The role of BMP15 and GDF9 in the pathogenesis of primary ovarian insufficiency

Endocrine and paracrine signals can be key regulators of ovarian physiology. The oocyte secretes growth factors which directly induce follicular development by a complex paracrine signalling process, and the transforming growth factorβ (TGF-β) superfamily has a pivotal role in this process. The bone morphogenetic protein 15 (BMP15) and growth differentiation factor 9 (GDF9) genes are relevant members of the TGF-β superfamily that encode proteins secreted by the oocytes into the ovarian follicles, where they contribute to creating an environment supporting follicle selection and growth. Their main functions include regulating cellular proliferation/differentiation, follicular survival/atresia, and oocyte maturation. Recent functional studies have validated genetic factors (Progesterone receptor membrane component 1 (PGRMC1)), Fragile X mental retardation 1 (FMR1, GDF9 and BMP15) as being causative of primary ovarian insufficiency (POI), BMP15/GDF9 gene variants were found to have a high incidence on the POI phenotype. This review considers the most recent research regarding the role of BMP15 and GDF9 in the genetic control of follicular development, paying special attention to the pathogenesis of POI.