First evidence showing the involvement of hormone GnIH in pubertal disorders induced by abnormal thyroid status

Waseda University researchers are taking on one of the major themes in medical research, the hormonal mechanism that induces pubertal disorders, by investigating whether thyroid dysfunction affects pubertal onset.

“Elucidating how thyroid abnormalities have affected those who struggle from pubertal disorders will help develop effective treatment in the future and have major impact on society, says Professor Kazuyoshi Tsutsui of Waseda’s Center for Medical Life Science. Professor Tsutsui is known for discovering hypothalamic gonadotropin-inhibitory hormones (GnIH), which actively inhibit the secretion of gonadotropin-releasing hormone (GnRH). GnIH is, therefore, a negative regulator of reproduction.

This study, published in Scientific Reports, is the first evidence showing the involvement of GnIH in pubertal disorder induced by abnormal thyroid status.

Thyroid hormones regulate metabolism, development and growth. They play an important role in properly developing the reproductive system, pubertal onset to be exact, which is in part controlled by a brain-dependent process.

There are some explanations on how abnormal thyroid status leads to pubertal disorders based on the multilevel interactions of two groups of endocrine glands, the hypothalamus-pituitary-thyroid (HPT) axis and the hypothalamus-pituitary-gonadal (HPG) axis, but the mechanism underlying how thyroid hormones specifically act on the HPG axis has not been fully found. Professor Tsutsui’s research group hypothesized that HPG regulation by thyroid hormones may be initiated by controlling the expressions of GnIH, which may act on the most upstream level of the HPG axis by inhibiting some neuronal activities.

To investigate, the researchers designed experiments to determine the possible role of GnIH as a novel mediator between the HPT and HPG axis by examining the effect of abnormal thyroid status on the pubertal onset in female mice and assessing the changes of various HPG indicators.

The results showed that the receptors of thyroid hormones are expressed in the GnIH neurons of the brain, and that thyroid hormones regulate GnIH expressions by affecting GnIH neurons. Furthermore, the decrease of thyroid hormones significantly increases the GnIH expressions by leading an epigenetic modification of the GnIH DNA promoter, and induces the secretion decrease of hypothalamic gonadotropin-releasing hormones (GnRH) and delay in pubertal onset.

“Our findings suggest that GnIH is an important factor to keep the balance of thyroid hormone-mediated HPG regulation for the proper pubertal development,” explains Professor Tsutsui. “This indicates a novel function of GnIH to mediate the cross-talk between the HPT and HPG axes that contribute to proper timing of pubertal onset.”

Publication information

Article title: Involvement of gonadotropin-inhibitory hormone in pubertal disorders induced by thyroid status
Published in: Scientific Reports
DOI: 10.1038/s41598-017-01183-8
Corresponding authors: You Lee Son or Kazuyoshi Tsutsui