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. 2016 Apr;157(4):1546-54.
doi: 10.1210/en.2015-1923. Epub 2016 Jan 29.

Estradiol Restrains Prepubertal Gonadotropin Secretion in Female Mice via Activation of ERα in Kisspeptin Neurons

Sharon L Dubois  1 , Andrew Wolfe  1 , Sally Radovick  1 , Ulrich Boehm  1 , Jon E Levine  1
Affiliations

Estradiol Restrains Prepubertal Gonadotropin Secretion in Female Mice via Activation of ERα in Kisspeptin Neurons

Sharon L Dubois et al. Endocrinology. 2016 Apr.

Abstract

Elimination of estrogen receptorα (ERα) from kisspeptin (Kiss1) neurons results in premature LH release and pubertal onset, implicating these receptors in 17β-estradiol (E2)-mediated negative feedback regulation of GnRH release during the prepubertal period. Here, we tested the dependency of prepubertal negative feedback on ERα in Kiss1 neurons. Prepubertal (postnatal d 14) and peripubertal (postnatal d 34) wild-type (WT) and Kiss1 cell-specific ERα knockout (KERαKO) female mice were sham operated or ovariectomized and treated with either vehicle- or E2-containing capsules. Plasma and tissues were collected 2 days after surgery for analysis. Ovariectomy increased LH and FSH levels, and E2 treatments completely prevented these increases in WT mice of both ages. However, in prepubertal KERαKO mice, basal LH levels were elevated vs WT, and both LH and FSH levels were not further increased by ovariectomy or affected by E2 treatment. Similarly, Kiss1 mRNA levels in the medial basal hypothalamus, which includes the arcuate nucleus, were suppressed with E2 treatment in ovariectomized prepubertal WT mice but remained unaffected by any treatment in KERαKO mice. In peripubertal KERαKO mice, basal LH and FSH levels were not elevated vs WT and were unaffected by ovariectomy or E2. In contrast to our previous findings in adult animals, these results demonstrate that suppression of gonadotropins and Kiss1 mRNA by E2 in prepubertal animals depends upon ERα activation in Kiss1 neurons. Our observations are consistent with the hypothesis that these receptors play a critical role in restraining GnRH release before the onset and completion of puberty.

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Figures

Figure 1.
Figure 1.
E2 suppresses gonadotropin secretion and Fshb mRNA expression in prepubertal WT mice but has no effect on gonadotropin secretion or Lhb and Fshb mRNA expression in prepubertal KERαKO mice. Shown are mean plasma LH (A) and FSH (B) levels, as well as relative Lhb (C) and Fshb (D) mRNA expression levels, for WT and KERαKO mice that were left intact (sham) or bilaterally OVX and implanted with a capsule containing vehicle (V) or E2 on P14 and then euthanized 2 days later (P16). All Lhb and Fshb mRNA expression levels are normalized to Rn18s and compared relative to expression levels in sham WT mice. Two-way ANOVA analyses indicated a significant interaction between genotype and treatment for FSH and Fshb mRNA expression levels (P < .01) but not LH (P = .50) or Lhb mRNA expression (P = .07) levels. Genotype significantly affected all measurements independent of treatment (P < .05), whereas treatment significantly affected all measurements independent of genotype (P < .05), except for Lhb mRNA expression levels (P = .29). *, P < .05; **, P < .01; ***, P < .001 as determined by post hoc comparisons. All data represented as mean ± SEM.
Figure 2.
Figure 2.
E2 suppresses gonadotropin secretion and Lhb and Fshb mRNA expression in peripubertal WT mice but has no effect on FSH secretion or Lhb and Fshb mRNA expression in peripubertal KERαKO mice. Mean plasma LH (A) and FSH (B) levels, as well as relative Lhb (C) and Fshb (D) mRNA expression levels, for WT and KERαKO mice that were left intact (sham) or bilaterally OVX and implanted with a capsule containing vehicle (V) or E2 on P34 and then euthanized 2 days later (P36). All Lhb and Fshb mRNA expression levels are normalized to Rn18s and compared relative to expression levels in sham WT mice. Two-way ANOVA analyses indicated a significant interaction between genotype and treatment for all measurements (P < .05), except for LH levels (P = .08). Genotype significantly affected all measurements independent of treatment (P < .01), except for LH levels (P = .42), whereas treatment significantly affected all measurements independent of genotype (P < .05). *, P < .05; **, P < .01; ***, P < .001 as determined by post hoc comparisons. All data represented as mean ± SEM.
Figure 3.
Figure 3.
Gnrhr mRNA expression levels in the pituitary glands of prepubertal KERαKO mice are elevated relative to prepubertal WT mice. Relative Gnrhr mRNA expression levels for WT and KERαKO mice that were left intact (sham) on P14 or P34 and then euthanized 2 days later (P16 or P36, respectively). Gnrhr mRNA expression levels are normalized to Rn18s and compared relative to expression levels in P16 WT mice. Two-way ANOVA analysis indicated no significant interaction between genotype and age (P = .10). Age significantly affected Gnrhr mRNA expression independent of genotype (P < .05). *, P < .05; **, P < .01 as determined by post hoc comparisons. All data represented as mean ± SEM.
Figure 4.
Figure 4.
E2 suppresses Kiss1 mRNA expression in prepubertal WT mice but has no effect on Kiss1 mRNA expression in prepubertal KERαKO mice. Relative Kiss1 mRNA expression levels for WT and KERαKO mice that were left intact (sham) or bilaterally OVX and implanted with a capsule containing vehicle (V) or E2 on P14 and then euthanized 2 days later (P16). Kiss1 mRNA expression levels are normalized to Rn18s and compared relative to expression levels in sham WT mice. Two-way ANOVA analysis indicated a significant interaction between genotype and treatment (P < .05). Genotype and treatment significantly affected Kiss1 mRNA expression independent of each other (P < .05). *, P < .05; **P, < .01; ***, P < .001 as determined by post hoc comparisons. All data represented as mean ± SEM.
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