Estrogen Neuroendocrine Feedback is Mediated Distinctly via Estrogen Response Element Dependent and Independent Estrogen Receptor Alpha SignalingPublic Deposited
Gonadotropins LH and FSH are secreted by the pituitary in response to hypothalamic GnRH and act to stimulate ovarian follicle development, steroid production and ovulation. Gonadal steroids, including estrogen, enter the circulation and provide neuroendocrine feedback at the hypothalamus and/or pituitary. Estrogen provides negative feedback to suppress gonadotropin release throughout most of the estrous cycle. Until, on the afternoon of proestrus, when estrogen feedback switches to positive resulting in a gonadotropin surge. Both estrogen negative and positive feedback have both been shown to require ERα and the mechanism s behind this dual role for estrogen remain a mystery. The purpose of this study was to examine the relative roles of distinct ERα signaling pathways in estrogen negative and positive feedback. ERα, in response to estrogen, translocates into the nucleus, binds at estrogen responsive elements (ERE) in target gene promoters and modulates transcription. Recently, ERα has been shown to also signal through ERE-independent pathways. ERα is able to modulate transcription through protein-protein interactions at non-ERE sites and signal through rapid, nongenomic membrane initiated pathways. In previous work, an in vivo model of isolated ERE-independent ERα signaling was created using transgenic mouse models and a mutant ERα with disrupted ERE-dependent activity. In this study, this model is used to examine the relative roles of ERα signaling pathways in estrogen neuroendocrine feedback. Female mice with isolated ERE-independent ERα signaling were compared to wild-type and ERα null mice for their serum LH response using a physiologic paradigm of estrogen negative and positive feedback. ERE-independent ERα signaling was sufficient for 70% of estrogen negative feedback and the addition of ERE-dependent signaling was required for full suppression. In contrast, positive feedback required ERE-dependent signaling. Additional electrophysiology studies indicated both estrogen negative and positive feedback effects on GnRH neuron firing required ERE-dependent ERα signaling. Thus, estrogen negative feedback is mediated through multiple ERα pathways but the greater portion is conveyed by ERE-independent ERα signaling. In contrast, estrogen negative feedback suppression of FSH required ERE-dependent ERα signaling. In conclusion, multiple ERα signaling pathways provide the mechanisms which underlie the dual role of estrogen in neuroendocrine feedback.
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