James Segars, MD, Head, Unit on Reproductive Endocrinology and Infertility
Phyllis Leppert, MD, PhD, Senior Scientist
Alicia Armstrong, MD, Associate Fellowship Program Director, Reproductive Endocrinology and Infertility
Pamela Stratton, MD, Head, Gynecology Consult Service
Eve Feinberg, MD, Clinical Fellow
Robert Gustofson, MD, Clinical Fellow
Jason Parker, DO, Clinical Fellow
Mark Payson, MD, Clinical Fellow
Ninet Sinaii, MPH, PhD, Research Fellow
Rebecca Rogers, BA, Predoctoral Fellow
Jennifer Wadell, BS, Predoctoral Fellow

We investigate underlying causes of and treatment effectiveness for a variety of clinical reproductive disorders. Most recently, we have focused on uterine leiomyoma (commonly known as fibroids), endometriosis, and reproductive disorders leading to infertility. Our mission is to conduct basic, translational, and clinical studies of importance to reproduction in the context of the multi-institutional clinical training program in Reproductive Endocrinology and Infertility. Thus, our objective is to conduct reproductive research while training young clinical investigators who will continue to pursue reproductive research as a life-long career.

Uterine leiomyoma

Leppert, Armstrong, Feinberg, Payson, Segars, Rogers; in collaboration with Catherino, DeCherney, Neiman

Uterine leiomyomas, commonly called "fibroids," are one of the most common and prevalent diseases of the female reproductive tract. As a condition, uterine fibroids result in over $2 billion in direct costs and $1.7 billion in inpatient costs annually to the health care system in the United States (Flynn et al., Am J Obstet Gynecol 2006;195:955). Fibroids disproportionately affect African American women. Uterine fibroids strongly increase the likelihood of pre-term delivery, infertility, and cesarean section, in addition to causing excessive menstrual bleeding and pelvic pain. As a result of fibroid-associated disease, fibroids represent a considerable health burden on women.

Despite the prevalence of fibroids and the spectrum of disease caused by these common growths, the disease remains poorly understood. In the past year, we continued our basic science and translational research studies of uterine fibroids. Expanding on gene profiling studies, our molecular studies have suggested that, while fibroids appear to be similar in appearance, clear differences between fibroids arise from rare genetic syndromes, such as hereditary leiomyomatosis and renal cell cancer (HLRCC). The implication is that fibroids may arise from different molecular mechanisms and that there are different types of fibroid disease. Similarly, it has been known that uterine fibroid disease is more severe in African American women than in Caucasian women, given that 73 percent of African American women have several tumors compared with 43 percent of Caucasian women. Our recent molecular profiling experiments suggest that the molecular signatures of the two conditions differ.

Also in the past year, our results led to a new hypothesis about the development and growth of fibroids, namely, that uterine fibroid growth is accompanied by abnormal tissue repair. The abnormal tissue repair appears to result in formation of an altered extracellular milieu for cells within the fibroid and may in turn contribute to continued fibroid growth. Our studies on TGF-beta signaling and extracellular matrix formation in fibroids suggested that the progression of normal repair mechanisms was altered, resulting in remodeling that was not accompanied by apoptosis. Our studies and the concept of fibroids not as pre-malignant tumors but rather as tissues with altered TGF-beta signaling and wound repair have led our group to institute a clinical trial based on interruption of TGF-beta signaling.

Endometriosis and chronic pelvic pain

Stratton, Gustofson, Sinaii, Parker, Segars; in collaboration with DeCherney, Nieman

Endometriosis is a prevalent condition occurring in up to 10 percent of reproductive-age women. In many women, the condition results in pelvic pain and infertility. In the past year, we concluded a randomized, double-blind, placebo-controlled clinical trial of raloxifene for treatment of pelvic pain due to endometriosis. Women with biopsy-proven endometriosis were randomized to daily raloxifene (180 mg) or placebo for six months. Results indicated that women treated with raloxifene experienced return of pain significantly sooner than those taking placebo. The study is one of the largest randomized studies of medical endometriosis treatment in the literature. In the coming year, we plan to complete analysis of the study results, including the effect of raloxifene on menstrual cycle length and adverse events during treatment.

In the past year, we evaluated, as part of the larger prospective clinical trial, adhesion reformation following laparoscopic excision of endometriosis and adhesiolysis in a subgroup of 38 women with chronic pelvic pain who completed two surgeries. We noted that pelvic adhesions were more likely to form, or reform if the adhesions were thicker, in areas of earlier adhesions, or if adhesions involved the ovary. Most patients developed adhesions after radical surgical excision of endometriosis for pelvic pain. The high incidence of adhesion formation following surgery for endometriosis underscores the importance of optimizing surgical techniques to reduce adhesion formation.

Also as part of the same clinical trial, we examined, by magnetic resonance imaging, whether persistence of dysmenorrhea (pain with menses) and non-menstrual pelvic pain at three months after excision of endometriosis was associated with adenomyosis, as defined by a thickened uterine junctional zone (JZ). Chronic pelvic pain was significantly more likely to be associated with a JZ thickness greater than 11 mm on preoperative magnetic resonance imaging, indicating that adenomyosis may contribute to chronic pelvic pain in a considerable number of women with endometriosis. We also found that appendiceal endometriosis is extremely rare in the general population (0.4 percent). Although relatively common in patients with endometriosis (4.1 percent in our series and 2.8 percent in a literature review), we concluded that the appendix should be inspected for endometriosis and evidence of non-gynecologic disease in patients with right lower-quadrant or pelvic pain.

In the coming year, we plan to expand on our previous histopathologic finding that only about 70 percent of endometriosis lesions seen at surgery are biopsy-proven. We plan to examine the complete data set from our endometriosis cohort and develop a predictive logistic regression model that might assist surgeons in deciding which lesions to excise at surgery. We also plan to examine the relationship between disease severity and patient characteristics in endometriosis by analyzing questionnaires from 1,000 women in the Oxford Endometriosis Gene (OXEGENE) Study.

Cytoplasmic regulation of hormone action by Brx

Segars, Wadell; in collaboration with Chrousos, Driggers, Kino

Our interest in the molecular mechanism of estrogen action in reproductive tissues led to the cloning of a large modular protein from a breast cancer expression library. We called the protein Brx for Breast Receptor Auxiliary Factor (also known as AKAP-13). Past research revealed that Brx augmented ligand-dependent activation of estrogen receptors alpha and beta and was capable of interacting with the receptors in vivo. This year, researchers (Wirtenberger et al., Carcinogenesis 2006;27:593) reported an association of genetic variants of Brx with familial breast cancer. This finding supports our interest in the relationship of Brx to estrogen action, given that estrogens are widely recognized as playing a role in breast cancer growth.

To understand the role of Brx in the reproductive tract and hypothalamic-pituitary axis, we characterized the expression of Brx in the brain and pituitary of the mouse and in the human endometrium. We found that Brx protein was present in the anterior pituitary of male and female mice but present in significantly greater amounts in female murine pituitaries. Estrogen treatment augmented the expression of Brx in the pituitary, but not to a statistically significant degree. These observations suggest that Brx may play a role in the action of estrogens in the central nervous system. In the coming year, we plan to continue our in vivo study of Brx in the targeted loss-of-function model we created.

Also in the past year, we continued our study of Brx. In collaboration with George Chrousos and Tomoshige Kino, we tested whether Brx was capable of influencing the activity of other nuclear receptors, particularly the glucocorticoid receptor (GR). Using tissues from the mice haploinsufficient for the brx gene, Kino and colleagues found that lymphocyte responses to glucocorticoids were indeed blunted. In a detailed analysis, he demonstrated that Brx bound directly to the GR in a ligand-dependent manner and that Brx was required for activation of glucocorticoid-responsive genes by lysophosphatidic acid in vivo. These findings emphasize that Brx plays a role beyond estrogen action and may affect the action of nuclear receptors other than the estrogen receptor via its nuclear receptor-interacting domain.

COLLABORATORS

William H. Catherino, MD, PhD, Uniformed Services University of the Health Sciences, Bethesda, MD
George Chrousos, MD, University of Athens, Athens, Greece
Alan DeCherney, MD, Reproductive Biology and Medicine Branch, NICHD, Bethesda, MD
Paul Driggers, PhD, Uniformed Services University of the Health Sciences, Bethesda, MD
Tomoshige Kino, PhD, Reproductive Biology and Medicine Branch, NICHD, Bethesda, MD
Lynnette Nieman, MD, Reproductive Biology and Medicine Branch, NICHD, Bethesda, MD

For further information, contact segarsj@mail.nih.gov.