Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, United States.
Front Endocrinol (Lausanne). 2022 Aug 22;13:917464. doi: 10.3389/fendo.2022.917464. eCollection 2022.
Kisspeptins (KPs) secreted from the hypothalamic KP neurons act on KP receptors (KPRs) in gonadotropin (GPN) releasing hormone (GnRH) neurons to produce GnRH. GnRH acts on pituitary gonadotrophs to induce secretion of GPNs, namely follicle stimulating hormone (FSH) and luteinizing hormone (LH), which are essential for ovarian follicle development, oocyte maturation and ovulation. Thus, hypothalamic KPs regulate oocyte maturation indirectly through GPNs. KPs and KPRs are also expressed in the ovarian follicles across species. Recent studies demonstrated that intraovarian KPs also act directly on the KPRs expressed in oocytes to promote oocyte maturation and ovulation. In this review article, we have summarized published reports on the role of hypothalamic and ovarian KP-signaling in oocyte maturation. Gonadal steroid hormones regulate KP secretion from hypothalamic KP neurons, which in turn induces GPN secretion from the hypothalamic-pituitary (HP) axis. On the other hand, GPNs secreted from the HP axis act on the granulosa cells (GCs) and upregulate the expression of ovarian KPs. While KPs are expressed predominantly in the GCs, the KPRs are in the oocytes. Expression of KPs in the ovaries increases with the progression of the estrous cycle and peaks during the preovulatory GPN surge. Intrafollicular KP levels in the ovaries rise with the advancement of developmental stages. Moreover, loss of KPRs in oocytes in mice leads to failure of oocyte maturation and ovulation similar to that of premature ovarian insufficiency (POI). These findings suggest that GC-derived KPs may act on the KPRs in oocytes during their preovulatory maturation. In addition to the intraovarian role of KP-signaling in oocyte maturation, , a direct role of KP has been identified during maturation of sheep, porcine, and rat oocytes. KP-stimulation of rat oocytes, , resulted in Ca release and activation of the mitogen-activated protein kinase, extracellular signal-regulated kinase 1 and 2. treatment of rat or porcine oocytes with KPs upregulated messenger RNA levels of the factors that favor oocyte maturation. In clinical trials, human KP-54 has also been administered successfully to patients undergoing assisted reproductive technologies (ARTs) for increasing oocyte maturation. Exogenous KPs can induce GPN secretion from hypothalamus; however, the possibility of direct KP action on the oocytes cannot be excluded. Understanding the direct and roles of KP-signaling in oocyte maturation will help in developing novel KP-based ARTs.
Kisspeptins (KPs) 由下丘脑的 KP 神经元分泌，作用于促性腺激素释放激素 (GnRH) 神经元中的 KP 受体 (KPRs) 以产生 GnRH。GnRH 作用于垂体促性腺细胞，诱导促性腺激素的分泌，即卵泡刺激素 (FSH) 和黄体生成素 (LH)，这对于卵巢卵泡的发育、卵母细胞的成熟和排卵是必不可少的。因此，下丘脑的 KPs 通过 GPNs 间接调节卵母细胞的成熟。KP 和 KPR 也在不同物种的卵巢卵泡中表达。最近的研究表明，卵巢内的 KPs 也可以直接作用于卵母细胞中表达的 KPRs，促进卵母细胞的成熟和排卵。在这篇综述文章中，我们总结了关于下丘脑和卵巢 KP 信号在卵母细胞成熟中的作用的已发表报告。性腺类固醇激素调节下丘脑 KP 神经元的 KP 分泌，反过来又诱导下丘脑-垂体 (HP) 轴的 GPN 分泌。另一方面，HP 轴分泌的 GPN 作用于颗粒细胞 (GCs)，上调卵巢 KP 的表达。虽然 KPs 主要在 GCs 中表达，但 KPRs 在卵母细胞中表达。随着发情周期的进展，卵巢中 KPs 的表达增加，并在促性腺激素峰前达到高峰。卵巢内卵泡内 KP 水平随着发育阶段的进展而升高。此外，在小鼠中敲除卵母细胞中的 KPRs 会导致卵母细胞成熟和排卵失败，类似于卵巢早衰 (POI)。这些发现表明，GC 衍生的 KPs 可能在卵母细胞的促性腺激素峰前成熟过程中作用于卵母细胞中的 KPRs。除了 KP 信号在卵母细胞成熟中的卵巢内作用外，在绵羊、猪和大鼠卵母细胞的成熟过程中也确定了 KP 的直接作用。大鼠卵母细胞的 KP 刺激导致 Ca2+释放和丝裂原活化蛋白激酶、细胞外信号调节激酶 1 和 2 的激活。用 KP 处理大鼠或猪的卵母细胞可上调有利于卵母细胞成熟的因子的信使 RNA 水平。在临床试验中，人类 KP-54 也成功地用于接受辅助生殖技术 (ART) 的患者，以增加卵母细胞成熟。外源性 KPs 可以从下丘脑诱导 GPN 的分泌；然而，不能排除 KP 对卵母细胞的直接作用的可能性。了解 KP 信号在卵母细胞成熟中的直接 和 作用将有助于开发新的基于 KP 的 ARTs。
