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

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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, non-obese 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 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.

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Acknowledgments

We are indebted to Danco Laboratories, LLC, for assistance in the purchase and acquisition of mifepristone for this research study. We thank Lauren Lockhart, M.P.H., Quirine Lamberts Okonkwo, M.D., and Chandan Chopra for subject recruitment, study scheduling, and assistance with data management; Kristin D. Helm, M.D., and Sandhya Chhabra, M.D., for assistance with subject screening and GCRC admission oversight; the nurses and staff of the General Clinical Research Center at the University of Virginia for implementation of these sampling protocols; the Center for Research in Reproduction Ligand Core Laboratory for performance of all assays; Michael L. Johnson, Ph.D., for provision of and assistance with pulse detection programs. Grants: This research was supported by K23 HD044742 (C.R.M.); the Eunice Kennedy Shriver NICHD/NIH through cooperative agreement U54 HD28934 as part of the Specialized Cooperative Centers Program in Reproduction and Infertility Research (J.C.M.); General Clinical Research Center Grant M01 RR00847; and F32 HD055014 (S.K.B.).

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Authors and Affiliations

  1. Center for Research in Reproduction, University of Virginia Health System, Box 800391, Charlottesville, VA, 22908, USA

    Christopher R. McCartney, Susan K. Blank & John C. Marshall

  2. Division of Endocrinology, Department of Internal Medicine, University of Virginia Health System, Charlottesville, VA, 22908, USA

    Christopher R. McCartney, Susan K. Blank & John C. Marshall

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  1. Christopher R. McCartney
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Correspondence to Christopher R. McCartney.

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McCartney, C.R., Blank, S.K. & Marshall, J.C. Estradiol and progesterone-induced slowing of gonadotropin-releasing hormone pulse frequency is not reversed by subsequent administration of mifepristone. Endocr 36, 239–245 (2009). https://doi.org/10.1007/s12020-009-9215-x

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