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Estrogen-Induced Hypothalamic Synaptic Plasticity and Pituitary Sensitization in the Control of the Estrogen-Induced Gonadotrophin Surge

Reproductive Neuroscience Unit, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut, Department of Obstetrics and Gynecology, New York University School of Medicine, New York, New York, frederick.naftolin{at}med.nyu.edu

Luis Miguel Garcia-Segura, PhD

Instituto Cajal, CSIC, Madrid, Spain

Tamas L. Horvath, DVM, PhD

Reproductive Neuroscience Unit, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut

Attila Zsarnovszky, DVM, PhD

Reproductive Neuroscience Unit, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut

Necdet Demir, PhD

Reproductive Neuroscience Unit, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut, Department of Histology & Embryology, Medical Faculty, Akdeniz University, Antalya,Turkey

Ahmed Fadiel, PhD

Reproductive Neuroscience Unit, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut, Department of Obstetrics and Gynecology, New York University School of Medicine, New York, New York

Csaba Leranth, MD, PhD

Reproductive Neuroscience Unit, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut

Susanne Vondracek-Klepper, PhD

Reproductive Neuroscience Unit, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut

Carole Lewis, PhD

Reproductive Neuroscience Unit, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut

Aimee Chang, MD

Reproductive Neuroscience Unit, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut

Arpad Parducz, PhD

Institute of Biophysics. Szeged, Hungary

Proper gonadal function requires coordinated (feedback) interactions between the gonads, adenohypophysis, and brain: the gonads elaborate sex steroids (progestins, androgens, and estrogens) and proteins (inhibin-activin family) during gamete development. In both sexes, the brain-pituitary gonadotrophin-regulating interaction is coordinated by estradiol through its opposing actions on pituitary gonadotrophs (sensitization of the response to gonadotrophin-releasing hormone [GnRH]) versus hypothalamic neurons (inhibition of GnRH secretion). This dynamic tension between the gonadotrophs and the GnRH cells in the brain regulates the circulating gonadotrophins and is termed reciprocal/negative feedback. In females, reciprocal/negative feedback dominates 90% of the ovarian cycle. In a spectacular exception, the dynamic tension is broken during the surge of circulating estrogen that marks follicle and oocyte(s) maturation. The cause is an estradiol-induced disinhibition of the GnRH neurons that releases GnRH secretion to the highly sensitized pituitary gonadotrophs that in turn release the gonadotrophin surge (the estrogen-induced gonadotrophin surge [EIGS], also known as positive feedback). Studies during the past 4 decades have shown this disinhibition to result from estrogen-induced synaptic plasticity (EISP), including a reversible 50% loss in arcuate nucleus synapses. The disinhibited GnRH secretion occurs during maximal gonadotroph sensitization and results in the EIGS. Specific immunoneutralization of estradiol blocks the EISP and EIGS. The EISP is accompanied by increases in insulinlike growth factor 1, polysialylated neural cell adhesion molecule, and ezrin, 3 proteins that the authors believe are the links between estrogen-induced astroglial extension and the EISP that releases GnRH secretion at the moment of maximal sensitization of the pituitary gonadotrophs. The result is the paradoxical surge of gonadotrophins at the peak of ovarian estrogen secretion and the triggering of ovulation. This enhanced understanding of the mechanics of gonadotrophin control clarifies elements of the involved feedback loops and opens the way to a better understanding of the neurobiology of reproduction.

Key Words: Periventriculararea • luteinizinghormone • follicle-stimulating hormone • gonadotrophin feedback • hypothalamus • estradiol • synaptic plasticity • pituitary • GnRH

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