Molecular mechanisms underlying luteinization (terminal differentiation of granulosa and theca cells after ovulation) and luteolysis (demise of corpus luteum) are poorly understood in human ovary. Here we report that activin-A, after binding to its cognate receptors induces a functional luteolytic state and reverses luteinization phenotype by downregulating the expression of the steroidogenic enzymes, LH receptor and VEGF and reducing estradiol (E₂) progesterone (P₄) production and upregulating FSH receptor and cyclin D1 expression in human primary luteinized granulosa cells. Further, this action of activin-A involves downregulation of JNK signaling pathway and is opposite to that of human chorionic gonadotropin (hCG), which acts as a luteotropic hormone and improves luteal function through the activation of JNK pathway in the same cell type. Reversal of luteinization phenotype in luteal granulosa cells by activin-A potentially makes this hormone an attractive candidate for use under certain clinical situations, where induction of luteolysis and rapid reduction of endogenous sex steroid levels are beneficial such as ovarian hyperstimulation syndrome (OHSS), in which the ovaries hyper-respond to gonadotropin stimulation by producing too many growing follicles along with development of ascites, pleural effusion, and hemo-concentrations as a result of increased vascular permeability and leakage of intravascular volume into third spaces. Our work unveils a previously undefined role for activin-A and JNK signaling pathway in human corpus luteum biology, that might have a direct clinical impact in assisted reproductive technologies.

在人类卵巢中，黄体化（排卵后颗粒细胞和卵泡膜细胞的终末分化）和黄体溶解（黄体死亡）的分子机制知之甚少。在这里，我们报道，激活素-A 在与其同源受体结合后，可诱导功能性黄体溶解状态，并通过下调类固醇生成酶、LH 受体和 VEGF 的表达以及减少雌二醇 (E 2 ) 黄体酮 (P 4 ) 的产生和逆转黄体_化表_型。上调人原代黄素化颗粒细胞中 FSH 受体和细胞周期蛋白 D1 的表达。此外，激活素 A 的这种作用涉及 JNK 信号通路的下调，与人绒毛膜促性腺激素 (hCG) 的作用相反，人绒毛膜促性腺激素 (hCG) 充当促黄体激素，通过激活相同细胞类型中的 JNK 通路来改善黄体功能。激活素 A 逆转黄体颗粒细胞中的黄体化表型可能使该激素成为某些临床情况下使用的有吸引力的候选者，其中诱导黄体溶解和快速降低内源性类固醇水平是有益的，例如卵巢过度刺激综合征（OHSS），卵巢对促性腺激素刺激反应过度，产生过多生长的卵泡，同时由于血管通透性增加和血管内容量渗漏到第三空间而导致腹水、胸腔积液和血液浓缩。我们的工作揭示了激活素 A 和 JNK 信号通路在人类黄体生物学中先前未定义的作用，这可能对辅助生殖技术产生直接的临床影响。