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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.

The development of fertilized eggs and their transport through the oviduct were studied in rats treated orally with 3-methylether of ethinylestradiol (mestranol) at a single administration in different doses. The ED50 values were in the same range (0.11--0.34 mg mestranol/kg b.w.) as well in postcoital pregnancy inhibition test as in the experiments on tubal egg contents on day 3 as in implantation sites in niagara blue test on day 6. This suggests that the uniform cause of pregnancy inhibition of postcoital mestranol treatment on day 1 in rats is the acceleration of tubal egg transport. The ED50 of mestranol given on day 1 shortened the stay of eggs in tubes to 24 hours. Mestranol dosage above the ED50 reduced the tubal stay towards two days in comparison to five days in control animals. The number of eggs prematurely expelled from the tubes into the uterus was relatively high on day 2 and 3 in animals treated with mestranol in high dosage and with ligated cervix, compared with animals without ligation. But on day 4 on blastocysts were found. This result shows that the prevention of pregnancy is caused by the expulsion of blastocysts from uterus and/or the degeneration of zygotes in utero. Blastocysts or morulae recovered from treated rats in high dosage were transferred to the uteri of pseudopregnant recipients: 29% developed into normal term foetuses compared to 29 or 30% for both untreated control groups.

In immature male Wistar rats levonorgestrel and STS 557 (17 alpha-cyanomethyl-17 beta-hydroxyestra-4,9(10)-diene-3-one) reduced testicular growth, testicular DNA contents and plane of tubular cross-section in a dose dependent manner. In this respect, STS was less active than levonorgestrel. In immature castrated male rats the LH-suppressing effect of STS 557 was about 15 times lower than that of levonorgestrel. The results suggested that peripheral inhibitory effect of the two progestins was coupled with central LH suppression. On the other hand, in mating tests with male hybrid mice STS 557 possessed high fertility inhibiting activities in comparison to levonorgestrel and chlormadinone acetate. Limited dissociation has been shown between fertility inhibition and mating rate. All changes were reversible. Findings are discussed in view of development of male contraceptives.

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.

STS 557 (17 alpha-cyanomethyl-17 beta-hydroxy-estra-4, 9-dien-3-one) was tested for progestagenic activity in rabbits and for ovulation-inhibiting activities in rabbits and rats in comparison with levonorgestrel and, in some cases, with norethisterone acetate or chlormadinone acetate. In the immature rabbit, the endometrium transformation-inducing activity of STS 557 was about 5 times higher than levonorgestrel for both oral and subcutaneous administration. The ovulation-inhibiting effect of STS 557 was 3.5 times higher than that of levonorgestrel in the rabbit after oral administration, and about 7 times higher in the rat. After subcutaneous injection, however, the antiovulatory activity of STS 557 in rats was only about 4% of that of levonorgestrel when the ED 50 were compared.

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.

STS 557 (17 alpha-cyanomethyl-17 beta-hydroxy-estra-4,9(10)-diene-3-one) or levonorgestrel was given orally as a single dose of 0.4 mg per animal. Treatment was performed immediately after the 6 h mating period. In 30 control cycles (18 animals) 9 pregnancies (30%) and in 26 cycles (17 animals) with levonorgestrel treatment 3 pregnancies (11.5%) were observed. In 46 cycles (21 animals) with STS 557 treatment only one pregnancy (2.2%) occurred (chi 2-test: P less than 0.01 as compared to control cycles). Therefore, STS 557 showed high interceptive activities in this nonhuman primate model. In contrast with levonorgestrel, STS 557 did not decrease the postovulatory rise of plasma progesterone.

Two synthetic estrogens, STS 456 and STS 593, with noteworthy post-coital antifertility properties in the rat were studied for their estrogenic, antiestrogenic, progestagenic, antiprogestagenic, antigonadotrophic, androgenic and antiandrogenic effects in laboratory animals. Beside their weak estrogenic activity which corresponds to their slight affinity to the uterine estrogen receptor in the rat, both steroids show remarkable antiestrogenic effects. No progestagenic, androgenic and antiandrogenic effects were found but STS 593 showed some antiprogestagenic activity. The antigonadotrophic efficacy of STS 456 was relatively high while STS 593 was scarcely active. The results are discussed with respect to possible application of these drugs for interceptive purposes.

STS 557 (17 alpha-cyanomethyl-17 beta-hydroxy-estra-4, 9-dien-3-one) or levonorgestrel was given orally as a single dose of 0.4 mg per animal. Treatment was performed immediately after the 18 h or 6 h mating period. Regarding the 18 h mating period, in 30 control cycles (20 animals) 11 pregnancies (36.7%) and in 20 cycles (16 animals) with levonorgestrel treatment 2 pregnancies (10.0%) were observed. In 80 cycles (31 animals) with STS 557 treatment 7 pregnancies occurred (8.7%). With regard to the 6 h mating period, in 30 control cycles (18 animals) 9 pregnancies (30%) and in 26 cycles (17 animals) with levonorgestrel administration 3 pregnancies were recorded (11.5%). In 50 cycles (21 animals) with postcoital administration of STS 557 only two pregnancies occurred (4%). Therefore, after the 6 h mating period STS 557 showed high interceptive activities in this non-human primate model. In comparison with controls, STS 557 did not decrease the postovulatory rise of plasma progesterone. This finding demonstrates that postcoital STS 557 in the chosen dosage does not suppress ovulation. Repeated STS 557 administration starting early in the follicular phase was without marked influence on cycle characteristics. On the other hand, treatment start in the middle or at the end of the cycle caused cycle lengthening and reduced progesterone levels in some animals.

The steroidal estrogens ethinylestradiol, mestranol and the synthetic "impeded" estrogen derivatives STS 456, STS 593 and J 628 were studied for their postcoital antifertility activity and estrogenicity in mice, rats and rabbits. Results of these studies suggest a positive relationship between these two biological endpoints with the exception of the findings in rats. As seen in uterotrophic--anti-implantation ratio, in view of only one species it is possible to dissociate the interceptive and the unwanted uterotrophic activities. The profound species differences in the effects of exogenous estrogens on the nidation phase are discussed.

To ascertain the effects of STS 557 (17 alpha-cyanomethyl-17 beta-hydroxy-estra-4, 9-dien-3-one) on the reproductive and endocrine functions, male rabbits were given the substance orally daily over 8 weeks. In doses of 10 and 20 mg STS 557 per animal per day fertility inhibition was accompanied by a decrease of spermatogenesis and sexual activity. At the chosen dose of 5 mg per day, STS 557 caused a decrease of sperm motility, semen fructose content and sterility of the bucks. On the other hand, libido, semen volume, sperm number, sialic acid content in semen, serum LH and testosterone remained unaffected. Concomitant injection of testosterone did not reverse the suppressive effect of STS 557 on fertility. Motility of human sperm was lowered markedly by STS 557 in vitro. The human sperm penetration and pronuclear formation were significantly reduced in the vitro fertilization assay with zona-free hamster eggs. Findings are discussed in view of the development of male contraceptives.

The influence of testosterone propionate, 17 alpha-methyl-testosterone and cyproterone acetate on isolation induced fighting behaviour of mice was studied in a simple testing procedure. Decreased aggressiveness has been established in mature, sexual experienced and isolated male mice both following castration and administration of the antiandrogen cyproterone acetate, respectively. Replacement therapy with testosterone propionate s.c. and 17 alpha-methyl-testosterone p.o. has been shown to restore the decreased level of aggresiveness after castration.

In course of studies for the chronic toxicity of estrogens after oral application two parameters of the unspecific resistance - complement (CH50U and CB50U) and lysozyme - in sera of 30 beagle-dogs were studied. The doses of the daily (over 6 months) applicated hormones were 1,0 mg/kg ethinylöstradiol and 1,0, 0,1 and 0,01 mg/kg ethinylöstradiolsulfonate (depotform). In the majority of all measurements no significant variations of serum complement and -lysozyme could be detected, however after application of high doses of the hormone ethinylöstradiol a little reduction of complement and significant elevations of lysozyme were observed.