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Chapter: Basic & Clinical Pharmacology : The Gonadal Hormones & Inhibitors

Androgen Suppression & Antiandrogens

The treatment of advanced prostatic carcinoma often requires orchiectomy or large doses of estrogens to reduce available endog-enous androgen.



The treatment of advanced prostatic carcinoma often requires orchiectomy or large doses of estrogens to reduce available endog-enous androgen. The psychological effects of the former and gynecomastia produced by the latter make these approaches unde-sirable. As noted, the GnRH analogs such as goser-elin, nafarelin, buserelin, and leuprolide acetate produce effective gonadal suppression when blood levels are continuous rather than pulsatile.


The potential usefulness of antiandrogens in the treatment of patients producing excessive amounts of testosterone has led to the search for effective drugs that can be used for this purpose. Several approaches to the problem, especially inhibition of synthesis and receptor antagonism, have met with some success.

Steroid Synthesis Inhibitors

Ketoconazole, used primarily in the treatment of fungal disease,is an inhibitor of adrenal and gonadal steroid synthesis, as described. It does not affect ovarian aromatase, but it reduces human placental aromatase activity. It displaces estradiol and dihydrotestosterone from sex hormone-binding protein in vitro and increases the estradiol:testosterone ratio in plasma in vivo by a different mechanism. However, it does not appear to be clinically useful in women with increased androgen levels because of the toxicity associated with prolonged use of the 400–800 mg/d required. The drug has also been used experimentally to treat prostatic carcinoma, but the results have not been encouraging. Men treated with ketoconazole often develop reversible gyneco-mastia during therapy; this may be due to the demonstrated increase in the estradiol:testosterone ratio.

Conversion of Steroid Precursors to Androgens

Several compounds have been developed that inhibit the 17-hydroxylation of progesterone or pregnenolone, thereby pre-venting the action of the side chain-splitting enzyme and the further transformation of these steroid precursors to active androgens. A few of these compounds have been tested clinically but have been too toxic for prolonged use. As noted, abiraterone, a newer 17-hydroxylase inhibitor, may prove to be clinically successful.

Since dihydrotestosterone—not testosterone—appears to be the essential androgen in the prostate, androgen effects in this and similar dihydrotestosterone-dependent tissues can be reduced by an inhibitor of 5α-reductase (Figure 40–6). Finasteride, a steroid-like inhibitor of this enzyme, is orally active and causes a reduction in dihydrotestosterone levels that begins within 8 hours after administration and lasts for about 24 hours. The half-life is about 8 hours (longer in elderly individuals). Forty to 50 percent of the dose is metabolized; more than half is excreted in the feces. Finasteride has been reported to be moderately effective in reduc-ing prostate size in men with benign prostatic hyperplasia and is approved for this use in the USA. The dosage is 5 mg/d. Dutasteride is a similar orally active steroid derivative with a slowonset of action and a much longer half-life than finasteride. The dosage is 0.5 mg daily. These drugs are not approved for use in women or children, although finasteride has been used success-fully in the treatment of hirsutism in women and early male pat-tern baldness in men (1 mg/d).

Receptor Inhibitors

Cyproterone and cyproterone acetate are effective antiandrogensthat inhibit the action of androgens at the target organ. The ace-tate form has a marked progestational effect that suppresses the feedback enhancement of LH and FSH, leading to a more effec-tive antiandrogen effect. These compounds have been used in women to treat hirsutism and in men to decrease excessive sexual drive and are being studied in other conditions in which the reduction of androgenic effects would be useful. Cyproterone acetate in a dosage of 2 mg/d administered concurrently with an estrogen is used in the treatment of hirsutism in women, doubling as a contraceptive pill; it has orphan drug status in the USA.

Flutamide, a substituted anilide, is a potent antiandrogen thathas been used in the treatment of prostatic carcinoma. Although not a steroid, it behaves like a competitive antagonist at the androgen receptor. It is rapidly metabolized in humans. It frequently causes mild gynecomastia (probably by increasing testicular estrogen production) and occasionally causes mild reversible hepatic toxicity. Administration of this compound causes some improvement in most patients with prostatic carcinoma who have not had prior endocrine therapy. Preliminary studies indicate that flutamide is also useful in the management of excess androgen effect in women.

Bicalutamide and nilutamide are potent orally active antian-drogens that can be administered as a single daily dose and are used in patients with metastatic carcinoma of the prostate. Studies in patients with carcinoma of the prostate indicate that these agents are well tolerated. Bicalutamide is recommended for use in combination with a GnRH analog (to reduce tumor flare) and may have fewer gastrointestinal side effects than flutamide. A dos-age of 150–200 mg/d (when used alone) is required to reduce prostate-specific antigen levels to those achieved by castration, but, in combination with a GnRH analog, 50 mg/d may be ade-quate. Nilutamide is approved for use following surgical castration in a dosage of 300 mg/d for 30 days followed by 150 mg/d.

Spironolactone, a competitive inhibitor of aldosterone, also competes with dihydrotestosterone for the andro-gen receptors in target tissues. It also reduces 17α-hydroxylase activity, lowering plasma levels of testosterone and androstene-dione. It is used in dosages of 50–200 mg/d in the treatment of hirsutism in women and appears to be as effective as finasteride, flutamide, or cyproterone in this condition.

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