Estradiol amplifies the amount of luteinizing hormone (LH) secreted in response to increasing doses of gonadotropin-releasing hormone by specifically augmenting the duration of evoked LH secretory events and hence their mass.
Amplification of LH release during the preovulatory LH surge could result from increased GnRH secretion and/or estradiol's facilitation of the dose-dependent actions of GnRH. We have investigated the mechanisms of estrogen's enhancement of GnRH action by evaluating LH release in response to four consecutive iv doses of GnRH (7.5, 25, 75, and 250 ng/kg) administered in randomized order followed by a fifth (maximal) dose of 750 ng/kg GnRH. The GnRH dose-response study was carried out before and after 10 days of estradiol treatment (0.2 mg/day percutaneously) in nine healthy postmenopausal women. Deconvolution analysis was used to quantitate specific measures of GnRH-stimulated LH secretion as well as estimate the half-life of endogenous LH. We found that 10 days of estradiol delivery did not alter the calculated half-life of immunoradiometric LH (126 +/- 10 min basally vs. 135 +/- 14 min during estrogen), but amplified the total mass of LH secreted in response to the five doses of GnRH; viz. 201 +/- 29 (control) vs. 406 +/- 58 IU/L (estrogen) (P < 0.001). Estradiol specifically enhanced the maximal value of the GnRH dose-LH secretory response curve; viz. from a mass of LH secreted of 46 (41-51) IU/L (basal) vs. 113 (93-139) IU/L (estrogen) (P < 0.001). Estradiol did not induce a significant leftward shift of the GnRH dose-LH secretory response curve, since the half-maximally effective dose of GnRH (ED50) was 9 (3.6-18) (control) vs. 19 (10-31) ng/kg (estradiol). The increased mass of LH secreted in the estrogen-rich milieu was due to a doubling of LH secretory burst duration, with no change in amplitude. We conclude that amplified LH secretory burst duration constitutes a novel neuroendocrine mechanism by which estradiol can promote GnRH self-priming of LH release by the previously estrogen-deprived human anterior pituitary gland in vivo.
Quyyumi
S A
SA
Department of Internal Medicine, University of Virginia Health Sciences Center, Charlottesville 22908.
Pinkerton
J V
JV
Evans
W S
WS
Veldhuis
J D
JD
D000704:Analysis of Variance; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004958:Estradiol / Q000097:blood / Q000494:pharmacology*; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000494:pharmacology*; D006801:Humans; D015592:Immunoradiometric Assay; D007986:Luteinizing Hormone / Q000097:blood / Q000378:metabolism*; D008875:Middle Aged; D009994:Osmolar Concentration; D013997:Time Factors
D007987:Gonadotropin-Releasing Hormone; D004958:Estradiol; D007986:Luteinizing Hormone