Until 1993, when Congress passed legislation changing the way clinical trials are conducted, it was possible to bring a drug or device to market without including women in its evaluation. For many years, it was the rule, rather than the exception, to exclude women from the studies that are required to prove the safety and effectiveness of new treatments.
Two seemingly reasonable ideas in particular contributed to this gap in data. One was that women of child-bearing age should not be exposed to experimental risk. The other was that the hormonal changes associated with the reproductive cycle would add a level of complexity to trials that would be unmanageable. Yet excluding women has left major areas of human health unexplored, says Carolyn M. Mazure, Ph.D., a professor of psychiatry who heads the research arm of the Women's Health Program at Yale. “It is essential to study women,” she says, “because the treatments and procedures developed on men may not always be appropriate for women.” And while cyclic variation does bring complexity to many research questions, scientific methods have evolved to better handle that complexity. In fact, since enactment of the 1993 legislation, the inclusion of women in trials must be carefully considered when federal dollars are used.
Just how far has the issue evolved during the past decade? At Yale, one indication came in February with the announcement of a $6.5 million grant for women's health research. The five-year award from The Patrick and Catherine Weldon Donaghue Medical Research Foundation of West Hartford, Conn., will support interdisciplinary research that advances knowledge in women's health. One of the most exciting aspects of the new program is its potential to bring together researchers from a wide range of scientific fields, each with a unique perspective on how gender may factor into disease processes and health. “We don't want people to think that women's health must be a separate area of research,” says Dr. Mazure, who directs the Ethel F. Donaghue Women's Health Investigator Program at Yale, the new entity created by the grant. “Instead, the hope is that more and more investigators will think about gender in the research they are actively pursuing, and think more about research collaborations to answer relevant questions.”
The Donaghue funding was announced at a press conference in Yale's Medical Historical Library, a balconied room with a 50-foot ceiling, leather sofas, reading tables, a massive stone fireplace and books lining every square foot of wall space. “This is the perfect setting for this special event,” Dean David A. Kessler, M.D., told the group. “Research has always been central to the school's academic mission. That commitment will continue to be at the very core of all we do here in the future.” The Donaghue support, he added, provides the opportunity to expand that commitment “while building on an already exemplary program in women's health.”
In addition to its research component, the Women's Health Program at Yale has developed new models for patient care and the training of physicians, and in 1996 was designated by the U.S. Public Health Service as one of the first six Centers of Excellence for women's health nationally. According to Director Janet B. Henrich, M.D., advances in women's health overall will depend to a large extent on good science. “We want to add to the knowledge base,” she says, “with the ultimate goal of improving care for women. The goal is to integrate these elegant findings from the laboratory into practice.”
During late winter and spring, Donaghue program staff sent out requests for applications to researchers around the medical school, University and at each of the Yale-affiliated hospitals. In total, 81 applications were submitted by investigators in 15 medical school departments and other corners of Yale including the School of Nursing, departments of chemistry, sociology and psychology, the Institute for Social and Policy Studies and the John B. Pierce Laboratory. “If we were able to fund all of them,” says Dr. Mazure, “we would need $10 million.” Among the topics: the influence of sex-related hormones in a variety of disorders including cardiovascular disease and osteoporosis, the molecular mechanisms of breast, cervical and ovarian cancer, gender differences in surgical recovery, HIV risk behavior in women, the relationship between health and employment in women, the relationship of breast cancer to environmental exposure variables, and the biological basis for a variety of psychiatric conditions that women experience at a higher rates than men, such as depression, eating disorders and post-traumatic stress disorder following abuse. The program's scientific review committee was to meet in July, with the first awards expected in August. Subsequent requests for research applications will go out each year to encourage new work.
Three pilot projects
Even before the Donaghue program was announced in February, women's health research at Yale was off and running, supported by modest startup grants during the 1997-98 academic year. Three of those projects, co-sponsored by the Department of Diagnostic Radiology, the Claude D. Pepper Older Americans Independence Center and the Yale Liver Center, illustrate the kinds of research topics Dr. Mazure and her colleagues hope to shed light on.
Diagnostic radiologist Liane E. Philpotts, M.D., saw a difficult clinical problem affecting breast cancer patients and has used the women's health funding to look for a solution to improve diagnosis and quality of life. Because the disease often spreads to the axillary nodes (glands in the armpit), patients usually have the nodes removed surgically as a precaution. The complications of surgery include swelling, significant pain and decreased range of motion. Dr. Philpotts is evaluating how well magnetic resonance imaging may be able to show the spread of cancer cells to the nodes. “If we can say they look fine, maybe we won't have to take them out in the future,” she says. “To the patient, it could make a fairly big difference in terms of comfort and morbidity.”
Another researcher who received program support is endocrinologist Karl L. Insogna, M.D., who studies the underlying mechanisms of osteoporosis. This weakening of the skeleton, more common among women than men, occurs at a rate three to four times faster after menopause than in younger women. Hormone replacement therapy has been proven to slow and even halt the damage. Because estrogen therapy is known to carry health risks as well as benefits, the search is under way for more specific agents that might interfere with bone breakdown.
For the last several years, Dr. Insogna and colleagues have been working to explain the mechanism by which bone loss occurs. Starting with the knowledge that parathyroid hormone (PTH) regulates bone breakdown and the metabolism of calcium, they looked for clues to how estrogen is involved in that process. Last year they identified a molecule produced by osteoblasts, the cells that form bone tissue, that appears to play an important role. Interleuken-6 (IL-6), says Dr. Insogna, is required in order for parathyroid hormone to break down bone. With support from the Women's Health Program, he and his colleagues published data correlating high blood levels of IL-6 with higher rates of bone breakdown in women with disturbances in parathyroid function and are chasing down new leads that may one day improve treatment.
Allen E. Bale, M.D., associate professor of genetics, is searching for genes associated with hereditary breast cancer. He has developed automated technology for determining the DNA sequence of BRCA1 and BRCA2, two genes that are frequently altered in families with breast cancer. In analyzing a large series of breast cancer kindreds, he found that a significant number lacked mutations in these genes, and he is searching for new genes that may underlie the disease.
One possible candidate is the gene for Cowden syndrome, a rare disorder associated with breast, thyroid and skin cancer. Dr. Bale thinks that mild mutations in the Cowden syndrome gene might cause breast cancer alone without thyroid or skin disease. “Beside the Cowden gene, there must be other genes we haven't yet discovered,” says Dr. Bale. “We're continuing to look for them so we can offer diagnostic testing and early detection of breast cancer to more families.”
A short history
Women's health came into focus at Yale in the early 1990s, as more women entered the faculty and as Yale practitioners in internal medicine, obstetrics and gynecology, and other specialties began discussing the need for a streamlined clinical service where women could receive care in a more coordinated fashion. At about the same time, the issue of women's health was coming sharply into focus in Washington. The General Accounting Office issued a detailed report in 1990 documenting the disparity between women and men as subjects in federally funded clinical research. The same year, the National Institutes of Health created the Office of Research on Women's Health, followed in 1991 by the establishment of the Office of Women's Health at the U.S. Public Health Service. Meanwhile, the NIH was launching the Women's Health Initiative, a long-term study of more than 100,000 women that will seek to document the causes of disease and premature death in women from all social and economic groups.
Dr. Kessler, who was the Food and Drug Administration commissioner from 1990 to 1997, recalls asking his staff in the early '90s, “ 'Should we have required women to be included in the clinical trials?' Some of the agency's best reviewers said no, that the pharmacokinetics and pharmacodynamics of the drugs worked the same in men as in women,” Dr. Kessler recalls. “But later, as more studies were done, they started looking at the data and saying it really did make a difference.” Perhaps the most influential piece of legislation relevant to women's health is contained in the NIH Revitalization Act of 1993, which requires that an appropriate number of women be included in clinical trials that are federally funded. One of the people who shepherded the act through Congress was Ruth J. Katz, J.D., M.P.H., now the School of Medicine's associate dean for administration. As counsel to the U.S. House of Representatives subcommittee on health and the environment, she organized the hearings for the act and helped write the legislation that President Clinton signed into law. When she arrived at Yale last July, one of the first projects she was given was to help pull together the agreement that became the basis for the Donaghue Foundation grant.
The Donaghue research initiative is a key component of a highly active Yale program that drew the attention of Health and Human Services Secretary Donna Shalala, who named it one of the first six Centers of Excellence in Women's Health. This spring, the designation and funding were renewed for a second 18-month period, allowing the faculty here to focus in greater depth on issues concerning patient care and physician education as well as research.
In its first incarnation as the Women's Health Initiative at Yale, the program provided a one-stop service catering to women throughout New Haven and Fairfield counties. Led by Dr. Henrich and Florence Comite, M.D. '76, HS '76-78, it also brought together a diverse group at the medical center who were focused on women's health issues and who began discussing the framework for a broader program. Gerard N. Burrow, M.D. '58, then the medical school dean and now a special advisor to President Levin for health affairs, saw a need to combine the clinical progress with advances in education and research. “The exclusion of women was so ingrained,” he recalls of his own research training in the 1950s, “that even as students working in the lab, we were told not to include female mice.” But over the last several decades that attitude has changed, and not only in the lab. Yale established the Office of Women in Medicine in 1975 and began actively recruiting women to the faculty and student body. Four years ago, the medical school enrolled more women than men in its entering class for the first time in its history. “The last 20 years,” says Merle Waxman, M.A., associate dean and director of the Office of Women in Medicine, “has seen the dissolution of many of the barriers that hindered the entry of women into some of the specialties.” As a result, says Dr. Henrich, more women are in a position to pursue research that is relevant to women, which may in part explain the groundswell of interest that bubbled to the surface in 1990.
According to Dr. Henrich, who spent 18 months at the NIH working with the Office of Research on Women's Health, one of the major challenges in delivering care to women stems from a division that dates back 75 years or more. “There's a fragmentation that has developed more around women than around men, with both internal medicine and obstetrics and gynecology providing primary care,” she says. “What this has done is separate reproductive and non-reproductive issues in a way that became institutionalized early in the century.” This schism produces gaps in care due to a lack of communication, Dr. Henrich says. “There's been a lot of talk about developing a women's health specialty,” she adds. “I have a strong bias against that because I think it would only lead to greater fragmentation of care. We need the expertise of diverse specialties.”
In early 1996, the Yale activities were reorganized as the Women's Health Program at Yale, with Dr. Henrich as its leader. She and many of her medical school and hospital colleagues have spent long hours hashing out new methods for organizing women's care. A committee chaired by ob/gyn associate professor Ervin E. Jones, M.D., Ph.D., and assistant clinical professor of psychiatry Robert M. Rohrbaugh, M.D., is developing a proposal for a required medical school clerkship in women's health that would draw from the departments of Internal Medicine, Obstetrics and Gynecology, and Psychiatry. Similar plans are being considered for residency training. “The idea,” says Dr. Henrich, “is to have the internal medicine residents learn more about reproductive issues and the ob/gyn residents better prepared to recognize and treat hypertension, diabetes and thyroid disease. The goal is to increase the knowledge base.”
That seems to be happening at Yale over a relatively short period of time. Lawrence S. Cohen, M.D., HS '58-65, a cardiology professor and special advisor to the dean, was among those involved in the school's early discussions of women health and served on the committee appointed by Dean Burrow in 1992. “They've more than exceeded the expectations in a very short period of time. Women's health is off to a great start.” The true test of the research program's success, says director Mazure, will be seen in the clinical setting several years down the road. “Politically, a lot has happened to move this all forward,” she says, “but the science has changed, too. Everybody knows that with most diseases, there isn't just one factor that influences onset or treatment outcome–rather there are many factors. Now we have tools to understand multiple variables in health outcomes.” What will be the practical value of this investment in research? “There's the promise of very significant transfer of this knowledge to clinicians and to the community,” says Dr. Mazure. “This initial funding will help us generate a lot of new research that can change both the health and health care of women.” YM