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 t he 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 a lpha administration in OVX monkeys and in OVX animals replaced with es tradiol (E) to reproduce E concentrations typical of the early-mid fol licular phase. Cortisol, LH and FSH were measured after an icy infusio n of physiological saline or IL-1 alpha (2.1 or 4.2 mu g/30 min) in bo th groups. E-containing capsules were implanted sc 5 days prior to the experiment. In OVX, E concentrations were < 5 pg/ml. Cortisol concent rations decreased throughout the afternoon after saline infusion (to 4 9.7 +/- 5.1% of baseline at 5 h; n = 7), but increased significantly a fter IL-1 alpha to 158.3 +/- 13.8% (n = 7). In OVXE, cortisol also dec lined after saline (to 76.4 +/- 16.2%; n = 5). There were 2 types of r esponse to IL-1 alpha in grp 1 (mean E: 18.0 +/- 0.7 pg/ml), the corti sol response was similar to that in OVX (160.8 +/- 17.0%; n = 5), whil e 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 co rtisol response to IL-lv. was restored in 2 monkeys when E was increas ed 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 de crease 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 anima ls: By 5 h, areas under the LH curve were 62.8 +/- 10.9% of baseline i n grp 1 and 85.3 +/- 7.9% in grp 2 (NS vs saline), while those under t he FSH curve were 84.0 +/- 6.5% in grp 1 and 77.7 +/- 4.3% in grp 2 (N S vs saline). The data demonstrate a striking effect of a 5-day estrad iol treatment in preventing the HPA axis response to the cytokine IL-1 alpha in the OVX monkey. This action, however, occurs only within res tricted estradiol concentrations that reproduce E levels typical of th e early-mid follicular phase of the menstrual cycle. While the precise mechanism through which estradiol exerts this action remains to be in vestigated, the results may have clinical relevance to the issue of es trogen replacement therapy in physiology and pathology.