Genomic markers of ovarian reserve

Abstract

Ovarian reserve and its utilization, over a reproductive life span, are determined by genetic, epigenetic, and environmental factors. The establishment of the primordial follicle pool and the rate of primordial follicle activation have been under intense study to determine genetic factors that affect reproductive lifespan. Much has been learned from transgenic animal models about the developmental origins of the primordial follicle pool and mechanisms that lead to primordial follicle activation, folliculogenesis, and the maturation of a single oocyte with each menstrual cycle. Recent genome-wide association studies on the age of human menopause have identified approximately 20 loci, and shown the importance of factors involved in double-strand break repair and immunology. Studies to date from animal models and humans show that many genes determine ovarian aging, and that there is no single dominant allele yet responsible for depletion of the ovarian reserve. Personalized genomic approaches will need to take into account the high degree of genetic heterogeneity, family pedigree, and functional data of the genes critical at various stages of ovarian development to predict women's reproductive life span.

Figure 1

Genes Essential for Preservation of Ovarian Reserve. (A) Primordial follicle activation to develop to primary follicles requires a delicate balance of both promoting and inhibiting factors. The transition from germ cell cysts to primordial follicles requires stimulatory signals from Figla, Mcm8, Mcm6, and Bcl2. Bax, Casp2, and Casp3 can all inhibit this initial transition to primordial follicles. The decision to become a primary follicle requires action from Nobox, Kit/Kitl, Mtor, GDF9, and Akt1/Pik3c signaling. Alternatively, SOHLH1, SOHLH2, LHX8, Pten, Pdk1, Rps6, S6K1, Foxo3, Galt, Cdkn1b, Foxl2, and Amh/Amhr2 function to prevent premature activation of the primordial follicle. (B) Folliculogenesis beyond the primary follicle also requires orchestration of multiple protein factors. The transition from primary to preantral follicles requires the action of Gdf9 and Igf1 and communication of the oocyte with supporting cells. The transition from early preantral follicles to antral follicles requires hormonal control, through Lh/Lhcgr, Fsh/Fshr, Esr1, and ESR2. Additionally, the action of Cyp19a1, GDF9, and Fmr1 are essential for antral follicle formation while Tp53 and Bax may inhibit this activation. Beyond antral follicle formation, release of the oocyte at ovulation requires activation by Bmp15, Esr1/2, Cyp19a1, Pparg, and Cyp11b1. Pde3a and Mb21d1 can prevent ovulation by maintaining oocyte arrest. Function implied based on association but not directly studied in ovarian physiology.