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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.

352 rats were used to study the effects of graded levels of lactogenic hormone (LGH) alone and in combination with PMS and HCG, on the formation of the decidual cell reaction (DCR) in intact and in hypophysectomized rats. Maximal DCR occurred in intact rats and in hypophysectomized rats treated with LGH + HCG and with LGH + HCG + PMS. A marked but significant smaller DCR was found in hypophysectomized rats treated with PMS + LGH. The DCR was absent or very minute in hypophysectomized, LGH-, PMS- or HCG-treated rats. The results indicate, that LGH alone is not capable of inducing a DCR. The addition of ICSH to LGH results in an adequate condition for the production of the DCR by uterine trauma.

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.

The antagonistic action of 1,2α-methylene-6-chloro-Δ4,6-pregnadiene-17α-ol-3,20-dione-17α-acetate (cyproterone acetate) to testosterone propionate (TP) on the testes and accessory glands was investigated in hypophysectomized adult male rats. Treatment of the animals began on the day of hypophysectomy and was continued for 21 days.Daily subcutaneous injections of 0·3 or 1·5 mg. TP/100 g. body weight almost completely inhibited testicular atrophy and involution of the germinal epithelium.Simultaneous administration of 0·3 mg. oestradiol/100 g. body weight did not influence the effect of testosterone propionate.Cyproterone acetate inhibited the effect of testosterone propionate. The extent of inhibition was dose dependent. The antagonism to testosterone was manifested by reduction of testicular weight and by the inhibition of spermiogenesis. The latest stages of spermiogenesis were primarily influenced.Intratesticular cyproterone acetate together with subcutaneous administration of TP caused similar effects in the testes to those of subcutaneous administration. However, regression of the germinal epithelium in the injected testis seemed to be more pronounced than in the contralateral testis.The effects of TP on the accessory sex glands (prostate, seminal vesicles) were inhibited by simultaneous administration of cyproterone acetate. It is concluded that cyproterone acetate competitively inhibits the action of testosterone propionate on the target organs.

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.

The release of lactogenic hormone (LGH) was studied at the onset of pseudopregnancy in 90 rats. The LGH-content of the pituitary glands was determined by the pigeon crop sac assay. Glass rod stimulation of the cervix during vaginal oestrus was followed by a significant decrease in the LGH-content of the pituitary glands, thus demonstrating a correlation between LGH-release and beginning pseudopregnancy.Anaesthesia by Nembutal almost prevented this effect of cervical stimulation.

Daily administration of 1 μg EB plus 3 mg P to mature ovary-thyro-para-thyroidectomized rats for 19 days stimulated mammary gland growth (DNA) comparable to ovariectomized rats receiving same treatment. Replacement therapy with 10 and 20 μ AT 10/100 g/day, respectively, in combination with 1 μg EB plus 3 mg P increased total DNA significantly. No benefit was observed by increasing ovarian hormones to 2 μg EB plus 6 mg P. Combined administration of AT 10 at above mentioned levels and 1.5 μg and 3 μg T4/100 g depressed DFFT significantly resulting in reduced total DNA.

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.