The genetics of premature ovarian failure: current perspectives

Abstract

Premature ovarian failure (POF) is a common cause of infertility in women, characterized by amenorrhea, hypoestrogenism, and elevated gonadotropin levels in women under the age of 40. Many genes have been identified over the past few years that contribute to the development of POF. However, few genes have been identified that can explain a substantial proportion of cases of POF. The unbiased approaches of genome-wide association studies and next-generation sequencing technologies have identified several novel genes implicated in POF. As only a small proportion of genes influencing idiopathic POF have been identified thus far, it remains to be determined how many genes and molecular pathways may influence idiopathic POF development. However, owing to POF's diverse etiology and genetic heterogeneity, we expect to see the contribution of several new and novel molecular pathways that will greatly enhance our understanding of the regulation of ovarian function. Future genetic studies in large cohorts of well-defined, unrelated, idiopathic POF patients will provide a great opportunity to identify the missing heritability of idiopathic POF. The identification of several causative genes may allow for early detection and would provide better opportunity for early intervention, and furthermore, the identification of specific gene defects will help direct potential targets for future treatment.

Keywords: POF; genetics; genome-wide association studies; next-generation sequencing; ovarian aging; premature ovarian failure.

Figure 1

A schematic representation of the process of folliculogenesis in the mammalian ovary from primordial follicles through to follicle ovulation and subsequent corpus luteum formation. Notes: Initial recruitment is gonadotropin independent and involves the differentiation of primordial follicles into primary and preantral follicles, the majority of which undergo atresia prior to puberty. Cyclic recruitment occurs after puberty and is gonadotropin dependent. Cyclic recruitment involves the growth and development of antral follicles through to mature preovulatory follicle selection and ovulation or atresia. This process continues throughout a female’s reproductive lifespan until the primordial follicle pool is depleted.