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

Horacio J. Novaira, Ariel L. Negron, Jones B. Graceli, Silvia Capellino, Andrew Schoeffield, Gloria E. Hoffman, Jon E. Levine, Andrew Wolfe, Fredric E. Wondisford, Sally Radovick

Research output: Contribution to journalArticle

Abstract

The effect of estrogen on the differentiation and maintenance of reproductive tissues is mediated by two nuclear estrogen receptors (ERs), ERα, and 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 (CERβKO) and a GnRH neuron-specific ERβKO (GERβKO) mouse models. Both ERβKO mouse models displayed a delay in vaginal opening and first estrus. Hypothalamic gonadotropin-releasing hormone (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 luteinizing hormone and follicle-stimulating hormone levels were observed as compared with 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 hypothalamic-pituitary-gonadal axis.

Original languageEnglish (US)
Pages (from-to)E1019-E1033
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume315
Issue number5
DOIs
StatePublished - Nov 1 2018

Fingerprint

Estrogen Receptors
Gonadotropin-Releasing Hormone
Neurons
Kisspeptins
Estrogens
Serum
Pituitary Hormone-Releasing Hormones
Estrogen Replacement Therapy
Ovarian Follicle
Estrus
Follicle Stimulating Hormone
Ovariectomy
Puberty
Luteinizing Hormone
Gonadotropins
Hypothalamus
Reproduction
Fertility
Estradiol
Maintenance

Keywords

  • Estrogen receptor β
  • Fertility
  • GnRH
  • Gonadotropins
  • Puberty

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Physiology (medical)

Cite this

Novaira, H. J., Negron, A. L., Graceli, J. B., Capellino, S., Schoeffield, A., Hoffman, G. E., ... Radovick, S. (2018). Impairments in the reproductive axis of female mice lacking estrogen receptor β in gnrh neurons. American Journal of Physiology - Endocrinology and Metabolism, 315(5), E1019-E1033. https://doi.org/10.1152/ajpendo.00173.2018

Impairments in the reproductive axis of female mice lacking estrogen receptor β in gnrh neurons. / Novaira, Horacio J.; Negron, Ariel L.; Graceli, Jones B.; Capellino, Silvia; Schoeffield, Andrew; Hoffman, Gloria E.; Levine, Jon E.; Wolfe, Andrew; Wondisford, Fredric E.; Radovick, Sally.

In: American Journal of Physiology - Endocrinology and Metabolism, Vol. 315, No. 5, 01.11.2018, p. E1019-E1033.

Research output: Contribution to journalArticle

Novaira, HJ, Negron, AL, Graceli, JB, Capellino, S, Schoeffield, A, Hoffman, GE, Levine, JE, Wolfe, A, Wondisford, FE & Radovick, S 2018, 'Impairments in the reproductive axis of female mice lacking estrogen receptor β in gnrh neurons', American Journal of Physiology - Endocrinology and Metabolism, vol. 315, no. 5, pp. E1019-E1033. https://doi.org/10.1152/ajpendo.00173.2018
Novaira, Horacio J. ; Negron, Ariel L. ; Graceli, Jones B. ; Capellino, Silvia ; Schoeffield, Andrew ; Hoffman, Gloria E. ; Levine, Jon E. ; Wolfe, Andrew ; Wondisford, Fredric E. ; Radovick, Sally. / Impairments in the reproductive axis of female mice lacking estrogen receptor β in gnrh neurons. In: American Journal of Physiology - Endocrinology and Metabolism. 2018 ; Vol. 315, No. 5. pp. E1019-E1033.
@article{7ef80334075149a797f8646776c67dca,
title = "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), ERα, and 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 (CERβKO) and a GnRH neuron-specific ERβKO (GERβKO) mouse models. Both ERβKO mouse models displayed a delay in vaginal opening and first estrus. Hypothalamic gonadotropin-releasing hormone (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 luteinizing hormone and follicle-stimulating hormone levels were observed as compared with 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 hypothalamic-pituitary-gonadal axis.",
keywords = "Estrogen receptor β, Fertility, GnRH, Gonadotropins, Puberty",
author = "Novaira, {Horacio J.} and Negron, {Ariel L.} and Graceli, {Jones B.} and Silvia Capellino and Andrew Schoeffield and Hoffman, {Gloria E.} and Levine, {Jon E.} and Andrew Wolfe and Wondisford, {Fredric E.} and Sally Radovick",
year = "2018",
month = "11",
day = "1",
doi = "10.1152/ajpendo.00173.2018",
language = "English (US)",
volume = "315",
pages = "E1019--E1033",
journal = "American Journal of Physiology",
issn = "0193-1849",
publisher = "American Physiological Society",
number = "5",

}

TY - JOUR

T1 - Impairments in the reproductive axis of female mice lacking estrogen receptor β in gnrh neurons

AU - Novaira, Horacio J.

AU - Negron, Ariel L.

AU - Graceli, Jones B.

AU - Capellino, Silvia

AU - Schoeffield, Andrew

AU - Hoffman, Gloria E.

AU - Levine, Jon E.

AU - Wolfe, Andrew

AU - Wondisford, Fredric E.

AU - Radovick, Sally

PY - 2018/11/1

Y1 - 2018/11/1

N2 - The effect of estrogen on the differentiation and maintenance of reproductive tissues is mediated by two nuclear estrogen receptors (ERs), ERα, and 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 (CERβKO) and a GnRH neuron-specific ERβKO (GERβKO) mouse models. Both ERβKO mouse models displayed a delay in vaginal opening and first estrus. Hypothalamic gonadotropin-releasing hormone (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 luteinizing hormone and follicle-stimulating hormone levels were observed as compared with 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 hypothalamic-pituitary-gonadal axis.

AB - The effect of estrogen on the differentiation and maintenance of reproductive tissues is mediated by two nuclear estrogen receptors (ERs), ERα, and 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 (CERβKO) and a GnRH neuron-specific ERβKO (GERβKO) mouse models. Both ERβKO mouse models displayed a delay in vaginal opening and first estrus. Hypothalamic gonadotropin-releasing hormone (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 luteinizing hormone and follicle-stimulating hormone levels were observed as compared with 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 hypothalamic-pituitary-gonadal axis.

KW - Estrogen receptor β

KW - Fertility

KW - GnRH

KW - Gonadotropins

KW - Puberty

UR - http://www.scopus.com/inward/record.url?scp=85056605148&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85056605148&partnerID=8YFLogxK

U2 - 10.1152/ajpendo.00173.2018

DO - 10.1152/ajpendo.00173.2018

M3 - Article

C2 - 30040478

AN - SCOPUS:85056605148

VL - 315

SP - E1019-E1033

JO - American Journal of Physiology

JF - American Journal of Physiology

SN - 0193-1849

IS - 5

ER -