Department of Life Science and Institute for Natural Sciences, Hanyang University, Seoul, 04760, Korea.
Department of Pediatrics, Sanggye Paik Hospital, Inje University College of Medicine, Seoul, 01757, Korea.
Reprod Biol Endocrinol. 2022 Apr 23;20(1):72. doi: 10.1186/s12958-022-00944-z.
In children, recombinant human growth hormone (rhGH) therapy for treatment of short stature has raised concerns of the early onset of puberty. Puberty is initiated by the activation of the hypothalamus-pituitary-gonad axis. Insulin-like growth factor-1 (IGF1) has been known to mediate physiologic effects of GH. To understand the mechanism of precocious sexual maturation following prepubertal GH therapy, the effects of rhGH on the hypothalamus-pituitary-gonad axis were examined in the immature male rats.
Immature male rats were given by daily injection of rhGH (1 or 2 IU/kg) from postnatal day (PND) 21 to PND 23 or 30. The effects of rhGH on kisspeptin-GnRH-LH system in the hypothalamus-pituitary axis, systemic and testicular IGF1, spermatogenesis, steroidogenesis, and circulating testosterone levels were examined. The effects of rhGH on the IGF1 expression and steroidogenesis were examined in progenitor LCs in vitro.
Testicular steroidogenic pathway and spermatogenesis marker mRNA levels, number and size of 17β-hydroxysteroid dehydrogenase (+) LCs, and blood testosterone levels of rhGH rats were significantly higher than those of controls on PNDs 24 and 31. Hypothalamic Kiss1 and Gnrh1 mRNA of rhGH rats were significantly higher than those of controls on PND 24, indicating early activation of hypothalamic kisspeptin-GnRH neurons by rhGH. Hypothalamic Igf1 mRNA levels of rhGH rats were significantly higher than those of controls on PND 24 but significantly lower than those of controls on PND 31. Testicular Igf1 mRNA levels were significantly higher in rhGH rats than in the controls on PNDs 24 and 31 whereas circulating IGF1 levels were not. In progenitor LCs, rhGH significantly increased Igf1 and steroidogenic pathway mRNA levels and testosterone production.
Local increases in testicular IGF1 might be an important mediator of gonadal maturation via activation of LCs steroidogenesis in immature rats given rhGH.
在儿童中，重组人生长激素（rhGH）治疗身材矮小症引起了人们对青春期提前的担忧。青春期是由下丘脑-垂体-性腺轴的激活引起的。胰岛素样生长因子-1（IGF1）已被证明介导 GH 的生理效应。为了了解青春期前 GH 治疗后性早熟的机制，本研究在未成熟雄性大鼠中研究了 rhGH 对下丘脑-垂体-性腺轴的影响。
从出生后第 21 天（PND）至 PND 23 或 30 天，每天给未成熟雄性大鼠注射 rhGH（1 或 2IU/kg）。检查 rhGH 对下丘脑-垂体轴 kisspeptin-GnRH-LH 系统、全身和睾丸 IGF1、精子发生、类固醇生成和循环睾酮水平的影响。在体外研究 rhGH 对祖细胞 LC 的 IGF1 表达和类固醇生成的影响。
rhGH 大鼠的睾丸类固醇生成途径和精子发生标志物 mRNA 水平、17β-羟类固醇脱氢酶（+）LC 的数量和大小以及血液睾酮水平在 PND 24 和 31 时明显高于对照组。rhGH 大鼠的下丘脑 Kiss1 和 Gnrh1 mRNA 水平在 PND 24 时明显高于对照组，表明 rhGH 早期激活了下丘脑 kisspeptin-GnRH 神经元。rhGH 大鼠的下丘脑 Igf1 mRNA 水平在 PND 24 时明显高于对照组，但在 PND 31 时明显低于对照组。rhGH 大鼠的睾丸 Igf1 mRNA 水平在 PND 24 和 31 时均明显高于对照组，而循环 IGF1 水平则不然。在祖细胞 LC 中，rhGH 显著增加 Igf1 和类固醇生成途径 mRNA 水平和睾酮生成。
rhGH 治疗未成熟大鼠可使睾丸 IGF1 水平局部升高，可能通过激活 LC 类固醇生成而成为促进性腺成熟的重要介质。
