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

Abstract

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.

FANCL gene mutations in premature ovarian insufficiency

“…It is well documented that the maintenance of genome stability and integrity is a vital determinant of cell viability, and the germ cell genome is especially vulnerable to ubiquitous DNA insults (Winship, Stringer, Liew, & Hutt, 2018). Moreover, increasing evidence suggests that mutations of the genes involved in DNA repair underlie the pathogenesis of POI (Huhtaniemi et al, 2018; Jiao et al, 2018). ICLs, which are among the most harmful DNA lesions and impede both transcription and replication, can be induced by endogenous metabolites (e.g., alcohol and acetaldehyde) and exogenous inducers (e.g., MMC and platinum compounds; Clauson, Schärer, & Niedernhofer, 2013).…”

Inhibition of the NLRP3 inflammasome prevents ovarian aging

“…POI is a critical fertility defect characterized by an anticipated impairment of the follicular reserve for which pathophysiological mechanisms are not understood. Different genetic and molecular alterations have been proposed such as mutations in genes associated with DNA repair or meiosis, bioenergetics alterations and mitochondrial dysfunction (2). The clinical characteristics of POI patients and controls are listed in Table S1 and low ovarian reserve were confirmed by transvaginal ultrasound (Supplementary Figure 1).…”

“…These pathologies can be managed by different strategies including pharmacological intervention, lifestyle modifications, and prevention of harmful environmental exposures. However, the ovarian aging process is currently a pharmacologically uncontrollable process that impairs female fertility; the infertility correlates with a rapid decline after age 35, and is attributable to the impairment of the quantity and/or the quality of oocytes (2). Female infertility is exacerbated by socioeconomic changes in developed countries, which enable women to progressively delay the age at which they have their first child.…”

Identification of MCM8IP, an interactor of MCM8-9 and RPA1 that promotes homologous recombination and DNA synthesis in response to DNA damage

“…POI is an infertility syndrome caused by mutations in at least 60 genes 71 . Among these genes are MCM8 and MCM9, whose mutations in patient-derived cells cause elevated ICL-induced chromosomal instability 41,42,72 .…”