Effect of Progesterone and its 5α-Reduced Metabolites on Gonadotropin Levels in Estrogen-Primed Ovariectomized Rats1 2

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Abstract
In an effort to determine whether the metabolic conversion of progesterone may be important in the feedback effects of this steroid, serum LH [luteinizing hormone] and FSH [follicle stimulating hormone] levels were measured after administration of progesterone, 5.alpha.-dihydroprogesterone or 3.alpha.-hydroxy-5.alpha.-pregnan-20-one to estrogen-primed ovariectomized rats. A single injection of 2 or 4 mg progesterone, 4 mg 5.alpha.-dihydroprogesterone or 4 mg 3.alpha.-hydroxy-5.alpha.-pregnan-20-one 72 h (day 3) after estrogen pretreatment increased serum LH and FSH 6 h later (1800 h). Although serum gonadotropin levels had begun to decrease 12 h after administration of the progestins, they were still significantly higher than control values and did not return to baseline levels until noon on day 4. When either progesterone or 3.alpha.-hydroxy-5.alpha.-pregnan-20-one was administered at noon on days 3 and 4, there was a significant reduction in LH levels 6 h after the 2nd injection. Serum LH levels were slightly elevated 3-6 h (1500-1800 h) after the 2nd injection of 5.alpha.-dihydroprogesterone and did not decrease until 2100 h. There was no effect on FSH concentrations after a 2nd injection of any of the progestins. Loss of uterine luminal fluid was observed within 24 h after a single injection of progesterone. Neither of the 5.alpha.-reduced metabolites had an effect on uterine ballooning until after the 2nd injection, and, even then, nonfluid-filled uteri were observed in only 20-30% of the animals. The conversion of progesterone to 5.alpha.-dihydroprogesterone and 3.alpha.-hydroxy-5.alpha.-pregnan-20-one by neuroendocrine tissues may be necessary for the positive and negative feedback effects of progesterone on gonadotropin secretion. The diverse effects of progesterone may be due to progesterone per se, e.g., in the uterus, and/or its metabolites, e.g., in the hypothalamus and pituitary.