Does ovarian autoimmunity play a role in the pathophysiology of premature ovarian insufficiency?

Premature Ovarian Failure (POF) is an important cause of amenorrhoea and infertility. However some women may spontaneously ovulate and conceive. Primary ovarian insufficiency (POI) is thus the preferred term. POF / POI is multifactorial in etiology. Autoimmunity is an important mechanism for accelerated destruction of ovarian follicles. The present review focuses on the role of autoimmunity in the pathophysiology of POI. Antibodies to multiple ovarian antigens have been proposed as markers of ovarian autoimmunity. However, there has been lack of clinically proven sensitive and specific serum tests to confirm autoimmune involvement in POI. The review details recently developed specific test for antiovarian antibodies (AOA) that has enabeled identification of different molecular antigenic targets in the ovary. The application of this specific test for AOA has brought to light the need for screening for autoimmunity prior to patients undergoing IVF technique

Genes and translocations involved in POF

Changes at a single autosomal locus and many X-linked loci have been implicated in women with gonadal dysgenesis [premature ovarian failure (POF) with deficits in ovarian follicles]. For the chromosome 3 locus, a forkhead transcription factor gene (FOXL2) has been identified, in which lesions result in decreased follicles by haploinsufficiency. In contrast, sporadic X; autosomal translocations are distributed at many points on the X, but concentrate in a critical region on Xq. The association of the breakpoints with genes involved in ovarian function is thus far weak (in four analyzed cases) and has not been related to pathology in other POF patients. While many more translocations can be analyzed in detail as the human genome sequence is refined, it remains possible that translocations like X monosomy (Turner syndrome) lead to POF not by interrupting specific genes important in ovarian development, but by causing aberrations in pairing or X-inactivation during folliculogenesis. It is noted that the critical region has unusual features, neighboring the X-inactivation center and including an 18 Mb region of very low recombination. These suggest that chromosome dynamics in the region may be sensitive to structural changes, and when modified by translocations might provoke apoptosis at meiotic checkpoints. Choices among models for the etiology of POF should be feasible based on studies of ovarian follicle development and attrition in mouse models. Studies would prominently include gene expression profiling of developmental-specific pathways in nascent ovaries with controlled levels of Fox12 and interacting proteins, or with defined changes in the X chromosome. Published 2002 Wiley-Liss, Inc