Vanderbilt University School of Medicine - The Endometriosis ...

THE ENDOMETRIOSIS ASSOCIATION OPENS A NEW CHAPTER IN RESEARCH PROGRAM AT VANDERBILT From Endometriosis Association Newsletter Volume 29, No. 3 Since 1999, the Endometriosis Association has partnered with Vanderbilt University School of Medicine to fund and coordinate a “dream team” of scientists to research endometriosis (endo). The program has been highly successful, resulting in truly excellent research that has helped move our scientific understanding of endo forward at a fast clip. A second contract was recently completed to continue the partnership for seven more years. To celebrate this benchmark, Vanderbilt hosted a gala, a scientific presentation for other scientists at Vanderbilt, a reception for Vanderbilt dignitaries and members of the Endometriosis Association, and a community educational event. The Endometriosis Association’s partnership with Vanderbilt is unique in the world of science. Never before has a major medical institution made such a bold commitment to true partnership with a nonprofit — that is, Endometriosis Association members, via the headquarters staff, constantly feed information about the experience of endo to the team, who then coordinates it with scientific thought. That powerful combination has made a huge difference and greatly encourages the scientists. Too often scientists work in a vacuum without knowing how their work actually makes a difference for people. The Endometriosis Association has taken many steps to make sure that Vanderbilt scientists understand the major difference they make. As Kevin Osteen, Ph.D., the visionary Director of the Endometriosis Association Research Program at Vanderbilt has written: “I’m glad that the Endometriosis Association sponsored lectures were so well-received . . . such contact with patients and their partners always gives my research team a boost. We work hard, sometimes under circumstances that make us feel isolated. Knowing who we are working for and that our efforts are appreciated makes all the difference.” The Vanderbilt team has four U.S. National Institutes of Health (NIH) grants — an almost unheard of level of funding given the NIH budget restrictions in the last eight years. Osteen and Kaylon Bruner-Tran, Ph.D., Associate Director of the Endometriosis Association Research Program at Vanderbilt University School of Medicine, attribute this to the leverage they can create with the Endometriosis Association’s support. Osteen is the primary investigator for three NIH grants: one examining progesterone failure in the endometrium of patients with endo; another examines the relationship between endo and the failure of a protective anti-inflammatory protein; a third studies the relationship between environmental toxins, particularly dioxins, and endo. Bruner-Tran is the primary investigator for an NIH study to develop a new model of experimental endo that will allow a closer examination of the role of the immune system in the development of endo. Truly, as a recent article in a Vanderbilt publication states, the work has been “highly influential for today’s emerging understanding of endometriosis.” The new understanding of endo, based on many scientific discoveries over the last ten years, paints a picture of a far more complex disease than ever imagined when the Endometriosis Association started twenty-nine years ago. This has increased the excitement among researchers worldwide. Now, if funding can match that excitement, we will perhaps be able to break through to a complete picture of the disease that should open the door to much better treatments and perhaps even a cure and prevention.

At the same time, the team has not forgotten the clinical aspects of the disease. As Esther Eisenberg, M.D., Professor of Obstetrics and Gynecology, and a key member of the Vanderbilt endometriosis team, states, “in harsh cases, on a scale from 1 to 10, the pain is 15.” It was Dr. Eisenberg who adopted a new treatment in her clinical practice in recent years. For patients with intractable pelvic pain, she uses a combination of fish oil and progesterone. As Dr. Eisenberg has noted, even in patients who have come in on high levels of narcotics, this approach has helped. It seems to counteract some of the inflammation that may cause pain and, as the research in the lab shows, the fish oil may even help dampen the impact of dioxin exposure. Osteen and Bruner-Tran shared information on this new clinical research at a panel the Endometriosis Association presented in San Francisco last year. (This was reported on in the Endometriosis Association’s Volume 27, No. 5-6 newsletter.) In addition, the Vanderbilt team’s work has helped lead to potential new treatments. “The core mechanisms of the disease and the potential therapeutic targets are beginning to be revealed,” said Osteen. Our lab has taken a lead in helping pharmaceutical companies identify potential therapies. . . .” One of the requirements in the Endometriosis Association’s contract with Vanderbilt is that the team will always include an international scientist, typically at the junior level when scientists travel for additional training. The newest international fellow is Tianbing Ding, Ph.D. (continued page 2)

(Left to right) Harry Jacobson, M.D, Vice-Chancellor for Health Affairs, Vanderbilt University School of Medicine; Tracy H. Dickinson, Endometriosis Association board member; Mary Lou Ballweg, Endometriosis Association President/Executive Director; Esther Eisenberg, M.D., M.P.H., Professor of Obstetrics and Gynecology and Director of the Division of Reproductive Endocrinology and Infertility at Vanderbilt as well as a Project Scientist/Research Coordinator in the Reproductive Sciences Branch at NIH; Antoni Duleba, M.D.; Kaylon Bruner-Tran, Ph.D., Associate Director of the Endometriosis Association Research Program at Vanderbilt University School of Medicine; Kevin Osteen, Ph.D, Director of the Endometriosis Association Research Program at Vanderbilt University School of Medicine; and Hugh Taylor, M.D. Dr. Duleba, on the faculty of the University of California-Davis, was formerly on the faculty at Yale University, where he and Dr. Taylor, an Advisor to the Association, collaborated with the Vanderbilt team on scientific projects.

1

There are still many questions facing scientists about endo. The Vanderbilt team has noted the following that they find particularly intriguing. l “Is the immunological dimension of endometriosis a cause or a result of the disease? l How might inflammation promote endometriosis, and what is the association with other inflammatory processes in the pelvic theater, such as that leading to irritable bowel? l How does progesterone inhibit inflammation? l What’s the significance of the association between endometriosis and increased exposure to certain environmental toxins? l What underlies the association of ovarian cancer and endometriosis in the ovary? l In what sense is endometriosis an inherited disease? l By way of strengthening anti-inflammatory mechanisms, how effective could nutrition be in inhibiting endometriosis? l Could more powerful, synthetic versions of progesterone stop endometriosis?” “The broad scope of these questions explains why people once typically gave up on finding a cure,” Osteen has said. But as members and donors involved with the Endometriosis Association will agree, we will not give up! With the support and vision of this “dream team” we can find even more answers! New Horizons DVD New Horizons in Understanding Endometriosis and Its Treatments contains all presentations by the panel of experts at Vanderbilt’s gala, including “Basic Therapy of Endometriosis” by Dan Martin, M.D.; “The Science of Developing New Therapies” by Kevin G. Osteen, Ph.D., and Kaylon L. Bruner-Tran, Ph.D.; “New and Future Therapy of Endometriosis” by Esther Eisenberg, M.D., M.P.H. Purchase online or by calling headquarters at 414-355-2200.

KEY FINDINGS FROM VANDERBILT ENDOMETRIOSIS ASSOCIATION RESEARCH Demonstrated a critical role of retinoic acid, the bioactive form of Vitamin A, in controlling normal endometrial expression of matrix degrading enzymes Found that a loss of progesterone sensitivity is a central component of the pathophysiology of endometriosis Identified that in utero and developmental dioxin exposure in mice creates the same endometrial phenotype observed in women with endometriosis. (Recognized by the European Teratology Society as the best Reproductive Toxicology paper of 2007) Discovered an epigenetic link between dioxin action and the loss of progesterone response observed in women with endometriosis Presented evidence that dioxin exposure leads to an altered pathway of cell-cell communication in the endometrium that mimics an inflammatory-like event Discovered developmental exposure of mice to dioxin leads to disruption of endometrial function for multiple generations, suggesting this toxicant can impact endometrial biology thru the germline Demonstrated that nutritional anti-inflammatory agents such as fish oil can provide some protection against the disruptive impact of dioxin on endometrial function Developed a novel model system in which the role of immune cells can be examined in the development, progression, and therapeutic treatment of endometriosis Developed a unique model of surgical adhesions that allows the role of inflammation to be examined during the earliest stages of endometriosis-mediated adhesion development In collaboration with multiple pharmaceutical companies and other NIH-funded investigators, continue to screen new compounds for potential use as therapeutics for women with endometriosis

Laura, Beth, and David Arnold enjoy the reception at Vanderbilt University School of Medicine. The reception was followed by a presentation by a panel of experts from Vanderbilt as well as Dan Martin, M.D., Endometriosis Association Advisor from Memphis, and an invigorating question and answer session. 2

Tracey Crudup-Arata and Scott Arata assist at the Endometriosis Association’s displays at the gala reception.

TRACY H. DICKINSON EPIGENETICS RESEARCH LABORATORY The Endometriosis Association Research Program at behooves us to determine if children exposed at early developmental Vanderbilt University School of Medicine has led the way timepoints demonstrate an increased sensitivity to additional adult in understanding the impact of embryonic* exposure to toxicant exposures and whether repeat exposures are necessary for dioxins. The horrific findings are clear: exposure to dioxins in the the development of adult diseases such as endometriosis.” womb during the early part of pregnancy is toxic, and that toxicity The Vanderbilt team continues: “The Tracy H. Dickinson Epiextends into many generations in the future. This work has helped ex- genetics Research Laboratory will have a strong focus on examining plain why we are now seeing so the potential role of epigenetic many families with endometrioalterations in endometriosissis across generations, and it also associated endometrial dysmakes it clear how important this function. Epigenetics refers research and potential preventato hereditable changes to an tive efforts are! Because of the individual’s genetic make-up, importance of this research and and numerous environmental to honor Endometriosis Associafactors (including TCDD) have tion board member and longtime been found to be epigenetic donor Tracy H. Dickinson, the modifiers. Importantly, TCDD Endometriosis Association has can activate an inflammanamed a new research laboration-like cascade, potentially tory at Vanderbilt “The Tracy H. amplifying the risk of epigenDickinson Epigenetics Research etic modification. Our data has Laboratory.” pointed to the influence of local More and more, science is inflammation in the loss of prounderstanding that the “programgesterone sensitivity observed ming” of the embryo impacts in the uteruses of women with that individual’s functioning endometriosis.” for life. This programming can Thank you to Tracy H. be impacted by the toxins in the Dickinson for making this immother’s body (and also toxins Mary Lou Ballweg, President/Executive Director of the Endometriosis portant work possible! Many the father was exposed to in at Association; Kaylon Bruner-Tran, Ph.D., Associate Director of the other donors also contribute to least two months before concepEndometriosis Association Research Program at Vanderbilt; and the Endometriosis Association’s tion), nutrition, stress, et cetera. Tracy H. Dickinson, Endometriosis Association board member and work at Vanderbilt and other There is now data to support a longtime donor to the Endometriosis Association research programs, research programs, including link between early exposures stand in front of the Tracy H. Dickinson Epigenetics Research Labo- the Harry & Betty Quadracci in the uterus and obesity, heart ratory at Vanderbilt. The Epigenetics Laboratory will continue the family. We and those affected disease, and cancer in addition groundbreaking work of the Endometriosis Association's Vanderbilt by endometriosis appreciate all to endometriosis. Therefore, the team in showing the multi-generational effects of dioxins and related our donors! Endometriosis Association’s scientific concerns. continuing work in this area will Another plaque, honoring the the generous donation of * Embryonic: in early preghave benefits across many areas the Harry and Betty Quadracci family, including Elizabeth nancy, the embryo is laying of human and animal health. Quadracci Harned, Kathryn Quadracci-Flores, Joel Quadrac- down the very beginnings of Here is how the Endomeci, and Richard Quadracci, is also being placed at Vander- what will become organs and triosis Association’s Vanderbilt bilt in honor of their contribution toward the Endometriosis other major functional expresteam describes some of their Association Research Program at Vanderbilt. sion in the future. recent work in epigenetics: “We have recently demonstrated adult endometrial dysfunction in mice following developmental **TCDD: dioxins, specifically, 2,3,7,8-tetrachlorodibenzo-p-di[in the uterus during organ development] exposure to TCDD** oxin — the most toxic of all the dioxins. For more information, [dioxin]. Endometrial changes were markedly similar to alterations see the Endometriosis Association’s book, The Endometriosis observed in the endometrium of women with endometriosis, and it Sourcebook. Order it online or from the Endometriosis Association resulted in reduced progesterone responsiveness and infertility. . . . It headquarters.

3