Estrogen receptor-β in the gonadotropin-releasing hormone neuron

Abstract

Estrogen regulation of gonadotropin-releasing hormone (GnRH) neuronal activity plays a crucial role in homeostatic regulation of the hypothalamic-pituitary-gonadal axis. Estrogen also coordinates a complex series of physiological changes culminating with a surge of gonadotropin secretion that triggers ovulation of a developed follicle from the ovary. The coordinated functions of estrogen ensure that the female will elaborate appropriate reproductive behaviors ultimately designed to deliver sperm to the oocyte and to provide a receptive uterine environment for the fertilized embryo. Although the effects of estrogen on GnRH neuronal function have long been proposed to be indirect due to the presumed lack of estrogen receptors in GnRH neurons, the identification of alternative estrogen signaling pathways, including estrogen receptor (ER)β and membrane ERs such as GPR30, has put the focus back on estrogen's effect at the level of the GnRH neuron itself. One candidate to mediate the effects of estrogen is the β isoform of the estrogen receptor. We review the evidence for a role for ERβ-mediated regulation of GnRH neuronal function.

Figure 1

(A) Model of estradiol (E2) regulation of different kiss1 neuronal populations in rodents. Shaded regions represent neurons expressing kiss1. E2 negatively regulates arcuate kiss1 expression and positively regulates anteroventral periventricular nucleus (AVPV) kiss1 expression. (B) Model of E2 regulation of different kiss1 neuronal populations in sheep or primates. E2 negatively regulates kiss1 expression in the rostral arcuate but positively regulates kiss1 in the caudal arcuate. E2 also positively regulates kiss1 expression in the preoptic area (POA).

Figure 2

Human and mouse estrogen receptor (ER)β splice variants. Human (h)ERβ1 is encoded by eight exons; the splice variant hERβ2 is encoded by the alternative cx exon. The cx exon produces a truncated AF2 domain (26 amino acids versus 61 amino acids). The full-length mERβ1 is also encoded by eight exons, and mERβ2 is produced by splice insertion of an 18aa fragment in the ligand binding domain (INS).

Figure 3

Gonadotropin-releasing hormone (GnRH) gene expression in GN11 and GT1–7 cells treated with estrogen receptor (ER) agonists. (A) GN11 and (B) GT1–7 neuronal cells were treated with 1 nM, 10 nM, or 100 nM of an estrogen receptor (ER)β agonist (diarylpropionitrile [DPN]) or ER-α agonist (propyl pyrazole triol [PPT]) for 16 hours. Total RNA was extracted, and quantitative real-time polymerase chain reaction was performed with primers specifically designed to amplify mGnRH. GN11 data are expressed as the mean plus or minus the standard error of mean (SEM) (n = 6). GT1–7 data are expressed as the mean plus or minus SEM (n = 5). *p < 0.001 versus control. **p < 0.05 versus control.

Figure 4

Model for estradiol (E2) regulation of gonadotropin-releasing hormone (GnRH) neuronal function. Kiss1 neurons in the Arc and anteroventral periventricular nucleus (AVPV) nuclei mediate negative and positive feedback regulation of the GnRH neuron, respectively. Estrogen receptor (ER)β expressed in the GnRH neuron allows for cell autonomous E2 regulation. E2 regulates various functional properties in GnRH neurons including biophysical function, GnRH gene expression, and GnRH secretion.