Norethindrone Blockade of Pituitary Gonadotropin Release; Counteraction by Estrogen1

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Abstract
Norethindrone (0.5 mg/kg combined with 3.0 [mu]g of estrogen), injected sc 15-24 hr prior to mating, prevents ovulation in rabbits. Following norethindrone the postcoital elevation in ovarian progestin output, indicative of the discharge of pituitary ovulating hormone, failed to occur, and no increase in gonadotropin activity could be demonstrated in the peripheral circulation. Ovarian progestin output was rapidly activated, however, by iv injection of a minimal stimulating amount of LH (luteinizing hormone) or by intra-arterial ovarian infusion of peripheral blood from mated control donors. Estradiol benzoate (0.1 mg in oil) injected sc at 48 and 24 hr. before mating partially overcame the blocking action of norethindrone. In the estrogen-primed, norethindrone-treated series, 7/16 rabbits ovu-lated to mating, and this ratio, as well as the average number of ruptured follicles per ovulating rabbit (3.8), approximated the effect induced by a single iv injection of 2 [mu]g/kg LH; whereas, in the control series, 100% of the animals ovulated to mating and the rupture point average (10.6) was similar to that following 5 [mu]g/kg LH. These results show that in the rabbit norethindrone blocks the release of pituitary ovulating hormone and does not act directly on the ovary. They also suggest that the gonadotropin blocking action of norethindrone may be related to the anti-estrogenic properties which have been assigned to this 19-nortestosterone.

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