Recent advances in understanding primary ovarian insufficiency

Abstract

Primary ovarian insufficiency (POI) is an uncommon yet devastating occurrence that results from a premature depletion of the ovarian pool of primordial follicles. Our understanding of both putative and plausible mechanisms underlying POI, previously considered to be largely "idiopathic", has been furthered over the past several years, largely due to advances in the field of genetics and through expansion of translational models for experimental research. In this review, our goal is to familiarize the multidisciplinary readers of the F1000 platform with the strides made in the field of reproductive medicine that hold both preventative and therapeutic implications for those women who are at risk for or who have POI.

Keywords: Primary ovarian insufficiency; fertility; hypergonadotropic hypogonadism.

Figure 1.. Selected genes involved in ovarian follicle activation, maturation, and death.

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; GDF9, 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.

Figure 2.. Selected pathways relevant for plausible salvaging of residual ovarian function in primary ovarian insufficiency.

(1) Ovarian cortex fragmentation disrupts the Hippo signaling pathway leading to dephosphorylation of YAP and TAZ, which (2) stimulates transcription of growth factors (GFs), including GDF9 and BMP15 (transforming growth factor-beta family). (3) GF and Kit-ligand (Kit-L) as well as (4) 740YP administration increase PI3K activity, whereas PTEN serves to keep follicles dormant. (5) Activation of the PI3K complex activates PIP2 to PIP3, which (6) leads to increased Akt expression. (7) Phosphorylated Akt upregulates mTOR, leading to downstream GF transcription, and (8) inhibits activation of RAD51 and FOXO3A. (9) This prevents nuclear export of FOXO3A, decreasing primordial follicle activation. Similarly, (10) anti-Müllerian hormone (AMH) decreases activation of phosphorylation of FOXO3A. Green arrows represent activation steps, and red bar-headed lines represent inhibition. AKT, protein kinase B; FOXO3, forkhead box O3; mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol-3-kinase; PIP2, phosphatidylinositol-4,5-bisphosphate; PIP3, phosphatidylinositol-3,4,5-bisphosphate; PMF, primordial follicle; PTEN, phosphatase and tensin homolog deleted on chromosome 10; TAZ, transcriptional coactivator with PDZ-binding motif; YAP, Yes-associated protein.