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

The luteal-follicular transition is characterized by decreasing plasma levels of E-2, 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 mid-cycle 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 E-2 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 E-2 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 E-2 [similar to360 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 E-2 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 E-2 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.