Absence of Estradiol-Induced LH Surges in Kisspeptin Cell-Specific ERα Knockout (KERαKO) Mice

Presentation Number: OR30-1
Date of Presentation: June 23rd, 2014

Sharon Lauretta Dubois*1, Andrew Wolfe2, Sally Radovick3, Ulrich Boehm4 and Jon E Levine1
1University of Wisconsin-Madison, Madison, WI, 2Johns Hopkins University School of Medicine, Baltimore, MD, 3Johns Hopkins School of Medicine, Baltimore, MD, 4University of Saarland School of Medicine, Homburg, Germany


The kisspeptin signaling pathway is an integral component of neuroendocrine systems governing fertility in humans and rodents. Kisspeptin is mainly expressed in the anteroventral periventricular nucleus (AVPV) and the arcuate nucleus (ARC) in the rodent brain, the majority of which co-express estrogen receptor α (ERα). In females, estradiol (E2) activation of ERα stimulates kisspeptin expression in the AVPV while suppressing kisspeptin expression in the ARC. Thus, it has been proposed that E2 activation of ERα in AVPV kisspeptin neurons mediates release of ovulatory GnRH/LH surges (positive feedback), while ERα activation in ARC kisspeptin neurons maintains basal GnRH/LH secretion (negative feedback). To test these hypotheses, we generated mice bearing kisspeptin cell-specific deletion of ERα (KERαKO) and challenged them with E2 regimens that evoke either positive or negative feedback effects. To induce an LH surge, KERαKO mice and wild-type (WT) littermates were ovariectomized (OVX) and treated with low dose E2 capsules. Mice were then injected s.c. with vehicle or estradiol benzoate (EB) 6d post-OVX and euthanized the following evening. As expected, 75% of WT mice treated with EB exhibited an LH surge; however, none of the KERαKO mice exhibited LH surges. Thus, ERα activation in kisspeptin neurons is required for E2-mediated positive feedback. Next, WT and KERαKO mice were OVX, received oil or E2-filled capsules, and euthanized at 3wk post-OVX. In both WT and KERαKO mice, E2 treatment significantly decreased LH levels to those seen in intact mice, demonstrating that E2-mediated negative feedback remains intact in long-term OVX KERαKO mice. Finally, to test whether pituitary sensitivity to E2 was altered in KERαKO mice, WT and KERαKO mice were OVX, treated with E2 capsules, and injected s.c. with GnRH or saline. GnRH treatment significantly elevated LH to a similar degree in WT and KERαKO mice, indicating no differences in pituitary responsiveness. These experiments clearly demonstrate that ERα signaling in kisspeptin neurons is required for the expression of positive, but not negative feedback actions of E2 on GnRH/LH secretion. It remains to be determined if the obligatory involvement of these receptors in positive feedback reflects their role in the development and maturation of kisspeptin neurons, or in the active signaling processes leading to release of GnRH/LH surges, or both.


Nothing to Disclose: SLD, AW, SR, UB, JEL