Time- and dose-dependent alterations of basal and LH-RH-stimulated LH-release during treatment with various hormonal contraceptives.

The dose- and time-dependent effect of treatment with estrogen and progestogens on serum LH before and 15 min. after the i.v. injection of 150 ng LH-RH was investigated in intact female rats. The animals were injected s.c. daily with ethinyl estradiol (EE), levonorgestrel (NG), desogestrel (DG), norethisterone (NET), chlormadinone acetate (CMA) or cyproterone acetate (CPA) alone or in various combinations, and LH was measured after 1, 2, 3, and 4 weeks of treatment and 2 weeks after termination of the injections. The treatment with low- and high-dosed combined preparations caused a marked decrease of basal LH levels which was not reversed 2 weeks after discontinuation. The combination of 30 and 50 micrograms EE with 125 or 250 micrograms NG was more effective in depressing LH-RH-induced LH release than that with 125 or 250 micrograms DG which were, however, reversible in all cases. The increase in the estrogen dose intensified the suppressive effect to a greater extent than the doubling of the progestogen dose. The suppression of the LH-RH-stimulated LH release occurred in a time-dependent manner; there was, however, a transitory amplification after 1 week when 50 micrograms EE/125 micrograms DG were tested. The high-dosed combinations of 50 micrograms EE with 500 micrograms NG, 2 mg NET, 2 mg CMA or 2 mg CPA brought about a very strong blockade of both basal and LH-RH-induced LH secretion which persisted 2 weeks after termination of treatment. The results indicate that even minor alterations in the doses of the estrogen and progestogen components of combined oral contraceptives (OC) may lead to considerable differences in the functional stage of the gonadotrophs which also depend on the duration of treatment.