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STS 557, a new orally active progestin with antifertility properties has been tested for uterotrophic, antiuterotrophic, vaginotrophic, and antiovulatory effects. Further, maintenance of pregnancy in ovariectomized mice, influence on pregnancy in mice and rats, and conditioning of the immature rat uterus for decidual response were investigated. Both estrogenic and anti-estrogenic activities in mice and rats were found to be very low. STS 557 fails to maintain pregnancy in ovariectomized animals but does not interfere with pregnancy in intact mice if implantation already took place. Moreover, no effects have been found regarding the influence on the first ovulation in prepuberal rats. The biological profile of STS 557 in animals seems to make this compound suitable for use as a post-coital contraceptive.

Studies with mice, rats, guinea pigs and baboons were undertaken to define the interceptive action of the new progestin STS 557 (17 alpha -cyanomethyl-17 beta-hydroxy-estra-4.9(10)-diene-3-one) and to compare it with other progestins used in oral contraceptives. STS 557, norethindrone and norethindrone acetate reduced deciduoma formation as well as the number of implantations in mice and rats. Chlormadinone acetate and levonorgestrel when administered at the appropriate dose could not prevent early pregnancy or deciduoma formation. But in contrast to STS 557, levonorgestrel maintained early pregnancy in ovariectomized rats. On the other hand, STS 557 was ineffective as a postcoital agent in guinea pigs. When 0.4 mg STS 557 was orally administered to 37 female baboons 3 or 6 h after the mating period, only one pregnancy occurred in a total of 60 cycles investigated (controls: 11 pregnancies in 12 cycles investigated). The results are discussed in view of the development of an interceptive method based on STS 557.

The toxicity of 17 alpha-cyanomethyl-17 beta-hydroxy-estra-4, 9-dien-3-one (STS 557) was studied by its oral administration of 0.1, 1.0 or 10.0 mg/kg/day to Wistar rats for six months, and of 0.01, 0.1 or 1.0 mg/kg/day to beagle dogs for six months, respectively. Levonorgestrel at a dose of 1.0 mg/kg/day was used as the standard in the dog study. With respect to the progestational activity of the compound the main target organs were the hypophysis, the reproductive organs and the adrenals. Mammary hyperplasia was observed in dogs treated with STS 557 or levonorgestrel at the dose of 1.0 mg/kg/day, but in no case mammary nodules could be detected. At the dose of 1.0 mg/kg/day STS 557 and levonorgestrel were found to increase the plasma insulin response to i.v. glucose in bitches, but neither the mean blood glucose levels nor the glucose utilization were affected. Moreover, during administration of both steroids to dogs temporary changes in serum concentrations of triglycerides and total cholesterol were noted. The results obtained in rats and dogs from functional and morphological investigations did not reveal any toxic side effects of STS 557 on the liver, the kidneys, the bone marrow or on blood coagulation. The effects on the reproductive organs observed following STS 557 especially in dogs are related to both the hormonal effects of the compound and the specific response of the dog to potent progestagens.

Adult, female baboons (Papio hamadryas) were administered orally once 18 h p.c., either 1.6 mg STS 557 (17 alpha-cyanomethyl-17 beta-hydroxy-estra-4;9(10)-dien-3-one) or 1.6 mg levonorgestrel. Investigations of the bone-marrow cells of these animals showed, compared to untreated controls, no signs of increased chromosome aberrations caused by the substances. The relative frequency of chromosome aberrations were estimated for controls: STS 557: levonorgestrel with 0.60 +/- 0.35 : 0.55 +/- 0.39 : 0.92 +/- 0.46%, respectively. The differences between the three groups investigated in the exact Fisher-test (2 alpha = 0.05) were not significant.

STS 557 (17 alpha-cyanomethyl-17 beta-hydroxy-estra-4, 9-dien-3-one) is a interceptive agent in rabbits, mice and rats. In rats, it also shows post-implantational pregnancyterminating activity. In rabbits treated orally before mating or after ovulation for three consecutive days, it inhibited pregnancy largely at total doses of 0.08 mg/kg in the former and completely with 8.0 mg/kg in the latter case. A single subcutaneous dose of 40 mg/kg given on day 1 of pregnancy inhibited completely nidation in rats. In inhibition of pregnancy in rats could also be realized when the dose of 40 mg/kg was distributed on several days and given subcutaneously at daily doses of 5.0 mg/kg on days 1--8 of pregnancy, and even only daily doses of 2 mg STS 557/kg were needed in this respect, if animals which showed no living conceptuses were scored as "non-pregnant". STS 557 was effective in terminating pregnancy in rats, too, when given subcutaneously after implantation for 4 days at daily doses of 50 mg/kg, beginning on day 5 or on day 8 of pregnancy. The nidation inhibiting effects of STS 557 in rabbits treated pre-coitally, and in mice as well as in rats treated post-coitally were more marked than those of levonorgestrel. The interceptive and post-implantational inhibiting activity of STS 557 may be based on its antiprogestagenic properties. Luteolysis in the nidation phase can be excluded as shown by radioimmunoassay of progesterone in rats. The antigestagenic effects on the endometrium in rats were evident in the diamine oxidase assay. The acceleration of tubal egg transport, the morphological changes of the endometrium shown by scanning electron microscopy, and the effects on blastocyst transfer, all investigated in rats, suggest peripheral mechanisms of action.