Involvement of gonadotropin-inhibitory hormone in pubertal disorders induced by thyroid status.
Involvement of gonadotropin-inhibitory hormone in pubertal disorders induced by thyroid status.
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DOI：
10.1038/s41598-017-01183-8
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发表时间：
2017-04-21
影响因子：
4.6
通讯作者：
Tsutsui K
中科院分区：
文献类型：
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作者：
Kiyohara M;Son YL;Tsutsui K
甲状腺疾病导致青春期异常，表明下丘脑-垂体-甲状腺（HPT）和下丘脑-垂体-性腺（HPG）轴之间的相互作用，这在青春期发育中很重要。下丘脑促性腺激素抑制激素（GnIH）被证明是减少在青春期前的早期阶段，这表明GnIH的青春期开始的作用。在这里，我们调查是否甲状腺功能障碍影响青春期的发病雌性小鼠通过GnIH调节。甲状腺功能减退症表现为青春期延迟发作，GnIH表达增加，垂体性腺活动减少。值得注意的是，GnIH基因敲除阻止了甲状腺功能减退症延迟青春期开始的作用，导致对照组和甲状腺功能减退症诱导组之间GnIH基因敲除雌性小鼠的青春期时间无法区分，表明甲状腺功能减退症诱导的GnIH表达增加可能导致青春期延迟。相比之下，甲状腺功能亢进导致GnIH表达减少，但青春期开始是正常的，这意味着抑制性GnIH的进一步减少对表型变化影响不大。关键是，甲状腺激素抑制下丘脑外植体中的GnIH表达，GnIH神经元表达甲状腺激素受体以传达甲状腺状态。此外，甲状腺状态高度调节GnIH启动子的染色质修饰、H3乙酰化和H3 K9三甲基化。这些发现表明GnIH介导HPT-HPG相互作用的新功能，有助于适当的青春期发育。
Thyroid disorders cause abnormal puberty, indicating interactions between the hypothalamus-pituitary-thyroid (HPT) and hypothalamus-pituitary-gonadal (HPG) axes, which are important in pubertal development. The hypothalamic gonadotropin-inhibitory hormone (GnIH) was shown to be decreased in the early prepubertal stage, suggesting the role of GnIH on pubertal onset. Here, we investigated whether thyroid dysfunction affects pubertal onset in female mice via GnIH regulation. Hypothyroidism showed delayed pubertal onset with increased GnIH expression and reduced pituitary-gonadal activity. Remarkably, knockout of GnIH prevented the effect of hypothyroidism to delay the pubertal onset, resulting in indistinguishable pubertal timing in GnIH-knockout female mice between control and hypothyroidism-induced group, indicating that increased GnIH expression induced by hypothyroidism may lead to delayed puberty. In contrast, hyperthyroidism led to a decrease in GnIH expression, however pubertal onset was normal, implying further reduction of the inhibitory GnIH had little effect on the phenotypical change. Critically, thyroid hormone suppressed GnIH expression in hypothalamic explants and GnIH neurons expressed thyroid hormone receptors to convey the thyroid status. Moreover, the thyroid status highly regulated the chromatin modifications of GnIH promoter, H3acetylation and H3K9tri-methylation. These findings indicate a novel function of GnIH to mediate HPT-HPG interactions that contribute to proper pubertal development.