Uterine leiomyoma? ? Uterine leiomyoma, commonly called fibroids, disproportionately affect African American women and are associated with adverse pregnancy outcomes, such as pre-term delivery, miscarriage, and cesarean section. The condition adversely impacts the health of millions of women, leading to excessive menstrual bleeding and pelvic pain. Despite their prevalence, leiomyoma growth and development remain poorly understood, and there are few non-surgical, long-term treatment options for women with fibroids. ? ? In order to gain insight into strategies that may be developed for medical treatment of fibroids, our unit has used a gene profiling approach to uncover genes associated with leiomyoma development. This approach led to the realization that genes encoding the connective tissue between cells, the extracellular matrix (ECM), were altered in expression in uterine leiomyoma. Further studies showed that the structure of the ECM was altered in leiomyoma. Together, these findings raised the question whether the altered ECM might contribute to growth of the fibroids through mechanical signaling, since the ECM is a load-bearing structure and increases in loading can affect the growth rate of cells. To test that hypothesis, in the past year in collaboration with Drs. Tuan and Chen in NIAMS, we measured tissue stiffness and found that cells within fibroid tumors were exposed to increased mechanical stress. The increased mechanical stress was accompanied by cellular changes, such as alteration in the actin cytoskeleton and biochemical evidence of activation of solid state signaling. In brief, the studies support the conclusion that cells within a fibroid have fundamental alterations in mechanical signaling and that altered mechanical signaling may contribute to growth of uterine leiomyoma. In the coming year, we plan to characterize the altered mechanical signaling in fibroids in greater detail and characterize factors that might be responsible for the alterations in cell growth. ? ? The unit has also continued clinical studies related to leiomyoma. Information about the possible impact of myomectomy on ovarian function is important in the clinical management of patients with fibroids who desire fertility. This question has not been systematically investigated. Specifically, the estimates of subsequent fertility rates in fertile women (or at least in women not proved to be infertile) are not available. To address this gap in the current knowledge, in the past year we examined the impact of leiomyoma on fertility and ovarian reserve. We plan to expand this investigation to include evaluation of anti-mullerian hormone pre and post myomectomy.? ? Endometriosis and Chronic Pelvic Pain? ? Chronic pelvic pain significantly affects the health of up to 10 percent of women with endometriosis. The diagnosis of endometriosis is established at a surgical procedure. One persistent issue in surgical diagnosis is whether histologic confirmation of the disease should be obtained, given the variable appearance of lesions. In the past year, we have correlated biopsy results with lesion appearance in two different ways. In the first study, we reported on the histologic confirmation given varying lesion characteristics, illustrating that no single color was associated with endometriosis and that surgeons should biopsy any suspicious lesion. Subtle lesions were as likely to contain endometriosis as classic lesions (64%) and 40% of women who had only small, subtle lesions had biopsy-proven endometriosis. Mixed color lesions and endometriomas were the only two lesion types that were more commonly biopsy-proven (78%). In a second study, we created a logistic model to predict endometriosis. This model identified characteristics which indicated a high and low probability of biopsy-proven endometriosis. It was useful as a guide in choosing appropriate lesions for biopsy, but should not be used as a substitute for histologic confirmation. ? In collaboration with Drs. Greene and Sinaii, the group led by Dr. Stratton described the diagnostic experience of women with chronic pelvic pain and endometriosis responding to the Endometriosis Association Survey. The group examined the relationship between disease severity and patient characteristics in endometriosis by analyzing questionnaires from 1000 women in the Oxford Endometriosis Gene (OXYGENE) study. In the coming year, this group will continue examining aspects of the health of women with endometriosis by analyzing the Endometriosis Association Survey, continue efforts to define the pain outcomes in endometriosis clinical trials, and conduct analyses of the hypothalamic pituitary-adrenal-axis in women with chronic pelvic pain and endometriosis. ? ? Assessment and preservation of ovarian function in women and girls undergoing cancer treatment? ? As a result of more successful cancer treatments, many young girls and women are now cancer survivors but find that their reproductive function is irreparably damaged by their treatment. Dr. Armstrong recently led an initiative to devise strategies to enable women who are cancer survivors to maximize and preserve reproductive function. In the past year, we have continued our study of treatment regimens designed to minimize the effect of cancer treatments on the later reproductive function of women. To move toward that goal we helped to initiate a large multicenter, randomized trial of gonadotropin-releasing hormone antagonists (GnRH-ant) in young women before cancer treatments. This study will test the hypothesis that medical treatment would benefit young girls undergoing chemotherapy. In addition we have begun basic science studies designed to elucidate the mechanism of the possible protective effect attributable to GnRH-ant treatment prior to chemotherapy. ? ? Infertility and reproductive health disparities? ? Reproductive health disparities exist for many women. Our unit has been interested in examining the causes and consequences of these disparities in an effort to devise strategies to optimize reproductive outcome across racial and ethnic groups. In the past year we have continued our study of reproductive health disparities and the context of multicenter investigations. Specifically, Dr. Armstrong was an investigator in a study of racial disparities that examined over 130,000 IVF cycles. The results of this investigation confirmed the findings of disparate outcomes among African American women. In the past year we also evaluated ART utilization and outcome among Hispanic couples. That study suggested that contrary to claims of some that economic barriers accounted for lower rates of utilization, other factors may be responsible for reproductive health disparities. In the coming year we plan to continue to investigate racial disparities in reproductive health in multicenter trials of women in assisted reproduction and infertility care.
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