PGD, CVS, and amniocentesis are options for prenatal diagnosis in situations with maternal premutation or full mutation (50)
There is a need for each woman diagnosed with spontaneous POF to be informed of her increased risk for carrying a premutation in the FMR1 gene and about the availability of genetic testing to detect this condition. Identification of families that carry the FMR1 premutation would permit women of childbearing age to be counseled about their reproductive options and monitored more closely for the possible development of premature ovarian failure.
Heterozygous mutation of the bone morphogenetic protein 15 (BMP15) gene has been reported in two sisters with POF (52). Galactosemia is a rare autosomal recessive disorder which arises due to a deficiency in the enzyme GALT (53). The exact mechanism of ovarian failure has not been elucidated in patients with galactosemia and POF.
POF related infertility is an adjunct to BPES type I. In previous reports, all mutations were exclusively localized in the FOXL2 gene (56). However, in recent studies, it was discovered that two other members of this family, FOXO1A and FOXO3A, are candidate genes for the development of POF (57). Mutation in AIRE gene has been identified in patients with hypogonadism and ovarian insufficiency (53).
Defects in the steroidogenic acute regulatory enzyme (StAR), CYP17, and aromatase enzymes cause prienorrhea and POF (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).
Some studies reported inactivating mutations of the FSH or LH receptor genes in connection with prienorrhea and hypergonadotropic ovarian failure (60, 61). Polymorphisms in estrogen receptor -? (ESR-1) and L- isoaspartyl- 0-methytransferase (PCMTI) genes are associated with idiopathic POF (63, 70).
A recent study among the Iranian population has showed that inhibin ?-subunit (INHA) gene mutation is more frequent in patients with POF than in the normal fertile Iranian population (67).
Karyotypes should be performed as a part of basic evaluation of women diagnosed with POF due to frequent abnormal karyotypes (13-50%) in this condition. Having this information ily members (53). If Y chromosome material presents, gonadectomy would be mandatory for the prevention of gonadoblastoma (53).
The pathophysiology of ovarian damage in this condition could be due to the toxic effect of galactose (or one of the metabolites) on follicular structures or defective gonadotropin function and structure
Some cases of POF may be due to an abnormal self-recognition by the immune system. The exact mechanism remains obscure (71). Presence of lymphocytic oophoritis (72, 73, 74), demonstration of ovarian autoantibodies (73, 74), and association with other autoimmune disorders (75) are evidences of the presence of autoimmune mechanisms in the pathophysiology of POF.
An increasing number of studies have documented autosomal involvement in ovarian dysfunction
Antiovarian antibodies in POF have been reported in several studies, but their specificity and pathogonomic roles are questionable. Antiovarian antibodies do not correlate with the presence or severity of oophritis, so the measurement of these antibodies is not recommended. The measuring of CD8 density on T cells could provide a reliable indicator of the involvement of the immune system in POF (87).
Autoimmune Polyglandular Syndrome (APS) type I is a rare autosomal recessive disorder in young children, characterized by multiple organ-specific autoimmunity secondary to a variety of autoantibodies directed against key intracellular enzymes. POF in the form of prienorrhea develops in 60% of these patients.
Autoimmunity against the adrenal gland has been shown in 2-10% of POF cases (71, 83). Sharing of autoantigens between ovary and adrenal glands, particularly the P450 side-chain cleavage enzyme, may explain the association of ovarian failure and Addison’s disease. In subclinical patients (presence of adrenal antibodies in absence of hypocortisolism), Addison’s disease may develop by the age of 8-14 (83). Circulating 21-hydroxilase antibodies are the best immune marker of autoimmune adrenal insufficiency (75). Testing for anti-adrenal and anti-21-hydroxylase antibodies are the best biochemical tests for the detection of steroidogenic cell autoimmunity and occult adrenal insufficiency, and identification of the patients who should be monitored for the subsequent development of adrenal insufficiency (15, 75, 83). Morning serum cortisol level has low sensitivity and specificity, when used as a screening test in these patients (83). The ACTH stimulation test should be used as a diagnostic test for patients with symptoms of adrenal insufficiency or with positive adrenal autoantibodies. Women with positive adrenal antibodies will require referral to a medical endocrinologist for additional evaluation and long-term follow-up of their adrenal function.