We have used complete and conditional ERα gene targeting and a mutant ERα knock-in strategy to characterize signaling pathways that mediate estrogen actions in neuroendocrine systems. Our studies reveal that "non-classical" (ERE-independent) ERα signaling conveys homeostatic effects of estrogen on both reproductive and metabolic control systems. Surprisingly, conditional ERα ablation in kisspeptin peptidergic cells abrogates estrogen negative feedback actions and gives rise to both reproductive and metabolic phenotypes that resemble those observed in PCOS.