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Two types of so-called "depot contraceptives", long-acting steroids which are of interest for human use, were studied in animals.Norethisterone oenanthate, mainly gestagenic in the human and other species, turned out to be predominantly oestrogenic in rats. This oestrogenicity caused indirectly, viaan enhanced hypophysial prolactin secretion, the well-known hypophysial and mammary tumours in rats.Another synthetic gestagen, 4,6-dichloro- 17- acetoxy- 16α-methyl-4,6-pregnadiene-3,20-dione, which might be considered in its biological actions similar to preparations containing chlormadinone acetate or medroxy-progesterone acetate, induced no signs of oestrogenicity in dogs. It is surmised that its gestagenic influence indirectly, and probaby, viaan enhanced hypophysial prolactin secretion caused "mammary nodules" in this "non-rodent" species. These studies have born out mainly two facts:A synthetic steroid, norethisterone oenanthate, exerted different biological effects in different species: it was a gestagen in the rabbit, whereas in rats, its predominant influence was oestrogenic.The hypophysial prolactin secretion was enhanced in various species by different mechanisms: in rats, the oestrogenicity caused an increased prolactin plasma level, whereas in dogs, a gestagen with obviously no inherent oestrogenicity, 4,6-dichloro-17-acetoxy-16α-methyl-4,6-pregnadiene-3,20-dione, converted the histological appearance of the anterior pituitary into a condition with a greatly increased number of eosinophils. This histological finding was interpreted as an indicator for a hypersecretion of prolactin.Hence, animal work with "gestagens" has only limited predictive value with respect to their possible effects in the human species. Therefore, inflexible recommendations are not helpful in solving the safety problem of long-acting steroids which affect primarily reproductive processes.

The influence of the antiandrogen 1,2α-methylene-6-chloro-pregna-4,6-dien-17α-ol-3,20-dion-17-acetate (= Cyproterone acetate)** on testes and accessory sexual glands was investigated in intact immature, intact adult and hypophysectomized adult rats treated with PMS or HCG, respectively. Within the testis, the antiandrogen failed to affect the gonadotrophinmediated stimulation of the Leydig cells. On the other hand, it depressed spermiogenesis as well as the accessory sexual gland weights. From histologic pictures it could be seen that Cyproterone acetate exerted its depressing effect on spermiogenesis and accessory sexual glands in the presence of highly stimulated and thus testosterone producing Leydig cells. It is concluded that Cyproterone acetate does not interfere with gonadotrophins directly but only with secondary androgen-mediated effects of gonadotrophins by means of a competitive block of androgen-receptors within the target organs.

From experiments with anti-androgens, it can be concluded which processes in the sex differentiation of dogs are androgen-dependent and which are not. In contrast to rats but as in rabbits, retrogression of the Wolffian ducts can be induced in the treated members of this species compared to their controls, but retrogression of the Müllerian ducts is uninfluenced in both treated and control animals. From this, it is concluded that the latter process is not androgen-dependent.

It was examined in how far the inhibition of the vaginal cycle and of the ovulation caused by testosterone propionate, 6α-methyl-17β-hydroxyprogesterone-acetate (MAP), 17α-ethynyl-19-nor-testosterone-acetate (ANTA), oestradiol and progesterone was influenced by simultaneous administration of an anti-androgenically effective steroid (1,2α-methylene-6-chloro-pregna-4,6-diene-17α-ol-3,20-dione = Cyproterone).The anti-ovulatory activity of testosterone propionate and MAP is considerably diminished under the influence of Cyproterone. The activity of ANTA is only influenced to a very slight extent, while that of oestradiol and progesterone is not influenced at all.The action of Cyproterone is explained with a blocking of the androgenreceptors of the hypothalamus. Interpretation of the results eventually give new indications that androgens are not directly involved in intraovarian mechanisms preparing ovulation. Possible application for clinical use in particular cases of sterility in women are discussed.

It is demonstrated that the effects of testosterone propionate in female rats can be inhibited by a potent anti-androgenic compound, viz.1,2α-methylene-6-chloro-pregna-4,6-diene-17α-ol-3,20-dione (= Cyproterone). Uterine and preputial growth, as stimulated by testosterone propionate, is inhibited by simultaneously administered Cyproterone in immature female rats, intact as well as spayed.This method is suitable as a test for anti-androgenic compounds. It is easy to perform, and its sensitivity, accuracy and specificity are satisfactory.

Summary In juvenile parabiotic rats it was found that the androgen antagonist (1,2α-methylene-6-chloro-Δ4,6-pregnadiene-17α-ol-3,20-dione) increased the hypophyseal gonadotrophic hormone secretion of the intact male partner. The sexual organs of the hypophysectomized female parabiont reflected this hypersecretion in the same way when it was joined with an orchidectomized untreated rat. It is concluded that in both cases (cyproterone therapy and orchidectomy, respectively) the so-called sexual center reacts because of the withdrawal of the testicular male hormone with an increased release (or even synthesis?) of releasers for gonadotrophic hormones. These findings are strongly supported by results of various other experiments which are strictly in line with the above mentioned interpretation.