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.     

Interaction of cyproterone acetate with rat prostatic androgen receptors

We have investigated the binding of cyproterone acetate (CA) to cytosolic androgen receptors (RC) and translocation of the RCCA complex into the nucleus. In a cell-free system (3H)CA binds to cytosolic androgen receptors with high affinity (KD = 11.6 nM) and limited capacity (180-200 femtomoles/mg protein). (3H)CA, however, dissociates very rapidly from the cytosolic and nuclear androgen receptors (Rn) at 0 degree C. Incubation of RC (3H)CA at 20 degrees C increased its ability to bind to nuclei. Translocation of RC (3H)CA to nuclei of intact cells was demonstrated after incubation of prostatic tissue with (3H)CA in tissue culture medium at 37 degrees C. In vivo administration of CA to castrated rats promoted RCCA translocation but did not induce androgen receptor replenishment. These data demonstrate that CA binds to and translocates androgen receptors to nuclei without concomitant receptor replenishment.     

Androgens and androgen-receptors in prostate tissue from patients with benign prostatic hyperplasia: effects of cyproterone acetate.

Testosterone, 5 alpha-dihydrotestosterone and cyproterone acetate (CPA) were estimated in samples of prostate tissue, obtained from benign prostatic hyperplasia (BPH) patients who were or were not pretreated with CPA. Furthermore, these steroids were estimated in various fractions of the BPH tissue, and the number of nuclear androgen-receptor sites was determined. CPA-treatment caused a 4-fold, significant suppression of 5 alpha-dihydrotestosterone levels in total prostate tissue and its subfractions, without affecting testosterone levels or the androgen-receptor contents of the nuclear extracts. Nuclear concentrations of CPA were twice as high as those of 5 alpha-dihydrotestosterone. It is concluded that effects of CPA may have been caused through a combination of the following mechanisms: (1) suppression of peripheral androgen levels; (2) competition with androgens for (nuclear) androgen-receptors; and (3) suppression of prostatic 5 alpha-reductase.     

Testicular phosphatase activity in rats treated with cyproterone acetate & flutamide

Cyproterone acetate (CPA) and flutamide (F), 2 antiandrogens were tested in the rat, to determine their effect on acid (ACP) and alkaline (ALP) phosphatase activity. 70 fertile male rats were injected with either CPA, F, or testosterone propionate (TP) at either 2.5 or 10 mg. TP was injected either alone or in combination with the others. Histological examinations of the testes were performed. Spermatogenesis was arrested and Leydig cells atrophied in animals treated with CPA or F. Histochemical examination revealed that CPA enhanced ALP and ACP in the testes while F decreased ALP and ACP. TP treatment in combination with either antiandrogens was unable to overcome their effect. The changes in the 2 phosphatases depending on which antiandrogen was injected suggests different modes of action.     

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)     

Androgen dynamics in vitro in the human prostate gland. Effect of cyproterone and cyproterone acetate

Hyperplastic and adenocarcinomatous human prostatic tissue was superfused in vitro with radioactively labelled androst-4-ene-3,17-dione, testosterone and 5alpha-dihydrotestosterone (17beta-hydroxy-5alpha-androstan-3-one), with and without addition of the anti-androgens cyproterone and cyproterone acetate. Cyproterone competitively inhibited the entry of the androgens into the majority of the tissues, whereas cyproterone acetate increased this entry. These findings indicated that transport of androstenedione, testosterone and 5alpha-dihydrotestosterone into prostatic tissue is performed by a specific mechanism, possibly involving a carrier situated in the cell membrane. The extent of metabolism of the three androgens was also modified: formation of 5alpha-dihydrotestosterone from testosterone, and of the latter from androstenedione, was decreased by cyproterone and increased by the acetate. Acetate was more effective than cyproterone in decreasing the ;uptake' of the perfused androgens by the tissue; at the same time, it increased the androgen clearance from the tissue. As cyproterone acetate is the more potent of the two anti-androgens, the possibility that these findings in vitro are related to the different anti-androgenic potency exhibited by the two compounds in vivo is discussed. ;Uptake' of the two anti-androgens and the response to their action on androgen dynamics were similar in adenocarcinomatous and hyperplastic glands.     

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.     

Isolation and identification of 15-beta-hydroxy cyproterone acetate as a new metabolite of cyproterone acetate in dog, monkey and man.

15-beta-hydroxy cyproterone acetate could be identified by thin layer chromatography, mass spectrum, NMR and IR spectrum as a major unconjugated metabolite of cyproterone acetate in plasma and urine of dog, monkey and man. This metabolite has been found to interferein the Mattingly method for the determination of 11-hydroxy-corticosteroids which suggests, that this method is inadequate in controling the adrenal function of subjects treated with cyproterone acetate.     

Urinary androgen response of 8 girls with precocious puberty given cyproterone acetate.

The effects of cyproterone acetate (CA), daily oral administration of 100 mg/m2, on the levels of urinary androgen excretion and velocity of skeletal maturation were studied in 8 girl patients with precocious puberty. Under therapy, testosterone excretion fell within a short time, and velocity of skeletal maturation normalized when the treatment was prolonged. Other beneficial effects such as stoppage of vaginal bleeding and no further growth of breast size and public hair, were also observed. Of 3 subjects, who were given CA for a period of 2--3 yrs, 2 showed further increments in testosterone excretion levels.     

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.     

Effect of cyproterone acetate on active and inactive renin secretion in patients with precocious puberty and genetic short stature.

To evaluate the effect of cyproterone acetate (CA) on the renin-angiotensin-aldosterone axis, we measured the plasma active, inactive and total renin concentrations (PARC, PIRC and PTRC) during and after CA treatment in patients with precocious puberty and genetic short stature. CA was administered at a daily dose of 150-170 mg/m2 in all subjects. PARC and PTRC were measured by immunoradiometric assays. During CA treatment, PARC, PIRC, PTRC and the PARC/PTRC ratio were significantly decreased. The plasma renin activity, measured by enzymatic assay, and the plasma aldosterone concentration were also decreased. After CA discontinuation, all of these were increased immediately along normal ranges. PARC closely correlated with plasma renin activity. These results suggest that CA produces mineralocorticoid action and suppresses the production and activation of renin.     

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     

Effects of cyproterone acetate on adrenal steroidogenesis in vitro

The effects of cyproterone acetate (CA) on steroidogenesis in isolated guinea-pig adrenal cells have been investigated by measuring the production of cortisol, its immediate precursors (11-deoxycortisol and 17-hydroxyprogesterone), and adrenal androgens (delta 4-androstenedione and dehydroepiandrosterone). Used at a dose of 2 micrograms/ml, CA provoked a sharp drop in the production of cortisol, aldosterone and 11-deoxycortisol. By contrast, 17-hydroxyprogesterone, delta 4-androstenedione and dehydroepiandrosterone were increased, which suggests that 21-hydroxylase activity is inhibited. With concentrations above 2 micrograms/ml CA, it would seem to be the 3-beta-ol-dehydrogenase-delta 4,5-isomerase complex that is affected, since dehydroepiandrosterone exhibited a sudden increase, whereas 17-hydroxyprogesterone and delta 4-androstenedione showed a relative decrease. The enzymatic system or systems involved therefore appear to be linked to the concentration of CA used but, whatever the case, the drop in cortisol production is accompanied by a decrease in aldosterone and an increase in adrenal androgen levels.     

Effect of cyproterone acetate acutely administered on the pituitary-testicular axis.

The effect of cyproterone acetate (CA) on the pituitary-testicular axis was studied in 6 healthy men. A dose of 300 mg of CA was administered orally in the early morning, after 3 h blood samples were collected using a multiple sample technique. Testosterone (T) levels were decreased by CA in all subjects (p 0.01), LH in all (p less than 0.01) but one whereas 17-hydroxyprogesterone did not show any significant variation. In vitro, using an equilibrium dialysis, CA displaced T from plasma-binding proteins in males at 37 degrees C. The role of testosterone-binding globulin on the effects of CA on the pituitary-testicular axis remains to be clarified.