Advances in the Molecular Pathophysiology, Genetics, and Treatment of Primary Ovarian Insufficiency

The mechanisms underlying the formation of the ovarian reserve are generally well conserved, from Drosophila to mammals. Owing to this high degree of conservation, factors shown to regulate the ovarian reserve in mouse models are all potential candidates for identifying mutations associated with POI in humans. With the generation of genetically modified mice, much insight has been gained into the mechanisms that control the formation of the ovarian reserve and trigger the activation of primordial follicles. Comparison with animal models is complicated by the fact that the phenotype of complete gene deletion in knockout models may not be mimicked by single gene mutations. Recently innovative treatment for POI based on in vitro activation of the dormant primordial follicular pool has been developed. Primary ovarian insufficiency (POI) affects ∼1% of women before 40 years of age. The recent leap in genetic knowledge obtained by next generation sequencing (NGS) together with animal models has further elucidated its molecular pathogenesis, identifying novel genes/pathways. Mutations of >60 genes emphasize high genetic heterogeneity. Genome-wide association studies have revealed a shared genetic background between POI and reproductive aging. NGS will provide a genetic diagnosis leading to genetic/therapeutic counseling: first, defects in meiosis or DNA repair genes may predispose to tumors; and second, specific gene defects may predict the risk of rapid loss of a persistent ovarian reserve, an important determinant in fertility preservation. Indeed, a recent innovative treatment of POI by in vitro activation of dormant follicles proved to be successful. Primary ovarian insufficiency (POI) affects ∼1% of women before 40 years of age. The recent leap in genetic knowledge obtained by next generation sequencing (NGS) together with animal models has further elucidated its molecular pathogenesis, identifying novel genes/pathways. Mutations of >60 genes emphasize high genetic heterogeneity. Genome-wide association studies have revealed a shared genetic background between POI and reproductive aging. NGS will provide a genetic diagnosis leading to genetic/therapeutic counseling: first, defects in meiosis or DNA repair genes may predispose to tumors; and second, specific gene defects may predict the risk of rapid loss of a persistent ovarian reserve, an important determinant in fertility preservation. Indeed, a recent innovative treatment of POI by in vitro activation of dormant follicles proved to be successful. a growth factor produced by the granulosa cells of growing follicles. Serum AMH level is an indirect marker of the ovarian reserve and declines with increasing age. a pituitary-derived hormone that stimulates estrogen production, follicle growth, and selection of the preovulatory follicle. Serum FSH levels are elevated upon ovarian aging due to the loss of negative feedback signals. Normal FSH concentrations (IU/l) are: during follicular phase, 3.5–9.0; ovulatory phase, 7.0–21.5; luteal phase, 1.7–7.0; postmenopause, 26–140. a process that assures faithful repair of double strand breaks, one of the most dangerous DNA damages. HR relies on the invasion of a similar DNA matrix (the homologous chromosome during meiosis) as a template to repair the broken DNA. The products of this repair can either be a local replacement of DNA sequence or exchange of large chromosome fragments, respectively termed non-crossover and crossover. The meiotic crossovers are mandatory for proper segregation of chromosomes, thus precisely halving the genome in gametes. although menstrual cycles cease in POI patients, some of them retain residual dormant ovarian follicles. A new infertility treatment has been developed, which enables POI patients to conceive using their own eggs, by activation of the residual dormant follicles through in vitro manipulation of signaling pathways responsible for follicular quiescence. a pituitary-derived hormone that triggers ovulation. Serum LH levels increase upon ovarian aging due to the loss of negative feedback signals. meiosis is the universal cellular process in eukaryotes that allows formation of the haploid reproductive cells. DSBs are programmed DNA breaks generated early during prophase I and catalyzed by the sporulation 11 homolog (SPO11) enzyme. DSBs are concentrated in ‘hotspots’ designated by PR domain containing 9 (PRDM9), through the deposition of trimethylation on lysine 4 of histone 3. also known as high-throughput sequencing, describes modern sequencing technologies that allow the sequencing of thousands to millions of DNA molecules simultaneously. It allows sequencing multiple genes and multiple individuals at the same time. a DSB repair pathway often opposed to HR. NHEJ directly ligates broken DNA ends together. It is believed to result in low repair fidelity in the absence of a homologous sequence to guide DNA repair, as in HR. a term describing the quality and number of resting oocytes within primordial follicles, and considered as a female’s reproductive potential. the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway, regulating various stages of folliculogenesis. Studies in most genetic mouse models have revealed an essential role of this pathway in primordial follicle activation. the primary cells that form the progenitors of gametes. PGCs will populate the embryonic gonads and differentiate into either oocytes or spermatocytes. sequencing by NGS, the protein-coding region of the human genome (exome) that represents <2% of the genome, but contains most known disease-related variants.