There are major gaps in knowledge regarding the etiologic mechanisms, psychosocial effects, natural history, and medical and psychosocial management of women with disorders of the hypothalamic-pituitary-ovarian axis. An international research consortium and disease registry formed under the guidance of an umbrella organization would provide a pathway to comprehensively increase basic and clinical knowledge about these conditions. Such a consortium and patient registry also would provide clinical samples and clinical data with a goal toward defining the specific pathogenic mechanisms. An international collaborative approach that combines the structure of a patient registry with the principles of integrative care and community-based participatory research is needed to advance the field of primary ovarian insufficiency. The program is in the early phases of organizing such an international effort using primary ovarian insufficiency as the primary focus. Primary ovarian insufficiency (POI) resulting from ovarian autoimmunity is a poorly understood clinical condition lacking in effective treatments. Understanding the targets of the autoimmune response and induction of ovarian-specific tolerance would allow development of focused therapies to preserve fertility in an at-risk population. MATER (maternal antigen that embryos require) is a known ovarian autoantigen targeted in autoimmune syndromes of POI. We induced ovarian-specific tolerance via transgenic expression of the MATER antigen on potentially tolerogenic antigen-presenting cells (APC), which typically present antigen via the major histocompatibility complex (MHC) class II molecule. We hypothesized that expression of MATER in a MHC class II-dependent manner on APC can mediate induction of ovarian tolerance. We utilized a well-characterized murine model of ovarian autoimmunity, whereby oophoritis develops after d 3 neonatal thymectomy (NTx). Wild-type and transgenic mice, carrying an MHC Class II-driven Mater gene (IE-Mater), were subjected to NTx and assessed for evidence of autoimmune oophoritis. After disease induction by NTx, female mice carrying the IE-Mater transgene had significant reductions in histological oophoritis (56%) and circulating ovarian autoantibodies (28%) compared with wild-type females (94% and 82%, respectively). Incidence of other autoimmunity was unaffected as assessed by antinuclear autoantibodies. Transgenic expression of MATER in APC can induce antigen-specific tolerance with a significant reduction in ovarian autoimmunity. Lack of complete disease protection suggests that other antigens may also play a role in autoimmune oophoritis. As a known autoantigen in the human APS1 (autoimmune polyglandular syndrome type 1), which is associated with POI, MATER may represent a relevant target for future diagnostic and therapeutic clinical interventions. A high prevalence of depressive symptoms is observed in women with primary ovarian insufficiency (POI) compared with women in whom the menopause is normally timed. Indeed, studies suggest that depression and/or its pharmacological treatment contribute to the onset of POI. We characterized the prevalence of psychiatric disorders and the timing of onset of clinically significant depression relative to both the diagnosis of POI and the onset of menstrual irregularity in women with POI. We conducted a cross-sectional clinic-based study at the National Institutes of Health Clinical Research Center. A total of 174 women with spontaneous 46, XX POI and 100 women with Turner syndrome participated in the study. The structured clinical interview for DSM-IV was performed. Lifetime histories of depression in POI exceeded rates of depression reported in women with Turner syndrome and community-based samples of women (P <0.001). The onset of depression frequently preceded the diagnosis of POI but occurred after the onset of menstrualirregularity. Analyses standardizingthe periods of risk for depression showed that similar numbers of depressions occurred before and after these events. POI is associated with an increased lifetime risk for major depression. Attention to the presence of depression in POI should become an important part of the care for these women. The onset of depression frequently occurs after signs of altered ovarian function but before the diagnosis of POI. Thus, in some women the association between POI and depression suggests an overlapping pathophysiology rather than a causal relationship. Osteoporosis primarily affects postmenopausal women. However, young women with estrogen deficiency also are at increased risk for low bone density. We assessed bone density and associated risk factors for reduced bone density in young, estrogen-deficient women using primary ovarian insufficiency (POI) as the disease model. From this work we conclude that women with POI have lower bone density compared to regularly menstruating control women. Compared to Caucasians, minority women with estrogen deficiency are more likely to have BMD below the expected range for age. This racial disparity appears to be related to a combined effect of several modifiable risk factors. Delay in diagnosis of POI also contributes to reduced bone density by delaying proper therapy. We also examined factors associated with emotional well-being in women with spontaneous primary ovarian insufficiency (POI) using a cross-sectional and case-control study. Clinicians could improve the emotional well-being of their patients with POI by 1) informing them better, 2) helping them to feel less stigmatized, and 3) assisting them in developing alternative goals with regard to family planning as well as other goals. We also found that women with POI had significantly lower scores than controls on both the perceived social support scale and the self-esteem scale. Strategies to improve social support and self-esteem might provide a therapeutic approach to reduce the emotional suffering that accompanies the life-altering diagnosis of spontaneous POI. We studied the psychosocial implications for teens that develop POI and their parents. The goal for parent and clinician is to help the girl formulate positive self-esteem and body image, despite impaired fertility

Project Start
Project End
Budget Start
Budget End
Support Year
23
Fiscal Year
2013
Total Cost
$2,140,585
Indirect Cost
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State
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Guerrieri, Gioia M; Martinez, Pedro E; Klug, Summer P et al. (2014) Effects of physiologic testosterone therapy on quality of life, self-esteem, and mood in women with primary ovarian insufficiency. Menopause 21:952-61
Nelson, Lawrence M (2014) The Flat Earth Society: a rose by any other name? Hum Reprod 29:190-2
Popat, Vaishali B; Calis, Karim A; Kalantaridou, Sophia N et al. (2014) Bone mineral density in young women with primary ovarian insufficiency: results of a three-year randomized controlled trial of physiological transdermal estradiol and testosterone replacement. J Clin Endocrinol Metab 99:3418-26
Nelson, Lawrence M (2011) One world, one woman: a transformational leader's approach to primary ovarian insufficiency. Menopause 18:480-487
Nelson, Lawrence M; Captain, U.S. Public Health Service (2011) Synchronizing the world of women's health: young Turks and transformational leaders report for duty. Fertil Steril 95:1902
Rossetti, Raffaella; Di Pasquale, Elisa; Marozzi, Anna et al. (2009) BMP15 mutations associated with primary ovarian insufficiency cause a defective production of bioactive protein. Hum Mutat 30:804-10
Hubayter, Ziad R; Popat, Vaishali; Vanderhoof, Vien H et al. (2009) A prospective evaluation of antral follicle function in women with 46,XX spontaneous primary ovarian insufficiency. Fertil Steril :
Bourgeois, James A; Coffey, Sarah M; Rivera, Susan M et al. (2009) A review of fragile X premutation disorders: expanding the psychiatric perspective. J Clin Psychiatry 70:852-62
Nelson, Lawrence M (2009) Clinical practice. Primary ovarian insufficiency. N Engl J Med 360:606-14
Orshan, Susan A; Ventura, June L; Covington, Sharon N et al. (2009) Women with spontaneous 46,XX primary ovarian insufficiency (hypergonadotropic hypogonadism) have lower perceived social support than control women. Fertil Steril 92:688-93

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