EVIDENCE THAT LONG-TERM ESTROGEN-TREATMENT DISRUPTS OPIOID INVOLVEMENT IN THE INDUCTION OF PITUITARY LH SURGE

Recent evidence suggests that a decrease in the inhibitory opioid influence is a necessary hypothalamic neural event in the preovulatory and ovarian steroid-induced luteinizing hormone (LH) surge. Whether shifts in ovarian steroidal milieu disrupts this neural event is not known. Therefore, the effects of short-term (3 days) and long-term (13 or 17 days) estradiol 17-beta (E2) exposure on spontaneous, naloxone (NAL) and progesterone (P)-induced LH surges were assessed in ovariectomized (ovx) rats. Two weeks after ovariectomy, rats received subcutaneous Silastic capsules filled with crystalline E2. In rats exposed to E2 for 3 days and infused with saline intravenously between 11.00-14.00 h, plasma LH rose significantly at 17.00 h. NAL infusion between 11.00-14.00 h in these rats to decrease the inhibitory opioid influence, advanced both the onset of LH rise and amplified the secretion of LH in the afternoon. Continuation of E2 exposure for 13 days produced no deleterious effects on either the spontaneous or NAL-induced augmentation in LH responses. However, uninterrupted E2 exposure for 17 days abolished the spontaneous afternoon LH rise and drastically diminished the ability of NAL to advance and amplify the LH response. In the next experiment, we evaluated the effect of P injection (2 mg/rat) at 11.00 h on the afternoon LH release in rats similarly exposed to E2 for either 3 or 17 days. In rats exposed to E2 for 3 days, the P-induced LH release was significantly greater than that observed after saline or NAL infusion. In marked contrast to the abolition of spontaneous and diminution of NAL-induced LH response in rats exposed to E2 for 17 days, P injection elicited an undiminished LH response. These findings show that the neural circuitry involved in elicitation of LH surge in ovx rats fails to operate after uninterrupted E2 exposure for longer than 13 days, but it can be readily reactivated by P and not by opiate receptor antagonism with NAL infusion. These observations demonstrate that expression of the hypothalamic opioid link necessary for induction of LH surge is disrupted by prolonged E2 exposure.