PHARMACOLOGY

Topic: Steroids & Gonadal Drugs

Chapter: 39 & 40

TYPES OF STEROID HORMONES

 Glucocorticoids: Cortisol is the major representative in most
mammals
 Mineralocorticoids: Aldosterone being most prominent
 Androgens: Such as testosterone
 Estrogens: Including estradiol and estrone
 Progestogens: (Also known as “progestins”) Such as progesterone

ADRENAL GLAND
Figure Above: HPA Axis
Control of Endocrine Activity
 The physiologic effects of hormones depend largely on their
concentration in blood and extracellular fluid
 Almost inevitably, disease results when hormone concentrations are
either too high or too low, and precise control over circulating
concentrations of hormones is therefore crucial

Steroid Hormones
 Located above the kidney, retroperitoneally
 Combined weight: 7-10 g
 3 different zones of adrenal cortex:
o Outer zona glomerulosa  mineralocorticoid aldosterone
o Middle zona fasciculata  corticosteroid cortisol
o Inner zona reticularis  DHEA and its sulfated derivatives
(androgens)
 Adrenal medulla: 20% norepinephrine; 80% epinephrine
 All steroid hormones are derived from cholesterol and differ only in
the ring structure and side chains attached to it
 All steroid hormones are lipid soluble
 Pregnenolone is the major precursor of corticosterone and
aldosterone
 17-hydroxypregnenolone is the major precursor of cortisol

Adrenal Cortex
Outer Zone (Zona Glomerulosa)
 Secretes mineralocorticoids (aldosterone)
ACTH (pituitary release of corticotropin) produces moderate
stimulation of its release

 Aldosterone is under the influence of angiotensin

Angiotensin attaches to receptors for angiotensin II and express
aldosterone synthase  aldosterone synthesis

 Do not atrophy in the absence of ACTH

Inner Zone (Zona Fasciculata & Reticularis)

 Secrete glucocorticoids and adrenal androgens respectively Steroid Hormone Production
 Absence of ACTH results in atrophy  Rate limiting step  conversion of cholesterol to pregnenolone
 Sources of cholesterol:
Adrenocorticotropic Hormone (ACTH) o Circulating cholesterol (LDL)
 A peptide of 39 amino acids o Cholesterol esterase
 Amino acids 15-18: high affinity binding o De novo biosynthesis
 Amino acids 6-10: receptor activation
 Lack of:
 Synthesized from pro-opiomelanocortin (POMC)
o 21-β-hydroxylase (CYP21A2)  virilization
o 11-β-deoxycorticosterone (CYP11β1)  hypertension
Physiologic Effect:
o 17-α-hydroxypregnenolone (CYP17)  hypogonadism
 Stimulates the synthesis and release of adrenocortical hormones
 Human ACTH – G-protein coupled receptor  activates adenylyl
Steroidogenic Enzymes
cyclase  ↑ intracellular cAMP (2nd messenger for most
steroidogenesis) Common Name “Old” Name Current Name
Side-chain cleavage enzymes;
P450SCC CYP11A1
desmolase
Regulation of ACTH secretion
3 beta-hydroxysteroid
 Hypothalamic-Pituitary-Adrenal axis (HPA axis) dehydrogenase
3 beta-HSD 3 beta-HSD
 3 levels of regulation: 17-α-hydroxylase/17,20 lyase P450C17 CYP17
1. Diurnal rhythm in basal steroidogenesis 21-hydroxylase P450C21 CYP21A2
2. Negative feedback regulation 11-β-hydroxylase P450C11 CYP11B1
Aldosterone synthase P450C11AS CYP11B2
3. Marked increases in steroidogenesis in response to stress
Aromatase P450aro CYP19

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 PHARMACOLOGY
Topic: Steroids & Gonadal Drugs
Chapter: 39 & 40
Adrenocorticosteroids
Classification:
 Mineralocorticoids
 Glucocorticoids
 Adrenal Androgens (DHEAs)
This now follows the flow of information from the Katzung 14 th Ed.
NATURAL-OCCURING GLUCOCORTICOIDS
Cortisol (Hydrocortisone; Compound F)
Pharmacokinetics:
 Cortisol is synthesized from cholesterol (See page 8 for pathway)
 In the absence of stress, 10-20 mg of cortisol is excreted daily
 Rate of secretion follows a circadian rhythm
 In plasma, cortisol is bound to circulating proteins:
o 90% is bound to Corticosteroid-binding globulin (CBG)
o 5% is free
o 5% is bound to albumin
 Half-life: 60-90 minutes
 Metabolized in the liver
Many cortisol metabolites are conjugated with glucuronic acid or
sulfate at the C3 and C21 hydroxyls
 Elimination:
o 1% excreted in the urine
Measured as 17-hydroxysteroid
o 20% of cortisol is converted to cortisone by 11-
hydroxysteroid dehydrogenase in the kidney
 CBG (transcortin)
o α2 globulin synthesized by the liver
o Elevated:
Pregnancy, hyperthyroidism, estrogen administration
o Diminished:
Hypothyroidism, protein deficiency, genetic defects
Pharmacodynamics:
 MOA: Diffusion of glucocorticoid across the membrane of the target
cell to bind to a glucocorticoid-receptor heat-shock-protein complex
in the plasma
o Release of heat-shock protein and transport of the
hormone-receptor complex into the nucleus
o Binding of the hormone-receptor complex to specific
nucleotide sequences along the DNA called the
glucocorticoid response elements (GREs)
o Decreased or increased accumulation of mRNA, within
the target cell (alteration of transcription)
o Changes in the rate of synthesis of specific patterns that
carry the biological actions of the hormones
MOA based from Manual:
Binds to glucocorticoid receptors (cytosol)
(Steroid-receptor complex)
↓ 
Interact with promoter and regulates transcription (Hsp 90)
↓ nucleus
Alters gene expression by binding to glucocorticoid-response
element (GREs) and other transcription factors (e.g. API and NF-
κβ) which act on non-GRE containing promoters
↓
Contribute to the regulation of transcription of their responsive
genes causing regulation of growth factors, proinflammatory
cytokines and mediate anti-growth, anti-inflammatory and
immunosuppressive effects of glucocorticoids
#RoadToVNeck
Physiologic Effects:
 Widespread effects because they influence 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 important effects are the result of homeostatic
responses by insulin and glucagon
 Permissive effects (this means that without cortisol  normal function
becomes deficient):
o Diminished catecholamine response in vascular and
bronchial smooth muscle
o Attenuated lipolytic response to catecholamine ACTH
and GH in the absence of glucocorticoids
Metabolic Effects:
 Glucocorticoids have important dose-related effects on
carbohydrate, protein, and fat metabolism
 Glucocorticoids stimulate and are required for gluconeogenesis and
glycogen synthesis in fasting state
 Glucocorticoids increase serum glucose levels  thus stimulate
insulin release but inhibit the uptake of glucose by muscle cells 
stimulate hormone-sensitive lipase and thus lipolysis
From Manual:
Carbohydrate Metabolism
o Protect glucose-dependent tissues from starvation
o Stimulate gluconeogenesis, glycogen synthesis in the fasting
state  ↑ glucose  lipolysis ↑ FFA  insulin release 
periphery: ↓ glucose utilization and lipogenesis (fat
deposition)
Muscle Catabolism
o ↑ protein breakdown (amino acids
o Stimulate phosphoenol pyruvate carboxylase, G6-
phosphatase and glycogen synthase
o Catabolic effects: ↓ muscle mass, atrophy of lymphoid
tissue, negative nitrogen balance, thinning of the skin
Lipid Metabolism:
o Redistribution of body fat (buffalo hump, moon facies,
supraclavicular are with loss of fat in the extremities)
o Induce lipolysis in adipocytes (FFA and glycerol)
o Lipogenesis
Electrolyte:
o ↑ Ca2+ excretion by the kidneys (antagonize vitamin D effect
on Ca2+ absorption)
Catabolic and Antianabolic Effects:
 Glucocorticoids stimulate RNA and protein synthesis in the liver
o Catabolic and antianabolic effects in lymphoid and
connective tissue, muscle, peripheral fat, and skin
 Supraphysiologic amounts of glucocorticoids lead to ↓ muscle mass
and weakness and thinning of the skin
Catabolic and antianabolic effects on bone – causes osteoporosis in
Cushing’s syndrome
Major limitation in the therapeutic use of glucocorticoids
 Children  glucocorticoids reduce growth
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 PHARMACOLOGY
Topic: Steroids & Gonadal Drugs
Chapter: 39 & 40
Cortisol continued…..
Anti-Inflammatory and Immunosuppressive Effects:
 Glucocorticoids dramatically reduce the manifestations of
inflammation
Suppressive effects on inflammatory cytokines, chemokine and
other mediators of inflammation
 Glucocorticoids also inhibit the functions of tissue macrophages and
other antigen-presenting cells
 Glucocorticoids influence the inflammatory response by inhibiting
phospholipase A2
↓ synthesis of arachidonic acid (the precursor of prostaglandins
and leukotrienes) and of platelet-activating factor
 Glucocorticoids reduce expression of cyclooxygenase 2 (the
inducible form of this enzyme) in inflammatory cells
↓ amount of enzyme available to produce prostaglandins
 Glucocorticoids cause vasoconstriction when applied directly to the
skin, possibly by suppressing mast cell degranulation
 ↓ capillary permeability by ↓ amount of histamine released by
basophils and mascells
 ↓ antibody production (large doses >20 g/d prednisone)
 Inhibits complement activation
 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
#RoadToVNeck
Other Effects:
 Glucocorticoids have important effects on the nervous system
o Adrenal insufficiency – causes marked slowing down of
alpha rhythm of EEG: associated with depression
o Initial behavior disturbance is insomnia and euphoria,
then depression
 Large doses:
o ↑ intracranial pressure – pseudotumor cerebri
o Large doses also associated with development of peptic
ulcer
o Vitamin D antagonist on Ca2+ absoprtion
 Important effects of hematopoietic system – effect on leukocyte but
also may increase platelets and RBC
 Glucocorticoids play a role in the development of fetal lungs
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
 Chronic use: suppress pituitary release of ACTH, GH, TSH, LH
Page 3 of 21
 PHARMACOLOGY
Topic: Steroids & Gonadal Drugs
Chapter: 39 & 40

Synthetic Corticosteroids Adrenocortical Hypo- and Hyperfunction

Chemistry/Pharmacokinetics:  Congenital Adrenal Hyperplasia
 Source: Synthesized from cholic acid (from cattle or steroid o Group of disorders characterized by specific defects in the
sapogenins in plants synthesis of cortisol
o Most common defect: decrease in or lack of P450c21 (21-
 Disposition:
α-hydroxylase) activity
o Most rapidly and completely absorbed when given by
 Diversion of steroid precursors to the
mouth
androgen-producing pathway:
o Alterations in the glucocorticoid molecule influence its
↑ adrenal androgens
affinity for glucocorticoid and mineralocorticoid receptor
↓ glucocorticoids & ↓ mineralocorticoid
 Characterized by virilization of women, early
Pharmacodynamics:
acceleration of linear growth & early
 MOA: They bind to specific intracellular receptor proteins and
appearance of pubic hair
produce the same effects but have different ratios of glucocorticoid
o If defect is 11-hydroxylation – large amounts of
to mineralocorticoid potency (See table page 3)
deoxycorticosterone are produced
 Because this has mineralocorticoid activity 
Clinical Pharmacology:
hypertension with or without hypokalemic
 Diagnosis and Treatment of Disturbed Adrenal Function:
alkalosis may occur
o Adrenocortical Insufficiency
o If defect in 17-hydroxylation is detected in the adrenals
o Adrenocortical Hypo & Hyperfunction
and gonad  hypogonadism is present
o Congenital Adrenal Hyperplasia
 Increase 11-hydroxylation may occur due to
o Cushing’s Syndrome
the steroid precursors being diverted to the
o Aldosteronism
mineralocorticoid pathway
o Primary generalized glucocorticoid resistance (Chrousos
 Symptoms of glucocorticoid deficiency may
Syndrome)
also occur
 Stimulation of lung maturation in the fetus
o Management:
 Treatment of Non-Adrenal disorders
 Infant with adrenal crisis due to CAH:
 IV hydrocortisone in stress dose
Adrenocortical Insufficiency  Electrolyte solution to correct
 Chronic (Addison’s Disease) imbalance
o Can be caused by autoimmune destruction of the adrenal  Once patient is stabilized, treatment is:
cortex or certain infections  Oral hydrocortisone 12-18
o Characterized by: mg/m2/day in 2 unequally divided
 Weakness doses (2/3 in am, 1/3 in pm)
 Fatigue  Dosage should be adjusted to allow
 Weight loss normal growth and bone
 Hypotension maturation
 Hyperpigmentation
 Cushing’s Syndrome
 Inability to maintain the blood glucose level
o Result of bilateral adrenal hyperplasia secondary to ACTH-
during fasting
secreting pituitary adenoma (Cushing’s disease)
o Management: 20-30 mg of hydrocortisone daily, with
o Occasionally is due to tumors or nodular hyperplasia of
increased amounts during period of stress
adrenal gland or ectopic production of ACTH by other
 Acute tumors
o Management: o Signs & Symptoms:
 Large amount of IV hydrocortisone +  Rounded, plethoric face and trunk obesity are
correction of fluid and electrolyte striking in appearance
abnormalities + treatment of precipitating  Muscle wasting; thinning, purple striae, and
factors easy bruising of the skin; poor wound healing;
 Hydrocortisone sodium succinate or and osteoporosis
phosphate in doses of 100 mg IV every 8 hours  Mental disorders, hypertension, and diabetes
until patient is stable – gradually reduce dose, o Treatment:
achieving maintenance dose within 5 days  Surgical removal of tumor-producing ACTH or
 Administration of salt-retaining hormone is cortisol resection of adrenal
resumed when the total hydrocortisone  Irradiation of pituitary tumors
dosage has been reduced to 50 mg/day  Resection of 1 or both adrenals
 Patients should receive doses of up
to 300 mg soluble hydrocortisone
or continuous IV on day of surgery
(to prevent adrenal crisis)
 Dose must be slowly reduced to
normal replacement levels
(to prevent withdrawal symptoms,
e.g, fever, joint pain)

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 PHARMACOLOGY
Topic: Steroids & Gonadal Drugs
Chapter: 39 & 40
Adrenocortical Hypo- and Hyperfunction continued…..
 Primary Generalized Glucocorticoid Resistance
o a.k.a. Chrousos Syndrome
o Rare, sporadic or familial genetic condition due to
inactivating mutations of the glucocorticoid receptor
gene
o The HPA axis hyperfunctions in an attempt to compensate
for the defect
 ↑ ACTH leads to high-circulating levels of
cortisol and cortisol precursors eg,
corticosterone, 11-hydroxycorticosterone
with mineralocorticoid activity as well as
androgens
 Signs and Symptoms:
 Hypertension with or without
hypokalemic alkalosis
 Hyperandrogenism (virilization and
precocious puberty in children;
acne, hirsutism, male pattern
baldness and menstrual
irregularities in women)
 Treatment:
 High doses of synthetic
glucocorticoids
(e.g, dexamethasone)
Glucocorticoids for Diagnostic Purposes
 Suppress the production of ACTH to identify the source of a particular
hormone or establish whether production influenced by the
secretion of ACTH
 Dexamethasone Suppression Test
o Used for diagnosis of Cushing’s Syndrome
o Used also in:
 Differential diagnosis of depressive psychiatric
state
 Differentiating between hypercortisolism due
to anxiety, alcoholism (pseudo-Cushing
syndrome) and bona fide Cushing’s syndrome
o Screening is given orally at 11 pm, plasma sample is
obtained in the following morning:
 Normal individual morning cortisol: <3 mcg/dL
 Cushing’s syndrome: >5 mcg/dL
o Combined test
 Carried out by giving dexamethasone (0.5 mg
orally every 6 hrs. for 2 days) followed by
standard corticotropin-releasing hormone
(CRH) test (1 mg/kd given as bolus IV infusion
2 hours after last dose of dexamethasone)
Corticosteroid & Stimulation of Lung Maturation in Fetus
 Treatment of mother with large doses of glucocorticosteroid reduces
the incidence of respiratory distress syndrome (RDS) in infants
delivered prematurely
 Betamethasone 12 mg IM followed by additional dose of 12 mg 18-
24 hours later
 Betamethasone is chosen because maternal protein binding and
placental metabolism is less than that of cortisol  allows ↑ transfer
across the placenta to the fetus
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Non-Adrenal Disorders
 Synthetic analog of cortisol are useful in the treatment of diverse
group of diseases unrelated to any known disturbance of adrenal
function
Toxicity of Glucocorticoids
 Insomnia
 Behavioral changes (primary hypomania)
 Acute peptic ulcers
 Acute pancreatitis is rare but serious adverse effects of high dose
glucocorticoids
 Iatrogenic Cushing’s Syndrome
o Metabolic effects that occur when administering daily
dose of hydrocortisone or more, for >2 weeks
o Signs & Symptoms:
 Round, puffiness, fat deposition of face (moon
facies)
 Fat redistribution from the extremities to the
trunk, back of neck and supraclavicular fossa
 Punctate acne
 Insomnia & increased appetite
o Other complications:
 Bacterial and mycotic infection
 Severe myopathy is more frequent in patients
treated with long-acting glucocorticoids
 Hypomania or acute psychosis
 Depression
 Development of subcapsular cataracts
 ↑ intraocular pressure; glaucoma
 Benign intracranial hypertension
 Growth retardation in children given doses of
45 mg/m2/d or more hydrocortisone or
equivalent
 Sodium and fluid retention
Complications: edema, heart failure
 Loss of potassium
Hypokalemic, hypochloremic alkalosis
↓
↑ blood pressure
o Adrenal Suppression
 >2 weeks administration leads to adrenal
suppression
 Corticosteroid should be tapered slowly
 PHARMACOLOGY
Topic: Steroids & Gonadal Drugs
Chapter: 39 & 40

Precautions ADRENOCORTICAL ANTAGONISTS

 Carefully monitoring for development of: Synthesis Inhibitors & Glucocorticoid Antagonist
o Hyperglycemia  Block conversion of cholesterol to pregnenolone
o Glycosuria  Causes reduction in the synthesis of all
o Sodium retention hormonally active steroid
o Edema Clinical Use:
o Hypertension  Used in conjunction with dexamethasone or
 Dosage should be kept as low as possible and intermittent hydrocortisone (eliminate estrogen production
in breast CA)
administration (alternate day)
Aminogluthetimide  Used in conjunction with metyrapone or
 Contraindications: ketoconazole to reduce steroid secretion in
o Observe great caution with peptic ulcer disease, heart patients with Cushing’s syndrome due to
disease or hypertension with heart failure, certain adrenocortical cancer who do not respond to
mitotane
infectious diseases (such as Varicella, TB)
o Psychosis, DM, osteoporosis, or glaucoma  Dosage: 1 g/d (well tolerated)
 Toxicity: Lethargy and skin rash are common
effects in higher doses
MINERALOCORTICOIDS
 Antifungal imidazole derivative
Aldosterone, Deoxycorticosterone (DOC), Fludrocortisone
 Potent and rather nonselective inhibitor of
 Most important mineralocorticoid is aldosterone adrenal and gonadal steroid synthesis
 Small amounts of DOC (Deoxycorticosterone) are also formed and Clinical Use:
released  Used for treatment of patient with Cushing’s
Ketoconazole
 Fludrocortisone syndrome due to several causes
o Synthetic corticosteroid  Dosage: 200-1200 mg/d
 Toxicity: Hepatotoxic (should be started with
o Most commonly prescribed salt retaining hormone
200 mg/d slowly increased by 200 mg/d every 2-
3 days to total daily dose of 1000 mg)
Mineralocorticoids  Used for induction of general anesthesia and
 Synthesized mainly in zona glomerulosa of sedation
adrenal cortex  At subhypnotic doses of 0.1 mg/kg/h this drug
 Secreted at rate of 100-200 mcg/d in normal Etomidate inhibits adrenal steroidogenesis at the level of
individual with moderate dietary salt intake 11β-hydroxylase
 Electrolyte-balance regulating, salt-retaining  Used as parenteral medication available in the
activity treatment of severe Cushing’s syndrome
 Promotes reabsorption of Na+ from the DCT and  Relative selective inhibitor of 11-hydroxylation,
PCT; loosely coupled with K+ and H+ ions interfering with cortisol and corticosterone
Aldosterone excretion synthesis
 ↑ Na+ reabsorption in sweat, salivary glands,  Dosage: 0.25 mg 2x daily to 1g 4x daily
gastric mucosa
Clinical Use:
 MOA: binds with mineralocorticosteroid
 It is the only adrenal-inhibiting medication that
receptor
can be administered to pregnant women with
 Half-life: 15-20 minutes
Cushing’s syndrome
 Excretion: 5-15 mcg/24 hr appearing in the urine
 Commonly used for test of adrenal function
as conjugated tetrahydroaldosterone
Metyrapone  Pituitary function may be tested by
 Precursor of aldosterone administering metyrapone, 2–3 g orally at
 Secreted in amounts of 200 mcg/d midnight and by measuring the level of ACTH or
 Half-life: 70 minutes 11-deoxycortisol in blood drawn at 8 am or by
Deoxycorticosterone (DOC)  Concentration in plasma is approximately 0.03 comparing the excretion of 17-
mcg/dL hydroxycorticosteroids in the urine during the
 Secretion is ↑ patients with adrenocortical 24-hour periods preceding and following
carcinoma & congenital adrenal hyperplasia administration of the drug
 Potent steroid with both glucocorticoid and
 Adverse Effect: transient dizziness, GI
mineralocorticoid activity
disturbances, salt and water retention,
 Widely used mineralocorticoid
Fludrocortisone  Oral dose: 0.1 mg (2-7x weekly)  Is a 3β-17 hydroxysteroid dehydrogenase
inhibitor
 Used in the treatment of adrenocortical
insufficiency associated with mineralocorticoid  Interferes with the synthesis of adrenal and
Trilostane
deficiency gonadal hormones and is comparable to
aminoglutethimide
 Adverse Effects: predominantly GI disturbance
ADRENAL ANDROGENS  Newest of the steroid synthesis inhibitors to be
 Adrenal cortex secretes: approved
o Large amounts of DHEA  Blocks 17α-hydroxylase (P450c17) and 17,20-
o Small amounts of androstenedione & testosterone lyase
Abiraterone
 Reduces synthesis of cortisol in the adrenal and
 They do not stimulate or support major androgen-dependent gonadal steroids in gonads
pubertal changes in humans  Clinical Use: Treatment of refractory prostate
 Used in SLE and women with adrenal insufficiency cancer

Continued next page…..

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 PHARMACOLOGY
Topic: Steroids & Gonadal Drugs
Chapter: 39 & 40

Synthesis Inhibitors & Glucocorticoid Antagonist Clinical Pharmacology: Hyperaldosteronism

 11β-aminophenyl-substituted 19-norsteroid  Primary Aldosteronism (Conn Syndrome)
 Pharmacologic antagonist at the steroid o Excessive production of aldosterone by adrenal adenoma
receptor (blocks glucocorticoid receptor)
o Result in abnormal secretion by hyperplastic glands or
 Has strong antiprogestin activity and initially
was proposed as a contraceptive-contragestive from a malignant tumor
agent o Can also be caused by enzyme defects that increase
Mifepristone (RU-486)  Causes generalized glucocorticoid resistance synthesis of steroid precursors with mineralocorticoid
Clinical Use: activity (eg, DOC, corticosterone)
 Given orally to several patients with Cushing’s o Clinical findings:
syndrome due to ectopic ACTH production or  Hypertension
adrenal carcinoma who have failed to respond
 Hypokalemia
to other therapeutic manipulations
 Related to the DDT class of insecticides  Weakness
 Non-selectively cytotoxic action on adrenal  Tetany are related to the continued renal loss
cortex in dogs and to a lesser extent in humans of potassium
Mitotane  Clinical Use: 12 g/daily results in reduction in  Alkalosis
tumor mass in patients with adrenal carcinoma
 Hypernatremia
 Toxicity: diarrhea, nausea, vomiting,
depression, somnolence, and skin rashes
 Secondary Aldosteronism
Mineralocorticoid Antagonist o These patient have high levels of plasma renin activity and
 7α-acetylthiospironolactone angiotensin II
 Onset- Slow
 Effect – lasts for 2-3 days after drug is  Treatment:
discontinued
o Fludrocortisone (0.2 mg 2x daily orally for 3 days), or
Clinical Uses: o Deoxycorticosterone acetate (20 mg/d IM for 3 days)
 Used in treatment of primary aldosteronism
o Aldosterone antagonists (eg, spironolactone)
Dose: 50-100 mg/d
 When used diagnostically for the detection of
aldosteronism in hypokalemic patients with
hypertension
Spironolactone Dose: 400-500 mg/d for 4-8 days
 Useful in preparing patients for surgery
Dose: 300-400 mg/d for 2 weeks to reduce
incidence of cardiac arrhythmias
 Hirsutism and acne in women
Dose: 50-100 mg/d (effects in 2 months)
Toxicity:
 Gyncomastia (in males), menstrual irregularities
(in females), hyperkalemia, cardiac arrhythmia,
sedation, headache, GI disturbances, & skin
rashes
 Aldosterone antagonist
 Approved for treatment of hypertension and
heart failure
 It is more selective than spironolactone and has
Epleronone no reported effects on androgen receptors
 Reduces mortality in heart failure
 Dosage in hypertension: 50-100 mg/d
 Toxicity: Hyperkalemia (mild)
 Progestin
Drospirenone  An oral contraceptive
 Antagonizes the effect of aldosterone

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 PHARMACOLOGY
Topic: Steroids & Gonadal Drugs
Chapter: 39 & 40

Figure Above: Outline of major pathways in adrenocortical hormone biosynthesis

The major secretory products are underlined. Pregnenolone 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

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 PHARMACOLOGY
Topic: Steroids & Gonadal Drugs
Chapter: 39 & 40

#RoadToVNeck Page 9 of 21
 PHARMACOLOGY
Topic: Steroids & Gonadal Drugs
Chapter: 39 & 40

OVARY Menstrual Cycle

 The ovary has important gametogenic functions that are integrated  Vesicular follicles (each containing an ovum) enlarge responding to
with its hormonal activity FSH
 In childhood:  Follicles granulose cells multiply
o The ovary is quiescent during rapid growth & maturation o Estrogen synthesis (LH influence) and release rate ↑
 Puberty: o Estrogen inhibits FSH release (estrogen causes
o Begins a 30- to 40-year period of cyclic function called regression of smaller, less mature follicles)
the menstrual cycle because of the regular episodes of  Corpus luteum cells produce (for the remainder of the cycle or
bleeding longer if pregnancy occurs):
 Menopause o Estrogen
o Failure to respond to gonadotropins and cessation of o Progesterone
cyclic bleeding

Puberty
 Onset of ovarian function at the time of puberty is thought to be
neuronal in origin
Immature gonad can be stimulated by gonadotropins already
present in the pituitary and because the pituitary is responsive to
exogenous hypothalamic GnRH

Disturbance in Ovarian Function

 Secretion of GnRH is regulated by:  Minor causes:
o Kisspeptin o Inflammatory or neoplastic processes the influence
o Neurokinin B function of the ovaries, uterus or pituitary
o Dynorphin neuron (KNDy) system Leads to periods of amenorrhea or anovulatory cycles
Recently, makorin ring finger protein 3 (MKRN3) was
 Often associated with environmental or emotional stress
also implicated in pubertal onset by contributing to
the regulation of the KNDy system  Anovulatory cycles are also associated with:
o Eating disorders (bulimia, anorexia nervosa)
 Gonadarche  This is the change of ovarian function at puberty o Severe exercise (distance running & swimming)
 Result in:  Common causes:
o Removal of hypothalamic median eminence cellular o Pituitary prolactinomas and syndromes
inhibition  permitting pulsed GnRH release  resulting o Tumors characterized by excessive ovarian or adrenal
to stimulation of FSH and LH release androgen production
 FSH and LH release (initially small amounts) inducing estrogen Normal ovarian function can be modified by
androgens produced by the adrenal cortex or tumors
secretion (in small amounts) cause:
arising from it
o Breast development
o Changes in adipose tissue distribution (fat distribution)
 The ovary also gives rise to androgen-producing neoplasms such as
o Growth spurt (ending in epiphyseal closure- long bones)
arrhenoblastomas, as well as to estrogen-producing granulosa cell
 One year later:
tumors
o ↑ estrogen levels induce:
 Endometrial change
 Periodic bleeding (Menarche)
o After the first few irregular cycles, which may be
anovulatory, normal cyclic function is established

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 PHARMACOLOGY
Topic: Steroids & Gonadal Drugs
Chapter: 39 & 40

ESTROGENS Pharmacokinetics continued…..

 Catechol Estrogens: neurotransmitters
Natural Estrogens
 Major estrogen produced by the ovary o Converted to 2- and 4-methoxy derivatives by catechol-O-
Estradiol (E2) methyltransferase
 Estradiol-17β
 Some are produced in the ovary  Estrogen is secreted in small amounts in breast milk
Estrone (E1)  Produced in the liver from estradiol or from peripheral tissues  High biliary excretion and intestinal reabsorption (enterohepatic
from androstenedione and other androgens
circulation) leads to significant hepatic : peripheral effect ratio
 Produced in the liver from estradiol or from peripheral tissues
Estriol (E3)
from androstenedione and other androgens
o Significance: hepatic concentration  undesirable actions
may result:
Nonsteroidal Agents with  ↑ clotting factor synthesis
Synthetic Estrogen  ↑ plasma renin substrate
Estrogenic Activity
 Etinyl estradiol  Dienestrol o To minimize enterohepatic effects
 Quinesterol  Diethylstilbestrol  Estrogen to be used for peripheral actions
 Mestranol  Benzestrol (postmenopausal women): use different route
 Hexestrol that avoids first-pass effect:
 Methestrol  Vaginal route
 Methallenestril  Transdermal route
 Chlorotrianisene  Injection route

 Immediate precursors: Androstenedione, Testosterone Mechanism of Action

 Ovaries  principal source of circulating estrogen  MOA: Primarily by regulating gene expression
 Estrogen dissociates from SHBG and enter cells and bind to a receptor
Significant Sources of Estrogen:  Receptors
 Liver o Superfamily of steroid, thyroid, retinoic acid and vit D
o Estrone, estriol from estradiol o Located in the nucleus
 Peripheral tissues o Hormone + receptor interaction causes a conformational
o From androstenedione & other androgens change with release of associated, stabilizing proteins
 Pregnancy o Bind to specific sequence of nucleotides: influence gene
o Fetoplacental unit (fetal adrenal zone, secreting transcription
androgen precursor, placenta) Diagram from Manual:
 Stallions SHBG-bound estrogens
o They liberate more estrogen than the pregnant mare or ↓
pregnant woman Dissociate & enter cell
 Equine Estrogen ↓
o Recovered from urine Bind to their receptor
o May be used for medical applications ↓
o Equilenin Receptor-hormone complex
o Equilin ↓
Bind to Estrogen Response Elements (EREs)
[EREs are specific sequence of nucleotides]
Pharmacokinetics ↓
 Binds strong to an α2 globulin (sex hormone–binding globulin Regulate gene transcription
[SHBG]) and with lower affinity to albumin
 Only free E2 is physiologically active Physiologic Effects
 E1 and E3 have low receptor affinity 1.) Female Maturation
 Required for the normal sexual maturation and growth of the female
 Stimulate the development of vagina, uterus and uterine tubes
 Breast development  stromal development & ductal growth
 Accelerated growth phase and closure of epiphysis
 Axillary and pubic hair
 Alter distribution of fat to produce typical female body contours
 Regional pigmentation of axilla, areola & genital area

2.) Endometrial Effects

Conversion Steps:
 Estradiol is converted by the liver and other tissues to estrone and
estriol and their 2-hydroxylated derivatives and conjugated
metabolites
 Lipid insolubility leads to biliary excretion but then these conjugates
will undergo hydroxylation in the intestine to be activated and be
reabsorbed
 Reabsorption from the intestine results to the undesirable effects in
the enterohepatic circulation
 Development of endometrial lining
 Continuous exposure to estrogens for prolonged periods leads to
hyperplasia of the endometrium that is usually associated with
abnormal bleeding patterns
3.) Metabolic and Cardiovascular Effects
 ↓ rate of bone resorption
 ↑ leptin production from adipose tissues
 ↑ plasma TAG, HDL; ↓ LDL, total plasma cholesterol
 ↓ hepatic oxidation; ↑ synthesis of TAGs

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 PHARMACOLOGY
Topic: Steroids & Gonadal Drugs
Chapter: 39 & 40

4.) Blood Coagulation o But following estrogen replacement:

 Enhances blood coagulability  ↓ total cholesterol
 ↑ factors II, VII, IX, and X  ↓ LDL cholesterol
 ↑ plasminogen levels  ↑ HDL cholesterol
 ↓ antithrombin III  50% reduction in myocardial infarction
 ↓ platelet adhesiveness frequency
 As much as 40% reduction in fatal stroke
5.) Other Effects: frequency
 Induce synthesis of progesterone receptors  Management of hot flushes and sleep disturbance
 Influence behavior and libido o Symptomatic relief-use lowest estrogen dose possible
 Promotes sense of well-being to estrogen-deficient women  Limited period of treatment to reduce breast
 Facilitate the loss of intravascular fluid into the extracellular space, cancer risk
producing edema  Following hysterectomy
 Retention of sodium and water by the kidney o Symptoms relieved by estrogen replacement
 Modulate sympathetic nervous system control of smooth muscle o Hot flushes, sweating, insomnia, atrophic vaginitis
function o Symptoms which may or may not be relieved by estrogen
replacement
 Psychopathological conditions, including
Clinical Uses
depression
 Primary Hypogonadism
 Atrophic vaginitis
o Estrogen replacement therapy
o Estrogen deficiency due to: o Topical treatment: not subject to first-pass effect
 Primary failure of ovarian development  Cancer
 Castration o Estrogen monotherapy causing ↑ risk of endometrial
 Premature menopause carcinoma
 Menopause o Progesterone (Progestational agent) + Estrogen:
o Treatment of primary hypogonadism prevents endometrial hyperplasia; markedly reduce
 Initiation time: 11-13 years of age cancer risk
 Stimulation of secondary sex characteristics  Combinations: estrogen + progestin
and menses (medroxyprogesterone)
 Stimulation of growth  Reduced risk (protocol: estrogen first 25 days
 Prevent osteoporosis of the month; progestin medroxyprogesterone
 Avoiding psychological effects of the delayed (10 mg/d) added during last 10-14 days of
puberty month)
o Agent used  Cyclic bleeding may occur: eliminated with
 Conjugated estrogen (0.3 mg) treatment combining conjugated equine
 Ethinyl estradiol (5-10 µg) estrogens + medroxyprogesterone; this
combination will also:
o When growth is completed  chronic therapy with both  Control vasomotor symptoms
estrogens and progestins  Prevent genital atrophy
 Maintain bone density
Postmenopausal Hormonal Therapy:  Promote favorable lipid profiles
 Changes associated with menopause: those that may influence  Other uses:
health/well-being of postmenopausal women: o Estrogen + Progestins
 Accelerated bone loss (osteoporosis) predisposing to:  Suppress ovulation in patients with intractable
o Wrist, vertebral, hip fracture dysmenorrhea
o Factor influencing osteoporosis development  Suppression of ovarian function is used in the
 Amount of initial bone present treatment of hirsutism and amenorrhea due
 Calcium intake to excessive secretion of androgens by the
 Physical activity ovary
o Risk highest
 Smokers who are thin; Caucasian; inactive Adverse Effects
women with low calcium intake; strong family  Uterine Bleeding
history; depression Estrogen therapy is a major cause of postmenopausal uterine
o Estrogen replacement bleeding  patients should be treated with the smallest amount
 Conjugated estrogen or ethinyl estradiol of estrogen possible
effective Endometrial Hyperplasia  add progesterone to prevent it
 Cardiovascular effects:
o Lipid changes due to estrogen may contribute to  Cancer
acceleration of atherosclerotic cardiovascular disease ↑ risk of endometrial carcinoma, breast cancer,
o Following oophorectomy or menopause, estrogen falls adenocarcinoma of vagina
causing:
 ↑ plasma cholesterol + LDL  Other Effects
 ↓ LDL receptors Nausea, breast tenderness, hyperpigmentation, migraine
 +/- HDL headaches, cholestasis, gallbladder disease, hypertension

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 PHARMACOLOGY
Topic: Steroids & Gonadal Drugs
Chapter: 39 & 40

Contraindications PROGESTINS
 Estrogen-dependent neoplasm (eg, endometrial carcinoma) Progesterone
 Those at higher risk for or with breast carcinoma  Natural progestins
 Undiagnosed genital bleeding  Most important human progestin
 Liver disease o Precursor to estrogen, androgens, and adrenocortical
 History of thromboembolic disorder steroids
 Heavy smokers  Synthesized in the ovary (corpus luteum), testis, and adrenal cortex
(from circulating cholesterol) and placenta (during pregnancy)

Synthetic Progestins: Physiologic Effects

 Most closely related, pharmacologically and chemically to  Stimulates lipoprotein lipase
progesterone  Promotes fat deposition
 21-carbon agents  Significant effect in carbohydrate metabolism
o Hydroxyprogesterone o ↑ basal insulin level
o Medroxyprogesterone o ↑ insulin response to glucose
o Megestrol o ↑ glycogen storage
o Dimethisterone o ↑ ketogenesis
 Newer “third-generation” synthetic progesterones o ↓ Na reabsorption (compete with aldosterone)
o Components of oral contraceptives with lower  ↑ body temperature
androgenic activity  ↑ ventilator response to CO2
o “19-nor, 13-ethyl” steroids  Depressant & hypnotic effects
 Desogestrel  Sexual characteristics:
 Gestodene o Breast: alveolobular development of the secretory
 Norgestimate apparatus
o Endometrium: maturation & secretory changes
Pharmacokinetics o Important in the maintenance of pregnancy
 Rapidly absorbed  ↓ plasma amino acid levels  ↑ urinary nitrogen excretion
 T ½: approximately 5 minutes
 Small amounts are stored temporarily in body fat Synthetic Progestins:
 Extensive first-pass metabolism  Induces Na retention (competes with aldosterone)
o Ineffective when administered orally  “19-nortestosterone” third-generation agents:
 Hepatic metabolism o Produce a decidual change in the endometrial stroma
o Metabolized to pregnanediol o Do not support pregnancy in test animals
o Urinary excretion product: pregnanediol glucuronide o Effective gonadotropin inhibitors
(used in assessing progesterone secretion) o May have minimal estrogenic and androgenic or anabolic
o Other metabolites formed in small quantities activity

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 PHARMACOLOGY
Topic: Steroids & Gonadal Drugs
Chapter: 39 & 40

Synthetic Progestins Physiologic Effect continued….. HORMONAL CONTRACEPTION

o They are sometimes referred as “impeded androgens”  Two types of preparations are used for oral contraception:
o Progestins WITHOUT androgenic activity: 1. Combinations of estrogens and progestins
 Desogestrel 2. Continuous progestin therapy without concomitant
 Norgestimate administration of estrogens
 Gestodene  The combination agents are further divided into:
o Monophasic forms (constant dosage of both components
Clinical Uses during the cycle)
Major Uses: o Biphasic or triphasic forms (dosage of one or both
 Hormone replacement therapy components is changed once or twice during the cycle)
 Hormonal contraception Special Contraceptive Preparations:
Other Uses:  Implantable:
 Introduction of long-ovarian suppression and may be used to treat: o Etonogestrel  available in the subcutaneous implant
o Dysmenorrhea, endometriosis, & hirsutism  Vaginal rings
o Bleeding disorders (Where estrogen is contraindicated)  Intrauterine devices
o Treatment of premenstrual syndrome (PMS) and women  IM injection of large doses of medroxyprogesterone also provides
with difficulty of conceiving contraception of long duration
Diagnostic Uses:
 Used as a test of estrogen secretion Mechanism of Action
o Progesterone (150 mg/d) or Medroxyprogesterone (10  Estrogen + Progestin contraception:
mg/d) for 5–7 days  withdrawal bleeding in o Selective inhibition of pituitary function that results in
amenorrheic patients (when stimulated by estrogen) inhibition of ovulation
o Estrogen + Progestin  test the responsiveness of the o Change in the cervical mucus, in the uterine
endometrium in patients with amenorrhea endometrium
o Change in motility and secretion in the uterine tubes
Contraindications, Cautions & Adverse Effects All of these decrease the likelihood of conception and
 Progestational compounds alone and with combination oral implantation
contraceptives indicate that the progestin in these agents may
 NOTE: The continuous use of progestins alone does NOT always
increase blood pressure in some patients
inhibit ovulation
 The more androgenic progestins also reduce plasma HDL levels in
 They are very effective in general
women
 Failure is observed in some patients with:
 When used with estrogen, may increase the risk of breast cancer
o One or more missed doses
o Concomitant use of phenytoin - ↑ catabolism of
OTHER OVARIAN HORMONES
contraceptive compounds
 Small amount produced o Antibiotics which alter enterohepatic cycling of
 Physiological significance  may be partly responsible for metabolites
normal hair growth at puberty, for stimulation of female
Testosterone libido, and, possibly, for metabolic effects
 Ovarian androgen production markedly increased in some Pharmacologic Effects
abnormal states, usually in association with hirsutism and  Inhibits ovulation
amenorrhea
 Chronic use of Estrogen/Progesterone combinations:
 Peptides with multi-dimeric forms o Ovarian function depression
 α and β subunits Ovary
o Minimal follicular development
o Inhibin (αβ subunit combination) inhibits FSH secretion o Absence of: Corpus lutea, Larger follicles, Stromal
Inhibin & Activin
o Activin (ββ subunit combination) increases FSH edema
secretion  Cervix – hypertrophy and polyp formation
 Physiologic roles are not fully understood  Endometrium – decidual stroma and glandular atrophy
 Peptide related to growth-promoting peptides (stromal-glandular dissociation)
 Similar to insulin  Following prolonged use:
 Localization: Ovary, Blood, Uterus, Placenta o Possible cervical hypertrophy
 Relaxin – synthesized in corpus luteal granulosa cells o Polyp formation
 Several other nonsteroidal substances such as corticotropin o Changes in cervical mucus
releasing hormone, follistatin, and prostaglandins are Uterus
 Resemble postovulation mucus
produced by the ovary. These probably have paracrine  Thick and less copious
effects within the ovary  Estrogen/Progesterone combinations
 Physiologic Effects: o Result to stromal deciduation at cycle end
o ↓ uterine contractility  Combination agents contain 19-nor progestins
Relaxin
o ↑ glycogen synthesis & water uptake by myometrium o Increased glandular atrophy
o Changes in the mechanical characteristics of pubic o Less bleeding
ligaments and cervix promoting delivery  Decrease motility
o In women, relaxin has been measured by immunoassay Fallopian Tubes
 Altered secretion
o Levels were highest immediately after the LH surge and
 Intermediate cells predominate
during menstruation Vagina
 Increase vulvovaginitis
o Have been conducted in patients in premature labor and
 Suppress lactation
during prolonged labor
o When applied to the cervix of a woman at term, it  Stimulation of breast and some enlargement
facilitates dilation and shortens labor Breast  Happens when administered estrogen or estrogen/
progesterone combination
 Only small amounts of compounds cross the milk

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 PHARMACOLOGY
Topic: Steroids & Gonadal Drugs
Chapter: 39 & 40

 Mood, affect, and behavior changes are low  Withdrawal bleeding – sometimes may fail to occur
 Estrogen: decrease threshold of excitability o Sometimes may fail to occur
CNS  Progesterone: increase threshold of excitability o Most often seen with combination preparations
 Progesterone and Synthetic progestins: Thermogenic effect o May cause confusion with pregnancy
(possibly mediated in the CNS) o Remedy: change in formulation
Effects of Estrogen:  Breakthrough bleeding
 ↓ FSH & LH o Most common problem in using progestational agents
 Change in adrenal structure and function alone for contraception
 ↑ corticosteroid-binding globulin concentration in plasma  Weight gain
 Changes in RAAS o More common with combinational agents containing
Endocrine o ↑ plasma renin activity androgen-like progestins
o ↑ aldosterone secretion  Increased skin pigmentation
 ↑ thyroxine binding globulin (TBG) o Though to be exacerbated by vitamin B deficiency
 ↑ plasma thyroxine (T4) levels  Acne
 ↑ sex hormone-binding globulin (SHBG) o Improved by contraceptives containing large estrogen
 ↓ free androgen plasma levels content
 ↑ risk of thromboembolic phenomena Moderate  Hirsutism
o Aggravated by the “19-nortestosterone” derivatives
 Inconsisten alteration in blood coagulation times
o ↑ factors VII, VIII, IX, and X (7,8,9,10)  Ureteral dilatation
o ↓ antithrombin III o Associated with bacteriuria
Blood o ↑ Coumarin anticoagulants amounts required to ↑  Vaginal infection
prothrombin time in patient on oral contraceptives o More common
 ↑ serum iron and total iron-binding capacity o More difficult to manage n patient taking oral
contraceptives
 Some develop folic acid deficiency anemia
 Amenorrhea
 ↓ serum haptoglobulins
o Prolactin levels should be measured
 Changes in hepatic drug excretion/metabolism
o Many have prolactinomas
 Delayed clearance of sulfobromophthalein
o May require discontinuance of oral contraceptives
Hepatic  Reduced bile flow
 Vascular disorders:
 Proportion of cholic acid in bile acids is ↑
o Venous Thromboembolic Disease
 Proportion of chenodeoxycholic acid is ↓
o Myocardial Infarction
 ↑ risk for cholelithiasis o Cerebrovascular Disease
 Estrogen  GI: cholestatic jaundice with progestin-containing oral
o ↑ serum TAGs, free and esterified cholesterol Severe contraceptives
Lipid o ↑ phospholipids  Depression
Metabolism o ↑ HDL
 Cancer
o ↓ LDL
o Risk reduction: endometrial and ovarian cancer
 Progestin antagonizes theses estrogen effects o ↑ risk in breast cancer of young women
 Decrease glucose tolerance  Alopecia
 Effects are similar to those observed in pregnancy Other Adverse  Erythema miltiforme
 ↓ GI tract carbohydrate absorption  Erythema nodosum
Carbohydrate Effects
 Progesterone: increases basal insulin; increases insulin rise  Other skin disorders
Metabolism induced by carbohydrates
 Reduced carbohydrate tolerance associate with long-term
potent progestin use (e.g, norgestrel) – effect reversible Contraindications & Caution
Cardiovascular  ↑ systolic BP, diastolic BP, HR, CO  Thrombophlebitis, thromboembolic phenomena, & cardiovascular
 ↑ pigmentation (chloasma) & cerebrovascular disorders
o Enhanced by exposure to UV light  They should not be used to treat vaginal bleeding with unknown
o Enhanced in women with darker complexion
cause
Skin  Acne – androgen-like progestins caused increased sebum
o However, since ovarian androgen is suppressed, many  They should be avoided in patients with known or suspected tumors
patients note ↓ sebum production, acne, and terminal of the breast or other estrogen-dependent neoplasms
hair growth  They should be avoided or used with caution in patients with liver
disease, asthma, eczema, migraine, diabetes, hypertension, optic
Clinical Uses neuritis, retrobulbar neuritis, or convulsive disorders
 Most important use of combined estrogens and progestins is for oral  Caution in patients with heart failure
contraception Because oral contraceptives may produce edema
 They are also useful in the treatment of endometriosis,
dysmenorrhea, acne, hirsutism  Estrogens increase rate of growth of fibroids
Therefore, for women with these tumors, agents with the
Adverse Effects smallest amounts of estrogen and the most androgenic
 Usually reversible progestins should be selected
 Nausea, mastalgia (breast pain), edema, breakthrough
bleeding  Contraindicated in adolescents in whom epiphyseal closure has not
o Remedy: smaller amounts of estrogen or agents yet been completed
containing progestins with more androgenic effects
 Changes in serum protein  Antimicrobial drugs that interfere with normal GI flora and may
Consider when evaluating thyroid function, pituitary reduce the efficacy of oral contraceptives
Mild function, adrenal function test results Normal gastrointestinal flora increase the enterohepatic cycling
(and bioavailability) of estrogens
 Increase sedimentation rates (ESR) secondary to increased
fibrinogen levels
 Headache: mild, transient
 Rifampin, Phenytoin  increase liver catabolism of estrogens or
 Migraine – often worsened by treatment progestins and diminish their efficacy

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 PHARMACOLOGY
Topic: Steroids & Gonadal Drugs
Chapter: 39 & 40

ESTROGEN AND PROGESTERONE INHIBITORS AND ANTAGONISTS

Drug Properties
 Competitive partial agonist – inhibitor of estradiol at
estrogen receptors
 First SERM (Selective estrogen receptor modulator) to be
introduced
 MOA: Recruitment of different coregulators to the estrogen
receptor when it binds tamoxifen rather than estrogen,
differential activation of heterodimers (ERα-ERβ) versus
homodimers, competition of ERα by ERβ and others
Clinical Use:
 Palliative treatment of breast cancer in postmenopausal
women
 Approved for chemoprevention of breast cancer in high-risk
women
Drug Properties
 Potent experimental progesterone inhibitor
Lilopristone  Abortifacient in doses of 25 mg twice daily
(ZK 98734)  Like mifepristone, it also appears to have antiglucocorticoid
activity
 Isoxazole derivative of ethisterone (17α-ethinyltestosterone)
 Weak progestational, androgenic, and glucocorticoid
activities, is used to suppress ovarian function
MOA:
 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

Good Effects: Pharmacodynamics:

Tamoxifen
 Prevention of the expected loss of lumbar spine bone density  It binds to androgen, progesterone, and glucocorticoid
and plasma lipid changes consistent with a reduction in the receptors  translocate the androgen receptor into the
risk for atherosclerosis nucleus  initiate androgen-specific RNA synthesis
 It does not bind to intracellular estrogen receptors
Pharmacokinetics:  It does bind to sex hormone–binding and corticosteroid-
 Nonsteroidal; orally active binding globulins
 Peak plasma levels within hours  It inhibits the following:
 T ½: 7-14 hrs. o P450scc (the cholesterol side chain–cleaving enzyme)
 Excreted by the liver o 3β-hydroxysteroid dehydrogenase
Adverse Effects: o 17α-hydroxysteroid dehydrogenase
 Hot flushes o P450c17 (17α-hydroxylase)
 Nausea and vomiting o P450c11 (11β-hydroxylase)
 Stimulates the endometrium; increasing endometrial CA risk o P450c21 (21β-hydroxylase)
– due to its agonist property  It does not inhibit aromatase
 Similar to Tamoxifen  It ↑ mean clearance of progesterone
Toremifene
 Ethiserone  major metabolite – with progestational and
 Partial estrogen agonist-antagonist at some but not all Danazol
mild androgenic effects
tissues
 It has estrogenic effects on lipids and bone but appears NOT Pharmacokinetics:
to stimulate the endometrium or breast  Slowly metabolized
 T ½: >15 hours
Pharmacokinetics:
Raloxifene  Highly concentrated in the liver, adrenals, kidneys
 Very large volume of distribution
 Excreted in both feces and urine
 Long half-life (>24 hours), so it can be taken once a day
Clinical Use:
Clinical Use:
 Inhibitor of gonadal function
 Used for the prevention of postmenopausal osteoporosis
 Major use in the treatment of endometriosis
 Prophylaxis of breast cancer in women with risk factors
 Treatment of fibrocystic disease of the breast and
 Newer SERM developed
hematologic or allergic disorders, including hemophilia,
 In combination with conjugated estrogens, is approved for
Bazedoxifene Christmas disease, idiopathic thrombocytopenic purpura,
treatment of menopausal symptoms and prophylaxis of
and angioneurotic edema
postmenopausal osteoporosis
 Older partial agonist Adverse Effects:
Clomiphene  A weak estrogen  Weight gain, edema, ↓ breast size, acne and oily skin, ↑ hair
(discussed further next growth, deepening of the voice, headache, hot flushes,
 Also acts as a competitive inhibitor of endogenous estrogens
page) changes in libido, and muscle cramps
 Used as an ovulation-inducing agent
 “19-norsteroid” that binds strongly to the progesterone and  Mild to moderate hepatocellular damage
glucocorticoid receptors and inhibits the activity of  Adrenal suppression
progesterone and that of glucocorticoids
 Has luteolytic properties in 80% of women when given in the Contraindication & Caution:
midluteal period  Should be used with great caution in patients with hepatic
dysfunction
Pharmacokinetics:  Pregnancy and breast-feeding  urogenital abnormalities in
 Long half-life: (20-40 hrs.) may prolong progesterone offspring
receptor and makes it difficult to be used continuously as a ANASTRAZOLE & LETROZOLE
contraceptive  Selective nonsteroidal inhibitor of aromatase (the enzyme
Clinical Use: required for estrogen synthesis)
Mifepristone  Effective emergency postcoital contraceptive  Effective in some women whose breast tumors have become
(RU-486)  Has antiglucocorticoid activity resistant to tamoxifen
 May be useful in the treatment of endometriosis, Cushing’s EXEMESTANE
syndrome, breast cancer, and possibly other neoplasms such  Steroid molecule, is an irreversible inhibitor of aromatase
as meningiomas that contain glucocorticoid or progesterone Aromatase  Like anastrozole and letrozole, it is approved for use in
receptors Inhibitors women with advanced breast cancer
 Major use: terminate early pregnancies FADRAZOLE
 Oral nonsteroidal (triazole) inhibitor of aromatase activity
Adverse Effects:
 As effective as tamoxifen
 Prolonged bleeding
 In addition to their use in breast cancer, aromatase inhibitors
 If with vaginal pessary (prostaglandin E1 or misoprostol):
have been successfully employed as adjuncts to androgen
o Vomiting
antagonists in the treatment of precocious puberty and as
o Diarrhea
primary treatment in the excessive aromatase syndrome
o Abdominal or pelvic pain

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 PHARMACOLOGY
Topic: Steroids & Gonadal Drugs
Chapter: 39 & 40

Drug Properties TESTIS

 Pure estrogen receptor antagonist  Function:
 It is somewhat more effective than those with partial agonist o Gametogenic – onset controlled largely by FSH secretion
effects in some patients who have become resistant to
tamoxifen
o Endocrine – high concentration of testosterone are locally
required for continuing sperm production in the
Clinical Use:
 Approved for use in breast cancer patients who have
seminiferous tubules
Fulvestrant
become resistant to tamoxifen  Secretes small amounts of:
o Dihydrotestosterone (potent androgen)
ICI 164,384 o Weak androgens:
 Is a newer antagonist
 Androstenedione
 it inhibits dimerization of the occupied estrogen receptor
and interferes with its binding to DNA  Dehydroepiandrosterone
GnRH and its  GnRH analogs  NAFARELIN, BUSERELIN o Pregnenolone
analogs  They important in both stimulating and inhibiting ovarian o Progesterone and 17-hydroxylated derivatives
function
Sertoli Cells
Clomiphene Citrate  Located in the seminiferous tubules
 Partial estrogen agonist
 May be the source of estradiol produced in the testes via
 Closely related to the estrogen chlorotrianisene aromatization of locally produced testosterone
 Synthesize and secrete a variety of active proteins including:
Pharmacokinetics:
o Mullerian duct inhibitory factor
 Well absorbed when taken orally o Inhibin and Activin
 T ½: 5-7 days  Inhibins A and B
 Excreted in the urine  α subunit + one of the β subunit
 Exhibits significant protein binding and enterohepatic circulation and  In conjunction with testosterone
is distributed to adipose tissues and dihydrotestosterone  are
responsible for feedback inhibiton
Mechanism of Action: of pituitary FSH secretion
 Partial agonist at estrogen receptors  Activin
 It leads to an increase in the secretion of gonadotropins and  Composed of two β subunits (βAβB)
estrogens by inhibiting estradiol’s negative feedback effect on the  Stimulates pituitary FSH release
release of gonadotropins
Interstitial Cells of Leydig
Effects:  Found in the spaces between seminiferous tubules
 It has the ability to stimulate ovulation in women with  LH stimulation  testosterone production
oligomenorrhea or amenorrhea and ovulatory dysfunction
 Used in patients with polycystic ovary syndrome (characterized by ANDROGENS
gonadotropin-dependent ovarian hyperandrogenism associated with Testosterone
anovulation and infertility)  Most important androgen
 Clomiphene probably blocks the feedback inhibitory influence of  Synthesized from progesterone and dehydroepiandrosterone (DHEA)
estrogens on the hypothalamus, causing a surge of gonadotropins,  8 mg is produced daily
which leads to ovulation  Leydig cells production – 95%
 Adrenal cells production – 5%
Clinical Uses:
 Treatment of disorders of ovulation in patients who wish to become Pharmacokinetics
pregnant  65% are bound to sex hormone-binding globulin (SHBG)
 Dose of 100 mg/d for 5 days: rise in plasma LH and FSH o Factors that ↑ SHBG:
 Thyroid hormone, Estrogen, Liver Cirrhosis
Adverse Effects: o Factors that ↓ SHBG:
 Hot flushes (most common; mild and disappear when drug is  Androgen, Growth Hormone, Obesity
discontinued)  33% are bound to albumin
 Eye symptoms (rare)  2% are Free and they enter the cells and bind to intracellular
 Headache, constipation, allergic skin reactions, and reversible hair receptors
loss Mechanism of Action
 Ovarian enlargement  At intracellular target sites:
 A/E usually associated with hormonal changes in cycle (instead of o Converted to 5α-dihydrotestosterone (primary
caused by the drug): androgen) by 5α-reductase in certain tissues:
o Nausea & vomiting, ↑ nervous tension, depression, Skin, Seminal Vesicles, Epididymis, Prostate
fatigue, breast soreness, weight gain, urinary frequency,
 Testosterone/Dihydrotestosterone:
heavy menses
o Binds to cytosolic androgen receptor
Contraindications: o Subsequent process is similar to that for
 Enlarged ovaries estradiol/progesterone  growth differentiation, and
 Patients with visual symptoms  drug makes driving more hazardous synthesis of various enzymes and other functional
proteins

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 PHARMACOLOGY
Topic: Steroids & Gonadal Drugs
Chapter: 39 & 40

Physiologic Effects Clinical Uses

 Changes during puberty in male (Adrenarche)  Androgen Replacement Therapy in Men
o Penile & scrotal growth Replacement or augmentation of endogenous androgen
 Testosterone & 5α-dihydrotestosterone secretion in men with hypogonadism
o Skin changes  pubic, axillary & beard hair; more active o Preferred in pituitary deficiency except when normal
sebaceous glands (thicker & oilier skin) spermatogenesis is to be achieved
 Androstenedione, DHEA o In patients with hypopituitarism:
o Larynx  vocal cords thicker  low pitch voice  Not added to treatment regimen until puberty
 Skeletal growth is stimulated and epiphyseal closure accelerated  Instituted in gradually increasing doses to
 Increase lean body mass achieve:
 Male development (Secondary sexual characteristics)  Growth spurt
o Stimulate development & maturation of sperm  Development of secondary
o Stimulate development of the epididymis, vas deferens, hormones
seminal vesicles, scrotum, penis, prostate o Therapy started with long-acting agents (e.g,
 Anabolic effects on muscle & bone mass testosterone enanthate or cypionate)
o Increase protein synthesis, decrease protein breakdown  Dose: 50 mg IM initially every 4 week  every
o Measured by ↓ urine nitrogen secretion 3 weeks  finally every 2 weeks
 Masculinization in females Each change taking place at 3-month
 Metabolic effects: interval
o ↓ hormone binding and other carrier proteins
o ↓ HDL  Doubled to 100 mg every 2 weeks until
o ↑ liver synthesis of clotting factors completion of maturation
o ↑ triglyceride lipase  Finally changed to adult replacement dose of
o ↑ α1-antitrypsin 200 mg at 2-week intervals
o Stimulate renal erythropoietin secretion o Testosterone propionate
 Potent and short-acting
Synthetic Steroids with Androgenic & Anabolic Action  Not practical for long-term use
o Testosterone undecanoate
 Administered PO in large amounts (e.g, 40
mg/d) BID
Not recommended because oral
testosterone is associated with liver
tumors

o Transdermal testosterone
 Skin patches or gels available for scrotal or
other skin area application
 Two applications daily usually required for
replacement therapy
 Implanted pellets and other longer-acting
preparation understudy
o Development of polycythemia or hypertension
 May require some reduction in dose

 Gynecologic Disorders
o Occasional use in the treatment of certain gynecologic
 Used for their anabolic effects
disorder
 Treatment of testosterone deficiency
 Used with great caution because of pronounce
undesirable effects in women
 Rapidly absorbed when administered by mouth
 Largely converted to inactive metabolites (only 1/6 of o In conjunction with estrogens:
administered dose available is in active form)  Reduce breast engorgement during
 Can be administered parenterally but has more postpartum
Testosterone
prolonged absorption time due to greater activity in  Postmenopausal period to eliminate
propionate, enanthate, undecanoate, and cypionate
endometrial bleeding
ester forms: hydrolyzing the release of free testosterone
at injection site  Enhance libido
Methyltestosterone  Testosteron derivative alkylated at 17 position  Breast tumors in premenopausal women
Fluoxymesterone  Active when given orally o Danazol  weak androgen used in the treatment of
endometriosis

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 PHARMACOLOGY
Topic: Steroids & Gonadal Drugs
Chapter: 39 & 40

Clinical Uses continued….. Adverse Effects

 Use as Protein Anabolic Agents  Masculinizing effects
o In conjunction with dietary measures and exercises:  In women
 Reverses protein loss after trauma, surgery, o Administration of >200-300 mg testosterone per month
or prolonged immobilization and in patients is usually associated with:
with debilitating diseases  Hirsutism
 Acne
 Anemia  Amenorrhea
o Large doses of androgens employed in treatment of  Clitoral enlargement
refractory anemias such as:  Deepening of voice
 Aplastic anemia  Progestational activity of some androgenic steroids  endometrial
 Fanconi’s anemia bleeding upon discontinuation
 Sickle cell anemia  Alter serum lipids
 Myelofibrosis  Conceivably increase susceptibility to atherosclerotic disease in
 Hemolytic anemia women
Recombinant erythropoietin replaced  Not used in infants
androgens for this purpose o Administration in early life may have profound effects on
maturation of CNS centers governing sexual development
 Osteoporosis  Administration in pregnant women may lead to either:
o Androgens and anabolic agents + estrogens o Masculinization of female external genitalia
 Have been used in the treatment of o Undermasculinization of male fetus external genitalia
osteoporosis  Sodium retention and edema
 Largely replaced by biphosphonates o Not common
o Carefully watched for in patients with heart and kidney
 Growth Stimulation disease
o Stimulate growth in boys with delayed puberty  Hepatic dysfunction
 If used carefully: o Reversible upon cessation of therapy
Expected adult height will probably  In older males:
achieved o Prostatic hyperplasia  urinary retention
 Effects of replacement therapy in men
 If treatment is too vigorous: o Acne
Patient may grow rapidly at first but will o Sleep apnea
not achieve full predicted full stature o Erythrocytosis
because of accelerated epiphyseal closure o Gynecomastia
↓ o Azoospermia
 Difficult to control such type of therapy o Decrease in testicular size
adequately even with frequent X-ray  Effects of high-dose 17-alkylated androgens
examination of epiphysis o Peliosis hepatica
 Action of hormones in epiphyseal centers may o Cholestasis
continue for many month after o Hepatic failure
discontinuation  ↓ plasma HDL
 ↑ plasma LDL
 Abuse in Sports  Hepatic adenomas and carcinomas
o Use of anabolic steroid has received worldwide attention  Behavioral effects:
 In doses: 10-200 times larger than daily normal o Psychological dependence
physiologic production: o Increased aggressiveness
 Increase strength and o Psychotic symptoms
aggressiveness  improves
competitive performance Contraindications & Cautions
 Unequivocally demonstrated only
 Pregnant women or women who may become pregnant
in women
 Male patients with prostate or breast carcinoma
o Adverse effects of these drugs clearly make their use
 Infants and young children  CNS effects
inadvisable
 Renal & cardiac disease  predisposed to edema
 Methyltestosterone associated with creatinuria
 Aging
 Patients with aplastic anemia treated with androgen anabolic
o Androgen production
therapy  hepatocellular cancer
 Falls with age in men
 Many contribute to decline in muscle mass,
strength and libido
o Androgen replacement in aging males with low androgen
levels:
 ↑ in lean body mass and hematocrit
 ↓ bone turnover

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 PHARMACOLOGY
Topic: Steroids & Gonadal Drugs
Chapter: 39 & 40

ANDROGEN SUPPRESSION Ketoconazole continued…..

 Used for the treatment of advanced prostatic carcinoma
 Achieved by:
o Sustained nonpulsatile doses of GnRH analogs (preferred)
E.g, goserelin, nafarelin, buserelin, leuprolide
o Orchietomy
Adverse Effect: Psychological disturbance
o Large doses of estrogen to reduce available endogenous
androgen
Adverse Effect: Gynecomastia
ANTIANDROGENS
Figure on Left: Control of
androgen secretion and
activity and some sites of
action of antiandrogens:
1.) Competitive inhibitors of
GnRH receptors
2.) Stimulation (+, pulsatile
administration) or inhibition
via desensitization of GnRH
receptors (-, continuous
administration)
3.) Decreased synthesis of
testosterone in the testis;
4.) Decreased synthesis of
dihydrotestosterone by
inhibition 5α-reductase
5.) Competition for binding
for binding to cytosol
androgen receptors
 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
 Experimentally used to treat prostatic carcinoma
 Adverse effect: reversible gynecomastia
Inhibition of Conversion of Steroid Precursors to Androgens
Abiraterone
 MOA: Inhibit the 17-hydroxylation of progesterone or
pregnenolone  ↓ active androgens
 It is a newer 17α-hydroxylase inhibitor
 Approved for use in metastatic prostate cancer
Finasteride
 5α-reductase inhibitor
 An orally active enzyme inhibitors that decreases
dihydrotestosterone levels
 Effects starts within 8 hours and lasts after 24 hours
o Half-life: 8 hours
o Dose: 5 mg/day
 Uses:
o May be moderately effective in reducing prostate size in
men with BPH
o Hirsutism in women
o Early male pattern baldness in men
Dutasteride
 A similar orally active steroid derivative with a slow onset of action
and a much longer half-life than finasteride
 Dose: 0.5 mg/day
 Used for the treatment of BPH
Receptors Inhibitors
Flutamide
 A substituted anilide
 MOA: Behaves like a competitive antagonist at the androgen
receptor
 Rapidly metabolized
Clinical Use:
 A potent antiandrogen that has been used in the treatment of
prostatic carcinoma
 Also useful in the management of excess androgen effect in women

Adverse Effects:
 Often causes mild gynecomastia
Antiandrogens:
 Mild reversible hepatic toxicity
 Drugs that are available that acts on different sites of the androgen
pathway
 Used for treatment of patients producing excessive amounts of Bicalutamide, Nilutamide, & Enzalutamide
testosterone  Potent orally active antiandrogens
 Administered as a single daily dose
Steroid Synthesis Inhibitors
Ketoconazole Clinical Use:
 Used in patients with metastatic carcinoma of the prostate
 Used primarily for fungal diseases
o Bicalutamide is recommended (to reduce tumor flare) +
 MOA: Inhibitor of adrenal and gonadal steroid synthesis WITHOUT
GnRH analog  may have fewer GI side effects than
affecting ovarian aromatase BUT reduces human placental
flutamide
aromatase activity
o Nilutamide or Enzalutamide for use following surgical
 ↑ estradiol:testosterone ratio
castration
By displacing estradiol and dihydrotestosterone from sex
hormone-binding protein

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 PHARMACOLOGY
Topic: Steroids & Gonadal Drugs
Chapter: 39 & 40

Receptor Inhibitors continued…..

Cyproterone & Cyproterone Acetate
 Effective antiandrogens 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

Clinical Use:
 Hirsutism in women
o Dose: 2 mg/day
o Co-administered with estrogen
o Doubles as contraceptive
 Reduction of sexual drive in men
 It has orphan drug status in the U.S.

Spironolactone
 Competitive inhibitor of aldosterone
 It also competes with dihydrotestosterone for the androgen
receptors in target tissues
 It also reduces 17α-hydroxylase activity, lowering plasma levels of
testosterone and androstenedione

Clinical Use:
 Treatment of hirsutism in women
Appears to be as effective as finasteride, flutamide, or
cyproterone in this condition

Chemical Contraception in Men

 An effective oral contraceptive for men has not been found
 Options:
o Testosterone/testosterone enanthate 400 mg/month
produces azoospermia
 Toxicity: Gynecomastia, Acne
o Testosterone + Danazol was well tolerated but no more
effective than testosterone alone
o IM testosterone enanthate + levonorgestrel (oral) also
produces azoospermia (94% of men)
o Cyproterone acetate, a very potent progestin and
antiandrogen, also produces oligospermia  but DOES
NOT cause reliable contraception
o Testosterone + GnRH  reversible azoospermia in
nonhuman primates

Gossypol
 Cottonseed derivative (Chinese study)
 This compound destroys elements of the seminiferous epithelium
but does NOT significantly alter the endocrine function of the testis
 99% of men developed sperm counts below 4 million/mL
Recovery (return of normal sperm count) following
discontinuance of gossypol administration is more apt to occur in
men whose counts do not fall to extremely low levels and when
administration is not continued for >2 years

 Major adverse effect: Hypokalemia  leads to transient paralysis

References:
 Basic & Clinical Pharmacology by Katzung
(14th ed.)
 Pharmacology Lecture Guide (2020)

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