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The nonsteroidal anntiandrogen, flutamide (α-α-α-trifluoro-2-methyl-4′-nitro-m-propionotoluidide or SCH 13521), suppresses the retention of a specific 5α-dihydrotestosteronereceptor complex by cell nuclei of rat ventral prostate in vivo. At 1–10 µ-M concentrations, flutamide also inhibits the binding of 5α-dihydrotestosterone in vitro by a receptor protein in the prostate cytosol, and the nuclear retention of the androgen-receptor complex during the incubation of minced prostate. The nonantiandrogenic analogue, acetanilide, at 100 µM, does not show such an inhibitory effect. While flutamide and cyproterone are equipotent as antiandrogens in vivo, cyproterone is about 10 times more active than flutamide in inhibiting the receptor binding of 5 αdihydrotestosterone. This discrepancy may be due to a metabolic activation in the whole animal and' or inactivation of flutamide in the prostate. The suppressive action of flutamide (or its active metabolite) may be related to its geometrical structure, which is simi...

Preliminary studies indicated that low doses of cyproterone acetate (Cyp Ac) potentiated the action of testosterone on mouse kidney. This unexpected observation prompted a more extensive evaluation of several progestins (progesterone, progesterone caproate, Cyp Ac, medroxyprogesterone acetate and megestrol acetate) as well as nonprogestational antiandrogens (flutamide, BOMT, cyproterone). The effects of these agents, both alone and in combination with testosterone, on the kidney arid male reproductive tract of the mouse were determined. Testosterone (0.1 mg/day) resulted in a 2- to 5-fold increase in kidney β3-glucuronidase activity after 6 days of treatment. Of the progestins tested, only medroxyprogesterone acetate (MPA) and megestrol acetate stimulated β-glucuronidase in the kidney. Androgen-insensitive (tfm/y) mice with defective androgen receptors did not respond to high doses of MPA, suggesting that androgens and progestins share a common mechanism of action on kidney. With the exception of progeste...

To study the regulation of the development of myoid cells, seminiferous tubules of adult and prepubertal rats were grown in organ culture under the influence of testosterone, HCG and cyproterone acetate. Contractility, EM-structure and histochemical activities of alkaline phosphatase and ATPase of the myoid cells were studied in the adult rat tubules at one week intervals up to 5 weeks in culture, in the prepubertal rat tubules at the age of 15 days and after 15 and 21 days in culture. As in vivo, contractions appear in cultured tubules of prepubertal rats at the age of 15 days. Testosterone and HCG increase the percentage of contractile tubules and the number of filaments of the myoid cells. Cyproterone acetate inhibits both functional and structural development and tends to decrease the enzyme activities. In the cultured adult rat tubules cyproterone acetate causes disappearance of contractility within one week, while contractions normally are found for 3 weeks. Testosterone and HCG have no notable effects on the contractility of adult rat tubules, but they lengthen the persistence of alkaline phosphatase activity. It is concluded that the maturation and also the functioning of the myoid cells are subject to androgenic regulation.

The most undesirable side effect of a new gestagen intended for the treatment of pregnancy disturbances is the virilization of female foetuses. In 1961, our drug company developed a new highly effective gestagen, cyproterone acetate (figure 1) (Wiechert & Neumann 1965). We were given the task to test this substance in animal experiments for desirable and undesirable effects, particularly for the occurrence of virilization. As this drug was intended for the treatment of pregnancy disturbances, such as threatening or habitual abortion, it had to be free of virilizing side effects.

In der vorliegenden Arbeit wird die Wirkung der Antiandrogene Cyproteron und Cyproteronacetat auf einige Enzyme in den Leydigzellkomplexen (LZK) des Hodens infantiler und ausgewachsener Ratten untersucht. Neben einer Vergroserung der LZK — Ausdruck einer vermehrten Gonadotropin-Ausschuttung als Folge eines Kastrations-effektes — ergab sich eine Aktivitatssteigerung der Enzyme des Steroidstoffwechsels (β-Hydroxybuttersauredehydrogenase, Steroid-3β-ol-Dehydrogenase), des Energiestoffwech-sels (Laktatdehydrogenase, Succinodehydrogenase) und der Atmungskette (NADH-Cyto-chrom-c-Reduktase). Die Glukose-6-Phosphatdehydrogenase wies dagegen keine Aktivitatsveranderung auf. Unbeeinflust blieben auch die unspezifischen Esterasen und die sauren Phosphatasen. Der erwartete Unterschied zwischen Cyproteron und Cyproteronacetat blieb aus. Die Grunde hierfur werden diskutiert.

The effect on adult sexual behavior of high doses of progesterone and testosterone given to neonatal male rats were tested and compared with the effects of administered estrogen, cyproterone, and cyproterone acetate. Results indicated that high doses of all the test substances affect male sexual performance; the direction of change, however, is dependent upon the parameter measured. It is asserted that not only must a critical period be considered in evaluating developmental influences on sexual performance but so too must the steroidal environment in terms of type and dosage. High dosages used in the study are seen as possible experimental models of the abnormal hormonal milieu associated with certain clinical situations.

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.

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.

The most potent antiandrogenic compounds so far in clinical use are very strongly progestogenic derivatives of progesterone, e.g. eyproterone acetate, chlormadinone acetate (Fig. 1 and Table 1) [29, 33].

The neural structures which are decisive for induction and maintenance of the sexual instinct are situated at circumscribed sites in the diencephalon. Here a functional and localisatory distinction is made between a so-called hormonal sex centre, which is connected with the pituitary by the neurovascular route, and a sex behaviour centre, for which the synonymous term mating centre is also used.

The action of estradiol-17β, ICI 46,474 (antiestrogen), testosterone, and cyproterone and cyproterone acetate (antiandrogens) on gonadal sex differentiation was studied in the tadpoles of Rana esculenta . Testosterone masculinizes the embryonic gonads, and so also do the antiandrogens. Estradiol-17β feminizes the tadpole gonads, but the antiestrogen has no definite effect, either feminizing or masculinizing. However, these antihormones compete with the sex hormones at the target sites in the adult frog. It is apparent from these results, as also from the data available elsewhere, that embryonic sex inductors are not similar to sex hormones.

Normal somatic sex differentiation with its fundamental differences between the female and the male pattern is discussed. Animal experiments with androgens revealed that virilization involves the external genitalia, the accessory sexual glands, parts of the internal genitalia, and the mammary gland of female fetuses. Compounds having antiandrogenic properties have feminizing effects on male fetuses which involve the same organs and organ structures as virilization in female fetuses. The anogenital distance of fetuses served as a dose-dependent parameter for both effects. Within this framework, progestogens, androgens, estrogens with various analogs and derivatives were evaluated for their disturbing effects on sexual somatic differentiation. Also “pure” progestogens, having no classical side effects as other synthetic progestogens, selectively affected the caudal parts of the Muellerian ducts of both sexes. This observation, neglected so far, could be of importance because derivatives of fetal structures were involved in human ‘Vaginal’ cancer which occurred later in patients as a consequence of DES (diethylstilbestrol) medication administered to their mothers during pregnancy. Virilization, androgenicity, feminization and antiandrogenicity, respectively, were found to be not necessarily correlated, whether or not these actions originated from side effects of progestogens or from androgens or antiandrogens. Undesirable virilizing properties which were recorded in humans after the application of synthetic progestogens are discussed and compared with animal experiments. Many paradoxical effects are listed for which no explanations exist. In some species, for instance the guinea pig, an antiandrogen – cyproterone acetate – partially virilized female fetuses and partially feminized male fetuses. Whereas androgens, anabolics, and antiandrogens mainly lead to “malformations,” which reflect the potential of the undifferentiated genital tract for following the masculine or feminine pattern of development; the effects of estrogens and gestagens could not be satisfactorily interpreted within this schema. It remains to be shown whether DES is directly cancerogenic for the caudal parts of the Muellerian ducts or whether these epithelia become particularly susceptible to harmful influences after having been forced to spread out into the vagina.

A reviev is given on a seven-year-teamwork of the departments of youth psychiatry and psychoendocrinology. In 10% of all patients of the department of youth psychiatry (100 clinical; 600–700 ambulant cases/year) an endocrine disorder is the determinant factor. The essential causes of psychic retardation and disturbances of personality are: dystopia testes (not noted; treated insufficiently; operated unsuccessfully), testes and ovary dysgenesia, pubertas tarda, pituitary dvarfism, primary and secondary amenorrhea, cycle-dependent female hypersexuality and depressive reactions. An experienced hormonal treatment must be combined vith youth psychiatric treatment. The possibility to reduce or inhibit male sexuality temporarily and reversibly by antiandrogens (cyproterone acetate) opens new aspects for the treatment of juvenile sex offenders.

In the immature castrate rat, the antiandrogens cyproterone (C) (30 or 150 mg⁄ kg) and cyproterone acetate (CA) (10 or 50 mg⁄kg) inhibited the growth of the ventral prostate and seminal vesicles that was induced by dehydroepiandrosterone (DHA), androstenedione (A), or testosterone (T) injected at various doses for 7 days. When the lowest doses of androgen were used (DHA 0.4 mg, A 0.02 mg, and T 0.015 mg), C and CA were often able to maintain the weights of target organs at castrate levels. CA was about 3 times more potent than C in antiandrogenic activity. CA also significantly inhibited the increase in prostatic weight that occurred after 14 days of administration of ACTH (20 U⁄day), prolactin (1 mg⁄day) plus ACTH (5 mg⁄day), or prolactin (1 mg⁄day) plus DHA (0.2 mg⁄day). It is concluded that C and CA can inhibit the known extratesticular stimuli to prostatic growth in the rat. These stimuli may all be mediated by an androgendependent cellular response. (Endocrinology 87: 624, 1970)

Summary The classical method for the investigation of a hormone is that of its elimination by removing the gland where it is formed. From the deficit symtoms, conclusions can be drawn regarding its physiological importance. The application of antiandrogens presented itself as a simple method for eliminating testosterone (androgens) at any point in embryological development without the necessity of surgical procedure. This is of special value where classical procedures are impossible because of methodical difficulties. With experiments in rabbits, rats and mice we investigated the role of testosterone in the differentiation of the gonads, the sexual draining ducts, the urogenital sinus, the external genitalia, the mammary gland and the sexual centers located in the diencephalon, respectively In early phases of development in mammals all the above mentioned organs are basically uniform in design, both in male and in female fetuses. Without hormonal impulses, development always takes the female course, independent of genetical sex. From our experiments with antiandrogens we learned that in male fetuses only a portion of the differentiation processes is androgen-dependent; this means they will be affected by antiandrogens, whereas other processes are not androgen-dependent. The latter are controlled by hormones of the fetal gonad, which have not been elucidated as yet: Not androgen-dependent are: 1 the differentiation of the gonads, 2 the testicular descent, 3 the regression of the Muellerian ducts. Androgen-dependent are: 1 the stabilisation of the Wolffian ducts (the future seminal ducts), 2 the male-type differentiation of the urogenital sinus (development of a prostate and a male urethra), 3 the male differentiation of the external genitalia, 4 the male differentiation of the mammary glands (rudimentary formation in males), 5 the male differentiation of the sexual centers of the diencephalon (acyclic sexual function, male-type behavioral patterns).

Since it became possible to do experiments with synthetic androgens, the role of androgens in the differentiation of the male external genital organs could be elucidated (Dantchakoff, 1936; Jost, 1947, 1955).

Antiandrogens are substances which competitively inhibit the action of male sex hormones on their target organs (Neumann et al., 1965). Neumann’sidea (Neumann and Elger, 1966) that these substances act via the hypothalamus is deduced from the observation that cyproterone induces an increase in the level of gonadotropin. Since the action of testosterone on the hypothalamic receptors is inhibited competitively, an increase in hypothalamic activity is observed, which results in an increase of gonadotropin production in the anterior lobe of the pituitary. Neumann’sconcept was the starting point for our studies and we investigated by histochemical means in which way antiandrogens affect the hypothalamus.

Publisher Summary This chapter discusses the aspects of androgen-dependent events as studied by antiandrogens. The individual studies covered in the chapter are related only insofar as antiandrogens were used in all of them. The chapter focuses on processes of differentiation, studies on the feedback mechanism, and libido and testicular function. It discusses the processes of spermatogenesis that are FSH-dependent. Androgens also play an important role in mammary gland differentiation. It has been known that testicular hormones are responsible for the differences in differentiation of the mammary glands in males and females. All androgen-related sexual differences in mammary gland differentiation can be abolished by the simultaneous administration of antiandrogens. Androgens are also known to be responsible for the differentiation of certain hypothalamic centers into the female or male functional type, and behavioral patterns too are determined hormonally.

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.

SUMMARY.– Recent work on steroid metabolism in skin is discussed and it is shown that many metabolic transformations involve the 3β− and 17β−hydroxysteroid dehydrogenases. Histochemical techniques which are used are outlined, and the distribution of the 3β− and 17β−HSD within human sebaceous glands is described. The interesting patchy distribution of 17β-HSD is described and an hypothesis concerning the pathogenesis of acne vulgaris is tentatively put forward. The basis for the use of antiandrogens in human skin is discussed and the definition of an antiandrogen using the histochemical screening method outlined. For the purpose of this paper the term antiandrogen is restricted to substances which directly inhibit certain enzymes of androgen metabolism in a histochemical system at the level of the sebaceous glands. A histochemical method for the screening of antiandrogens using human skin is described and the results with a few compounds reported and compared with the results of bioassay. The advantages and disadvantages of the technique are described and it is emphasized that the method is not intended to be used on its own, but simply as a screening technique.

ANTIANDBOGBNS are substances which prevent androgens from expressing their activity at target sites. The inhibitory effect of these substances, therefore, would be differentiated from compounds which decrease the synthesis and/or release of hypothalamic (releasing factors) and anterior pituitary hormones (gonadotrophins, particularly luteinizing hormone) and materials which act directly on the gonads to inhibit biosynthesis and/or secretion of androgens. Substances possessing antiandrogenic activity are of practical as well as theoretical interest. Systemically active compounds of this class would be expected to benefit women suffering from certain types of hirsutism and men suffering from androgendependentprostatic tumors or benign prostatic hypertrophy. Local use of antiandrogenic compounds also could be of use in women with hypertrichosis, in prevention of certain types of male baldness, for the inhibition of facial hair growth in men, and for the treatment and/or prevention of acne in young men and women. This communication will be concerned with the biology of antiandrogens, particularly from the viewpoint of bioassay models that are available for prediction of useful therapeutic activity on human skin.