Androgen metabolism in hirsute patients treated with cyproterone acetate

Cyproterone acetate (CPA) in association with percutaneously administered estradiol has been used for the treatment of 150 hirsute patients for periods ranging from 6 months to 3 years. A spectacular clinical improvement ensued. Plasma testosterone (T) and androstenedione (A) fell from 69.0 +/- 24 to 33.0 +/- 8 and 210 +/- 103 to 119 +/- 25 ng/dl (mean +/- SD) respectively after 3 months of treatment and remained low thereafter. In contrast, T glucuronide (TG) and 3 alpha-androstanediol (Adiol) remained high during the whole course of treatment: 37 +/- 9 and 115 +/- 43 micrograms/24 h respectively. In vitro T 5 alpha-reductase activity (5 alpha-R) in pubic skin decreased from 147 +/- 34 to 79 +/- 17 fmol/mg skin after 1 year of treatment. To elucidate the discrepancy between plasma and urinary androgens levels, T production rate (PR) and metabolic clearance rate (MCR) were measured with the constant infusion technique in 7 patients before and after 6 months of treatment. PR decreased from 988 +/- 205 to 380 +/- 140 micrograms/24 h (mean +/- SD). In contrast MCRT increased from 1275 +/- 200 to 1632 +/- 360 1/24 h; this increase in MCRT explains the striking plasma T concentration fall and the high TG and Adiol excretion relative to the decrease in PR. Antipyrine clearance rate (n = 8) increased from 36.3 +/- 5.2 to 51.5 +/- 7.4 ml/min whereas 6 beta hydroxycortisol remained unchanged. In conclusion, CPA acts through several mechanisms: (1) it lowers the androgen input to the target cells by (a) depressing T production through its antigonadotropic effect and (b) accelerating T metabolic inactivation due to a partial enzymatic inducer effect on the liver; (2) at the target cell level it competes with any remaining T for the receptor binding sites; (3) the decrease in the androgen-dependent skin 5 alpha-R is a consequence of both actions of androgen suppression and androgen receptor blockade; it reinforces the antiandrogenic effect of CPA.     

Oestrogenic activity of cyproterone acetate in female mice

Effects of cyproterone acetate, a synthetic steroidal compound, on the reproductive organs of female mice have been investigated. This agent caused reduction of ovarian weights indicative of suppression of pituitary gonadotrophins. Oestrogenic nature of cyproterone acetate was investigated in intact and ovariectomized animals taking uterine weight, vaginal keratinization and other biochemical oestrogen sensitive parameters. Cyproterone acetate in ovariectomized animals induced vaginal keratinization increase in uterine weight and uterine protein, RNA, glycogen and sialic acid contents. These effects were parallel to the effects of oestradiol dipropionate in ovariectomized animals, thus indicating oestrogenic activity of the compound.     

Proliferation of lamellar whorls in arcuate neurons of the hypothalamus of male rats treated with estradiol benzoate or cyproterone acetate

Summary The arcuate nucleus of the hypothalamus (AH) of male rats which had been treated either with estradiol benzoate (E²B) or cyproterone acetate (CPA) was examined ultrastructurally for the presence of whorls of endoplasmic reticulum. The incidence of whorl containing neurons (WCN) was 2–4 times higher in the AH of animals treated for 2–3 weeks with E²B or for 2 weeks with CPA than in the AH of oil treated controls. CPA is a powerful anti-androgen while E²B acts both peripherally and centrally to limit testosterone production. These findings, together with previous evidence that whorls proliferate in AH of male rats deprived of androgen by morphine treatment or castration, suggest that steroid feedback (androgen alone or both androgen and estrogen) plays an important role in AH whorl proliferation. The possibility that WCN may be LH-RH containing neurons is suggested by the close correspondence between the number and location of WCN within AH as determined in this study and the distribution of LH-RH containing cells reported by others.The authors are indebted to Schering AG for supplying cyproterone acetate for this study. This work was supported by grants DA-00259, NS-09156 and MH-14677 from U.S.P.H.S.Research Scientist Development Award MH-38894Research Scientist Development Award MH-70180     

The effect of short term treatment with cyproterone acetate or flutamide on the metabolism of 5 alpha-dihydrotestosterone in human testicular tissue

Testicular tissue obtained from ten patients orchiectomized for prostatic cancer was incubated with [3H]5 alpha-dihydrotestosterone (DHT) in order to study the metabolic transformation into 5 alpha-androstane-3 alpha,17 beta-diol (3 alpha-diol) and 5 alpha-androstane-3 beta,17 beta-diol (3 beta-diol). Throughout 5 days before surgery four subjects were treated with cyproterone acetate (CA). To three patients flutamide (F) was administered for the same period of time. Three subjects remained untreated. Compared to the control group the administration of CA decreased the formation of 3 beta-diol whereas that of 3 alpha-diol increased. Treatment with F lead to an elevated formation of both diols. However, the 3 alpha/3 beta ratio did not change. As 3 beta-diol is considered to be an index of tubular function in the human testis it is concluded that CA has a direct inhibitory effect upon this testicular compartment whereas F has none.     

Final height attainment and gonadal function in girls with precocious puberty treated with cyproterone acetate.

Thirty-four girls with precocious puberty (27 idiopathic, 6 cerebral, 1 McCune-Albright syndrome) were treated with cyproterone acetate (CPA) for 1.2-8.4 years (3.71 +/- 0.31; mean +/- SEM) at a daily dosage of 66-150 mg/m2 (103.7 +/- 6.2). The mean chronological age (CA) and bone age at the beginning of treatment were 5.99 +/- 0.31 and 8.6 +/- 0.39 years, respectively, and 9.78 +/- 0.19 and 12.44 +/- 0.22 years, respectively, at the end of therapy. At the last evaluation, mean CA was 14.23 +/- 0.4 years, and 32 girls had reached final height. The control group consisted of 10 girls with idiopathic precocious puberty who, at their parents' request, were not treated. Mean CA at the onset of pubertal signs was 6.05 +/- 0.25 years. All patients had reached final height at the time of the last observation. There was no significant difference between final height of treated (152.43 +/- 1.36 cm) and untreated (149.55 +/- 1.99 cm) girls. Final height was significantly lower than target height in both treated (155.08 +/- 0.92 cm; p < 0.025) and untreated (156.45 +/- 1.29 cm; p < 0.0005) patients, but the mean height of treated patients is nearer to target height than that of untreated ones. A positive correlation was found between final height and target height both in treated (p < 0.005) and untreated (p < 0.05) patients. After the discontinuation of CPA treatment all girls resumed the progressive course of puberty.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of the antiandrogens cyproterone acetate and flutamide on male reproductive behavior in a lizard (Anolis sagrei)

This study examined the effects of the antiandrogens cyproterone acetate (CA) and flutamide (F) on male reproductive behavior in the lizard Anolis sagrei. Reproductively active males were implanted with subcutaneous pellets of either CA, F, or placebo (P). Pellets delivered CA and F at a constant rate of 0.1 mg/day. Three weeks after implantation, males were tested with stimulus males and two days later with stimulus females. Cyproterone acetate inhibited aspects of male aggressive and sexual behavior, and reduced testis weight and size of the renal sex segment. Plasma testosterone (T) levels in CA-treated males were not significantly different than those of P-treated males. Flutamide did not inhibit aggressive or sexual behavior, but did decrease testis weight as well as the size of the renal sex segment. Plasma T levels were significantly higher in F-treated males than in P-treated males. These data suggest that CA, an antiandrogen with antigonadotropic activity, may be used to inhibit reproductive behavior in male lizards.     

Short-term effect of cyproterone acetate on testicular FSH binding in immature rats

Male rats, aged 19 days, were injected with 1 mg cyproterone acetate, an antiandrogen, and killed 24 h later. In 9 out of 10 experiments this increased the apparent FSH-binding capacity by testicular tissue in vitro. In 4 out of 5 similar experiments, injection of 500 micrograms testosterone propionate caused a significant reduction in FSH binding. Observed changes were small but this does not preclude the possibility that androgens contribute to the physiological control of FSH receptor numbers.     

Different behavior of the rat vas deferens of castrated animals and those treated with cyproterone acetate

The effects of castration and treatment with the antiandrogen cyproterone acetate (CPA) on the responses of the vas deferens of the rat induced by phenylephrine, KCl and BaCl2 has been studied. Both castration and CPA induced a spontaneous motility in the rat vas deferens. Castration produces a decrease of the response amplitude induced by phenylephrine and KCl and an increase of those induced by BaCl2 in animals killed 30 days after castration. CPA increases the response amplitude induced by phenylephrine and KCl without modifying those induced by BaCl2. These results suggest that the antiandrogen CPA produces modifications qualitatively different from castration.