Adrenal
Cortical Hyperfunction
Hypersecretion of one or more adrenocortical
hormones produces distinct clinical syndromes. Excessive
production of androgens results in adrenal virilism;
hypersecretion of glucocorticoids produces Cushing's syndrome; and
excess aldosterone output results in hyperaldosteronism (aldosteronism).
These syndromes frequently have overlapping features. Adrenal
hyperfunction may be compensatory, as in congenital adrenal
hyperplasia, or may be due to acquired hyperplasia, adenomas, or
adenocarcinomas.
ADRENAL
VIRILISM
(Adrenogenital
Syndrome)
Any syndrome, congenital or acquired, in which
excessive output of adrenal androgens causes virilization.
Symptoms
and Signs
The effects depend on the sex and age of the
patient at disease onset and are more marked in women than in men.
In adult women, adrenal virilism is caused by adrenal hyperplasia
or an adrenal tumor. In either case, symptoms and signs include
hirsutism, baldness, acne, deepening of the voice, amenorrhea,
atrophy of the uterus, clitoral hypertrophy, decreased breast
size, and increased muscularity. Libido may increase. Hirsutism may be the only sign in mild cases.
Diagnosis
and Treatment
CT or MRI of the adrenal is useful in ruling out a
tumor as the cause of virilism. If a tumor is found, considerable
information can be obtained from a small-needle aspiration biopsy
under x-ray or ultrasound.
Delayed virilizing adrenal hyperplasia
is a variant of congenital adrenal hyperplasia, and both are
caused by a defect in hydroxylation of cortisol precursors.
Urinary dehydroepiandrosterone (DHEA) and its sulfate (DHEAS) are
elevated; pregnanetriol excretion is often increased; and
urinary-free cortisol is diminished. Plasma DHEA, DHEAS,
17-hydroxyprogesterone, testosterone, and androstenedione are
elevated. The diagnosis is confirmed by suppression of urinary
DHEAS and pregnanetriol excretion with dexamethasone 0.5 mg po q 6
h. The recommended treatment is dexamethasone 0.5 to 1 mg po at
bedtime, but even these small doses may produce signs of Cushing's
syndrome in some patients. Cortisol (25 mg/day) or prednisone (5
to 10 mg/day) can be used also. Though most symptoms and signs of
virilism disappear, the hirsutism and baldness disappear slowly,
the voice may remain deep, and fertility may be impaired.
In contrast to adrenal hyperplasia, dexamethasone
administration either does not suppress or only partially
suppresses androgen excretion in virilizing adenomas
or adenocarcinomas. The tumor site may be
determined by CT. Treatment requires adrenalectomy. In some cases,
the tumor secretes both excess androgens and cortisol, resulting
in Cushing's syndrome with suppression of ACTH secretion and
atrophy of the contralateral adrenal. If this is the case,
hydrocortisone should be given preoperatively and postoperatively
as described below. Mild hirsutism and virilization with
hypomenorrhea and elevated plasma testosterone may be seen in the polycystic
ovary (Stein-Leventhal) syndrome.
CUSHING'S
SYNDROME
A constellation of clinical abnormalities due
to chronic exposure to excesses of cortisol (the major
adrenocorticoid) or related corticosteroids.
Etiology
Hyperfunction of the adrenal cortex may be
ACTH-dependent, or it may be independent of ACTH regulation, eg,
production of cortisol by an adrenocortical adenoma or carcinoma.
Therapeutic administration of supraphysiologic quantities of
exogenous cortisol or related synthetic analogs suppresses
adrenocortical function and mimics ACTH-independent hyperfunction.
ACTH-dependent hyperfunction of the adrenal cortex may be due to
(1) hypersecretion of ACTH by the pituitary gland; (2) secretion
of ACTH by a nonpituitary tumor, such as small cell carcinoma of
the lung (the ectopic ACTH syndrome); or (3)
administration of exogenous ACTH. Whereas the term Cushing's
syndrome has been applied to the clinical picture
resulting from cortisol excess regardless of the cause,
hyperfunction of the adrenal cortex resulting from pituitary ACTH
excess has frequently been referred to as Cushing's
disease, implying a particular physiologic abnormality.
Patients with Cushing's disease may have a basophilic or a
chromophobe adenoma of the pituitary gland.
Symptoms
and Signs
Clinical manifestations include rounded
"moon" facies with a plethoric appearance. There is
truncal obesity with prominent supraclavicular and dorsal cervical
fat pads ("buffalo hump"); the distal extremities and
fingers are usually quite slender. Muscle wasting and weakness are
present. The skin is thin and atrophic, with poor wound healing
and easy bruising. Purple striae may appear on the abdomen.
Hypertension, renal calculi, osteoporosis, glucose intolerance,
reduced resistance to infection, and psychiatric disturbances are
common. Cessation of linear growth is characteristic in children.
Females usually have menstrual irregularities. In adrenal tumors,
an increased production of androgens, in addition to cortisol, may
lead to hypertrichosis, temporal balding, and other signs of
virilism in the female.
Diagnosis
Plasma cortisol is normally 5 to
25 µg/dL (138 to 690 nmol/L) in the early morning hours (6 to 8
am) and declines gradually to < 10 µg/dL (< 276 nmol/L) in
the evening (6 pm and later). Patients with Cushing's syndrome
usually have elevated morning cortisol levels and lack the normal
diurnal decline in cortisol production, so that evening plasma
cortisol levels are above normal and total 24-h cortisol
production is elevated. Single plasma cortisol samples may be
difficult to interpret because of the episodic secretion that
produces the wide range in normal values. Plasma cortisol may be
spuriously elevated in patients with congenital increases of
corticosteroid-binding globulin, but diurnal variation is normal
in these patients. Free urinary cortisol, the
best assay for urinary excretion (normal 20 to 100 µg/24 h [55.2
to 276 nmol/24 h]), is elevated > 120 µg/24 h (> 331 nmol/24
h) in Cushing's patients and is only minimally increased in obese
patients, in whom it is < 150 µg/24 h (< 414 nmol/24 h).
Traditionally, the dexamethasone test,
in which 1 mg of dexamethasone is administered orally at 11 to 12
pm and plasma cortisol is measured at 7 to 8 am the next morning,
has been used to screen for Cushing's syndrome. Most normal
patients will suppress their morning plasma cortisol to <= 5 µg/dL
(<= 138 nmol/L) after this test, whereas most patients with
nonpituitary Cushing's syndrome will have a morning cortisol level
of at least 9 µg/dL (248 nmol/L) and will maintain their plasma
cortisol at its original level.
Giving oral dexamethasone 0.5 mg q 6 h for 2 days
("low dose") to normal subjects leads to inhibition of
ACTH secretion. Consequently, urinary-free cortisol will usually
decrease to 50% or less than the pretreatment level but, in any
case, to < 10 µg/24 h (< 27.6 nmol/24 h) on the 2nd day. In
patients with Cushing's disease, pituitary ACTH secretion is relatively
resistant to suppression, thus urinary-free cortisol will not
decrease in a normal fashion. When the oral dose of dexamethasone
is increased to 2 mg q 6 h for 2 days ("high dose"),
urinary-free cortisol will usually decrease by at least 50% from
the baseline values in patients with Cushing's disease, which is
dependent on pituitary ACTH.
In patients with adrenal tumors, cortisol
production is independent of ACTH, thus dexamethasone will have no
suppressive effect. In patients with ectopic ACTH syndrome, the
production of ACTH by the nonpituitary tumor is almost always
unaffected by dexamethasone, hence urinary steroids remain
unchanged. The dexamethasone test distinguishes a pituitary
abnormality from other forms of Cushing's syndrome.
A more precise variant is to give dexamethasone 1
mg/h by constant IV infusion for 7 h. Patients with Cushing's
disease reduce their plasma cortisol level by at least 7 µg/dL
(193 nmol/L) by the 7th hour. Patients with adrenal tumors or the
ectopic ACTH syndrome do not respond. Dexamethasone suppression is
blocked by rifampicin, so tests of this type are useless in
patients receiving the drug.
The overnight metyrapone test is
useful in determining the etiology of Cushing's syndrome. Patients
with pituitary-dependent Cushing's disease have a marked increase
in plasma 11-deoxycortisol, but patients with adrenal tumors or
ectopic ACTH syndrome do not show this increase. The total amount
of steroid produced (as metyrapone blocks 11-hydroxylation of
cortisol) must be determined. Therefore, total cortisol and
11-deoxycortisol levels are measured to that an increase in total
steroid has occurred, and not just that 11-deoxycortisol has
replaced cortisol in the plasma.
Less useful in evaluating patients with Cushing's
syndrome is the ACTH stimulation test. Infusion
of ACTH 50 U over an 8-h period produces a two- to fivefold
increase in urinary cortisol in patients with Cushing's disease,
in whom the adrenals show bilateral hyperplasia and
hyperresponsiveness due to chronic endogenous ACTH excess. In
about 50% of cases of adrenal adenoma, ACTH stimulation will
produce a clear and sometimes marked increase in plasma and
urinary cortisol. Adrenal carcinomas are generally unresponsive to
ACTH.
Pituitary microadenomas can usually be visualized
by CT, but MRI is better, especially with a high-resolution
technique augmented by gadolinium. Some microadenomas are
difficult to visualize even with these modalities. In some cases,
no histologic abnormality is found in the pituitary gland despite
clear evidence of ACTH overproduction.
Differential
Diagnosis
If the dexamethasone test points to the cause as
being either an adrenal tumor or the ectopic ACTH syndrome, then a
determination can be made by the plasma ACTH level.
The plasma ACTH level will be markedly elevated in the ectopic
ACTH syndrome (usually > 200 pg/mL) but will be too low to
measure in Cushing's syndrome due to an adrenal tumor, except in
the rare instances in which the adrenal tumor produces ACTH.
Patients with Cushing's disease usually have moderately elevated
plasma ACTH levels (75 to 200 pg/mL). Laboratory test results also
favoring ectopic ACTH as the cause of Cushing's syndrome include
hypokalemic alkalosis with a serum K of < 3.0 mEq/L and HCO3
of > 30 mEq/L, serum cortisol of > 200 µg/dL (> 5520
nmol/L) at 9 am, and urinary-free cortisol excretion of > 450
µg/24 h (> 1242 nmol/24 h).
The corticotropin-releasing hormone (CRH) test
usually distinguishes between
hyperadrenocorticism associated with ectopic ACTH secretion and
hypersecreting adrenal tumors, in which no response occurs, and
the pituitary form of Cushing's disease, in which the response is
normal or increased. However, this test is sometimes misleading
because of large overlap in normal and abnormal responses. It is
most valuable when combined with a positive dexamethasone
suppression test.
After adrenal hyperfunction is established, the
evaluation of the patient with Cushing's syndrome should also
include CT or, preferably, MRI for a pituitary tumor. If the
presence or location of a pituitary tumor is uncertain, it is
useful to sample simultaneously the ACTH level in plasma from the
two inferior petrosal sinuses before and after giving 1 µg/kg
body weight of CRH. Normally, both sides respond equally; the
sinus draining an adenoma has a higher level before stimulation
than the tumor-free side and has a greater response to CRH. In
patients with ectopic ACTH, both sides are equal and elevated and
do not respond to CRH. In addition, signs of a nonpituitary
ACTH-producing neoplasm must be carefully sought. Adrenal
scanning, after the patient ingests radioactive iodinated
cholesterol, may differentiate hyperplasia from adenoma or
carcinoma; however, CT (MRI is no better than CT in this instance)
of the adrenal region is the procedure of choice if biochemical
tests suggest the presence of an adrenal tumor.
Diagnostic procedures and criteria for diagnosis
are the same for children and adults, except that MRI is preferred
in pregnant women to avoid fetal exposure to radiation.
Hyperadrenocorticism
in liver disease: In
some patients with chronic liver disease, especially associated
with alcoholism, a clinical picture similar to Cushing's syndrome
may appear. Laboratory tests show a high plasma level of cortisol,
with limited diurnal variation. Cortisol secretory rates are
normal. The elevated plasma cortisol levels are partly a result of
reduced ability of the liver to oxidize cortisol to its inactive
metabolite, cortisone, but persistence of elevated plasma cortisol
levels also implies reduced sensitivity of the
hypothalamic-pituitary-adrenal feedback mechanism, which should
(but does not) reduce ACTH secretion. Improvement in liver
function may correct the abnormality. Blockers of corticosteroid
activity, such as ketoconazole, may help.
Treatment
Treatment is directed at correcting the
hyperfunction of the pituitary gland or the adrenal cortex; the
precise approach depends on the underlying abnormality.
Initially, the patient's general condition should
be supported by appropriate administration of K and a high protein
intake. If clinical manifestations are severe, it may be
reasonable to block steroid secretion with aminoglutethimide (250
mg po bid) or ketoconazole (400 mg/day increasing to a maximum of
1200 mg/day). When the pituitary is the source of excessive ACTH
secretion, the standard approach is to perform a transsphenoidal
exploration of the pituitary and excise a tumor, if one
is found. This surgical procedure is demanding and should be
performed only in experienced centers. The operation is successful
in about 70% of cases and works best with microadenomas < 1 cm
in diameter. About 20% of tumors recur, and larger tumors are more
likely to return than small ones. Reoperation of a recurrent tumor
is often successful. Pregnancy is not a contraindication to the
operation.
If no tumor is found, some physicians proceed to
hypophysectomy, but most believe that the next step is supervoltage
irradiation of the pituitary, delivering 40 to 50 Gy. In
children, pituitary irradiation may reduce secretion of growth
hormone and may cause precocious puberty occasionally. In special
centers, heavy particle beam irradiation, providing about 100 Gy,
is often successful. Response to irradiation may require several
months. Bilateral adrenalectomy is reserved for
patients with pituitary hyperadrenocorticism who do not respond to
both pituitary exploration (with possible adenomectomy) and
irradiation, which usually restore pituitary function to normal.
Adrenalectomy requires steroid replacement for the remainder of
the patient's life, in the same pattern as is required for primary
adrenal failure.
There is also a serious risk of developing Nelson
syndrome, which occurs in 5 to 10% of patients who have
undergone adrenalectomy for Cushing's disease. The risk is reduced
if the patient has undergone pituitary radiation and is very low
in patients > 35 yr old at the time of the operation. In Nelson
syndrome, the pituitary gland continues to expand, causing a
marked increase in ACTH and 
-melanocyte-stimulating
hormone secretion, resulting in severe hyperpigmentation. Although
irradiation may arrest continued pituitary growth in these
patients, many patients also require hypophysectomy. The
indications for hypophysectomy are the same as for any pituitary
tumor--an increase in size such that the tumor encroaches on
surrounding structures, producing visual field defects, pressure
on the hypothalamus, or other complications. Routine irradiation
is often performed after hypophysectomy.
Adrenocortical tumors are surgically removed.
Patients must receive supplementary cortisol during the surgical
and postoperative periods, since their nontumorous adrenal cortex
will be atrophic and suppressed. Benign adenomas can be
successfully removed laparoscopically. With multinodular adrenal
hyperplasia, bilateral adrenalectomy may be necessary. Even after
a presumed total adrenalectomy, functional regrowth occurs in
about a third of patients. Where possible, treatment of the
ectopic ACTH syndrome consists of removing the nonpituitary tumor
producing the ACTH. However, in most cases, the tumor is
disseminated and cannot be excised. Adrenal inhibitors such as
metyrapone 250 mg qid combined with aminoglutethimide 250 mg bid
po, increasing to a maximum of no more than 2 g/day; or mitotane (o,p´-DDD)
0.5 g qid po, increasing to a maximum total dose of 8 to 12 g/day,
will usually control severe metabolic disturbances (eg,
hypokalemia) resulting from hyperfunction of the adrenal cortex.
When mitotane is used, 20 mg/day of cortisol should be added to
the regimen to protect the patient against the effects of complete
abolition of corticosteroid secretion. However, ketoconazole (400
to 1200 mg/day) probably best blocks steroid synthesis, though it
carries a risk of liver toxicity and, like mitotane, can cause
addisonian symptoms. Alternatively, the corticosteroid receptors
can be blocked with mifepristone. This raises the plasma
cortisol level but blocks effects of the steroid. Sometimes tumors
causing the ectopic ACTH syndrome respond to long-acting
somatostatin analogs such as octreotide 100 to 125 µg given sc
tid. Administration of octreotide for > 2 yr requires careful
follow-up, since it may be associated with mild gastritis,
formation of gallstones, cholangitis, jaundice, and malabsorption
of vitamin B12.
HYPERALDOSTERONISM
(Aldosteronism)
The clinical syndrome resulting from excess
aldosterone secretion.
Aldosterone is the most potent mineralocorticoid
produced by the adrenals. It causes Na retention and K loss. In
the kidney, aldosterone causes transfer of Na from the lumen of
the distal tubule into the tubular cells in exchange for K and
hydrogen. The same effect occurs in the salivary glands, sweat
glands, and cells of the intestinal mucosa and in exchanges
between intra- and extracellular fluids.
Aldosterone secretion is regulated by the renin-angiotensin
mechanism and to a lesser extent by ACTH. Renin, a
proteolytic enzyme, is stored in the juxtaglomerular cells of the
kidney. Reduction in blood volume and flow in the afferent renal
arterioles induces renin secretion. Renin causes transformation of
angiotensinogen (an 
2
globulin) in the liver to angiotensin I, a 10-amino acid
polypeptide, which is converted to angiotensin II, an 8-amino acid
polypeptide. Angiotensin II causes secretion of aldosterone and,
to a much lesser extent, secretion of cortisol and
deoxycorticosterone. The Na and water retention resulting from
increased aldosterone secretion increases the blood volume and
reduces renin secretion. Aldosterone is measured by
radioimmunoassay.
Primary
Aldosteronism
(Conn's
Syndrome)
Primary aldosteronism is due to an adenoma,
usually unilateral, of the glomerulosa cells of the adrenal cortex
or, more rarely, to an adrenal carcinoma or hyperplasia. Adenomas
are extremely rare in children, but the syndrome is sometimes part
of the pattern in childhood adrenal carcinoma or adrenal
hyperplasia. The clinical picture is also mimicked by congenital
adrenal hyperplasia from deficiency of 11 -hydroxylase.
In children, the hypokalemia and hyperaldosteronism of Bartter's
syndrome are distinguished from Conn's syndrome by the absence of
hypertension.
Symptoms
and Signs
Hypersecretion of aldosterone may result in
hypernatremia, hyperchlorhydria, hypervolemia, and a hypokalemic
alkalosis manifested by episodic weakness, paresthesias, transient
paralysis, and tetany. Diastolic hypertension and a hypokalemic
nephropathy with polyuria and polydipsia are common. Aldosterone
excretion on a high Na intake (> 10 g/day) is usually > 200
µg/day if a tumor is present. Deprivation of Na causes K
retention. Personality disturbances, hyperglycemia, and glycosuria
occasionally occur. In many cases, the only manifestation is mild
to moderate hypertension.
Diagnosis
A helpful test is to give spironolactone 200 to
400 mg/day po because it reverses the manifestations of the
disease, including hypertension, within 5 to 8 wk. (This reversal
rarely occurs in patients with hypertension not due to increased
aldosterone.) Measuring plasma renin is helpful in the diagnosis
and is usually performed by determining the plasma renin level in
the morning with the patient recumbent, giving furosemide 80 mg po,
and then repeating the renin determination after the patient has
remained upright for 3 h. Normal persons will have a marked
increase in renin in the upright position, whereas the patient
with hyperaldosteronism will not. About 20% of patients with
essential hypertension who do not necessarily have
hyperaldosteronism have a low renin that does not respond to the
upright position. Measurements of plasma aldosterone, either
peripherally or after catheterization of the adrenal veins, may be
helpful. Diagnosis is thus dependent on demonstrating elevated
aldosterone secretion in urine or blood, expansion of the
extracellular space as demonstrated by lack of increase in plasma
renin in the upright posture, and the K abnormalities noted. CT
often demonstrates a small adenoma in these cases. MRI does not
improve diagnostic capability.
Treatment
Once the diagnosis of primary aldosteronism is
made, both adrenal glands should be explored for possible multiple
adenomas. It may be necessary to dissect the gland to demonstrate
a tumor. The prognosis is good in overt aldosteronism when a
solitary adenoma can be defined. In such cases, removal by
laparoscopy may be possible. After removal of an aldosterone-producing
adenoma, all patients have lowering of BP; complete remission
occurs in 50 to 70%. With adrenal hyperplasia and
hyperaldosteronism, about 70% remain hypertensive, although there
is a lowering of BP in most patients. Hyperaldosteronism in these
patients can usually be controlled by spironolactone, starting
with 300 mg/day and decreasing to a maintenance dose, usually
around 100 mg/day over a month, or by canrenoate potassium,
starting at 200 mg/day and titrating down over 3 mo to a
maintenance dose of about 100 mg/day. Additional antihypertensive
treatment is needed in about half of the patients. Bilateral adrenalectomy is rarely necessary. In
normokalemic aldosteronism, diagnosis and definition are
difficult, and surgical exploration may be unrewarding.
Secondary
Aldosteronism
Secondary aldosteronism, an increased production
of aldosterone by the adrenal cortex caused by stimuli originating
outside the adrenal, mimics the primary condition and is related
to hypertension and edematous disorders (eg, cardiac failure,
cirrhosis with ascites, the nephrotic syndrome). Secondary
aldosteronism occurring with the accelerated phase of hypertension
is believed to be due to renin hypersecretion secondary to renal
vasoconstriction. Hyperaldosteronism is also seen in hypertension
due to obstructive renal artery disease (eg, atheroma, stenosis).
This is caused by reduced blood flow in the affected kidney.
Hypovolemia, which is common in edematous disorders, particularly
during diuretic therapy, stimulates the renin-angiotensin
mechanism with hypersecretion of aldosterone. Secretion rates may
be normal in cardiac failure, but hepatic blood flow and
aldosterone metabolism are reduced so that circulating levels of
the hormone are high.