Tumurbaatar Tuvshintugs, Kanasaki Haruhiko, Cairang Zhuoma, Lkhagvajav Batjargal, Oride Aki, Okada Hiroe, Kyo Satoru
Department of Obstetrics and Gynecology, Shimane University Faculty of Medicine, Izumo 693-8501, Japan.
Endocr J. 2025 Sep 5;72(9):1011-1021. doi: 10.1507/endocrj.EJ25-0044. Epub 2025 May 23.
The hypothalamic-pituitary-gonadal (HPG) axis is primarily regulated by kisspeptin neurons. In addition, activin and inhibin within the central nervous system might contribute to the regulation of the HPG axis because they are expressed near kisspeptin and gonadotropin-releasing hormone (GnRH) neurons. We investigated the effects of inhibin and activin within the hypothalamus in the estradiol (E2)-induced negative feedback mechanism. Inhibin α subunit gene within the posterior hypothalamus in female rats increased after ovariectomy, and this increase was completely suppressed by E2 supplementation. In contrast, inhibin βA subunit decreased after ovariectomy and this reduction was recovered by E2. In ovary-intact rats, E2 reduced inhibin α subunit and increased inhibin βA expression within the hypothalamus. In the rHypoE8 and GT1-7 hypothalamic cell models, E2 stimulation increased inhibin α subunit gene expression. Activin and inhibin A increased Kiss1 gene expression in GT1-7 cells, while inhibin B reduced it. Kisspeptin increased inhibin α subunit expression in rHypoE8 cells, GT1-7 cells, and the mHypoA55 hypothalamic KNDy neuron cell model. Our findings suggest that the expression of inhibin subunits, especially inhibin α, could be increased by E2 in hypothalamic cells and that kisspeptin, inhibin, and activin mutually influence each other under the actions of E2, but their regulation might be controlled mainly by kisspeptin neurons in vivo. Although the effects of activin and inhibin on Kiss1 gene expression varied depending on the hypothalamic cell model examined, intracerebral inhibin and activin might have potential roles in the E2-induced negative feedback mechanism under the influence of kisspeptin neurons.
下丘脑-垂体-性腺（HPG）轴主要由 kisspeptin 神经元调节。此外，中枢神经系统中的激活素和抑制素可能参与 HPG 轴的调节，因为它们在 kisspeptin 和促性腺激素释放激素（GnRH）神经元附近表达。我们研究了下丘脑内抑制素和激活素在雌二醇（E2）诱导的负反馈机制中的作用。雌性大鼠下丘脑后部的抑制素α亚基基因在卵巢切除术后增加，而这种增加被补充 E2 完全抑制。相反，抑制素βA 亚基在卵巢切除术后减少，而这种减少通过 E2 得以恢复。在卵巢完整的大鼠中，E2 降低下丘脑内抑制素α亚基并增加抑制素βA 的表达。在 rHypoE8 和 GT1-7 下丘脑细胞模型中，E2 刺激增加抑制素α亚基基因表达。激活素和抑制素 A 增加 GT1-7 细胞中的 Kiss1 基因表达，而抑制素 B 则降低该表达。Kisspeptin 增加 rHypoE8 细胞、GT1-7 细胞和 mHypoA55 下丘脑 KNDy 神经元细胞模型中的抑制素α亚基表达。我们的研究结果表明，E2 可增加下丘脑细胞中抑制素亚基的表达，尤其是抑制素α，并且在 E2 的作用下，Kisspeptin、抑制素和激活素相互影响，但它们的调节在体内可能主要由 kisspeptin 神经元控制。尽管激活素和抑制素对 Kiss1 基因表达的影响因所检测的下丘脑细胞模型而异，但脑内抑制素和激活素在 kisspeptin 神经元的影响下，可能在 E2 诱导的负反馈机制中发挥潜在作用。
