Friedmund Neumann

Pharmacology of antiandrogens.

Principally, antiandrogens affect all androgen-dependent organs and functions as for instance accessory sexual glands, spermatogenesis, skin and skin appendages, libido and potency, male sexual differentiation, longitudinal bone growth and bone maturation. Pharmacologically, it is important to distinguish between the steroidal antiandrogens of the cyproterone acetate type and the nonsteroidal pure antiandrogens (flutamide, anandrone). For the clinical use of cyproterone acetate and similar antiandrogens in both men and women the three main properties are important: Cyproterone acetate is antiandrogenic, it is a quite potent progestogen and it is antigonadotrophic. Based on pharmacological and biochemical backgrounds cyproterone acetate is used in the following indications: Androgen mediated disorders of the skin such as acne, seborrhoea, hirsutism, alopecia, advanced prostatic carcinoma, precocious puberty and male hypersexuality. In order to avoid undesired systemic side effects local application of antiandrogens, e.g. of cyproterone acetate, has been tried several times. All these attempts have failed probably because insufficient concentration of the antiandrogen at the pilo sebaceous unit. 17 alpha-propylmesterolone is active when given topically (hamster ear model) and has no systemic antiandrogenic effects. This antiandrogen is highly lipophilic and does penetrate preferentially through the hair follicle as has been shown by autoradiography.

The Influence of Pharmaceutical Compounds on Male Fertility

1. Steroid hormones can affect spermatogenesis and thereby fertility directly and/or indirectly. All antigonadotropically active steroids inhibit spermatogenesis via inhibition of gonadotropin secretion, mainly that of H. Androgens and steroids occurring in the biosynthetic chain of testosterone synthesis have a direct promoting effect on spermatogenesis if applied in high doses. It has not been possible as yet to make clinical use of this positive effect since it is obviously not possible to achieve the necessary intratesticular androgen concentrations. 2. As concerns the different androgens and the steroids in the androgen biosynthetic chain, and also all synthetic anabolics, there is no parallelism between the direct spermatogenic activity, the androgenic activity and the antigonadotropic activity. 3. Estrogens and synthetic gestagens do not inhibit spermatogenesis directly at the testicular level. All effects of estrogens can be abolished experimentally by adequate substitution with gonadotropins or androgens, or a combination of androgens and gonadotropins. 4. Only those antiandrogens inhibit spermatogenesis with additional antigonadotropic properties (e.g. cyproterone acetate). Pure antiandrogens, like flutamide or cyproterone, have a slight and transient influence on spermatogenesis at the most. If at all, they merely cause transient subfertility. 5. Beside steroids and several centrally active pharmaceutics (e.g. psychotropic drugs and several antihypertensive compounds), only siloxanes and methallibur seem to affect spermatogenesis via inhibition of gonadotropin secretion. Other antispermatogenic agents act by inhibition of mitosis (Colchicine, alkylating agents) or presumably via damage of the Sertoli cells. 6. Based on present knowledge, contraception in men could be principally managed by administration of a) androgens alone, b) gestagen/androgen combinations, c) estrogen/androgen combinations, d) certain antiandrogens. 7. The difficulties of contraception in men by steroid hormones or steroid hormone combinations have been pointed out. As regards the usefulness of antiandrogens for contraception, no definite conclusions can be drawn at the moment. All non-steroidal inhibitors of spermatogenesis which have been found up to the present are not suitable because of toxic effects.

Evaluation of Effects of Sexual Steroids on the Hypothalamic-Pituitary System of Animals and Man

Specific neuroendocrine regulatory mechanisms in rats and mice are known to be involved in the development of pituitary tumours (prolactinomas) in systemic tolerance and carcinogenicity studies of oestrogens, certain progestagens and their combinations. However, the susceptibility of the strain used seems to be of decisive importance. High doses of oestrogens may also, in special cases, stimulate development of PRL cell hyperplasia and tumours in humans. In other species such as the hamster long-term treatment with oestrogens results in hyperplastic and neoplastic changes in MSH-producing cells of the pars intermedia of the pituitary gland. On the other hand, in the dog and monkey, steroid-related pituitary tumours were not observed, in spite of long-term treatment with high doses of oestrogens, progestagens and their combinations. The capability of certain progestagens to stimulate canine GH secretion seems to play a major role as mediator of the species-specific progestagen-induced changes (mammary tumours, diabetes- and acromegalic-like syndrome) in the beagle dog. These progestagens also seem to have, in addition to their antigonadotrophic properties, an inhibitory effect on CRH-ACTH and TRH-TSH activity in the beagle bitch. These effects can be demonstrated in both the hypothalamic-pituitary system and in the corresponding peripheral target organs. These findings in the dog were not comparable to the situation in other species including man. The extent to which all these results in different species are applicable to other species depends on whether their neuroendocrine control systems are qualitatively and/or quantitatively similar. The physiological significance of the different pituitary hormones, sensitivity of target organs as well as a certain genetic disposition in the different species should also be considered. All these factors can vary from species to species. From these facts, it can be easily appreciated that results of experiments on different species with a substance possessing the same quality of biological effect in these species (e.g., oestrogen, progestagen, etc.) can only be compared when the experimental procedure takes account of the effect of this substance on the neuroendocrine system of the different species, and when dosage, mode of administration and period of treatment are correspondingly matched to the physiological conditions of each species.

Pharmacological basis for clinical use of antiandrogens

UNLABELLED The first antiandrogen which was also of clinical interest--cyproterone acetate (CPA)--was discovered at the beginning of the 60th. CPA acts in all target organs for androgens and in principle affects all functions which are governed or influenced by androgens under physiological or pathophysiological conditions. EXAMPLES Accessory sexual gland function and spermatogenesis are inhibited, there is a loss of libido in most species, the onset of puberty and bone maturation is delayed, sebaceous gland function and lipogenesis is inhibited, androgen mediated steps in male sexual differentiation do not occur. CPA is also a highly effective progestrogen and it inhibits gonadotrophine secretion. The progestational partial effect is especially important for the use of this drug in women in the treatment of certain dermatological disorders. CPA has certain glucocorticoid-like properties in animals. In humans these effects were only seen under high-dose therapy of children with precocious puberty (greater than 80 to 100 mg/m3 body area) but never in adults. Proven indications for CPA: Prostatic carcinoma, precocious puberty, hypersexuality and sexual deviations, androgenization in women (hirsutism, acne, seborrhoea oleosa, alopecia androgentica).

Hormone-Induced Disturbances in Sexual Differentiation

Abstract: 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.

Suitability of the beagle dog as a test model for the tumorigenic potential of contraceptive steroids “short review”

Abstract The purpose of this short review is to assess the present state of knowledge on the suitability of the beagle dog as a test model for the tumorigenic potential of contraceptive steroids. The beagle dog differs markedly from other species, including man, as regards its reproductive physiology and endocrinology. Studies on the influence of contraceptive steroids on canine mammary gland, pituitary gland and uterus have led to the conclusion that the stimulation of development of mammary tumours in dogs by certain progestagens or progestagen-oestrogen combinations must be considered as being a species-specific effect, related to the high hormonal potency (progestational activity) of these compounds in the dog and their stimulatory effect on canine growth hormone. Based on the present state of our knowledge and because of the marked interspecies differences of action of contraceptive steroids in dog and man, the steroid-related canine mammary tumours, especially with regard to the doses necessary for contraception, are unlikely to be indicative of a potential hazard to the human female.

Role of the pituitary gland in experimental hormonal induction and prevention of benign prostatic hyperplasia in the dog

SummaryThe antiandrogen, cyproterone acetate (CPA), prevents development of prostatic hyperplasia, induced in castrated dogs by a 6 month-treatment with 5α-androstane-3α,l 7β-diol (A)alone or in combination with 17β-oestradiol (E2). The immunoperoxidase technique was used to study functional cell types in the pars distalis of the pituitary gland and to detect growth hormone (GH) and prolactin (PRL) target sites in the prostate gland. Homologous radioimmunoassays for estimation of serum canine GH and PRL concentrations were also performed. Treatment with the combinations A + E2 and A + E2+ CPA resulted in morphological indications of stimulated GH and PRL cells and depressed gonadotrophs. This correlates well with an increase in PRL-dependent staining in glandular epithelium and fibromuscular tissue of the prostate gland. However, basal serum PRL and GH levels were not significantly affected. Treatment with A and A + E2 stimulated, while additional treatment with CPA clearly suppressed adrenocorticotrophin/melanotrophin (ACTH/MSH) cells. These findings indicate that an endocrine imbalance in hypothalamic-pituitary-adrenal function may be involved in induction and prevention of prostatic hyperplasia in the dog.

Comparative evaluation of the dissociation rate between the vaginotrophic and uterotrophic activities of 1-hydroxy-1,3,5(10)-estratriene derivatives with natural and unnatural configuration at C8 using ovariectomized mice

Influences on estrogenic.activities of 1-hydroxylation and C8-isomerization in the molecules of naturally occurring estrogens have been studied. All compounds tested behaved qualitatively in the same manner as estradiol, as far as the decrease in the vaginal and uterine sialic acid levels and the increase in the organ weights of the vagina and uterus of castrated mice are concerned. They were, however, different not only in the relative ptoencies of the estrogenic effects, but also in the dissociation rate between the vaginotrphic and uterotrophic activities. Of the compounds tested, 1-hydroxy-8alpha-estrone, 1-hydroxy-8alpha-estradiol and their acetates had a higher value of the dissociation index than that of estriol. These compounds seemed to exert a predominant effect on the vagina rather than on the uterus. Following structural factors seem to be of significance for the dissociation of estrogenic effects: the 1- or 16alpha- hydroxy group and 8alpha-configuration decrease the uterotrophic activity more intensely than the vaginotrophic activity, and the 17alpha-ethinyl group selectively increases the uterotrophic activity.

Influence of an aromatase inhibitor (4-acetoxy-4-androstene-3,17-dione) on experimentally induced impairment of spermatogenesis in immature rats.

Summary: Subcutaneous treatment of immature male rats with an estrogen precursor, 19‐hydroxy‐testosterone (19‐OHT), at a daily dose of 1 mg/animal for 14 days leads to a significant decrease in the weight of testis, ventral prostate and seminal vesicle. The peripheral levels of LH are lowered. Testicular histology indicates that the effects of 19‐OHT are very similar to the known effect induced by estradiol‐17ß. 19‐OHT induces a marked impairment of spermato‐ and spermiogenesis. The maturation division is completely inhibited.

8α-estra-1,3,5(10)-triene-1,3,17β-triol as a special type of estrogen having a high vaginotrophic activity and a low uterotrophic activity in castrated mice

Abstract The vaginotrophic and uterotrophic activities of 1-OH-8α-E2 and its acetate in comparison with E2 and E3 were assessed on the basis of the effect on weights, water/fat- and RNA/DNA-contents of mouse vagina and uterus. The multiple doses of 8α-steroids or E3 sufficient to achieve a maximal effect on the vagina were not enough to stimulate the uterus fully. At various periods of time after multiple injections, 1-OH-8α-E2 acetate was found to have a higher vaginotrophic potency than the uterotrophic potency, when compared with E2 as a standard. The study on the time course of organ response to 8α-steroids, E2 and E3 after a single injection of daily dose, being equipotent when injected once daily for 3 days, demonstrated that 1-OH-8α-E2 and E3 were less vaginotrophic and uterotrophic than E2 and had a short duration of action. 1-OH-8α-E2 acetate in comparison with E2produced a long-lasting vaginotrophic effect and an early regressing uterotrophic effect. It can be confirmed that 8α-steroids, like E3, are a special type of estrogen having a high vaginotrophic activity and a low uterotrophic activity.