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Converse Regulatory Functions of Estrogen Receptor- and -β Subtypes Expressed in Hypothalamic Gonadotropin-Releasing Hormone Neurons

Endocrinology and Reproduction Research Branch, Program in Developmental Endocrinology and Genetics, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-4510

Address all correspondence and requests for reprints to: Lazar Z. Krsmanovic, Ph.D. Endocrinology and Reproduction Research Branch, PDEGEN, National Institue of Child Health and Human Development, National Institutes of Health, Building 49, Room 6A-36, Bethesda, Maryland 20892-4510. E-mail: lazar{at}mail.nih.gov.

Estradiol (E₂) acts as a potent feedback molecule between the ovary and hypothalamic GnRH neurons, and exerts both positive and negative regulatory actions on GnRH synthesis and secretion. However, the extent to which these actions are mediated by estrogen receptors (ERs) expressed in GnRH neurons has been controversial. In this study, Single-cell RT-PCR revealed the expression of both ER and ERβ isoforms in cultured fetal and adult rat hypothalamic GnRH neurons. Both ER and ERβ or individual ERs were expressed in 94% of cultured fetal GnRH neurons. In adult female rats at diestrus, 68% of GnRH neurons expressed ERs, followed by 54% in estrus and 19% in proestrus. Expression of individual ERs was found in 24% of adult male GnRH neurons. ER exerted marked G_i-mediated inhibitory effects on spontaneous action potential (AP) firing, cAMP production, and pulsatile GnRH secretion, indicating its capacity for negative regulation of GnRH neuronal function. In contrast, increased E₂ concentration and ERβ agonists increase the rate of AP firing, GnRH secretion, and cAMP production, consistent with ERβ-dependent positive regulation of GnRH secretion. Consonant with the coupling of ER to pertussis toxin-sensitive G_i/o proteins, E₂ also activates G protein-activated inwardly rectifying potassium channels, decreasing membrane excitability and slowing the firing of spontaneous APs in hypothalamic GnRH neurons. These findings demonstrate that the dual actions of E₂ on GnRH neuronal membrane excitability, cAMP production, and GnRH secretion are mediated by the dose-dependent activation of ER and ERβ expressed in hypothalamic GnRH neurons.

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Nuclear Receptors:   ERα  |  ERβ

Ligands:   17β-Estradiol  |  Fulvestrant