Synthesis Inhibitors & Glucocorticoid Antagonists

ANTAGONISTS OF ADRENOCORTICAL AGENTS

SYNTHESIS INHIBITORS & GLUCOCORTICOID ANTAGONISTS

Inhibitors of steroid synthesis act at several different steps and one glucocorticoid antagonist acts at the receptor level.

Aminoglutethimide

Aminoglutethimide (Figure 39–5) blocks the conversion of cho-lesterol to pregnenolone (see Figure 39–1) and causes a reduction in the synthesis of all hormonally active steroids. 

It has been used in conjunction with dexamethasone or hydrocortisone to reduce or eliminate estrogen production in patients with carcinoma of the breast. In a dosage of 1 g/d it was well tolerated; however, with higher dosages, lethargy and skin rash were common effects. The use of aminoglutethimide in breast cancer patients has now been supplanted by tamoxifen or by another class of drugs, the aro-matase inhibitors. Aminoglutethimide can be used in conjunction with metyrapone or ketoconazole to reduce steroid secretion in patients with Cushing’s syndrome due to adrenocortical cancer who do not respond to mitotane.

Aminoglutethimide also apparently increases the clearance of some steroids. It has been shown to enhance the metabolism of dexamethasone, reducing its half-life from 4–5 hours to 2 hours.

Ketoconazole

Ketoconazole, an antifungal imidazole derivative , is a potent and rather nonselective inhibitor of adrenal and gonadal steroid synthesis. This compound inhibits the cholesterol side-chain cleavage, P450c17, C17,20-lyase, 3β-hydroxysteroid dehydrogenase, and P450c11 enzymes required for steroid hor-mone synthesis. The sensitivity of the P450 enzymes to this com-pound in mammalian tissues is much lower than that needed to treat fungal infections, so that its inhibitory effects on steroid biosynthesis are seen only at high doses.

Ketoconazole has been used for the treatment of patients with Cushing’s syndrome due to several causes. Dosages of 200–1200 mg/d have produced a reduction in hormone levels and clinical improvement in some patients. This drug has some hepatotoxicity and should be started at 200 mg/d and slowly increased by 200 mg/d every 2–3 days up to a total daily dose of 1000 mg.

Metyrapone

Metyrapone (Figure 39–5) is a relatively selective inhibitor of steroid 11-hydroxylation, interfering with cortisol and corticoster-one synthesis. In the presence of a normal pituitary gland, there is a compensatory increase in pituitary ACTH release and adrenal 11-deoxycortisol secretion. This response is a measure of the capacity of the anterior pituitary to produce ACTH and has been adapted for clinical use as a diagnostic test. Although the toxicity of metyrapone is much lower than that of mitotane (see text that follows), the drug may produce transient dizziness and gastroin-testinal disturbances. This agent has not been widely used for the treatment of Cushing’s syndrome. However, in doses of 0.25 g twice daily to 1 g four times daily, metyrapone can reduce cortisol production to normal levels in some patients with endogenous Cushing’s syndrome. Thus, it may be useful in the management of severe manifestations of cortisol excess while the cause of this condition is being determined or in conjunction with radiation or surgical treatment. Metyrapone is the only adrenal-inhibiting medication that can be administered to pregnant women with Cushing’s syndrome. The major adverse effects observed are salt and water retention and hirsutism resulting from diversion of the 11-deoxycortisol precursor to DOC and androgen synthesis.

Metyrapone is commonly used in tests of adrenal function. The blood levels of 11-deoxycortisol and the urinary excretion of 17-hydroxycorticoids are measured before and after administra-tion of the compound. Normally, there is a twofold or greater increase in the urinary 17-hydroxycorticoid excretion. A dose of 300–500 mg every 4 hours for six doses is often used, and urine collections are made on the day before and the day after treatment. In patients with Cushing’s syndrome, a normal response to metyrapone indicates that the cortisol excess is not the result of a cortisol-secreting adrenal carcinoma or adenoma, since secretion by such tumors produces suppression of ACTH and atrophy of normal adrenal cortex.

Pituitary function may also be tested by administering metyrapone, 2–3 g orally at midnight and by measuring the level of ACTH or 11-deoxycortisol in blood drawn at 8 AM or by comparing the excretion of 17-hydroxycorticosteroids in the urine during the 24-hour periods preceding and following administra-tion of the drug. In patients with suspected or known lesions of the pituitary, this procedure is a means of estimating the ability of the gland to produce ACTH. Metyrapone has been with-drawn from the market in the USA but is available on a compas-sionate basis.

Trilostane

Trilostane is a 3β-17 hydroxysteroid dehydrogenase inhibitor that interferes with the synthesis of adrenal and gonadal hormones and is comparable to aminoglutethimide. Trilostane’s adverse effects are predominantly gastrointestinal; adverse effects occur in about 50% of patients with both trilostane and aminoglutethimide. There is no cross-resistance or crossover of side effects between these compounds. Trilostane is not available in the USA.

Abiraterone

Abiraterone is the newest of the steroid synthesis inhibitors to enter clinical trials. It blocks 17α-hydroxylase (P450c17) and 17,20-lyase (Figure 39–1), and predictably reduces synthesis of cortisol and gonadal steroids in the adrenal and gonadal steroids in the gonads. A compensatory increase occurs in ACTH and aldosterone synthesis, but this can be prevented by concomitant administration of dexamethasone. Abiraterone is an orally active steroid prodrug and has been studied in the treatment of refrac-tory prostate cancer.

Mifepristone (RU-486)

The search for a glucocorticoid receptor antagonist finally suc-ceeded in the early 1980s with the development of the 11β-aminophenyl-substituted 19-norsteroid called RU-486, later named mifepristone. Unlike the enzyme inhibitors previously discussed, mifepristone is a pharmacologic antagonist at the ste-roid receptor. This compound has strong antiprogestin activity and initially was proposed as a contraceptive-contragestive agent. High doses of mifepristone exert antiglucocorticoid activity by blocking the glucocorticoid receptor, since mifepristone binds to it with high affinity, causing (1) some stabilization of the hsp-glucocorticoid receptor complex and inhibition of the disso-ciation of the RU-486–bound glucocorticoid receptor from the hsp chaperone proteins; and (2) alteration of the interaction of the glucocorticoid receptor with coregulators, favoring the formation of a transcriptionally inactive complex in the cell nucleus. The result is inhibition of glucocorticoid receptor activation.

The mean half-life of mifepristone is 20 hours. This is longer than that of many natural and synthetic glucocorticoid agonists (dexamethasone has a half-life of 4–5 hours). Less than 1% of the daily dose is excreted in the urine, suggesting a minor role of kid-neys in the clearance of the compound. The long plasma half-life of mifepristone results from extensive and strong binding to plasma proteins. Less than 5% of the compound is found in the free form when plasma is analyzed by equilibrium dialysis. Mifepristone can bind to albumin and α₁-acid glycoprotein, but it has no affinity for corticosteroid-binding globulin.

In humans, mifepristone causes generalized glucocorticoid resis-tance. Given orally to several patients with Cushing’s syndrome due to ectopic ACTH production or adrenal carcinoma, it was able to reverse the cushingoid phenotype, to eliminate carbohy-drate intolerance, normalize blood pressure, to correct thyroid and gonadal hormone suppression, and to ameliorate the psychological sequelae of hypercortisolism in these patients. At present, this use of mifepristone can only be recommended for inoperable patients with ectopic ACTH secretion or adrenal carcinoma who have failed to respond to other therapeutic manipulations.

Mitotane

Mitotane (Figure 39–5), a drug related to the DDT class of insec-ticides, has a nonselective cytotoxic action on the adrenal cortex in dogs and to a lesser extent in humans. This drug is administered orally in divided doses up to 12 g daily. About one third of patients with adrenal carcinoma show a reduction in tumor mass. In 80% of patients, the toxic effects are sufficiently severe to require dose reduction. These include diarrhea, nausea, vomiting, depression, somnolence, and skin rashes. The drug has been with-drawn from the market in the USA but is available on a compas-sionate basis