下丘脑-垂体-性腺轴在哺乳动物的内分泌调节和生殖功能中扮演着至关重要的角色。任何参与激素或受体功能的变化都可能导致性别分化、青春期开始、不育、癌症发展以及其他功能障碍的改变。在这项研究中，我们分析了持续升高的人绒毛膜促性腺激素(hCG)水平，一种强有力的垂体促黄体生成素(LH)激动剂，对雌性小鼠生殖轴的影响。由于转基因(TG)雌性小鼠全身表达hCGβ亚单位而导致慢性hCG高分泌，一系列事件扰乱了未成年期到青春期的过渡阶段。促性腺激素作用的不平衡首次表现为早熟和性腺激素产生的改变，导致成年后卵巢功能紊乱和不育。3周大的TG雌性小鼠在荷尔蒙刺激后，体内和体外卵丘细胞的扩增、排卵能力和促排卵相关标记基因的基因表达正常。然而，与之相关的类固醇合成和黄体化基因如Lhcgr、Prlr和类固醇合成酶Cyp11a1、Cyp17a1和Cyp19a1的表达在TG雌性小鼠中显著升高。本研究表明，与高泌乳素一起的hCG过度分泌，诱发了早期黄体化和增强的卵巢类固醇合成，如上调TG小鼠的黄体细胞标志基因和孕酮合成。此外，TG雌性在青春期至成年期逐渐受到生殖功能障碍的影响，最终导致不育。版权所有 © 2023 Elsevier Inc.。保留所有权利。

The hypothalamic-pituitary-gonadal axis plays a fundamental role in the endocrine regulation of the reproductive function in mammals. Any change in the function of the participating hormones or their receptors can lead to alterations in sexual differentiation, the onset of puberty, infertility, cancer development, and other dysfunctions. In this study, we analyzed the influence of persistently elevated levels of the human chorionic gonadotropin hormone (hCG), a powerful agonist of pituitary luteinizing hormone (LH), on the reproductive axis of female mice. As a consequence of chronic hCG hypersecretion through a global expression of the hCGbeta-subunit in transgenic (TG) female mice, a series of events perturbed the prepubertal to juvenile transition. The imbalance in gonadotropin action was first manifested by precocious puberty and alterations in gonadal hormone production, with the consequent ovarian function disruption and infertility in adulthood. The expansion of cumulus cells in vivo and in vitro, ovulatory capacity, and gene expression of ovulation-related marker genes after hormone stimulation were normal in 3-week-old TG females. However, the expression of genes related to steroidogenesis and luteinization such as Lhcgr, Prlr, and the steroidogenic enzymes Cyp11a1, Cyp17a1, and Cyp19a1 were significantly elevated in the TG females. This study demonstrates that the excessive secretion of hCG in concert with high prolactin, induced premature luteinization, and enhanced ovarian steroidogenesis, as was shown by the up-regulation of luteal cell markers and progesterone synthesis in the TG mice. Furthermore, progressively impaired reproductive function of the TG females occurred from the peripubertal stage to adulthood, thus culminating in infertility.Copyright © 2023 Elsevier Inc. All rights reserved.