甲状腺ホルモンによる生殖制御におけるＧｎＩＨシステムの作用機構

甲状腺疾病会导致青春期发育异常。尽管甲状腺和生殖内分泌系统之间的相互作用已被提出，但甲状腺激素如何影响青春期开始的详细机制仍不清楚。下丘脑肽促性腺激素抑制激素(GnIH)在青春期前早期下降，提示GnIH在青春期发病中可能起作用。因此，我们研究了促性腺激素释放激素(GnIH)在甲状腺功能状态所致的青春期疾病中的作用。为此，我们诱导了幼年雌性小鼠甲状腺功能减退和甲亢，然后分析了生殖轴调节因子的变化。甲状腺功能减退症表现为青春期延迟，GnIH表达增加，但GnIH基因敲除可阻止甲状腺功能减退症所致的青春期延迟，提示GnIH可能介导了甲状腺功能减退症对青春期延迟的影响。相反，甲亢对青春期发病无影响，而GnIH的表达显著降低，表明甲状腺状况与GnIH的表达呈负相关。此外，我们发现下丘脑GnIH神经元表达甲状腺激素受体(TRs)，该受体可能直接将甲状腺激素信号传递给GnIH神经元。尽管TRs不直接与GnIH启动子区域结合，但甲状腺状况会主动改变GnIH启动子区域的染色质修饰。我们的研究结果表明，GnIH在青春期的正常发育中具有一种新的功能，即调节下丘脑-垂体-甲状腺和下丘脑-垂体-性腺轴之间的串扰。

Thyroid disorders lead to abnormal pubertal development. Although interactions between the thyroid and reproductive endocrine systems are suggested, the detailed mechanisms of how thyroid hormone influences pubertal onset remain unclear. The hypothalamic peptide, gonadotropin-inhibitory hormone (GnIH) was shown to be decreased in the early prepubertal stage, suggesting the possible role of GnIH on pubertal onset. Therefore, we investigated the involvement of GnIH in thyroid status-induced pubertal disorders.To do this, we induced hypothyroidism and hyperthyroidism in juvenile female mice, then analyzed the change in the regulatory factors of the reproductive axis. Hypothyroidism showed delayed pubertal onset with increased GnIH expression, however hypothyroidism-induced delayed puberty was prevented by GnIH-knockout, suggesting that GnIH may mediate the effect of hypothyroidism on pubertal delay. Reversely, hyperthyroidism had no effect on pubertal onset, however GnIH expression was significantly decreased, indicating the negative correlation between thyroid status and GnIH expression. Further, we found that hypothalamic GnIH neurons express thyroid hormone receptors (TRs), which may convey thyroid hormone signals directly to GnIH neurons. Although TRs did not directly bind to GnIH promoter region, thyroid status actively altered the chromatin modifications in GnIH promoter region.Our findings indicate a novel function of GnIH to mediate the cross-talk between the hypothalamus-pituitary-thyroid and hypothalamus-pituitary-gonadal axes in proper pubertal development.