Cyproterone: effect on serum gonadotropins in the male.

The exact mechanisms involved in the feedback regulation of follicle stimulating hormone (FSH) in the male are uncertain. Although large doses of testosterone can suppress serum FSH levels, this effect may represent either a direct androgenic influence or an indirect one mediated by the peripheral conversion of testosterone to estrogen. In this study, the effect of an antiandrogen, cyproterone, on serum FSH levels was tested to further clarify whether androgens can directly influence the feedback regulation of FSH. Additionally, the ability of cyproterone to provide a luteinizing hormone (LH) reserve test in men is studied. In immature male rats, cyproterone 2 mg/d produced no effect on ventral prostate weight (VPW) but 10 mg/d suppressed VPW to 50% of control weight. Serum LH concentrations were increased by both doses of cyproterone, 22% by 2 mg and 40% by 10 mg; serum FSH was unchanged. In adult rats, cyproterone failed to decrease VPW but did increase serum LH 25% by 50 mg/d and 50% by 100 mg/d; again serum FSH was unchanged. In castrated adult rats, treatment with testosterone propionate 400 ng/d increased VPW and decreased serum LH and FSH concentrations; simultaneous treatment of these rats with cyproterone 30 mg/d decreased VPW by 41% and increased both serum LH and FSH (45 and 34%). In three adult men treated with cyproterone (100, 200 and 400 mg/d) for 8-14 days, serum LH remained within the normal range. It is concluded: 1) cyproterone, in very large doses, increases serum LH but not FSH levels in male rats; 2) the suppression of FSH produced by treatment of castrate rats with testosterone can be partially reversed by an antiandrogen, indicating that androgens may have at least a partial role in the feedback control of FSH in the male; 3) because very large doses of cyproterone were necessary to stimulate LH levels in the rat and pharmacologic amounts failed to produce changes in the human, it is unlikely that cyproterone will provide an effective LH reserve test in the male. {Endocrinology 90: 1655, 1972) C 1 is a potent antiandrogen which inhibits exogenous and endogenous androgenic effect at target tissues (1). The mechanism proposed for this inhibition is twofold: inhibition of the formation of a specific 5ct-dihydrotestosterone protein complex in target cells (2) and interference with the biogenesis of Cio steroids from C21 precursors (3). Cyproterone, unlike its acetylated derivative (cyproterone acetate) which is highly progestational, is neither progestational nor antiestrogenic (1,4). We felt that cyproterone, a pure antiandrogen, would be useful in investigations of the feedback control of gonadotropins in the male. Although it is generally agreed that testosterone is the major feedback regulator of LH secretion in the male, the exact mechanism for the control of FSH release is uncertain. Several studies have demonstrated that selective loss of spermatogenesis results in increased serum conReceived December 10, 1971. 1 Trivial names used: cyproterone (free alcohol) = l,2oc-methylene-6-chloro-V-pregnadiene-17ocol-3,20-dione; cyproterone acetate = l,2cc-methylene-6-chloro-V 4 • °-pregnadiene-17 oc -ol-3,20-dione-17 oc -acetate. centrations of FSH, suggesting that spermatogenesis is involved in the feedback regulation of FSH (5-7). However, it has shown that despite complete inhibition of spermatogenesis, serum FSH does not increase to levels as high as those seen in castrate animals (5, 8), indicating that in addition, testosterone or a testosterone metabolite may influence FSH regulation. If castrate rats are treated with sufficiently large doses of testosterone, both serum LH and FSH concentrations fall to intact levels (9,10). This effect of testosterone may represent either a direct androgenic influence or an indirect one mediated by the peripheral conversion of testosterone to estrogen. In this study, the effect of an antiandrogen on serum FSH levels was studied to clarify whether androgens can directly influence the feedback regulation of FSH. Studies were first performed to test the ability of cyproterone to increase serum concentrations of radioimmunoassayable LH and FSH in intact male rats. Both weanling and adult rats were used for these studies in order to evaluate whether the presence of mature spermatogenic tissue would influence the effect of cyproterone