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

Abstract

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 (ERbeta) mutant mice, but absent in ERalpha mutant mice. An ERalpha-selective compound was sufficient to generate positive feedback in wild-type mice. As GnRH neurons do not express ERalpha, estrogen positive feedback upon GnRH neurons must be indirect in nature. To establish the cell type responsible, we generated a neuron-specific ERalpha mutant mouse line. These mice failed to exhibit estrogen positive feedback, demonstrating that neurons expressing ERalpha are critical. We then used a GnRH neuron-specific Pseudorabies virus (PRV) tracing approach to show that the ERalpha-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 ERalpha-expressing neuronal afferents to GnRH neurons.

New insights into the classical and non-classical actions of estrogen: Evidence from estrogen receptor knock-out and knock-in mice

“…Positive feedback actions of estrogen on GnRH neurons, which drive the preovulatory LH surge, are mediated by ERα-expressing neuronal afferents within the GnRH neuronal network (Wintermantel et al, 2006). Similar to ERα −/− females, ERα −/AA females do not exhibit an LH surge, spontaneous ovulation, or estrous cyclicity, indicating that they do not respond to the positive feedback actions of E 2 (Fig.…”

“…However, as estrogen levels rise from the growing ovarian follicle, their effects become stimulatory, evoking a preovulatory GnRH surge and subsequent LH surge, which triggers ovulation. While it is known that estrogen feedback appears to be primarily mediated by ERα (Couse et al, 2003;Wintermantel et al, 2006), the underlying signaling mechanisms that contribute to estrogen positive and negative feedback remain unclear. To address this question, we have used the ERα −/AA mouse model to examine the relative contributions of ERE-dependent and -independent ERα signaling pathways in conveying estrogen feedback in vivo .…”

Membrane-initiated estrogen signaling in hypothalamic neurons

“…However, both negative and positive (induction of the LH surge) feedback regulation of LH (GnRH) secretion can be restored by replacement with E2. The positive feedback is believed to be by an action of E2 in the anteroventral periventricular (AVPV) nucleus (Herbison, 1998, Han et al, 2005, Smith et al, 2006, Wintermantel et al, 2006. Neurons in the AVPV express kisspeptin, a neuropeptide encoded by the Kiss gene, GABA and opioid peptides, all of which are important for regulation of GnRH neurosecretion (Simerly et al, 1988, Wagner et al, 2001a, Jackson and Kuehl, 2002, DeFazio et al, 2002, Smith et al, 2006, Christian and Moenter, 2007.…”

“…Neurons in the AVPV express kisspeptin, a neuropeptide encoded by the Kiss gene, GABA and opioid peptides, all of which are important for regulation of GnRH neurosecretion (Simerly et al, 1988, Wagner et al, 2001a, Jackson and Kuehl, 2002, DeFazio et al, 2002, Smith et al, 2006, Christian and Moenter, 2007. The AVPV area expresses high levels of ERα and also ERβ, and the actions of the gonadal steroids are mediated, in part, via the nuclearinitiated signaling (genomic) mechanism (Shughrue et al, 1997, Wintermantel et al, 2006. However, the AVPV is also sensitive to the rapid actions of gonadal steroids.…”

“…The latter findings combined with recent technological advances, such as the development of ER mutants and transgenic animals expressing green fluorescent protein (GFP) in GnRH neurons, have greatly facilitated studies to understand the cellular mechanisms by which GnRH neurons are regulated by estrogen (Spergel et al, 1999, Suter et al, 2000, Kato et al, 2003, Han et al, 2005, Abraham et al, 2003, Smith et al, 2006, Wintermantel et al, 2006. A series of recent publications show that in mouse hypothalamic neuronal explants and in primate nasal placode cultures, E2 augments synchronous intracellular Ca 2+ oscillations in GnRH neurons (Temple et al, 2004, Temple and Wray, 2005, Abe et al, 2007.…”