About 12% of women with idiopathic POF were found in one recent study to have familial POF. The pattern of inheritance may be X-linked or autosomal-dominant sex limited, paternal and maternal, transmission. The most common chromosomal abnormality in women with POF is X chromosome mosaicism, which has been found in 40% to 50% of women with primary amenorrhea. The karyotype may show 45,XO/46,XX or 46,XX/47XXX. The POF1 gene is located on the long arm of the X chromosome and is felt to be involved in the development of ovarian function. There is also a POF2 gene on the long arm of the X chromosome, which has been suggested to cause ovarian failure and another locus for POF on the short arm. The FOXL2 gene mutation on chromosome 3 has been recently described to cause POF, but probably accounts for only a small number of POF cases. This mutation is associated with BPES (blepharophimosis/ptosis/epicanthus inversus syndrome), an autosomal dominant disorder that may be associated with POF. The FRAXA premutation, located on the long arm of the X chromosome and associated with fragile X syndrome, is also associated with POF, being present in 3% to16% of women with familial POF. The molecular mechanism causing POF in these cases is unknown.
Without two active X chromosomes, follicular atresia is accelerated. Therefore, although normal fetal ovarian development may occur in women with Turner's syndrome, ovarian failure occurs because of follicular atresia.
Inhibin is a glycoprotein product of the ovarian follicle, which plays a role in the pituitary secretion of FSH. Because inhibin selectively inhibits FSH secretion, it has been suggested that decreased inhibin production may induce POF because of increased FSH production accelerating follicular depletion. A recent study has shown that 7% of women with POF have a mutation of the inhibin gene located on the long arm of chromosome 2 and is associated with ovarian failure at an early age.
Mutations in the genes coding for the FSH and LH receptors have also been identified in women with primary ovarian failure.
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Autoimmune
POF is frequently associated with autoimmunity. It may be an element of autoimmune polyglandular syndrome (APS) in combination with adrenal insufficiency (Addison's disease), hypothyroidism, hypoparathyroidism, or mucocutaneous candidiasis. In APS type I, an autosomal recessive disorder, POF is present in 60% of women. It is very common for women with POF to have autoimmune hypothyroidism. In a recent study of women with karyotypically normal POF, 27% were hypothyroid, 2.5% had hypoparathyroidism, and 2.5% had diabetes mellitus.
Ovarian autoimmunity may be mediated either cellularly or humorally. Lymphocytic oophoritis has been described in association with Addison's disease, with inflammatory lymphocytic infiltration of the theca interna, primarily in mature follicles. Antiovarian antibodies have been found with greater frequency in women with POF without evidence of other autoimmune disease, however the antibodies may also be present in normal women.
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