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-1α (IL-1α) 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-1α 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-1α (2.1 or 4.2 μg/ 30 min; group 2) on LH, FSH, and cortisol were compared. IL-1α 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-1α (147.3 ± 12.6%; P < 0.05 vs. saline). In Exp 2, we determined whether the stimulatory effects of IL-1α on LH result from the central activation of CRH release (group 3). Infusion of the CRH antagonist, D-Phe¹², Nle^21,38,C^aMe,Leu³⁷-CRF-(12-41) (240 or 360 μg/2 h) prevented the increase in LH seen after IL-1α 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-1α. In Exp 3, we tested whether the stimulatory effect of IL-1α on LH secretion can be simulated by ACTH infusion (group 4). ACTH-(1-24) (10-μg bolus plus 50 μg/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. The data demonstrate that E modulates the response of the hypothalamo-pituitary-gonadal axis to HPA axis activation by IL-1α in the primate. In the presence of E concentrations representative of the late follicular phase, LH secretion in response to IL-1α is stimulated rather than inhibited. This effect is presumably related to an increased release of progesterone from the adrenals in response to HPA axis activation. It is postulated that progesterone, in turn, facilitates the E positive feedback on LH secretion.