EXECUTIVE SUMMARY

Many people in the biomedical research community, including those who fund research and those who conduct it, have detected what they believe to be signs of weakness in the research capabilities of academic departments of obstetrics and gynecology (OB/GYN).

If weakness, indeed, exists, its implications would be extensive, both for present and future generations: research that might be undertaken in these departments has great potential for improving the health of women of all ages and the outcomes of pregnancy, and for reducing health care expenditures for such conditions as the sequelae of low birth weight. This gives a sense of urgency to questions about OB/GYN research capabilities. Below are a few examples of large-scale problems that could be ameliorated by a strengthened OB/GYN research capability:

  • the percentage of infants who are born weighing less than 2,000 grams, which has remained at about 7 percent throughout the 1980s;

  • pregnancy-induced hypertension, which complicates about 2.6 percent of all deliveries and increases the risk of poor outcomes for both mother and child;

  • ectopic pregnancies, which have increased every year since 1970 and have a fatality rate of 42 per 1,000 cases;

  • infertility, which affects about 10 percent of married couples who want children; and

  • an epidemic of sexually transmitted diseases that include 4 million cases annually of chlamydial infection and 24 million people in the United States infected with human papillomavirus, many types of which are associated with cervical carcinomas and severe dysplasia.

To address the question of whether the field of OB/GYN lacks a sufficiently vigorous research capability, the National Institute of Child Health and Human



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Strengthening Research in Academic OB/GYN Departments EXECUTIVE SUMMARY Many people in the biomedical research community, including those who fund research and those who conduct it, have detected what they believe to be signs of weakness in the research capabilities of academic departments of obstetrics and gynecology (OB/GYN). If weakness, indeed, exists, its implications would be extensive, both for present and future generations: research that might be undertaken in these departments has great potential for improving the health of women of all ages and the outcomes of pregnancy, and for reducing health care expenditures for such conditions as the sequelae of low birth weight. This gives a sense of urgency to questions about OB/GYN research capabilities. Below are a few examples of large-scale problems that could be ameliorated by a strengthened OB/GYN research capability: the percentage of infants who are born weighing less than 2,000 grams, which has remained at about 7 percent throughout the 1980s; pregnancy-induced hypertension, which complicates about 2.6 percent of all deliveries and increases the risk of poor outcomes for both mother and child; ectopic pregnancies, which have increased every year since 1970 and have a fatality rate of 42 per 1,000 cases; infertility, which affects about 10 percent of married couples who want children; and an epidemic of sexually transmitted diseases that include 4 million cases annually of chlamydial infection and 24 million people in the United States infected with human papillomavirus, many types of which are associated with cervical carcinomas and severe dysplasia. To address the question of whether the field of OB/GYN lacks a sufficiently vigorous research capability, the National Institute of Child Health and Human

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Strengthening Research in Academic OB/GYN Departments Development asked the Institute of Medicine to convene a study committee. The committee took OB/GYN research to mean research that would be most advantageously conducted in academic departments of OB/GYN, whether for reasons of patient availability, locus of expertise, or because of the particular concerns of the physicians in the specialty. At the heart of this activity are investigators who are trained in the specialty of OB/GYN but who often work alongside physicians from other specialties and investigators trained in basic science. An integral part of the background to the study is widespread distress about the general state of clinical investigation and the diminishing interest and participation of physicians in research. Thus, other clinical specialties confront many of the difficulties that OB/GYN departments face in generating and sustaining research manpower. Although the committee's charge was confined to finding ways of advancing and strengthening OB/GYN research, to the extent that the solutions recommended here are helpful to other disciplines, there may be additional benefits from this study. The committee viewed its charge as encompassing three major tasks: developing indicators of the research strengths of academic departments of OB/GYN to assess whether a problem exists; examining the causes of problems or the barriers to improvement and identifying possible solutions; and developing a research agenda for OB/GYN that would both contribute to the resolution of the question of whether a problem in OB/GYN research exists and provide priorities for future research. The committee used several mechanisms to gather the information necessary to fulfill its charge. It held four meetings of the full committee and established two task forces, one on NIH and the other on the research agenda. To learn about the concerns of the OB/GYN academic research community, the committee sent letters to all chairs of academic OB/GYN departments in the United States and Canada; it received replies from 50 individuals, some of whom responded as representatives of leading OB/GYN professional societies. The committee also commissioned background papers and authorized interviews of a wide array of knowledgeable individuals.

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Strengthening Research in Academic OB/GYN Departments The Current Situation Data on total federal support of research or research training in academic departments of OB/GYN were not available, but the committee was able to examine detailed data on NIH support: NIH funding of research in academic departments of OB/GYN increased from $16.1 million in 1978 to $46.5 million in 1989, representing an increase of 180 percent in current dollars and 43 percent in constant dollars. However, the increase in the proportion of total NIH resources going to OB/GYN departments was very small. More importantly, departments of OB/GYN continued to receive a small share (7.5 percent in 1989) of the funds of the National Institute of Child Health and Human Development (NICHD)—the institute that provides the majority of funds from NIH to departments of OB/GYN and that has a mandate to improve reproductive health. Between 1980 and 1989, OB/GYN had a low success rate, compared with other departments, in securing funding for its NIH grant applications. Success rates were 37.6 percent for internal medicine, 33.4 percent for radiology, 31.0 percent for pediatrics, and 28.5 percent for surgery—but only 26.5 percent for OB/GYN. Physicians in departments of OB/GYN made a particularly poor showing. Not only did they submit relatively few applications, but their success rate was lower than that of Ph.D.s from OB/GYN departments and of M.D.s in the four comparison departments noted above. There were relatively few applications for or awards of NIH training and career development awards to departments of OB/GYN, particularly for physicians. It is estimated that only 50 physicians in departments of OB/GYN received NIH research training or career development support between 1980 and 1989—a finding that bodes ill for the future of OB/GYN research manpower. Initiation of the Reproductive Scientist Development Program is a promising sign. This program provides postresidency or postsubspecialty fellowship support for two or three years of training in a basic science laboratory. Grantees thereafter spend three years, with at least 75 percent of that time in research, as junior faculty in the sponsoring department of OB/GYN. The program, which generally accepts three individuals per year, is funded jointly by NIH, OB/GYN professional groups, and industry. Information on support of research and research training by the private sector provides a less complete but equally disturbing picture, particularly with

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Strengthening Research in Academic OB/GYN Departments regard to training future generations of investigators. Industry contributed $19.3 million to research in departments of OB/GYN in 1990. It is not known how this level of funding compares with that of past years. In earlier decades. organizations such as the Josiah Macy, Jr., Rockefeller, Ford, and Mellon foundations played an important role both in supporting research and training and in providing early support for the careers of many of today's most prominent investigators in OB/GYN. Today, however, these foundations have withdraw or radically reduced their support of research in reproduction and of the training of young investigators who intend to pursue careers in reproductive research. Private-sector support of training for young investigators now comes mainly from industry and from OB/GYN professional associations and their foundations. It is estimated that six to eight physician/scientists each year are recipients of major training support from these sources. The pattern of NIH and private funding confirms what knowledgeable individuals have known for a long time: only a handful of the nation's academic departments of OB/GYN host the kind of research enterprise that provides a truly vibrant environment for research training. There are several specific grounds for this statement. Only me departments reported receiving more than $2 million in federal funds in 1990. The involvement in research by faculty of departments of OB/GYN is low by two measures: the percentage of M.D.s and M.D./Ph.D.s who are principal investigators on NIH or Alcohol, Drug Abuse, and Mental Health Administration grants, compared with other clinical departments; and the proportion of M.D.s and M.D./Ph.D.s who spent more than 20 percent of their time in research activities in 1990 compared with departments of internal medicine in 1983. (This last is admittedly a poor comparison both because of the different time periods and because the procedural demands of OB/GYN make it more like a department of surgery than a department of medicine; however, it is the only department for which comparison data are available.) Finally, there are large numbers of women at the lower academic levels of departments of OB/GYN whose full participation and productivity in research is not likely to occur unless attention is paid to their special requirements, which may include flexible work arrangements and extended time to tenure. Committee Findings All pertinent data, as well as the impressions gathered by the committee in interviews and from responses by OB/GYN department chairs to a request for

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Strengthening Research in Academic OB/GYN Departments information, indicate present as well as potential future weakness in the research capabilities of academic departments of OB/GYN. In particular, there is cause for acute concern about the research capabilities of physicians in such departments: too few are entering research, and those who do are often not competitive with their Ph.D. colleagues or with physicians in other disciplines. More ominously, the future is compromised because there are too few centers of excellence in OB/GYN research that can serve as research training grounds, and because the level of support for the next generation of investigators is not sufficient to sustain, let alone expand, existing research capabilities. Although it is appropriate for many departments of OB/GYN to preserve their clinical focus, it is also important to expand the number of departments that are competitive players in the research arena, so that OB/GYN can fulfill its potential for improving the health of women. Findings Related to Career Choices It is vital for the health of the OB/GYN research enterprise that individuals with the talent and inclination for research be identified early and that obstacles to their growth as investigators be diminished. In particular, since women represent nearly half of all OB/GYN residents and are therefore a very significant component of the pool from which investigators are drawn, it is important that they not be lost to research because of the particular obstacles they face. These include coping with pregnancy and childcare during crucial early faculty years; isolation from traditional information and support networks that guide young investigators; and a dearth of women role models and mentors. OB/GYNs who intend to pursue a career in research must complete a four-year residency, usually followed by two to three years of subspecialty fellowships. It is difficult, however, to interleave research training with clinical training; as a result, these physicians are not equipped with the methodological tools for research nor with the basic science knowledge that would allow them to undertake investigation in the molecular aspects of biology—if that is where their interests lie. Acquiring this knowledge requires at least two to three years. Many in the field have noted that much of the education of the generalist OB/GYN is wasted when an individual selects a subspecialty. Some specialties have made arrangements that allow those destined for an academic career to reduce the time needed to complete clinical and research training. The committee found that the extended duration of training for a physician

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Strengthening Research in Academic OB/GYN Departments investigator in OB/GYN and the difficulties of interleaving clinical and research training deter some individuals who would otherwise enter a research career. As a result, there is an urgent need to reexamine OB/GYN residency and subspecialty training requirements to decrease the total time needed to tram academicians. OB/GYN, like other clinical departments, loses investigators because of the discrepancy between practice and academic income. Data show little difference in this income discrepancy between OB/GYN and other specialties, but a young academician (under the age of 36) earns only approximately 80 percent of the earnings of his or her peers in practice. The experience of many academicians is that this gap (particularly if combined with high debt) deters some potential investigators. A heartening note for OB/GYN is that the specialty choices of women physicians may be driven less by income than by other considerations, suggesting that they may be less deterred from investigation by the difference between academic and practice income if their other needs are met. Debt, when combined with the many other deterrents to an investigative career, does result in the loss of talented individuals from the pool of OB/GYN investigators. Although there is little information on the role of debt in the decision to enter a career in investigation, analysis of the income needed to repay various levels of debt shows that entry-level academic salaries—let alone training and fellowship stipends—do not allow for comfortable repayment of the average debt accrued by the time an individual enters OB/GYN residency. Furthermore, anecdotes abound of individuals in OB/GYN who are unable to pursue an inclination for research because of the burden of debt. The income that OB/GYNs can expect from practice would make debt repayment less burdensome and practice an attractive alternative. Findings Related to NIH and Other External Support Although the weakness of OB/GYN research stems in part from factors within the discipline, external factors also play a role. The committee therefore deliberated over what might have caused foundations to decrease their support of research and training in reproductive science, and whether there might be factors at NIH that work against OB/GYN research. In the past, foundation support (e.g., from the Mary R. Markle, Josiah Macy Jr., Rockefeller, Ford, Mellon foundations), was an important factor in the OB/GYN research enterprise and in the training and development of today's

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Strengthening Research in Academic OB/GYN Departments OB/GYN investigators and academic leaders. These foundations have either withdraw from or substantially diminished such support. The committee found cause for alarm in this decline—which appeared to be the result of changes in foundation leadership, changes in the magnitude of government support, and a sense that the interests of OB/GYN investigators do not sufficiently meld with the interests of the foundations. The absence of an OB/GYN intramural program at NIH places OB/GYN at a disadvantage in several ways. In particular, an outstanding training and research environment is lost. Efforts by individuals in the OB/GYN community and by Congress have resulted in welcome moves to establish intramural programs in OB/GYN at NICHD and the National Cancer Institute (NCI). The effectiveness of these efforts points to the importance of leaders of the discipline engaging themselves in endeavors to advance OB/GYN research. OB/GYN is funded primarily by NICHD, whose principal focus is not OB/GYN and whose staffing reflects this lack of emphasis on the reproductive sciences. As a result, OB/GYN lacks the strength that a focal point within the NIH provides, and it also lacks NIH leaders for whom enhancing the field is a high priority. This, too, puts the discipline at a disadvantage. OB/GYN is sparsely represented on NIH study sections—in 1989, only 3 members of NIH initial review groups listed OB/GYN as their area of expertise, compared with 21 in surgery, 19 in pediatrics, 124 in dentistry, and 117 in internal medicine. Despite this lack of representation, however, there is no evidence that applications from OB/GYN receive unbalanced reviews. Scientific Review Administrators possess valuable knowledge that could enable investigators to improve their grant applications. Findings Relating to Departments of OB/GYN There is a pervasive sense among chairs of departments of OB/GYN that they operate in an environment in which it is particularly difficult to conduct research. For example, high salaries must be paid to recruit OB/GYNs into academia. In 1990, average salaries for M.D. assistant professors in OB/GYN departments were $121,500, and them are reports that today $150,000 is needed to recruit newly qualified subspecialists. These salaries can only be supported if practice income is substantial; faculty must therefore spend significant time in clinical activities—often at the expense of investigation. The need to generate income to support high salaries also makes it difficult to protect the time of young faculty to allow them to gain the experience necessary to become independent investigators. Added to this financial burden is the fact that many

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Strengthening Research in Academic OB/GYN Departments OB/GYN departments provide large amounts of uncompensated care. The committee thus concluded the following: Academic departments of OB/GYN face particular difficulties in establishing the infrastructure for research and expanding their research capability. Two central problems are the need for clinical income to support salaries and the difficulty of sustaining young investigators until they become independent. Most importantly, chairs of OB/GYN departments play a pivotal role in establishing the importance of research in a department, securing external support and providing internal leadership. Three critical areas for their leadership are ensuring a cross-subsidy of research by clinical income, recruitment of promising investigators, and establishing research collaboration with other departments. Findings Related to Professional Organizations The professional organizations of a discipline play a role in informing members of the discipline, and others, of the priorities and values of the discipline and in enlisting members in efforts to further those priorities. Thus, OB/GYN professional organizations have considerable opportunities to encourage young people who may be considering research careers, to assert to the discipline the importance of supporting research, and to ensure that influential groups and decision makers are apprised of the potential social and financial return on investment in OB/GYN research. The ethos of a discipline determines its direction. In the case of OB/GYN, the discipline has not developed a critical mass of leaders for whom the advancement of research within the specialty is a high priority. This lack reflects the small number of academic departments of major research status: 38 departments receive no federal research funds; 10 departments receive 50 percent of the NIH funds that are directed to departments of OB/GYN; and there is substantial agreement among knowledgeable people that between 6 and 12 departments can be counted as serious research centers. There has been a recent surge of interest in research to improve the health of women. This is reflected in a major new research initiative proposed by Bernadine Healy, director of NIH, the establishment at NIH of the Office of Research on Women's Health, and an array of legislative proposals from

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Strengthening Research in Academic OB/GYN Departments Congress. The emerging realization of a need to foster research on issues related to women's health offers an unprecedented opportunity to make the case for the role of OB/GYN research in women's health and the need to support OB/GYN research. However, this opportunity will be missed unless vocal OB/GYN leaders emerge. Despite what appears to be a generally gloomy picture, several encouraging events have occurred in the area of OB/GYN research. Organizations are supporting the training of investigators through such programs as the Reproductive Scientist Development Program and the James Kennedy Fellowship Award. In addition, the American College of Obstetricians and Gynecologists (ACOG) and other OB/GYN groups have become engaged with groups concerned about strengthening women's health research. Interest in stimulating research has also been expressed by the Council of University Chairs of the Association of Professors of Gynecology. There are lessons to be learned from activities undertaken by other specialties that are attempting to stimulate interest in research. One such example is the Office of Research of the American Psychiatric Association, which undertakes numerous activities to promote research. Committee Recommendations The committee concluded that, in order to accomplish the proposed agenda of important research it is necessary to strengthen the OB/GYN research enterprise. The highest priority should be the building of physician research manpower so that more departments of OB/GYN would be able to successfully compete for research support. The committee therefore focused its recommendations on ways of recruiting and sustaining OB/GYNs in investigative careers, and on developing research capabilities in departments that have the potential to become first-rank centers of OB/GYN research. The committee was also acutely aware of the interaction between research manpower and the research funding needed to strengthen investigation. First-rate investigators must be given time to develop, but this cannot occur in the absence of adequate funds to support their work. Similarly, funds will be forthcoming only if first-rate investigators are available to use them. Therefore, in addition to recommendations to strengthen physician research manpower, the committee considered strategies that would result in increased funding for OB/GYN research. Investigation in a particular field will thrive only if those who fund research are knowledgeable about its importance. The research agenda that constitutes Chapter 6 of this report therefore emphasizes the

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Strengthening Research in Academic OB/GYN Departments significance of the proposed research to the prevention, cure, or amelioration of major health problems. In addition, the committee encourages OB/GYN leaders to educate decision makers and to stimulate support for OB/GYN research. The committee was aware that many of the problems being confronted by the discipline are also faced by other clinical departments that are trying to develop or sustain clinical investigation. This does not lessen the problems for OB/GYN. Moreover, each clinical discipline has unique characteristics that must be accommodated in arriving at solutions to its problems. No one entity bears total responsibility for this effort. Rather, the following recommendations are directed toward those in positions of leadership at NIH and in foundations, in the departments of OB/GYN, and, most importantly, in the profession of OB/GYN itself. This is the main source from which must flow the leadership that is the prerequisite for development of a strong research community. The committee's conviction that members of the discipline of OB/GYN must play leading roles in strengthening support for research in the profession itself and in the organizations that fund training and research underlies many of the following recommendations. Recommendations for NIH and NICHD NICHD program staff should exercise to the fullest extent possible their ability to target training support to expand the number of research training opportunities for physicians in OB/GYN. The committee also recommends that NICHD tailor another career development award to OB/GYN physicians. Because of the importance of the program, NICHD should continue to sustain the Reproductive Scientist Development Program. Institutes at NIH whose missions include areas of science to which OB/GYN contributes should affirm their commitment to reproductive health and ensure its appropriate priority in their programs. The committee believes that there is an urgent need for changes that emphasize the importance of OB/GYN research. Actions that would help overcome some of the problems OB/GYN research now confronts might include the National Institute of Child Health and Human Development's changing its name to signal to the public and institute staff its commitment to and responsibility for reproductive health. NICHD could also recognize the importance of programs in reproductive health by establishing the position of deputy director for reproductive health or by appointing a board-certified OB/GYN to the position of deputy director. Further actions that might be considered by NICHD include increased representation of

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Strengthening Research in Academic OB/GYN Departments OB/GYN on its staff, and the development of requests for applications (RFAs) on high-priority OB/GYN research topics identified in institute plans. NIH should develop a system to track OB/GYNs who are receiving federal training and career development support. Recommendations for Other External Support Congress should ensure the success of recent initiatives to establish intramural programs in OB/GYN by appropriating the necessary funds. Leaders of the profession of OB/GYN have the responsibility to educate and inform those in decision-making positions about the importance and promise of an intramural program of OB/GYN research. Decision makers in foundations that are concerned with the development of scientific personnel—or with population problems, women's health, cancer, pregnancy outcomes, and other topics that OB/GYN is well positioned to address—should be aware of the role that their support of training and research could play at this crucial time in the development of OB/GYN research. A foundation should set up a program to assist the advancement of potential research leaders. The Markle Scholars Program and other efforts to develop academic leaders should be examined to determine which of their characteristics should be replicated. Recommendations for Which Multiple Groups Have Responsibility The committee recommends that a program to alleviate the burden of debt (e.g., loan forgiveness, deferral of repayment, targeted fellowships or awards that eliminate the need to recur further debt, etc.) be established for physicians qualified in the specialty of OB/GYN who have demonstrated a serious intention to pursue a career in research. Program costs will not be large and should be home by a consortium of OB/GYN professional associations, the pharmaceutical industry, academic departments of OB/GYN, and the Public Health Service. Professional groups and other private-sector organizations that support the Reproductive Scientist Development Program should ensure its stability through a long-term commitment of resources.

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Strengthening Research in Academic OB/GYN Departments Medical Abortifacients Identify an antiprogestin that can be used as a substitute for RU 486 in a new medical abortifacient. Test combinations of an antiprogestin, anordrin analogs, progesterone synthesis inhibitors, and prostaglandins in pregnant animals to determine the lowest effective dosages in terminating pregnancy. Determine the window of effectiveness during the postcoital period when the combined drugs could be most effectively administered. Select the most promising combination of drugs for small-scale clinical trials, and perform the appropriate toxicology. Develop an appropriate delivery system so that the drug combination could be administered in only one clinical visit. Investigate the acceptability of new delivery systems to users and providers. Infertility A structured, comprehensive research program, including an epidemiologic description of the etiologies of infertility and basic research in cervical, tubal, and sperm development and function, would both expand our knowledge and the therapies available for infertile couples. Specific disease processes associated with infertility, such as endometriosis and tubal adhesions, need investigation. The new reproductive technologies of in vitro fertilization and gamete intrafallopian transfer (GIFT) offer a tremendous opportunity for understanding the specific cellular processes of human reproduction. Epidemiology Research is needed on the effect of chemical contaminants on sperm and oocyte function. In addition, more research on the effect of such substances as alcohol, tobacco, and drags on gametogenesis and fertilization is necessary. Firm, normative data on normal fecundity and fertility, and a multitude of other reproductive issues, are needed for comparative data as the newer reproductive technologies continue to expand. There is a need to ascertain the relationship between age and human (both male and female) fertility.

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Strengthening Research in Academic OB/GYN Departments Cervical Physiology and Function Research is needed to understand the physical and chemical properties of cervical mucus that facilitate sperm motility and to develop solid criteria for diagnostic tests of mucus function. Study is needed of the relationship of cellular and antibody mediated immunologic function to normal sperm motility, as well as to the prevention of pelvic infection. More research is needed to define normal cervical function and immunology with the goal of improved therapies for cervical factor infertility. Fallopian Tube Function New techniques must be developed to evaluate tubal function and to describe the specific etiologies of abnormal tubal function. Studies are required to assess ciliary function and the role of muscular contractions in transporting the embryo into the uterus. The area of steroid and growth factor interactions with tubal epithelium requires a major research commitment. Normal implantation in the endometrium is modulated by a number of growth factors, and research into the role of growth factors in tubal function may provide important answers on the etiology and genesis of tubal ectopic pregnancies. Endometriosis Research is needed on the relationship of endometriosis to infertility. Basic and clinical research into questions of who needs treatment and what is the best modality could yield an excellent societal return on investment. Male Infertility Research at the basic science level must be initiated before a true understanding of the causes and possible treatments of male infertility can be proposed.

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Strengthening Research in Academic OB/GYN Departments Research is needed into sperm-oocyte interaction, including details of fertilization and chromosome exchange, sperm acrosome reaction, sperm maturation, sperm metabolism, and detailed sperm morphology. In Vitro Fertilization and New Reproductive Technologies Research using appropriate animal model systems in the primate and research utilizing human follicular fluid, corona, and cumulus cells should investigate the molecular biology of human fertilization and early cell division. Research should be conducted on the involvement of growth factors, activation of the embryonic genome, and metabolism in the very early embryo. Premenstrual Syndrome The metabolism and bioactions of progesterone and its metabolites are fruitful areas for research to define the biological muses of symptoms referred to as the premenstrual syndrome. The Brain and Reproduction The nature, specific localization, and mode of operation of the gonadtrophin-releasing hormone (GnRH) pulse generator must remain a critically important subject for intensive investigation at the systems, cellular, and subcellular levels. While estradiol can initiate the preovulatory gonadotropin surge in the absence of changes in GnRH production, what actually happens during the normal menstrual cycle is not known and should be investigated. The quantitative role of neuroendocrine deficits in the causation of infertility in women must be defined. The mechanisms whereby ''stress'' inhibits the GnRH pulse generator and consequent ovarian function must be elucidated. The mechanisms whereby lactation, severe exercise, and caloric deficits lead to amenorrhea and infertility must be characterized. The mechanisms of action of a variety of modulators of GnRH pulse generator activity must be elucidated.

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Strengthening Research in Academic OB/GYN Departments It is now clear that the control of LH and FSH secretion by the pituitary gland is not the same. The role of activins and inhibins and other factors in the control of FSH secretion must be investigated in a physiological context. The mechanisms that cause the inhibition of the GnRH pulse generator shortly after birth and its reawakening at the time of puberty remain a complete mystery. The initiation of puberty continues to be a central, unsolved problem in human biology. The functional relationship between the hourly activation of the GnRH pulse generator and "hot flashes," synchronous events in postmenopausal women, should be a subject of concerted study with the aim of discovering the physiological basis of the phenomenon and its potential alleviation by alternatives to estrogen therapy. Menopause Long-term, prospective studies to evaluate the effects and side effects of combinations of estrogen and progestins in the treatment of postmenopausal women should be conducted. Studies are needed to explain why very few postmenopausal women are treated with estrogen. Studies are needed to discover and assess the risks of adding progestin to estrogen treatment. Oncology Ovarian Cancer What are the factors that predispose the development of ovarian cancer? What preventive measures can be identified that could be implemented on a wide scale? Is there a cost-effective method for early detection, such as the development and refinement of sensitive vaginal ultrasound, that would greatly improve survival? Which genetic alterations, if any, play a causative role in neoplastic transformation merits further investigation.

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Strengthening Research in Academic OB/GYN Departments Are there methods, including human minor clonogenic assay, which can provide useful information and important clues to guide therapists to the optimal form of chemotherapy for specific patients? What new agents or new approaches can be developed to kill the cancer cell—for example, novel delivery systems or specialized treatment approaches such as the improved use of intraperitoneal therapy as well as the immunologic development of new biological response modifiers? Uterine Neoplasms Can transvaginal ultrasonography become a cost-effective tool for early uterine cancer detection, similar to the project described in the discussion on ovarian cancer? Specialized treatment trials are needed to determine optimal methods for combining chemotherapy and radiation therapy, as well as chemotherapy and hormone manipulation, to enhance responses in survival. What is the safety and risk of estrogen replacement therapy in those who have been successfully treated for uterine cancer? Cervical Cancers What is the influence of human immunodeficiency virus (HIV)-related immunosuppression upon the risk of cervical human papillomavirus (HPV) infection, cervical dysplasia and cervical neoplasia? This requires population studies. Do HPV infections require therapy and if so, which types are needed to reduce the frequency of cervical cancer? Can a methodology be developed to identify which "premalignant" cervical neoplastic conditions are at risk for progression? What are the optimal intervals for cervical cytologic screening? What are the optimal methods of treating various degrees of cervical intraepithelialaeoplasia, and which are most cost-effective? What is the role of HPV in the genesis and progression of cervical neoplasia? What characteristics (oncogene amplification, for example) can be identified that will reliably predict aggressive tumor behavior and thus provide the basis for improved initial treatment strategies?

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Strengthening Research in Academic OB/GYN Departments How can the standard therapies of radiation or operation for cervical cancer be combined with newer modalities of chemotherapy or immunotherapy to improve survival? What new strategies can be developed to improve the therapy of recurrent cervical cancer, which currently is almost uniformly fatal? Vulvar Malignancies Clinical trials are needed to establish efficacy and safety of new treatments. What is the optimal method of therapy of premalignant lesions of the vulva, and can one identify which of these lesions actually require therapy? This should include investigation of rates of progression and regression, identification of lesions that require therapy, and determination of optimal screening intervals. Understanding the molecular biology of premalignant vulvar disease should help in this area of research. Breast Cancer What is the potential effect of oral contraceptives on pre- and postmenopausal breast cancer? Does prolonged oral contraceptive use or early initiation of use (prior to age 20) alter the risk of the development of breast cancer? Does prolonged estrogen replacement therapy alter the risk of breast cancer? Does the addition of a progestin (protective for endometrial carcinoma) alter breast cancer risks? Can estrogen replacement therapy be safely used in patients who have been successfully treated for breast cancer to avoid the morbidity of estrogen deprivation? Does tamoxifen therapy for breast cancer alter the risk of endometrial neoplasia? Can groups of high-risk and low-risk women be identified through metabolic hormonal investigation or through molecular studies such as those involving proto-oncogenes?

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Strengthening Research in Academic OB/GYN Departments Trophoblastic Disease What are the effects on future fertility of successful chemotherapy of trophoblastic diseases? What are the effects of chemotherapy in the mother on future genetic abnormalities in the offspring? What improved treatment strategies can be developed to help patients who currently succumb to the disease? What are the genetic or other muses that lead to the development of gestational trophoblastic diseases? Sexually Transmitted Diseases Prevent Sexually Transmitted Diseases by Developing Clinically Effective and Safe Vaccines Basic research on the microbiology, immunology, and pathogenesis of STDs is essential to the eventual design and development of effective vaccines against them. Development of prototypes of vaccines for use in the prevention of N. gonorrhoeae, C. trachomatis, HIV, and herpes simplex virus (HSV), is under way and should be intensified with additional resources. The mucosal immune response to organisms that cause STDs is critical for the development of successful vaccines, which may stimulate both B- and T-cell limbs of the immune response. Consequently, detailed mapping and analysis of the epitomes of the proteins associated with STD organisms in eliciting immune response are necessary. The mucosal immune system of the human female genital tract and its role in the prevention of infection and/or susceptibility to infection should be studied more intensely. The function of the mucosal immune system, specifically antigen-processing, humoral, and cellular immune responses and the effects of hormones on these responses, should be studied.

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Strengthening Research in Academic OB/GYN Departments Develop Cost-Effective Tests for Early Diagnosis of STDs Develop simple, inexpensive, rapid STD detection methods that are accurate in both symptomatic and asymptomatic women. Highest priority in this area is the development of a test for chlamydial infections. Development of a similar test for vital STDs, such as HSV, HPV, and HIV, is also critical. Investigate the safety and efficacy of experimental drugs antiviral against HIV and treatment of opportunistic infections in both pregnant and nonpregnant women. Evaluate the efficacy of treatment regimens for pelvic inflammatory disease in relation to preservation of normal reproductive function. This will require a long-term multicenter trial to adequately assess long-term outcomes. Develop improved methods to diagnose pelvic inflammatory disease (PID) and to identify women at high risk for reproductive sequelae. Accurate, noninvasive approaches must be developed, particularly to address the challenges posed by atypical infections. Virulence factors and immunologic markers should be sought that are predictive of postinfectious infertility or ectopic pregnancy. Develop New Therapies Where Needed and New Cost-Effective Antibiotics That are Easily Administered and Sufficiently Acceptable to Maximize Compliance Develop curative antiviral agents for infections with HPV, HSV, and HIV. Studies are also needed to better define the effect of existing palliative therapies on transmission and progression of their infections. Evaluate PID treatment regimens for efficacy in preserving normal reproductive function, as well as for ability to achieve clinical and microbiological resolution of acute infection. This will require a multicenter clinical trial, with support for a minimum of 7 to 10 years, to permit adequate assessment of relevant long-term outcomes. The role of adjunctive PID therapy using anti-inflammatory or immunomodulating agents to reduce long-term sequelae should also be examined. Conduct further studies to document the safety and efficacy of STD/HIV regimens during pregnancy. Evaluate the safety and efficacy of experimental antiviral drugs against HIV and treatment of opportunistic infections in both pregnant and nonpregnant women.

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Strengthening Research in Academic OB/GYN Departments Expand community research programs for treatment of HIV, and identify mechanisms to increase access to care, particularly for low-income women. Develop an understanding of the nature of pathogen-cell interactions, especially virus attachment and entry, in order to formulate effective strategies for interruption of transmission. Natural history studies of HPV infection and the influence of the immune system are critically important in attempts to prevent the development of cervical cancer. Encourage therapeutic studies of STDs that specifically address efficacy and safety as well as compliance and cost. Develop inexpensive, accessible therapeutics that can be used reliably by women who must frequently manage multiple responsibilities (e.g., family, job) despite declining health. Evaluate and develop clinical trial recruitment and retention procedures to facilitate enrollment and follow-up of women (e.g., access to primary medical care, child care, transportation to clinic sites, as well as other support services). Review clinical trial eligibility criteria in ongoing studies, specifically, inclusion/exclusion criteria that may be too restrictive and thus prohibit the participation of women (e.g., definitions of active drug use, pregnancy, anemia, elevated liver enzymes, etc.). Study and develop better barrier/contraceptive methods (e.g., condoms vs. female-controlled methods) and viricides that are effective, safe, and acceptable to women; especially needed are methods that can be controlled by women and that may be used without detection by their sexual partners. Clarify the Natural History of Genital Infections Describe the full spectrum of HIV-related illnesses and malignancies in women to fully evaluate current AIDS case definitions and standards of medical care for women. Establish prospective cohorts of women to determine the natural history and clinical presentation of HIV infection in women. Factors that affect the progression to AIDS among HIV-infected women should be identified, and the types of opportunistic infections that occur in women should be studied more intensively. Clinical, virologic, and immunologic markers of disease progression should be evaluated to the female-specific endpoints of disease progression, To better understand, prevent, and treat HI infection in women, conduct studies to address the frequency and factors responsible for transmission

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Strengthening Research in Academic OB/GYN Departments of HIV to women with specific focus on STDs, stage of disease, hormonal influence, and age. Continue studies on the frequency and factors responsible for transmission of HIV from mother to child, and evaluate the use of therapy that prevents transmission. Initiate detailed studies on the impact of STD infections on HIV transmission and the impact of HIV on STD infections. For example, detailed studies on HPV infection in HIV-infected women should be conducted to determine the impact of HIV on HPV in the subsequent development of cervical cancer. Define the factors and mechanisms that alter risk of disease progression, such as HPV infection and its association with premalignant and malignant lesions of the genital tract. Epidemiologic studies are necessary to further define the factors required for initiation versus potentiation of typical cell growth. Conduct epidemiological and basic studies to better define the risk factors and biological mechanisms that influence progression of HPV infection to anogenital neoplasia. Urgently needed are HPV natural history studies that examine the roles of vital type and immune status. Examine the mucosal immune system of the human female genital tract, its relationship to other mucosal immune systems, and its role in the prevention of STDs and HIV infection. Specifically, antigen-processing, humoral, and cellular immune responses and the effects of hormones on the responses should be studied. Define the chronology and the host and pathogen factors involved in ascent of lower tract organisms into the endometrium and fallopian tubes, and subsequent tubal scarring. Development of improved animal models for PID would greatly facilitate this research. Determine the clinical and microbiological spectrum, the frequency, and the natural history of atypical PID. Seroepidemiological studies of infertile women and women with tubal pregnancies strongly suggest that atypical or subclinical PID is responsible for a substantial proportion of these disorders. Define Behaviors Associated with the Acquisition and Spread of STDs Investigate determinants of health care-seeking behavior in women, including the role of social networks and support systems in facilitating women's access to services.

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Strengthening Research in Academic OB/GYN Departments Develop a specific behavioral research agenda in STD prevention. Epidemiologic studies are needed to identify the type and prevalence of behaviors that put individuals at risk for transmission or progression of an STD. Identify behavioral risk factors; this work would be facilitated by a national survey of sexual behavior. Determine population rates for STDs, and conduct natural history studies for disease progression in specific, well-characterized populations. Study the psychosocial needs of HIV-positive women and their family systems (traditional and nontraditional, including lesbian women) as they cope with the chronic, crisis-oriented, and usually fatal nature of HIV disease. Give special attention to adolescent psychosocial needs with emphasis on suicide prevention and support strategies. Characterize the Role of STDs in Adverse Pregnancy Outcomes Study factors such as the infecting pathogen, the stage of gestation during which infection occurs, chronicity of infection, and behavioral patterns such as drug abuse. Organisms should be specifically examined for virulence factors and for other markers associated with specific patterns of fetal or neonatal morbidity. Conduct further studies to demonstrate whether drugs such as acyclovir and zidovudine are safe and effective for use during pregnancy. Direct immunologic studies toward the protective immune responses during breastfeeding to identify the components in breast milk that axe primarily responsible for inhibition of specific pathogens. Similarly, identify the role that breastfeeding plays in the transmission of certain infections such as HIV. Examine such factors as chronicity of infection and stage of gestation during which infection occurs to identify specific pathogens. Improved understanding of the immunobiology of pregnancy and the use of both natural and artificial animal models of STDs in pregnancy are likely to be important to productive research in this area. In addition, organisms should be examined for virulence factors or other markers associated with specific patterns of fetal or neonatal morbidity.