Positive, But Not Negative Feedback Actions of Estradiol in Adult Female Mice Require Estrogen Receptor α in Kisspeptin Neurons

Hypothalamic kisspeptin (Kiss1) neurons express estrogen receptor alpha (ER alpha) and exert control over GnRH/LH secretion in female rodents. It has been proposed that estradiol (E-2) activation of ER alpha in kisspeptin neurons in the arcuate nucleus (ARC) suppressesGnRH/LHsecretion (negative feedback), whereas E-2 activation of ER alpha in kisspeptin neurons in the anteroventral periventricular nucleus (AVPV) mediates the release of preovulatory GnRH/LH surges (positive feedback). To test these hypotheses, we generated mice bearing kisspeptin cell-specific deletion of ER alpha (KER alpha KO) and treated them with E-2 regimens that evoke either negative or positive feedback actions on GnRH/LH secretion. Using negative feedback regimens, as expected, E-2 effectively suppressed LH levels in ovariectomized (OVX) wild-type (WT) mice to the levels seen in ovary-intact mice. Surprisingly, however, despite the fact that E-2 regulation of Kiss1 mRNA expression was abrogated in both the ARC and AVPV of KER alpha KO mice, E-2 also effectively decreased LH levels in OVX KER alpha KO mice to the levels seen in ovary-intact mice. Conversely, using a positive feedback regimen, E-2 stimulated LH surges in WT mice, but had no effect in KER alpha KO mice. These experiments clearly demonstrate that ER alpha in kisspeptin neurons is required for the positive, but not negative feedback actions of E-2 on GnRH/LH secretion in adult female mice. It remains to be determined whether the failure of KER alpha KO mice to exhibit GnRH/LH surges reflects the role of ER alpha in the development of kisspeptin neurons, in the active signaling processes leading to the release of GnRH/LH surges, or both.