A 5-DAY ESTRADIOL THERAPY, IN AMOUNTS REPRODUCING CONCENTRATIONS OF THE EARLY-MID FOLLICULAR PHASE, PREVENTS THE ACTIVATION OF THE HYPOTHALAMO-PITUITARY-ADRENAL AXIS BY INTERLEUKIN-1-ALPHA IN THE OVARIECTOMIZED RHESUS-MONKEY

In a previous report, we have shown that intracerebroventricular (icv) administration of the cytokine interleukin-1 alpha. (IL-1 alpha) in the ovariectomized (OVX) rhesus monkey results in the acute activation of the hypothalamo-pituitary-adrenal (HPA) axis and the inhibition of LH and FSH secretion. Here, we compare the cortisol response to IL-1 alpha administration in OVX monkeys and in OVX animals replaced with estradiol (E) to reproduce E concentrations typical of the early-mid follicular phase. Cortisol, LH and FSH were measured after an icy infusion of physiological saline or IL-1 alpha (2.1 or 4.2 mu g/30 min) in both groups. E-containing capsules were implanted sc 5 days prior to the experiment. In OVX, E concentrations were < 5 pg/ml. Cortisol concentrations decreased throughout the afternoon after saline infusion (to 49.7 +/- 5.1% of baseline at 5 h; n = 7), but increased significantly after IL-1 alpha to 158.3 +/- 13.8% (n = 7). In OVXE, cortisol also declined after saline (to 76.4 +/- 16.2%; n = 5). There were 2 types of response to IL-1 alpha in grp 1 (mean E: 18.0 +/- 0.7 pg/ml), the cortisol response was similar to that in OVX (160.8 +/- 17.0%; n = 5), while in grp 2 (E: 30.7 +/- 3.1 pg/ml), the cortisol response was absent (66.6 +/- 7.2% of baseline at 5 h; NS vs saline in OVXE; n = 7). The cortisol response to IL-lv. was restored in 2 monkeys when E was increased to > 100 pg/ml, confirming our previous observations. While saline infusion did not affect LH (102.3 +/- 10.2% of baseline at 5 h) or FSH (102.5 +/- 4.4%) secretion in OVX monkeys, there was a significant decrease in both hormones after IL-1 alpha (LH: 33.3 +/- 3.7%, FSH: 66.2 +/- 6.5%; P < 0.05 vs saline). This effect was lessened in OVXE animals: By 5 h, areas under the LH curve were 62.8 +/- 10.9% of baseline in grp 1 and 85.3 +/- 7.9% in grp 2 (NS vs saline), while those under the FSH curve were 84.0 +/- 6.5% in grp 1 and 77.7 +/- 4.3% in grp 2 (NS vs saline). The data demonstrate a striking effect of a 5-day estradiol treatment in preventing the HPA axis response to the cytokine IL-1 alpha in the OVX monkey. This action, however, occurs only within restricted estradiol concentrations that reproduce E levels typical of the early-mid follicular phase of the menstrual cycle. While the precise mechanism through which estradiol exerts this action remains to be investigated, the results may have clinical relevance to the issue of estrogen replacement therapy in physiology and pathology.