FURTHER STUDIES OF COMPOUNDS EXHIBITING PROLONGED ANTIOESTROGENIC AND ANTIFERTILITY ACTIVITY IN THE MOUSE

Summary. Groups of twenty female QS-strain mice were injected with a single dose of 0, 1, 3 or 9 mg of the triarylalkene H-774. Males were introduced 3, 30 or 60 days after injection. Mating was not greatly affected, but very few females mating within the first 23 days after injec-tion became pregnant. At 30 days, fertility varied from 62 % (1-mg dose) to 17 % (9-mg dose) of that in controls. At 60 days, it was sub-stantially back to normal but the numbers/litter were still lower than in controls. In females receiving the same oral doses, fertility was initially as severely affected, but recovery was more rapid. Further groups of mice were injected with single doses of 0, 2 or 5 mg of the closely related compound, H-1076, vaginal smears were taken daily from some, and others were killed at varying periods between 3 and 119 days afterwards. Some were allowed to mate, others were not. In unmated mice, initial responses were oestrogenic in the uterus and vagina, and oestrous cycles were lengthened at first but later reverted to normal. In the uterus, the glands started to enlarge by Day 7 and pro-ceeded to maximal distention by Day 63. Later, they deflated and five out of six uteri appeared normal by Day 119. In the ovaries, follicles appeared normal in size and numbers, but corpora lutea were few and appeared degenerate. Mating was followed by pregnancy after the 2-mg injections in much the same pattern as with H-774, despite the uterine abnormalities, but only three out of eighteen females became pregnant after 5-mg injections. Implantation numbers and weights were affected in some mice. These results suggest a lack of progesterone, with little effect on oestrogen production, mediated through reduced ovulation rates and reduced production of progesterone from such corpora lutea as were formed. It is postulated that these compounds may inhibit LH release and/or production