Two forms have been described: in type I, POF related infertility is an adjunct to the condition, and type II is not associated with POF (55). BPES type I is mapped to 3q22-23(54). Two genes are identified within the breakpoint region. One of the genes, termed FOXL2 appears predominantly in the ovaries of adult humans. In previous reports, all mutations had been exclusively localized in the FOXL2 gene (56). However, two other members of this family, FOXO1A and FOXO3A, are candidate genes for the development of POF (57).
Autoimmune polyendocrinopathy- candidiasisectodermal dystrophy (APECED)
AIRE gene, is responsible for autoimmune polyendocrinopathy- candidiasis-ectodermal dystrophy syndrome (APECED) (53). This mutation, which is mapped to chromosome 21q23, can lead to hypogonadism and ovarian insufficiency (53).
Steroidogenic enzyme defect
Several congenital enzyme defects can disrupt estrogen synthesis; these defects result in low estrogen, delayed puberty, amenorrhea, and high serum FSH concentration levels despite the existence of normal-appearing primordial follicles in the ovary. Defects in the steroidogenic acute regulatory enzyme (StAR), CYP17, and aromatase enzymes cause these clinical and histological abnormalities (58, 59). Lack of appropriate negative feedback by peripheral estrogen on gonadotropins may lead to excessive follicular growth and increased risk of ovarian torsion and infarction in these hypoestrogenized patients (59).
Gonadotropin receptor dysfunction
FSH and luteinizing hormone (LH) have important roles in the recruitment, development, and maturation of ovarian follicles. FSH and LH receptor genes map to 2p21. Some studies have reported inactivating mutations of the FSH or LH receptor Bonga Cam price genes in connection with prienorrhea and hypergonadotropic ovarian failure (60, 61). Histological studies of ovaries in patients with FSH receptor gene mutations have showed a streak or hypoplastic gonad with impaired follicular development of the primordial and primary follicles. POF has been identified in patients with a defect in the guanine nucleotide regulatory protein of adenylate cyclase (G-protein), which is linked to the FSH and LH receptors as a second-messenger system. Due to the multiplicity of receptors activated by the same G-protein, pseudohypoparathroidism and hypothyroidism may be observed in these patients (62).
Breetherick et al. suggested that estrogen receptor-? (ESR-1) poly morphisms are associated with idiopathic POF; however they recommended further studies in larger patient samples to confirm this finding (63).
Inhibin gene mutation
The glycoprotein inhibin plays an important role in the recruitment and development of ovarian follicles by the negative feedback control of FSH. Inhibin ? (INHA), Inhibin ?-a (INHBA), and Inhibin ?-b (INHBB) genes are responsible for inhibin coding. Mutation in the INHA gene was seen in POF patients (64-66). A recent study has shown that inhibin ?-subunit (INHA) gene mutation is more frequent in patients with POF than in the normal fertile Iranian population (67).
Noggin mutation
Proximal symphalangism (SYM1) is an autosomal dominant disorder with characteristic skeletal abnormalities and conductive deafness. This disease has been shown to result from haploinsufficiency of the NOG gene on 17q22 encoding Noggin. NOG is expressed in the ovary and acts as an antagonist for BMPs, which play an important role in ovarian function (68). Kosaki et al (69). reported a case of POF and SYM1 with mutation in NOG. They proposed that NOG mutation may constitute one of the multiple susceptibility genes for the development of POF.
A recent study has shown that four polymorphisms in the protein L- isoaspartyl-0-methytransferase (PCMTI) gene, a protein repair enzyme, are associated with POF (70).
Autoimmune causes
Some cases of POF may be due to an abnormal self-recognition by the immune system. The exact mechanism remains obscure (71); probably the genetic or environmental factors initiate the immune response. The major histocompatibility complex antigen, cytokines, cell-mediated immunity and antibody-mediated immunity have important roles. Autoimmune mechanisms are involved in the pathogenesis of 4-30% of POF cases (10, 72). The evidences for an autoimmune etiology are:
