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

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Abstract

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.

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Authors and Affiliations

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

    Frederick Naftolin MD, DPhil, Tamas L. Horvath DVM, PhD, Attila Zsarnovszky DVM, PhD, Necdet Demir PhD, Ahmed Fadiel PhD, Csaba Leranth MD, PhD, Susanne Vondracek-Klepper PhD, Carole Lewis PhD & Aimee Chang MD

  2. Department of Obstetrics and Gynecology, New York University School of Medicine, 550 First Avenue, MSB TH, New York, New York, 10016, USA

    Frederick Naftolin MD, DPhil & Ahmed Fadiel PhD

  3. Instituto Cajal, CSIC, Madrid, Spain

    Luis Miguel Garcia-Segura PhD

  4. Department of Histology & Embryology, Medical Faculty, Akdeniz University, Antalya, Turkey

    Necdet Demir PhD

  5. Institute of Biophysics, Szeged, Hungary

    Arpad Parducz PhD

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  1. Frederick Naftolin MD, DPhil
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  2. Luis Miguel Garcia-Segura PhD
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Correspondence to Frederick Naftolin MD, DPhil.

Additional information

Supported by NIH HD 13587 and NS36111 (F.N.), NSF IBN-IBN-9728581 (T.L.H.), and SAF 2005-00272, Ministerio de Educacion y Ciencia, Spain (L.-M.G.S.).

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Naftolin, F., Garcia-Segura, L.M., Horvath, T.L. et al. Estrogen-Induced Hypothalamic Synaptic Plasticity and Pituitary Sensitization in the Control of the Estrogen-Induced Gonadotrophin Surge. Reprod. Sci. 14, 101–116 (2007). https://doi.org/10.1177/1933719107301059

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