Drugs Used in the Diagnosis or Treatment of Adrenocortical Abnormalities

DRUGS USED IN THE DIAGNOSIS OR TREATMENT OF ADRENOCORTICAL ABNORMALITIES

Corticotropin

Corticotropin (ACTH, Acthar, Cortrophin Gel) is an open-chain polypeptide that consists of 39 amino acid residues, the first 24 of which are essential for its biolog-ical activity. The remainder of the amino acids are also clinically important, since they may be involved in stim-ulating antibody formation and causing allergic reac-tions.This is true especially when corticotropin of animal origin is injected into humans. Commercially available corticotropin is prepared from animal pituitary glands.

Absorption, Metabolism, Excretion

Corticotropin is rapidly inactivated by gastrointestinal proteolytic enzymes and therefore must be administered parenterally. It is rapidly removed from the circulation (T_1/2, 15 minutes) and is probably inactivated in body tis-sues, since no intact compound is found in the urine.

Clinical Uses

The rationale for using corticotropin instead of phar-macological concentrations of glucocorticoids stems from the fact that corticotropin provides enhanced amounts of all endogenously secreted adrenocortical hormones, including androgens. However, obvious dis-advantages are associated with the use of this polypep-tide: (1) It must be given daily parenterally. (2) It is quite expensive. (3) It is antigenic and thus can produce resistance and hypersensitivity reactions. Corticotropin is used as a diagnostic tool for the identification of pri-mary adrenal insufficiency or as a method for evaluat-ing the hypothalamic–pituitary–adrenal axis before sur-gery in patients previously treated with glucocorticoids.

Adverse Effects

Aside from hypersensitivity and allergic reactions, cor-ticotropin administration has been associated with elec-trolyte disturbances and masculinization in women.

Cosyntropin

Cosyntropin (Cortrosyn) is a polypeptide that consists solely of the first 24 amino acids of corticotropin. It appears to offer an advantage over the naturally occurring hormone in that it has a longer duration of action and lacks the antigenic portion of corticotropin. Although the short cosyntropin test is recognized as a valid screening test to assess adrenocortical insufficiency, the overnight metyrapone test or insulin hypoglycemia test may prove more sensitive.

Metyrapone

Mechanism of Action

Metyrapone (Metopirone) produces its primary phar-macological effect by inhibiting 11- -hydroxylase, thereby causing diminished production and release of cortisol. The resulting reduction in the negative feed-back of cortisol on the hypothalamus and pituitary causes an increase in corticotrophin release and in the secretion of precursor 11-deoxysteroids.

Clinical Uses

Metyrapone is used in the differential diagnosis of both adrenocortical insufficiency and Cushing’s syndrome (hypercortisolism). The drug tests the functional com-petence of the hypothalamic–pituitary axis when the adrenals are able to respond to corticotrophin; that is, when primary adrenal insufficiency has been ruled out.

After metyrapone administration, a patient with a disease of pituitary origin cannot achieve a compensa-tory increase in the urinary excretion of 17-hydroxycorti-costeroids or 11-deoxysteroids. Moreover, if pituitary corticotrophin is suppressed by an autonomously secret-ing adrenal carcinoma, there will be no increase in re-sponse to metyrapone. On the other hand, if pituitary corticotrophin secretion is maintained, as occurs in adre-nal hyperplasia, the inhibition of corticoid synthesis pro-duced by metyrapone will stimulate corticotrophin secre-tion and the release of metabolites of precursor urinary steroids, which can be measured as 17-hydroxycortico-steroids. Metyrapone is now used less frequently in the differential diagnosis of Cushing’s syndrome because of the ability to measure plasma corticotrophin directly.

The steroid-inhibiting properties of metyrapone have also been used in the treatment of Cushing’s syn-drome, and it remains one of the more effective drugs used to treat this syndrome. However, the compensa-tory rise in corticotrophin levels in response to falling cortisol levels tends to maintain adrenal activity. This re-quires that glucocorticoids be administered concomi-tantly to suppress hypothalamic–pituitary activity. Although metyrapone interferes with 11 - and 18-hydroxylation reactions and thereby inhibits aldos-terone synthesis, it may not cause mineralocorticoid de-ficiency because of the compensatory increased produc-tion of 11-desoxycorticosterone.

Adverse Effects

Side effects associated with the use of metyrapone in-clude gastrointestinal distress, dizziness, headache, seda-tion, and allergic rash. The drug should not be used in cases of adrenocortical insufficiency or when hypersen-sitivity reactions can be expected. When administered to pregnant women during the second or third tri-mesters, the drug may impair steroid biosynthesis in the fetus. Because metyrapone is relatively nontoxic, it is used in combination therapy with the more toxic amino-glutethimide to reduce its dosage.

Aminoglutethimide

Aminoglutethimide (Cytadren) is a competitive in-hibitor of desmolase, the enzyme that catalyzes the con-version of cholesterol to pregnenolone; it also inhibits 11-hydroxylase activity. This drug also reduces estrogen production by inhibiting the aromatase enzyme com-plex in peripheral (skin, muscle, fat) and steroid target tissues.

Such a medical adrenalectomy is an efficacious treatment for metastatic breast and prostate cancer, since it diminishes the levels of circulating sex hor-mones. Glucocorticoids are administered concomitantly to suppress enhanced corticotrophin release. Cortisol is preferable to dexamethasone in this situation because aminoglutethimide markedly enhances the hepatic microsomal metabolism of dexamethasone. Hepatic en-zyme induction may be responsible for the develop-ment of tolerance to the side effects of aminoglu-tethimide, such as ataxia, lethargy, dizziness, and rashes.

Aminoglutethimide is suitable for use in Cushing’s syndrome that results from adrenal carcinoma and in congenital adrenal hyperplasia, in which it protects the patient from excessive secretion of endogenous andro-gens. The drug is not curative, and relapse occurs when treatment is terminated. Since aminoglutethimide ther-apy is frequently associated with mineralocorticoid de-ficiency, mineralocorticoid supplements may be needed. Aminoglutethimide and metyrapone are frequently used in combination at lower doses of both drugs as an adjunct to radiation or surgical therapy.

Mitotane

Mitotane (Lysodren) produces selective atrophy of the zona fasciculata and zona reticularis, which results in a decrease in the secretion of 17-hydroxycorticosteroids. Direct inhibition of cholesterol side-chain cleavage and 11 /18-hydroxylase activities has also been demon-strated. Mitotane is capable of inducing remission of Cushing’s disease, but only after several weeks of ther-apy and at the price of severe gastrointestinal distress. Moreover, more than half of patients relapse following cessation of therapy. Other side effects include lethargy,

mental confusion, skin rashes, and altered hepatic func-tion. Being a lipid-soluble substance, mitotane remains stored in body tissues for extended periods. This may account for the marked patient-to-patient variability in its therapeutic and/or toxic effects.

Mitotane is the drug of choice for the treatment of primary adrenal carcinoma when surgery or radiation therapy is not feasible . Its effective-ness in curtailing adrenal activity is due to an action on adrenocortical mitochondria to impair cytochrome P450 steps in steroid biosynthesis. Mitotane requires metabolic transformation to exert its therapeutic ac-tion, and the differential ability of tumors to metabolize the drug may determine its clinical effectiveness. It is advised to measure serum mitotane levels and urinary free cortisol excretion to ensure adequate therapeutic concentrations. Mitotane increases circulating choles-terol by inhibiting cytochrome P450–mediated reac-tions and therefore contributes to the cardiovascular events that are a significant cause of mortality in un-treated Cushing’s syndrome.

Mitotane, being closely related to the organochlo-rine insecticides, shares its inductive effects on the liver microsomal drug-metabolizing enzyme system, and its use may therefore alter the requirement for concomi-tantly administered drugs that are also metabolized by this pathway.

Ketoconazole

Ketoconazole (Nizoral), an orally effective broad-spectrum antifungal agent , blocks hy-droxylating enzyme systems by interacting with cy-tochrome P450 at the heme iron site to inhibit steroid and/or androgen synthesis in adrenals, gonads, liver, and kidney. The most sensitive site of action appears to be the C17-20 lyase reaction involved in the formation of sex steroids. This explains the greater suppressibility of testosterone production than with cortisol. Cholesterol side-chain cleavage and 11 /18-hydroxylase are second-ary sites of inhibition.

Ketoconazole can be used as palliative treatment for Cushing’s syndrome in patients undergoing surgery or receiving pituitary radiation and in those for whom more definitive treatment is still contemplated. Because surgical treatment is not always well tolerated by eld-erly patients, ketoconazole 200 to 1,000 mg/day can be a valuable alternative for the control of hypercortisolism. Common side effects include pruritus, liver dysfunction, and gastrointestinal symptoms.

Because of its effectiveness in blocking C17-20 lyase activities, ketoconazole does not enhance existing hir-sutism associated with metyrapone. On the other hand, the antiandrogenic effects of ketoconazole may prove disconcerting to male patients.

Mifepristone (RU 486)

Mifepristone is a progesterone receptor antagonist that has a high affinity for glucocorticoid receptors and little agonist effect. This drug has recently been approved for use in the United States for the treatment of hypercor-tisolism. At high doses, mifepristone blocks negative feedback of the hypothalamic–pituitary axis, thereby in-creasing endogenous corticotrophin and cortisol levels. Because mifepristone exerts its effects at the receptor level and not by altering glucocorticoid production, ele-vated serum cortisol and corticotrophin levels may not accurately reflect the effectiveness of the therapeutic regimen. Mifepristone does not inhibit cortisol binding to the mineralocorticoid receptor, so that the resulting corticotrophin disinhibition may cause potassium de-pletion. Thus, administration of a mineralocorticoid re-ceptor antagonist such as spironolactone may be indicated with mifepristone. Hypoadrenalism, nausea, and drowsiness have been reported during prolonged ad-ministration of mifepristone.

Dexamethasone

Cushing’s disease is defined as hypercortisolism due to chronic overproduction of corticotrophin by a corti-cotroph adenoma. Cortisol’s lack of suppressibility dur-ing the administration of low doses of dexamethasone but suppressibility during high-dose dexamethasone is the key diagnostic finding in 99% of the patients with Cushing’s disease. This contrasts with the lack of gluco-corticoid suppressibility typically found in patients with corticotrophin-independent hypercortisolism (Cushing’s syndrome). A judicious selection of the available tests may be necessary to obtain an accurate diagnosis in pa-tients with Cushing’s syndrome.