In contrast to the lack of strong indications for the use of androgen supplementation (except in the case of hypogonadism), the use of inhibitors of androgen synthesis and of androgen antagonists has
CHAPTER 40 The Gonadal Hormones & Inhibitors 743 several well-documented applications. The treatment of advanced prostatic carcinoma often requires orchiectomy or large doses of estrogens to reduce available endogenous androgen. The psychological effects of the former and gynecomastia produced by the latter make these approaches undesirable. As noted in Chapter 37, the GnRH analogs, such as goserelin, nafarelin, buserelin, and leuprolide acetate, produce effective gonadal suppression when blood levels are continuous rather than pulsatile (see Chapter 37 and Figure 40–6).
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.
Ketoconazole, used primarily in the treatment of fungal disease, is an inhibitor of adrenal and gonadal steroid synthesis, as described in Chapter 39. 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 gynecomastia during therapy; this may be due to the demonstrated increase in the estradiol:testosterone ratio.
Inhibition of Conversion of Steroid Precursors to Androgens
Several compounds have been developed that inhibit the 17-hydroxylation of progesterone or pregnenolone, thereby preventing 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 in Chapter 39, abiraterone, a newer 17α-hydroxylase inhibitor, has been approved for use in metastatic prostate cancer.
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). About 40–50% of the dose is metabolized; more than half is excreted in the feces. Finasteride has been reported to be moderately effective in reducing prostate size in men with benign prostatic hyperplasia and is
Ketoconazole,
Flutamide, cyproterone, (5) spironolactone Androgen-receptor complex
Expression of appropriate genes in androgen-responsive cells