Progesterone (P) powerfully inhibits gonadotropin-releasing hormone (GnRH) secretion in ewes, as in other species, but the neural mechanisms underlying this effect remain poorly understood. Using an estrogen (E)-free ovine model, we investigated the immediate GnRH and luteinizing hormone (LH) response to acute manipulations of circulating P concentrations and whether this response was mediated by the nuclear P receptor. Simultaneous hypophyseal portal and jugular blood samples were collected over 36 hr: 0-12 hr, in the presence of exogenous P (P treatment begun 8 days earlier); 12-24 hr, P implant removed; 24-36 hr, P implant reinserted. P removal caused a significant rapid increase in the GnRH pulse frequency, which was detectable within two pulses (175 min). P insertion suppressed the GnRH pulse frequency even faster: the effect detectable within one pulse (49 min). LH pulsatility was modulated identically. The next two experiments demonstrated that these effects of P are mediated by the nuclear P receptor since intracerebroventricularly infused P suppressed LH release but 3␣-hydroxy-5␣-pregnan-20-one, which operates through the type A ␥-aminobutyric acid receptor, was without effect and pretreatment with the P-receptor antagonist RU486 blocked the ability of P to inhibit LH. Our final study showed that P exerts its acute suppression of GnRH through an E-dependent system because the effects of P on LH secretion, lost after long-term E deprivation, are restored after 2 weeks of E treatment. Thus we demonstrate that P acutely inhibits GnRH through an E-dependent nuclear P-receptor system. Progesterone (P) is the dominant ovarian steroid present in the peripheral circulation during the mammalian reproductive cycle and serves a number of important regulatory roles. The luteal phase elevation in P inhibits pulsatile gonadotropinreleasing hormone (GnRH) and luteinizing hormone (LH) secretion (1-4) and prevents the occurrence of GnRH (5) and LH (6, 7) surges in response to fluctuations in peripheral estrogen (E) levels that accompany the waves of follicular growth occurring in the ovary (8). We have also recently demonstrated that the luteal phase elevation of P affects both the timing of the LH surge relative to E stimulation and the magnitude of the coincident GnRH surge (D.C.S., N.P.E., and A.C., unpublished results). Despite its obvious importance in regulating reproduction, little is known about how and where P acts to powerfully inhibit the neuroendocrine reproductive axis.Our first study, using the hypophyseal portal cannulation approach, assessed directly the timing of the changes in GnRH secretion that follow both an abrupt decrease and an increase in circulating P concentrations. To avoid potential P-E interactions, short-term ovariectomized (OVX) ewes were used.Since P modulates tonic LH secretion by affecting GnRH pulse frequency (1-4), it is held that P acts through neural targets and putative candidates include the opioidergic, noradrenergic, and ␥-aminobutyric acid (GABA) systems (9, 10). The p...

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