Definition of estrogen receptor pathway critical for estrogen positive feedback to gonadotropin-releasing hormone neurons and fertility

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 beta knockout (ER beta) mutant mice, but absent in ER alpha mutant mice. An ER alpha-selective compound was sufficient to generate positive feedback in wild-type mice. As GnRH neurons do not express ER alpha, estrogen positive feedback upon GnRH neurons must be indirect in nature. To establish the cell type responsible, we generated a neuron-specific ERa mutant mouse line. These mice failed to exhibit estrogen positive feedback, demonstrating that neurons expressing ER alpha are critical. We then used a GnRH neuron-specific Pseudorabies virus (PRV) tracing approach to show that the ER alpha-expressing neurons innervating GnRH neurons are located within rostral periventricular regions of the hypothalamus. These studies demonstrate that ovulation is driven by estrogen actions upon ER alpha-expressing neuronal afferents to GnRH neurons.