image: The effects of HPG axis,ovary function,granulosa cells, key subcellular structures, maternal mRNA, and microenvironment on human oocyte quality.
Credit: ©Science China Press
Declining female fertility is a health issue that has received broad global attention. Oocyte quality is the key limiting factor of female fertility, and factors affecting oocyte quality involve the secretion and response of hormones, ovarian function, oogenesis, oocyte maturation, and meiosis. Advances in assisted reproductive technology, single-cell omics, and high-precision real-time imaging technology have greatly promoted the study of human oocyte quality. In recent years, researchers have made some breakthroughs. However, compared with other species, the research and understanding of human oocyte quality and reproductive health is still limited.
Recently, Lei Wang and Qing Sang’s lab in Fudan University published a literature review entitled "Human oocyte quality and reproductive health" in Science Bulletin. This review systematically summarizes the physiological regulating mechanism of human oocyte quality, highlights the pathogenic factors of oocyte quality decline and involving signal pathways, explores the potential therapeutic strategies and targets, and outlines the emerging scientific prospects and challenges for future explorations of biological mechanisms and clinical treatments.
In physiology, this review discusses the regulation of the hypothalamic-pituitary-gonadal axis, granulosa cells, key subcellular structures, maternal mRNA homeostasis, the extracellular matrix, maternal microenvironment, and multi-omics resources related to human oocyte quality. The HPG axis controls the human sexual development and reproductive capacity by GnRH, FSH, and LH. Recently, it has been reported that muscle-derived myostatin can function as an endocrine hormone promoting FSH synthesis and regulating ovarian function. It is suggested that key subcellular structures of oocyte specificity can regulate the quality of human oocytes, such as mitochondria-associated membrane-less compartment (MARDO) stores maternal mRNA, cytoplasmic lattices (CPLs) mediated by the subcortical maternal complex regulate embryonic development competence, and oocytes maintain ROS-free mitochondrial metabolism by inhibiting mitochondrial respiratory chain complex I assembly. The founding of the human oocyte microtubule organizing center (huoMTOC) and the mechanisms of minor pole-mediated spindle bipolarization both reveal the uniqueness of human oocyte development. In addition, this paper further summarizes the transcriptome, proteome, and epigenome studies of human oocytes and early embryos, and proposes that effective use of omics data will promote the physiological mechanism of human oocyte development.
In pathology, the authors review the hypothalamic-pituitary-gonadal defects, ovarian dysfunction, human oocyte development defects, and aging. Defects in the hypothalamic-pituitary-gonadal axis often lead to congenital hypogonadotropic hypogonadism (CHH). Nearly 49 genes are associated with CHH, among which 19 genes are involved in GnRH neurons and axon projection, and 11 genes affect GnRH neuron homeostasis. Premature ovarian insufficiency (POI) and polycystic ovary syndrome (PCOS) are two major ovarian disorders. Previous studies have shown that nearly 60 genes are associated with POI, among which 45% (27/60) genes are enriched in the meiosis pathway, and 28.33% (17/60) genes are associated with follicle and granulosa cell function. A total of 43 genetic loci related to PCOS were identified by genome-wide association analysis, and the affected genes were mainly involved in obesity, insulin, menopause, hyperandrogenism, anovulation, and inflammation. The genetic factors affecting human oocyte development have remained poorly understood for many years, but emerging studies indicate that human oocyte development defects have Mendelian inheritance patterns. Till now, 37 mutant genes have been reported to be responsible for defects in human oocyte quality and oocyte development. Nearly half of the genes (17/37, 45.95%) are involved in meiosis in oocytes, while the remainder are involved in maternal mRNA regulation, the subcortical maternal complex, zona pellucida formation, ion channels and protein transport, and mitochondrial function.
Strategies to improve oocyte quality and female fertility are also discussed. It is pointed out that discovering novel genes will further improve the genetic diagnoses of patients. Targeting these proven factors and their associated signaling pathways via small molecule inhibitors and agonists will likely bring breakthroughs for restoring human oocyte quality. In the end, the authors outline that studies on the spindle assembly and mitochondrial remodeling of human oocytes might be helpful to reveal the unique mechanism of human oocyte development. This review will deepen the understanding of mechanisms regulating human oocyte quality and provide novel insights into clinical female infertility characterized by defects in oocyte quality and oocyte development.