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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

Division of Endocrinology, Department of Internal Medicine (C.R.M., W.S.E., J.C.M.); Center for Research in Reproduction (C.R.M., M.B.G., Y.H., W.S.E., J.C.M.); and Department of Obstetrics and Gynecology (W.S.E.), University of Virginia Health System, Charlottesville, Virginia 22908

Address all correspondence and requests for reprints to: Christopher R. McCartney, M.D., Box 800746, Division of Endocrinology, Department of Internal Medicine, University of Virginia Health System, Charlottesville, Virginia 22908. E-mail: . cm2hq{at}virginia.edu

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.

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