Androgens: Antiandrogens

ANTIANDROGENS

By definition, antiandrogens are substances that pre-vent or depress the action of male hormones in their target organs. Potential sites of action include go-nadotropin suppression, inhibition of androgen synthe-sis, and androgen receptor blockade. Compounds that affect each of these sites are available. Potential clinical uses of antiandrogens include suppression of androgen excess and treatment of androgen-dependent tumors.

Extreme clinical examples of androgen excess include central precocious puberty, the adrenogenital syn-dromes, and androgen-secreting adrenal, ovarian, or testicular tumors. Less severe problems include idio-pathic hirsutism, premenstrual syndrome, and severe cystic acne.

Inhibitors of Androgen Biosynthesis

Ketoconazole (Nizoral) is a broad-spectrum antifungal agent  that in very high doses inhibits several steps in the biosynthesis of both adrenal and gonadal steroids. While the normal antifungal dose is 200 mg/day, testosterone biosynthesis in both the adre-nal and testis is completely abolished by doses of 800 to 1,600 mg/day. This drug is used most commonly for large virilizing adrenal tumors that cannot be surgically removed.

Androgen Receptor Antagonists

Spironolactone (Aldactone) is a compound originally developed as a mineralocorticoid antagonist and is used as a diuretic and antihypertensive agent . However, at high doses spironolactone binds to the androgen receptor. In clinical practice it is a weak an-drogen antagonist used to treat hirsutism in women by blocking testosterone binding to androgen receptors in hair follicles. Use of spironolactone in women for the treatment of hirsutism or male pattern baldness can re-sult in elevated serum potassium levels; these levels should be checked within 1 month of starting the med-ication.

Flutamide (Eulexin) is a nonsteroidal androgen re-ceptor antagonist that inhibits androgen binding to its nuclear receptor. It is effective in inducing prostatic re-gression and is approved for the treatment of prostatic carcinoma. For maximum clinical effectiveness it has to be used in combination with a GnRH antagonist (e.g., leuprolide acetate) that inhibits androgen production. Flutamide may eventually be used for the treatment of hirsutism and male pattern baldness in women if a top-ical preparation is developed.

Cyproterone acetate is a progestational antiandro-gen that blocks androgen receptor binding and sup-presses androgen-sensitive tissues. It is available in a topical form in Europe for the treatment of hirsutism.

5 α -Reductase Inhibitors

Finasteride (Proscar) is a 5 -reductase inhibitor that blocks the conversion of testosterone to DHT in target tissues. Since DHT is the major intracellular androgen in the prostate, finasteride is effective in suppressing DHT stimulation of prostatic growth and secretory function without markedly affecting libido. It is ap-proved for the treatment of benign prostatic hyperpla-sia. Although there is usually some regression in the size of the prostate gland following administration of finas-teride, clinical response may take 6 to 12 months. If the obstructive symptoms are severe, there is often not enough time to allow this compound to work. The prin-cipal adverse effects of finasteride are impotence, de-creased libido, and decreased volume of ejaculate. The compound is generally well tolerated in men.

Gonadotropin-Releasing Hormone Analogues

GnRH analogues  can induce chemical castration by suppressing the pulsatile release of LH and FSH, hence inhibiting testicular steroidogenesis. Administration of these compounds reduces circulating testosterone levels. These compounds are inhaled, in-jected subcutaneously, or implanted subcutaneously. They are used in males in the treatment of precocious puberty and carcinoma of the prostate.