Disorders of the Endocrine System and Metabolism 591
• Diffuse goiter:
Simple Goiter: no cause is found for the generalised
enlargement of the thyroid, which is usually smooth
and soft.
Firm di use goiter of variable size is usually associated
with Hashimoto’s thyroiditis and thyrotoxicosis.
Painful, tender goiter with diffuse swelling of the thy-
roid gland, sometimes with severe pain, is suggestive of
an acute viral thyroiditis (de Quer vain’s thyroiditis). It
can produce transient clinical features of hyperthyroid-
ism and serological changes, with an increase in the
serum T4.
• Nodular goiter:
Multinodular goiter is the commonest goiter found, espe-
cially in older patients. The patient is usually euthyroid, but
may be hyperthyroid or borderline with suppressed TSH
levels but normal free T4 and T3. Multinodular goiter is the
commonest cause of tracheal and/or esophageal compression
and can cause laryngeal nerve palsy.
Solitary nodular goiter is a difficult clinical problem. Mal-
ignancy should be excluded with the presence of any soli-
tary nodule. However, most nodules are cystic or benign and
indeed, may simply be the largest nodule of a multinodular
goiter. Solitary toxic nodules are quite uncommon and may
be associated with T3 toxicosis.
Fibrotic goiter (Riedel ’s thyroiditis) is rare and associated
with a feeling of a ’woody’ gland. It can be difficult to distin-
guish from carcinoma, being irregular and hard. Of interest is
that it has been shown to be an IgG4-related disease.
Malignancy presenting as masses is most likely to be a
thyroid carcinoma, but the thyroid gland can occasionally be
a site for either primary lymphoma or metastases.
Investigations
Blood Tests: thyroid function tests: TSH plus free T4 or T3
and thyroid antibodies to exclude autoimmune causes.
Imaging: Ultrasound can delineate nodules and demon-
strate whether they are cystic or solid. Chest and thoracic
inlet plain film radiographs or CT scan can detect tracheal
compression in patients with large goiters or clinical symp-
toms indicative of tracheal compression. Thyroid scanning
(99mTc, 125I, or 131I) can be useful to distinguish between
functioning (hot) and nonfunctioning (cold) nodules, but it
has largely been replaced by the use of ultrasound-guided
fine needle aspiration (FNA) biopsy.
Thyroid Masses
Thyroid carcinoma, is not common, but these tumors have
an annual incidence of 30 000 cases in the USA. Over 75
occur in women. In 90 of cases they present as thyroid
nodules (see above), but occasionally with cervical lymph-
adenopathy (about 5 ), or with lung, cerebral, hepatic or
bone metastases.
Carcinomas derived from thyroid epithelium may be
papillary, follicular (differentiated), or anaplastic (undiffer-
entiated). Medullary carcinomas (about 5 of all thyroid
cancers) arise from the calcitonin-producing C cells. The
pathogenesis of thyroid epithelial carcinomas is not under-
stood except for occasional familial papillary carcinoma and
those cases related to previous head and neck irradiation
or exposure to and ingestion of radioactive iodine (e.g.
post-Chernobyl). These tumors are minimally active hor-
monally and so rarely associated with hyperthyroidism, but
as over 90 do secrete thyroglobulin, this can be used as a
tumor marker after thyroid ablation.
The primary treatment is surgical, normally total or near-
total thyroidectomy. Regional or more extensive neck dis-
section is only needed when there is local nodal spread or
involvement of local structures. Most tumors will take up
iodine, so current guidelines recommend postoperative use
of RAI for ablation of any residual thyroid tissue in patients
with well-differentiated thyroid cancer. To further minimize
the risk of recurrence, patients are treated with suppressive
doses of levothyroxine (sufficient to suppress TSH levels
below the normal range). Patient progress is monitored both
clinically and biochemically using serum thyroglobulin levels
as a tumor marker. Prognosis is extremely good in patients
with well-differentiated thyroid cancer confined to the fully
excised thyroid gland. Poor prognosis is associated with
being 40 years or older, larger primary tumor size ( 4 cm),
and macroscopic invasion of the capsule and surrounding
tissues.
Medullary carcinoma (MTC) is a neuroendocrine tumor
of the calcitonin-producing C cells of the thyroid. This con-
dition is often associated with MEN 2. Patients with MEN2
mutations are advised to have a prophylactic thyroidectomy
(as early as 5 years of age) to prevent the development of
MTC. Total thyroidectomy and wide regional lymph node
dissection is indicated for MTC.
Hypothyroidism
In hypothyroidism, the orofacial findings include
myxedema of the skin, an enlarged tongue (macroglossia),
compromised periodontal health, delayed tooth eruption,
delayed wound healing, and a hoarse voice. Salivary gland
enlargement, changes in taste, and burning mouth symp-
toms have also been reported.46,47 Hashimoto’s thyroiditis
has been associated with xerostomia and impaired salivary
output.48,49
Hyperthyroidism
Hyperthyroidism can exacerbate the patient’s response to
dental pain and anxiety. Routine examination of the head
and neck may disclose signs of thyroid disease, including
changes in oculomotor function, protrusion of the eyes,
excess sweating, enlargement of the thyroid or the tongue,
lingual thyroid tissue, and difficulty in swallowing.
592 Burket’s Oral Medicine
Dental Management of the Patient with
Thyroid Gland Disorders
The first concern in treating the patient with thyroid disease
is the level of metabolic control and the second concern is
the concomitant medications. Well-controlled hyper-/hypo-
thyroidism does not present any major risks to the patient
undergoing dental care. A complete history and physical
examination are necessary to define the particular thyroid
disease and assess its level of control. If the thyroid disorder
is untreated or unstable the patient’s physician should be
consulted to determine possible risks associated with the
surgical stress due to the use of local anesthetics, infection,
bleeding, and wound healing. Inquiry about cardiovascular
status, coagulation factors, level of disease control, and a his-
tory of other disease complications should be discussed with
the patient’s physician. Drug interactions may result from
the increased metabolic rate associated with hyperthyroid-
ism or the decreased rate in hypothyroidism. Before pre-
scribing any medications for a poorly controlled patient with
hyper- or hypothyroidism, the clinician should consult with
the patient’s physician to determine the appropriate medic-
ation regimen.
Patients with a history of thyroid cancer have probably
undergone surgery or radioactive iodine therapy that can
affect the adjacent regional tissues. Salivary gland dysfunc-
tion is one of the most common side effects of high-dose 131I
therapy for thyroid cancer.50,51 131I targets the salivary glands,
where it is concentrated and secreted into saliva. Dose-
related damage to the salivary parenchyma results from the
131
I irradiation and causes parotid swelling, pain, and hypo-
function.52,53,54 As with the complications of other head and
neck cancer therapies, postsurgical or post-radiation compli-
cations may require special oral health care measures. Tooth
loss, diminished mandibular bone density, decreased salivary
flow, dysgeusia, dysphagia, and skin and mucosal ulceration
are potential complications of radiation therapy.55
Patients with autoimmune thyroid diseases (Hashimoto’s
thyroiditis) may also be susceptible to other autoimmune
connective tissue disorders, including Sjögren’s syndrome.
Antinuclear antibodies (ANAs) are found in one-third of
patients with autoimmune thyroid disorders, and Sjögren’s
syndrome is found in nearly one-tenth of ANA-positive
patients with autoimmune thyroid disorders.56 The most
common additional autoimmune disease identified in
patients with primary Sjögren’s syndrome has been identi-
fied as hypothyroidism57; also, there is a 7-17 prevalence
of detectable thyroid antibodies in patients with Sjögren’s
syndrome and rheumatoid arthritis.58 Therefore, for the thy-
roid patient who presents with signs of hyposalivation and
xerophthalmia should be evaluated for evidence of Sjögren’s
syndrome.59 Similarly, a patient with Sjögren’s syndrome
should be monitored for developing thyroid disease.60 Oral
health complications resulting from salivary hypofunc-
tion are preventable for those patients who have received
head and neck radiotherapy or 131I treatment or those with
autoimmune thyroid diseases. Patients should be counseled
on their increased risk of developing dental caries, gingival
and periodontal problems, oral candidiasis, dysgeusia, diffi-
culty wearing dentures, and dysphagia.
Hypothyroidism
Patients with hypothyroidism are susceptible to cardiovascu-
lar diseases; therefore, consultation with the patients’ medical
providers is indicated. Patients who have atrial fibrillation
may be taking anticoagulants. Coagulation tests (prothrom-
bin time, partial thromboplastin time, international normal-
ized ratio) are required when the patient is taking an oral
anticoagulant and thyroid hormone replacement therapy.
The use of epinephrine-containing local anesthetics is not
contraindicated if the patient’s hypothyroidism is well con-
trolled, but in patients who have cardiovascular disease or
who have uncertain control of their thyroid disease, local
anesthetic and retraction cord soaked with epinephrine can
be used, but cautiously. Hypothyroidism, especially if uncon-
trolled, can also lead to respiratory depression, so patient
positioning should be carefully considered when treating
such patients. Consider treating patients in a semi-upright
position, with oxygen supplementation via nasal prongs or by
means of the nitrous oxide mask.
Hypothyroidism patients are sensitive to CNS depress-
ants and barbiturates, so these medications should be used
carefully, with input from the patient’s physician. For post-
operative pain control, narcotic use should be limited since
there is greater susceptibility to these agents in these patients.
Patients with long-standing hypothyroidism may exper-
ience increased bleeding after trauma or surgery. The pres-
ence of excess subcutaneous mucopolysaccharides (due to
its decreased degradation) may impair the ability of small
vessels to constrict if severed or traumatized, and this may
result in increased postoperative hemorrhage from such
infiltrated tissues, including mucosa and skin. The extended
application of firm local pressure should control the bleed-
ing from any small vessels affected in such cases.
Patients with hypothyroidism may have delayed wound
healing due to decreased metabolic activity of the fibroblasts.
However, a study of well-controlled primary hypothyroid
patients who had been provided with dental implants
demonstrated no significantly increased risk for implant fail-
ure when compared with matched normal controls.61
Hyperthyroidism
The most important concern in treating the patient with
hyperthyroidism is the risk of development of thyrotox-
icosis or a “thyroid storm,” which includes symptoms of
extreme irritability and delirium, hypotension, vomiting, and
diarrhea.62 It can be triggered by surgery, sepsis, and trauma.
Emergency medical treatment is required for this condition.
Epinephrine is contraindicated, and elective dental care
should be deferred for patients who have hyperthyroidism
and exhibit signs or symptoms of thyrotoxicosis. In general,

stress management and short appointments are recommen-
ded for these patients, and treatment should be discontinued
if signs or symptoms of a thyrotoxic crisis develop.
Patients who have hyperthyroidism are highly susceptible
to cardiovascular diseases, including atrial dysrhythmias,
tachycardia, and hypertension. Patients with high arteriolar
pressures may require increased attention and a longer dur-
ation of local pressure to stop bleeding. Consultation with
the patient’s physician is required to document these and
other organ system problems and to ascertain the level of
control of hyperthyroidism.
Chronic medication use for hyperthyroidism brings
the risk of developing polypharmacy problems, so the oral
health practitioner should be familiar with the patient’s cur-
rent medications. Increased susceptibility to infection may
develop as a drug side effect since the antithyroid agents can
cause agranulocytosis or leukopenia. Propylthiouracil can
also cause sialolith formation and can increase the antico-
agulant effects of warfarin. Certain analgesics must be used
with caution in these patients. Aspirin and NSAIDs may
cause increased levels of circulating T4, leading to thyrotox-
icosis. NSAIDs can also decrease the effect of β-blockers.52
The use of epinephrine and other sympathomimetics
requires special consideration when treating hyperthyroid
patients and those taking nonselective β-blockers. Epineph-
rine acts on α-adrenergic receptors, causing vasoconstric-
tion, and on β2 receptors, causing vasodilation. Nonselective
β-blockers eliminate the vasodilatory effect, potentiating
an α-adrenergic increase in blood pressure. This patho-
physiology is applicable to any patient taking nonselective
β-blockers and those with hyperthyroidism due to con-
current cardiovascular complications.
Disorders of the Adrenal Glands (Cortex)
The normal adrenal glands weigh 6–11 g each and are loc-
ated above the kidneys; they have their own rich blood sup-
ply. Within the glands is the adrenal cortex, which produces
three classes of corticosteroid hormones: (1) glucocorticoids
(e.g. cortisol), (2) mineralocorticoids (e.g. aldosterone) and
(3) adrenal androgen precursor (e.g. dehydroepiandroster-
one DHEA ) prohormones that become the sex steroids.
The sex steroids, also known as gonadal steroids, are steroid
hormones that interact with androgen receptors that stimu-
late or control the development and maintenance of male
characteristics (testosterone) or with the estrogen receptors
(regulating both the menstrual and the reproductive cycles).
Glucocorticoids and mineralocorticoids act through
specific nuclear receptors, regulating aspects of the response
to physiologic stress, as well as blood pressure, electrolyte,
and glucose homeostasis. Adrenal androgen precursors are
converted in peripheral target cells, principally found in the
gonads, to become the sex steroids that, in turn, act via nuc-
lear androgen and estrogen receptors.
Adrenal steroidogenesis occurs in a zone-specific fashion,
with mineralocorticoid synthesis occurring in the outer zona
Disorders of the Endocrine System and Metabolism 593
glomerulosa, glucocorticoid synthesis in the zona fasciculata,
and adrenal androgen synthesis in the inner zona reticularis.
All the steroid hormones are derivatives of cholesterol. The
steroidogenic pathway requires the import of cholesterol
into the mitochondrion, a process initiated by the action of
the steroidogenic acute regulatory (StAR) protein, which
shuttles cholesterol from the outer to the inner mitochon-
drial membrane. The majority of steroidogenic enzymes are
cytochrome (cyp) P450 enzymes. Disorders of the adrenal
cortex are characterized by deficiency or excess of one or sev-
eral of the three major corticosteroid classes of hormones.
Hormone deficiency can be caused by inherited glandular
or enzymatic disorders or by destruction of the pituitary or
adrenal gland by autoimmune disorders, infection, infarction,
or by iatrogenic causes such as surgery or hormonal sup-
pression. Hormone excess is usually the result of neoplasia,
leading to increased production of ACTH by the pituitary
or neuroendocrine cells or increased production of gluco-
corticoids or mineralocorticoids by adrenal nodules. Adrenal
nodules are increasingly identified incidentally on abdominal
imaging.
Regulation of the production of glucocorticoids and
adrenal androgens is under the control of the HPA axis. Min-
eralocorticoids are regulated by the renin-angiotensin-aldos-
terone (RAA) system.
Glucocorticoid synthesis is under inhibitory feedback
control by the hypothalamus and the pituitary. Hypothalamic
release of corticotrophin-releasing hormone (CRH) occurs
in response to endogenous or exogenous stress. CRH in turn
stimulates the release of ACTH by the cells of the anterior
pituitary. ACTH is the pivotal regulator of cortisol synthesis,
with additional short-term effects on mineralocorticoid and
adrenal androgen synthesis. The release of CRH, and sub-
sequently ACTH, occurs in a pulsatile fashion that follows
a circadian rhythm, under the control of the hypothalamus.
Reflecting this pattern of ACTH secretion, adrenal cortisol
secretion is also circadian, with peak levels in the morning
and low levels in the evening.
Diagnostic tests assessing the HPA axis makes use of
its regulation by negative feedback. Glucocorticoid excess
is diagnosed by the  dexamethasone suppression test. Dexa-
methasone, a potent glucocorticoid, suppresses CRH/
ACTH  and, therefore, lowers endogenous  cortisol levels. If
cortisol production is autonomous (e.g. from an adrenal nod-
ule), ACTH is already suppressed, and the dexamethasone
has little additional effect. If cortisol production is driven by
an ACTH-producing pituitary adenoma, dexamethasone
suppression is ineffective at low doses, but usually induces
suppression at high doses. If cortisol production is driven by
an ectopic source of ACTH, such as an ACTH-producing
tumor, these are usually unaffected by dexamethasone sup-
pression. Therefore, the dexamethasone suppression test is
useful both in establishing a diagnosis of Cushing’s syndrome
(corticoid excess) and in differentiating the cause. Conversely,
to assess glucocorticoid deficiency, ACTH stimulation of
594 Burket’s Oral Medicine

cortisol production is used. The standard ACTH stimula- excess glucocorticoid secretion overcomes the ability of a key
tion test involves administration of cosyntropin (Synacthen, a kidney enzyme system (11β-HSD2) to rapidly inactivate
potent ACTH agonist) IM or IV and the collection of blood cortisol to cortisone (cortisone has minimal mineralocor-
samples at 0, 30, and 60 min to check the cortisol level. A ticoid activity), thereby exerting mineralocorticoid actions,
normal response is defined as a cortisol level 20 g/dL or an manifest as diastolic hypertension, hypokalemia, and edema.
increment of 10 g/dL over baseline. Alternatively, an insulin Excess glucocorticoids also interfere with central regulat-
tolerance test (ITT) can be used to assess adrenal insuffi- ory systems, leading to suppression of gonadotropins with
ciency. It involves injection of insulin to induce  hypogly- subsequent hypogonadism and amenorrhea and suppres-
cemia, which represents a strong stress signal that triggers sion of the hypothalamic-pituitary-thyroid axis, resulting in
hypothalamic CRH release and activation of the entire HPA decreased TSH (thyroid-stimulating hormone) secretion.
axis. The ITT involves administration of regular insulin (0.1 The diagnosis of Cushing’s syndrome (or disease) should
U/kg IV—a dose is needed if hypopituitarism is suspected) be considered when the following key clinical features, are
and collection of blood samples at 0, 30, 60, and 120 min evident in the patient (Figures 23-9 and 23-10): fragility
for serum glucose, cortisol, and GH levels. Oral or intraven-
ous glucose is administered once the patient has achieved
symptomatic hypoglycemia (usually glucose 40 mg/dL). A
normal response is defined as a cortisol 20 g/dL.
Mineralocorticoid production is controlled by the RAA
regulatory cycle, which is initiated by the release of renin
from the juxtaglomerular cells in the kidney, resulting in
cleavage of angiotensinogen to angiotensin I in the liver.
Angiotensin-converting enzyme (ACE) cleaves angiotensin
I to angiotensin II, which binds and activates the angiotensin
II receptor Type 1 (AT1 receptor), resulting in increased
aldosterone production and vasoconstriction. Aldosterone
enhances sodium retention and potassium excretion, and
increases the renal arterial perfusion pressure, which in turn
regulates renin release. As mineralocorticoid synthesis is pri-
marily under the control of the RAA system, disorders of the
hypothalamic-pituitary axis generally do not adversely affect
adrenal gland synthesis of aldosterone.

Cushing’s Syndrome (Glucocorticoid Excess) FIGURE 23-9 Cushing’s syndrome features appearing as
a round (moon) face caused by excessive fat deposition in
Cushing’s syndrome reflects a constellation of clinical features
the temporal fossae. The face is plethoric with fullness in the
that result from the chronic effects of glucocorticoid excess. supraclavicular area.
Cushing’s syndrome is rare, with an annual incidence of 1–2 per
100,000 in population. The disorder can be ACTH-dependent
(e.g., pituitary corticotrope adenoma) or ACTH-independent
(e.g., adrenocortical tumor). Overwhelmingly, the medical use
of glucocorticoids is the commonest cause of Cushing’s syn-
drome. Only 10 of patients with Cushing’s syndrome have
a primary, adrenal cause of their disease. The term Cushing’s
disease refers specifically to Cushing’s syndrome caused by a
pituitary adenoma secreting ACTH.
Ectopic ACTH production is predominantly caused
by occult carcinoid tumors, most frequently in the lung,
but also in thymus or pancreas. Advanced small cell lung
cancer can also cause ectopic ACTH production. In rare
cases, ectopic ACTH production has been found to ori-
ginate from medullary thyroid carcinoma or from a
pheochromocytoma.

Clinical Manifestations FIGURE 23-10 The presence of wide purple striae on the skin
is an additional feature of Cushing’s syndrome. The purple hue
Glucocorticoids affect almost all cells of the body, so excess is due to the proximity of the underlying blood vessels to the
cortisol impacts multiple physiologic systems. In addition, surface from thinning of the skin by excess glucocorticoids.

of the skin, with easy bruising and broad ( 1 cm), purplish
striae, signs of proximal myopathy, with the patient struggling
to stand up from a chair (without the use of hands). Patients
with Cushing’s syndrome may develop marked hypercoagulo-
pathy, so are at acutely increased risk of deep vein thrombosis
and subsequent pulmonary embolism. Psychiatric symptoms
of marked anxiety and/or depression are also common, but
acute paranoia or frank psychosis may also occur.
Overt, untreated Cushing’s is associated with a poor
prognosis. In ACTH-independent disease, treatment con-
sists of surgical removal of the adrenal tumor. In Cushing’s
disease, the treatment of choice is selective removal of the
pituitary corticotrophic-producing tumor, usually via a trans-
sphenoidal approach.
Mineralocorticoid Excess (Conn’s syndrome)
Hyperaldosteronism, the excessive release of the principal
mineralocorticoid, aldosterone, typically presents as hyper-
tension, given the adverse effects on the renin-angiotensin
system which so powerfully controls renal perfusion and
homeostasis and blood pressure. Recent studies have demon-
strated that the screening of all patients with hypertension,
demonstrates a much higher prevalence aldosterone excess
(Conn’s syndrome) than was previously thought, ranging
from 5 to 12 .
The commonest cause of primary hyperaldosteronism is
that of excess production of aldosterone by the adrenal zona
glomerulosa, typically occurring with bilateral micronodular
adrenal hyperplasia. Infrequently, Conn’s syndrome occurs
because of an adrenocortical carcinoma. Another rare cause
of aldosterone excess is glucocorticoid-remediable aldoster-
onism (GRA), which is caused by a chimeric gene result-
ing from the crossover of promoter sequences between the
CYP11B1 and CYP11B2, the genes that are involved in
glucocorticoid and mineralocorticoid synthesis, respectively.
This rearrangement brings CYP11B2 under the control of
ACTH receptor signaling so that consequently, aldosterone
production is regulated by ACTH rather than by renin.
The clinical hallmark of mineralocorticoid excess is
hypokalemic hypertension, but not hypernatremia, with the
serum sodium tending to be normal because of concurrent
fluid retention, which in some cases can lead to marked
peripheral edema. Severe hypokalemia can be associated
with muscle weakness, overt proximal myopathy, or in severe
cases, hypokalemic paralysis or tetany. Diagnostic screening
for mineralocorticoid excess is not currently recommen-
ded for all patients with hypertension, but should be con-
sidered in hypertensive patients younger than 40 years of
age, patients with hypertension resistant to drug therapy,
hypokalemia, or the finding of an adrenal mass. The accep-
ted screening test is concurrent measurement of plasma
renin and aldosterone with subsequent calculation of the
aldosterone-renin ratio, but the serum potassium needs to
be normalized prior to testing.
Disorders of the Endocrine System and Metabolism 595
With the diagnosis of hyperaldosteronism, adrenal ima-
ging is needed, best undertaken by fine-cut CT scanning. The
treatment provided is dependent on the patients’ age and fit-
ness for surgery. Laparoscopic adrenalectomy is the preferred
approach. Medical treatment, which can also be considered
prior to surgery to avoid postsurgical hypoaldosteronism,
is usually with the mineralocorticoid receptor antagonist,
i.e. spironolactone.
Adrenal Insuf ciency (Addison’s Disease)
The US prevalence of adrenal insufficiency is 5 in 10,000
in the general population. Disorders of the hypothalamic-
pituitary axis are frequent, with a prevalence of 3 in 10,000
whereas primary adrenal insufficiency has a prevalence of 2
in 10,000, with about half of the cases due to genetic causes
(e.g. congenital adrenal hyperplasia). Primary adrenal insuffi-
ciency is most commonly caused by autoimmune destruction
of the adrenal gland, with some 60–70 developing adrenal
insufficiency as part of an autoimmune polyglandular syn-
drome (APS) APS1, an autosomal recessive disorder also
termed APECED (autoimmune polyendocrinopathy-
candidiasis-ectodermal dystrophy), is the underlying cause
in 10 of patients affected by APS. APS1 patients invari-
ably develop chronic mucocutaneous candidiasis, usually
manifest in childhood, which precedes adrenal insufficiency
by years or decades. Coincident autoimmune-induced endo-
crinopathy most frequently includes thyroid autoimmune
disease, vitiligo, and premature ovarian failure. Less com-
monly, Type 1 DM and pernicious anemia (with consequent
vitamin B12 deficiency) may occur. Rare causes of adrenal
insufficiency involve destruction of the adrenal glands as
a consequence of infection; with tuberculous, adrenalitis
is still a frequent cause of disease in developing countries;
hemorrhage; or more rarely, bilateral bulky metastatic infilt-
ration with replacement of the adrenal glands resulting in
hypoadrenalsim.
The commonest cause of adrenal insufficiency is iatro-
genic, arising from suppression of the HPA axis as a con-
sequence of exogenous glucocorticoid treatment. This has
a reported prevalence of some 0.5–2 of the population
in developed countries. Secondary adrenal insufficiency
is the consequence of dysfunction of the hypothalamic-
pituitary component of the HPA axis. Excluding iatro-
genic impairment of the HPA axis (exogenous corticos-
teroid use) the majority of cases are caused by pituitary
or hypothalamic tumors, or their treatment by surgery or
radiotherapy.
In principle, the clinical features of primary adrenal insuf-
ficiency are characterized by the loss of both glucocorticoid
and mineralocorticoid secretion, but in contrast, in secondary
adrenal insufficiency, only glucocorticoid deficiency is evid-
ent, as the adrenal itself is intact and can still be regulated
by the RAA system. Adrenal androgen secretion is disrup-
ted in both primary and secondary adrenal insufficiency.