Estradiol and progesterone-induced slowing of gonadotropin-releasing hormone pulse frequency is not reversed by subsequent administration of mifepristone

Abstract

Subsequent to suppression of LH (GnRH) pulse frequency by progesterone (P) and estradiol (E(2)), LH pulse frequency remains slow for 7 days after P withdrawal if mid-luteal E(2) concentrations are maintained. This may reflect an ability of E(2) to potentiate the suppressive effects of low P levels. We explored this notion in a similar experimental paradigm by administering a P-receptor antagonist (mifepristone) after P withdrawal while continuing E(2). Studies were performed in seven ovulatory, non-obese women. Transdermal E(2) (0.2 mg/day) and oral micronized P (100 mg every 8 h) were started within 24 h of the LH surge and continued for 10 days. Subjects then underwent a 13-h blood sampling protocol for determination of LH pulse characteristics and various hormone concentrations. Oral P was then discontinued, and oral mifepristone (50, 100, or 200 mg daily) and transdermal E(2) (0.2 mg/day) were administered for 7 days, after which the above sampling protocol was repeated. Results with all mifepristone doses were similar and therefore pooled. Mean LH, LH amplitude, and mean FSH markedly decreased after 7 days of mifepristone, but LH pulse frequency did not change (3.3 +/- 1.5 vs. 2.4 +/- 1.5 pulses/13 h). Prolactin and androstenedione increased between the first and second admissions, with no changes in E(2), cortisol, testosterone, or DHEAS. In conclusion, blockade of P action by mifepristone does not reverse a suppressed LH pulse frequency within 7 days when E(2) concentrations are maintained, suggesting that P withdrawal alone may not explain the luteal-follicular increase of GnRH pulse frequency.