Estradiol Restrains Prepubertal Gonadotropin Secretion in Female Mice via Activation of ERα in Kisspeptin Neurons

Elimination of estrogen receptor alpha (ER alpha) from kisspeptin (Kiss1) neurons results in premature LH release and pubertal onset, implicating these receptors in 17 beta-estradiol (E-2)-mediated negative feedback regulation of GnRH release during the prepubertal period. Here, we tested the dependency of prepubertal negative feedback on ER alpha in Kiss1 neurons. Prepubertal (postnatal d 14) and peripubertal (postnatal d 34) wild-type (WT) and Kiss1 cell-specific ER alpha knockout (KER alpha KO) female mice were sham operated or ovariectomized and treated with either vehicle-or E-2-containing capsules. Plasma and tissues were collected 2 days after surgery for analysis. Ovariectomy increased LH and FSH levels, and E-2 treatments completely prevented these increases in WT mice of both ages. However, in prepubertal KER alpha KO mice, basal LH levels were elevated vs WT, and both LH and FSH levels were not further increased by ovariectomy or affected by E-2 treatment. Similarly, Kiss1 mRNA levels in the medial basal hypothalamus, which includes the arcuate nucleus, were suppressed with E-2 treatment in ovariectomized prepubertal WT mice but remained unaffected by any treatment in KER alpha KO mice. In peripubertal KER alpha KO mice, basal LH and FSH levels were not elevated vs WT and were unaffected by ovariectomy or E-2. In contrast to our previous findings in adult animals, these results demonstrate that suppression of gonadotropins and Kiss1 mRNA by E-2 in prepubertal animals depends upon ER alpha activation in Kiss1 neurons. Our observations are consistent with the hypothesis that these receptors play a critical role in restraining GnRH release before the onset and completion of puberty.