This project seeks to improve the clinical care available to patients with disorders of ovarian follicle function. In pursuing this goal, we expect to expand basic science understanding of the ovarian follicle in health and disease. We have focused on premature ovarian failure, a condition that prematurely terminates normal ovarian function and fertility in 1% of women. We have particular interest in autoimmunity as a cause of ovarian failure. Our strategies to investigate the mechanisms of premature ovarian failure involve work in the basic science laboratory as well as in the clinic. In a mouse model, we found that autoantibodies from mice with experimental autoimmune oophoritis bind to Mater, a novel 120 kd protein that is specific to the oocyte cytoplasm. Mater is a novel oocyte-specific maternal effect gene whose product we previously demonstrated is essential for embryonic development beyond the two-cell stage. During the past year we defined the human homologue of mouse Mater, a maternal effect gene critical to female fertility. The human and mouse cDNA share 67% homology while their deduced polypeptide chains have 53% identity of amino acids. Also, their proteins have a number of similar structures. Characterization of the human MATER gene and its protein provides a basis for investigating their clinical implications in autoimmune premature ovarian failure and infertility in women. We are now evaluating the antigenic role of Mater in a mouse model of autoimmune ovarian failure. Also, we have generated a mouse line lacking Mater and we are investigating this mouse as a model for human idiopathic infertility. For most young women with premature ovarian failure the most troubling part of the diagnosis is the associated infertility. This is the primary focus of our research. Nonetheless, young women with this condition have other needs that must be met by their health care providers. During the past year we investigated the clinical experiences of young women with premature ovarian failure using a structured interview survey. Disturbance in menstrual pattern was the most common initial symptom. We found that over one half of the women reported visiting a clinician's office three or more times before laboratory testing was performed to determine the diagnosis. In one-fourth of the women it took longer than 5 years for the diagnosis to be established. We found that women with spontaneous premature ovarian failure perceive a need for more aggressive evaluation of secondary amenorrhea and oligomenorrhea. Loss of menstrual regularity can be a sign of ovarian insufficiency, and the associated estrogen deficiency is a well-established risk factor for osteoporosis. There is a need for more public health education regarding this association. Also, it is well established that patients with spontaneous premature ovarian failure are at increased risk of developing autoimmune adrenal insufficiency, a potentially fatal disorder. There has been ongoing controversy regarding the best clinical strategy by which to detect adrenal insufficiency at an early stage in these young women. During the past year we demonstrated that the presence of anti-adrenal antibodies in the serum was highly associated with adrenal insufficiency while a negative test was associated with normal adrenal function in all cases. Our findings demonstrate that measuring adrenal antibodies is an effective screening method by which to detect asymptomatic autoimmune adrenal insufficiency in young women with spontaneous premature ovarian failure.