Involvement of gonadotropin-inhibitory hormone in pubertal disorders induced by thyroid status

Abstract

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.

Reproductive neuroendocrinology of mammalian gonadotropin‐inhibitory hormone

“…Administration of thyroid hormone suppresses GnIH expression in hypothalamic explants, and GnIH neurons express thyroid hormone receptors to convey thyroid status. These findings indicate a novel function of GnIH to mediate interactions of the hypothalamic‐pituitary‐thyroid (HPT) and gonadal axes that contribute to pubertal regulation …”

“…Kiyohara et al investigated whether thyroid dysfunction affects pubertal onset through GnIH in female mice. Hypothyroidism shows delayed pubertal onset with increased GnIH expression.…”

Editorial: Progress in Reproductive Neuroendocrinology in Vertebrates

“…It was demonstrated that GnIH inhibits the adenylate cyclase (AC)/cAMP/protein kinase A (PKA)-dependent pathway both in GnRH neurons and gonadotropes (9, 10). The article further summarizes the mechanisms of how GnIH expression is regulated by glucocorticoid (18) and thyroid hormone (19). The third review article by Angelopoulou et al introduces that RFRP-3, mammalian GnIH, is involved in the central control of daily and seasonal rhythms of reproduction to synchronize reproductive activity to environmental challenges.…”

Ontogeny of gonadotrophin‐inhibitory hormone in the cichlid fish Cichlasoma dimerus

“…Little is known about spatial‐temporal expression patterns and roles of GnIH during development because most published work focused on GnIH anatomical distribution and function in adult vertebrates . Even though some studies have evaluated GnIH (gene: gnih ) expression during embryonic stages in birds and mammals, the GnIH system has been examined to a greater extent throughout sexual development and the pre‐pubertal period . To our knowledge, only 3 studies have examined GnIH during fish development.…”

“…[2][3][4][5][6] Even though some studies have evaluated GnIH (gene: gnih) expression during embryonic stages in birds and mammals, [15][16][17] the GnIH system has been examined to a greater extent throughout sexual development and the pre-pubertal period. [18][19][20][21][22][23][24][25] To our knowledge, only 3 studies have examined GnIH during fish development.…”