Premature Ovarian Insufficiency: Past, Present, and Future

Abstract

Premature ovarian insufficiency (POI) is the loss of normal ovarian function before the age of 40 years, a condition that affects approximately 1% of women under 40 years old and 0.1% of women under 30 years old. It is biochemically characterized by amenorrhea with hypoestrogenic and hypergonadotropic conditions, in some cases, causing loss of fertility. Heterogeneity of POI is registered by genetic and non-genetic causes, such as autoimmunity, environmental toxins, and chemicals. The identification of possible causative genes and selection of candidate genes for POI confirmation remain to be elucidated in cases of idiopathic POI. This review discusses the current understanding and future prospects of heterogeneous POI. We focus on the genetic basis of POI and the recent studies on non-coding RNA in POI pathogenesis as well as on animal models of POI pathogenesis, which help unravel POI mechanisms and potential targets. Despite the latest discoveries, the crosstalk among gene regulatory networks and the possible therapies targeting the same needs to explore in near future.

Keywords: early menopause; ovarian aging; ovary; premature ovarian failure; premature ovarian insufficiency.

FIGURE 1

Folliculogenesis and ovulation in normal ovary versus POI ovary (impaired folliculogenesis). Under the regulation of intraovarian factors and gonadotropins, primary follicles develop into preantral and early antral follicles, which are the most susceptible to atresia, or follicle death. Then, they become preovulatory follicles, resulting in oocyte release and corpora lutea formation. Defects in folliculogenesis (e.g., decrease in primordial follicles, increase in atresia, and altered follicular maturation) causes POI. Selected genes that are involved in ovarian follicle activation, maturation, and death and the effect of POI on health (see also in Table 2 and section “Clinical view of POI”) are shown. AMHR2, anti-Müllerian hormone receptor 2; BMP15, bone morphogenic protein 15; BMPR2, bone morphogenetic protein receptor 2; FMR1, fragile X mental retardation; FSHR, follicle-stimulating hormone receptor; FOXO3A, forkhead box O3; FOXL2, forkhead box L2; GDF-9, growth differentiation factor 9; KHDRBS1, heteronuclear ribonucleoprotein particle K homology domain RNA binding S1; LHX8, LIM homeobox 8; NOBOX, newborn ovary homeobox; NR5A1, nuclear receptor subfamily 5 group A member 1; PGRMC1, progesterone receptor membrane component 1; POLR3H, RNA polymerase III subunit H; SOHLH1, spermatogenesis and oogenesis specific basic helix–loop–helix 1.