Identification of premature ovarian failure patients with underlying autoimmunity

Although known causes of premature ovarian failure (POF) include X chromoso me deletions, radiation and chemotherapy, and genetic defects of the gonado tropin hormones or receptors, at least one third to one half of cases remai n idiopathic. A significant proportion of patients with apparently idiopath ic POF have some evidence for an autoimmune etiology. However, the only gol d standard for detecting autoimmune causes of immune ovarian destruction ha s been invasive ovarian biopsy. Serum antibodies to ovarian and other self- tissue have been described in up to one third of women with POF, but the te sts are not well standardized, not well correlated with ovarian histology, and highly variable. Recently, specific defects of expression of cell surfa ce markers on peripheral blood lymphocytes have been shown to identify, in population-based studies, individuals destined to develop autoimmune pancre atic destruction and type I diabetes mellitus, even before any other eviden ce of autoimmunity. We, therefore, sought to test the ability of cell surfa ce marker expression in women with POF to identify autoimmune defects. Seve nteen women with POF, 11 of whom had positive antibody titers to ovary, thy roid, or antinuclear antibody, were studied on at least two occasions and c ompared in blinded fashion with normal controls and patients with autoimmun e type I diabetes mellitus. The most useful marker for identifying autoimmu nity was the surface density of conformationally correct HLA class I molecu les on macrophages, a structure essential for T cell education. Using this marker, 7 of the 9 patients with autoantibodies and 3 of the 8 patients wit hout autoantibodies were identified as having evidence of a defect in self- antigen presentation similar to that of type I diabetics (chi-square, p = 0 .03). Subsequent testing identified antismooth muscle antibodies in 1 of th e women with a defect of HLA class I molecules but no previously identified autoimmunity. In addition, there were increased numbers of CD8 T cells in both autoimmune POF and insulin-dependent diabetes mellitus (IDDM) patients . Exclusive to POF patients was a statistically significant increase in CD8 density on T cells. This was most prominent in POF patients with an underl ying autoimmune etiology. These data further support a role for autoimmunit y in POF patients and suggest that the further development of cell surface markers in combination with other diagnostic tests could result in diagnosi s before the development of complete ovarian failure. The possibility for d isease-specific therapy to prevent further autoimmune ovarian damage in sel ected POF patients is also envisioned.