Estradiol and progesterone-induced slowing of gonadotropin-releasing hormone pulse frequency is not reversed by subseque
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ORIGINAL PAPER
Estradiol and progesterone-induced slowing of gonadotropinreleasing hormone pulse frequency is not reversed by subsequent administration of mifepristone Christopher R. McCartney Æ Susan K. Blank Æ John C. Marshall
Received: 16 April 2009 / Accepted: 4 June 2009 / Published online: 16 July 2009 Ó Humana Press 2009
Abstract Subsequent to suppression of LH (GnRH) pulse frequency by progesterone (P) and estradiol (E2), LH pulse frequency remains slow for 7 days after P withdrawal if mid-luteal E2 concentrations are maintained. This may reflect an ability of E2 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 E2. Studies were performed in seven ovulatory, nonobese women. Transdermal E2 (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 E2 (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
C. R. McCartney (&) S. K. Blank J. C. Marshall Center for Research in Reproduction, University of Virginia Health System, Box 800391, Charlottesville, VA 22908, USA e-mail: [email protected] C. R. McCartney S. K. Blank J. C. Marshall Division of Endocrinology, Department of Internal Medicine, University of Virginia Health System, Charlottesville, VA 22908, USA
first and second admissions, with no changes in E2, cortisol, testosterone, or DHEAS. In conclusion, blockade of P action by mifepristone does not reverse a suppressed LH pulse frequency within 7 days when E2 concentrations are maintained, suggesting that P withdrawal alone may not explain the luteal-follicular increase of GnRH pulse frequency. Keywords Gonadotropin-releasing hormone Luteinizing hormone Progesterone Mifepristone Estradiol Luteal-follicular transition
Introduction Pulsatile secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus stimulates pituitary synthesis and pulsatile secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Differential secretion of LH and FSH throughout ovulatory cycles is in part related to variations of GnRH pulse frequency, which can differentially regulate LHb and FSHb transcription and mRNA expression [1–5]. Thus, the regulation of GnRH pulse frequency is of critical importance. Progesterone (P) appears to be the principal mediator of GnRH pulse frequency slowing in women, as LH (and b
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