Impairments in the reproductive axis of female mice lacking estrogen receptor β in GnRH neurons

Abstract

The effect of estrogen on the differentiation and maintenance of reproductive tissues is mediated by two nuclear estrogen receptors (ERs), ER alpha (ERα) and beta (ERβ). Lack of functional ERα and ERβ genes in vivo significantly affects reproductive function, however, the target tissues and signaling pathways in the hypothalamus are not clearly defined. Here, we describe the generation and reproductive characterization of a complete-ERβ KO mouse (CERβKO) and a GnRH neuron-specific ERβKO mouse model (GERβKO). Both ERβKO mouse models displayed a delay in vaginal opening and first estrus. Hypothalamic GnRH mRNA expression levels in both ERβKO mice were similar to control mice; however female CERβKO and GERβKO mice had lower basal and surge serum gonadotropin levels. Although a GnRH stimulation test in both female ERβKO models showed preserved gonadotropic function in the same animals, a kisspeptin stimulation test revealed an attenuated response by GnRH neurons suggesting a role for ERβ in normal GnRH neuron function. No alteration in estrogen negative feedback was observed in either ERβKO mouse models after ovariectomy and estrogen replacement. Further, abnormal development of ovarian follicles with low serum estradiol levels and impairment of fertility were observed in both ERβKO mouse models. In male ERβKO mice, no differences in the timing of pubertal onset or serum LH and FSH levels were observed as compared to controls. Taken together, these data provide in vivo evidence for a role of ERβ in GnRH neurons in modulating puberty and reproduction, specifically through kisspeptin responsiveness in the female HPG axis.

ERβ Regulation of Gonadotropin Responses during Folliculogenesis

“…In contrast, a recent study has demonstrated that expression of ERβ in hypothalamic GnRH neurons is essential for induction of the preovulatory gonadotropin surge [30]. Moreover, loss of ERβ also reduces pulsatile GnRH production, and this mutation led to delayed onset of puberty in the Erβ KO female mice [30]. In ERβ KO mice and rats, steroidogenesis and follicle maturation are significantly reduced, which is associated with an attenuated gonadotropin surge [10][11][12][13][14].…”

“…This study emphasizes the presence of ERβ within the ovary for providing the required signals to the H–P axis, and suggests that estradiol alone may not be sufficient to induce the gonadotropin surge [ 14 ]. In contrast, a recent study has demonstrated that expression of ERβ in hypothalamic GnRH neurons is essential for induction of the preovulatory gonadotropin surge [ 30 ]. Moreover, loss of ERβ also reduces pulsatile GnRH production, and this mutation led to delayed onset of puberty in the Erβ KO female mice [ 30 ].…”

“…In contrast, a recent study has demonstrated that expression of ERβ in hypothalamic GnRH neurons is essential for induction of the preovulatory gonadotropin surge [ 30 ]. Moreover, loss of ERβ also reduces pulsatile GnRH production, and this mutation led to delayed onset of puberty in the Erβ KO female mice [ 30 ].…”

“…Gonadotropins play a vital role in ovarian development and onset of puberty [ 1 ]. Impaired gonadotropin secretion results in a something is missing here [ 30 , 33 ]. In the adult females, gonadotropins regulate the major ovarian functions: steroidogenesis and oogenesis [ 2 , 6 ].…”

“…Thus, ERα is important for gonadotropin secretion whereas ERβ is essential for gonadotropin responses in the ovary [ 10 ]. Nevertheless, ERβ also regulates gonadotropin secretion acting in GnRH neurons [ 30 ] and ERα also regulates steroidogenesis acting in TCs.…”