Stimulatory effects of interleukin-induced activation of the hypothalamo-pituitary-adrenal axis on gonadotropin secretion in ovariectomized monkeys replaced with estradiol.

In a previous report, we have shown that acute activation of the hypothalamo-pituitary-adrenal (HPA) axis by the cytokine interleukin-1 alpha (IL-1 alpha) in the ovariectomized (OVX) rhesus monkey results in an inhibition of LH secretion. Here, we study whether estradiol (E) replacement therapy, at a level that reproduces E concentrations typical of the late follicular phase, modifies the gonadotropin and cortisol responses to IL-1 alpha administration. For E replacement, two Silastic capsules containing E were implanted sc 5 days before the experiment. The serum E concentration increased from less than 5 in OVX to 103.0 +/- 5.2 pg/ml in OVX and E-replaced monkeys. The experimental protocols were carried out 24 h or more after the LH surge that had been induced by E. In Exp 1, the effects of an intracerebroventricular (icv) infusion of physiological saline (group 1) or IL-1 alpha (2.1 or 4.2 micrograms/30 min; group 2) on LH, FSH, and cortisol were compared. IL-1 alpha administration resulted in a progressive release of LH (to 159.0 +/- 8.3% of baseline at 5 h; P < 0.05, 3-5 h vs. saline). Cortisol decreased in group 1 (84.5 +/- 1.3% by 5 h), but increased after IL-1 alpha (147.3 +/- 12.6%; P < 0.05 vs. saline). In Exp 2, we determined whether the stimulatory effects of IL-1 alpha on LH result from the central activation of CRH release (group 3). Infusion of the CRH antagonist, D-Phe12, Nle21,38, CaMe,Leu37-CRF-(12-41) (240 or 360 micrograms/2 h) prevented the increase in LH seen after IL-1 alpha treatment (67.3 +/- 12.5% at 5 h, NS vs. saline). The CRH antagonist also prevented the increase in cortisol and progesterone induced by IL-1 alpha. In Exp 3, we tested whether the stimulatory effect of IL-1 alpha on LH secretion can be simulated by ACTH infusion (group 4). ACTH-(1-24) (10-micrograms bolus plus 50 micrograms/5 h, iv) induced a progressive increase in LH secretion (to 221.5 +/- 27.8% of baseline by 5 h; P < 0.05, 3-5 h vs. saline). ACTH also stimulated cortisol secretion (to 203.3 +/- 30.7% by 5 h). In Exp 4, we investigated the role of adrenal progesterone in the LH response observed in groups 2 and 4. This increase in LH did not occur after pretreatment with RU486, a progesterone antagonist (5 mg Mifepristone; 77 +/- 24.2% by 5 h; P = NS vs. saline), although the increases in cortisol and progesterone were not prevented.(ABSTRACT TRUNCATED AT 400 WORDS)