Definition of Estrogen Receptor Pathway Critical for Estrogen Positive Feedback to Gonadotropin-Releasing Hormone Neurons and Fertility

Abstract

Summary The mechanisms through which estrogen regulates gonadotropin-releasing hormone (GnRH) neurons to control mammalian ovulation are unknown. We found that estrogen positive feedback to generate the preovulatory gonadotropin surge was normal in estrogen receptor β knockout (ERβ) mutant mice but absent in ERα mutant mice. An ERα-selective compound was sufficient to generate positive feedback in wild-type mice. As GnRH neurons do not express ERα, estrogen positive feedback upon GnRH neurons must be indirect in nature. To establish the cell type responsible, we generated a neuron-specific ERα mutant mouse line. These mice failed to exhibit estrogen positive feedback demonstrating that neurons expressing ERα are critical. We then used GnRH neuron-specific Cre-dependent Pseudorabies virus tracing to show that the ERα-expressing neurons modulating GnRH neurons are located within rostral periventricular regions of the hypothalamus. These studies demonstrate ovulation is driven by estrogen actions upon ERα-expressing neuronal afferents to GnRH neurons.