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Does Cortisol Mediate Endotoxin-Induced Inhibition of Pulsatile Luteinizing Hormone and Gonadotropin-Releasing Hormone Secretion?

Reproductive Sciences Program (N.D, K.M.B, H.J.B, M.B., E.A.Y., F.J.K.), Departments of Physiology (K.M.B., F.J.K.), Mental Health Research Institute (E.A.Y.), University of Michigan, Ann Arbor, Michigan 48109-0404; and Animal and Food Sciences Division (G.K.B.), Lincoln University, Canterbury 8150, New Zealand

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

Bacterial endotoxin (lipopolysaccharide), a commonly used model of immune/inflammatory stress, inhibits reproductive neuroendocrine activity and concurrently induces a profound stimulation of the hypothalamo-pituitary-adrenal axis. We employed two approaches to test the hypothesis that enhanced secretion of cortisol mediates endotoxin-induced suppression of pulsatile GnRH and LH secretion in the ovariectomized ewe. First, we mimicked the endotoxin-induced increase in circulating cortisol by delivering the glucocorticoid in the absence of the endotoxin challenge. Within 1–2 h, experimentally produced increments in circulating cortisol suppressed pulsatile LH secretion in a dose-dependent fashion. Second, we blocked the endotoxin-induced stimulation of cortisol secretion using the drug metyrapone, which inhibits the 11-ß hydroxylase enzyme necessary for cortisol biosynthesis. In the absence of a marked stimulation of cortisol secretion, endotoxin still profoundly inhibited pulsatile GnRH and LH secretion. We conclude that, although enhanced cortisol secretion may contribute to endotoxin-induced suppression of reproductive neuroendocrine activity, the marked stimulation of the glucocorticoid is not necessary for this response. Our findings are consistent with the hypothesis that immune/inflammatory stress inhibits reproductive neuroendocrine activity via more than one inhibitory pathway, one involving enhanced secretion of cortisol and the other(s) being independent of this glucocorticoid.

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