The Negative Feedback Actions of Progesterone on Gonadotropin-Releasing Hormone Secretion are Transduced by the Classical Progesterone Receptor

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 95; no. 18; pp. 10978 - 10983
• Main Authors: Skinner, Donal C., Evans, Neil P., Delaleu, Bernadette, Goodman, Robert L., Bouchard, Philippe, Caraty, Alain
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 01-09-1998; National Academy of Sciences
• Subjects: Animals; Computer Science; Endocrinology; Ewes; Feedback; Female; Gonadotropin-Releasing Hormone - metabolism; Hormones; Injections, Intraventricular; Life Sciences; Neurology; Neurons; Ovariectomy; Physiology; Progesterone - administration & dosage; Progesterone - analogs & derivatives; Progesterone - physiology; Radioimmunoassay; Receptors; Receptors, Progesterone - physiology; Secretion; Sex hormones; Sheep; Signal Transduction - physiology; Steroids; LH; HORMONE GONADOTROPE
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.95.18.10978

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 3α -hydroxy-5α -pregnan-20-one, which operates through the type A γ -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.