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Endotoxin Inhibits the Surge Secretion of Gonadotropin-Releasing Hormone via a Prostaglandin-Independent Pathway

Reproductive Sciences Program and Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109

Address all correspondence and requests for reprints to: Fred J. Karsch, Reproductive Sciences Program, University of Michigan, 300 North Ingalls Building, Room 1101 SW, Ann Arbor, Michigan 48109-0404. E-mail: fjkarsch{at}umich.edu.

Immune/inflammatory challenges, such as bacterial endotoxin, disrupt gonadotropin secretion and ovarian cyclicity. We previously determined that endotoxin can block the estradiol-induced LH surge in the ewe. Here, we investigated mechanisms underlying this suppression. First, we tested the hypothesis that endotoxin blocks the estradiol-induced LH surge centrally, by preventing the GnRH surge. Artificial follicular phases were created in ovariectomized ewes, and either endotoxin or vehicle was administered together with a surge-inducing estradiol stimulus. In each ewe in which endotoxin blocked the LH surge, the GnRH surge was also blocked. Given this evidence that endotoxin blocks the estradiol-induced LH surge at the hypothalamic level, we began to assess underlying central mechanisms. Specifically, in view of the prior demonstration that prostaglandins mediate endotoxin-induced suppression of pulsatile GnRH secretion in ewes, we tested the hypothesis that prostaglandins also mediate endotoxin-induced blockade of the surge. The prostaglandin synthesis inhibitor flurbiprofen was delivered together with endotoxin and the estradiol stimulus. Although flurbiprofen abolished endotoxin-induced fever, which is a centrally generated, prostaglandin-mediated response, it failed to reverse blockade of the LH surge. Collectively, these results indicate endotoxin blocks the LH surge centrally, suppressing GnRH secretion via a mechanism not requiring prostaglandins. This contrasts with the suppressive effect of endotoxin on GnRH pulses, which requires prostaglandins as intermediates.

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