Molecular Mechanisms and Consequences of Premature Ovarian Aging. (2012)

Premature ovarian aging is an important disorder associated with infertility, osteoporosis and cardiovascular disease. Mechanisms that underlie premature ovarian aging are heterogeneous, and involve genetic, environmental and iatrogenic factors. Current practice in the evaluation of a woman with premature ovarian aging involves differentiating gonad dysfunction from pituitary and central nervous system dysfunction, and testing for X chromosome abnormalities as well as FMR1 pre-mutation status. Despite this testing, the diagnosis is unclear in majority of cases and algorithms regarding follow up, family planning, oocyte or embryo cryopreservation is lacking. The medical intervention to preserve fertility, and when to do it in families at risk, is limited by the low predictive value of current markers of ovarian reserve. Vast majority of premature ovarian aging cases are due to dysfunction in the ovarian function. Man made and spontaneous mutations in mice have given us great insights into the genetic components that are critical for ovarian development, and folliculogenesis. Both ubiquitous and ovary specific pathways, are critical for oogenesis and egg maturation. Oocyte differentiation into a totipotent cell requires initial germ cell cyst breakdown to form primordial follicles, recruitment of primordial follicles for development into primary follicles and remarkable growth of the ovarian follicle, which culminates in ovulation. During oogenesis, oocyte undergoes dynamic alterations in gene expressions that are regulated by a set of well-coordinated transcription factors active in the germ line and soma. Early embryogenesis begins during oogenesis, as many maternal effect genes (genes that are inherited from the egg, and affect post-fertilization events) commence transcription during early stages of folliculogenesis. A number of germ cell specific as well as somatic expressed transcriptional regulators are critical in ovarian formation, folliculogenesis and expression of maternal effect genes. These transcriptional regulators include: Foxo3a, Foxl2, Figla, Lhx8, Nobox, Pou5f1, Sohlh1 and Sohlh2. A subset of these transcriptional regulators is mutated in women with ovarian insufficiency and infertility. Studies on transcriptional regulators preferentially expressed in the ovary are important to develop a better understanding of the mechanisms of activation and survival of ovarian follicles, as well as an understanding of ovary specific pathways that can be modulated in the future to regulate fertility and protect against external insults such as chemotherapy. Spontaneous mutations in humans and many Mendelian disorders have also given us an insight into the role of multiple genes in ovarian aging, and aging in general. Genome-wide association studies have identified several loci that modulate the age of menopause, and indicate that ovarian aging is a window to accelerated aging in general. Whole genome sequencing approaches by ours and other laboratories are being applied to identify genetic markers that cause premature ovarian aging. It is hoped that a combination of genetic markers and extensive blood profiling will provide reliable biomarkers that can predict reproductive life span and allow timely cryopreservation of ovarian tissues and oocytes to women at risk for premature loss of ovarian function. Moreover, it is hoped that such biomarkers will help stratify women who are at increased risk for adverse outcomes.