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Premature Ovarian Failure (POF)
Premature ovarian failure (POF), or premature ovarian insufficiency (POI), is a female reproductive disorder characterised by at least 4 months of primary or secondary amenorrhea, before the age of 40.1 It is caused by either a decrease in the primordial follicle pool, accelerated atresia of follicles or altered maturation or recruitment of primordial follicles and is associated with menopausal levels of follicle stimulating hormones, exceeding 40 Ul/L.1,2 Specific activator and suppressor genes are implicated in ovarian follicle activation and recent research suggests that POF may be the consequence of a genetic mutation in one or more of these genes.

FOXL2 - FOXL2 knockout mouse models showed failure of granulosa cell differentiation, which led to the premature activation and depletion of primordial follicles, characteristic of POF. Two different variations of mutations in the FOXL2 gene, which cause different forms of POF, one with earlier onset and the other with later onset and incomplete penetrance, have been identified.4 Additionally, mutations in the FOXL2 gene have been found in approximately 5% of nonsyndromic POF patients, which suggests that FOXL2 mutations are also associated with idiopathic POF.3

BMP15 and GDF9 - Mutations in BMP15 and GDF9 genes can be involved in POF, but are not major causes of the disease. For example, low GDF9 mutation frequency has been found in a large cohort of Indian cases of POF.5

SOHLH1 - Little is known about the causative association of SOHLH1 and POF, however three novel SOHLH1 variants have been found to potentially cause the disease and when studied, they were absent in controls.3

AMH - A decrease in AMH expression in POF antral follicles leads to defective antral development.6

mTORC1 and PI3K - Deregulation of mTORC1 and PI3K signaling pathways in oocytes results in ovarian pathological conditions, including POF and subsequent infertility.7

PTEN - Studies of mice with a deletion in PTEN in the oocytes showed early activation of the entire pool of primordial follicles, leading to a lack of primordial follicles in adulthood, resulting in a POF phenotype.8,9

Foxo3a - Studies into mice with complete and partial Foxo3a deletions also showed premature activation of the entire primordial follicle pool, destroying the ovarian reserve and leading to oocyte death. This led to a POF phenotype, seen in studies in a range of countries.10,11

TSC - In the oocytes of Tsc2 knockout mice, elevated mTORC1 activity causes the pool of primordial follicles to become activated prematurely. This results in follicle depletion in early adulthood, causing POF.12