Antiandrogen Cyproterone Acetate Research Articles

The crystal structure of a potent anti-androgen: cyproterone acetate (6-chloro-17-hydroxy-1α,2α-methylenepregna-4,6-diene-3,20-dione acetate)

The crystal structure of the anti-androgen cyproterone acetate (CPA, 6-chloro-17-hydroxy-le,2emethylenepregna-4,6-diene-3,20-dione acetate, C24H2904C1) was determined with the aid of symbolic addition. The steroid crystallized in the orthorhombic space group P212121 with a= 10.757 (2), b= 12.266 (3), e-16.623 (3) A,, and Z=4. A three-dimensional data set was collected with Cu Ke radiation (2= 1.5418 A,) on a Syntex P1 diffractometer to a maximum 20 value of 100 ° employing a 0-20 scan technique. The coordinates of the non-hydrogen atoms and their anisotropic temperature factors were refined in a full matrix least-squares manner to a final R index of 0.054 based on F 2. Bond distances around the cyclopropane ring were shortened, implying an interaction with the carbonyl group in ring A.

Characterization of a specific androgen receptor in rat prostate cytosol by agargel electrophoresis. In vivo and in vitro studies

In the 105,000 g prostate cytosol fraction of rats a specific receptor for 5α-dihydrotestosterone and testosterone has been demonstrated under in vivo and in vitro conditions. Six criteria which allow conclusions regarding the specificity of an androgen receptor have been elaborated: (1) A binding has been obtained in the target organ only, not in skeletal muscle and in plasma. (2) The thermolability of the receptor has been proved. (3) The plasma contamination of the cytosol fraction in question could not account for the binding. (4) A complete displacement of the labelled androgen by a 100-fold excess of the unlabelled compound was obtained. In this respect, too, a higher affinity of the receptor to 5α-dihydrotestosterone has been observed. (5) The non-androgen cortisol was ineffective in displacing the androgen from its receptor. (6) An inhibition of binding of the androgen was demonstrated with the anti-androgen cyproterone acetate in vivo as well as in vitro. The relevance of these findings in regard to androgen receptors and to the problem of androgen binding in human prostatic hypertrophy has been discussed.

Uptake of 3H-Testosterone and influence of an antiandrogen in tissues of rainbow trout ( Salmo gairdneri)

3H-Testosterone was administered to yearling rainbow trout ( Salmo gairdneri) of both sexes to establish accumulation and retention of androgen by various organs and tissues. Radioactivity in plasma, liver, and gonad were determined six times during the 24 hours post treatment. Radionuclide uptake in plasma was rapid, while the retention time in the liver was several times that of the blood, and no sexual dimorphism was found. The testes accumulated significantly more radionuclide than did ovaries; the former retained the radionuclide longer than any other tissue. Pretreatment of trout with the potent antiandrogen cyproterone acetate significantly reduced radioactivity in plasma of both sexes, in testes but not ovaries, and possibly in the liver of the male. No effect due to the androgen antagonist was apparent in kidney, spleen, gall bladder, brain, pituitary, or epaxial muscle. High levels of radioactivity found in the bile indicates that the trout were using a hepatic route for clearance of the exogenous steroid.

Effect of human chorionic gonadotrophin on testicular 5 -adnrostane-3 -hydroxysteroid dehydrogenase, 3 -hydroxydehydroepiandrosterone dehydrogenase and alcohol dehydrogenase of immature rats.

SUMMARY Testicular enzymes related to steroid conversion were studied in infantile rats during sexual maturation, and the effect of human chorionic gonadotrophin (HCG) on the specific activities of the enzymes was analysed. Activity of 5α-androstane-3β-hydroxysteroid dehydrogenase, which increases between days 20 and 30, was markedly enhanced after administration of HCG. Alcohol dehydrogenase activity, which is related to 3β-hydroxysteroid dehydrogenase activity, also increased after HCG treatment. The other enzyme activities investigated, i.e. 3β-hydroxyde-hydroepiandrosterone dehydrogenase and testosterone-17β-dehydrogenase, did not respond to HCG administration. These results suggest that different enzymes are responsible for the conversion of 3β-hydroxylated androgenic steroids and that the testicular alcohol dehydrogenase is not identical to the 3β-hydroxysteroid dehydrogenase described here. On the assumption that HCG enhances enzyme activities indirectly by stimulating the synthesis of androgens which in turn produce the observed effect, different androgenic steroids (epiandrosterone, 5α-androstane-3,17-dione, 5α-dihydrotestosterone, 5α-androstane-3β,17β-diol) were tested for their ability to increase enzyme activities. None of these metabolites had an effect similar to that of HCG. The antiandrogen cyproterone (1,2α-methyl-6-chloro Δ4,6-pregnadien-17β-ol-3,20-dione) acetate, which was administered simultaneously with HCG, did not prevent the effect of HCG. From these results and other published reports it is concluded that in the testis of the infantile rat the metabolism of 5α-hydrogenated androgenic metabolites is stimulated by HCG.

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.

The ultrastructure of the pars distalis of the hypophysis in males of Triturus cristatus carnifex Laur., treated with the antiandrogen cyproterone acetate.

The adenohypophysis of the newt Triturus cristatus carnifex Laur. shows three types of cells: 1) cells with granules of about 350–550 mμ in diameter, 2) cells with small granules of 200–250 mμ in diameter and globules with a cristal-like arrangement containing cylinders with a diameter of about 960 A and 3) cells containing small granules only. The AA. discuss the ultrastructural changes of the gland and the modifications of sexual secondary characters (S.S.C.) in animals given Cyproterone acetate (1/2 mg every three days). The animals have been treated for a period of time varying between 3 and 5 months, starting in October-November, when S.S.C. begin to develop again. At the end of the treatment the newths showed a loss of S.S.C., and the ultrastructure of the adenohypophysis resembled that of castrated animals, i.e.: great swelling of R.E.R. and partial degranulation of glycoprotein secreting cells which contain the 200 mμ granules and the globules. The S.E.R. showed also swelling and hyperactivity.

Resocialization of sexually abnormal patients by a combination of anti-androgen administration and psychotherapy

The sexual dynamics of the personality with anomalous sexual attitudes and perversions are often so powerful that psychotherapy is without effect. In order to render such patients accessible to psychotherapy, I have used the antiandrogen cyproterone acetate (Schering). By means of this combined therapy, sex deviants such as compulsive masturbators and sadists, and delinquents such as exhibitionists, pederasts, rapists and kleptomaniacs can be rehabilitated socially and professionally. In many cases, it was necessary to treat the wives also, as they had been frustrating their husbands sexually and thus driving them to deviant or delinquent behaviour.

Failure of antiandrogen cyproterone acetate to modify sexual stimulation induced byp-Chlorophenylalanine and testosterone

p-Chlorophenylalanine (p-CPA) has been shown to produce compulsive sexual activity in rats, cats, and rabbits (Shillito, 1970; Ferguson et al., 1969; Gessa et al., 1970; Tagliamonte et al., 1969); however, not all authors have been successful in inducing more frequent sexual performance in rats and cats (Whalen and Luttge, 1970; Zitrin et al., 1970). The compulsive sexual behavior in castrated rats can be induced in p-CPAtreated animals by testosterone. Combination of p-CPA and testosterone produces in male castrated rats hypersexuality which can be inhibited by 5-hydroxytryptophan (Gessa et al., 1970). It appeared important to see whether the combined action of p-CPA and testosterone could be inhibited by an antiandrogen, cyproterone acetate. The experiments were carried out as described by Gessa et aL (1970). Male albino Wistar rats weighing 300-320 g were castrated 20 days before the experiment began. All rats were caged individually and divided into three groups. The first group of castrated rats was treated with p-CPA (100 mg/kg, intraperitoneally); the second received p-CPA and testosterone propionate (1.2 mg/kg, subcutaneously). The third group received p-CPA, testosterone, and cyproterone acetate (12 mg/kg, subcutaneously). The drugs were given once daily at noon for 5 days; 6 hr after the last treatment, the animals were placed in cages in groups of eight and observed for 2 hr. The observations were repeated on 3 consecutive days. The animals which made at least one attempt to mount another male rat during the observation period were considered as sexually excited. The results are shown in Table I. Cyproterone acetate did not exeit any inhibitory effect upon sexual behavior of castrated male rats treated with p-CPA and testosterone. The results confirm the findings of several authors (Whalen and Edwards, 1969; Zucker, 1966; Beach and Westbrook, 1968) who failed to demonstrate an inhibition of sexuality with cyproterone acetate in intact or castrated testosterone-treated rats and are in contrast to the report of inhibition of sexuality in men (Laschet and Laschet, 1967; Hoffet, 1968). Cyproterone acetate, which is capable of inducing hypogonadism in male rats, does

Androgenicity in the rat fetus of metabolites of testosterone and antagonism by cyproterone acetate.

The degree to which various androgens increase anogenital distance in the female rat fetus and the degree of antagonism of this androgenic action by simultaneous administration of the antiandrogen cyproterone acetate, have been determined. The virilizing potency in order of decreasing effectiveness is dihydrotestosterone (DHT), 5α-androstan-3α,17β-diol (3α-diol), testosterone, androst-4-en-3,17-dione, 5α-androstane, 3β,17β-diol, androst-5-en-3β-ol-17-one and androsterone. The androgens, except 3a-diol, also reduce fetal adrenal weight, while cyproterone acetate prevents this effect. DHT and 3α-diol correct the degree of hypospadias produced by cyproterone acetate in male fetuses to a greater degree than testosterone but the antiandrogen blocks the androgenic action of the testosterone metabolites more than it does testosterone. These results suggest that the metabolites of testosterone can be responsible for the organizing action of testosterone in the fetus. (Endocrinology89: 276, 1971)

Clinical-pharmacological investigation of cyproterone acetate.

(1) The antiandrogenic steroid cyproterone acetate exerted a strongly negative nitrogen balance in 8 young male volunteers, the degree of which correlated with the dose administered. In a male patient of 77 years with cancer of the prostate, this catabolic effect proved to be much weaker. In 8 female patients with hirsutism, administration of cyproterone acetate resulted only then in a negative nitrogen balance when the food was deficient in calories and protein. Continuous treatment with cyproterone acetate in female patients is not feasible because of strongly progestational side-effects. These side effects can be avoided by combining cyproterone acetate with ethinyl estradiol as an ‘inverted sequential scheme’, according to Hammerstein and Cupceancy [2]. In most female patients with hirsutism, good or satisfactory results can be obtained by a continuous cyproterone acetate therapy or by the combination treatment of Hammerstein and CUPCEANCY [2].

Effects of antiestrogen and antiandrogen in amphibia.

The antiestrogen (ICI 46,474) and antiandrogen (cyproterone acetate) provoke castration-like changes in the pars distalis cytology of adult <i>Rana esculenta</i>. In males, cyproacetate also causes regression of androgen-dependent thumb pads. Effects upon the pars distalis are not direct but rather through the hypothalamus. Stimulatory effects of exogenous estrogen and androgen upon their target organs (both peripheral and central) are selectively inhibited by the respective antisteroidal compound. It seems that these compounds act by competitive action against steroid hormones at the receptor sites in target organs, as has also been suggested in mammals. The antiandrogens, cyproterone and cyproterone acetate, exert masculinizing effects in the course of sex differentiation of gonads of <i>Rana esculenta</i>. These effects are similar to those obtained by androgens.

Effect of the antiandrogen cyproterone acetate on estradiol production and metabolism in man

Two men with benign prostatic hypertrophy were studied before and after treatment with the antiandrogen cyproterone acetate. Following treatment the production rate of estradiol as calculated from the specific activity of urinary estrone or estriol decreased by approximately one half. The treatment altered the metabolism of estradiol in that less estrone, 2-hydroxyestrone and 2-methoxyestrone but more estriol was formed, a pattern similar to that found in men with breast cancer.

Die medizinische und soziale Indikation der Antiandrogen-Behandlung

The therapy with antiandrogen Cyproteroneacetate (Schering) represents a treatment of libido and sexual potency in men suffering under hypersexuality or deviation of sexual motive power; the method is reversible and always assessable to regulation. Since 2 1/2 years a total of 27 repeatedly prosecuted delinquents have been treated with this orally applied drug. There was no counter-indication related to the age of the men observed. A change of sexual motive powers or any result over and above the medication may not be expected. The best effects are to be expected from old men or younger married persons standing under afflicted power. Character defects or under-standard intelligence oppose long-term, binding measures.

Contraceptive properties of the anti-androgen cyproterone acetate.

Male rats were treated with injections of cyproterone acetate (CA) a synthetic steroidal antiandrogen to study its potential as a contraceptive agent. In control experiments all of the 7 males studied were able to impregnate at least 1 of the 2 females to which they were exposed. After a series of 16 CA injections only 5 of the 7 were able to impregnate 1 of 2 females and only 1 was able to impregnate both (p<.02). After 48 injections no female became pregnant. 45 days after cessation of treatment all of the males impregnated at least 1 of the 2 females. The vigor of mating behavior was not affected by CA. The contraceptive effect is thought to be due to the effect of CA on the storage of sperm possibly through the change produced in the chemistry of the seminal fluid.

Effects of the anti-androgen cyproterone acetate on the uptake of 1,2-3H-testosterone in neural and peripheral tissues of the castrate male rat.

The anti-androgen cyproterone acetate (CA) causes regression of the seminal vesicle when administered to the mature male rat, and CA treatment of the pregnant rat permits vaginal development in male offspring. CA, however, does not inhibit androgen controlled sexual behavior in male rats. It was therefore hypothesized that CA might inhibit the uptake and retention of l,2-3H-testosterone in peripheral genital tissues, but not in central neural tissues which mediate mating behavior. To test this hypothesis, castrate males were administered tritiated testosterone following pretreatment with CA or oil and sacrificed 5 or 60 min after testosterone treatment. All tissue samples showed androgen uptake. CA had no influence on uptake measured at 5 min. In pituitary, brain and muscle, radioactivity levels were lower in the 60 min samples than in the 5 min samples. CA had no effect upon retention of testosterone measured at 60 min in these tissues. Radioactivity levels were the same or higher at 60 min in the seminal vesicle, glans penis and plasma samples. In these samples CA reduced radioactivity levels (seminal vesicle and glans penis) and heightened plasma radioactivity in the 60 min samples relative to the 5 min samples. Steroid separations showed that CA had its influence in those tissues which contain a significant amount of androstenedione. (Endocrinology 84: 217,1969)

Effects of the Anti-androgen Cyproterone Acetate on Mating Behavior and Seminal Vesicle Tissue in Male Rats

The synthetic steroid cyproterone acetate (6-chloro-17-hydroxy-lα,2α-methylenepregna- 4,6-diene-3,20-dione acetate) exerts strong antiandrogenic properties with respect to the seminal vesicles, but not with respect to androgen dependent mating behavior in male rats. Gonadectomized, sexually experienced male rats were treated with 1) testosterone propionate (TP); 2) TP plus cyproterone acetate, or 3) oil for 3 weeks, and given 3 mating tests at weeklyintervals. The seminal vesicles of all males were removed after 2 weeks of treatment. The intensity of mating behavior declined progressively in the oil treated castrates but not the androgen or androgen plus anti-androgen treated males. The seminal vesicles of the oil treated and androgen plus anti-androgen treated rats regressed in comparison with the seminal vesicles of males treated only with testosterone. (Endocrinology 84:155, 1969)