Nonclassical estrogen receptor α signaling mediates negative feedback in the female mouse reproductive axis

Ovarian estrogen exerts both positive and negative feedback control over luteinizing hormone (LH) secretion during the ovulatory cycle. Estrogen receptor (ER) a but not ERP knockout mice lack estrogen feedback. Thus, estrogen feedback appears to be primarily mediated by ER alpha. However, it is now recognized that, in addition to binding to estrogen response elements (EREs) in DNA to alter target gene transcription, ERa signals through ERE-independent or nonclassical pathways, and the relative contributions of these pathways in conveying estrogen feedback remain unknown. Previously we created a knockin mouse model expressing a mutant form of ERa (AA) with ablated ERE-dependent but intact ERE-independent activity. Breeding this allele onto the ER alpha-null (-/-) background, we examine the ability of ERE-independent ER alpha signaling pathways to convey estrogen feedback regulation of the female hypothalamic-pituitary axis in vivo. ER alpha(-/AA) exhibited 69.9% lower serum LH levels compared with ER alpha(-/-) mice. Additionally, like wild type, ERa-/AA mice exhibited elevated LH after ovariectomy (OVX). Furthermore, the post-OVX rise in serum LH was significantly suppressed by estrogen treatment in OVX ER alpha(-/AA) mice. However, unlike wild type, both ER alpha(-/AA) and ER alpha(-/-) mice failed to exhibit estrous cyclicity, spontaneous ovulation, or an afternoon LH surge response to estrogen. These results indicate that ERE-independent ER alpha signaling is sufficient to convey a major portion of estrogen's negative feedback actions, whereas positive feedback and spontaneous ovulatory cyclicity require ERE-dependent ER alpha signaling.