Ca2+ channel
GLUT2
(depolarization
Glucose Metabolism – + opens channel)

Ca2+ Ca2+
Insulin

Exocytosis

Insulin

FIGURE 41–2  One model of control of insulin release from the pancreatic beta cell by glucose and by sulfonylurea drugs. In the resting
cell with normal (low) ATP levels, potassium diffuses down its concentration gradient through ATP-gated potassium channels, maintaining the
intracellular potential at a fully polarized, negative level. Insulin release is minimal. If glucose concentration rises, ATP production increases,
potassium channels close, and depolarization of the cell results. As in muscle and nerve, voltage-gated calcium channels open in response to
depolarization, allowing more calcium to enter the cell. Increased intracellular calcium results in increased insulin secretion. Insulin secreta-
gogues close the ATP-dependent potassium channel, thereby depolarizing the membrane and causing increased insulin release by the same
mechanism.

and adipose tissue. The receptors bind insulin with high specificity
and affinity in the picomolar range. The full insulin receptor con-
sists of two covalently linked heterodimers, each containing an α
subunit, which is entirely extracellular and constitutes the recogni-
tion site, and a β subunit that spans the membrane (Figure 41–3).
The β subunit contains a tyrosine kinase. The binding of an
insulin molecule to the α subunits at the outside surface of the
cell activates the receptor and through a conformational change
brings the catalytic loops of the opposing cytoplasmic β subunits
into closer proximity. This facilitates mutual phosphorylation of
tyrosine residues on the β subunits and tyrosine kinase activity
directed at cytoplasmic proteins.
The first proteins to be phosphorylated by the activated recep-
tor tyrosine kinases are the docking proteins: insulin receptor
substrates (IRS). After tyrosine phosphorylation at several critical
sites, the IRS molecules bind to and activate other kinases subserv-
ing energy metabolism—most significantly phosphatidylinositol-
3-kinase—which produce further phosphorylations. Alternatively,
they may stimulate a mitogenic pathway and bind to an adaptor
protein such as growth factor receptor–binding protein 2, which
translates the insulin signal to a guanine nucleotide-releasing
factor that ultimately activates the GTP binding protein, Ras,
and the mitogen-activated protein kinase (MAPK) system. The
particular IRS-phosphorylated tyrosine kinases have binding
specificity with downstream molecules based on their surround-
ing 4–5 amino acid sequences or motifs that recognize specific Src
homology 2 (SH2) domains on the other protein. This network
of phosphorylations within the cell represents insulin’s second
message and results in multiple effects, including translocation of
glucose transporters (especially GLUT 4, Table 41–2) to the cell
membrane with a resultant increase in glucose uptake; increased
glycogen synthase activity and increased glycogen formation; mul-
tiple effects on protein synthesis, lipolysis, and lipogenesis; and
activation of transcription factors that enhance DNA synthesis
and cell growth and division.
Various hormonal agents (eg, glucocorticoids) lower the affin-
ity of insulin receptors for insulin; growth hormone in excess
increases this affinity slightly. Aberrant serine and threonine
phosphorylation of the insulin receptor β subunits or IRS mol-
ecules may result in insulin resistance and functional receptor
down-regulation.
Effects of Insulin on Its Targets
Insulin promotes the storage of fat as well as glucose (both sources
of energy) within specialized target cells (Figure 41–4) and influ-
ences cell growth and the metabolic functions of a wide variety of
tissues (Table 41–3).
■■ GLUCAGON
Chemistry & Metabolism
Glucagon is synthesized in the alpha cells of the pancreatic
islets of Langerhans (Table 41–1). Glucagon is a peptide—
identical in all mammals—consisting of a single chain of
750    SECTION VII  Endocrine Drugs

Vagus

α Insulin
Insulin molecule Liver
subunits
+
Receptor
Pancreas
β +
subunits
Substrate
Extracellular
Betacytotropic
hormones Fat

Cytoplasm
Tyrosine
kinase Muscle
domains
P
Intestine

P
FIGURE 41–4  Insulin promotes synthesis (from circulating nutrients)
and storage of glycogen, triglycerides, and protein in its major target tissues: liver,
ATP fat, and muscle. The release of insulin from the pancreas is stimulated by increased
Tyr
blood glucose, incretins, vagal nerve stimulation, and other factors (see text).

IRS

Tyr – P
Glucagon is extensively degraded in the liver and kidney as
ADP well as in plasma and at its tissue receptor sites. Its half-life in
IRS plasma is between 3 and 6 minutes, which is similar to that of
insulin.
+ +
Phosphatidylinositol-3
kinase pathway
MAP kinase
pathway
Pharmacologic Effects of Glucagon
A. Metabolic Effects
The first six amino acids at the amino terminal of the gluca-
FIGURE 41–3  Schematic diagram of the insulin receptor het- gon molecule bind to specific Gs protein–coupled receptors on
erodimer in the activated state. IRS, insulin receptor substrate; MAP,
liver cells. This leads to an increase in cAMP, which facilitates
mitogen-activated protein; P, phosphate; Tyr, tyrosine.
catabolism of stored glycogen and increases gluconeogenesis and
ketogenesis. The immediate pharmacological result of glucagon
29 amino acids, with a molecular weight of 3485. Selective infusion is to raise blood glucose at the expense of stored hepatic
proteolytic cleavage converts a large precursor molecule of glycogen. There is no effect on skeletal muscle glycogen, presum-
approximately 18,000 MW to glucagon. One of the precur- ably because of the lack of glucagon receptors on skeletal muscle.
sor intermediates consists of a 69-amino-acid peptide called Pharmacological amounts of glucagon cause release of insulin
glicentin, which contains the glucagon sequence interposed from normal pancreatic beta cells, catecholamines from pheochro-
between peptide extensions. mocytoma, and calcitonin from medullary carcinoma cells.

TABLE 41–2  Glucose transporters.

Glucose Km
Transporter Tissues (mmol/L) Function

GLUT 1 All tissues, especially red cells, brain 1–2 Basal uptake of glucose; transport across the blood-brain barrier
GLUT 2 Beta cells of pancreas; liver, kidney; gut 15–20 Regulation of insulin release, other aspects of glucose homeostasis
GLUT 3 Brain, placenta <1 Uptake into neurons, other tissues
GLUT 4 Muscle, adipose ~5 Insulin-mediated uptake of glucose
GLUT 5 Gut, kidney 1–2 Absorption of fructose

TABLE 41–3  Endocrine effects of insulin.
Effect on liver:
  Reversal of catabolic features of insulin deficiency
  Inhibits glycogenolysis
   Inhibits conversion of fatty acids and amino acids to keto acids
   Inhibits conversion of amino acids to glucose
  Anabolic action
  Promotes glucose storage as glycogen (induces glucokinase and
glycogen synthase, inhibits phosphorylase)
  Increases triglyceride synthesis and very-low-density lipoprotein
formation
Effect on muscle:
  Increased protein synthesis
   Increases amino acid transport
   Increases ribosomal protein synthesis
  Increased glycogen synthesis
   Increases glucose transport
   Induces glycogen synthase and inhibits phosphorylase
Effect on adipose tissue:
  Increased triglyceride storage
  Lipoprotein lipase is induced and activated by insulin to hydro-
lyze triglycerides from lipoproteins
  Glucose transport into cell provides glycerol phosphate to permit
esterification of fatty acids supplied by lipoprotein transport
   Intracellular lipase is inhibited by insulin
B. Cardiac Effects
Glucagon has a potent inotropic and chronotropic effect on the
heart, mediated by the cAMP mechanism described above. Thus,
it produces an effect very similar to that of β-adrenoceptor ago-
nists without requiring functioning β receptors.
C. Effects on Smooth Muscle
Large doses of glucagon produce profound relaxation of the intes-
tine. In contrast to the above effects of the peptide, this action
on the intestine may be due to mechanisms other than adenylyl
cyclase activation.
Clinical Uses
A. Severe Hypoglycemia
The major clinical use of glucagon is for emergency treatment
of severe hypoglycemic reactions in patients with type 1 diabetes
when unconsciousness precludes oral feedings and intravenous
glucose treatment is not possible. Recombinant glucagon is cur-
rently available in 1-mg vials for parenteral (IV, IM, or SC) use
(Glucagon Emergency Kit).
B. Endocrine Diagnosis
Several tests use glucagon to diagnose endocrine disorders. In
patients with type 1 diabetes mellitus, a classic research test
of pancreatic beta-cell secretory reserve uses 1 mg of glucagon
CHAPTER 41  Pancreatic Hormones & Antidiabetic Drugs     751
administered as an intravenous bolus. Because insulin-treated
patients develop circulating anti-insulin antibodies that interfere
with radioimmunoassays of insulin, measurements of C-peptide
are used to indicate beta-cell secretion.
C. Beta-Adrenoceptor Blocker Overdose
Glucagon is sometimes useful for reversing the cardiac effects of
an overdose of β-blocking agents because of its ability to increase
cAMP production in the heart independent of β-receptor func-
tion. However, it is not clinically useful in the treatment of heart
failure.
D. Radiology of the Bowel
Glucagon has been used extensively in radiology as an aid to
x-ray visualization of the bowel because of its ability to relax the
intestine.
Adverse Reactions
Transient nausea and occasional vomiting can result from glu-
cagon administration. These are generally mild, and glucagon is
relatively free of severe adverse reactions. It should not be used in
a patient with pheochromocytoma.
■■ DIABETES MELLITUS
Diabetes mellitus is defined as an elevated blood glucose associ-
ated with absent or inadequate pancreatic insulin secretion, with or
without concurrent impairment of insulin action. The disease states
underlying the diagnosis of diabetes mellitus are now classified into
four categories: type 1, type 2, other, and gestational diabetes
mellitus.
Type 1 Diabetes Mellitus
The hallmark of type 1 diabetes is selective beta cell (B cell)
destruction and severe or absolute insulin deficiency. Type 1 dia-
betes is further subdivided into immune-mediated (type 1a) and
idiopathic causes (type 1b). The immune form is the most com-
mon form of type 1 diabetes. Although most patients are younger
than 30 years of age at the time of diagnosis, the onset can occur
at any age. Type 1 diabetes is found in all ethnic groups, but the
highest incidence is in people from northern Europe and from
Sardinia. Susceptibility appears to involve a multifactorial genetic
linkage, but only 10–15% of patients have a positive family his-
tory. Most patients with type 1 diabetes have one or more circu-
lating antibodies to glutamic acid decarboxylase 65 (GAD 65),
insulin autoantibody, tyrosine phosphatase IA2 (ICA 512), and
zinc transporter 8 (ZnT8) at the time of diagnosis. These anti-
bodies facilitate the diagnosis of type 1a diabetes and can also be
used to screen family members at risk for developing the disease.
Most type 1 patients with acute symptomatic presentation have
significant beta cell loss and insulin therapy is essential to control
glucose levels and to prevent ketosis.
Some patients have a more indolent autoimmune process
and initially retain enough beta cell function to avoid ketosis.
752    SECTION VII  Endocrine Drugs
They can be treated at first with oral hypoglycemic agents
but then need insulin as their beta cell function declines.
Antibody studies in northern Europeans indicate that up to
10–15% of “type 2” patients may actually have this milder
form of type 1 diabetes (latent autoimmune diabetes of adult-
hood; LADA).
Type 2 Diabetes Mellitus
Type 2 diabetes is a heterogenous group of conditions charac-
terized by tissue resistance to the action of insulin combined
with a relative deficiency in insulin secretion. A given indi-
vidual may have more resistance or more beta-cell deficiency,
and the abnormalities may be mild or severe. Although the
circulating endogenous insulin is sufficient to prevent ketoaci-
dosis, it is inadequate to prevent hyperglycemia. Patients with
type 2 diabetes can initially be controlled with diet, exercise
and oral glucose lowering agents or non-insulin injectables.
Some patients have progressive beta cell failure and eventually
may also need insulin therapy.
Other Specific Types of Diabetes Mellitus
The “other” designation refers to multiple other specific causes
of an elevated blood glucose: pancreatectomy, pancreatitis, non-
pancreatic diseases, drug therapy, etc. For a detailed list the reader
is referred to the reference Expert Committee, 2003.
Gestational Diabetes Mellitus
Gestational diabetes (GDM) is defined as any abnormality in glu-
cose levels noted for the first time during pregnancy. Gestational
diabetes is diagnosed in approximately 7% of all pregnancies in
the United States. During pregnancy, the placenta and placental
hormones create an insulin resistance that is most pronounced in
the last trimester. Risk assessment for diabetes is suggested start-
ing at the first prenatal visit. High-risk women should be screened
immediately. Screening may be deferred in lower-risk women
until the 24th to 28th week of gestation.
TABLE 41–4  Diagnostic criteria for diabetes.
Normal Glucose
Tolerance, mg/dL
  (mMol/L)
Fasting plasma glucose mg/dL (mmol/L) <100 (5.6)
1
Two hours after glucose load mg/dL <140 (7.8)
(mmol/L)
HbA1c (%) (ADA criteria) <5.7
1
Give 75 g of glucose dissolved in 300 mL of water after an overnight fast in persons who have been receiving at least 150–200 g of carbohydrate daily for 3 days
before the test.
2
A fasting plasma glucose ≥126 mg/dL (7.0 mmol) or HbA1c ≥ 6.5% is diagnostic of diabetes if confirmed by repeat testing.
Symptoms and random glucose level >200 mg/dL (11.1 mmol/L) are diagnostic, and there is no need to do additional testing.
Laboratory Findings
A. Plasma or Serum Glucose
A plasma glucose level of 126 mg/dL (7 mmol/L) or higher
on more than one occasion after at least 8 hours of fasting is
diagnostic of diabetes mellitus (Table 41–4). Fasting plasma
glucose levels of 100–125 mg/dL (5.6–6.9 mmol/L) are associ-
ated with increased risk of diabetes (impaired fasting glucose
tolerance).
If the fasting plasma glucose level is less than 126 mg/dL
(7 mMol/L) but diabetes is nonetheless suspected, then a stan-
dardized oral glucose tolerance test may be done (Table 41–4).
The patient should eat nothing after midnight prior to the test
day. On the morning of the test, adults are then given 75 g of
glucose in 300 mL of water; children are given 1.75 g of glucose
per kilogram of ideal body weight. The glucose load is consumed
within 5 minutes. Blood samples for plasma glucose are obtained
at 0 and 120 minutes after ingestion of glucose. An oral glucose
tolerance test is normal if the fasting venous plasma glucose value
is less than 100 mg/dL (5.6 mmol/L) and the 2-hour value falls
below 140 mg/dL (7.8 mmol/L). A fasting value of 126 mg/dL
(7 mmol/L) or higher or a 2-hour value of greater than 200 mg/dL
(11.1 mmol/L) is diagnostic of diabetes mellitus. Patients with
2-hour value of 140–199 mg/dL (7.8–11.1 mmol/L) have
impaired glucose tolerance.
B. Hemoglobin A1c Measurements
When plasma glucose levels are in the normal range, about 4–6%
of hemoglobin A has one or both of the N terminal valines of their
beta chains irreversibly glycated by glucose—referred to as hemo-
globin A1c (HbA1c). The HbA1c fraction is abnormally elevated
in people with diabetes with chronic hyperglycemia. Since red
cells have a lifespan of up to 120 days, the HbA1c value reflects
plasma glucose levels over the preceding 8–12 weeks. In patients
who monitor their glucose levels, the HbA1c value provides a
valuable check on the accuracy of their monitoring. In patients
who do not monitor their glucose levels, HbA1c measurements
are essential for adjusting treatment. HbA1c can be used to
Prediabetes Diabetes Mellitus2
100–125 (5.6–6.9) ≥126
(impaired fasting glucose) (7.0)
≥140–199 ≥200
(7.8–11.0) (11.1)
(impaired glucose tolerance)
5.7–6.4 ≥6.5

diagnose diabetes. An HbA1c of 6.5% or greater if confirmed by
repeat testing is diagnostic of diabetes. Less than 5.7% is normal,
and patients with levels of 5.7–6.4% are considered at high risk
for developing diabetes (Table 41–4).
C. Urine or Blood Ketones
Qualitative detection of ketone bodies can be accomplished by
nitroprusside tests (Acetest or Ketostix). Although these tests do
not detect beta-hydroxybutyric acid, which lacks a ketone group,
the semiquantitative estimation of ketonuria thus obtained is
nonetheless usually adequate for clinical purposes. Many laborato-
ries now measure beta-hydroxybutyric acid, and meters are avail-
able (Precision Xtra; Nova Max Plus) for patient use that measure
beta-hydroxybutyric acid levels in capillary glucose samples. Beta-
hydroxybutyrate levels >0.6 mmol/L require evaluation. A level
>3.0 mmol/L, which is equivalent to very large urinary ketones,
will require hospitalization.
D. Self-Monitoring of Blood Glucose
Capillary blood glucose measurements performed by patients
themselves, as outpatients, are extremely useful. In type 1
patients in whom “tight” metabolic control is attempted, they
are indispensable. Several paper strip methods and a large
number of blood glucose meters are now available for measur-
ing glucose on capillary blood samples. All are accurate, but
they vary with regard to speed, convenience, size of blood
samples required, reporting capability, and cost. Some meters
are designed to communicate with an insulin pump. A number
of continuous glucose monitoring (CGM) systems are also avail-
able for clinical use. The systems utilize a subcutaneous sensor
that measures glucose concentrations in the interstitial fluid
for 3–7 days. Studies show that adult type 1 patients who use
continuous systems have improved glucose control without an
increased incidence of hypoglycemia. There is great interest in
using continuous glucose monitoring systems to automatically
deliver insulin by continuous subcutaneous insulin infusion
pump. The first artificial pancreas system has been approved by
the U.S. Food and Drug Administration (FDA) and will become
available in 2017. With this system, the continuous glucose
monitor readings are used to automatically adjust the basal insu-
lin dosing by the insulin pump.
TABLE 41–5  Summary of bioavailability characteristics of the insulins.
Insulin Preparations Onset of Action
Insulins lispro, aspart, glulisine 5–15 min
Human regular 30–60 min
Technosphere inhaled insulin 5–15 min
Human NPH 2–4 h
Insulin glargine 0.5–1 h
Insulin detemir 0.5–1 h
Insulin degludec 0.5–1.5 h
CHAPTER 41  Pancreatic Hormones & Antidiabetic Drugs     753
■■ MEDICATIONS FOR
HYPERGLYCEMIA
Insulin Preparations
Human insulin is dispensed as regular (R) and neutral protamine
hagedorn (NPH) formulations. There are also six analogs of human
insulin. Three of the analogs are rapidly acting: insulin lispro, insu-
lin aspart, and insulin glulisine; and three are long acting: insulin
glargine, insulin detemir, and insulin degludec. Animal insulins
are not available in the United States. Pork and beef preparations
(isophane, neutral, 30/70, and lente) are still available in other parts
of the world. All the insulins in the United States are available in
a concentration of 100 units/ML (U100) and dispensed as 10-mL
vials or 0.3-mL cartridges or prefilled disposable pens. Several
insulins are also available at higher concentrations in the prefilled
disposable pen form: insulin glargine 300 units/mL (U300); insulin
degludec (U200); insulin lispro 200 units/mL (U200); and regular
insulin 500 units/mL (U500) (Tables 41–5, 41–6).
A. Short-Acting Insulin Preparations (Tables 41–5, 41–6)
The short-acting preparations include regular human insulin
and the three rapidly acting insulin analogs. All are clear solu-
tions at neutral pH. The insulin molecules exist as dimers that
assemble into hexamers in the presence of two zinc ions. The
hexamers are further stabilized by phenolic compounds such as
phenol and meta-Cresol. The mutations engineered into the rap-
idly acting insulin analogs are designed to disrupt the stabilizing
intermolecular interactions of the dimers and hexamers, leading
to more rapid absorption into the circulation after subcutaneous
injection.
1. Regular insulin—Regular insulin is a short-acting, soluble
crystalline zinc insulin whose hypoglycemic effect appears within
30 minutes after subcutaneous injection, peaks at about 2 hours,
and lasts for 5–7 hours when usual quantities (ie, 5–15 U) are
administered. For very insulin-resistant subjects who would oth-
erwise require large volumes of insulin solution, a U500 prepara-
tion of human regular insulin is available both in a vial form and
a disposable pen. If the vial form is used, it is necessary to use
a U100-insulin syringe or tuberculin syringe to measure doses.
Peak Action Effective Duration
1–1.5 h 3–4 h
2h 6–8 h
1h 3h
6–7 h 10–20 h
Flat ~24 h
Flat 17 h
Flat >42 h
754    SECTION VII  Endocrine Drugs

TABLE 41–6  Some insulin preparations available in the United States.1

Preparation Species Source Concentration

Short-acting insulins    
  Insulin lispro (Humalog, Lilly) Human analog U100, U200
  Insulin aspart (Novolog, Novo Nordisk) Human analog U100
  Insulin glulisine (Apidra, Sanofi Aventis) Human analog U100
  Regular insulin (Humulin R, Lilly; Novolin R, Novo Nordisk) Human U100, U500
  Regular insulin inhaled (MannKind) Human —
Long-acting insulins    
  NPH insulin (Humulin N, Lilly, Novolin N, Novo Nordisk) Human U100
  Insulin glargine (Lantus, Toujeo, Sanofi Aventis, Basaglar, Lilly) Human analog U100, U300
  Insulin detemir (Levemir, Novo Nordisk) Human analog U100
  Insulin degludec (Tresiba, Novo Nordisk) Human analog U100, U200
Premixed insulins    
 70 NPH/30 regular (Novolin, Novo Nordisk; Humulin, Lilly) Human U100
  75/25 NPL, Lispro (Humalog mix 75/25, Lilly) Human analog U100
  50/50 NPL, Lispro (Humalog mix 50/50, Lilly) Human analog U100
  70/30 NPA, Aspart (Novolog mix 70/30, Novo Nordisk) Human analog U100
  70/30 Degludec/Aspart (Ryzodeg, Novo Nordisk) Human analog U100
All insulins are now made by recombinant technology; they should be refrigerated and brought to room temperature just before injection.
NPA, neutral protamine aspart; NPL, neutral protamine lispro.

The physician should then carefully note dosages in both units
and volume to avoid overdosage. The disposable pen avoids this
conversion issue and dispenses the regular U500 insulin in 5-unit
increments.
Intravenous infusions of regular insulin are particularly useful
in the treatment of diabetic ketoacidosis and during the periopera-
tive management of insulin-requiring diabetics.
2. Rapidly acting insulin analogs—Insulin lispro (Huma-
log) is an insulin analog in which the proline at position B28 is
reversed with the lysine at B29. Insulin aspart (Novolog) is a single
substitution of proline by aspartic acid at position B28. Insulin
glulisine (Apidra) differs from human insulin in that the amino
acid asparagine at position B3 is replaced by lysine and the lysine
in position B29 by glutamic acid. When injected subcutaneously,
these three analogs quickly dissociate into monomers and are
absorbed very rapidly, reaching peak serum values in as little as
1 hour. The amino acid changes in these analogs do not interfere
with their binding to the insulin receptor, with the circulating
half-life, or with their immunogenicity, which are all identical to
those of human regular insulin.
Clinical trials have demonstrated that the optimal times
of preprandial subcutaneous injection of comparable doses of
the rapid-acting insulin analogs and of regular human insulin
are 15 minutes and 45 minutes before the meal, respectively.
Although the more rapid onset of action has been welcomed as a
great convenience by patients with diabetes who object to wait-
ing as long as 45 minutes after injecting regular human insulin
before they can begin their meal, patients must be taught to ingest
adequate absorbable carbohydrate early in the meal to avoid hypo-
glycemia during the meal. The analogs also have lowest variability
of absorption: approximately 5%. This compares with 25% for
regular insulin. Another desirable feature of rapidly acting insulin
analogs is that their duration of action remains at about 4 hours
for most commonly used dosages. This contrasts with regular
insulin, whose duration of action is significantly prolonged when
larger doses are used.
The rapidly acting analogs are commonly used in insulin
pumps. In a double-blind crossover study comparing insulin lis-
pro with regular insulin in insulin pumps, persons using insulin
lispro had lower HbA1c values and improved postprandial glucose
control with the same frequency of hypoglycemia. However, the
concern remains that in the event of pump failure, users of the
rapidly acting insulin analogs will have more rapid onset of hyper-
glycemia and ketosis.
While insulin aspart has been approved for intravenous
use (eg, in hyperglycemic emergencies), there is no advantage
in using insulin aspart over regular insulin by this route. A
U200 concentration of insulin lispro is available in a disposable
prefilled pen. The only advantage of the U200 over the U100
insulin lispro preparation is that it delivers the same dose in half
the volume.

B. Long-Acting Insulin Preparations (Tables 41–5, 41–6)
1. NPH (neutral protamine Hagedorn, or isophane)
insulin—NPH insulin is an intermediate-acting insulin whose
absorption and onset of action are delayed by combining appropri-
ate amounts of insulin and protamine so that neither is present
in an uncomplexed form (“isophane”). After subcutaneous injec-
tion, proteolytic tissue enzymes degrade the protamine to permit
absorption of insulin. NPH insulin has an onset of approximately
2–5 hours and duration of 4–12 hours (Figure 41–5); it is usually
mixed with regular, lispro, aspart, or glulisine insulin and given two
to four times daily for insulin replacement. The dose regulates the
action profile; specifically, small doses have lower, earlier peaks and
a short duration of action with the converse true for large doses.
2. Insulin glargine—Insulin glargine is a soluble, “peakless”
(ie, having a broad plasma concentration plateau), long-acting
insulin analog. The attachment of two arginine molecules to
the B-chain carboxyl terminal and substitution of a glycine for
asparagine at the A21 position created an analog that is soluble
in an acidic solution but precipitates in the more neutral body
pH after subcutaneous injection. Individual insulin molecules
slowly dissolve away from the crystalline depot and provide a low,
continuous level of circulating insulin. Insulin glargine has a slow
onset of action (1–1.5 hours) and achieves a maximum effect after
4–6 hours. This maximum activity is maintained for 11–24 hours
or longer. Glargine is usually given once daily, although some
very insulin-sensitive or insulin-resistant individuals benefit from
split (twice a day) dosing. To maintain solubility, the formulation
is unusually acidic (pH 4.0), and insulin glargine should not be
mixed with other insulins. Separate syringes must be used to mini-
mize the risk of contamination and subsequent loss of efficacy.
The absorption pattern of insulin glargine appears to be indepen-
dent of the anatomic site of injection, and this drug is associated
8
Insulin lispro, aspart, glulisine
7
Glucose infusion rate (mg/kg/min)
6
5
4
3
2 Insulin glargine
1
1 2 3 4
FIGURE 41–5  Extent and duration of action of various types of insulin as indicated by the glucose infusion rates (mg/kg/min) required to
maintain a constant glucose concentration. The durations of action shown are typical of an average dose of 0.2–0.3 U/kg. The durations of regu-
lar and NPH insulin increase considerably when dosage is increased.
CHAPTER 41  Pancreatic Hormones & Antidiabetic Drugs     755
with less immunogenicity than human insulin in animal studies.
Glargine’s interaction with the insulin receptor is similar to that of
native insulin and shows no increase in mitogenic activity in vitro.
It has sixfold to sevenfold greater binding than native insulin to
the insulin-like growth factor 1 (IGF-1) receptor, but the clinical
significance of this is unclear.
3. Insulin detemir—In this insulin the terminal threonine is
dropped from the B30 position and myristic acid (a C-14 fatty
acid chain) is attached to the B29 lysine. These modifications
prolong the availability of the injected analog by increasing both
self-aggregation in subcutaneous tissue and reversible albumin
binding. The affinity of insulin detemir is four- to fivefold lower
than that of human soluble insulin and, therefore, the U100 for-
mulation of insulin detemir has a concentration of 2400 nmol/mL
compared with 600 nmol/mL for NPH. The duration of action
for insulin detemir is about 17 hours at therapeutically relevant
doses. It is recommended that the insulin be injected once or
twice a day to achieve a stable basal coverage. This insulin has been
reported to have lower within-subject pharmacodynamic variabil-
ity compared with NPH insulin and insulin glargine.
4. Insulin Degludec—In this insulin analog, the threonine at
position B30 has been removed and the lysine at position B29 is
conjugated to hexadecanoic acid via a gamma-l-glutamyl spacer.
In the vial, in the presence of phenol and zinc, the insulin is
in the form of dihexamers but, when injected subcutaneously,
it self-associates into large multihexameric chains consisting of
thousands of dihexamers. The chains slowly dissolve in the sub-
cutaneous tissue, and insulin monomers are steadily released into
the systemic circulation. The half-life of the insulin is 25 hours.
Its onset of action is in 30–90 minutes, and its duration of action
is more than 42 hours. It is recommended that the insulin be
Regular
NPH
Insulin degludec
Insulin detemir
5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Time (h)
756    SECTION VII  Endocrine Drugs
injected once or twice a day to achieve a stable basal coverage.
Insulin degludec is available in two concentrations, U100 and
U200, and dispensed in pre-filled disposable pens.
5. Mixtures of insulins—Because intermediate-acting NPH
insulins require several hours to reach adequate therapeutic levels,
their use in patients with diabetes usually requires supplements of
rapid- or short-acting insulin before meals. For convenience, these
are often mixed together in the same syringe before injection. The
regular insulin or rapidly acting insulin analog is withdrawn first,
then the NPH insulin and then injected immediately.
Stable premixed insulins (70% NPH and 30% regular) are
available as a convenience to patients who have difficulty mix-
ing insulin because of visual problems or insufficient manual
dexterity. Premixed preparations of rapidly acting insulin analogs
(lispro, aspart) and NPH are not stable because of exchange of
the rapidly acting insulin analog for the human regular insulin
in the protamine complex. Consequently, over time, the soluble
component becomes a mixture of regular and rapidly acting
insulin analog at varying ratios. To remedy this problem, inter-
mediate insulins composed of isophane complexes of protamine
with the rapidly acting insulin analogs were developed (neutral
protamine lispro [NPL]; aspart protamine). Premixed combina-
tions of NPL and insulin lispro are now available for clinical use
(Humalog Mix 75/25 and Humalog Mix 50/50). These mixtures
have a more rapid onset of glucose-lowering activity compared
with 70% NPH/30% regular human insulin mixture and can be
given within 15 minutes before or after starting a meal. A similar
70% insulin aspart protamine/30% insulin aspart (NovoLog Mix
70/30) is now available. The main advantages of these new mix-
tures are that (1) they can be given within 15 minutes of starting
a meal and (2) they are superior in controlling the postprandial
glucose rise after a carbohydrate-rich meal.
Insulin glargine or insulin detemir cannot be acutely mixed with
either regular insulin or the rapid-acting insulin analogs. Insulin
degludec, however, can be mixed and is available as 70% insulin
degludec/30% insulin aspart and is injected once or twice a day.
Insulin Delivery Systems
A. Insulin Syringes and Needles
Disposable plastic syringes with needles attached are available
in 1-mL (100 units), 0.5-mL (50 units), and 0.3-mL (30 units)
sizes. The “low-dose” 0.3-mL syringes are popular because many
patients with diabetes do not take more than 30 units of insulin
in a single injection except in rare instances of extreme insulin
resistance. They are also available in half-unit marking. Three
lengths of needles are available; longer needles are preferable in
obese patients to reduce variability of insulin absorption. If the
skin is clean it is not necessary to use alcohol. Rotation of sites is
recommended to avoid problems with absorption due to lipohy-
pertrophy from overuse of injection sites.
B. Insulin Pens
The pens eliminate the need for carrying insulin vials and syringes.
Cartridges of insulin lispro, insulin aspart, and insulin glargine
are available for reusable pens (Lilly, Novo Nordisk, and Owen
Mumford). Disposable prefilled pens are also available for regular
insulin (U100, U500), insulin lispro, insulin aspart, insulin gluli-
sine, insulin detemir, insulin glargine, insulin degludec, NPH, 70%
NPH/30% regular, 75% NPL/25% insulin lispro, 50% NPL/50%
insulin lispro, 70% insulin aspart protamine/30% insulin aspart,
and 70% insulin degludec/30% insulin aspart (Table 41–6).
C. Continuous Subcutaneous Insulin Infusion Devices
(CSII, Insulin Pumps)
Continuous subcutaneous insulin infusion devices are external
open-loop pumps for insulin delivery. The devices have a user-
programmable pump that delivers individualized basal and bolus
insulin replacement doses based on blood glucose self-monitoring
results.
Normally, the 24-hour background basal rates are prepro-
grammed and relatively constant from day to day, although
temporarily altered rates can be superimposed to adjust for a
short-term change in requirement. For example, the basal delivery
rate might need to be decreased for several hours because of the
increased insulin sensitivity associated with strenuous activity.
Boluses are used to correct high blood glucose levels and to
cover mealtime insulin requirements based on the carbohydrate
content of the food and concurrent activity. Bolus amounts are
either dynamically programmed or use pre-programmed algo-
rithms. When the boluses are dynamically programmed, the
user calculates the dose based on the amount of carbohydrate
consumed and the current blood glucose level. Alternatively, the
meal or snack dose algorithm (grams of carbohydrate covered by
a unit of insulin) and insulin sensitivity or blood glucose correc-
tion factor (fall in blood glucose level in response to a unit of
insulin) can be preprogrammed into the pump. If the user enters
the carbohydrate content of the food and current blood glucose
value, the insulin pump will calculate the most appropriate dose of
insulin. Advanced insulin pumps also have an “insulin on board”
feature that adjusts a high blood glucose correction dose to correct
for residual activity of previous bolus doses.
The traditional pump (by MiniMed, Animas, Roche, Sooil)—
which contains an insulin reservoir, the program chip, the keypad,
and the display screen—is about the size of a pager. It is usually
placed on a belt or in a pocket, and the insulin is infused through
thin plastic tubing that is connected to the subcutaneously
inserted infusion set. The abdomen is the favored site for the
infusion set, although flanks and thighs are also used. The insulin
reservoir, tubing, and infusion set need to be changed using sterile
techniques every 2 or 3 days. Currently, only one pump does not
require tubing (OmniPod, Insulet). In this model, the pump is
attached directly to the infusion set (electronic patch pump). Pro-
gramming is done through a hand-held unit that communicates
wirelessly with the pump.
Optimal use of these devices requires responsible involve-
ment and commitment by the patient. Insulin aspart, lispro,
and glulisine all are specifically approved for pump use and are
preferred pump insulins because their favorable pharmacokinetic
attributes allow glycemic control without increasing the risk of
hypoglycemia.

A mechanical patch pump (V-Go, Valeritas) designed spe-
cifically for patients with type 2 diabetes is available on a basal-
plus-bolus insulin regimen. The device is preset to deliver one of
three fixed and flat basal rates (20, 30, or 40 units) for 24 hours
(at which point it must be replaced), and there is a button that
delivers two units per press to help cover meals.
D. Inhaled Insulin
A dry powder formulation of recombinant regular insulin (techno-
sphere insulin, Afrezza) is now approved for use in adults with dia-
betes. It consists of 2- to 2.5-μm crystals of the excipient, fumaryl
diketopiperazine, that provide a large surface area for adsorption
of proteins like insulin. After inhalation from the small, single-use
device, pharmacokinetic studies show that peak levels are reached
in 12–15 minutes and decline to baseline in 3 hours, significantly
faster in onset and shorter in duration than subcutaneous insulin.
Pharmacodynamic studies show that median time to maximum
effect with inhaled insulin is approximately 1 hour and declines to
baseline by about 3 hours. In contrast, the median time to maxi-
mum effect with subcutaneous insulin lispro is about 2 hours and
declines to baseline by 4 hours. In trials, inhaled insulin combined
with injected basal insulin was as effective in lowering glucose
as injected rapid-acting insulin combined with basal insulin. It
is formulated as a single-use color coded cartridge delivering 4,
8 or 12 units immediately before the meal. The manufacturer
provides a dose conversion table; patients injecting up to 4 units
of rapid-acting insulin analog should use the 4-unit cartridge.
Those injecting 5–8 units should use the 8-unit cartridge. If the
dose is 9–12 units of rapid-acting insulin pre-meal then one 4-unit
cartridge and one 8-unit cartridge or one 12-unit cartridge should
be used. The inhaler is about the size of a referee’s whistle. The
most common adverse effect of inhaled insulin was cough, affect-
ing 27% of trial patients. A small decrease in pulmonary function
(forced expiratory volume in 1 second [FEV1]) was seen in the first
3 months of use, which persisted over 2 years of follow-up. Inhaled
insulin is contraindicated in smokers and patients with chronic
lung disease, such as asthma and chronic obstructive pulmonary
disease. Spirometry should be performed to identify potential lung
disease prior to initiating therapy. During the clinical trials, there
were two cases of lung cancer in patients who were taking inhaled
insulin and none in the comparator-treated patients.
Immunopathology of Insulin Therapy
At least five molecular classes of insulin antibodies may be pro-
duced in diabetics during the course of insulin therapy: IgA, IgD,
IgE, IgG, and IgM. There are two major types of immune disor-
ders in these patients:
1. Insulin allergy—Insulin allergy, an immediate type hyper-
sensitivity, is a rare condition in which local or systemic urticaria
results from histamine release from tissue mast cells sensitized by
anti-insulin IgE antibodies. In severe cases, anaphylaxis results.
Because sensitivity is often to non-insulin protein contaminants,
the human and analog insulins have markedly reduced the inci-
dence of insulin allergy, especially local reactions.
CHAPTER 41  Pancreatic Hormones & Antidiabetic Drugs     757
2. Immune insulin resistance—A low titer of circulating IgG
anti-insulin antibodies that neutralize the action of insulin to a
negligible extent develops in most insulin-treated patients. Rarely,
the titer of insulin antibodies leads to insulin resistance and may
be associated with other systemic autoimmune processes such as
lupus erythematosus.
Lipodystrophy at Injection Sites
Injection of animal insulin preparations sometimes led to atrophy
of subcutaneous fatty tissue at the site of injection. Since the
development of human and analog insulin preparations of neutral
pH, this type of immune complication is almost never seen. Injec-
tion of these newer preparations directly into the atrophic area
often results in restoration of normal contours.
Hypertrophy of subcutaneous fatty tissue remains a problem
if injected repeatedly at the same site. However, this may be cor-
rected by avoiding the specific injection site.
■■ MEDICATIONS FOR
TREATMENT OF TYPE 2 DIABETES
Several categories of glucose-lowering agents are available for
patients with type 2 diabetes: (1) agents that bind to the sulfo-
nylurea receptor and stimulate insulin secretion (sulfonylureas,
meglitinides, d-phenylalanine derivatives); (2) agents that lower
glucose levels by their actions on liver, muscle, and adipose tissue
(biguanides, thiazolidinediones); (3) agents that principally slow
the intestinal absorption of glucose (α-glucosidase inhibitors);
(4) agents that mimic incretin effect or prolong incretin action
(GLP-1 receptor agonists, dipeptidyl peptidase 4 [DPP-4] inhibi-
tors), (5) agents that inhibit the reabsorption of glucose in the
kidney (sodium-glucose co-transporter inhibitors [SGLTs]), and
(6) agents that act by other or ill-defined mechanisms (pramlint-
ide, bromocriptine, colesevelam).
DRUGS THAT PRIMARILY
STIMULATE INSULIN RELEASE BY
BINDING TO THE SULFONYLUREA
RECEPTOR
SULFONYLUREAS
Mechanism of Action
The major action of sulfonylureas is to increase insulin release
from the pancreas (Table 41–7). They bind to a 140-kDa high-
affinity sulfonylurea receptor that is associated with a beta-cell
inward rectifier ATP-sensitive potassium channel (Figure 41–2).
Binding of a sulfonylurea inhibits the efflux of potassium ions
through the channel and results in depolarization. Depolariza-
tion opens a voltage-gated calcium channel and results in calcium
influx and the release of preformed insulin.
758    SECTION VII  Endocrine Drugs
TABLE 41–7  Regulation of insulin release in humans.
Stimulants of insulin release
 Humoral: Glucose, mannose, leucine, arginine, other amino acids,
fatty acids (high concentrations)
 Hormonal: Glucagon, glucagon-like peptide 1 (7–37), glucose-
dependent insulinotropic polypeptide, cholecystokinin, gastrin
 Neural: β-Adrenergic stimulation, vagal stimulation
 Drugs: Sulfonylureas, meglitinide, nateglinide, isoproterenol,
acetylcholine
Inhibitors of insulin release
  Hormonal: Somatostatin, insulin, leptin
 Neural: α-Sympathomimetic effect of catecholamines
  Drugs: Diazoxide, phenytoin, vinblastine, colchicine
Adapted, with permission, from Greenspan FS, Gardner DG [editors]: Basic & Clinical
Endocrinology, 6th ed. McGraw-Hill, 2001. Copyright © The McGraw-Hill Companies, Inc.
Efficacy & Safety of the Sulfonylureas
Sulfonylureas are metabolized by the liver and, with the exception
of acetohexamide, the metabolites are either weakly active or inac-
tive. The metabolites are excreted by the kidney and, in the case
of the second-generation sulfonylureas, partly excreted in the bile.
Idiosyncratic reactions are rare, with skin rashes or hematologic
toxicity (leukopenia, thrombocytopenia) occurring in less than
0.1% of cases. The second-generation sulfonylureas have greater
affinity for their receptor compared with the first-generation
agents. The correspondingly lower effective doses and plasma
levels of the second-generation drugs therefore lower the risk of
drug-drug interactions based on competition for plasma binding
sites or hepatic enzyme action.
In 1970, the University Group Diabetes Program (UGDP) in
the United States reported that the number of deaths due to car-
diovascular disease in diabetic patients treated with tolbutamide
was excessive compared with either insulin-treated patients or
those receiving placebos. Owing to design flaws, this study and its
conclusions were not generally accepted. In the United Kingdom,
the UKPDS did not find an untoward cardiovascular effect of
sulfonylurea usage in their large, long-term study. The sulfonyl-
ureas continue to be widely prescribed, and six are available in the
United States.
FIRST-GENERATION SULFONYLUREAS
Tolbutamide is well absorbed but rapidly metabolized in the
liver. Its duration of effect is relatively short (6–10 hours), with
an elimination half-life of 4–5 hours, and it is best administered
in divided doses (eg, 500 mg before each meal). Some patients
only need one or two tablets daily. The maximum dosage is
3000 mg daily. Because of its short half-life and inactivation by
the liver, it is relatively safe in the elderly and in patients with
renal impairment. Prolonged hypoglycemia has been reported
rarely, mostly in patients receiving certain antibacterial sulfon-
amides (sulfisoxazole), phenylbutazone for arthralgias, or the oral
azole antifungal medications to treat candidiasis. These drugs
inhibit the metabolism of tolbutamide in the liver and increase
its circulating levels.
Chlorpropamide has a half-life of 32 hours and is slowly
metabolized in the liver to products that retain some biologic
activity; approximately 20–30% is excreted unchanged in the
urine. The average maintenance dosage is 250 mg daily, given as a
single dose in the morning. Prolonged hypoglycemic reactions are
more common in elderly patients, and the drug is contraindicated
in this group. Other adverse effects include a hyperemic flush after
alcohol ingestion in genetically predisposed patients and hypona-
tremia due to its effect on vasopressin secretion and action.
Tolazamide is comparable to chlorpropamide in potency
but has a shorter duration of action. Tolazamide is more slowly
absorbed than the other sulfonylureas, and its effect on blood
glucose does not appear for several hours. Its half-life is about
7 hours. Tolazamide is metabolized to several compounds that
retain hypoglycemic effects. If more than 500 mg/d are required,
the dosage should be divided and given twice daily.
Acetohexamide is no longer available in the United States.
Its half-life is only about 1 hour but its more active metabolite,
hydroxyhexamide, has a half-life of 4–6 hours; thus the drug
duration of action is 8–24 hours. Where available, its dosage is
0.25–1.5 g/d as single dose or in two divided doses.
Chlorpropamide, tolazamide, and acetohexamide are now
rarely used in clinical practice.
SECOND-GENERATION
SULFONYLUREAS
Glyburide, glipizide, gliclazide, and glimepiride are 100–200 times
more potent than tolbutamide. They should be used with caution in
patients with cardiovascular disease or in elderly patients, in whom
hypoglycemia would be especially dangerous.
Glyburide is metabolized in the liver into products with very
low hypoglycemic activity. The usual starting dosage is 2.5 mg/d
or less, and the average maintenance dosage is 5–10 mg/d given as
a single morning dose; maintenance dosages higher than 20 mg/d
are not recommended. A formulation of “micronized” glyburide
(Glynase PresTab) is available in a variety of tablet sizes. However,
there is some question as to its bioequivalence with non-micron-
ized formulations, and the FDA recommends careful monitoring
to re-titrate dosage when switching from standard glyburide doses
or from other sulfonylurea drugs.
Glyburide has few adverse effects other than its potential for
causing hypoglycemia. Flushing has rarely been reported after
ethanol ingestion, and the compound slightly enhances free water
clearance. Glyburide is contraindicated in the presence of hepatic
impairment and in patients with renal insufficiency.
Glipizide has the shortest half-life (2–4 hours) of the more
potent agents. For maximum effect in reducing postprandial
hyperglycemia, this agent should be ingested 30 minutes before
breakfast because absorption is delayed when the drug is taken
with food. The recommended starting dosage is 5 mg/d, with
up to 15 mg/d given as a single dose. When higher daily dos-
ages are required, they should be divided and given before meals.

The maximum total daily dosage recommended by the manufac-
turer is 40 mg/d, although some studies indicate that the maxi-
mum therapeutic effect is achieved by 15–20 mg of the drug. An
extended-release preparation (Glucotrol XL) provides 24-hour
action after a once-daily morning dose (maximum of 20 mg/d).
However, this formulation appears to have sacrificed its lower pro-
pensity for severe hypoglycemia compared with longer-acting gly-
buride without showing any demonstrable therapeutic advantages
over the latter (which can be obtained as a generic drug). At least
90% of glipizide is metabolized in the liver to inactive products,
and the remainder is excreted unchanged in the urine. Glipizide
therapy is therefore contraindicated in patients with significant
hepatic impairment. Because of its lower potency and shorter
duration for action, it is preferable to glyburide in the elderly and
for those patients with renal impairment.
Glimepiride is approved for once-daily use as monotherapy
or in combination with insulin. Glimepiride achieves blood
glucose lowering with the lowest dosage of any sulfonylurea
compound. A single daily dose of 1 mg has been shown to be
effective, and the recommended maximal daily dosage is 8 mg.
Glimepiride’s half-life under multidose conditions is 5–9 hours.
It is completely metabolized by the liver to metabolites with
weak or no activity.
Gliclazide (not available in the United States) has a half-life of
10 hours. The recommended starting dosage is 40–80 mg daily
with a maximum dosage of 320 mg daily. Higher dosages are usu-
ally divided and given twice a day. It is completely metabolized by
the liver to inactive metabolites.
MEGLITINIDE ANALOGS
Repaglinide is the first member of the meglitinide group of insu-
lin secretagogues. These drugs modulate beta-cell insulin release
by regulating potassium efflux through the potassium channels
previously discussed. There is overlap with the sulfonylureas in
their molecular sites of action because the meglitinides have two
binding sites in common with the sulfonylureas and one unique
binding site.
Repaglinide has a fast onset of action, with a peak concentra-
tion and peak effect within approximately 1 hour after ingestion,
but the duration of action is 4–7 hours. It is cleared by hepatic
CYP3A4 with a plasma half-life of 1 hour. Because of its rapid
onset, repaglinide is indicated for use in controlling postprandial
glucose excursions. The drug should be taken just before each
meal in doses of 0.25–4 mg (maximum 16 mg/d); hypoglycemia
is a risk if the meal is delayed or skipped or contains inadequate
carbohydrate. It can be used in patients with renal impairment
and in the elderly. Repaglinide is approved as monotherapy or in
combination with biguanides. There is no sulfur in its structure,
so repaglinide may be used in type 2 diabetics with sulfur or sul-
fonylurea allergy.
Mitiglinide (not available in the United States) is a benzylsuc-
cinic acid derivative that binds to the sulfonylurea receptor and is
similar to repaglinide in its clinical effects. It has been approved
for use in Japan.
CHAPTER 41  Pancreatic Hormones & Antidiabetic Drugs     759
d-PHENYLALANINE DERIVATIVE
Nateglinide, a d-phenylalanine derivative, stimulates rapid and
transient release of insulin from beta cells through closure of the
ATP-sensitive K+ channel. It is absorbed within 20 minutes after
oral administration with a time to peak concentration of less than
1 hour and is metabolized in the liver by CYP2C9 and CYP3A4
with a half-life of about 1 hour. The overall duration of action
is about 4 hours. It is taken before the meal and reduces the
postprandial rise in blood glucose levels. It is available as 60- and
120-mg tablets. The lower dose is used in patients with mild eleva-
tions in HbA1c. Nateglinide is efficacious when given alone or in
combination with non-secretagogue oral agents (such as metfor-
min). Hypoglycemia is the main adverse effect. It can be used in
patients with renal impairment and in the elderly.
DRUGS THAT PRIMARILY LOWER
GLUCOSE LEVELS BY THEIR
ACTIONS ON THE LIVER, MUSCLE, &
ADIPOSE TISSUE
BIGUANIDES
The structure of metformin is shown below. Phenformin (an
older biguanide) was discontinued in the United States because
of its association with lactic acidosis. Metformin is the only bigu-
anide currently available in the United States.
NH
H2N CH3
C N C N
H 2N CH3
Metformin
Mechanisms of Action
A full explanation of the mechanism of action of the biguanides
remains elusive, but their primary effect is to activate the enzyme
AMP-activated protein kinase (AMPK) and reduce hepatic glu-
cose production. Patients with type 2 diabetes have considerably
less fasting hyperglycemia as well as lower postprandial hypergly-
cemia after administration of biguanides; however, hypoglycemia
during biguanide therapy is rare. These agents are therefore more
appropriately termed “euglycemic” agents.
Metabolism & Excretion
Metformin has a half-life of 1.5–3 hours, is not bound to plasma
proteins, is not metabolized, and is excreted by the kidneys as the
active compound. As a consequence of metformin’s blockade of
gluconeogenesis, the drug may impair the hepatic metabolism
of lactic acid. In patients with renal insufficiency, the biguanide
accumulates and thereby increases the risk of lactic acidosis, which
appears to be a dose-related complication. Metformin can be
safely used in patients with estimated glomerular filtration rates
(eGFR) between 60 and 45 mL/min per 1.73 m2. It can be used
cautiously in patients with eGFR between 45 and 30 mL/min per
760    SECTION VII  Endocrine Drugs
1.73 m2. It is contraindicated if the eGFR is less than 30 mL/min
per 1.73 m2.
Clinical Use
Biguanides are recommended as first-line therapy for type
2 diabetes. Because metformin is an insulin-sparing agent and
does not increase body weight or provoke hypoglycemia, it
offers obvious advantages over insulin or sulfonylureas in treat-
ing hyperglycemia in such persons. The UKPDS reported that
metformin therapy decreases the risk of macrovascular as well as
microvascular disease; this is in contrast to the other therapies,
which only modified microvascular morbidity. Biguanides are also
indicated for use in combination with insulin secretagogues or
thiazolidinediones in type 2 diabetics in whom oral monotherapy
is inadequate. Metformin is useful in the prevention of type
2 diabetes; the landmark Diabetes Prevention Program concluded
that metformin is efficacious in preventing the new onset of type
2 diabetes in middle-aged, obese persons with impaired glucose
tolerance and fasting hyperglycemia. It is interesting that metfor-
min did not prevent diabetes in older, leaner prediabetics.
Although the recommended maximal dosage is 2.55 g daily,
little benefit is seen above a total dosage of 2000 mg daily. Treat-
ment is initiated at 500 mg with a meal and increased gradually
in divided doses. Common schedules would be 500 mg once or
twice daily increased to 1000 mg twice daily. The maximal dosage
is 850 mg three times a day. Epidemiologic studies suggest that
metformin use may reduce the risk of some cancers. These data
are still preliminary, and the speculative mechanism of action is a
decrease in insulin (which also functions as a growth factor) levels
as well as direct cellular effects mediated by AMPK. Other studies
suggest a reduction in cardiovascular deaths in humans and an
increase in longevity in mice (see Chapter 60).
Toxicities
The most common toxic effects of metformin are gastrointestinal
(anorexia, nausea, vomiting, abdominal discomfort, and diarrhea),
occurring in up to 20% of patients. They are dose related, tend
to occur at the onset of therapy, and are often transient. However,
metformin may have to be discontinued in 3–5% of patients
because of persistent diarrhea.
Metformin interferes with the calcium-dependent absorption
of vitamin B12–intrinsic factor complex in the terminal ileum,
and vitamin B12 deficiency can occur after many years of metfor-
min use. Periodic screening for vitamin B12 deficiency should be
considered, especially in patients with peripheral neuropathy or
macrocytic anemia. Increased intake of calcium may prevent the
metformin-induced B12 malabsorption.
Lactic acidosis can sometimes occur with metformin therapy.
It is more likely to occur in conditions of tissue hypoxia when
there is increased production of lactic acid and in renal failure
when there is decreased clearance of metformin. Almost all
reported cases have involved patients with associated risk factors
that should have contraindicated its use (kidney, liver, or cardio-
respiratory insufficiency; alcoholism). Acute kidney failure can
occur rarely in certain patients receiving radiocontrast agents.
Metformin therapy should therefore be temporarily halted on the
day of radiocontrast administration and restarted a day or two
later after confirmation that renal function has not deteriorated.
Renal function should be checked at least annually in patients on
metformin therapy, and lower doses should be used in the elderly
who may have limited renal reserve and in those with eGFR
between 30 and 45 mL/min per 1.73 m2.
THIAZOLIDINEDIONES
Thiazolidinediones act to decrease insulin resistance. They are
ligands of peroxisome proliferator-activated receptor gamma
(PPAR-f), part of the steroid and thyroid superfamily of nuclear
receptors. These PPAR receptors are found in muscle, fat, and liver.
PPAR-γ receptors modulate the expression of the genes involved
in lipid and glucose metabolism, insulin signal transduction, and
adipocyte and other tissue differentiation. Observed effects of the
thiazolidinediones include increased glucose transporter expression
(GLUT 1 and GLUT 4), decreased free fatty acid levels, decreased
hepatic glucose output, increased adiponectin and decreased release
of resistin from adipocytes, and increased differentiation of preadi-
pocytes to adipocytes. Thiazolidinediones have also been shown to
decrease levels of plasminogen activator inhibitor type 1, matrix
metalloproteinase 9, C-reactive protein, and interleukin 6. Two
thiazolidinediones are currently available: pioglitazone and rosigli-
tazone. Their distinct side chains create differences in therapeutic
action, metabolism, metabolite profile, and adverse effects. An
earlier compound, troglitazone, was withdrawn from the market
because of hepatic toxicity thought to be related to its side chain.
Pioglitazone has some PPAR-α as well as PPAR-γ activity. It
is absorbed within 2 hours of ingestion; although food may delay
uptake, total bioavailability is not affected. Absorption is decreased
with concomitant use of bile acid sequestrants. Pioglitazone is metab-
olized by CYP2C8 and CYP3A4 to active metabolites. The bioavail-
ability of numerous other drugs also degraded by these enzymes may
be affected by pioglitazone therapy, including estrogen-containing
oral contraceptives; additional methods of contraception are advised.
Pioglitazone may be taken once daily; the usual starting dosage is
15–30 mg/d, and the maximum is 45 mg/d. Pioglitazone is approved
as a monotherapy and in combination with metformin, sulfonylureas,
and insulin for the treatment of type 2 diabetes.
Rosiglitazone is rapidly absorbed and highly protein bound.
It is metabolized in the liver to minimally active metabolites,
predominantly by CYP2C8 and to a lesser extent by CYP2C9.
It is administered once or twice daily; 2–8 mg is the usual total
dosage. Rosiglitazone is approved for use in type 2 diabetes as
monotherapy, in double combination therapy with a biguanide
or sulfonylurea, or in quadruple combination with a biguanide,
sulfonylurea, and insulin.
The combination of a thiazolidinedione and metformin has
the advantage of not causing hypoglycemia.
These drugs also have some additional effects apart from
glucose lowering. Pioglitazone lowers triglycerides and increases
high-density lipoprotein (HDL) cholesterol without affecting
total cholesterol and low-density lipoprotein (LDL) cholesterol.

Rosiglitazone increases total cholesterol, HDL cholesterol, and
LDL cholesterol but does not have significant effect on triglyc-
erides. These drugs have been shown to improve the biochemical
and histologic features of nonalcoholic fatty liver disease. They
seem to have a positive effect on endothelial function: pioglitazone
reduces neointimal proliferation after coronary stent placement,
and rosiglitazone has been shown to reduce microalbuminuria.
Safety concerns and troublesome side effects have significantly
reduced the use of this class of drugs. A meta-analysis of 42 ran-
domized clinical trials with rosiglitazone suggested that this drug
increased the risk of angina pectoris or myocardial infarction. As
a result, its use was suspended in Europe and severely restricted
in the United States. A subsequent large prospective clinical trial
(the RECORD study) failed to confirm the meta-analysis finding
and so the United States restrictions have been lifted. The drug
remains unavailable in Europe.
Fluid retention occurs in about 3–4 % patients on thiazoli-
dinedione monotherapy and occurs more frequently (10–15%) in
patients on concomitant insulin therapy. Heart failure can occur,
and the drugs are contraindicated in patients with New York
Heart Association class III and IV cardiac status (see Chapter 13).
Macular edema is a rare adverse effect that improves when the
drug is discontinued. Loss of bone mineral density and increased
atypical extremity bone fractures in women are described for both
compounds; this is postulated to be due to decreased osteoblast
formation. Other adverse effects include anemia, which might be
due to a dilutional effect of increased plasma volume rather than
a reduction in red cell mass. Weight gain occurs, especially when
used in combination with a sulfonylurea or insulin. Some of the
weight gain is fluid retention but there is also an increase in total
fat mass. In preclinical trials, bladder tumors were observed in
male rats on pioglitazone. Initial clinical reports indicated that
this might also be true in humans. A 10-year observational cohort
study of patients taking pioglitazone, however, failed to find an
association with bladder cancer. A large multi-population pooled
analysis (1.01 million persons over 5.9 million person-years)
also failed to find an association between cumulative exposure
of pioglitazone or rosiglitazone and incidence of bladder cancer.
Another population based study generating 689,616 person-years
of follow-up did find that pioglitazone but not rosiglitazone was
associated with an increased risk of bladder cancer.
Troglitazone, the first medication in this class, was withdrawn
because of cases of fatal liver failure. Although rosiglitazone and
pioglitazone have not been reported to cause liver injury, the drugs
are not recommended for use in patients with active liver disease
or pretreatment elevation of alanine aminotransferase (ALT) 2.5
times greater than normal. Liver function tests should be per-
formed prior to initiation of treatment and periodically thereafter.
DRUGS THAT AFFECT ABSORPTION
OF GLUCOSE
The `-glucosidase inhibitors competitively inhibit the intestinal
α-glucosidase enzymes and reduce post-meal glucose excursions by
delaying the digestion and absorption of starch and disaccharides.
CHAPTER 41  Pancreatic Hormones & Antidiabetic Drugs     761
Acarbose and miglitol are available in the United States. Voglibose
is available in Japan, Korea, and India. Acarbose and miglitol are
potent inhibitors of glucoamylase, α-amylase, and sucrase but have
less effect on isomaltase and hardly any on trehalase and lactase.
Acarbose has the molecular mass and structural features of a tet-
rasaccharide and very little is absorbed. In contrast, miglitol has
structural similarity to glucose and is absorbed.
Acarbose treatment is initiated at a dosage of 50 mg twice daily
with gradual increase to 100 mg three times a day. It lowers post-
prandial glucose levels by 30–50%. Miglitol therapy is initiated
at a dosage of 25 mg three times a day. The usual maintenance
dosage is 50 mg three times a day, but some patients may need
100 mg three times a day. The drug is not metabolized and is
cleared by the kidney. It should not be used in renal failure.
Prominent adverse effects of α-glucosidase inhibitors include
flatulence, diarrhea, and abdominal pain and result from the
appearance of undigested carbohydrate in the colon that is then
fermented into short-chain fatty acids, releasing gas. These adverse
effects tend to diminish with ongoing use because chronic expo-
sure to carbohydrate induces the expression of α-glucosidase in
the jejunum and ileum, increasing distal small intestine glucose
absorption and minimizing the passage of carbohydrate into the
colon. Although not a problem with monotherapy or combina-
tion therapy with a biguanide, hypoglycemia may occur with con-
current sulfonylurea treatment. Hypoglycemia should be treated
with glucose (dextrose) and not sucrose, whose breakdown may be
blocked. An increase in hepatic aminotransferases has been noted
in clinical trials with acarbose, especially with dosages greater than
300 mg/d. The abnormalities resolve on stopping the drug.
These drugs are infrequently prescribed in the United States
because of their prominent gastrointestinal adverse effects and
relatively modest glucose-lowering benefit.
DRUGS THAT MIMIC INCRETIN
EFFECT OR PROLONG INCRETIN
ACTION
An oral glucose load provokes a higher insulin response com-
pared with an equivalent dose of glucose given intravenously.
This is because the oral glucose causes a release of gut hormones
(“incretins”), principally GLP-1 and glucose-dependent insuli-
notropic peptide (GIP), that amplify the glucose-induced insulin
secretion. When GLP-1 is infused in patients with type 2 diabetes,
it stimulates insulin release and lowers glucose levels. The GLP-1
effect is glucose dependent in that the insulin release is more
pronounced when glucose levels are elevated but less so when
glucose levels are normal. For this reason, GLP-1 has a lower risk
for hypoglycemia than the sulfonylureas. In addition to its insulin
stimulatory effect, GLP-1 has a number of other biologic effects.
It suppresses glucagon secretion, delays gastric emptying, and
reduces apoptosis of human islets in culture. In animals, GLP-1
inhibits feeding by a central nervous system mechanism. Type 2
diabetes patients on GLP-1 therapy are less hungry. It is unclear
whether this is mainly related to the deceleration of gastric emp-
tying or whether there is a central nervous system effect as well.
762    SECTION VII  Endocrine Drugs
GLP-1 is rapidly degraded by dipeptidyl peptidase 4 (DPP-4)
and by other enzymes such as endopeptidase 24.11 and is also
cleared by the kidney. The native peptide therefore cannot be used
therapeutically. One approach to this problem has been to develop
metabolically stable analogs or derivatives of GLP-1 that are not
subject to the same enzymatic degradation or renal clearance. Four
such GLP-1 receptor agonists, exenatide, liraglutide, albiglutide,
and dulaglutide are available for clinical use. The other approach
has been to develop inhibitors of DPP-4 and prolong the action of
endogenously released GLP-1 and GIP. Four oral DPP-4 inhibi-
tors, sitagliptin, saxagliptin, linagliptin, and alogliptin, are avail-
able in the United States. An additional inhibitor, vildagliptin, is
available in Europe.
GLUCAGON-LIKE PEPTIDE-1 (GLP-1)
RECEPTOR AGONISTS
Exenatide, a derivative of the exendin-4 peptide in Gila monster
venom, has a 53% homology with native GLP-1 and a glycine
substitution to reduce degradation by DPP-4. Exenatide is
approved as an injectable, adjunctive therapy in persons with type
2 diabetes treated with metformin or metformin plus sulfonyl-
ureas who still have suboptimal glycemic control.
Exenatide is dispensed as fixed-dose pens (5 mcg and 10 mcg).
It is injected subcutaneously within 60 minutes before breakfast
and dinner. It reaches a peak concentration in approximately
2 hours with a duration of action of up to 10 hours. Therapy
is initiated at 5 mcg twice daily for the first month and if toler-
ated can be increased to 10 mcg twice daily. Exenatide LAR is a
once-weekly preparation that is dispensed as a powder (2 mg). It
is suspended in the provided diluent just prior to injection. When
exenatide is added to preexisting sulfonylurea therapy, the oral
hypoglycemic dosage may need to be decreased to prevent hypo-
glycemia. The major adverse effect is nausea (about 44% of users),
which is dose dependent and declines with time. Exenatide mono-
therapy and combination therapy results in HbA1c reductions of
0.2–1.2%. Weight loss in the range of 2–3 kg occurs and contrib-
utes to the improvement of glucose control. In comparative trials
the long-acting (LAR) preparation lowers the HbA1c level a little
more than the twice-daily preparation. Exenatide undergoes glo-
merular filtration, and the drug is not approved for use in patients
with estimated GFR of less than 30 mL/min.
High-titer antibodies against exenatide develop in about 6% of
patients, and in half of these patients an attenuation of glycemic
response has been seen.
Liraglutide is a soluble fatty acid-acylated GLP-1 analog. The
half-life is approximately 12 hours, permitting once-daily dosing.
It is approved in patients with type 2 diabetes who achieve inad-
equate control with diet and exercise and are receiving concurrent
treatment with metformin, sulfonylureas, or thiazolidinediones.
Treatment is initiated at 0.6 mg and increased after 1 week to
1.2 mg daily. If needed the dosage can be increased to 1.8 mg
daily. In clinical trials liraglutide results in a reduction of HbA1c
of 0.8–1.5%; weight loss ranges from none to 3.2 kg. The most
frequent adverse effects are nausea (28%) and vomiting (10%).
Liraglutide at a dose of 3 mg daily has been approved for weight
loss.
Albiglutide is a human GLP-1 dimer fused to human albu-
min. The half-life of albiglutide is about 5 days and a steady state
is reached after 4–5 weeks of once weekly administration. The
usual dose is 30 mg weekly by subcutaneous injection. The drug
is supplied in a self-injection pen containing a powder that is
reconstituted just prior to administration. Weight loss is much less
common than with exenatide and liraglutide. The most frequent
adverse effects were nausea and injection-site erythema.
Dulaglutide consists of two GLP-1 analog molecules cova-
lently linked to an Fc fragment of human IgG4. The GLP-1 mol-
ecule has amino acid substitutions that resist DPP-4 action. The
half-life of dulaglutide is about 5 days. The usual dose is 0.75 mg
weekly by subcutaneous injection. The maximum recommended
dose is 1.5 mg weekly. The most frequent adverse reactions were
nausea, diarrhea, and vomiting.
All of the GLP-1 receptor agonists may increase the risk of
pancreatitis. Patients on these drugs should be counseled to seek
immediate medical care if they experience unexplained persistent
severe abdominal pain. Cases of renal impairment and acute renal
injury have been reported in patients taking exenatide. Some of
these patients had preexisting kidney disease or other risk factors
for renal injury. A number of them reported having nausea, vom-
iting, and diarrhea and it is possible that volume depletion con-
tributed to the development of renal injury. Both exenatide and
liraglutide stimulate thyroidal C-cell (parafollicular) tumors in
rodents. Human thyroidal C cells express very few GLP-1 recep-
tors, and the relevance to human therapy is unclear. The drugs,
however, should not be used in persons with a past medical or
family history of medullary thyroid cancer or multiple endocrine
neoplasia (MEN) syndrome type 2.
DIPEPTIDYL PEPTIDASE 4 (DPP-4)
INHIBITORS
Sitagliptin is given orally as 100 mg once daily, has an oral
bioavailability of over 85%, achieves peak concentrations within
1–4 hours, and has a half-life of approximately 12 hours. It is
primarily excreted in the urine, in part by active tubular secretion
of the drug. Hepatic metabolism is limited and mediated largely
by the cytochrome CYP3A4 isoform and, to a lesser degree, by
CYP2C8. The metabolites have insignificant activity. Dosage
should be reduced in patients with impaired renal function (50 mg
if estimated GFR is 30–50 mL/min and 25 mg if <30 mL/min.
Sitagliptin has been studied as monotherapy and in combination
with metformin, sulfonylureas, and thiazolidinediones. Therapy
with sitagliptin has resulted in HbA1c reductions of 0.5–1.0%.
Common adverse effects include nasopharyngitis, upper respi-
ratory infections, and headaches. Hypoglycemia can occur when
the drug is combined with insulin secretagogues or insulin. There
have been postmarketing reports of acute pancreatitis (fatal
and nonfatal) and severe allergic and hypersensitivity reactions.
Sitagliptin should be immediately discontinued if pancreatitis or
allergic and hypersensitivity reactions occur.

Saxagliptin is given orally as 2.5–5 mg daily. The drug reaches
maximal concentrations within 2 hours (4 hours for its active
metabolite). It is minimally protein bound and undergoes hepatic
metabolism by CYP3A4/5. The major metabolite is active, and
excretion is by both renal and hepatic pathways. The terminal
plasma half-life is 2.5 hours for saxagliptin and 3.1 hours for
its active metabolite. Dosage adjustment is recommended for
individuals with renal impairment and concurrent use of strong
CYP3A4/5 inhibitors such as antiviral, antifungal, and certain
antibacterial agents. It is approved as monotherapy and in com-
bination with biguanides, sulfonylureas, and thiazolidinediones.
During clinical trials, mono- and combination therapy with saxa-
gliptin resulted in an HbA1c reduction of 0.4–0.9%.
Adverse effects include an increased rate of infections (upper
respiratory tract and urinary tract), headaches, and hypersensitiv-
ity reactions (urticaria, facial edema). The dosage of a concurrently
administered insulin secretagogue or insulin may need to be low-
ered to prevent hypoglycemia. Saxagliptin may increase the risk of
heart failure. In a postmarketing study of 16,492 type 2 diabetes
patients, there were 289 cases of heart failure in the saxagliptin
group (3.5%) and 228 cases in the placebo group (2.8%)—a
hazard ratio of 1.27. Patients at the highest risk for failure were
those who had a history of heart failure or had elevated levels of
N-terminal of the prohormone brain natriuretic peptide (NT-
pBNP) or had renal impairment.
Linagliptin lowers HbA1c by 0.4–0.6% when added to met-
formin, sulfonylurea, or pioglitazone. The dosage is 5 mg daily
orally and, since it is primarily excreted via the bile, no dosage
adjustment is needed in renal failure.
Adverse reactions include nasopharyngitis and hypersensitivity
reactions (urticaria, angioedema, localized skin exfoliation, bron-
chial hyperreactivity). The risk of pancreatitis may be increased.
Alogliptin lowers HbA1c by about 0.5–0.6% when added to
metformin, sulfonylurea, or pioglitazone. The usual dose is 25 mg
orally daily. The 12.5-mg dose is used in patients with calculated
creatinine clearance of 30 to 60 mL/min; the dose is 6.25 mg for
clearance <30 mL/min. In clinical trials, pancreatitis occurred in
11 of 5902 patients on alogliptin (0.2%) and in 5 of 5183 patients
receiving all comparators (<0.1%). There have been reports of
hypersensitivity reactions (anaphylaxis, angioedema, Stevens-
Johnson syndrome). Cases of hepatic failure have been reported,
but it is unclear if alogliptin was the cause. The medication, how-
ever, should be discontinued in the event of liver failure.
Vildagliptin (not available in the United States) lowers HbA1c
levels by 0.5–1% when added to the therapeutic regimen of
patients with type 2 diabetes. The dosage is 50 mg orally once or
twice daily. Adverse reactions include upper respiratory infections,
nasopharyngitis, dizziness, and headache. Rarely, it can cause
hepatitis, and liver function tests should be performed quarterly
in the first year of use and periodically thereafter.
In animal studies, high doses of DPP-4 inhibitors and GLP-1
agonists cause expansion of pancreatic ductal glands and gen-
eration of premalignant pancreatic intraepithelial (PanIN) lesions
that have the potential to progress to pancreatic adenocarcinoma.
The relevance to human therapy is unclear and currently there is
no evidence that these drugs cause pancreatic cancer in humans.
CHAPTER 41  Pancreatic Hormones & Antidiabetic Drugs     763
SODIUM-GLUCOSE
CO-TRANSPORTER 2 (SGLT2)
INHIBITORS
Glucose is freely filtered by the renal glomeruli and is reabsorbed in
the proximal tubules by the action of sodium-glucose transporters
(SGLTs). Sodium-glucose transporter 2 (SGLT2) accounts for 90%
of glucose reabsorption, and its inhibition causes glycosuria and
lowers glucose levels in patients with type 2 diabetes. SGLT2 inhibi-
tors lower glucose levels by changing the renal threshold and not by
insulin action. The SGLT2 inhibitors canagliflozin, dapagliflozin,
and empagliflozin, all oral medications, are approved for clinical use.
Canagliflozin reduces the threshold for glycosuria from
a plasma glucose threshold of approximately 180 mg/dL to
70–90 mg/dL. It has been shown to reduce HbA1c by 0.6–1%
when used alone or in combination with other oral agents or
insulin. It also results in modest weight loss of 2–5 kg. The usual
dosage is 100 mg daily. Increasing the dosage to 300 mg daily in
patients with normal renal function can lower the HbA1c by an
additional 0.5%.
Dapagliflozin reduces HbA1c by 0.5–0.8% when used alone
or in combination with other oral agents or insulin. It also results
in modest weight loss of about 2–4 kg. The usual dosage is 10 mg
daily, but 5 mg daily is recommended initially in patients with
hepatic failure.
Empagliflozin reduces HbA1c by 0.5–0.7% when used alone
or in combination with other oral agents or insulin. It also results
in modest weight loss of 2–3 kg. The usual dosage is 10 mg daily,
but 25 mg/d may be used. In a postmarketing multinational study
of 7020 type 2 patients with known cardiovascular disease, the
addition of empagliflozin was associated with a lower primary
composite outcome of death from cardiovascular causes, nonfa-
tal myocardial infarction, or nonfatal stroke (hazard ratio, 0.86;
p = 0.04). The mechanisms regarding this benefit remain unclear.
Weight loss, lower blood pressure, and diuresis may have played a
role since there were fewer deaths from heart failure in the treated
group whereas the rates of myocardial infarction were unaltered.
As might be expected, the efficacy of the SGLT2 inhibitors
is reduced in chronic kidney disease. Canagliflozin and empa-
gliflozin are contraindicated in patients with estimated GFR less
than 45 mL/min per 1.73 m2. Dapagliflozin is not recommended
for use in patients with estimated GFR less than 60 mL/min per
1.73 m2. The main adverse effects are increased incidence of geni-
tal infections and urinary tract infections affecting about 8–9% of
patients. The osmotic diuresis can also cause intravascular volume
contraction and hypotension. Canagliflozin and empagliflozin
caused a modest increase in LDL cholesterol levels (4–8%). In
clinical trials patients taking dapagliflozin had higher rates of
breast cancer (nine cases versus none in comparator arms) and
bladder cancer (nine cases versus one in placebo arm). These can-
cer rates exceeded the expected rates in an age-matched reference
diabetes population. Canagliflozin has been reported to cause a
decrease in bone mineral density at the lumbar spine and the hip.
In a pooled analysis of 8 clinical trial (mean duration 68 weeks),
an increase in fractures by about 30% was observed in patients
764    SECTION VII  Endocrine Drugs
on canagliflozin. It is likely that the effect on the bones is a class
effect and not restricted to canagliflozin. A modest increase in
upper limb fractures was observed with canagliflozin therapy. It is
not known if this is due to an effect on bone strength or related
to falls due to hypotension. Interim analysis of the Canagliflozin
Cardiovascular Assessment Study clinical trial reported an approx-
imately doubled risk of leg and foot amputations in the trial group
assigned to Canagliflozin; in 2017 the FDA issued a drug safety
communication regarding the association. Cases of diabetic keto-
acidosis have been reported with off-label use of SGLT2 inhibitors
in patients with type 1 diabetes. Type 1 patients are taught to give
less insulin if their glucose levels are not elevated. Because type 1
patients on an SGLT2 inhibitor may have normal glucose levels,
they may either withhold or reduce their insulin doses to such
a degree as to induce ketoacidosis. Therefore, SGLT2 inhibitors
should not be used in patients with type 1 diabetes and in those
patients labelled as having type 2 diabetes but who are very insulin
deficient and prone to ketosis.
OTHER HYPOGLYCEMIC DRUGS
Pramlintide is an islet amyloid polypeptide (IAPP, amylin) ana-
log. IAPP is a 37-amino-acid peptide present in insulin secretory
granules and secreted with insulin. It has approximately 46%
homology with the calcitonin gene-related peptide (CGRP; see
Chapter 17) and physiologically acts as a negative feedback on
insulin secretion. At pharmacologic doses, IAPP reduces glu-
cagon secretion, slows gastric emptying by a vagally mediated
mechanism, and centrally decreases appetite. Pramlintide is an
IAPP analog with substitutions of proline at positions 25, 28,
and 29. These modifications make pramlintide soluble, non-self-
aggregating, and suitable for pharmacologic use. Pramlintide is
approved for use in insulin-treated type 1 and type 2 patients who
are unable to achieve their target postprandial blood glucose levels.
It is rapidly absorbed after subcutaneous administration; levels
peak within 20 minutes, and the duration of action is not more
than 150 minutes. It is metabolized and excreted by the kidney,
but even at low creatinine clearance there is no significant change
in bioavailability. It has not been evaluated in dialysis patients.
Pramlintide is injected immediately before eating; dosages
range from 15 to 60 mcg subcutaneously for type 1 patients and
from 60 to 120 mcg for type 2 patients. Therapy with this agent
should be initiated at the lowest dosage and titrated upward.
Because of the risk of hypoglycemia, concurrent rapid- or short-
acting mealtime insulin dosages should be decreased by 50%
or more. Pramlintide should always be injected by itself using
a separate syringe; it cannot be mixed with insulin. The major
adverse effects of pramlintide are hypoglycemia and gastrointes-
tinal symptoms, including nausea, vomiting, and anorexia. Since
the drug slows gastric emptying, recovery from hypoglycemia can
be problematic because of the delay in absorption of fast-acting
carbohydrates.
Selected patients with type 1 diabetes who have problems with
postprandial hyperglycemia can use pramlintide effectively to con-
trol the glucose rise especially in the setting of a high-carbohydrate
meal. The drug is not very useful in type 2 patients who can
instead use the GLP-1 receptor agonists.
Colesevelam hydrochloride, the bile acid sequestrant and
cholesterol-lowering drug, is approved as an antihyperglycemic
therapy for persons with type 2 diabetes who are taking other
medications or have not achieved adequate control with diet and
exercise. The exact mechanism of action is unknown but pre-
sumed to involve an interruption of the enterohepatic circulation
and a decrease in farnesoid X receptor (FXR) activation. FXR is a
nuclear receptor with multiple effects on cholesterol, glucose, and
bile acid metabolism. Bile acids are natural ligands of the FXR.
Additionally, the drug may impair glucose absorption. In clini-
cal trials, it lowered the HbA1c concentration 0.3–0.5%. Adverse
effects include gastrointestinal complaints (constipation, indiges-
tion, flatulence). It can also exacerbate the hypertriglyceridemia
that commonly occurs in people with type 2 diabetes.
Bromocriptine, the dopamine agonist, in randomized placebo-
controlled studies lowered HbA1c by 0–0.2% compared with base-
line and by 0.4–0.5% compared with placebo. The mechanism by
which it lowers glucose levels is not known. The main adverse events
are nausea, fatigue, dizziness, vomiting, and headache.
Colesevelam and bromocriptine have very modest efficacy
in lowering glucose levels, and their use for this purpose is
questionable.
■■ MANAGEMENT OF THE
PATIENT WITH DIABETES
Diet
A well-balanced, nutritious diet remains a fundamental element
of therapy for diabetes. It is recommended that the macronutri-
ent proportions (carbohydrate, protein, and fat) be individualized
based on the patient’s eating patterns, preferences, and goals.
Generally most patients with diabetes consume about 45% of
their calories as carbohydrates; 25–35% fats; and 10–35% pro-
teins. Limiting the carbohydrate intake and substituting some of
the calories with monounsaturated fats, such as olive oil, rapeseed
(canola) oil, or the oils in nuts and avocados, can lower triglycer-
ides and increase HDL cholesterol. A Mediterranean-style eating
pattern (a diet supplemented with walnuts, almonds, hazelnuts,
and olive oil) has been shown to improve glycemic control and
lower combined endpoints for cardiovascular events and stroke.
Caloric restriction and weight loss is an important goal for the
obese patient with type 2 diabetes.
Education
Education of the patient and family is a critical component of
care. The patient should be informed about the kind of diabetes
he or she has and the rationale for controlling the glucose levels
(see Box: Benefits of Tight Glycemic Control in Diabetes). Self-
monitoring of glucose levels should be emphasized, especially
if the patient is on insulin or oral secretagogues that can cause
hypoglycemia. The patient on insulin therapy should understand

the action profile of the insulins. He or she should know how to
determine if the basal insulin dose is correct and how to adjust
the rapidly acting insulin dose for carbohydrate content of meals.
Insulin adjustments for exercise and infections should be dis-
cussed. The patient and family members also should be informed
about the signs and symptoms of hypoglycemia.
Glycemic Targets
The American Diabetes Association criteria for acceptable control
include an HbA1c of less than 7% (53 mmol/mol) and pre-meal
glucose levels of 90–130 mg/dL (5–7.2 mmol/L) and less than
180 mg/dL (10 mmol/L) one hour and 150 mg/dL (8.3 mmol/L)
two hours after meals. While the HbA1c target is appropriate for
individuals treated with lifestyle interventions and euglycemic
therapy, it may need to be modified for individuals treated with
insulin or insulin secretagogues due to their increased risk of
hypoglycemia. Less stringent blood glucose control also is appro-
priate for children as well as patients with a history of severe hypo-
glycemia, limited life expectancy, and significant microvascular
Benefits of Tight Glycemic Control in Diabetes
A long-term randomized prospective study involving 1441 type
1 patients in 29 medical centers reported in 1993 that “near
normalization” of blood glucose resulted in a delay in onset
and a major slowing of progression of microvascular and neu-
ropathic complications of diabetes during follow-up periods of
up to 10 years (Diabetes Control and Complications Trial [DCCT]
Research Group, 1993). In the intensively treated group, mean
glycated hemoglobin (HbA1c) of 7.2% (normal <6%) and mean
blood glucose of 155 mg/dL were achieved, whereas in the
conventionally treated group, HbA1c averaged 8.9% with mean
blood glucose of 225 mg/dL. Over the study period, which aver-
aged 7 years, a reduction of approximately 60% in risk of diabetic
retinopathy, nephropathy, and neuropathy was noted in the
tight control group compared with the standard control group.
The DCCT study, in addition, introduced the concept of
glycemic memory, which comprises the long-term benefits of any
significant period of glycemic control. During a 6-year follow-up
period, both the intensively and conventionally treated groups
had similar levels of glycemic control, and both had progression of
carotid intimal-medial thickness. However, the intensively treated
cohort had significantly less progression of intimal thickness.
The United Kingdom Prospective Diabetes Study (UKPDS)
was a very large randomized prospective study carried out
to study the effects of intensive glycemic control with several
types of therapies and the effects of blood pressure control in
type 2 diabetic patients. A total of 3867 newly diagnosed type 2
diabetic patients were studied over 10 years. A significant frac-
tion of these were overweight and hypertensive. Patients were
given dietary treatment alone or intensive therapy with insulin,
chlorpropamide, glyburide, or glipizide. Metformin was an option
CHAPTER 41  Pancreatic Hormones & Antidiabetic Drugs     765
and macrovascular disease. For the elderly frail patient an HbA1c
greater than 8% may be appropriate.
Treatment
Treatment must be individualized on the basis of the type of dia-
betes and specific needs of each patient.
A. Type 1 Diabetes
For most type 1 patients, at least 3 or 4 insulin injections a day are
necessary for safe and effective control of glucose levels. A com-
bination of rapidly acting insulin analogs and long-acting insulin
analogs allow for more physiologic insulin replacement. Generally,
for an adult with type 1 diabetes, the total daily insulin require-
ment in units is equal to the weight in pounds divided by four, or
0.55 times the person’s weight in kilograms. Approximately 40%
of the total daily insulin dosage covers the background or basal
insulin requirements, and the remainder covers meal and snack
requirement and high blood sugar corrections. This is an approxi-
mate calculation and should be individualized. Examples of
for patients with inadequate response to other therapies. Tight
control of blood pressure was added as a variable, with an angio-
tensin-converting enzyme inhibitor, a β blocker, or in some cases,
a calcium channel blocker available for this purpose.
Tight control of diabetes, with reduction of HbA1c from 9.1%
to 7%, was shown to reduce the risk of microvascular complica-
tions overall compared with that achieved with conventional
therapy (mostly diet alone, which decreased HbA1c to 7.9%).
Cardiovascular complications were not noted for any particular
therapy; metformin treatment alone reduced the risk of macro-
vascular disease (myocardial infarction, stroke). Epidemiologic
analysis of the study suggested that every 1% decrease in the
HbA1c achieved an estimated risk reduction of 37% for micro-
vascular complications, 21% for any diabetes-related end point
and death related to diabetes, and 14% for myocardial infarction.
Tight control of hypertension also had a surprisingly sig-
nificant effect on microvascular disease (as well as more conven-
tional hypertension-related sequelae) in these diabetic patients.
Epidemiologic analysis of the results suggested that every
10-mmHg decrease in the systolic pressure achieved an esti-
mated risk reduction of 13% for diabetic microvascular complica-
tions, 12% for any diabetes-related complication, 15% for death
related to diabetes, and 11% for myocardial infarction.
Post-study monitoring showed that 5 years after the closure
of the UKPDS, the benefits of intensive management on diabetic
end points were maintained and the risk reduction for a myo-
cardial infarction became significant. The benefits of metformin
therapy were maintained.
These studies show that tight glycemic control benefits both
type 1 and type 2 patients.
766    SECTION VII  Endocrine Drugs

TABLE 41–8  Examples of intensive insulin regimens using rapid-acting insulin analogs
(insulin lispro, aspart, or glulisine) and NPH, or insulin detemir, glargine,
or degludec in a 70-kg man with type 1 diabetes.1–3

  Prebreakfast Prelunch Predinner Bedtime

Rapid-acting insulin 5U 4U 6U —
analog
NPH insulin 3U 3U 2U 8–9 U
or
Rapid-acting insulin 5U 4U 6U —
analog
Insulin glargine or — — — 15–16 U
degludec
Insulin detemir 6–7 U — — 8–9 U
1
Assumes that patient is consuming approximately 75 g carbohydrate at breakfast, 60 g at lunch, and 90 g at dinner.
2
The dose of rapid-acting insulin analogs can be raised by 1 or 2 U if extra carbohydrate (15–30 g) is ingested or if premeal blood glucose
is >170 mg/dL. The rapid-acting insulin analogs can be mixed in the same syringe with NPH insulin.
3
Insulin glargine or insulin detemir must be given as a separate injection.

reduced insulin requirement include newly diagnosed persons and
those with ongoing endogenous insulin production, long-standing
diabetes with insulin sensitivity, significant renal insufficiency, or
other endocrine deficiencies. Increased insulin requirements typi-
cally occur with obesity, during adolescence, and during the latter
trimesters of pregnancy. Table 41–8 illustrates regimens of rapidly
acting insulin analogs and basal analogs that might be appropriate
for a 70-kg person with type 1 diabetes. If the patient is on an
insulin pump, he or she may require about a basal infusion rate of
0.6 units per hour throughout the 24 hours with the exception of
4:00 am to 8:00 am, when 0.7 units per hour might be appropriate
(dawn phenomenon). The ratios might be one unit for 12 grams
carbohydrate plus one unit for 50 mg/dL (2.8 mmol/L) of blood
glucose above a target value of 120 mg/dL (6.7 mmol/L).
intensive lifestyle interventions (diet and exercise), diabetes self-
management education, and metformin. If clinical failure occurs
with metformin monotherapy, a second agent is added. Options
include sulfonylureas, repaglinide or nateglinide, pioglitazone,
GLP-1 receptor agonists, DPP-4 inhibitors, SGLT2 inhibitors,
and insulin. In the choice of the second agent, consideration
should be given to efficacy of the agent, hypoglycemic risk, effect
on weight, adverse effects, and cost. In patients who experience
Weight loss + exercise + metformin
*

B. Type 2 Diabetes Metformin + another agent

Normalization of glucose levels can occur with weight loss and
improved insulin sensitivity in the obese patient with type 2 diabetes.
A combination of caloric restriction and increased exercise is neces-
sary if a weight reduction program is to be successful. Understand-
ing the long-term consequences of poorly controlled diabetes may
motivate some patients to lose weight. For selected patients, medical
or surgical options should be considered. Orlistat, phentermine/
topiramate, lorcaserin, naltrexone plus extended release bupropion,
and high-dose liraglutide are approved weight loss medications
for use in combination with diet and exercise. Bariatric surgery
(Roux-en-Y, gastric banding, gastric sleeve, biliopancreatic diver-
sion/duodenal switch) typically result in significant weight loss and
can result in remission of the diabetes.
Nonobese patients with type 2 diabetes frequently have
increased visceral adiposity—the so-called metabolically obese
normal weight patient. There is less emphasis on weight loss in
such patients, but exercise is important.
Multiple medications may be required to achieve glycemic con-
trol (Figure 41–6) in patients with type 2 diabetes. Unless there
is a contraindication, medical therapy should be initiated with
*
Metformin + two other agents
*
Metformin + more complex insulin
regimen ± other non-insulin agent
* Step taken if needed to reach individualized HbA1c
target after ~ 3 months.
FIGURE 41–6  Suggested algorithm for the treatment of type
2 diabetes. The seven main classes of agents are metformin, sul-
fonylureas (includes nateglinide, repaglinide), pioglitazone, GLP-1
receptor agonists, DPP-4 inhibitors, SGLT2 inhibitors, insulins.
(α-Glucosidase inhibitors, colesevelam, pramlintide, and bromocrip-
tine not included because of limited efficacy and significant adverse
reactions). (Data from the consensus panel of the American Diabetes Association/
European Association for the Study of Diabetes, as described in Inzucchi SE et al:
Diabetes Care 2012;35:1364.)

hyperglycemia after a carbohydrate-rich meal (such as dinner), a
short-acting secretagogue before that meal may suffice to control
the glucose levels. Patients with severe insulin resistance may
be candidates for pioglitazone. Patients who are very concerned
about weight gain may benefit from a trial of a GLP-1 receptor
agonist, a DPP-4 inhibitor, or an SGLT2 inhibitor, although the
average weight loss with these medication is not great. If two
agents are inadequate a third agent is added, although data regard-
ing efficacy of such combined therapy are limited.
When the combination of oral agents and injectable GLP-1
receptor agonists fails to adequately control glucose levels, insulin
therapy should be instituted. Various insulin regimens may be
effective. Simply adding nighttime intermediate- or long-acting
insulin to the oral regimen may lead to improved fasting glucose
levels and adequate control during the day. If daytime glucose
levels are problematic, premixed insulins before breakfast and
dinner may help. If such a regimen does not achieve adequate
control or leads to unacceptable rates of hypoglycemia, a more
intensive basal bolus insulin regimen (long-acting basal insulin)
combined with rapid-acting analog before meals can be instituted.
Metformin has been shown to be effective when combined with
insulin therapy and should be continued. Pioglitazone can be used
with insulin, but this combination is associated with more weight
gain and peripheral and macular edema. Continuing with sulfo-
nylureas, GLP-1 receptor agonists, DPP-4 inhibitors, and SGLT2
inhibitors can be of benefit in selected patients. Cost, complexity,
and risk for adverse events should be considered when deciding
which drugs to continue once the patient starts on insulin therapy.
Acute Complications of Diabetes
A. Hypoglycemia
Hypoglycemic reactions are the most common complication of insulin
therapy. It can also occur in any patient taking oral agents that stimu-
late insulin secretion (eg, sulfonylureas, meglitinide, d-phenylalanine
analogs), particularly if the patient is elderly, has renal or liver disease,
or is taking certain other medications that alter metabolism of the
sulfonylureas (eg, phenylbutazone, sulfonamides, warfarin). It occurs
more frequently with the use of long-acting sulfonylureas.
Rapid development of hypoglycemia in persons with intact
hypoglycemic awareness causes signs of autonomic hyperactivity—
both sympathetic (tachycardia, palpitations, sweating, tremulous-
ness) and parasympathetic (nausea, hunger)—and may progress to
convulsions and coma if untreated.
In persons exposed to frequent hypoglycemic episodes during
tight glycemic control, autonomic warning signals of hypogly-
cemia are less common or even absent. This dangerous acquired
condition is termed hypoglycemic unawareness. When patients lack
the early warning signs of low blood glucose, they may not take
corrective measures in time. In patients with persistent, untreated
hypoglycemia, the manifestations of insulin excess may develop—
confusion, weakness, bizarre behavior, coma, seizures—at which
point they may not be able to procure or safely swallow glucose-
containing foods. Hypoglycemic awareness may be restored by
preventing frequent hypoglycemic episodes. An identification
bracelet, necklace, or card in the wallet or purse, as well as some
CHAPTER 41  Pancreatic Hormones & Antidiabetic Drugs     767
form of rapidly absorbed glucose, should be carried by every dia-
betic person who is receiving hypoglycemic drug therapy.
All the manifestations of hypoglycemia are relieved by glu-
cose administration. To expedite absorption, simple sugar or
glucose should be given, preferably in liquid form. To treat mild
hypoglycemia in a patient who is conscious and able to swallow,
dextrose tablets, glucose gel, or any sugar-containing beverage or
food may be given. If more severe hypoglycemia has produced
unconsciousness or stupor, the treatment of choice is 1 mg of
glucagon injected either subcutaneously or intramuscularly. This
may restore consciousness within 15 minutes to permit ingestion
of sugar. Emergency medical services should be called in the event
of loss of consciousness. The emergency personnel can restore
consciousness by giving 20–50 mL of 50% glucose solution by
intravenous bolus over a period of 2–3 minutes.
B. Diabetic Coma
1. Diabetic ketoacidosis—Diabetic ketoacidosis (DKA) is
a life-threatening medical emergency caused by inadequate or
absent insulin replacement, which occurs in people with type 1
diabetes and infrequently in those with type 2 diabetes. It typi-
cally occurs in newly diagnosed type 1 patients or in those who
have experienced interrupted insulin replacement, and rarely
in people with type 2 diabetes who have concurrent unusually
stressful conditions such as sepsis or pancreatitis or are on high-
dose steroid therapy. DKA occurs more frequently in patients on
insulin pumps. Poor compliance—either for psychological reasons
or because of inadequate education—is one of the most common
causes of DKA, particularly when episodes are recurrent.
Signs and symptoms include nausea, vomiting, abdominal pain,
deep slow (Kussmaul) breathing, change in mental status (including
coma), elevated blood and urinary ketones and glucose, an arterial
blood pH lower than 7.3, and low bicarbonate (15 mmol/L).
The fundamental treatment for DKA includes aggressive intrave-
nous hydration and insulin therapy and maintenance of potassium
and other electrolyte levels. Fluid and insulin therapy is based on
the patient’s individual needs and requires frequent reevaluation and
modification. Close attention must be given to hydration and renal
status, sodium and potassium levels, and the rate of correction of
plasma glucose and plasma osmolality. Fluid therapy generally begins
with normal saline. Regular human insulin should be used for intra-
venous therapy with a usual starting dosage of about 0.1 U/kg/h.
2. Hyperosmolar hyperglycemic syndrome—Hyperosmolar
hyperglycemic syndrome (HHS) is diagnosed in persons with
type 2 diabetes and is characterized by profound hyperglycemia
and dehydration. It is associated with inadequate oral hydration,
especially in elderly patients; with other illnesses; with the use of
medication that elevates the blood sugar or causes dehydration, such
as phenytoin, steroids, diuretics, and calcium channel blockers; and
with peritoneal dialysis and hemodialysis. The diagnostic hallmarks
are declining mental status and even seizures, a plasma glucose
>600 mg/dL, and a calculated serum osmolality >320 mmol/L.
Persons with HHS are not acidotic unless DKA is also present.
The treatment of HHS centers around aggressive rehydration
and restoration of glucose and electrolyte homeostasis; the rate of
768    SECTION VII  Endocrine Drugs

correction of these variables must be monitored closely. Low-dose
insulin therapy may be required.
Chronic Complications of Diabetes
Late clinical manifestations of diabetes mellitus include a number of
pathologic changes that involve small and large blood vessels, cranial
and peripheral nerves, the skin, and the lens of the eye. These lesions
lead to hypertension, end-stage chronic kidney disease, blindness,
autonomic and peripheral neuropathy, amputations of the lower
extremities, myocardial infarction, and cerebrovascular accidents.
These late manifestations correlate with the duration of the diabetic
state subsequent to the onset of puberty and glycemic control. In
type 1 diabetes, end-stage chronic kidney disease develops in up
to 40% of patients, compared with less than 20% of patients with
type 2 diabetes. Proliferative retinopathy ultimately develops in
both types of diabetes but has a slightly higher prevalence in type
1 patients (25% after 15 years’ duration). In patients with type 1
diabetes, complications from end-stage chronic kidney disease are
a major cause of death, whereas patients with type 2 diabetes are
more likely to have macrovascular diseases leading to myocardial
infarction and stroke as the main causes of death. Cigarette use adds
significantly to the risk of both microvascular and macrovascular
complications in diabetic patients.

SUMMARY Drugs Used for Diabetes

Mechanism of Clinical Pharmacokinetics,
Subclass, Drug Action Effects Applications Toxicities, Interactions

INSULINS
  • Rapid-acting: Lispro, aspart, Activate insulin receptor Reduce circulating glucose Type 1 and type 2 Parenteral (SC or IV) • duration
glulisine, inhaled regular diabetes varies (see text) • Toxicity:
  •  Short-acting: Regular Hypoglycemia, weight gain,
  •  Intermediate-acting: NPH lipodystrophy (rare)
  • Long-acting: Detemir, glargine,
degludec

SULFONYLUREAS
  •  Glipizide Insulin secretagogues: Reduce circulating glucose in Type 2 diabetes Orally active • duration 10–24 h
  •  Glyburide Close K+ channels in patients with functioning • Toxicity: Hypoglycemia, weight
  •  Glimepiride beta cells • increase beta cells gain
  • Gliclazide1 insulin release

  • Tolazamide, tolbutamide, chlorpropamide, acetohexamide: Older sulfonylureas, lower potency, greater toxicity; rarely used

MEGLITINIDE ANALOGS; d-PHENYLANALINE DERIVATIVE

  •  Repaglinide, nateglinide Insulin secretagogue: In patients with functioning Type 2 diabetes Oral • very fast onset of action
  •  Mitiglinide1 Similar to sulfonylureas beta cells, reduce circulating • duration 5–8 h, nateglinide • 4 h
with some overlap in glucose • Toxicity: Hypoglycemia
binding sites

BIGUANIDES
  •  Metformin Activates AMP kinase
• reduces hepatic and
renal gluconeogenesis
Decreases circulating Type 2 diabetes Oral • maximal plasma
glucose concentration in 2–3 h • Toxicity:
Gastrointestinal symptoms, lactic
acidosis (rare) • cannot use if
impaired renal/hepatic function
• congestive heart failure (CHF),
hypoxic/acidotic states, alcoholism

ALPHA-GLUCOSIDASE INHIBITORS
  •  Acarbose, miglitol Inhibit intestinal Reduce conversion of starch Type 2 diabetes Oral • rapid onset • Toxicity:
  •  Voglibose1 α-glucosidases and disaccharides to Gastrointestinal symptoms • cannot
monosaccharides • reduce use if impaired renal/hepatic
postprandial hyperglycemia function, intestinal disorders

THIAZOLIDINEDIONES
  •  Pioglitazone, rosiglitazone
Regulate gene
expression by binding
to PPAR-γ and PPAR-α
Reduce insulin resistance
Type 2 diabetes Oral • long-acting (>24 h) • Toxicity:
Fluid retention, edema, anemia,
weight gain, macular edema, bone
fractures in women • cannot use if
CHF, hepatic disease

(continued)
 CHAPTER 41  Pancreatic Hormones & Antidiabetic Drugs     769

Mechanism of Clinical Pharmacokinetics,

Subclass, Drug Action Effects Applications Toxicities, Interactions

GLUCAGON-LIKE POLYPEPTIDE-1 (GLP-1) RECEPTOR AGONISTS

  • Exenatide, liraglutide, Analogs of GLP-1: Bind Reduce post-meal glucose Type 2 diabetes, Parenteral (SC) • Toxicity: Nausea,
albiglutide, dulaglutide to GLP-1 receptors excursions: Increase glucose- liraglutide only: headache, vomiting, anorexia, mild
mediated insulin release, obesity weight loss, pancreatitis, C-cell
lower glucagon levels, slow tumors in rodents
gastric emptying, decrease
appetite

DIPEPTIDYL PEPTIDASE-4 (DPP-4) INHIBITORS

  • Sitagliptin, saxagliptin,
linagliptin, alogliptin,
vildagliptin1
Block degradation of Reduces post-meal glucose Type 2 diabetes Oral • half-life ~12 h • 24-h duration
GLP-1, raise circulating excursions: Increases of action • Toxicity: Rhinitis, upper
GLP-1 levels glucose-mediated insulin respiratory infections, headaches,
release, lowers glucagon pancreatitis, rare allergic reactions
levels, slows gastric
emptying, decreases
appetite

SODIUM-GLUCOSE CO-TRANSPORTER 2 (SGLT2) INHIBITORS

  • Canagliflozin, dapagliflozin, Block renal glucose Increase glucosuria, lower Type 2 diabetes Oral • half-life ~10–14 h • Toxicity:
empagliflozin resorption plasma glucose levels Genital and urinary tract infections,
polyuria, pruritus, thirst, osmotic
diuresis, constipation

ISLET AMYLOID POLYPEPETIDE ANALOG

  •  Pramlintide Analog of amylin: Binds Reduces post-meal glucose
to amylin receptors excursions: Lowers glucagon
levels, slows gastric
emptying, decreases
appetite
Type 1 and type 2 Parenteral (SC) • rapid onset
diabetes • half-life ~48 min • Toxicity: Nausea,
anorexia, hypoglycemia, headache

BILE ACID SEQUESTRANT

  •  Colesevelam hydrochloride Bile acid binder: Lowers Reduces glucose levels Type 2 diabetes Oral • 24-h duration of action
glucose through • Toxicity: Constipation, indigestion,
unknown mechanisms flatulence

DOPAMINE AGONIST
  •  Bromocriptine D2 receptor agonist: Reduces glucose levels Type 2 diabetes Oral • 24-h action • Toxicity: Nausea,
Lowers glucose through vomiting, dizziness, headache
unknown mechanism
1
Not available in United States.
770    SECTION VII  Endocrine Drugs

P R E P A R A T I O N S A V A I L A B L E*
GENERIC NAME AVAILABLE AS GENERIC NAME AVAILABLE AS
SULFONYLUREAS THIAZOLIDINEDIONE COMBINATION
Acetohexamide‡ Generic, Dymelor Pioglitazone plus glimepiride Duetact
Chlorpropamide Generic, Diabinese Alogliptin plus pioglitazone Oseni
Gliclazide‡ Generic, Diamicron Rosiglitazone plus glimepiride Avandaryl
Glimepiride Generic, Amaryl ALPHA-GLUCOSIDASE INHIBITORS
Glipizide Generic, Glucotrol, Glucotrol XL Acarbose Generic, Precose
Glyburide Generic, Diaβeta, Micronase, Miglitol Glyset
Glynase PresTab Voglibose‡
Tolazamide Generic, Tolinase GLUCAGON-LIKE POLYPEPTIDE-1 RECEPTOR AGONISTS
Tolbutamide Generic, Orinase Exenatide Byetta
MEGLITINIDES Liraglutide Victoza
Repaglinide Generic, Prandin Albiglutide Tanzeum, Eperzan
Mitiglinide‡   Dulaglutide Trulicity
d - PHENYLALANINE
DERIVATIVE DIPEPTIDYL PEPTIDASE-4 INHIBITORS
Nateglinide Generic, Starlix Linagliptin Tradjenta
BIGUANIDE Saxagliptin Onglyza
Metformin Generic, Glucophage, Sitagliptin Januvia
Glucophage XR
Alogliptin Nesina
METFORMIN COMBINATIONS †
Vildagliptin‡  
Glipizide plus metformin Generic, Metaglip
SODIUM GLUCOSE CO-TRANSPORTER 2 INHIBITORS
Glyburide plus metformin Generic, Glucovance
Canagliflozin Invokana
Pioglitazone plus metformin ACTOplus Met
Dapagliflozin Farxiga
Repaglinide plus metformin Prandi-Met
Empagliflozin Jardiance
Rosiglitazone plus metformin Avandamet
SODIUM GLUCOSE CO-TRANSPORTER
Saxagliptin plus metformin Kombiglyze INHIBITORS COMBINATION
Sitagliptin plus metformin Janumet Empagliflozin plus linagliptin Glyxambi
Linagliptin plus metformin Jentadueto ISMISCELLANEOUS DRUGSLET AMYLOID POLYPEPTIDE ANALOG
Alogliptin plus metformin Kazano Pramlintide Symlin
Dapagliflozin plus metformin Xigduo BILE ACID SEQUESTRANT
Canagliflozin plus metformin Invokamet Colesevelam hydrochloride Welchol
Empagliflozin plus metformin Synjardy DOPAMINE RECEPTOR AGONIST
THIAZOLIDINEDIONE DERIVATIVES Bromocriptine Generic, Parlodel, Cycloset
Pioglitazone Generic, Actos GLUCAGON
Rosiglitazone Avandia Glucagon Generic
*
See Table 41–5 for insulin preparations.
†
Other combinations are available.
‡
Not available in the United States.

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ADVANCE Collaborative Group: Intensive blood glucose control and vascular
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Butler PC et al: A critical analysis of the clinical use of incretin-based therapies: Are
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Gaede P et al: Effect of a multifactorial intervention on mortality in type 2
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Guo S: Insulin signaling, resistance, and the metabolic syndrome: Insights from
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C ASE STUDY ANSWER
This patient had significant insulin resistance, taking about
125 units of insulin daily (approximately 1 unit per kilogram).
He had had limited instruction on how to manage his dia-
betes. He had peripheral neuropathy, proteinuria, low HDL
cholesterol levels, and hypertension. The patient underwent
multifactorial intervention targeting his weight, glucose
levels, and blood pressure. He was advised to stop smoking.
He attended structured diabetes classes and received indi-
vidualized instruction from a diabetes educator and a dieti-
tian. Metformin therapy was reinitiated and his insulin doses
were reduced. The patient was then given the GLP1 receptor
CHAPTER 41  Pancreatic Hormones & Antidiabetic Drugs     771
Ratner RE et al: Amylin replacement with pramlintide as an adjunct to insulin
therapy improves long term glycemic and weight control in type 1 dia-
betes mellitus: A 1-year randomized controlled trial. Diabetic Med 2004;
21:1204.
Reitman ML et al: Pharmacogenetics of metformin response: A step in the path
toward personalized medicine. J Clin Invest 2007;117:1226.
Rizzo M et al: Non-glycemic effects of pioglitazone and incretin-based therapies.
Expert Opin Ther Targets 2013;17:739.
Rosenstock J, Ferrannini E: Euglycemic diabetic ketoacidosis: A predictable,
detectable, and preventable safety concern with SGLT2 inhibitors. Diabetes
Care 2015;38:1638.
Standl E, Schnell O: Alpha-glucosidase inhibitors 2012—cardiovascular consider-
ations and trial evaluation. Diab Vasc Dis Res 2012;9:163.
Switzer SM et al: Intensive insulin therapy in patients with type 1 diabetes mellitus.
Endocrinol Metab Clin North Am 2012;41:89.
Tuccori M et al: Pioglitazone use and risk of bladder cancer: population based
cohort study. BMJ 2016;352:i1541.
United Kingdom Prospective Diabetes Study (UKPDS) Group: Glycemic control
with diet, sulfonylurea, metformin, or insulin in patients with type 2 dia-
betes mellitus: Progressive requirement for multiple therapies: UKPDS 49.
JAMA 1999;281:2005.
United Kingdom Prospective Diabetes Study (UKPDS) Group: Tight blood pres-
sure control and risk of macrovascular and microvascular complications in
type 2 diabetes: UKPDS 38. BMJ 1998;317:703.
agonist, exenatide. The patient lost about 8 kg in weight over
the next 3 years and was able to stop his insulin. He had
excellent control with an HbA1c of 6.5 % on a combination
of metformin, exenatide, and glimepiride. His antihyperten-
sive therapy was optimized and his urine albumin excretion
declined to 1569 mg/g creatinine. This case illustrates the
importance of weight loss in controlling glucose levels in the
obese patient with type 2 diabetes. It also shows that simply
increasing the insulin dose is not always effective. Combin-
ing metformin with other oral agents and non-insulin inject-
ables may be a better option.
 42
C H A P T E R
Agents That Affect Bone
Mineral Homeostasis
Daniel D. Bikle, MD, PhD
C ASE STUDY
A 65-year-old man is referred to you from his primary care
physician (PCP) for evaluation and management of pos-
sible osteoporosis. He saw his PCP for evaluation of low
back pain. X-rays of the spine showed some degenerative
changes in the lumbar spine plus several wedge deformities
in the thoracic spine. The patient is a long-time smoker
(up to two packs per day) and has two to four glasses of
wine with dinner, more on the weekends. He has chronic
bronchitis, presumably from smoking, and has been treated
on numerous occasions with oral prednisone for exacerba-
tions of bronchitis. He is currently on 10 mg/d prednisone.
■■ BASIC PHARMACOLOGY
Calcium and phosphate, the major mineral constituents of bone,
are also two of the most important minerals for general cellular
function. Accordingly, the body has evolved complex mecha-
nisms to carefully maintain calcium and phosphate homeostasis
(Figure 42–1). Approximately 98% of the 1–2 kg of calcium and
85% of the 1 kg of phosphorus in the human adult are found in
bone, the principal reservoir for these minerals. This reservoir is
dynamic, with constant remodeling of bone and ready exchange
of bone mineral with that in the extracellular fluid. Bone also
serves as the principal structural support for the body and pro-
vides the space for hematopoiesis. This relationship is more
than fortuitous, as elements of the bone marrow affect skeletal
processes just as skeletal elements affect hematopoietic processes.
During aging and in nutritional diseases such as anorexia nervosa
and obesity, fat accumulates in the marrow, suggesting a dynamic
interaction between marrow fat and bone. Furthermore, bone has
772
Examination shows kyphosis of the thoracic spine, with
some tenderness to fist percussion over the thoracic spine.
The dual-energy x-ray absorptiometry (DEXA) measure-
ment of the lumbar spine is “within the normal limits,” but
the radiologist noted that the reading may be misleading
because of degenerative changes. The hip measurement
shows a T score (number of standard deviations by which
the patient’s measured bone density differs from that of
a normal young adult) in the femoral neck of –2.2. What
further workup should be considered, and what therapy
should be initiated?
been implicated as an endocrine tissue with release of osteocalcin,
which in its uncarboxylated form stimulates insulin secretion and
testicular function. Abnormalities in bone mineral homeostasis
can lead to a wide variety of cellular dysfunctions (eg, tetany,
coma, muscle weakness), disturbances in structural support of the
body (eg, osteoporosis with fractures), and loss of hematopoietic
capacity (eg, infantile osteopetrosis).
Calcium and phosphate enter the body from the intestine. The
average American diet provides 600–1000 mg of calcium per day,
of which approximately 100–250 mg is absorbed. This amount
represents net absorption, because both absorption (principally
in the duodenum and upper jejunum) and secretion (principally
in the ileum) occur. The quantity of phosphorus in the American
diet is about the same as that of calcium. However, the efficiency
of absorption (principally in the jejunum) is greater, ranging from
70% to 90%, depending on intake. In the steady state, renal
excretion of calcium and phosphate balances intestinal absorp-
tion. In general, more than 98% of filtered calcium and 85% of
 CHAPTER 42  Agents That Affect Bone Mineral Homeostasis     773
Ca, P
D(+) Serum D(+), PTH (+)
Gut Ca, P Bone
D(+), PTH (+)
CT(–)
Ca, P
Kidney
D(–)
D(–)
PTH(+)
PTH(–)
CT(+)
CT(+)
FGF23(+)
Ca P (1,25[OH]2D) in the kidney and elsewhere. PTH stimulates the
FIGURE 42–1  Mechanisms contributing to bone mineral
homeostasis. Serum calcium (Ca) and phosphorus (P) concentrations
are controlled principally by three hormones, 1,25-dihydroxyvitamin
D (D), fibroblast growth factor 23 (FGF23), and parathyroid hormone
(PTH), through their action on absorption from the gut and from
bone and on renal excretion. PTH and 1,25(OH)2D increase the input
of calcium and phosphorus from bone into the serum and stimulate
bone formation. 1,25(OH)2D also increases calcium and phosphate
absorption from the gut. In the kidney, 1,25(OH)2D decreases excre-
tion of both calcium and phosphorus, whereas PTH reduces calcium
but increases phosphorus excretion. FGF23 stimulates renal excretion
of phosphate. Calcitonin (CT) is a less critical regulator of calcium
homeostasis, but in pharmacologic concentrations can reduce serum
calcium and phosphorus by inhibiting bone resorption and stimulat-
ing their renal excretion. Feedback may alter the effects shown; for
example, 1,25(OH)2D increases urinary calcium excretion indirectly
through increased calcium absorption from the gut and inhibition
of PTH secretion and may increase urinary phosphate excretion
because of increased phosphate absorption from the gut and stimu-
lation of FGF23 production.
filtered phosphate are reabsorbed by the kidney. The movement
of calcium and phosphate across the intestinal and renal epithelia
is closely regulated. Dysfunction of the intestine (eg, nontropi-
cal sprue) or kidney (eg, chronic renal failure) can disrupt bone
mineral homeostasis.
Three hormones serve as the principal regulators of calcium
and phosphate homeostasis: parathyroid hormone (PTH),
fibroblast growth factor 23 (FGF23), and vitamin D via its
active metabolite 1,25-dihydroxyvitamin D (1,25[OH]2D)
(Figure 42–2). The role of calcitonin (CT) is less critical dur-
ing adult life but may play a greater role during pregnancy and
lactation. The term vitamin D, when used without a subscript,
refers to both vitamin D2 (ergocalciferol) and vitamin D3 (cho-
lecalciferol). This applies also to the metabolites of vitamin D2
and D3. Vitamin D2 and its metabolites differ from vitamin D3
and its metabolites only in the side chain where they con-
tain a double bond between C-22–23 and a methyl group at
C-24 (Figure 42–3). Vitamin D is considered a prohormone
because it must be further metabolized to gain biologic activity
(Figure 42–3). Vitamin D3 is produced in the skin under ultra-
violet B (UVB) radiation (eg, in sunlight) from its precursor,
7-dehydrocholesterol. The initial product, pre-vitamin D3, under-
goes a temperature-sensitive isomerization to vitamin D3. The
precursor of vitamin D2 is ergosterol, found in plants and fungi
(mushrooms). It undergoes a similar transformation to vitamin D2
with UVB radiation. Vitamin D2 thus comes only from the diet,
whereas vitamin D3 comes from the skin or the diet, or both.
The subsequent metabolism of these two forms of vitamin D is
essentially the same and follows the illustration for vitamin D3
metabolism in Figure 42–3. The first step is the 25-hydroxylation
of vitamin D to 25-hydroxyvitamin D (25[OH]D). A number of
enzymes in the liver and other tissues perform this function,
of which CYP2R1 is the most important. 25(OH)D is then
metabolized to the active hormone 1,25-dihydroxyvitamin D
production of 1,25(OH)2D in the kidney, whereas FGF23 is
inhibitory. Elevated levels of blood phosphate and calcium also
inhibit 1,25(OH)2D production in part by their effects on FGF23
(high phosphate stimulates FGF23 production) and PTH (high
calcium inhibits PTH production). 1,25(OH)2D regulates its
own levels by stimulating the enzyme 24-hydroxyase (CYP24A1),
which begins the catabolism of 1,25(OH)2D, suppressing PTH
production, and stimulating FGF23 production, all of which
combine to reduce 1,25(OH)2D levels. Other tissues also produce
1,25(OH)2D; the control of this production differs from that
in the kidney, as will be discussed subsequently. The complex
interplay among PTH, FGF23, and 1,25(OH)2D is discussed in
detail later.
To summarize: 1,25(OH)2D suppresses the production of PTH,
as does calcium, but stimulates the production of FGF23. Phos-
phate stimulates both PTH and FGF23 secretion. In turn PTH
stimulates 1,25(OH)2D production, whereas FGF23 is inhibitory.
1,25(OH)2D stimulates the intestinal absorption of calcium and
phosphate. 1,25(OH)2D and PTH promote both bone formation
and resorption in part by stimulating the proliferation and differen-
tiation of osteoblasts and osteoclasts. Both PTH and 1,25(OH)2D
enhance renal retention of calcium, but PTH promotes renal phos-
phate excretion, as does FGF23, whereas 1,25(OH)2D promotes
renal reabsorption of phosphate.
Other hormones—calcitonin, prolactin, growth hormone,
insulin, insulin-like growth factors, thyroid hormone, glucocorti-
coids, and sex steroids—influence calcium and phosphate homeo-
stasis under certain physiologic circumstances and can be considered
secondary regulators. Deficiency or excess of these secondary regula-
tors within a physiologic range does not produce the disturbance of
calcium and phosphate homeostasis that is observed in situations
of deficiency or excess of PTH, FGF23, and vitamin D. However,
certain of these secondary regulators—especially calcitonin, gluco-
corticoids, and estrogens—are useful therapeutically and discussed
in subsequent sections.
In addition to these hormonal regulators, calcium and phos-
phate themselves, other ions such as sodium and fluoride, and a
variety of drugs (bisphosphonates, anticonvulsants, and diuretics)
also alter calcium and phosphate homeostasis.
774    SECTION VII  Endocrine Drugs

A 1,25(OH)2D Bone
Gut
+ +

Ca2+
in blood

+ 1,25(OH)2D
–

Thyroid PTH + – FGF23

1,25(OH)2D

–
Kidney
PTH

Calcitonin 25(OH)D
Parathyroids

B Monocyte
Stem cells

+ +
Preosteoclast PTH
1,25(OH)2D Preosteoblasts
+ +

Osteoclast Osteoblasts

RANKL +
MCSF + Osteoid
OPG –
–
Calcified
Bisphosphonates bone
Calcitonin
Estrogen

FIGURE 42–2  The hormonal interactions controlling bone mineral homeostasis. In the body (A), 1,25-dihydroxyvitamin D (1,25[OH]2D)
is produced by the kidney under the control of parathyroid hormone (PTH), which stimulates its production, and fibroblast growth factor 23
(FGF23), which inhibits its production. 1,25(OH)2D in turn inhibits the production of PTH by the parathyroid glands and stimulates FGF23 release
from bone. 1,25(OH)2D is the principal regulator of intestinal calcium and phosphate absorption. At the level of the bone (B), both PTH and
1,25(OH)2D regulate bone formation and resorption, with each capable of stimulating both processes. This is accomplished by their stimulation
of preosteoblast proliferation and differentiation into osteoblasts, the bone-forming cell. PTH also stimulates osteoblast formation indirectly
by inhibiting the osteocyte’s production of sclerostin, a protein that blocks osteoblast proliferation by inhibiting the wnt pathway (not shown).
PTH and 1,25(OH)2D stimulate the expression of RANKL by the osteoblast, which, with MCSF, stimulates the differentiation and subsequent
activation of osteoclasts, the bone-resorbing cell. OPG blocks RANKL action, and may be inhibited by PTH and 1,25(OH)2D. FGF23 in excess leads
to osteomalacia indirectly by inhibiting 1,25(OH)2D production and lowering phosphate levels. MCSF, macrophage colony-stimulating factor;
OPG, osteoprotegerin; RANKL, ligand for receptor for activation of nuclear factor-κB.

PRINCIPAL HORMONAL Within the gland is a calcium-sensitive protease capable of cleav-

REGULATORS OF BONE MINERAL
HOMEOSTASIS
PARATHYROID HORMONE
Parathyroid hormone (PTH) is a single-chain peptide hormone
composed of 84 amino acids. It is produced in the parathyroid
gland in a precursor form of 115 amino acids, the excess 31
amino terminal amino acids being cleaved off before secretion.
ing the intact hormone into fragments, thereby providing one
mechanism by which calcium limits the production of PTH. A
second mechanism involves the calcium-sensing receptor (CaSR)
which, when stimulated by calcium, reduces PTH production
and secretion. The parathyroid gland also contains the vitamin
D receptor (VDR) and the enzyme, CYP27B1, that produces
1,25(OH)2D, thus enabling circulating or endogenously pro-
duced 1,25(OH)2D to suppress PTH production. 1,25(OH)2D
also induces the CaSR, making the parathyroid gland more sensi-
tive to suppression by calcium. Biologic activity resides in the
 CHAPTER 42  Agents That Affect Bone Mineral Homeostasis     775
amino terminal region of PTH such that synthetic PTH 1-34
(available as teriparatide) is fully active. However, a full length
form of PTH (rhPTH 1-84, Natpara) has recently been approved
for treatment of hypoparathyroidism, as has an analog of PTHrP
(abaloparatide). Loss of the first two amino terminal amino acids
eliminates most biologic activity.
The metabolic clearance of intact PTH is rapid, with a
half-time of disappearance measured in minutes. Most of the
clearance occurs in the liver and kidney. The inactive carboxyl
terminal fragments produced by metabolism of the intact hor-
mone have a much lower clearance, especially in renal failure. In
the past, this accounted for the very high PTH values observed
in patients with renal failure when the hormone was measured
by radioimmunoassays directed against the carboxyl terminal
region. Currently, most PTH assays differentiate between intact
PTH 1-34 and large inactive fragments, so that it is possible
to more accurately evaluate biologically active PTH status in
patients with renal failure.
PTH regulates calcium and phosphate flux across cellular
membranes in bone and kidney, resulting in increased serum
calcium and decreased serum phosphate (Figure 42–1). In bone,
PTH increases the activity and number of osteoclasts, the cells
responsible for bone resorption (Figure 42–2). However, this
stimulation of osteoclasts is not a direct effect. Rather, PTH acts
on the osteoblast (the bone-forming cell) to induce membrane-
bound and secreted soluble forms of a protein called RANK
ligand (RANKL). RANKL acts on osteoclasts and osteoclast pre-
cursors to increase both the numbers and activity of osteoclasts.
This action increases bone remodeling, a specific sequence of
cellular events initiated by osteoclastic bone resorption and fol-
lowed by osteoblastic bone formation. Denosumab, an antibody
that inhibits the action of RANKL, has been developed for the
treatment of excess bone resorption in patients with osteoporosis
and certain cancers. PTH also inhibits the production and secre-
tion of sclerostin from osteocytes. Sclerostin is one of several
proteins that blocks osteoblast proliferation by inhibiting the
wnt pathway. Antibodies against sclerostin (eg, romosozumab)
are in clinical trials for the treatment of osteoporosis. Thus, PTH
directly and indirectly increases proliferation of osteoblasts, the
cells responsible for bone formation. Although both bone resorp-
tion and bone formation are enhanced by PTH, the net effect of
excess endogenous PTH is to increase bone resorption. However,
administration of exogenous PTH in low and intermittent doses
increases bone formation without first stimulating bone resorp-
tion. This net anabolic action may be indirect, involving other
growth factors such as insulin-like growth factor 1 (IGF1) as well
as inhibition of sclerostin as noted above. These anabolic actions
have led to the approval of recombinant PTH 1-34 (teriparatide
and abaloparatide) for the treatment of osteoporosis. In the
kidney, PTH stimulates 1,25(OH)2D production, and increases
tubular reabsorption of calcium and magnesium, but reduces
reabsorption of phosphate, amino acids, bicarbonate, sodium,
chloride, and sulfate. As mentioned earlier, full-length PTH
(rhPTH 1-84) has been approved in part for these renal effects,
which otherwise limit standard calcium and calcitriol treatment
of hypoparathyroidism.
VITAMIN D
Vitamin D is a secosteroid produced in the skin from 7-dehydro-
cholesterol under the influence of ultraviolet radiation. Vitamin
D is also found in certain foods and is used to supplement dairy
products and other foods. Both the natural form (vitamin D3,
cholecalciferol) and the plant-derived form (vitamin D2, ergocal-
ciferol) are present in the diet. As discussed earlier these forms dif-
fer in that ergocalciferol contains a double bond and an additional
methyl group in the side chain (Figure 42–3). Ergocalciferol and
its metabolites bind less well than cholecalciferol and its metabo-
lites to vitamin D–binding protein (DBP), the major transport
protein of these compounds in blood, and have a somewhat dif-
ferent path of catabolism. As a result their half-lives are shorter
than those of the cholecalciferol metabolites. This influences
treatment strategies, as will be discussed. However, the key steps
in metabolism and biologic activities of the active metabolites are
comparable, so with this exception the following comments apply
equally well to both forms of vitamin D.
Vitamin D is a precursor to a number of biologically active
metabolites (Figure 42–3). Vitamin D is first hydroxylated in the
liver and other tissues to form 25(OH)D, (calcifediol). As noted
earlier there are a number of enzymes with 25-hydroxylase activity.
This metabolite is further converted in the kidney to a number of
other forms, the best studied of which are 1,25(OH)2D (calcitriol)
and 24,25-dihydroxyvitamin D (secalciferol, 24,25[OH]2D), by
the enzymes CYP27B1 and CYP24A1, respectively. The regula-
tion of vitamin D metabolism is complex, involving calcium,
phosphate, and a variety of hormones, the most important of
which are PTH, which stimulates, and FGF23, which inhibits
the production of 1,25(OH)2D by the kidney while recipro-
cally inhibiting or promoting the production of 24,25(OH)2D.
The importance of CYP24A1, the enzyme that 24-hydroxylates
25(OH)D and 1,25(OH)2D, is well demonstrated in chil-
dren lacking this enzyme who have high levels of calcium and
1,25(OH)2D resulting in kidney damage from nephrocalcinosis
and stones. Of the natural metabolites, vitamin D, 25(OH)D
(calcifediol) and 1,25(OH)2D (as calcitriol) are available for
clinical use (Table 42–1). A number of analogs of 1,25(OH)2D
have been synthesized to extend the usefulness of this metabolite
to a variety of nonclassic conditions. Calcipotriene (calcipotriol),
for example, is being used to treat psoriasis, a hyperproliferative
skin disorder (see Chapter 61). Doxercalciferol and paricalcitol
are approved for the treatment of secondary hyperparathyroidism
in patients with chronic kidney disease. Eldecalcitol is approved
in Japan for the treatment of osteoporosis. Other analogs are being
investigated for the treatment of various malignancies.
Vitamin D and its metabolites circulate in plasma tightly bound
to the DBP. This α-globulin binds 25(OH)D and 24,25(OH)2D
with comparable high affinity and vitamin D and 1,25(OH)2D
with lower affinity. There is increasing evidence that it is the free
or unbound forms of these metabolites that have biologic activity.
This is of clinical importance because patients with liver disease
or nephrotic syndrome have lower levels of DBP, whereas DBP
levels are increased with estrogen therapy and during the later
stages of pregnancy. Furthermore, there are several different forms
776    SECTION VII  Endocrine Drugs

21 22 26
24
20 23 25
18 27
19 12 17
11 13 16
CH3 14 15 CH3
1 9 1
2 10 8
Ultraviolet 2 10 Heat
3 5 67 3 5
4
HO HO 4

CH2

7-Dehydrocholesterol Pre D3 D3 (cholecalciferol)

HO

O
H O
H

+ P + Ca
+ 1,25(OH)2D
− PTH CH2
O + FGF23
H
HO
Liver Kidney
CH2 24,25 (OH)2D3 (secalciferol)

− P − Ca
HO CH2 + PTH
− FGF23
D3
HO O
H
25 (OH)D3
28
CH3

22 26 CH2
21
24
20 23 25 HO OH
27
1,25 (OH)2D3 (calcitriol)

FIGURE 42–3  Conversion of 7-dehydrocholesterol to vitamin D3 in the skin and its subsequent metabolism to 25-hydroxyvitamin D3
(25[OH]D3) in the liver and to 1,25-dihydroxyvitamin D3 (1,25[OH]2D3) and 24,25-dihydroxyvitamin D3 (24,25[OH]2D3) in the kidney. Control of
vitamin D metabolism is exerted primarily at the level of the kidney, where high concentrations of serum phosphorus (P) and calcium (Ca) as
well as fibroblast growth factor 23 (FGF23) inhibit production of 1,25(OH)2D3 (indicated by a minus [−] sign), but promote that of 24,25(OH)2D3
(indicated by a plus [+] sign). Parathyroid hormone (PTH), on the other hand, stimulates 1,25(OH)2D3 production but inhibits 24,25(OH)2D3
production. The insert (shaded) shows the side chain for ergosterol, vitamin D2, and the active vitamin D2 metabolites. Ergosterol is converted to
vitamin D2 (ergocalciferol) by UV radiation similar to the conversion of 7-dehydrocholesterol to vitamin D3. Vitamin D2, in turn, is metabolized to
25-hydroxyvitamin D2, 1,25-dihydroxyvitamin D2, and 24,25-dihydroxyvitamin D2 via the same enzymes that metabolize vitamin D3. In humans,
corresponding D2 and D3 metabolites have equivalent biologic effects, although they differ in pharmacokinetics. +, facilitation; –, inhibition; P,
phosphorus; Ca, calcium; PTH, parathyroid hormone; FGF23, fibroblast growth factor 23.

of DBP in the population with different affinities for the vitamin
D metabolites, and, as noted earlier, the affinity of DBP for the
D2 metabolites is less than that for the D3 metabolites. Thus
individuals can vary with respect to the fraction of free metabolite
available, so that measuring only the total metabolite concentra-
tion may be misleading with respect to assessing vitamin D status.
In normal subjects, the terminal half-life of injected calcifediol
(25[OH]D) is around 23 days, whereas in anephric subjects it is
around 42 days. The half-life of 24,25(OH)2D is probably similar.
Tracer studies with vitamin D have shown a rapid clearance from
the blood. The liver appears to be the principal organ for clear-
ance. Excess vitamin D is stored in adipose tissue. The metabolic
clearance of calcitriol (1,25[OH]2D) in humans likewise indicates
a rapid turnover, with a terminal half-life measured in hours.
Several of the 1,25(OH)2D analogs are bound poorly by DBP.
As a result, their clearance is very rapid, with a terminal half-life
of minutes. Such analogs have less hypercalcemic, hypercalciuric
effects than calcitriol, an important aspect of their use in the man-
agement of conditions such as psoriasis and hyperparathyroidism.
The mechanism of action of the vitamin D metabolites
remains under active investigation. However, 1,25(OH)2D is well
established as the most potent stimulant of intestinal calcium
and phosphate transport and bone resorption. 1,25(OH)2D
appears to act on the intestine both by induction of new protein
synthesis (eg, calcium-binding protein and TRPV6, an intestinal
calcium channel) and by modulation of calcium flux across the
 CHAPTER 42  Agents That Affect Bone Mineral Homeostasis     777
TABLE 42–1  Vitamin D and its major metabolites
and analogs.
Chemical and Generic Names Abbreviation
Vitamin D3; cholecalciferol D3
Vitamin D2; ergocalciferol D2
25-Hydroxyvitamin D3; calcifediol 25(OH)D3
1,25-Dihydroxyvitamin D3; calcitriol 1,25(OH)2D3
24,25-Dihydroxyvitamin D3; secalciferol 24,25(OH)2D3
Dihydrotachysterol DHT
Calcipotriene (calcipotriol) None
1α-Hydroxyvitamin D2; doxercalciferol 1α(OH)D2
19-nor-1,25-Dihydroxyvitamin D2; paricalcitol 19-nor-1,25(OH)D2
brush border and basolateral membranes by processes that do
not all require new protein synthesis. The molecular action of
1,25(OH)2D on bone is more complex and controversial as it is
both direct and indirect. Much of the skeletal effect is attributed
to the provision of adequate calcium and phosphate from the
diet by stimulation of their intestinal absorption. However,
like PTH, 1,25(OH)2D can induce RANKL in osteoblasts to
regulate osteoclast activity and proteins such as osteocalcin and
alkaline phosphatase, which may regulate the mineralization pro-
cess by osteoblasts. The metabolites 25(OH)D and 24,25(OH)2D
are far less potent stimulators of intestinal calcium and phosphate
transport or bone resorption.
Specific receptors for 1,25(OH)2D (VDR) exist in nearly all
tissues, not just intestine, bone, and kidney. As a result much
effort has been made to develop analogs of 1,25(OH)2D that will
target these non-classic target tissues without increasing serum
calcium. These non-classic actions include regulation of the secre-
tion of PTH, insulin, and renin; regulation of innate and adaptive
immune function through actions on dendritic cell and T-cell
differentiation; enhanced muscle function; and proliferation and
differentiation of a number of cancer cells. Thus, the potential
clinical utility of 1,25(OH)2D and its analogs is expanding.
FIBROBLAST GROWTH FACTOR 23
Fibroblast growth factor 23 (FGF23) is a single-chain protein with
251 amino acids, including a 24-amino-acid leader sequence. It
inhibits 1,25(OH)2D production and phosphate reabsorption
(via the sodium phosphate co-transporters NaPi 2a and 2c) in the
kidney and can lead to both hypophosphatemia and inappropri-
ately low levels of circulating 1,25(OH)2D. Whereas FGF23 was
originally identified in certain mesenchymal tumors, osteoblasts
and osteocytes in bone appear to be its primary site of production.
Other tissues can also produce FGF23, though at lower levels.
FGF23 requires O-glycosylation for its secretion, a glycosylation
mediated by the glycosyl transferase GALNT3. Mutations in
GALNT3 result in abnormal deposition of calcium phosphate in
periarticular tissues (tumoral calcinosis) with elevated phosphate
and 1,25(OH)2D. FGF23 is normally inactivated by cleavage at
an RXXR site (amino acids 176–179). Mutations in this site lead
to excess FGF23, the underlying problem in autosomal dominant
hypophosphatemic rickets. A similar disease, X-linked hypophos-
phatemic rickets, is due to mutations in PHEX, an endopeptidase,
which initially was thought to cleave FGF23. However, this concept
has been shown to be invalid, and the mechanism by which PHEX
mutations lead to increased FGF23 levels remains obscure. FGF23
binds to FGF receptors (FGFR) 1 and 3c in the presence of the
accessory receptor Klotho-α. Both Klotho and the FGFR must
be present for signaling in most tissues, although high levels of
FGF23 appear to affect cardiomyocytes lacking Klotho. Mutations
in Klotho disrupt FGF23 signaling, resulting in elevated phosphate
and 1,25(OH)2D levels, a phenotype quite similar to inactivating
mutations in FGF23 or GALNT3. FGF23 production is stimulated
by 1,25(OH)2D and phosphate and directly or indirectly inhibited
by the dentin matrix protein DMP1 found in osteocytes. Mutations
in DMP1 lead to increased FGF23 levels and osteomalacia.
INTERACTION OF PTH, FGF23, &
VITAMIN D
A summary of the principal actions of PTH, FGF23, and vitamin
D on the three main target tissues—intestine, kidney, and bone—
is presented in Table 42–2. The net effect of PTH is to raise
serum calcium and reduce serum phosphate; the net effect of
FGF23 is to decrease serum phosphate; the net effect of vitamin D
is to raise both. Regulation of calcium and phosphate homeostasis
is achieved through important feedback loops. Calcium is one
of two principal regulators of PTH secretion. It binds to a novel
ion recognition site that is part of a Gq protein–coupled recep-
tor called the calcium-sensing receptor (CaSR) that employs the
phosphoinositide second messenger system to link changes in the
extracellular calcium concentration to changes in the intracellular
free calcium. As serum calcium levels rise and activate this recep-
tor, intracellular calcium levels increase and inhibit PTH secretion.
This inhibition by calcium of PTH secretion, along with inhibi-
tion of renin and atrial natriuretic peptide secretion, is the opposite
of the effect in other tissues such as the beta cell of the pancreas,
in which calcium stimulates secretion. Phosphate regulates PTH
secretion directly and indirectly. Its indirect actions are the result
of forming complexes with calcium in the serum. Because it is the
ionized free concentration of extracellular calcium that is detected
by the parathyroid gland, increases in serum phosphate levels
reduce the ionized calcium levels, leading to enhanced PTH secre-
tion. Whether the parathyroid gland expresses phosphate receptors
that mediate the direct action of phosphate on PTH secretion
remains unclear. Such feedback regulation is appropriate to the net
effect of PTH to raise serum calcium and reduce serum phosphate
levels. Likewise, both calcium and phosphate at high levels reduce
the amount of 1,25(OH)2D produced by the kidney and increase
the amount of 24,25(OH)2D produced.
High serum calcium works directly and indirectly by reducing
PTH secretion. High serum phosphate works directly and indirectly
by increasing FGF23 levels. Since 1,25(OH)2D raises serum calcium
and phosphate, whereas 24,25(OH)2D has less effect, such feedback
778    SECTION VII  Endocrine Drugs
TABLE 42–2  Actions of parathyroid hormone (PTH), vitamin D, and FGF23 on gut, bone, and kidney.
PTH
Intestine Increased calcium and phosphate
absorption (by increased 1,25[OH]2D
production)
Kidney Decreased calcium excretion,
increased phosphate excretion,
stimulation of 1,25(OH)2D production
Bone Calcium and phosphate resorption
increased by high doses. Low doses
increase bone formation.
Net effect on Serum calcium increased, serum
serum levels phosphate decreased
1
Direct effect. Vitamin D also indirectly increases urine calcium owing to increased calcium absorption from the intestine and decreased PTH.
regulation is again appropriate. 1,25(OH)2D directly inhibits PTH
secretion (independent of its effect on serum calcium) by a direct
inhibitory effect on PTH gene transcription. The parathyroid gland
expresses both the VDR and CYP27B1, so that endogenous pro-
duction of 1,25(OH)2D within the parathyroid gland may be more
important for the regulation of PTH secretion than serum levels of
1,25(OH)2D. This provides yet another negative feedback loop. In
patients with chronic renal failure who frequently are deficient in
producing 1,25(OH)2D due in part to elevated FGF23 levels, loss
of this 1,25(OH)2D-mediated feedback loop coupled with impaired
phosphate excretion and intestinal calcium absorption leads to sec-
ondary hyperparathyroidism. The ability of 1,25(OH)2D to inhibit
PTH secretion directly is being exploited with calcitriol analogs
that have less effect on serum calcium because of their lesser effect
on intestinal calcium absorption. Such drugs are proving useful in
the management of secondary hyperparathyroidism accompany-
ing chronic kidney disease and may be useful in selected cases of
primary hyperparathyroidism. 1,25(OH)2D also stimulates the
production of FGF23. This completes the negative feedback loop
in that FGF23 inhibits 1,25(OH)2D production while promoting
hypophosphatemia, which in turn inhibits FGF23 production and
stimulates 1,25(OH)2D production. However, the rise in FGF23 in
the early stages of renal failure remains unexplained and is not due
to increases in either 1,25OH)2D or phosphate, and appears not
to be under the same feedback control as operates under normal
physiologic conditions.
SECONDARY HORMONAL
REGULATORS OF BONE MINERAL
HOMEOSTASIS
A number of hormones modulate the actions of PTH, FGF23,
and vitamin D in regulating bone mineral homeostasis. Com-
pared with that of PTH, FGF23, and vitamin D, the physiologic
impact of such secondary regulation on bone mineral homeostasis
is minor. However, in pharmacologic amounts, several of these
hormones, including calcitonin, glucocorticoids, and estrogens,
have actions on bone mineral homeostatic mechanisms that can
be exploited therapeutically.
Vitamin D FGF23
Increased calcium and phosphate Decreased calcium and phosphate
absorption by 1,25(OH)2D absorption by decreased 1,25(OH)2
production
Calcium and phosphate excretion may be Increased phosphate excretion, decreased
decreased by 25(OH)D and 1,25(OH)2D1 1,25(OH)2D production
Increased calcium and phosphate Decreased mineralization due to
resorption by 1,25(OH)2D; bone formation hypophosphatemia and low 1,25(OH)2D
may be increased by 1,25(OH)2D levels.
Serum calcium and phosphate both Decreased serum phosphate
increased
CALCITONIN
The calcitonin secreted by the parafollicular cells of the mam-
malian thyroid is a single-chain peptide hormone with 32
amino acids and a molecular weight of 3600. A disulfide bond
between positions 1 and 7 is essential for biologic activity. Cal-
citonin is produced from a precursor with a molecular weight
of 15,000. The circulating forms of calcitonin are multiple,
ranging in size from the monomer (molecular weight 3600) to
forms with an apparent molecular weight of 60,000. Whether
such heterogeneity includes precursor forms or covalently
linked oligomers is not known. Because of its chemical hetero-
geneity, calcitonin preparations are standardized by bioassay
in rats. Activity is compared to a standard maintained by the
British Medical Research Council (MRC) and expressed as
MRC units.
Human calcitonin monomer has a half-life of about 10 min-
utes. Salmon calcitonin has a longer half-life of 40–50 minutes,
making it more attractive as a therapeutic agent. Much of the
clearance occurs in the kidney by metabolism; little intact calcito-
nin appears in the urine.
The principal effects of calcitonin are to lower serum calcium and
phosphate by actions on bone and kidney. Calcitonin inhibits osteo-
clastic bone resorption. Although bone formation is not impaired at
first after calcitonin administration, with time both formation and
resorption of bone are reduced. In the kidney, calcitonin reduces
both calcium and phosphate reabsorption as well as reabsorption of
other ions, including sodium, potassium, and magnesium. Tissues
other than bone and kidney are also affected by calcitonin. Calcitonin
in pharmacologic amounts decreases gastrin secretion and reduces
gastric acid output while increasing secretion of sodium, potassium,
chloride, and water in the gut. Pentagastrin is a potent stimulator
of calcitonin secretion (as is hypercalcemia), suggesting a possible
physiologic relationship between gastrin and calcitonin. In the adult
human, no readily demonstrable problem develops in cases of calcito-
nin deficiency (thyroidectomy) or excess (medullary carcinoma of the
thyroid). However, the ability of calcitonin to block bone resorption
and lower serum calcium makes it a useful drug for the treatment of
Paget’s disease, hypercalcemia, and osteoporosis, albeit a less effica-
cious drug than other available agents.
 CHAPTER 42  Agents That Affect Bone Mineral Homeostasis     779
GLUCOCORTICOIDS
Glucocorticoid hormones alter bone mineral homeostasis by
antagonizing vitamin D–stimulated intestinal calcium transport,
stimulating renal calcium excretion, blocking bone formation,
and at least initially stimulating bone resorption. Although these
observations underscore the negative impact of glucocorticoids
on bone mineral homeostasis, these hormones have proved useful
in reversing the hypercalcemia associated with lymphomas and
granulomatous diseases such as sarcoidosis (in which unregulated
ectopic production of 1,25[OH]2D occurs) or in cases of vitamin
D intoxication. Prolonged administration of glucocorticoids is a
common cause of osteoporosis in adults and can cause stunted
skeletal development in children (see Chapter 39).
ESTROGENS
Estrogens can prevent accelerated bone loss during the immediate
postmenopausal period and at least transiently increase bone in
postmenopausal women.
The prevailing hypothesis advanced to explain these observa-
tions is that estrogens reduce the bone-resorbing action of PTH.
Estrogen administration leads to an increased 1,25(OH)2D level in
blood, but estrogens have no direct effect on 1,25(OH)2D produc-
tion in vitro. The increased 1,25(OH)2D levels in vivo following
estrogen treatment may result from decreased serum calcium and
phosphate and increased PTH. However, estrogens also increase
DBP production by the liver, which increases the total concentra-
tions of the vitamin D metabolites in circulation without necessar-
ily increasing the free levels. Estrogen receptors have been found
in bone, and estrogen has direct effects on bone remodeling. Case
reports of men who lack the estrogen receptor or who are unable
to produce estrogen because of aromatase deficiency noted marked
osteopenia and failure to close epiphyses. This further substantiates
the role of estrogen in bone development, even in men. The princi-
pal therapeutic application for estrogen administration in disorders
of bone mineral homeostasis is the treatment or prevention of
postmenopausal osteoporosis. However, long-term use of estrogen
has fallen out of favor due to concern about adverse effects. Selec-
tive estrogen receptor modulators (SERMs) have been developed to
retain the beneficial effects on bone while minimizing deleterious
effects on breast, uterus, and the cardiovascular system (see Box:
Newer Therapies for Osteoporosis and Chapter 40).
NONHORMONAL AGENTS
AFFECTING BONE MINERAL
HOMEOSTASIS
BISPHOSPHONATES
The bisphosphonates are analogs of pyrophosphate in which the
P-O-P bond has been replaced with a nonhydrolyzable P-C-P
bond (Figure 42–4). Currently available bisphosphonates include
etidronate, pamidronate, alendronate, risedronate, tiludronate,
OH OH
O P O P O Inorganic pyrophosphoric acid
OH OH
OH OH OH
O P C P O
Etidronate: ethane-1-hydroxy-1,
1-bisphosphonate
OH CH3 OH
OH OH OH
Pamidronate: 3-Amino-1-hydroxy-
O P C P O
propylidene bisphosphonate
OH CH2 OH
CH2 NH2
OH OH OH
Alendronate: 4-Amino-1-hydroxy-butylidene
O P C P O
bisphosphonate
OH CH2 OH
CH2 CH2 NH2
FIGURE 42–4  The structure of pyrophosphate and of the
first three bisphosphonates—etidronate, pamidronate, and
alendronate—that were approved for use in the United States.
ibandronate, and zoledronate. With the development of the more
potent bisphosphonates, etidronate is seldom used.
Results from animal and clinical studies indicate that less than
10% of an oral dose of these drugs is absorbed. Food reduces
absorption even further, necessitating their administration on
an empty stomach. A major adverse effect of oral forms of the
bisphosphonates (risedronate, alendronate, ibandronate) is esoph-
ageal and gastric irritation, which limits the use of this route by
patients with upper gastrointestinal disorders. This complication
can be circumvented with infusions of pamidronate, zoledronate,
and ibandronate. Intravenous dosing also allows a larger amount
of drug to enter the body and markedly reduces the frequency of
administration (eg, zoledronate is infused once per year). Nearly
half of the absorbed drug accumulates in bone; the remainder
is excreted unchanged in the urine. Decreased renal function
dictates a reduction in dosage. The portion of drug retained in
bone depends on the rate of bone turnover; drug in bone often is
retained for months to years.
The bisphosphonates exert multiple effects on bone mineral
homeostasis, which make them useful for the treatment of hyper-
calcemia associated with malignancy, for Paget’s disease, and for
osteoporosis (see Box: Newer Therapies for Osteoporosis). They
owe at least part of their clinical usefulness and toxicity to their
ability to retard formation and dissolution of hydroxyapatite
crystals within and outside the skeletal system. Some of the newer
bisphosphonates appear to increase bone mineral density well
beyond the 2-year period predicted for a drug whose effects are
limited to slowing bone resorption. This may be due to their
other cellular effects, which include inhibition of 1,25(OH)2D
production, inhibition of intestinal calcium transport, metabolic
780    SECTION VII  Endocrine Drugs
Newer Therapies for Osteoporosis
Bone undergoes a continuous remodeling process involving
resorption and formation. Any process that disrupts this bal-
ance by increasing bone resorption relative to formation results
in osteoporosis. Inadequate gonadal hormone production is
a major cause of osteoporosis in men and women. Estrogen
replacement therapy at menopause is a well-established means
of preventing osteoporosis in the female, but many women
fear its adverse effects, particularly the increased risk of breast
cancer from continued estrogen use (the well-demonstrated
increased risk of endometrial cancer is prevented by combining
the estrogen with a progestin) and do not like the persistence
of menstrual bleeding that often accompanies this form of
therapy. Medical enthusiasm for this treatment has waned with
the demonstration that it does not protect against and may
increase the risk of heart disease. Raloxifene was the first of the
selective estrogen receptor modulators (SERMs; see Chapter 40)
to be approved for the prevention of osteoporosis. Raloxifene
shares some of the beneficial effects of estrogen on bone with-
out increasing the risk of breast or endometrial cancer (it may
actually reduce the risk of breast cancer). Although not as effec-
tive as estrogen in increasing bone density, raloxifene has been
shown to reduce vertebral fractures.
Nonhormonal forms of therapy for osteoporosis have
been developed with proven efficacy in reducing fracture risk.
Bisphosphonates such as alendronate, risedronate, ibandronate,
and zoledronate have been conclusively shown to increase
bone density and reduce fractures over at least 5 years when
used continuously at a dosage of 10 mg/d or 70 mg/week for
alendronate; 5 mg/d or 35 mg/week for risedronate; 2.5 mg/d or
150 mg/month for ibandronate; and 5 mg annually for intrave-
nous zoledronate. Side-by-side trials between alendronate and
calcitonin (another approved nonestrogen drug for osteoporo-
sis) indicated a greater efficacy of alendronate. Bisphosphonates
are poorly absorbed and must be given on an empty stomach
changes in bone cells such as inhibition of glycolysis, inhibition of
cell growth, and changes in acid and alkaline phosphatase activity.
Amino bisphosphonates such as alendronate and risedronate
inhibit farnesyl pyrophosphate synthase, an enzyme in the mevalon-
ate pathway that appears to be critical for osteoclast survival. The cho-
lesterol-lowering statin drugs (eg, lovastatin), which block mevalonate
synthesis (see Chapter 35), stimulate bone formation, at least in ani-
mal studies. Thus, the mevalonate pathway appears to be important
in bone cell function and provides new targets for drug development.
The mevalonate pathway effects vary depending on the bisphospho-
nate used (only amino bisphosphonates have this property) and may
account for some of the clinical differences observed in the effects of
the various bisphosphonates on bone mineral homeostasis.
With the exception of the induction of a mineralization defect
by higher than approved doses of etidronate and gastric and
esophageal irritation by the oral bisphosphonates, these drugs
or infused intravenously. At the higher oral doses used in the
treatment of Paget’s disease, alendronate causes gastric irrita-
tion, but this is not a significant problem at the doses recom-
mended for osteoporosis when patients are instructed to take
the drug with a glass of water and remain upright. Denosumab
is a human monoclonal antibody directed against RANKL, and
it is very effective in inhibiting osteoclastogenesis and activity.
Denosumab is given in 60-mg doses subcutaneously every 6
months. All of these drugs inhibit bone resorption with second-
ary effects to inhibit bone formation. On the other hand, teripa-
ratide, the recombinant form of PTH 1-34 and abaloparatide, an
analog of PTHrP, directly stimulate bone formation as well as
bone resorption. However, teriparatide and abaloparatide are
given daily by subcutaneous injection. Their efficacy in prevent-
ing fractures is at least as great as that of the bisphosphonates.
In all cases, adequate intake of calcium and vitamin D needs to
be maintained.
Furthermore, there are several other forms of therapy in devel-
opment. In Europe, strontium ranelate, a drug that appears to
stimulate bone formation and inhibit bone resorption, has been
used for several years with favorable results in large clinical tri-
als; approval for use in the United States is expected. Additional
promising new treatments undergoing clinical trials include
antibodies against sclerostin. Romosozumab, for example,
is showing promising results in phase 3 trials by stimulating
bone formation and at least initially inhibiting bone resorption.
Phase 3 trials with odanacatib, an inhibitor of cathepsin K, an
enzyme in osteoclasts that facilitates bone resorption, showed
efficacy with respect to fracture reduction. However, this drug
also showed an unexpected increase in strokes, and it will
not be further developed. In Japan, eldecalcitol, an analog of
1,25(OH)2D, has been approved for the treatment of osteoporo-
sis with minimal effects on serum calcium. It is not yet available
in the United States.
have proved to be remarkably free of adverse effects when used
at the doses recommended for the treatment of osteoporosis.
Esophageal irritation can be minimized by taking the drug with
a full glass of water and remaining upright for 30 minutes or by
using the intravenous forms of these compounds. The initial infu-
sion of zoledronate is commonly associated with several days of a
flu-like syndrome that generally does not recur with subsequent
infusions. Of other complications, osteonecrosis of the jaw has
received considerable attention but is rare in patients receiving
usual doses of bisphosphonates (perhaps 1/100,000 patient-years).
This complication is more frequent when high intravenous doses
of zoledronate are used to control bone metastases and cancer-
induced hypercalcemia. More recently, concern has been raised
about over-suppressing bone turnover. This may underlie the
occurrence of subtrochanteric femur fractures in patients on long-
term bisphosphonate treatment. This complication appears to be
 CHAPTER 42  Agents That Affect Bone Mineral Homeostasis     781
rare, comparable to that of osteonecrosis of the jaw, but has led
some authorities to recommend a “drug holiday” after 5 years of
treatment if the clinical condition warrants it (ie, if the fracture
risk of discontinuing the bisphosphonate is not deemed high).
DENOSUMAB
Denosumab is a fully humanized monoclonal antibody that
binds to and prevents the action of RANKL. As described earlier,
RANKL is produced by osteoblasts and other cells, including
T lymphocytes. It stimulates osteoclastogenesis via RANK, the
receptor for RANKL that is present on osteoclasts and osteoclast
precursors. By interfering with RANKL function, denosumab
inhibits osteoclast formation and activity. It is at least as effective
as the potent bisphosphonates in inhibiting bone resorption and
has been approved for treatment of postmenopausal osteoporosis
and some cancers (prostate and breast). The latter application is
to limit the development of bone metastases or bone loss resulting
from the use of drugs that suppress gonadal function. Denosumab
is administered subcutaneously every 6 months. The drug appears
to be well tolerated, but three concerns remain. First, a number of
cells in the immune system also express RANKL, suggesting that
there could be an increased risk of infection associated with the use
of denosumab. Second, because the suppression of bone turnover
with denosumab is similar to that of the potent bisphosphonates,
the potential risk of osteonecrosis of the jaw and subtrochanteric
fractures is comparable. Third, denosumab can lead to transient
hypocalcemia, especially in patients with marked bone loss (and
bone hunger) or compromised calcium regulatory mechanisms,
including chronic kidney disease and vitamin D deficiency. That
said, denosumab can be used in patients with advanced renal dis-
ease, unlike the bisphosphonates, as it is not cleared by the kidney,
and it has the advantage over bisphosphonates in that it is readily
reversible because it does not deposit in bone.
CALCIMIMETICS
Cinacalcet is the first representative of a new class of drugs that
activates the calcium-sensing receptor (CaSR) described above.
CaSR is widely distributed but has its greatest concentration in
the parathyroid gland. By activating the parathyroid gland CaSR,
cinacalcet inhibits PTH secretion. Cinacalcet is approved for the
treatment of secondary hyperparathyroidism in chronic kidney
disease and for the treatment of parathyroid carcinoma. CaSR
antagonists are also being developed, and may be useful in condi-
tions of hypoparathyroidism or as a means to stimulate intermit-
tent PTH secretion in the treatment of osteoporosis.
THIAZIDE DIURETICS
The chemistry and pharmacology of the thiazide family of
drugs are discussed in Chapter 15. The principal application
of thiazides in the treatment of bone mineral disorders is in
reducing renal calcium excretion. Thiazides may increase the
effectiveness of PTH in stimulating reabsorption of calcium by
the renal tubules or may act on calcium reabsorption secondarily
by increasing sodium reabsorption in the proximal tubule. In
the distal tubule, thiazides block sodium reabsorption at the
luminal surface, increasing the calcium-sodium exchange at the
basolateral membrane and thus enhancing calcium reabsorption
into the blood at this site (see Figure 15–4). Thiazides have
proved to be useful in reducing the hypercalciuria and incidence
of urinary stone formation in subjects with idiopathic hypercal-
ciuria. Part of their efficacy in reducing stone formation may lie
in their ability to decrease urine oxalate excretion and increase
urine magnesium and zinc levels, both of which inhibit calcium
oxalate stone formation.
FLUORIDE
Fluoride is well established as effective for the prophylaxis of den-
tal caries and has previously been investigated for the treatment of
osteoporosis. Both therapeutic applications originated from epide-
miologic observations that subjects living in areas with naturally
fluoridated water (1–2 ppm) had fewer dental caries and fewer
vertebral compression fractures than subjects living in nonfluori-
dated water areas. Fluoride accumulates in bones and teeth, where
it may stabilize the hydroxyapatite crystal. Such a mechanism may
explain the effectiveness of fluoride in increasing the resistance of
teeth to dental caries, but it does not explain its ability to promote
new bone growth.
Fluoride in drinking water appears to be most effective in
preventing dental caries if consumed before the eruption of the
permanent teeth. The optimum concentration in drinking water
supplies is 0.5–1 ppm. Topical application is most effective if done
just as the teeth erupt. There is little further benefit to giving fluo-
ride after the permanent teeth are fully formed. Excess fluoride in
drinking water leads to mottling of the enamel proportionate to
the concentration above 1 ppm.
Fluoride has also been evaluated for the treatment of osteo-
porosis. Results of earlier studies indicated that fluoride alone,
without adequate calcium supplementation, produced osteoma-
lacia. Subsequent studies in which calcium supplementation has
been adequate demonstrated an improvement in calcium balance,
an increase in bone mineral, and an increase in trabecular bone
volume. Despite these promising effects of fluoride on bone mass,
clinical studies have failed to demonstrate a reliable reduction in
fractures, and some studies showed an increase in fracture rate.
At present, fluoride is not approved by the U.S. Food and Drug
Administration (FDA) for treatment or prevention of osteoporo-
sis, and it is unlikely to be.
Adverse effects observed—at the higher doses used for test-
ing fluoride’s effect on bone—include nausea and vomiting,
gastrointestinal blood loss, arthralgias, and arthritis in a
substantial proportion of patients. Such effects are usually
responsive to reduction of the dose or giving fluoride with
meals (or both).
782    SECTION VII  Endocrine Drugs
STRONTIUM RANELATE
Strontium ranelate is composed of two atoms of strontium bound
to an organic ion, ranelic acid. Although not yet approved for use
in the United States, this drug is used in Europe for the treatment
of osteoporosis. Strontium ranelate appears to block differentia-
tion of osteoclasts while promoting their apoptosis, thus inhibit-
ing bone resorption. At the same time, strontium ranelate appears
to promote bone formation. Unlike bisphosphonates, denosumab,
or teriparatide, this drug increases bone formation markers while
inhibiting bone resorption markers. Large clinical trials have
demonstrated its efficacy in increasing bone mineral density and
decreasing fractures in the spine and hip. Toxicities reported thus
far are similar to placebo.
■■ CLINICAL PHARMACOLOGY
Individuals with disorders of bone mineral homeostasis usually
present with abnormalities in serum or urine calcium levels (or
both), often accompanied by abnormal serum phosphate levels.
These abnormal mineral concentrations may themselves cause
symptoms requiring immediate treatment (eg, coma in malignant
hypercalcemia, tetany in hypocalcemia). More commonly, they
serve as clues to an underlying disorder in hormonal regula-
tors (eg, primary hyperparathyroidism), target tissue response
(eg, chronic kidney disease), or drug misuse (eg, vitamin D
intoxication). In such cases, treatment of the underlying disorder
is of prime importance.
Since bone and kidney play central roles in bone mineral
homeostasis, conditions that alter bone mineral homeostasis
usually affect one or both of these tissues secondarily. Effects
on bone can result in osteoporosis (abnormal loss of bone;
remaining bone histologically normal), osteomalacia (abnor-
mal bone formation due to inadequate mineralization), or
osteitis fibrosa (excessive bone resorption with fibrotic replace-
ment of resorption cavities and marrow). Biochemical markers
of skeletal involvement include changes in serum levels of the
skeletal isoenzyme of alkaline phosphatase, osteocalcin, and
N- and C-terminal propeptides of type I collagen (reflecting
osteoblastic activity), and serum and urine levels of tartrate-
resistant acid phosphatase and collagen breakdown products
(reflecting osteoclastic activity). The kidney becomes involved
when the calcium × phosphate product in serum rises above
the point at which ectopic calcification occurs (nephrocalci-
nosis) or when the calcium × oxalate (or phosphate) product
in urine exceeds saturation, leading to nephrolithiasis. Subtle
early indicators of such renal involvement include polyuria,
nocturia, and hyposthenuria. Radiologic evidence of neph-
rocalcinosis and stones is not generally observed until later.
The degree of the ensuing renal failure is best followed by
monitoring the decline in creatinine clearance. On the other
hand, chronic kidney disease can be a primary cause of bone
disease because of altered handling of calcium and phosphate,
decreased 1,25(OH)2D production, increased FGF23 levels,
and secondary hyperparathyroidism.
ABNORMAL SERUM CALCIUM &
PHOSPHATE LEVELS
HYPERCALCEMIA
Hypercalcemia causes central nervous system depression, including
coma, and is potentially lethal. Its major causes (other than thia-
zide therapy) are hyperparathyroidism and cancer, with or without
bone metastases. Less common causes are hypervitaminosis D,
sarcoidosis, thyrotoxicosis, milk-alkali syndrome, adrenal insuf-
ficiency, and immobilization. With the possible exception of
hypervitaminosis D, the latter disorders seldom require emergency
lowering of serum calcium. A number of approaches are used to
manage the hypercalcemic crisis.
Saline Diuresis
In hypercalcemia of sufficient severity to produce symptoms, rapid
reduction of serum calcium is required. The first steps include
rehydration with saline and diuresis with furosemide, although the
efficacy of furosemide in this setting has not been proved. Most
patients presenting with severe hypercalcemia have a substantial
component of prerenal azotemia owing to dehydration, which pre-
vents the kidney from compensating for the rise in serum calcium
by excreting more calcium in the urine. Therefore, the initial infu-
sion of 500–1000 mL/h of saline to reverse the dehydration and
restore urine flow can by itself substantially lower serum calcium.
The addition of a loop diuretic such as furosemide following rehy-
dration enhances urine flow and also inhibits calcium reabsorp-
tion in the ascending limb of the loop of Henle (see Chapter 15).
Monitoring of central venous pressure is important to forestall the
development of heart failure and pulmonary edema in predisposed
subjects. In many subjects, saline diuresis suffices to reduce serum
calcium to a point at which more definitive diagnosis and treatment
of the underlying condition can be achieved. If this is not the case or
if more prolonged medical treatment of hypercalcemia is required,
the following agents are available (discussed in order of preference).
Bisphosphonates
Pamidronate, 60–90 mg, infused over 2–4 hours, and zoledro-
nate, 4 mg, infused over at least 15 minutes, have been approved
for the treatment of hypercalcemia of malignancy and have largely
replaced the less effective etidronate for this indication. The
bisphosphonate effects generally persist for weeks, but treatment
can be repeated after a 7-day interval if necessary and if renal
function is not impaired. Some patients experience a self-limited
flu-like syndrome after the initial infusion, but subsequent infu-
sions generally do not have this side effect. Repeated doses of these
drugs have been linked to renal deterioration and osteonecrosis of
the jaw, but this adverse effect is rare.
Calcitonin
Calcitonin has proved useful as ancillary treatment in some
patients. Calcitonin by itself seldom restores serum calcium to
normal, and refractoriness frequently develops. However, its lack
 CHAPTER 42  Agents That Affect Bone Mineral Homeostasis     783
of toxicity permits frequent administration at high doses (200
MRC units or more). An effect on serum calcium is observed
within 4–6 hours and lasts for 6–10 hours. Calcimar (salmon
calcitonin) is available for parenteral and nasal administration.
Gallium Nitrate
Gallium nitrate is approved by the FDA for the management of
hypercalcemia of malignancy. This drug inhibits bone resorp-
tion. At a dosage of 200 mg/m2 body surface area per day given
as a continuous intravenous infusion in 5% dextrose for 5 days,
gallium nitrate proved superior to calcitonin in reducing serum
calcium in cancer patients. Because of potential nephrotoxicity,
patients should be well hydrated and have good renal output
before starting the infusion.
Phosphate
Intravenous phosphate administration is probably the fastest
and surest way to reduce serum calcium, but it is a hazardous
procedure if not done properly. Intravenous phosphate should
be used only after other methods of treatment (bisphosphonates,
calcitonin, and saline diuresis) have failed to control symptomatic
hypercalcemia. Phosphate must be given slowly (50 mmol or 1.5 g
elemental phosphorus over 6–8 hours) and the patient switched
to oral phosphate (1–2 g/d elemental phosphorus, as one of the
salts indicated below) as soon as symptoms of hypercalcemia have
cleared. The risks of intravenous phosphate therapy include sud-
den hypocalcemia, ectopic calcification, acute renal failure, and
hypotension. Oral phosphate can also lead to ectopic calcifica-
tion and renal failure if serum calcium and phosphate levels are
not carefully monitored, but the risk is less and the time of onset
much longer. Phosphate is available in oral and intravenous forms
as sodium or potassium salts. Amounts required to provide 1 g of
elemental phosphorus are as follows:
Intravenous:
In-Phos, 40 mL; or Hyper-Phos-K, 15 mL
Oral:
Fleet Phospho-Soda, 6.2 mL; or Neutra-Phos, 300 mL; or
K-Phos-Neutral, 4 tablets
Glucocorticoids
Glucocorticoids have no clear role in the immediate treatment of
hypercalcemia. However, the chronic hypercalcemia of sarcoid-
osis, vitamin D intoxication, and certain cancers may respond
within several days to glucocorticoid therapy. Prednisone in oral
doses of 30–60 mg daily is generally used, although equivalent
doses of other glucocorticoids are effective. The rationale for
the use of glucocorticoids in these diseases differs, however. The
hypercalcemia of sarcoidosis is secondary to increased production
of 1,25(OH)2D by the sarcoid tissue itself. Glucocorticoid therapy
directed at the reduction of sarcoid tissue results in restoration of
normal serum calcium and 1,25(OH)2D levels. The treatment
of hypervitaminosis D with glucocorticoids probably does not
alter vitamin D metabolism significantly but is thought to reduce
vitamin D–mediated intestinal calcium transport and increase
renal excretion of calcium. An action of glucocorticoids to reduce
vitamin D–mediated bone resorption has not been excluded,
however. The effect of glucocorticoids on the hypercalcemia of
cancer is probably twofold. The malignancies responding best to
glucocorticoids (ie, multiple myeloma and related lymphoprolif-
erative diseases) are sensitive to the lytic action of glucocorticoids.
Therefore part of the effect may be related to decreased tumor
mass and activity. Glucocorticoids have also been shown to inhibit
the secretion or effectiveness of cytokines elaborated by multiple
myeloma and related cancers that stimulate osteoclastic bone
resorption. Other causes of hypercalcemia—particularly primary
hyperparathyroidism—do not respond to glucocorticoid therapy.
HYPOCALCEMIA
The main features of hypocalcemia are neuromuscular: tetany, par-
esthesias, laryngospasm, muscle cramps, and seizures. The major
causes of hypocalcemia in the adult are hypoparathyroidism,
vitamin D deficiency, chronic kidney disease, and malabsorption.
Hypocalcemia can also accompany the infusion of potent bisphos-
phonates and denosumab for the treatment of osteoporosis, but
this is seldom of clinical significance unless the patient is already
hypocalcemic at the onset of the infusion. Neonatal hypocalcemia
is a common disorder that usually resolves without therapy. The
roles of PTH, vitamin D, and calcitonin in the neonatal syndrome
are under investigation. Large infusions of citrated blood can pro-
duce hypocalcemia secondary to the formation of citrate-calcium
complexes. Calcium and vitamin D (or its metabolites) form the
mainstay of treatment of hypocalcemia. However, in patients with
hypoparathyroidism, teriparatide or rhPTH 1-84 may prove use-
ful (only rhPTH 1-84 has been FDA approved for this condition).
Calcium
A number of calcium preparations are available for intravenous,
intramuscular, and oral use. Calcium gluceptate (0.9 mEq
calcium/mL), calcium gluconate (0.45 mEq calcium/mL), and
calcium chloride (0.68–1.36 mEq calcium/mL) are available for
intravenous therapy. Calcium gluconate is preferred because it
is less irritating to veins. Oral preparations include calcium car-
bonate (40% calcium), calcium lactate (13% calcium), calcium
phosphate (25% calcium), and calcium citrate (21% calcium).
Calcium carbonate is often the preparation of choice because of
its high percentage of calcium, ready availability (eg, Tums), low
cost, and antacid properties. In achlorhydric patients, calcium
carbonate should be given with meals to increase absorption, or
the patient should be switched to calcium citrate, which is some-
what better absorbed. Combinations of vitamin D and calcium
are available, but treatment must be tailored to the individual
patient and the individual disease, a flexibility lost by fixed-dosage
combinations.
Treatment of severe symptomatic hypocalcemia can be accom-
plished with slow infusion of 5–20 mL of 10% calcium gluco-
nate. Rapid infusion can lead to cardiac arrhythmias. Less severe
hypocalcemia is best treated with oral forms sufficient to provide
784    SECTION VII  Endocrine Drugs
approximately 1000–1500 mg of elemental calcium per day. Dos-
age must be adjusted to avoid hypercalcemia and hypercalciuria.
Vitamin D
When rapidity of action is required, 1,25(OH)2D3 (calcitriol),
0.25–1 mcg daily, is the vitamin D metabolite of choice because it
is capable of raising serum calcium within 24–48 hours. Calcitriol
also raises serum phosphate, although this action is usually not
observed early in treatment. The combined effects of calcitriol
and all other vitamin D metabolites and analogs on both calcium
and phosphate make careful monitoring of these mineral levels
especially important to prevent ectopic calcification secondary to
an abnormally high serum calcium × phosphate product. Since
the choice of the appropriate vitamin D metabolite or analog for
long-term treatment of hypocalcemia depends on the nature of
the underlying disease, further discussion of vitamin D treatment
is found under the headings of the specific diseases.
HYPERPHOSPHATEMIA
Hyperphosphatemia is a common complication of renal failure and
is also found in all types of hypoparathyroidism (idiopathic, surgi-
cal, and pseudohypoparathyroidism), vitamin D intoxication, and
the rare syndrome of tumoral calcinosis (usually due to insufficient
bioactive FGF23). Emergency treatment of hyperphosphatemia is
seldom necessary but can be achieved by dialysis or glucose and
insulin infusions. In general, control of hyperphosphatemia involves
restriction of dietary phosphate plus phosphate-binding gels such
as sevelamer, or lanthanum carbonate and calcium supplements.
Because of their potential to induce aluminum-associated bone dis-
ease, aluminum-containing antacids should be used sparingly and
only when other measures fail to control the hyperphosphatemia. In
patients with chronic kidney disease, enthusiasm for the use of large
doses of calcium to control hyperphosphatemia has waned because
of the risk of ectopic calcification.
HYPOPHOSPHATEMIA
Hypophosphatemia is associated with a variety of conditions,
including primary hyperparathyroidism, vitamin D deficiency,
idiopathic hypercalciuria, conditions associated with increased
bioactive FGF23 (eg, X-linked and autosomal dominant hypophos-
phatemic rickets and tumor-induced osteomalacia), other forms of
renal phosphate wasting (eg, Fanconi’s syndrome), overzealous use
of phosphate binders, and parenteral nutrition with inadequate
phosphate content. Acute hypophosphatemia may cause a reduc-
tion in the intracellular levels of high-energy organic phosphates
(eg, ATP), interfere with normal hemoglobin-to-tissue oxygen
transfer by decreasing red cell 2,3-diphosphoglycerate levels, and
lead to rhabdomyolysis. However, clinically significant acute effects
of hypophosphatemia are seldom seen, and emergency treatment
is generally not indicated. The long-term effects include proximal
muscle weakness and abnormal bone mineralization (osteomalacia).
Therefore, hypophosphatemia should be avoided when using forms
of therapy that can lead to it (eg, phosphate binders, certain types
of parenteral nutrition) and treated in conditions that cause it, such
as the various forms of hypophosphatemic rickets. Oral forms of
phosphate are listed above.
SPECIFIC DISORDERS INVOLVING
BONE MINERAL-REGULATING
HORMONES
PRIMARY HYPERPARATHYROIDISM
This rather common disease, if associated with symptoms, signifi-
cant hypercalcemia, and hypercalciuria, osteoporosis, and kidney
disease is best treated surgically. Oral phosphate and bisphospho-
nates have been tried but cannot be recommended. A substantial
proportion of asymptomatic patients with mild disease do not get
worse and may be followed without treatment, although a number
of such patients do end up requiring surgery. The calcimimetic agent
cinacalcet, discussed previously, has been approved for secondary
hyperparathyroidism and is in clinical trials for the treatment of
primary hyperparathyroidism. If such drugs prove efficacious and
cost effective, medical management of this disease will need to be
reconsidered. Primary hyperparathyroidism is often associated with
low levels of 25(OH)D, suggesting that mild vitamin D deficiency
may be contributing to the elevated PTH levels, although this could
also be due to the stimulation by PTH of 1,25(OH)2D produc-
tion that in turn induces CYP24A1, which will increase 25(OH)
D (and 1,25(OH)2D) catabolism. Vitamin D supplementation in
such situations has proved safe with respect to further elevations of
serum and urine calcium levels, but calcium should be monitored
nevertheless when vitamin D supplementation is provided.
HYPOPARATHYROIDISM
In PTH deficiency (idiopathic or surgical hypoparathyroidism) or
an abnormal target tissue response to PTH (pseudohypoparathy-
roidism), serum calcium falls and serum phosphate rises. In such
patients, 1,25(OH)2D levels are usually low, presumably reflecting
the lack of stimulation by PTH of 1,25(OH)2D production. The
skeletons of patients with idiopathic or surgical hypoparathyroidism
are normal except for a slow turnover rate. A number of patients
with pseudohypoparathyroidism appear to have osteitis fibrosa, sug-
gesting that the normal or high PTH levels found in such patients
are capable of acting on bone but not on the kidney. The distinction
between pseudohypoparathyroidism and idiopathic hypoparathy-
roidism is made on the basis of normal or high PTH levels but
deficient renal response (ie, diminished excretion of cAMP or phos-
phate) in patients with pseudohypoparathyroidism.
The principal therapeutic goal is to restore normocalcemia
and normophosphatemia. Standard therapy involves the use
of calcitriol and dietary calcium supplements. However, many
patients develop hypercalciuria with this regimen, which limits
the ability to correct the hypocalcemia. Full-length PTH (rhPTH
1-84, Natpara) has recently been approved for the treatment
 CHAPTER 42  Agents That Affect Bone Mineral Homeostasis     785
of hypoparathyroidism and reduces the need for large doses of
calcium and calcitriol with less risk of hypercalciuria.
NUTRITIONAL VITAMIN D DEFICIENCY
OR INSUFFICIENCY
The level of vitamin D thought to be necessary for good health
is being reexamined with the appreciation that vitamin D acts on
a large number of cell types beyond those responsible for bone
and mineral metabolism. A level of 25(OH)D above 10 ng/mL
is necessary for preventing rickets or osteomalacia. However,
substantial epidemiologic and some prospective trial data indicate
that a higher level, such as 20–30 ng/mL, is required to optimize
intestinal calcium absorption, optimize the accrual and mainte-
nance of bone mass, reduce falls and fractures, and prevent a wide
variety of diseases including diabetes mellitus, hyperparathyroid-
ism, autoimmune diseases, and cancer. An expert panel for the
Institute of Medicine (IOM) has recommended that a level of
20 ng/mL (50 nM) was sufficient, although up to 50 ng/mL
(125 nM) was considered safe. For individuals between the ages
of 1 and 70 years, 600 IU/d vitamin D was thought to be suffi-
cient to meet these goals, although up to 4000 IU was considered
safe. These recommendations are based primarily on data from
randomized placebo-controlled clinical trials (RCTs) that evalu-
ated falls and fractures; data supporting the nonskeletal effects of
vitamin D were considered too preliminary to be used in their
recommendations because of lack of RCTs for these other actions.
The lower end of these recommendations has been considered too
low and the upper end too restrictive by a number of vitamin D
experts, and the Endocrine Society has published a different set of
recommendations suggesting that 30 ng/mL was a more appropri-
ate lower limit. Nevertheless, the call for better clinical data from
RCTs, especially for the nonskeletal actions, is appropriate. The
IOM guidelines—at least with respect to the lower recommended
levels of vitamin D supplementation—are unlikely to correct
vitamin D deficiency in individuals with obesity, dark complex-
ions, limited capacity for sunlight exposure, or malabsorption.
Vitamin D deficiency or insufficiency can be treated by higher
dosages (either D2 or D3, 1000–4000 IU/d or 50,000 IU/week
for several weeks). No other vitamin D metabolite is indicated.
Because the half-life of vitamin D3 metabolites in blood is greater
than that of vitamin D2, there are advantages to using vitamin D3
rather than vitamin D2 supplements, although when administered
on a daily or weekly schedule these differences may be moot. The
diet should also contain adequate amounts of calcium as several
studies indicate a synergism between calcium and vitamin D with
respect to a number of their actions.
CHRONIC KIDNEY DISEASE
The major sequelae of chronic kidney disease (CKD) that impact
bone mineral homeostasis are deficient 1,25(OH)2D production,
retention of phosphate with an associated reduction in ionized
calcium levels, and the secondary hyperparathyroidism that results
from the parathyroid gland response to lowered serum ionized
calcium and low 1,25(OH)2D. FGF23 levels rise early in this dis-
order for unclear reasons and this can further reduce 1,25(OH)2D
production by the kidney. Moreover, the increase in FGF23 is
associated with increased morbidity and mortality in CKD in
part due to its impact on the heart. Although still investigational,
antibodies to FGF23 in the early stages of renal failure result in
normalization of 1,25(OH)2D levels, and may prove useful in
CKD treatment. However, inhibition of FGF23 may further the
rise in serum phosphate with the potential for increased vascular
calcification, a major issue in CKD. With impaired 1,25(OH)2D
production, less calcium is absorbed from the intestine, and less
bone is resorbed under the influence of PTH. As a result hypocal-
cemia usually develops, furthering the development of secondary
hyperparathyroidism. The bones show a mixture of osteomalacia
and osteitis fibrosa.
In contrast to the hypocalcemia that is more often associated
with chronic kidney disease, some patients may become hyper-
calcemic from overzealous treatment with calcium. However,
the most common cause of hypercalcemia is the development of
severe secondary (sometimes referred to as tertiary) hyperpara-
thyroidism. In such cases, the PTH level in blood is very high.
Serum alkaline phosphatase levels also tend to be high. Treatment
often requires parathyroidectomy. A less common circumstance
leading to hypercalcemia is development of a form of bone disease
characterized by a profound decrease in bone cell activity and loss
of the calcium buffering action of bone (adynamic bone disease).
In the absence of kidney function, any calcium absorbed from the
intestine accumulates in the blood. Such patients are very sensitive
to the hypercalcemic action of 1,25(OH)2D. These individuals
generally have a high serum calcium but nearly normal alkaline
phosphatase and PTH levels. The bone in such patients may have
a high aluminum content, especially in the mineralization front,
which blocks normal bone mineralization. These patients do not
respond favorably to parathyroidectomy. Deferoxamine, an agent
used to chelate iron (see Chapter 57), also binds aluminum and
is being used to treat this disorder. However, with the reduction
in use of aluminum-containing phosphate binders, most cases of
adynamic bone disease are not associated with aluminum deposi-
tion but are attributed in some cases to overzealous suppression of
PTH secretion.
Vitamin D Preparations
The choice of vitamin D preparation to be used in the setting of
chronic kidney disease depends on the type and extent of bone
disease and hyperparathyroidism. Individuals with vitamin D
deficiency or insufficiency should first have their 25(OH)D levels
restored to normal (20–30 ng/mL) with vitamin D. Calcifediol
or 1,25(OH)2D3 (calcitriol) rapidly corrects hypocalcemia and at
least partially reverses secondary hyperparathyroidism and osteitis
fibrosa. Many patients with muscle weakness and bone pain gain
an improved sense of well-being.
Two analogs of calcitriol—doxercalciferol and paricalcitol—
are approved in the United States for the treatment of second-
ary hyperparathyroidism of chronic kidney disease. (In Japan,
786    SECTION VII  Endocrine Drugs
maxacalcitol [22-oxa-calcitriol] and falecalcitriol [26,27 F6-
1,25(OH)2D3] are approved for this purpose.) Their principal
advantage is that they are less likely than calcitriol to induce
hypercalcemia for any given reduction in PTH (less true for fale-
calcitriol). Their greatest impact is in patients in whom the use
of calcitriol may lead to unacceptably high serum calcium levels.
Regardless of the drug used, careful attention to serum calcium
and phosphate levels is required. A calcium × phosphate product
(in mg/dL units) less than 55 is desired with both calcium and
phosphate in the normal range. Calcium adjustments in the diet
and dialysis bath and phosphate restriction (dietary and with oral
ingestion of phosphate binders) should be used along with vitamin
D metabolites. Monitoring of serum PTH and alkaline phospha-
tase levels is useful in determining whether therapy is correcting
or preventing secondary hyperparathyroidism. In patients on
dialysis, a PTH value of approximately twice the upper limits of
normal is considered desirable to prevent adynamic bone disease.
Although not generally available, percutaneous bone biopsies for
quantitative histomorphometry may help in choosing appropriate
therapy and following the effectiveness of such therapy, especially
in cases suspected of adynamic bone disease. Unlike the rapid
changes in serum values, changes in bone morphology require
months to years. Monitoring of serum vitamin D metabolite levels
is useful for determining adherence, absorption, and metabolism.
INTESTINAL OSTEODYSTROPHY
A number of gastrointestinal and hepatic diseases cause disordered
calcium and phosphate homeostasis, which ultimately leads to
bone disease. As bariatric surgery becomes more common, this
problem is likely to increase. The bones in such patients show a
combination of osteoporosis and osteomalacia. Osteitis fibrosa
does not occur, in contrast to renal osteodystrophy. The important
common feature in this group of diseases appears to be malabsorp-
tion of calcium and vitamin D. Liver disease may, in addition,
reduce the production of 25(OH)D from vitamin D, although its
importance in patients other than those with terminal liver failure
remains in dispute. The major explanation for the low 25(OH)D
levels in patients with liver disease is the reduction in D-binding
protein production, the major carrier of vitamin D metabolites
in the blood. Free 25(OH)D is generally normal in patients with
liver disease. The malabsorption of vitamin D is probably not
limited to exogenous vitamin D as the liver secretes into bile a
substantial number of vitamin D metabolites and conjugates that
are normally reabsorbed in (presumably) the distal jejunum and
ileum. Interference with this process could deplete the body of
endogenous vitamin D metabolites in addition to limiting absorp-
tion of dietary vitamin D.
In mild forms of malabsorption, high doses of vitamin D
(25,000–50,000 IU one to three times per week) should suffice
to raise serum levels of 25(OH)D into the normal range. Many
patients with severe disease do not respond to vitamin D. Clinical
experience with the other metabolites is limited, but both calcitriol
and calcifediol have been used successfully in doses similar to those
recommended for treatment of renal osteodystrophy. Theoretically,
calcifediol should be the drug of choice under these conditions,
because no impairment of the renal metabolism of 25(OH)D to
1,25(OH)2D and 24,25(OH)2D exists in these patients. However,
calcifediol is only approved in the United States for use in chronic
kidney disease and secondary hyperparathyroidism. Both calcitriol
and 24,25(OH)2D may be of importance in reversing the bone
disease. Intramuscular injections of vitamin D would be an alter-
native form of therapy, but there are currently no FDA-approved
intramuscular preparations available in the United States. The skin
remains a good source of vitamin D production, although care is
needed to prevent UVB overexposure (ie, by avoiding sunburn) to
reduce the risk of photoaging and skin cancer.
As in the other diseases discussed, treatment of intestinal
osteodystrophy with vitamin D and its metabolites should be
accompanied by appropriate dietary calcium supplementation and
monitoring of serum calcium and phosphate levels.
OSTEOPOROSIS
Osteoporosis is defined as abnormal loss of bone predisposing
to fractures. It is most common in postmenopausal women but
also occurs in men. The annual direct medical cost of fractures in
older women and men in the United States is estimated to be at
least $20 billion per year and is increasing as the population ages.
Osteoporosis is most commonly associated with loss of gonadal
function as in menopause but may also occur as an adverse effect
of long-term administration of glucocorticoids or other drugs,
including those that inhibit sex steroid production; as a manifesta-
tion of endocrine disease such as thyrotoxicosis or hyperparathy-
roidism; as a feature of malabsorption syndrome; as a consequence
of alcohol abuse and cigarette smoking; or without obvious cause
(idiopathic). The ability of some agents to reverse the bone loss of
osteoporosis is shown in Figure 42–5. The postmenopausal form
of osteoporosis may be accompanied by lower 1,25(OH)2D levels
and reduced intestinal calcium transport. This form of osteoporo-
sis is due to reduced estrogen production and can be treated with
estrogen (combined with a progestin in women with a uterus to
prevent endometrial carcinoma). However, concern that estrogen
increases the risk of breast cancer and fails to reduce or may actu-
ally increase the development of heart disease has reduced enthu-
siasm for this form of therapy, at least in older individuals.
Bisphosphonates are potent inhibitors of bone resorption.
They increase bone density and reduce the risk of fractures in
the hip, spine, and other locations. Alendronate, risedronate,
ibandronate, and zoledronate are approved for the treatment of
osteoporosis, using daily dosing schedules of alendronate, 10 mg/d,
risedronate, 5 mg/d, or ibandronate, 2.5 mg/d; or weekly sched-
ules of alendronate, 70 mg/week, or risedronate, 35 mg/week; or
monthly schedules of ibandronate, 150 mg/month; or quarterly
(every 3 months) injections of ibandronate, 3 mg; or annual infu-
sions of zoledronate, 5 mg. These drugs are effective in men as well
as women and for various causes of osteoporosis.
As previously noted, estrogen-like SERMs (selective estrogen
receptor modulators, Chapter 40) have been developed that prevent
the increased risk of breast and uterine cancer associated with estrogen
 CHAPTER 42  Agents That Affect Bone Mineral Homeostasis     787

Vitamin D, PTH,
40 Sr2+, anti-sclerostin

bone mineral density

Estrogen,

Percent change in
denosumab,
20 calcitonin, or
bisphosphonate

−10 No treatment

0 1 2 3 4 5
Time (y)

FIGURE 42–5  Typical changes in bone mineral density with time after the onset of menopause, with and without treatment. In the
untreated condition, bone is lost during aging in both men and women. Strontium (Sr2+), parathyroid hormone (PTH), and vitamin D promote
bone formation and can increase bone mineral density in subjects who respond to them throughout the period of treatment, although PTH
and vitamin D in high doses also activate bone resorption. Sclerostin antibodies, currently in clinical trials, provide a pure anabolic action in
the treatment of osteoporosis by promoting bone formation and inhibiting bone resorption. In contrast, estrogen, calcitonin, denosumab,
and bisphosphonates block bone resorption. This leads to a transient increase in bone mineral density because bone formation is not initially
decreased. However, with time, both bone formation and bone resorption decrease with these pure antiresorptive agents, and bone mineral
density reaches a new plateau.

while maintaining the benefit to bone. The SERM raloxifene is
approved for treatment of osteoporosis. Like tamoxifen, raloxifene
reduces the risk of breast cancer. It protects against spine fractures but
not hip fractures—unlike bisphosphonates, denosumab, and teripa-
ratide, which protect against both. Raloxifene does not prevent hot
flushes and imposes the same increased risk of venous thromboembo-
lism as estrogen. To counter the reduced intestinal calcium transport
associated with osteoporosis, vitamin D therapy is often used in com-
bination with dietary calcium supplementation. In several large stud-
ies, vitamin D supplementation (800 IU/d) with calcium has been
shown to improve bone density, reduce falls, and prevent fractures,
although calcium and vitamin D are generally used as supplements
with other drugs in the treatment of osteoporosis. Calcitriol and its
analog, 1α(OH)D3, have also been shown to increase bone mass and
reduce fractures. Use of these agents for osteoporosis is not FDA-
approved, although they are used for this purpose in other countries.
The 1,25(OH)2D analog eldecalcitol is approved for use in Japan,
largely replacing the use of 1α( OH)D3.
Teriparatide, the recombinant form of PTH 1-34, is approved
for treatment of osteoporosis. It is given in a dosage of 20 mcg
subcutaneously daily. Teriparatide stimulates new bone formation,
but unlike fluoride, this new bone appears structurally normal
and is associated with a substantial reduction in the incidence
of fractures. The drug is approved for only 2 years of use. Trials
examining the sequential use of teriparatide followed by a bisphos-
phonate after 1 or 2 years are in progress and look promising. Use
of the drug with a bisphosphonate has not shown greater efficacy
than the bisphosphonate alone, although recent trials with the
concomitant use of teriparatide and denosumab show promise.
Calcitonin is approved for use in the treatment of postmeno-
pausal osteoporosis. It has been shown to increase bone mass and
reduce fractures, but only in the spine. It does not appear to be as
effective as bisphosphonates or teriparatide.
Denosumab, the RANKL inhibitor, is of comparable efficacy
to bisphosphonates in the treatment of postmenopausal osteopo-
rosis. It is given subcutaneously every 6 months in 60-mg doses.
Like the bisphosphonates it suppresses bone resorption and sec-
ondarily bone formation. Denosumab reduces the risk of both
vertebral and nonvertebral fractures with comparable effectiveness
to the potent bisphosphonates.
Strontium ranelate has not been approved in the United States
for the treatment of osteoporosis but is being used in Europe,
generally at a dose of 2 g/d.
X-LINKED & AUTOSOMAL DOMINANT
HYPOPHOSPHATEMIA & RELATED
DISEASES
These disorders usually manifest in childhood as rickets and hypo-
phosphatemia, although they may first present in adults. In both
X-linked and autosomal dominant hypophosphatemia, biologi-
cally active FGF23 accumulates, leading to phosphate wasting in
the urine and hypophosphatemia. In autosomal dominant hypo-
phosphatemia, mutations in the FGF23 gene replace an arginine
required for proteolysis and result in increased FGF23 stability.
X-linked hypophosphatemia is caused by mutations in the gene
encoding the PHEX protein, an endopeptidase. Initially, it was
thought that FGF23 was a direct substrate for PHEX, but this no
longer appears to be the case. Tumor-induced osteomalacia is a
phenotypically similar but acquired syndrome in adults that results
from overexpression of FGF23 in tumor cells. The current concept
for all of these diseases is that FGF23 blocks the renal uptake of
phosphate and blocks 1,25(OH)2D production leading to rickets in
children and osteomalacia in adults. Phosphate is critical to normal
bone mineralization; when phosphate stores are deficient, a clinical
788    SECTION VII  Endocrine Drugs
and pathologic picture resembling vitamin D–dependent rickets
develops. However, affected children fail to respond to the standard
doses of vitamin D used in the treatment of nutritional rickets. A
defect in 1,25(OH)2D production by the kidney contributes to
the phenotype as 1,25(OH)2D levels are low relative to the degree
of hypophosphatemia observed. This combination of low serum
phosphate and low or low-normal serum 1,25(OH)2D provides
the rationale for treating these patients with oral phosphate (1–3 g
daily) and calcitriol (0.25–2 mcg daily). Reports of such combina-
tion therapy are encouraging in this otherwise debilitating disease,
although prolonged treatment often leads to secondary hyperpara-
thyroidism. More recently the use of FGF23 antibodies for children
with X-linked hypophosphatemic (XLH) rickets has shown promise
and may become the treatment of choice for these conditions.
PSEUDOVITAMIN D DEFICIENCY
RICKETS & HEREDITARY VITAMIN D–
RESISTANT RICKETS
These distinctly different autosomal recessive diseases present as child-
hood rickets that do not respond to conventional doses of vitamin D.
Pseudovitamin D–deficiency rickets is due to an isolated deficiency
of 1,25(OH)2D production caused by mutations in 25(OH)-D-
1α-hydroxylase (CYP27B1). This condition is treated with cal-
citriol (0.25–0.5 mcg daily). Hereditary vitamin D–resistant rickets
(HVDRR) is caused by mutations in the gene for the vitamin D
receptor. The serum levels of 1,25(OH)2D are very high in HVDRR
but inappropriately low for the level of calcium in pseudovitamin
D–deficient rickets. Treatment with large doses of calcitriol has been
claimed to be effective in restoring normocalcemia in some HVDRR
patients, presumably those with a partially functional vitamin D
receptor, although many patients are completely resistant to all forms
of vitamin D. Calcium and phosphate infusions have been shown
to correct the rickets in some children, similar to studies in mice in
which the VDR gene has been deleted. These diseases are rare.
IDIOPATHIC INFANTILE
HYPERCALCEMIA
Mutations in CYP24A1, the enzyme catabolizing 25(OH)D and
1,25(OH)2D, have recently been found to account for a number of
cases of idiopathic infantile hypercalcemia. However, these muta-
tions have also been described in adults with previously unexplained
hypercalcemia and elevated 1,25(OH)2D levels. At this point no
definitive therapy has been established, but vitamin D supplemen-
tation needs to be avoided. The diagnosis can be made by finding a
reduced ratio of 24,25(OH)2D to 25(OH)D in the blood.
NEPHROTIC SYNDROME
Patients with nephrotic syndrome can lose vitamin D metabolites in
the urine, presumably by loss of the vitamin D–binding protein.
Such patients may have very low 25(OH)D levels. Some of them
develop bone disease. It is not yet clear what value vitamin D ther-
apy has in such patients, because therapeutic trials with vitamin D
(or any vitamin D metabolite) have not yet been carried out.
Because the problem is not related to vitamin D metabolism, one
would not anticipate any advantage in using the more expensive
vitamin D metabolites in place of vitamin D.
IDIOPATHIC HYPERCALCIURIA
Individuals with idiopathic hypercalciuria, characterized by hyper-
calciuria and nephrolithiasis with normal serum calcium and PTH
levels, have been divided into three groups: (1) hyperabsorbers,
patients with increased intestinal absorption of calcium, resulting
in high-normal serum calcium, low-normal PTH, and a second-
ary increase in urine calcium; (2) renal calcium leakers, patients
with a primary decrease in renal reabsorption of filtered calcium,
leading to low-normal serum calcium and high-normal serum
PTH; and (3) renal phosphate leakers, patients with a primary
decrease in renal reabsorption of phosphate, leading to increased
1,25(OH)2D production, increased intestinal calcium absorption,
increased ionized serum calcium, low-normal PTH levels, and a
secondary increase in urine calcium. There is some disagreement
about this classification, and many patients are not readily catego-
rized. Many such patients present with mild hypophosphatemia,
and oral phosphate has been used with some success in reduc-
ing stone formation. However, a clear role for phosphate in the
treatment of this disorder has not been established and is not
recommended.
Therapy with hydrochlorothiazide, up to 50 mg twice daily, or
chlorthalidone, 50–100 mg daily, is recommended. Loop diuret-
ics such as furosemide and ethacrynic acid should not be used
because they increase urinary calcium excretion. The major toxic-
ity of thiazide diuretics, besides hypokalemia, hypomagnesemia,
and hyperglycemia, is hypercalcemia. This is seldom more than
a biochemical observation unless the patient has a disease such
as hyperparathyroidism in which bone turnover is accelerated.
Accordingly, one should screen patients for such disorders before
starting thiazide therapy and monitor serum and urine calcium
when therapy has begun.
An alternative to thiazides is allopurinol. Some studies indicate
that hyperuricosuria is associated with idiopathic hypercalcemia
and that a small nidus of urate crystals could lead to the calcium
oxalate stone formation characteristic of idiopathic hypercalcemia.
Allopurinol, 100–300 mg daily, may reduce stone formation by
reducing uric acid excretion.
OTHER DISORDERS OF BONE
MINERAL HOMEOSTASIS
PAGET’S DISEASE OF BONE
Paget’s disease is a localized bone disorder characterized by uncon-
trolled osteoclastic bone resorption with secondary increases in
poorly organized bone formation. The cause of Paget’s disease is
obscure, although some studies suggest that a measles-related virus
 CHAPTER 42  Agents That Affect Bone Mineral Homeostasis     789

may be involved. The disease is fairly common, although symp-
tomatic bone disease is less common. Recent studies indicate that
this infection may produce a factor that increases the stimulation
of bone resorption by 1,25(OH)2D. The biochemical parameters
of elevated serum alkaline phosphatase and urinary hydroxypro-
line are useful for diagnosis. Along with the characteristic radio-
logic and bone scan findings, these biochemical determinations
provide good markers by which to follow therapy.
The goal of treatment is to reduce bone pain and stabilize or
prevent other problems such as progressive deformity, fractures,
hearing loss, high-output cardiac failure, and immobilization
hypercalcemia. Calcitonin and bisphosphonates are the first-line
agents for this disease. Calcitonin is administered subcutaneously
or intramuscularly in doses of 50–100 MRC (Medical Research
Council) units every day or every other day. Nasal inhalation at
200–400 units/d is also effective. Higher or more frequent doses
have been advocated when this initial regimen is ineffective.
Improvement in bone pain and reduction in serum alkaline phos-
phatase and urine hydroxyproline levels require weeks to months.
Often a patient who responds well initially loses the response to
calcitonin. This refractoriness is not correlated with the develop-
ment of antibodies.
Sodium etidronate, alendronate, risedronate, and tiludronate
are the bisphosphonates currently approved for clinical use in Pag-
et’s disease of bone in the United States. Other bisphosphonates,
including pamidronate, are being used in other countries. The
recommended doses of bisphosphonates are etidronate, 5 mg/kg
per day; alendronate, 40 mg/d; risedronate, 30 mg/d; and tiludro-
nate, 400 mg/d. Long-term remission (months to years) may be
expected in patients who respond to a bisphosphonate. Treatment
should not exceed 6 months per course but can be repeated after
6 months if necessary. The principal toxicity of etidronate is the
development of osteomalacia and an increased incidence of frac-
tures when the dosage is raised substantially above 5 mg/kg per
day. The newer bisphosphonates such as risedronate and alendro-
nate do not share this adverse effect. Some patients treated with
etidronate develop bone pain similar in nature to the bone pain of
osteomalacia. This subsides after stopping the drug. The principal
adverse effect of alendronate and the newer bisphosphonates is
gastric irritation when used at these high doses. This is reversible
on cessation of the drug.
ENTERIC OXALURIA
Patients with short bowel syndromes and associated fat malab-
sorption can present with renal stones composed of calcium and
oxalate. Such patients characteristically have normal or low urine
calcium levels but elevated urine oxalate levels. The reasons for
the development of oxaluria in such patients are thought to be
twofold: first, in the intestinal lumen, calcium (which is now
bound to fat) fails to bind oxalate and no longer prevents its
absorption; second, enteric flora, acting on the increased sup-
ply of nutrients reaching the colon, produce larger amounts of
oxalate. Although one would ordinarily avoid treating a patient
with calcium oxalate stones with calcium supplementation, this
is precisely what is done in patients with enteric oxaluria. The
increased intestinal calcium binds the excess oxalate and prevents
its absorption. Calcium carbonate (1–2 g) can be given daily in
divided doses, with careful monitoring of urinary calcium and
oxalate to be certain that urinary oxalate falls without a danger-
ous increase in urinary calcium.

SUMMARY Major Drugs Used in Diseases of Bone Mineral Homeostasis

Mechanism of Clinical
Subclass, Drug Action Effects Applications Toxicities

VITAMIN D, METABOLITES, ANALOGS

  •  Cholecalciferol (D3) Regulate gene transcription Stimulate intestinal calcium Osteoporosis, Hypercalcemia, hypercalciuria
  •  Ergocalciferol (D2) via the vitamin D receptor absorption, bone resorption, renal osteomalacia, renal • the vitamin D preparations
  •  Calcitriol calcium and phosphate reabsorption failure, malabsorption, have much longer half-lives
  •  Calcifediol • decrease parathyroid hormone psoriasis than the metabolites and
  •  Doxercalciferol (PTH) • promote innate immunity analogs
  •  Paricalcitol • inhibit adaptive immunity
  •  Calcipotriene

BISPHOSPHONATES
  •  Alendronate Suppress the activity of Inhibit bone resorption and Osteoporosis, bone Adynamic bone, possible renal
  •  Risedronate osteoclasts in part via secondarily bone formation metastases, failure, rare osteonecrosis of the
  •  Ibandronate inhibition of farnesyl hypercalcemia jaw, rare subtrochanteric (femur)
  •  Pamidronate pyrophosphate synthesis fractures
  •  Zoledronate

(continued)
790    SECTION VII  Endocrine Drugs

Mechanism of Clinical
Subclass, Drug Action Effects Applications Toxicities
HORMONES
  •  Teriparatide These hormones act via their Teriparatide stimulates bone turnover Both are used in Teriparatide may cause
  •  Abaloparatide cognate G protein–coupled • calcitonin suppresses bone osteoporosis • calcitonin hypercalcemia and
  •  Calcitonin receptors resorption is used for hypercalcemia hypercalciuria
  •  rhPTH1-84 Recombinant full-length rhPTH1-84 increases RANKL, Hypoparathyroidism Hypercalcemia, hypercalciuria
PTH; acts on the same decreases sclerostin, enhances
receptors as teriparatide calcium reabsorption from the kidney

SELECTIVE ESTROGEN RECEPTOR MODULATORS (SERMs)

  •  Raloxifene Interacts selectively with Inhibits bone resorption without Osteoporosis Does not prevent hot flashes
estrogen receptors stimulating breast or endometrial • increased risk of venous
hyperplasia thromboembolism

RANK LIGAND (RANKL) INHIBITOR

  •  Denosumab Monoclonal antibody • binds Blocks bone resorption Osteoporosis May increase risk of infections
to RANKL and prevents it
from stimulating osteoclast
differentiation and function

CALCIUM RECEPTOR AGONIST

  •  Cinacalcet Activates the calcium- Inhibits PTH secretion Hyperparathyroidism Nausea
sensing receptor

MINERALS
  • Calcium, Multiple physiologic actions Strontium suppresses bone Osteoporosis Ectopic calcification
phosphate through regulation of resorption and increases bone • osteomalacia
  •  Strontium multiple enzymatic formation • calcium and phosphate • deficiencies in calcium
pathways required for bone mineralization or phosphate

P R E P A R A T I O N S A V A I L A B L E

GENERIC NAME AVAILABLE AS GENERIC NAME AVAILABLE AS

VITAMIN D, METABOLITES, AND ANALOGS PHOSPHATE AND PHOSPHATE BINDER
Calcifediol (25(OH)D3) Rayaldee Phosphate  
Calcitriol     Oral: solution Fleet Phospho-soda, K-Phos-
 Oral Generic, Rocaltrol Neutral, Neutra-Phos, Neutra-
Phos-K
 Parenteral Calcijex
Sevelamer carbonate or HCl Renagel, Renvela
Cholecalciferol (D3) Generic, Delta-D
(vitamin D3) Lanthanum carbonate Fosrenol
Doxercalciferol Generic, Hectorol BISPHOSPHONATES
Ergocalciferol (D2) (vitamin Generic, Drisdol, others Alendronate sodium Generic, Fosamax
D2, calciferol) Etidronate disodium Generic, Didronel
Paricalcitol Generic, Zemplar Ibandronate sodium Generic, Boniva
CALCIUM Pamidronate disodium Generic, Aredia
Calcium acetate (25% calcium) Generic, PhosLo Risedronate sodium Actonel, Atelvia
Calcium carbonate (40% calcium) Generic, Tums, Cal-Sup, Os-Cal 500 Tiludronate disodium Skelid
Calcium chloride (27% calcium) Generic Zoledronic acid Zometa
Calcium citrate (21% calcium) Generic, Cal-C-Caps, Cal-Cee OTHER DRUGS
Calcium glubionate Neo-Calglucon, Calcionate, Calcitonin-salmon Miacalcin, Calcimar, Salmonine
(6.5% calcium) Calciquid Cinacalcet Sensipar
Calcium gluceptate Generic Denosumab Prolia, Xgeva
(8% calcium)
Gallium nitrate Ganite
Calcium gluconate Generic
(9% calcium) Sodium fluoride Generic
Calcium lactate (13% calcium) Generic Teriparatide (1-34 active segment Forteo
of PTH)
Tricalcium phosphate Posture
(39% calcium) Recombinant human PTH 1-84 Natpara
 CHAPTER 42  Agents That Affect Bone Mineral Homeostasis     791
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gonadotropin production, leading to hypogonadism. Man-
agement should include measurement of serum testoster-
one, calcium, 25(OH)D, and the 24-hour urine calcium
and creatinine levels (to verify completeness of collection),
with treatment as appropriate for these secondary causes,
plus initiation of bisphosphonate or denosumab therapy as
primary treatment.