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

Abstract

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.

Psychosocial Stress Inhibits Amplitude of Gonadotropin-Releasing Hormone Pulses Independent of Cortisol Action on the Type II Glucocorticoid Receptor

“…Finally, we are puzzled why psychosocial stress enhanced GnRH pulse frequency in experiment 2 but not in experiment 1. Although we have no explanation for this, it is noteworthy that another stress type, immune-inflammatory stress (endotoxin), has caused an increase in GnRH pulse frequency in sheep, but this effect, too, was inconsistent across studies (5,16,17). Possibly related to this, endotoxin stimulates CRH secretion in sheep (38,39), and central delivery of CRH in sheep increased LH pulse frequency in some studies, but not in others (40 -42).…”

“…For example, psychosocial stress increases circulating levels of glucocorticoids and inhibits pulsatile LH secretion (1)(2)(3)(4). Recent studies in ovariectomized sheep have demonstrated that a stress-like elevation of plasma cortisol decreases pulsatile LH secretion in the absence of stress and that this occurs via suppression of pituitary responsiveness to GnRH (5)(6)(7). This effect of cortisol, which reflects a direct action on the pituitary and mediation by the type II glucocorticoid receptor (GR), occurs without concurrent inhibition of pulsatile GnRH secretion (6,8,9).…”

Projections to the Preoptic Area from the Paraventricular Nucleus, Arcuate Nucleus and the Bed Nucleus of the Stria Terminalis Are Unlikely to Be Involved in Stress-Induced Suppression of GnRH Secretion in Sheep

“…There are few reports of the effects of stress on GnRH secretion [1], although the pulsatile secretion of LH is taken to reflect GnRH secretion, due to the tight coupling of the secretion of these two hormones [22]. Cortisol suppresses secretion of LH [23, 24], which provides one mechanism by which the reproductive system can be affected by stress, but the central circuitry involved is not defined. Whether this is due to a direct input to GnRH cells from stress-activated neuronal systems, or to input to the region of the brain in which GnRH cells are found remains to be fully deciphered.…”

Neuroendocrine Control of Gonadotropin Secretion

“…371,372 Thus acute treatments with glucocorticoids have little effect on episodic LH secretion in rats, monkeys, and humans. Cortisol does act at the pituitary to suppress LH pulse amplitude in ewes 373 ; this action is not required for the inhibition of episodic LH secretion by endotoxin, 374 but may play an important role in the effects of psychosocial stress. 375,376 Moreover, cortisol clearly suppresses LH pulse frequency during the follicular phase of the ovine estrous cycle, 377 so sheep may be one species in which glucocorticoids have important inhibitory effects on GnRH secretion.…”