This project seeks to understand the physiology and pathophysiology of ovarian follicle development and function, and to thereby develop clinical diagnostic and therapeutic applications for women with ovulatory disorders. During this period we have focused on premature ovarian failure, a condition which prematurely terminates fertility in 1% of women. We have particular interest in autoimmune-mediated ovarian failure, and seek to improve understanding of this condition through clinical research and through basic research employing a murine model of autoimmune ovarian failure. At one time premature ovarian failure was assumed to be caused by depletion of ovarian follicles, and, like menopause, to be an irreversible condition. We continue to collect evidence to refute this view. A major goal of ours has been to define the mechanism causing follicle dysfunction in these women. By pelvic ultrasound we imaged an antral follicle in over 40% of our patients with premature ovarian failure. However, the follicles were dysfunctional as evidenced by the lack of strong correlation between follicle diameter and serum estradiol and progesterone that is found in normal women. We biopsied antral follicles in 6 women to determine if it was autoimmune oophoritis or some other mechanism impairing follicle function. Strikingly, we found luteinized graafian follicles in all cases. Inappropriate luteinization of graafian follicles appears to be the major pathophysiologic mechanism preventing normal follicle function in these women. There are well recognized increases in reproductive pathology that develop in maturing women. Our findings raise the distinct possibility that these result from a decline in follicle number that reduces negative feedback on luteinizing hormone rather than an intrinsic defect within the remaining primordial follicles. If true, this would have enormous public health implications. We did not find autoimmune oophoritis in any of 6 ovarian follicle biopsies. Insights gleaned from our work on murine experimental autoimmune oophoritis have been used to develop a novel ovarian biopsy strategy now under evaluation. During this period we have also demonstrated that blocking antibodies binding to human gonadotropins or gonadotropin receptors are an uncommon mechanism for premature ovarian failure. We also found that class II major histocompatibility phenotyping and testing for antibodies against the zona pellucida by indirect immunofluorescence are not useful markers for autoimmune premature ovarian failure. Intriguingly, our investigations in murine post-thymectomy polyglandular autoimmunity suggest that neonatal thymectomy causes a deficiency of CD4+ T helper 1 (TH1) activity that persists into adulthood. In ongoing work we are testing the hypothesis that this TH1-deficient state induces the autoimmune disease. Future clinical directions of the project involve development of a treatment to prevent inappropriate luteinization of follicles in patients with premature ovarian failure and a protocol to test the hypothesis that inappropriate luteinization plays a role in the infertility of maturing women.
| Popat, Vaishali B; Calis, Karim A; Vanderhoof, Vien H et al. (2009) Bone mineral density in estrogen-deficient young women. J Clin Endocrinol Metab 94:2277-83 |
| 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 : |
| Kalantaridou, Sophia N; Vanderhoof, Vien H; Calis, Karim A et al. (2008) Sexual function in young women with spontaneous 46,XX primary ovarian insufficiency. Fertil Steril 90:1805-11 |
| Ventura, June L; Fitzgerald, O Ray; Koziol, Deloris E et al. (2007) Functional well-being is positively correlated with spiritual well-being in women who have spontaneous premature ovarian failure. Fertil Steril 87:584-90 |
| Wittenberger, Michael D; Hagerman, Randi J; Sherman, Stephanie L et al. (2007) The FMR1 premutation and reproduction. Fertil Steril 87:456-65 |
| Armstrong, Alicia Y; Calis, Karim A; Nelson, Lawrence M (2007) Do survivors of childhood cancer have an increased incidence of primary ovarian insufficiency? Nat Clin Pract Endocrinol Metab 3:326-7 |
| McConkie-Rosell, Allyn; Abrams, Liane; Finucane, Brenda et al. (2007) Recommendations from multi-disciplinary focus groups on cascade testing and genetic counseling for fragile X-associated disorders. J Genet Couns 16:593-606 |
| Di Pasquale, Elisa; Rossetti, Raffaella; Marozzi, Anna et al. (2006) Identification of new variants of human BMP15 gene in a large cohort of women with premature ovarian failure. J Clin Endocrinol Metab 91:1976-9 |
| Tung, Joyce Y; Rosen, Mitchell P; Nelson, Lawrence M et al. (2006) Novel missense mutations of the Deleted-in-AZoospermia-Like (DAZL) gene in infertile women and men. Reprod Biol Endocrinol 4:40 |
| Corrigan, Emily C; Nelson, Lawrence M; Bakalov, Vladimir K et al. (2006) Effects of ovarian failure and X-chromosome deletion on body composition and insulin sensitivity in young women. Menopause 13:911-6 |
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