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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 beta-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 alpha2 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 beta-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.

From The Merck Manual of Diagnosis and Therapy, Edition 17, edited by Mark H. Beers and Robert Berkow. Copyright 1999 by Merck & Co., Inc., Whitehouse Station, NJ.

 

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