摘要:

The DMBA-induced mammary carcinogenesis in the Sprague-Dawley rat is known to be both estrogen and prolactin dependent. The experiments presented here show that 2-Br-α-ergocryptine (CB 154), an inhibitor of prolactin secretion, and nafoxidine (, 100 A), an estrogen antagonist, inhibit the U 11 successive stages of carcinogenesis, namely formation of preneo plastic nodules, transformation of the latter into tumors, and finally growth of the established tumors. Endocrine studies, involving histological examination of organs and serum prolactin determination by radioimmunoassay, show that CB 154 inhibits prolactin secretion and produces peripheral changes consistent with this effect, and that nafoxidine behaves as an antiestrogen in intact animals and in oophorectomized animals given estrogens, that it is devoid of intrinsic estrogenic properties but rather displays progestational-like effects, and that it inhibits prolactin stimulation by estrogens in oophorectomized rats. The antitumor effect of CB 154 can be ascribed to interference with prolactin secretion. That of nafoxidine may result from its antiestrogenic properties at the tumor tissue level, although part of it could be tentatively ascribed to inhibition of prolactin secretion.

ISSN:0378-7346    

DOI:10.1159/000301858

出版商:S. Karger AG    

年代:1971

数据来源: Karger

ISSN:0378-7346    

DOI:10.1159/000301859

出版商:S. Karger AG    

年代:1971

数据来源: Karger

摘要:

Cyproterone acetate (6-chloro-17-acetoxy -1α,2α- methylene – 4,6-pregnadiene-3,20-dione) is the strongest antiandrogen known. Beside its androgenicity, this steroid has a strong progestational and thereby a partial antigonadotropic effect. There is vast evidence that the antiandrogenic effect is mainly due to competitive antagonism with androgens at the receptor sites of target organs. Experimental efforts aimed at two directions: (1) Possibilities for clinical use were evaluated and (2) cyproterone acetate was used as a tool for further investigation of testosterone-dependent events, e.g. androgen-dependent processes in the course of sexual differentiation. Almost all androgen-dependent organs and organ systems are affected by cyproterone acetate. Its most important effects in animals and humans are summarized in the following table: Since cyproterone acetate is also a potent progestagen, it could be used in combination with an estrogen as a hormonal contraceptive for women. Its antiandrogenicity would have positive effects in the so-called gestagen/androgen type of women. For use in men, only those antiandrogens would be suitable that have not only antiandrogenic but also gestagenic, hence antigonadotropic properties like cyproterone acetate. ‘Pure’ antiandrogens lacking these partial effects stimulate the secretion of gonadotropins and cause thereby enhanced synthesis and secretion of androgens which would compensate for antiandrogenic effects.

ISSN:0378-7346    

DOI:10.1159/000301860

出版商:S. Karger AG    

年代:1971

数据来源: Karger

摘要:

his review paper, including some unpublished results, summarizes some of the effects on sex differentiation in male fetuses of drugs which inhibit enzymes involved in steroid hormone synesis or of antiandrogens, especially cyproterone acetate. The former have only very slight effects on morphological sex differentiation. Cyproterone acetate is a very potent antimasculine agent in several species (rabbit, dog and probably others); in other species (rat, guinea pig, calf) the results obtained so far are at variance. Several apparently contradictory data pertaining to the stabilization and differentiation of the Wolffian ducts of the rat fetus are discussed.

ISSN:0378-7346    

DOI:10.1159/000301861

出版商:S. Karger AG    

年代:1971

数据来源: Karger

ISSN:0378-7346    

DOI:10.1159/000301862

出版商:S. Karger AG    

年代:1971

数据来源: Karger

摘要:

Selective inhibition of rat fetal 3β-Hydroxy-Δ5-steroid dehydrogenase with certain substrate analogs has produced a precise animal model of human congenital adrenal hyperplasia due to a genetic deficiency of this enzyme system. Inhibition of fetal testicular dehydrogenase dehydrogenase by the analog produces testosterone-reversible blockade of penis formation and of nipple anlagen resorption in male fetuses. These observations have been duplicated by maternal administration of rabbit antisera to testosterone-3-bovine serum albumin. Inhibition of the fetal adrenal dehydrogenase system leads to excess dehydroepiandrosterone (DHA) production which, in turn, produces corticosterone-reversible virilization of female fetal genitalia and nipple anlagen. Inhibition-induced excess DHA production may also explain the persistence of wolffian duct structures in male fetuses since recent studies indicate presence of a ductal dehydrogenase system capable of transforming DHA into testosterone and dihydrotestosterone. The striking properties of these analogs, e.g., tight binding to the enzymatic active sites, potency, specificity, prolonged duration of action and intrauterine effectiveness before differentiation of the fetal enzyme, can be ascribed to active site-directedirreversible (ASDI) inhibition. Application of principles of ASDI inhibition has led to the discovery of new ASDI inhibitors with a differing specificity of enzymatic inhibition and sites of action. Steroidal excretion patterns determined by gasliquid chromatography – mass spectrometry produced by these inhibitors support the sites of action determined in vitro. These ASDI inhibitors and hormone-antibodies give promise of highly specific and precise molecular probes of the chemical controls of sexual differentiation.

ISSN:0378-7346    

DOI:10.1159/000301863

出版商:S. Karger AG    

年代:1971

数据来源: Karger

摘要:

The androgen 5α-dihydrotestosterone (DHT) has been isolated and identified in testicular tissue (rats, dogs) and in testicular venous blood of the canine testis. Conversion of 3H-testosterone (T) to 3H-DHT in vitro by testicular tissue from rats treated with follicle-stimulating hormone in vivo tended to increase. No such effect of human chorionic gonadotropin treatment could be observed. The Leydig cells of testes from mature rats contribute little to the formation in vitro of 3H-DHT from 3H-T. Both these androgens can be found in spermatic lymph and in epididymal tissue of the dog. In an isolated prostate preparation where the gland is infused via the prostatic arteries with the animal’s arterial blood at a constant rate, DHT can be found in effluent blood. The dog prostate both produces and secretes DHT. The purpose of DHT production and secretion by male reproductive organs is discussed.

ISSN:0378-7346    

DOI:10.1159/000301864

出版商:S. Karger AG    

年代:1971

数据来源: Karger

摘要:

The paper presents evidence indicating that, in an “in vitro” system, progesterone may interfere with the conversion of testosterone into its “active” metabolites (5 alpha-androstan-17 beta-ol-3-one, 5 alpha-androstan-3 beta, 17 beta-diol and 5 alpha-androstan-3 alpha, 17 beta-diol, etc.) both at the anterior pituitary and prostatic levels. Progesterone probably acts as a preferential substrate for the enzyme 5 alpha-reductase present in these structures. Other steroids are also active in diminishing the 5 alpha-reduction of testosterone in its target organs. Both corticoids and progestagens seem to be effective inhibitors for such a reduction. These observations open a new approach for developing anti-androgenic compounds.

ISSN:0378-7346    

DOI:10.1159/000301865

出版商:S. Karger AG    

年代:1971

数据来源: Karger

摘要:

The antiestrogen (ICI 46,474) and antiandrogen (cyproterone acetate) provoke castration-like changes in the pars distalis cytology of adult Rana esculenta. 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 Rana esculenta. These effects are similar to those obtained by androgens.

ISSN:0378-7346    

DOI:10.1159/000301866

出版商:S. Karger AG    

年代:1971

数据来源: Karger

摘要:

Explants of the ventral prostate of adult rats, were maintained in organ culture with various steroids and insulin. In addition to androgens glucocorticoids and insulin were necessary for the maximal stimulation of the explants as judged by measuring the incorporation of labeled precursors into DNA, RNA and protein and the formation of 14CO2 from 1FC-glucose by explants. The addition of cyproterone, a steroid with high antiandrogenic potency to the culture medium suppressed the testosterone action, but did not interfere withthe effects of insulin. These findings were taken as a proof of the direct and specific antiandrogenic action of cyproterone on the rat prostate.

ISSN:0378-7346    

DOI:10.1159/000301867

出版商:S. Karger AG    

年代:1971

数据来源: Karger