Studies on the Site of Action of Oral Contraceptive Steroids. I. Effect of Antifertility Steroids on Plasma LH Levels and on the Response to Luteinizing Hormone-Releasing Factor in Rats1
The effects of ovulation inhibiting steroids on plasma luteinizing hormone (LH) levels and on the response to LH-releasing factor (LRF) were studied in an attempt to learn whether these compounds exert part of their effect on the pituitary or on the hypothalamus. Ovariectomized rats were injected subcutaneously for 5 days with estrogens, progestins, and combinations thereof. Plasma LH levels were measured by the ovarian ascorbic acid depletion assay. The progestins: chlormadinone acetate (0.05–10 mg), ethynodiol diacetate (2 mg), norethynodrel (20 mg), norethindrone (5 mg), medroxyprogesterone (10 mg), norgestrel (1 mg) and dimethisterone (2.5–20 mg) given daily in doses indicated significantly depressed plasma LH. Administration of mestranol (0.001–0.2 mg) and ethinyl estradiol (0.1 mg) also significantly lowered plasma LH. The progestin/estrogen combinations: chlormadinone acetate/mestranol (C-Quens, 10.4 μg), ethynodiol diacetate/mestranol (Ovulen, 5.5 μg), norethynodrel/mestranol (Enovid, 12.5 μg), norethinodrone/mestranol (Ortho-Novum, 10.4 μg), norethindrone acetate/ethinyl estradiol (Norlestrin, 12.9 μg), dimethisterone/ethinyl estradiol (Oracon, 125.5 μg), norgestrel/ethinyl estradiol (Ovral, 5.5 μg), and medroxyprogesterone/ethinyl estradiol (Provest, 50.4 μg) given daily suppressed plasma LH levels in most cases more effectively than estrogen alone. Administration of 0.3–0.4 μg LRF to rats treated subcutaneously with very large doses of progestins, estrogens, or their combinations caused a highly significant elevation of plasma LH. Since these oral contraceptives did not suppress the stimulatory effect of LRF on on LH release, it is probable that they act mainly on the hypothalamus or on higher brain centers and not on the pituitary.