THE NEGATIVE FEEDBACK ACTIONS OF PROGESTERONE ON GONADOTROPIN-RELEASING-HORMONE SECRETION ARE TRANSDUCED BY THE CLASSICAL PROGESTERONE-RECEPTOR

Progesterone (P) powerfully inhibits gonadotropin-releasing hormone (G nRH) 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 concent rations and whether this response was mediated by the nuclear P recept or. Simultaneous hypophyseal portal and jugular blood samples were col lected over 36 hr: 0-12 hr, in the presence of exogenous P (P treatmen t begun 8 days earlier); 12-24 hr, P implant removed; 24-36 hr, P impl ant reinserted. P removal caused a significant rapid increase in the G nRH pulse frequency, which was detectable within two pulses (175 min). P insertion suppressed the GnRH pulse frequency even faster: the effe ct 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 intracerebroventricu larly infused P suppressed LH release but 3 alpha-hydroxy-5 alpha-preg nan-20-one, which operates through the type A gamma-aminobutyric acid receptor, was without effect and pretreatment with the P-receptor anta gonist RU486 blocked the ability of P to inhibit LH. Our final study s howed that P exerts its acute suppression of GnRH through an E-depende nt system because the effects of P on LH secretion, lost after long-te rm E deprivation, are restored after 2 weeks of E treatment. Thus we d emonstrate that P acutely inhibits GnRH through an E dependent nuclear P-receptor system.