Hypothalamic Regulation of Cyclic Ovulation: Evidence That the Increase in Gonadotropin-Releasing Hormone Pulse Frequency during the Follicular Phase Reflects the Gradual Loss of the Restraining Effects of Progesterone

Abstract

The luteal-follicular transition is characterized by decreasing plasma levels of E2, progesterone (P), and inhibin A, with concomitant increases in FSH and LH levels. LH (and by inference GnRH) pulse frequency increases from 1 pulse every 3–4 h during the luteal phase to approximately 1 pulse/h at the midcycle LH surge. To examine the regulation of GnRH pulse frequency, we gave 10 normally cycling women transdermal E2 and oral P to produce midluteal levels [364 ± 65.0 pmol/liter (99 ± 18 pg/ml) and 29.7 ± 6.8 nmol/liter (9.3 ± 2.1 ng/ml), respectively] for 10 d after the LH surge (d 0). P was then discontinued, and E2 was given alone for 3 additional wk. Pulsatile LH secretion and follicular size were assessed on d 10, 17, 24, and 31. Results are presented as the mean ± sem. LH pulse frequency was 3.1 ± 0.5 pulses/12 h after 10 d of E2 and P, and remained low on d 17 when P had fallen below 1.6 nmol/liter (<0.5 ng/ml). In the continued presence of midluteal levels of E2 [∼360 pmol/liter (100 pg/ml)], LH pulse frequency increased on d 24 and 31 to 5.5 ± 0.9 and 5.8 ± 0.5 pulses/12 h, respectively, whereas pulse amplitude remained unchanged. FSH increased 2-fold, but follicular size did not change. These results are consistent with E2 potentiating the effects of low concentrations of P on the GnRH pulse generator for at least 7 d, after which pulse frequency increases despite maintenance of E2 levels. This supports the hypothesis that the increasing GnRH pulse frequency throughout the follicular phase reflects the gradual loss of the inhibitory actions of low concentrations of P.