SUMMARY One hundred and twenty inseminated rats were ovariectomized 3 days after coitus and assigned to twelve treatment groups. Eleven groups were injected subcutaneously daily from day 3 to day 8 with 250, 1000 or 4000μg. progesterone alone and in combination with 0·01 or 0·1 μg. oestrone. The remaining group was injected with corn oil. All animals were injected daily with 4000 μg. progesterone and 1 μg. oestrone from day 9 to day 24 after coitus. Implantation was usually prevented permanently when animals were injected with oestrone or corn oil only from day 3 to day 8. The remaining treatments caused delayed implantation of ova. The numbers of implantation sites in groups treated with progesterone alone or in combination with oestrone were compared. Differences between groups were due to the dose of progesterone, the number of implantation sites increasing with the dose of the steroid. Addition of 0·01 or 0·1 μg. oestrone had no significant effect on the implantation site response. Survival of embryos after implantation decreased with increasing pre-nidation doses of progesterone in the absence of oestrone. In general, addition of oestrone to progesterone increased survival when oestrone was combined with the high dose of progesterone and decreased survival with the low dose of progesterone. Oestrone (0·01 μg.) given with progesterone produced consistently more frequent embryonic survival than addition of 0·1 μg. oestrone, regardless of the amount of progesterone given.

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Estratrien-17-one and its 3-methyl and 4-methyl derivatives have been converted into a number of new 17substituted estratrienes lacking the usual phenolic oxygen function in the A-ring. 2-Methylestratrien-17-one and 3-methylestratrien-17-one, previously unknown, were prepared by known methods from estrone and 19nortestosterone, respectively. The 3-desoxy-and A-ring-methylated 3-desoxy estratrienes are far less potent estrogens than the 3-phenols, being closer in this respect to the 3-methyl ethers, based on a mouse uterine growth assay. In lowering of the plasma cholesterol-phospholipid ratio in cholesterol-fed cockerels, a known effect of the natural estrogens, removal of the phenolic hydroxyl has little or no effect. Replacement with an A-ring methyl group at position 2, 3, or 4 lowers this lipid-shifting potency, though this effect is not as great as the decrease in estrogenicity.In view of the known low incidence of coronary atherosclerosis in premenopausal women and a possible direct relationship to estrogenic hormone levels,1 it seemed desirable to prepare some simple 3-desoxyestratrienes for pharmacological testing.3-Desoxyestrone and 3-desoxyestradiol have been shown to have weak estrogenic activity and normal estrogenic dose-response curves at high dose levels.2It was hoped that suitable analogs would retain desirable antiatherogenic properties3 with loss of the undesirable feminizing effects of this class of compounds. Reduction in the plasma cholesterol-phospholipid ratio is achieved with estrogens and is associated with inhibition of coronary lesions in cholesterol-fed cockerels.3 Also, in rats, a serum lipid elevation is observed with estradiol benzoate4 and this may be due to increased phospholipids. Efficacy of estrogens in clinical states related to atherosclerosis and associated with hypercholesterolemia has also been observed, though the treatment also resulted in undesirable estrogenic side effects.5It was the intent of this study to find compounds which would lower the plasma cholesterol-phospholipid ratio, but lack altogether, or have only very weak, estrogenic activity.A second point of interest concerned whether compounds for evaluation would be impeded estrogens,2 that is, have shallow estrogenic dose-response curves. This point has not as yet been thoroughly studied,(1) (a) D. L. Cook in "Drugs Affecting Lipid Metabolism," S. Garattini

SUMMARY Eighty-six female rats were ovariectomized 3 days after coitus and treated daily with 4000 μg. progesterone either alone, or in combination with 0·01–10 μg. oestrone from day 3 to day 8 after coitus. Ten additional animals with intact ovaries were treated daily with corn oil. Ovariectomized rats were treated with 4000 μg. progesterone and 1 μg. oestrone from day 9 to day 19, if nidation occurred by day 8, and from day 9 to 24, if implantation sites were absent 8 days after coitus. A delay of implantation usually occurred in animals treated with progesterone alone or in combination with 0·01, 0·03 or 0·1 μg. oestrone ('delay' class). Implantation occurred at about the normal time during treatment with progesterone combined with 0·3, 1 or 3 μg. oestrone and in non-ovariectomized animals treated with corn oil ('non-delay' class). Nidation was usually prevented permanently by 10 μg. oestrone in combination with progesterone. In the 'delay' class the addition of 0·01–0·1 μg. oestrone to progesterone did not alter the ability of blastocysts to undergo nidation or affect embryonic survival. In animals in the 'non-delay' class, nidation was induced with equal success when 0·3, 1, or 3 μg. oestrone were administered. Embryonic survival, however, was maximal in animals treated with 0·3 μg. oestrone and progressively less in rats treated with 1 and 3 μg. The number of implantation sites was larger in non-ovariectomized 'non-delay' animals than in ovariectomized 'non-delay' rats. The number of sites in the 'non-delay' class was consistently larger than the number of sites in the 'delay' class.

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Four luteolytic agents were administered to groups of pregnant rats to examine the quantitative relationship between serum progesterone levels and the maintenance of pregnancy. Each agent inhibited progesterone in a dose-dependent manner, however only three, azastene, thiosemicarbazone and dihydrotestosterone, adversely affected pregnancy. A statistical analysis of the data suggests that, regardless of the mechanism of action of a particular luteolytic agent, a treatment-induced depression of serum progesterone to concentrations less than 45% of that of the controls on day 11 of pregnancy is incompatible with pregnancy maintenance.

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