Editorial: AutoImmune Premature Ovarian Failure—Endocrine Aspects of a T Cell Disease1

Premature ovarian failure (POF) is the loss of ovarian function in women less than 40 yr of age (reviewed in Ref. 1). It is associated with sex steroid deficiency, amenorrhea, infertility, and elevated serum gonadotropins. While there are multiple etiologies of POF including the exposure to iatrogenic treatments (chemotherapy, radiation), viral agents, and rare genetic disorders, in most patients no etiology can be identified (idiopathic POF). Significant evidence suggests that autoimmunity is a cause of some forms of ovarian failure although specific ovarian antigens are not known and the mechanisms of autoimmune disease development are unclear. Autoimmune POF in humans is frequently associated with other manifestations of autoimmune disease. For example, POF can precede the onset of Addison’s disease or adrenal autoimmunity leading to a deficiency of adrenocortical hormones (1). Autoimmune POF is characterized by inflammatory infiltration of developing follicles, production of antiovarian antibodies, atrophy, and sparing of primordial follicles (1‐3). Autoantibodies in these diseases sometimes react with common antigens in steroid-producing cells of the ovary and adrenal cortex. Common antigens identified have been steroidogenic enzymes including P450 side-chain cleavage (P450scc), 17a-hydroxylase, and 3b-hydroxysteroid dehydrogenase (4 ‐ 6). The identification of specific antigens involved in POF is important for multiple reasons. First, the development of appropriate reagents to screen for the presence of antibodies to these antigens could provide an analytical tool for diagnosing the disease, identifying patients at risk for developing the disease, and detecting patients who may respond to immune-modulating therapies. Second, these tools could be used in research to further understand the mechanisms of disease development and the mechanisms of ovarian pathology associated with the disease. Lastly, the identification of these antigens provides new information on novel proteins in the ovary and their potential function. Animal models of autoimmune premature ovarian failure have yielded important insight into both potential mechanisms of autoimmune disease development and ovarian antigens that may affect disease progression. These models for autoimmune ovarian failure can be induced by multiple methods such as immunization with specific ovarian antigens or neonatal thymectomy in specific genetic strains of mice. A detailed review of the findings will not be repeated here but some major developments will be summarized. The most important development in these animal models of autoimmune ovarian failure comes from multiple studies, all suggesting that the basis of the disease is a cell-mediated autoimmune reaction caused by an alteration in T cell regulation (1, 3). This is most evident in the neonatal thymectomy animal model. The removal of the thymus in specific genetic strains of mice (e.g. BALB/c or A/J) between postnatal days 2 and 5 results in autoimmune ovarian failure. There is a progressive onset of the disease that is potentiated by puberty and the most severe inflammation occurs between 4 ‐14 weeks after thymectomy (3). The proposed mechanism of the disease (3) is that autoreactive T cells (CD41) are generated during normal processes such as apoptosis of follicles in the ovary. These autoreactive cells are normally controlled by CD41 T cells with suppressor activity. However, because these cells are generated in the thymus after the first week of life, neonatal thymectomy results in a dramatic loss in T cells with suppressor function. This animal model strongly implicates T cell regulation in the disease process.