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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.

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.

The uterotropic activity of thirty 3-methoxyestradiol derivatives is measured and discussed on the basis of X-ray crystallographic results and quantitative structure-activity relationship analyses involving hydrophobic substituent constants pi and f as well as steric parameters Pr and L. In addition, estrogenicity is compared to data of interceptive activity and receptor binding affinity. All the biological data exhibit a high degree of intercorrelation. 17 beta-Hydroxysteroids having 14 alpha configuration reveal a generally better capability of high-affinity binding than those being 14 beta configurated. Between the uterotropic activity and the hydrophobicity of C14, C15 substituents, statistically significant correlations are found which suggest a close contact between the steroidal D-ring subsite and the receptor protein (e.g. for 14 alpha steroids: log UDD = -0.996 pi -0.392; n = 9, r = -0.943, s = 0.235, t = -7.5, alpha less than 0.001). The hydrophobic nature of both 14 alpha and 14 beta medium-sized substituents employed is shown by QSAR regressions to exert a stronger influence than steric effects. Furthermore, there are indications to additional hydrogen bonding and steric repulsion phenomena. As to the receptor-binding models discussed in the literature, it is concluded that the receptor protein has a high conformational flexibility to accommodate very different drug structures all having the common phenolic ring A. But, if an appropriate spacing of steroidal key atoms is recognized by the receptor and, consequently, the steroid-receptor complex is formed, the binding is complemented by hydrophobic interactions also in the D-ring region.

The interceptive activity of 2 new synthesized steroid compounds: STS 153 (17 beta-Phenylaminocarbonyloxy-estra-1,3,5(10)-triene-3-methyl ether and STS 287 (16 alpha-Bromo-17 beta-[N',N'-dimethylhydrazino]-carbonyloxy-estra-1,3,5(10)-triene-3-methyl ether) and of 17 alpha-Ethynylestradiol was investigated in baboons.--Postcoital oral administration of 1--3 mg/kg b. w. STS 153 for 5--7 days and of 1 mg/kg b. w. STS 287 for 5 days resulted in a fertility inhibition of about 90% and 95% respectively. A dose of 2 mg/kg b. w. of ethynylestradiol was necessary to attain complete fertility inhibition. Following administration of STS 153 and STS 287, side effects were not observed. Pharmacokinetic aspects are discussed.

The inhibition of the hydrogenation of testerone to 5alpha-dihydrotestosterone in microsomes of female rat liver has been studied by progesterone-, testosterone- and estradiol derivatives. In the pregnane series, progesterone, 17alpha-OH-progesterone and its acetate were the strongest inhibitors. In the estradiol series, 3-hydroxy-compounds with a CH2X-substituent at 17alpha-position were stronger inhibitors than the respective 3-methoxy derivatives. The most potent inhibitor till now is an estradiol derivative with a SeCN group in 16alpha-position.

The chromosomal aberrations of the offsprings of four mothers of pavians which received the steroid substances STS 456 and J 628 postcoitally were investigated. The aberration rate was within the norm. Malformation of the offsprings did not occur.

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.

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.

Estrogen (in uterotropic test on sexually immature female rats), antifertile (in experiments on sexually mature pregnant female rats), and antigonadotropic (in a test on sexually immature male rats) properties of some 2- and 4-bromine and silylsubstituted estradiols were compared in oral administration. 4-silylestradiols expressed marked antigonadotropic effects equal by activity to mestranol standard, and reduced as compared with the standard antifertile and estrogenic properties. 2- and 4-bromide and 2-silylestradiols were weakly active or inactive oral estrogens and possessed no antifertile properties.

One single does of 0.4 mg of steroid compounds Levonorgestrel (13-ethyl-17alpha-ethinyl-17beta-hydroxy-gon-4-en-3-on) or STS 557 (17alpha-cyanomethyl-17beta-hydroxy-13beta-methylgona-4.9-dien-3-on) was administered to each of six baboon mothers, right after mating. No indication whatsoever to possible mutagenic action of the compounds applied under the given experimental conditions were recordable from the bone-marrow cells of the mothers nor from the lymphocytes of peripheral blood of their newborns. Chromosomal aberrations recorded from this species were within normal limits.

Male and female rats aged 3 days were injected intragastrically with methyltestosterone and STS 383 synthetic androgen in doses between 0.4-3.2 mg and 0.2-3.2 mg, respectively. The treated females showed disturbances in hypothalamic differentiation as demonstrated by changes of the day of vaginal opening and frequency of oestrus, by a decrease of ovarian weight and a loss of fertility. It is thus possible to investigate perorally active aromatizable androgens for their central activities. STS 383, a new p. o. active androgen showed a higher activity compared with methyltestosterone in this study, whereas in the Hershberger model methyltestosterone was previously found to be 4 times more active than STS 383. A possible dissociation of central and peripheral activities between these two substances is discussed.

With the substance STS 456, an estrogenic active steroid, a high fertility inhibition could be obtained in the pavian, when administered p. o. over a 5 day period postcoital. The effectiveness and also the side effects were dose dependent. The antifertility mechanism is based on an luteolytic effect, demonstrated by analytical hormonal investigations. The inhibition of the synthesis of steroids in the ovary affected not only progesterone but also the estrogens.