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DES Research Update 1999: Current Knowledge, Future Directions

William H. Natcher Center
National Institutes of Health
Bethesda, Maryland

Sponsored by
National Cancer Institute, NIH
National Institute of Environmental Health Sciences, NIH
Office of Research on Women's Health, NIH
Centers for Disease Control and Prevention

July 19-20, 1999

Meeting Summary

  1. Introduction/Background

    2. Diethylstilbestrol (DES), a synthetic estrogen produced in London by Sir Charles Dodds and colleagues in 19381, was first prescribed in the United States between 1938 and 1945 and continued to be used in this country until 1971 for the treatment of threatened, spontaneous abortions. DES was given primarily to women with a history of problem pregnancies; however, because DES was considered both safe and effective, many women with normal, healthy pregnancies and without a history of miscarriages initially also received the drug. Few reliable estimates exist of the number of U.S. women exposed to DES during pregnancy. Although available nationally, the use of DES, and the dosages administered, varied widely according to geographic area of the country. One source estimates that between 5 and 10 million Americans received DES during pregnancy (DES mothers) or were exposed to the drug in utero (DES daughters and sons) and that doses prescribed differed by a factor of 10 or more.2

    As use of DES increased, its efficacy in humans continued to be investigated. A landmark study conducted in the early 1950's at the University of Chicago was a randomized clinical trial that compared 840 women given DES during pregnancy with 806 women given a placebo. Results of this trial showed that DES was ineffective in preventing miscarriage and premature births.3 Subsequent studies confirmed these findings, and although use of DES in pregnancy gradually declined, the drug was prescribed in the United States until 1971 and in Europe until 1983.

    In 1970, a report was published documenting a rare form of vaginal cancer, clear cell adenocarcinoma (CCAC), in six women aged 14 to 22.4 Cancers at this site and of this cell type had previously been reported only in elderly women. Soon thereafter, the association between in utero exposure to DES and the subsequent development of CCAC in these young women was documented.5 In November 1971, the U.S. Food and Drug Administration (FDA) issued a drug bulletin calling attention to the potential adverse effects of DES and warned against its use during pregnancy.6 At that time, 21 cases of CCAC in DES-exposed daughters had been reported to a registry established to monitor this disease. By 1981, the registry contained reports of more than 400 cases of CCAC of the vagina or cervix. Among those cases with available maternal history, approximately two thirds reported in utero exposure to DES or similar estrogens, such as hexestrol and dienestrol.7

    With the discovery that in utero DES exposure was associated with CCAC in young women, researchers realized the importance of monitoring the health status of DES-exposed women and their children. To achieve this goal, since the mid-1970's, researchers have established several cohorts of DES-exposed individuals (see Table 1). The largest of these cohorts is the National Cooperative Diethylstilbestrol Adenosis (DESAD) Project, which was established in 1974; DES-exposed daughters and a comparison group of unexposed women were enrolled in the DESAD Project through five participating institutions (Baylor College of Medicine, Massachusetts General Hospital, the Mayo Clinic, the Gundersen Clinic, and the University of Southern California). Other cohorts include the original "Dieckmann" cohort, the DES Mothers Study, the Mayo Clinic Sons Study, the Connecticut Mothers' Study, the British Research Medical Council (BRMC) Study, the British Randomized Trial, and the Registry for Research on Hormonal Carcinogenesis.2

    Much of what is known about the effects of DES exposure has been inferred from the study of persons in these cohorts.2, 8 (See Table 2.) Well-established health effects associated with exposure of women to DES in utero (DES daughters) are: CCAC in young women, vaginal epithelial changes, reproductive tract abnormalities (e.g., gross anatomical changes of the cervix, T-shaped and hypoplastic uteri), ectopic pregnancies, miscarriages, and premature births. An increased risk for breast cancer also has been noted for DES mothers. Probable effects of DES exposure include infertility in DES daughters and reproductive tract abnormalities (e.g., epididymal cysts, hypoplastic testis, cryptochordism) in DES sons. Possible effects include cervical dysplasia and carcinoma in situ as well as autoimmune disorders (DES daughters), and infertility and testicular effects (DES sons). Suspected health effects include breast cancer (DES daughters), psychosocial effects (DES daughters and sons), prostatic hyperplasia and cancer (DES sons), and third-generation effects (DES grandchildren).

    In response to the growing concern regarding extensive use of DES in the United States and the studies showing an array of adverse outcomes associated with DES exposure, the Department of Health and Human Services (DHHS) convened two Public Health Service Task Forces-one in 1978 and another in 1985-to assess cancer risks associated with DES exposure. Each of these task forces produced reports of their findings.9 As the study of the effects of DES exposure continued, scientists and advocates expressed the need for a formal review and discussion of the wide range of DES-associated health effects, including the noncancer effects.

    This concern was raised during the 1991 Workshop on Opportunities for Research on Women's Health, sponsored by the NIH Office of Research on Women's Health (ORWH), National Institutes of Health (NIH). With this in mind, a planning committee for the 1992 NIH Workshop on Long-Term Effects of Exposure to DES was convened. The planning committee for the 1992 workshop understood the importance of taking a broad-based, multidisciplinary approach to the study of DES effects. This approach included both epidemiologic risk and etiology of cancer and noncancer endpoints. The specific goals of the 1992 workshop were to (1) review existing data, (2) assess areas where further research was required, and (3) foster collaborations between researchers from various disciplines. The meeting was held April 22-24, 1992, in Falls Church, Virginia.

    A report summarizing the presentations and discussions from the 1992 workshop was published and is titled, "NIH Workshop: Long-Term Effects of Exposure to Diethylstilbestrol (DES)."10 Recommendations from the 1992 meeting were divided into six broad research categories (epidemiologic studies, basic science research, studies of vaginal clear cell cancer, clinical studies of pregnancy outcomes in DES daughters, education and outreach efforts, and other). The recommendations from this meeting are presented in Appendix VI of this report.

    A large body of research has been undertaken since the 1992 DES workshop, in response to the recommendations from that workshop. Several factors have contributed to that growth. Two specific actions, in the form of Congressional mandates-the DES Education and Research Amendments of 1992 (passed and signed into law in 1992) and the DES Education and Research Amendments of 1997 (passed and signed into law in 1998)-provided new opportunities and funding for DES research and education between 1992 and 1999. The 1997 bill reauthorized DES research and gave DHHS the authority to expand DES education projects nationwide using the knowledge gained through the pilot projects.

    Interest in disseminating and discussing the latest research efforts led to the planning of a national DES meeting that would serve as a follow-up to the meeting held in April 1992. The planning of this second meeting by advocates and researchers from academia and several government agencies culminated in a 1 and 1/2 day workshop on the long-term health effects of exposure to DES, held July 19-20, 1999, on the campus of the NIH in Bethesda, Maryland. The 1999 workshop provided an update on research and on the progress in responding to the recommendations from the 1992 meeting; it also provided a platform for discussion of current and future needs and recommendations for addressing those needs. Research areas addressed during the meeting included biology/basic research, epidemiology research, clinical research, and education/ outreach. The format of the 1999 meeting included overview presentations, breakout sessions, and poster sessions in each of the four topic areas. Breakout sessions gave workshop attendees an opportunity to discuss the status of research and develop recommendations for the future. Participants included federal and nonfederal members of the basic and clinical research communities and patient advocates.

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Notes:

  1. Dodds EC, Goldberg L, Lawson W, Robinson R. Estrogenic activity of certain synthetic compounds. Nature 141:247-248, 1938

  2. Guiusti RM, Iwamoto K, Hatch EE. Diethylstilbestrol revisited: A review of the long-term health effects. Ann Intern Med 122:778-788, 1995

  3. Dieckmann WJ, Davis ME, Rynkiwwicz LM, Pottinger RE. Does the administration of diethylstilbestrol during pregnancy have therapeutic value? Am J Obstet Gynecol 66:1062-1081, 1953

  4. Herbst AL, Scully RE. Adenocarcinoma of the vagina in adolescence. A report of seven cases including six clear cell carcinomas (so-called mesonephromas). Cancer 25:745-757, 1970

  5. (a) Greenwald P, Barlow JJ, Nasca PC, Burnett WS. Vaginal cancer after maternal treatment with synthetic estrogens. N Engl J Med 285:390-392, 1971. (b) Herbst AL, Ulfelder H, Poskanzer DC. Adenocarcinoma of the vagina: Association of maternal stilbestrol therapy with tumor appearance in young women. N Engl J Med 284:878-881, 1971

  6. FDA Drug Bulletin: Diethylstilbestrol Contraindicated in Pregnancy. Washington, DC: U.S. Department of Health, Education and Welfare (DHEW), 1971

  7. Herbst AL. Clear cell adenocarcinoma and the current status of DES-exposed females. Cancer 48:484-488, 1981

  8. Hatch EE, Palmer JR, Titus-Ernstoff L, Noller KL, Kaufman RH, Mittendorf R, Robboy SJ, Hyer M, Cowan CM, Adam E, Colton T, Hartge P, Hoover RN. Cancer risk in women exposed to diethylstilbestrol in utero. JAMA 280:630-634, 1998

  9. (a) Fink DJ: DES Task Force Summary Report. Washington, D.C.: Government Printing Office (DHEW publication No. NIH 79-1688), 1978. (b) Report of the 1985 DES Task Force. U.S. Office of the Assistant Secretary of Health. Bethesda, MD: U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, 1987

  10. NIH Workshop: Long-term effects of exposure to diethylstilbestrol (DES), April 22-24, 1992



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