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. 2015 Mar;156(3):1111-20.
doi: 10.1210/en.2014-1851. Epub 2014 Dec 29.

Positive, but not negative feedback actions of estradiol in adult female mice require estrogen receptor α in kisspeptin neurons

Sharon L Dubois  1 , Maricedes Acosta-Martínez, Mary R DeJoseph, Andrew Wolfe, Sally Radovick, Ulrich Boehm, Janice H Urban, Jon E Levine
Affiliations

Positive, but not negative feedback actions of estradiol in adult female mice require estrogen receptor α in kisspeptin neurons

Sharon L Dubois et al. Endocrinology. 2015 Mar.

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.

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Figures

Figure 1.
Figure 1.
E2 decreases Kiss1 mRNA expression in the ARC of OVX WT mice, but has no effect on Kiss1 mRNA expression in the ARC of female KERαKO mice. A, Representative photomicrographs of Kiss1 mRNA expression in the ARC of WT (left panels) and KERαKO (right panels) mice at Bregma −1.94 (21). Mice were bilaterally OVX and implanted with a capsule containing vehicle (V) or E2. Brains were collected 7 days after OVX. B, Mean signal intensity of Kiss1 mRNA expression in the ARC. Scale bar = 100 μm. ***, P < .001 compared with V-treated mice. All data represented as mean ± SEM.
Figure 2.
Figure 2.
E2 increases Kiss1 mRNA expression in the AVPV of OVX WT and, to a lesser extent, KERαKO mice. A, Representative photomicrographs of Kiss1 mRNA expression in the AVPV of WT (left panels) and KERαKO (right panels) mice at Bregma 0.26 (21). Mice were bilaterally OVX and implanted with a capsule containing vehicle (V) or E2. Brains were collected 7 days after OVX. B, Mean signal intensity of Kiss1 mRNA expression in the AVPV. Scale bar = 100 μm. ***, P < .001 compared with V-treated mice. All data represented as mean ± SEM.
Figure 3.
Figure 3.
E2 exerts negative feedback effects on LH in short-term OVX WT and KERαKO mice. Mean plasma LH levels in WT and KERαKO female mice that were bilaterally OVX and implanted with a capsule containing vehicle (V) or E2. Blood was collected 7 days after OVX. ***, P < .001 compared with V-treated mice. All data represented as mean ± SEM.
Figure 4.
Figure 4.
E2 exerts negative feedback effects on LH in long-term OVX WT and KERαKO mice. Mean plasma LH levels from WT and KERαKO female mice that were bilaterally OVX and implanted with a capsule containing vehicle (V) or E2. Blood was collected 3 weeks after OVX. *, P < .05; **, P < .01; ***, P < .001. All data represented as mean ± SEM.
Figure 5.
Figure 5.
E2 induces LH surges in OVX WT, but not KERαKO, mice. Mean plasma LH levels from female WT and KERαKO mice that were bilaterally OVX, implanted with a capsule containing vehicle (V) or E2, and injected sc with vehicle or EB 6 days after OVX. Blood was collected after lights off (7:10–7:30 pm) 7 days after OVX. **, P < .01 compared with V-treated mice. All data represented as mean ± SEM.
Figure 6.
Figure 6.
Pituitary sensitivity to E2 and pituitary responsiveness to GnRH are normal in female KERαKO mice. Mean plasma LH levels from female WT and KERαKO mice that were bilaterally OVX, implanted with an E2-containing capsule, and injected sc with vehicle (V) or exogenous GnRH 7 days after OVX. Blood was collected 10 minutes after vehicle or GnRH injection. ***, P < .001 compared with V-treated mice. All data represented as mean ± SEM.
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