Positive, But Not Negative Feedback Actions of Estradiol in Adult Female Mice Require Estrogen Receptor α in Kisspeptin Neurons

Abstract

Hypothalamic kisspeptin (Kiss1) neurons express estrogen receptor α (ERα) and exert control over GnRH/LH secretion in female rodents. It has been proposed that estradiol (E2) activation of ERα in kisspeptin neurons in the arcuate nucleus (ARC) suppresses GnRH/LH secretion (negative feedback), whereas E2 activation of ERα in kisspeptin neurons in the anteroventral periventricular nucleus (AVPV) mediates the release of preovulatory GnRH/LH surges (positive feedback). To test these hypotheses, we generated mice bearing kisspeptin cell-specific deletion of ERα (KERαKO) and treated them with E2 regimens that evoke either negative or positive feedback actions on GnRH/LH secretion. Using negative feedback regimens, as expected, E2 effectively suppressed LH levels in ovariectomized (OVX) wild-type (WT) mice to the levels seen in ovary-intact mice. Surprisingly, however, despite the fact that E2 regulation of Kiss1 mRNA expression was abrogated in both the ARC and AVPV of KERαKO mice, E2 also effectively decreased LH levels in OVX KERαKO mice to the levels seen in ovary-intact mice. Conversely, using a positive feedback regimen, E2 stimulated LH surges in WT mice, but had no effect in KERαKO mice. These experiments clearly demonstrate that ERα in kisspeptin neurons is required for the positive, but not negative feedback actions of E2 on GnRH/LH secretion in adult female mice. It remains to be determined whether the failure of KERαKO mice to exhibit GnRH/LH surges reflects the role of ERα in the development of kisspeptin neurons, in the active signaling processes leading to the release of GnRH/LH surges, or both.

Control of puberty onset and fertility by gonadotropin-releasing hormone neurons

“…This rostral population of kisspeptin neuronswhich is distinct from that in the arcuate nucleus -is predominant in females; projects to the GnRH neurons; expresses ERα; has both Kiss1 and ion-channel gene expression modulated by oestradiol levels throughout the oestrous cycle; and is activated at the time of the surge 58-62 . Although not proven specifically for the RP3V kisspeptin population, the selective deletion of Εrα from all kisspeptin neurons abolishes the LH surge in mice 63 . The RP3V kisspeptin cells also receive synaptic inputs from suprachiasmatic nucleus vasopressin neurons 64,65 , although it remains unclear precisely how they modulate RP3V kisspeptin activity in a circadiandependent manner [66][67][68] .…”

60 YEARS OF NEUROENDOCRINOLOGY: The hypothalamo-pituitary–gonadal axis

“…Classical studies have indicated that the locus of the negative feedback action of estradiol is within the MBH, and, intuitively, it might be expected that ERα expressing KNDy neurons in the arcuate nucleus are the neuronal phenotype targeted. Intriguingly, however, a recent study by Levine and his colleagues employing transgenic mice null for ERα in kisspeptin neurons (not restricted to KNDy neurons) has failed to support this notion (Dubois, et al 2015). On the other hand, Herbison’s group using genetically engineered adult female mice and adeno-associated virus injection into the arcuate nucleus to delete approximately 75% of ERα positive cells in this nucleus abolished chronic negative feedback action of estradiol on LH secretion (Yeo and Herbison 2014) 4 .…”

Kisspeptin across the human lifespan:evidence from animal studies and beyond

“…Evidence suggests that oestrogen acts via the oestrogen receptor ERα on kisspeptin neurons (Dubois et al 2015) to exert negative feedback on GnRH release (Smith et al 2005a,b). Expression of Dyn and NKB is also influenced by oestrogen, with expression of Dyn, NKB, the KOR gene and the NKB receptor gene all inhibited by oestrogen in animal models created (Navarro et al 2009).…”