Does cortisol mediate endotoxin-induced inhibition of pulsatile luteinizing hormone and gonadotropin-releasing hormone secretion?
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-beta 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.
Debus
Nathalie
N
Reproductive Sciences Program, University of Michigan, Ann Arbor 48109-0404, USA.
Breen
Kellie M
KM
Barrell
Graham K
GK
Billings
Heather J
HJ
Brown
Martha
M
Young
Elizabeth A
EA
Karsch
Fred J
FJ
D000818:Animals; D004338:Drug Combinations; D004731:Endotoxins / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D006854:Hydrocortisone / Q000502:physiology*; D007986:Luteinizing Hormone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008797:Metyrapone / Q000494:pharmacology; D010902:Pituitary Gland / Q000187:drug effects / Q000502:physiology; D011374:Progesterone / Q000378:metabolism; D011673:Pulsatile Flow; D012756:Sheep
D004338:Drug Combinations; D004731:Endotoxins; D007987:Gonadotropin-Releasing Hormone; D011374:Progesterone; D007986:Luteinizing Hormone; D006854:Hydrocortisone; D008797:Metyrapone