Progesterone Effects on Gonadotropin Release in Women Pretreated with Estradiol*

Abstract

This study was designed to investigate whether the amounts of progesterone (P) normally present at midcycle, when administered to normal women pretreated with estradiol benzoate (E₂B), alter the release of LH and FSH. Twelve subjects (four groups of three) were studied during two menstrual cycles. On day 1 of both the initial (E₂ control) and a subsequent (study) cycle, each subject received E₂B im (2.5 μg/kg/12 h) for a total of seven injections. Twelve hours after the final injection, gonadotropin-releasing hormone (GnRH) was given. In the study cycle, P in oil was added to each of the last three injections of E₂B in doses of 1.25 (group I), 2.5 (group II), or 5.0 (group III) mg/12 h, and in one group (IV) in graded doses of 1.25, 2.5, and 5.0 mg/12 h. Estradiol levels were similar in both cycles, with a mean (± SE) of 271 ± 3 pg/ml. During the interval of P administration, mean P levels rose gradually from 0.3 ± 0.02 to 1.3 ± 0.12 ng/ml (mean ± SE of all groups). In the study cycle, an FSH rise occurred in 8 of 12 subjects, while an LH surge greater than that in the E₂ control cycle occurred in all but one subject. Peak levels of these surges usually occurred within 24 h of the initial P injection, which is similar to the relationship between the initial rise of P and the occurrence of peak gonadotropin levels at midcycle in normal women. The mean Δ max of FSH and LH in subjects exhibiting gonadotropin rises approximated the magnitude of the gonadotropin increases observed normally at midcycle. In response to GnRH during the study cycle, the magnitude of the FSH rise was augmented in 6 of 12 subjects and of LH in 9 of 12, when compared to the E₂ control cycles. These data suggest that P, in the presence of late follicular phase levels of E₂, 1) augments the release of LH, 2) may induce the release of FSH, and 3) further modulates pituitary responsiveness to GnRH. The data are consistent with the hypothesis that the rising concentrations of E₂ to which the hypothalamic-pituitary system is exposed for an appropriate duration serve to initiate the surge of LH at midcycle. This increased LH, in turn, stimulates the production of P, which not only further augments the LH surge but, when coupled with E₂, also can effect the midcycle FSH surge.