Home Inroduction/Background Opening Remarks State of the Research Advocates' Remarks Recommendations and Findings Closing Remarks Appendices

III.  State of the Research

Basic Research Overview
Clinical Research Overview
Epidemiology Research Overview
Education/Outreach Overview

Before turning this part of the meeting over to the presenters, Anne Sassaman, Ph.D., Director, Division of Extramural Research and Training, NIEHS, noted that NIEHS, which is a part of NIH, has a long-standing interest in DES research and education and has been involved in other DES-related meetings and conferences, including the 1992 DES Workshop. She noted that the NIEHS has taken a lead in promoting and funding research on environmental estrogens, which recently has evolved to include endocrine-disruptive compounds. Work conducted in the mid-1970's by NIEHS researchers led to the development of experimental models that predicted and, in some cases, replicated the effects of DES in humans. NIEHS research has also focused on effects of DES in perinatally exposed males. The Institute continues to support both intramural and extramural research investigating the mechanisms of DES effects, including lineage studies and studies of the impact of the drug on the immune system and implications for autoimmune diseases.

Basic Research Overview

Overview/presentation

Retha Newbold, M.S., Head, Developmental Endocrinology Section, Laboratory of Toxicology, NIEHS, provided a history of DES research and exposure and the resulting human experience. She summarized significant milestones in basic research during the past 20 years, more recent data, current basic research priorities, and research questions for the future.

The DES legacy has its origins in basic research. Sir Charles Dodds is credited with the synthesis of DES, and the discovery was met with great enthusiasm from the basic research and medical communities. Unlike other synthetic chemicals, DES was active and effective when administered orally and was more potent than naturally occurring estrogens. In addition, DES was easily dissolved in alcohol, oil, and water-a characteristic of a compound that researchers appreciate even today. Research conducted by Susan Bell shows the far-reaching impact that the discovery of DES has had in many fields: clinical chemistry, organic chemistry, endocrinology, gynecology and obstetrics, and oncology.11 Sir Dodds' discovery allowed basic researchers to gain a much better understanding of the structure and function of estrogenic compounds. The initial success of DES led to its use in a variety of applications, including threatened abortions.

As noted earlier, DES was first prescribed in the United States between 1938 and 1945 and continued to be prescribed until 1971 for the treatment of threatened, spontaneous abortions. At the time, because DES was considered safe and effective, it also was prescribed for a number of normal pregnancies. The total number of DES-treated pregnancies is unknown, although worldwide estimates of DES mothers range from 2 to 8 million. Research has documented DES-associated CCAC in young women exposed to DES in utero as well as a high rate of other reproductive tract abnormalities in DES children (both sons and daughters).

Researchers have made several landmark discoveries regarding DES function and mechanisms of action, as outlined by Ms. Newbold. These include:

Ms. Newbold then described two mouse models commonly used to study the range of effects and mechanisms of DES. To develop a prenatal model, researchers treat a pregnant, outbred mouse with DES and then examine the offspring of that treated mouse. To develop a neonatal model, researchers expose newborn mice to DES (described in more detail below). The DES "daughters" of the DES-exposed mouse mothers show abnormalities in the reproductive tract that include structural and epithelial changes in the oviduct, structural abnormalities of the uterus and cervical canal, cervical and vaginal polyps, and vaginal adenosis and adenocarcinoma. The mouse DES "daughters" also exhibit subfertility and infertility. Most of these findings have been seen in humans exposed to DES in utero.

As in young women, the induction of vaginal adenocarcinoma in the absence of DES exposure normally is rare in mice. Other effects observed in mice that parallel those in humans include infertility and subfertility; oviductal, cervical, and uterine malformations; paraovarian cysts of mesonephric origin; salpingitis isthnica nodosa of the oviduct (an epithelial change in the oviduct); immune dysfunction; and vaginal adenosis. Observations in DES-exposed male offspring (both humans and mice) include subfertility and infertility, decreased sperm counts, hypoplastic cryptorchid testes, epididymal cysts, testicular tumors, anatomical feminization, microphallus, hypospadias, retained Müllerian remnants, and prostatic inflammation. Thus, the prenatally DES-exposed mouse model appears to be valid and to parallel the human condition. To that end, the model has been used to replicate and predict many of the lesions observed in similarly exposed humans. Exposure to DES early in gestation results in structural, functional, and long-term changes, including neoplasia, in both humans and mice.

A large body of research has described the timing of differentiation of reproductive tract tissue during the human and the mouse gestation periods, and the impact of DES exposure at different times during and after gestation. In humans, differentiation of the reproductive tract occurs prenatally, with most of the development completed by the start of the second trimester. In contrast, in mice, reproductive tract differentiation occurs both prenatally and neonatally. Taking the mouse developmental path into consideration, Ms. Newbold noted that prenatal exposure to DES produces primarily teratogenic, or structural and functional, abnormalities, whereas neonatal exposure produces a higher incidence of cancer than either no exposure to DES or prenatal exposure to DES.

In studying the impact of neonatal exposure to DES (days 1 to 5 after birth only) in mice, Ms. Newbold and colleagues found a high incidence of uterine adenocarcinoma; at 18 months of age, 95 percent of the animals treated with DES during this time period presented with this cancer. These tumors were slow to metastasize and responded to hormone treatment; further, the tumors shrunk considerably following ovariectomy. The tumors possess the characteristics of frank cancer, Ms. Newbold pointed out, such as the ability to grow on soft agar and in nude mice.

In summary, DES animal studies, in conjunction with findings of human studies, have revealed four key points. First, the developing organism, whether human or mouse, is extremely susceptible to perturbations by estrogens. Second, exposure to DES during critical stages of reproductive tract differentiation results in structural, functional, and long-term abnormalities, including neoplasia. Third, the ultimate expression of an abnormality depends on stage of genital tract development during which DES exposure occurred. Fourth, the experimental DES animal model offers unique opportunities to study mechanisms associated with estrogen-induced differentiation defects.

As Ms. Newbold noted, several researchers have taken advantage of the DES mouse model to study the underlying genetic mechanisms of DES exposure. For example, early research suggests that DES-induced oviductal structural malformations in the mouse (which develop after prenatal exposure during gestation days 9 through 16) appear to be related to DES's ability to delay the expression of the specific Hox genes involved in structural differentiation of the reproductive tract in mice and humans.12 DES may also interfere with the expression of wnt genes, which are thought to have a role in structural differentiation of the reproductive tract. These data suggest that exposure to DES during critical stages of organogenesis inhibits expression of Hox and wnt genes that determine structural identity of the differentiating genital tract. These findings represent significant advances in the understanding of the mechanisms by which DES acts.

Another area of active research interest involves the estrogen receptor, which is a specialized protein located in certain target tissues. The estrogen receptor must be present to interact with DES or another agent to allow that agent to impart its full biologic effect. Receptors and agents that interact with receptors function similarly to a lock (the receptor) and key (DES or other agent). To examine the role of the estrogen receptor following DES exposure, Ms. Newbold and her colleagues conducted an experiment in which the estrogen receptor was overexpressed, or overproduced, in several target tissues (e.g., uterus) of the mouse model described earlier. The team then exposed newborn mice to DES (neonatal exposure during days 1 through 5 after birth) and monitored the animals as they grew. As expected, the exposed animals developed oviductal, cervical, and uterine malformations; squamous metaplasia in the uterus; cystic endometrial hyperplasia; atypical hyperplasia; and uterine adenocarcinoma.

In follow-up experiments, findings regarding the proportion of mice exposed to DES neonatally with tumors were particularly interesting. In CD-1 mice (the strain usually used in Ms. Newbold's experiments) exposed to DES right after birth, no tumors were present at 8 months; by 12 months, however, about 40 to 50 percent of these animals had tumors, and by 18 months, nearly all (90 to 95 percent) of the mice had tumors. In another strain of mice (the FVBIN strain), about 50 percent of animals developed cancer by 8 months after DES exposure, with steady increases in the proportion of mice with tumors at 12 and 18 months of age. Thus, this strain of mouse is more susceptible to tumor development than the strain usually used. When the CD-1 mice were modified (so that estrogen receptors were overexpressed) and then exposed neonatally to DES, tumor growth was highly accelerated so that at 8 and 12 months of age, tumors were present in 80 and 90 percent of animals, respectively. These results indicate that transgenic (genetically altered) mice that overexpress the estrogen receptor have earlier onset of preneoplastic and neoplastic uterine tumors after neonatal exposure to DES than similarly exposed nontransgenic mice. Thus, the estrogen receptor appears to play an important role in these DES-associated tumors.

In other studies, mice have been genetically altered so that the gene for the estrogen receptor is removed, or "knocked out." Studies using knock-out mice are underway and include experiments in which these animals are exposed to DES and other estrogen-like compounds at different stages of development. Researchers are also investigating the role of a new variant of the estrogen receptor in tumor development, the recently identified estrogen receptor-beta. Prior studies, including those just described, investigated the role of the classical estrogen receptor, the estrogen receptor-alpha. Further studies in this area of DES and estrogen research are clearly warranted.

Another area of study involves the possible transmission of DES-induced abnormalities and genetic alterations to subsequent generations. To study this question, Ms. Newbold and her team returned to the DES-exposed mouse model (i.e., in which the pregnant mice were given DES), bred the females exposed in utero, and are now examining the offspring of those females (the DES "grandchildren"). The female mice "DES grandchildren" exhibited normal fertility but still had increased numbers of reproductive tract tumors (uterine adenocarcinomas), compared with third-generation offspring of unexposed animals. In summary, the lineage studies using the DES mouse model suggest that no adverse effects on fertility are seen in third-generation females; however, increased susceptibility to tumors is transmitted. Additional studies are underway to examine the mechanisms involved in these events. Some of the factors being investigated include differences in methylation patterns in estrogen receptor genes and early genetic markers for DES-induced disease susceptibility.

In closing her presentation, Ms. Newbold outlined several reasons for continued DES research and identified future research questions. Key considerations for continuing research into the impact of DES on human health include:

Researchers may want to use the following as a springboard in identifying and directing future research efforts:

Breakout discussion summary (Co-chairs, John McLachlan, Ph.D., Pat Cody, M.A.)

Dr. McLachlan opened the discussion by asking participants to consider the question, "What is basic research?" In brief, he explained, those involved in basic research think through a problem, create a hypothesis or formulate a question to address that problem, and then test that hypothesis/question through established, validated methods. Like other areas of research, basic research is limited by the techniques used to answer fully the questions asked or to prove the hypotheses under test. With that introduction, the session opened up to a question, answer, and comment period, followed by identification of key research priorities and recommendations.

Among the points raised during the open discussion were:

Before the group formulated its recommendations, Ms. Pat Cody offered several comments. First, she noted that because basic science is essential to solving clinical problems, the interface between basic and clinical research is fundamental for advancing knowledge, screening, and treatment of DES-related health outcomes. Second, the DES community should continue to advocate for the continuance of multigenerational studies and the enrollment of more subjects of all generations--DES mothers, children, and grandchildren. The study of non-exposed siblings also could provide interesting information regarding the differential effects of genetics versus the effects of DES exposure on the development of adverse health outcomes in DES-exposed individuals. Third, researchers should also continue their attempts to tease out the effects of multiple DES exposures (is there a cumulative effect?) and varying DES dosages (are effects clearly dose dependent?). Fourth, studies of individual genetic susceptibility and predisposition to DES effects may be another area of investigation for basic researchers. Such studies may include variations in the responses of estrogen receptors for DES versus DES metabolites. Fifth, investigations of co-factors that may influence health outcomes, such as exposure to other hormones, xenoestrogens, or agents that could serve as co-carcinogens or tumor initiators, should continue. Sixth, advocates were reminded that animal models are fundamental to understanding mechanisms of action of DES and other hormones. Finally, the impact of DES research extends far beyond the DES community. DES can be viewed as a representative model of hormonal carcinogenesis and as a model for the activity of endocrine disruptors as a class of chemicals.

In closing this session, the group suggested the following primary recommendations and key points under those recommendations:

Co-chairs' report

In providing some background information, the co-chairs noted that the field of DES research is a pioneer in consumer-researcher partnerships. Long before NCI and other institutions and agencies routinely formed such partnerships, the DES community was well on its way to bringing together all key players and interested parties. As a result, the foundation of this community comprises three major contributors: health care providers, researchers, and consumers.

Another important concept distilled from the group's discussion was that basic DES research is a good model for studying hormone-responsive cancers as well as for comparing experimental results with human effects (i.e., "species extrapolation"). Thus, the interface between basic and clinical DES research, which includes epidemiologic investigations, provides researchers with opportunities to study issues such as the toxicology of DES and hormone-associated carcinogenesis. This interface is reflected in the need for tissues to advance basic DES research. The repository of tissue and cells from DES-exposed persons therefore helps fulfill the goal of identifying the molecular events of DES's actions in the body and developing new tools for prevention of further adverse outcomes resulting from DES exposure.

The group identified two major themes from which research recommendations were developed. The first theme focuses on continued research on DES mothers and daughters. The areas of greatest interest include:

The recommendation to address the concerns identified in the first theme is to formulate basic DES research strategies to:

The second major theme derived from the breakout discussion involved DES grandchildren. In addition to identifying future health outcomes for this group, the discussants believed the issue of current health indicators should be investigated. What issues and effects, if any, are relevant to DES grandchildren? Laboratory research shows definite effects on offspring born to animals exposed to DES in utero, but whether effects occur in humans needs to be monitored, defined, and quantified. The basic research recommendation developed from this theme involves strategies to:

Other issues that the breakout group participants considered relevant and important to basic DES research were:

Clinical Research Overview

Overview/presentation

Arthur L. Herbst, M.D., Professor and Chair, Department of Obstetrics and Gynecology, University of Chicago, provided an overview of the history and current status of clinical research on DES, with a focus on CCAC. He also provided a brief summary of recent findings regarding DES exposure and the development of non-clear cell carcinoma, along with a brief history of DES research findings.

As noted earlier by Ms. Newbold, DES was synthesized by Dodds, who won a Nobel prize in the same year for synthesizing the first orally active estrogen.1 The characteristics of DES, particularly its miscibility in water, oil, alcohol, and other solvents, made it uniquely poised to be used as a pharmaceutical agent. At that time, Dr. Herbst noted, in the absence of information regarding chromosomal abnormalities and miscarriage, pregnancy losses were thought to be due to the endocrine environment of the pregnancy, specifically to deficiencies of certain hormones in the fetal placental unit. In humans, the hormone progesterone was thought to be deficient in high-risk pregnancies; this hypothesis was based on findings of high concentrations of a progesterone metabolite, pregnendiol glucuronide, in the urine of women with threatened pregnancies. When DES was administered to these women, the amount of the progesterone metabolite in the urine returned to normal levels. Studies also showed that estrogen-deficient laboratory animals had a higher rate of miscarriages than non-estrogen-deficient laboratory animals.15

In the early 1950's, Dieckmann published the results of one of the first double-blind studies conducted in the United States; this report showed DES to be ineffective in preventing miscarriage and premature births in women.3 Landmark studies conducted by Dr. Herbst and colleagues at Massachusetts General Hospital in the early 1970's documented an association between in utero exposure to DES and the development of CCAC in young women.4, 5 (b) This type of cancer previously had been observed almost exclusively in elderly women. Thus, not only was DES ineffective in protecting threatened pregnancies, it was harmful to the female children of the women given DES during their pregnancies.

After this discovery, Dr. Herbst's team established a registry to monitor this disease. This registry has grown from 21 cases of CCAC of the vagina or cervix in 1971, to more than 400 cases in 1981, to approximately 715 cases in 1999. The age at diagnosis of the women in the registry ranges from 7 to 48 years, and cases include both DES-exposed (62 percent of cases) and non-DES-exposed women. As Dr. Herbst noted, the estimate of the absolute risk for DES daughters to develop CCAC is approximately 1:1,000. The histology/pathology of CCAC includes three major variants: papillary; tubulocystic (characterized by "hobnail"-like cells), which is seen most frequently in women more than 19 years old and has the best prognosis; and solid/clear-cell type, from which the CCAC is named. Near the areas of carcinoma in the vagina, researchers often find benign glands, referred to as vaginal adenosis. These glands are one of the following two types: the tuboendometrial glands, which possess cilia-like projections similar to those seen in normal fallopian tube tissue and which are thought to be the source or precursors of CCAC; and the more common mucinous adenosis glands, which are similar to those found in the cervix, but observed in the vagina. Dr. Herbst noted that a study published several years ago reported the interesting finding of progressive intestinal metaplasia in DES-induced vaginal adenosis.16 The possible role of intestinal metaplasia in the development of enteric neoplasias (i.e., mucinous adenocarcinoma of the vagina) was discussed by the authors of this study. (See also the abstract by Wu and Speigel in Appendix V of this report.) These variants may be of relevance to current and future research on CCAC, especially regarding DES exposure.

Early data from the United States indicated that the age at diagnosis of CCAC among DES-exposed daughters is most likely between 15 and 25 years, with the greatest rate in non-DES-exposed women occurring later in life, after menopause. Data from the Central Netherlands Registry show a similar pattern, with incidence peaking in young, DES-exposed CCAC patients aged 15 to 35 years and in non-DES-exposed CCAC patients aged 65 years and older. Preliminary analyses of updates of the Central Netherlands Registry indicate that the average age of diagnosis of CCAC in DES-exposed women is on the rise (see the abstract by Hanselaar et al., in Appendix V). Whether a spike in the second peak, that is, among DES-exposed women entering or going through menopause, will occur is not known at this time, but these data raise the possibility that this group of women may be at increased risk for CCAC as they enter perimenopause in their forties.

Case-control studies, in which the health of DES-exposed persons is compared with that of a similar group of non-exposed persons, have suggested several other possible mechanisms underlying cancer development in DES-exposed individuals. Such epidemiologic studies have identified characteristics other than DES exposure that differ between DES-exposed women with cancer and DES-exposed women without cancer. For example, the time during gestation when DES was administered influences cancer risk in DES daughters; research shows that exposure early in pregnancy is associated with a greater risk for CCAC than exposure later in pregnancy.17 Three other factors that also appear to be associated with increased cancer risk include the mother's history of prior miscarriages, which may suggest a genetic predisposition or susceptibility to DES's effects; season of birth, with fall births being associated with the greatest risk for cancer in these cohorts; and premature births/small birth weight.

Researchers are also monitoring cancer survival rates and CCAC recurrences by stage of tumor at the time of diagnosis, which indicates the degree to which a tumor has spread. The overall rates are encouraging for early-stage cancers. For example, the 5-year survival rate for stage I tumors (confined to the cervix or vagina) in DES-exposed women is 93 percent; the 10-year survival rate is 87 percent for women diagnosed with this stage tumor. Five-year survival rates for stage IIA, IIB, and II (vaginal) are 80 percent, 58 percent, and 83 percent, respectively. For women diagnosed with stage III tumors, the 5-year survival rate is much lower, at 37 percent. No women diagnosed with stage IV disease (most advanced) reached the 5-year milestone. These data underscore the importance of knowledge about the health effects of DES and regular screening of DES daughters for this type of cancer in particular. Dr. Herbst noted that most DES-exposed women with CCAC are diagnosed at stage I of the disease, and that most cancer recurrences occur within 3 years of initial diagnosis. Late recurrences are uncommon, Dr. Herbst reported. In a few cases, however, primary and secondary cancers at sites such as the lung, brain, and vagina, have recurred up to 20 years after treatment for initial disease. It is unclear why these tumors remained quiescent and then redevelop so long after treatment.

Access to and use of the University of Chicago registry allows investigators to pursue numerous lines of research regarding the unique characteristics of subjects with CCAC who are included in the registry cohort. At the Society of Behavioral Medicine Meeting in March 1998, Siston and colleagues reported that, based on the data from this registry, there are 165 DES-exposed daughters who are cancer survivors. Data from these women were collected using questionnaires, and highlights were provided by Dr. Herbst. The mean age of these women, when the survey was conducted, was 40 years. Most were white, married, and well educated. Approximately 85 percent of women in this group reported having some sexual function problems; 58 percent had medical and/or anatomic problems related to vaginal reconstruction; and 33 percent reported experiencing psychological problems with respect to sexual function and medical issues (e.g., depression, anxiety, lack of social support). Thus, as Dr. Herbst pointed out, these findings suggest that doctors and patients must be aware of and capable of addressing both physical and emotional problems related to survival and sexual function. Further research in this area is planned.

In 1994, Dr. Herbst, along with Dr. Steve Waggoner and colleagues at the University of Chicago, published a study on 318 CCAC cases in women with documented in utero DES exposure and in a control group of unexposed women with CCAC.18 In this study, DES-exposed women had higher 5- and 10-year survival rates than women not exposed to the drug. This finding suggests that the biology of the CCAC tumors in these two groups may differ; that is, the tumors in the DES-exposed group may possess estrogen receptors, whereas the tumors in the unexposed group may not contain these receptors. As Dr. Herbst noted, endometrial cancers that develop during estrogen treatment (e.g., HRT) generally afford a better prognosis and have a different biology than spontaneous endometrial tumors. Similarly, breast cancers that develop in women using OCs usually have a better prognosis and are more localized than breast tumors that develop in women not using OCs. Similar results have been reported for breast cancer in women taking HRT, compared with those that do not take HRT. In summary, these findings suggest that estrogen-associated tumors have a different biology than those that develop spontaneously in the absence of exogenous estrogen, or independent of estrogen. (A review of this subject in Gynecologic Oncology is in press.) Dr. Herbst encouraged researchers to access the University of Chicago registry to study the cell and molecular biology of tissues obtained from DES-exposed women to gain a better understanding of hormone-associated tumor behavior.

Cunha and coworkers in California have conducted some molecular studies on cancer tissue from DES-exposed women. Using tissue obtained between January 1997 and June 1997, the team first established protocols for collecting fresh CCAC tissue from women who were newly diagnosed with but not yet treated for the disease. The researchers successfully transplanted the tissue into nude mice to examine the ability of these human tumors to grow in laboratory animals. The researchers also found that the tumor tissue remained viable after being removed from the mice and cryopreserved. Dr. Cunha has cryopreserved tissue available to researchers who are interested in further study. Dr. Herbst expressed an interest in expanding the registry to include such human tissue samples (fresh, cryopreserved) to conduct molecular studies.

Additional accessions to the registry include vaginal and cervical CCAC tissue samples from women born after 1948, both with confirmed DES exposure and non-exposure. One new area of interest is the issue of mucinous carcinoma. Dr. Herbst reported that four cases of this type of neoplasia have been documented within the registry; four additional cases currently are undergoing confirmation. The registry will continue to be monitored for Müllerian-derived fallopian tube carcinomas, of which none have been detected yet. Non-neoplastic abnormalities seen through continued histopathologic examination of tissues from the registry include lower and upper Müllerian tract changes and other reproductive tract changes. Studies of menstrual abnormalities, infertility, and pregnancy-related issues as well as of the psychological and emotional challenges facing DES-exposed individuals also should continue.

Additional findings from a variety of studies of DES daughters (and unexposed controls) indicate an increased risk for premature births and ectopic pregnancies2, 19; a possible increased risk for squamous intraepithelial neoplasia of the cervix, as reported from the DESAD Project20; and abnormal hysterosalpingography.21 Exposure to DES during pregnancy has been associated with up to a two-fold increase in risk for breast cancer among DES mothers.2 A positive association between DES exposure and breast cancer mortality (RR, 1.34) also has been reported; this small increased risk does not appear to change over time.22 Such findings provide important information for the development of and adherence to age-appropriate breast cancer screening and treatment guidelines for DES-exposed women. Additional research shows that DES exposure in utero may not increase the risk for endometriosis or early menopause23; DES also does not appear to have an adverse effect on ovulation. In reporting these latter findings, Dr. Herbst commented on the importance of uncovering not only the factors that are relevant to DES-exposed persons but also those factors that do not appear to be affected by DES exposure.

Breakout discussion summary (Co-chairs, Kenneth Noller, M.D., Nora Cody, M.A.)

Participants in this breakout session identified 25 research-related questions/issues of interest that were then distilled into three primary areas for recommendations. The 25 questions/issues included:

After this brainstorming session, participants identified three primary areas of research that should be pursued and translated into recommendations for the clinical research community:

The co-chairs expanded on these points and discussed related areas of concern during their presentation.

Co-chairs' report

The co-chairs reported that the 25 issues the breakout group identified for ongoing and future DES-related clinical research served as the foundation for developing three research priorities for this field. From these points, the co-chairs also identified several key concerns. These key concerns include:

The three top research priorities/recommendations identified by the breakout group include:

Fundamental to all DES-related research is continued funding.

Epidemiology Research Overview

Overview/presentation

Robert Hoover, M.D., Sc.D., Director, Epidemiology and Biostatistics Program, Division of Epidemiology and Genetics, NCI, provided an overview of the epidemiology research on the effects of exposure to DES, which was first prescribed between 1938 and 1945, and was used through 1971 for the prevention of threatened, spontaneous abortions. The first application of epidemiologic methods to the study of DES effects on women began in the early 1950's with several randomized, controlled intervention trials, which showed that DES was not efficacious in preventing spontaneous abortions. Despite these facts, DES continued to be prescribed for the next 20 years. This unfortunate historical event highlights the difficulty of applying scientific findings to the practice of medicine.

Results of the British Research Medical Council Study, reported in 1995 at a conference on diabetes and pregnancy, indicated that neither oral stilbestrol nor ethisterone prevented fetal mortality in diabetic patients. In 1978 and again in a 1991 update and re-analysis of the large Dieckmann trial by Dr. Heinz Berendes, it was shown that DES was not only ineffective in preventing spontaneous abortions but was hazardous as well. There were more spontaneous abortions and premature births in women exposed to DES than in those not exposed.

Dr. Hoover summarized the findings of cohort and case-control studies, including the DES Combined Cohort Studies (DCCS). Since 1992, the DCCS has recontacted and combined the existing DES cohort studies in five clinical centers and at NCI to increase the statistical power of the findings. The lead investigator of the DCCS is Elizabeth Hatch, Ph.D., Epidemiologist, NCI. A steering committee made up of well-known principal investigators on DES effects and leaders of DES advocacy groups assists in directing the DCCS. Most clinical and epidemiology studies are concerned with the long-term effects of DES exposure on three main groups--mothers, daughters, and sons. The DCCS is following approximately 5,000 exposed and 4,000 unexposed mothers; 5,000 exposed and 2,500 unexposed daughters; and 2,000 exposed and 2,000 unexposed sons. The main objective of the study is to determine whether the risk for cancer among DES-exposed individuals is increased as a result of such exposure. Other health outcomes, such as infertility and pregnancy outcomes, also are being investigated through the DCCS.

Virtually all studies conducted on mothers who received DES during pregnancy have found an approximately 30 to 40 percent increased risk for breast cancer among exposed mothers when compared with unexposed mothers. In the DCCS, Titus-Ernstoff found a 20 to 30 percent excess risk of breast cancer, which first appeared 10 years after exposure (see the abstract by Titus-Ernstoff et al., in Appendix V and reference/footnote 8 of this report). This pattern is different from that for OCs and HRT, in which the risk is related to recency of exposure. The reduction of breast cancer risk after 10 years of non-use of these other estrogens is not found for those women exposed to DES.

Although DES daughters are at risk for CCAC, so far they do not appear to have an increased risk for cancers at other sites, including breast cancer. A DCCS analysis published in 1998 reported that the risk for CCAC in DES daughters was 40-fold higher than the risk for the general population.8 Estimates of the absolute risk for CCAC among DES daughters consistently have been reported to be between 1:1,000 and 1:1,500.5 (b), 8,24 The relative risk for breast cancer among DES daughters in the DCCS was 1.2, when compared with the general population and daughters known to be unexposed to DES; this slight increase in breast cancer risk was not statistically significant.8 Among women over 40 years old, there was a three-fold excess risk for breast cancer in the exposed compared with the unexposed; this result also was not statistically significant and appeared to be due to a much lower than expected rate of breast cancer among unexposed women.

Another area of interest is whether DES-exposed daughters may be at excess risk for squamous cell dysplasia and carcinoma of the cervix. In 1981, Robboy reported the results of the baseline examinations of the DESAD cohort and found a higher prevalence of squamous cell dysplasia among DES-unexposed daughters 25; however, a subsequent study of the incidence of this condition found a two-fold increased risk among DES daughters, compared with unexposed daughters.20 A recent DCCS analysis of the DESAD cohorts by Hatch and colleagues (see Appendix V) of 78 cases of moderate to severe dysplasia indicated a relative risk of 1.5 for DES-exposed daughters compared with unexposed daughters. When the analysis was restricted to those with frequent screening the increased relative risk disappeared; further, it is important to note that it is difficult to rule out a surveillance bias against DES-exposed women.

For DES-exposed sons, reproductive tract abnormalities have been found in a number of case-control and cohort studies. Studies of testicular cancer have produced mixed results; three showed excess risk and three showed no excess risk; however, it is difficult to assess accurately DES exposure retroactively. Thus, a primary challenge in such analyses involves determining the degree of exposure to DES. Data on the 2,000 DES-exposed sons followed in the DCCS currently are being analyzed; however, because of the rarity of testicular cancer in the general population, the results from this cohort may not be conclusive. It will be important to continue to follow these men for prostate cancer as they age. Another study of DES sons found no evidence of infertility in males due to DES exposure in utero.26 This analysis considered number of children, time for pregnancy to occur, and successful attempts at conception. The rates for all of these parameters were the same for DES-exposed and unexposed men.

Adverse pregnancy outcomes for women due to DES exposure in utero were reported by Shanna Swann, Ph.D., at the 1992 NIH Workshop on Long-Term Effects of Exposure to DES. A meta-analysis of all pregnancy outcome studies up to that time showed a two-fold increased relative risk for spontaneous abortion, a nine-fold increased risk for ectopic pregnancy, and a five-fold increased risk for premature birth for DES-exposed daughters compared with unexposed daughters. Women with abnormalities of the cervix, vagina, or uterus had an even greater risk for all three types of conditions. In a recent DCCS analysis of pregnancy outcome events by Raymond Kaufman, M.D., and Ervin Adam, M.D., at Baylor University College of Medicine, it was possible to obtain a higher statistical power than in previous studies (see the abstract by Kaufman et al., in Appendix V). In this analysis, these investigators found a four-fold excess risk of spontaneous abortions in the second trimester, a four-fold relative risk for ectopic pregnancies, and a three-fold increase in premature births for DES-exposed daughters.

Most of the other potential outcomes of DES exposure have not been fully evaluated, except possibly autoimmune diseases. In the 1980's, Kenneth Noller, M.D., and colleagues at the University of Massachusetts Medical School, used the DESAD Project database to study 51 autoimmune or other immune disorders in relation to DES exposure.14 From responses to mailed questionnaires, the research team compared 1,711 DES-exposed with 922 unexposed daughters and found marginally statistically significant excess risk for such conditions as pernicious anemia and a three-fold increased risk for rheumatoid arthritis. Another analysis of questionnaire responses from participants in the Dieckmann cohort found no excess in allergenic responses, including asthma, and no significant differences for other autoimmune diseases.27 There was, however, a small increased prevalence of rheumatoid arthritis among DES-exposed versus unexposed daughters. Dr. Hoover stated that future research in this area needs more rigorous study based on medical records, rather than mailed questionnaires, to validate this diagnosis.

In summary, Dr. Hoover presented the following conclusions:

Breakout discussion summary (Co-chairs, Elizabeth Hatch, Ph.D., Susan Helmrich, Ph.D.)

Dr. Hatch suggested a framework for the breakout session and asked participants to consider the following questions: (a) What research has been done? (b) What questions need to be addressed in these areas? and (c) What other potential health effects have not been studied and need to be? New research endeavors should focus on feasibility, benefit to DES-exposed persons, and benefit to other research, she added.

Epidemiologic studies and surveys

Following this outline, summaries of several epidemiologic studies were provided. Dr. Hatch presented a brief description of the NCI DES Combined Cohort Follow-Up Study. This study began in 1992 with the purpose of combining and recontacting all the participants in previous cohort studies from the 1970's at medical centers in five different geographic areas (Texas, Massachusetts, Minnesota, Wisconsin, California). There have been two rounds of follow-up: (1) In 1994, questionnaires were sent to mothers, daughters and sons; and (2) in 1997, questionnaires were sent to DES-exposed daughters and sons. A third round will take place in the years 2000 and 2001. The major focus is on long-term cancer risk. Other outcomes are reproductive effects, such as infertility, autoimmune disease, benign breast cancer, benign gynecological disease, and cervical dysplasia. The validity of the study is improved because medical records and tumor slides were obtained for many of the subjects.

Dr. Helmrich then provided some descriptive data from the Clear Cell Cancer Registry at the University of Chicago. Of 715 registered cases of clear cell cancer, 60 percent are known DES-exposures, and 40 percent are either known unexposed or unknown exposure. Sixty-five percent are still alive; 320 have survived 5 years or more; and 133 women have had recurrences of cancer. The average ages of diagnosis were 30 years for 56 cases and 40 years for 14 cases, with a range from 7 to 48 years of age.

In another study, researchers received 220 responses to a mailed questionnaire that provided descriptive data from women with confirmed CCAC.28 The average age at diagnosis for these women was 22.7 years; 83 percent of those diagnosed were DES-exposed in utero Characteristics of this cohort included: 96 percent were white, more than half were married and/or college educated, and family histories of cancer were divided equally between DES-exposed and non-DES-exposed. Most of the women in this survey reported being able to work, and about 48 percent had children. Approximately 80 percent had a gynecological examination once a year, but the rate of chest x-rays was lower than recommended. The high number of survey participants receiving an annual gynecologic examination may be a result of the high response rate among DES daughters to the questionnaire.

In a case-control study by Julie Palmer, Sc.D., and colleagues at Boston University School of Public Health, 224 women in the registry known to be DES-exposed and who have CCAC were matched to similar women in the DCCS follow-up study who did not have CCAC. Preliminary findings indicate that CCAC was not associated with pregnancy, other female hormones, age at menarche, adult height, or births occurring in the fall. No factor provided a clear explanation as to why some women develop CCAC and others do not.29

At the University of Chicago, a study of depression in CCAC survivors showed that 74 percent were not depressed, unless they had complications from surgeries. The CCAC treatment history showed that most women were treated with surgery only, some had both surgery and radiation, and a smaller number had surgery, radiation, and chemotherapy. Sixty percent of the women were receiving HRT. Among the surgery cases, 81 percent had radical hysterectomies, half retained their ovaries, 67 percent had lymphadenectomies, and, among those with vaginectomies, 56 percent were partial and 27 percent were total vaginectomies. Eleven percent had recurrences, and the mean years since recurrence was about 5.9 years.

Summary of posters/abstracts

In the next phase of the breakout session, researchers provided summaries of their poster sessions and accompanying abstracts. (See Appendix V for poster abstracts.) Carol L. Rosenberg, M.D., Cancer Research Center, Department of Medicine, Boston University, summarized the poster, "Genetic Profile of Breast Cancer in Women Exposed in utero to DES." This research investigates whether there is a distinct genetic profile for breast tumors occurring in DES-exposed daughters compared with unexposed. To date, Dr. Rosenberg and her colleagues have microdissected 20 of the 40 archival breast cancer tissue specimens from the DCCS. The group is searching for DES-induced in vivo and in vitro genotoxicities, such as microsatellite instability and loss of heterozygosity. The research is still in progress, with 20 additional cases to be examined. On the basis of this and other research, Dr. Rosenberg urged others to study estrogen and progesterone receptor status in DES-exposed tissues.

Jan Bernheim, M.D., Ph.D., Professor, Department of Human Ecology, Free University of Brussels Medical School, summarized four posters. The latter two were done in collaboration with Antonius Hanselaar and coworkers in The Netherlands to study the long-term trends in CCAC using the Netherlands comprehensive nationwide cancer registry of CCAC cases. The update of the registry (referred to by Dr. Herbst) showed a double-peak incidence of CCAC cases, which indicates that there is an equally important incidence of non-DES-exposed CCAC in elderly women. Researchers used The Netherlands' nationwide pathology archive and patient status to study the ability of Pap smears to detect early-stage CCAC of the cervix and vagina. The study of the cytologic examinations compared with the histologic diagnosis of CCAC showed that the Pap smears were positive at stage 1 in the vagina and cervix in 100 percent of the cases. The researchers concluded that with appropriate pathologic surveillance, there should be no advanced cases of CCAC among (known) DES-exposed women.

Next, Dr. Bernheim, discussed research on evidence for estrogen-imprinting in humans in the project, "Midlife Status of Health of Antenatally DES-Exposed Persons." The primary question under investigation in this study is whether antenatal exposure to estrogen can result in lifetime alteration of estrogen-mediated functions ("estrogen imprinting") and, in turn, be manifested in midlife to protect women from osteoporosis, cardiovascular disease, and central nervous system diseases that are hormone sensitive. The last poster discussed by Dr. Bernheim represented a study investigating whether DES-exposed persons whose mothers had multiple spontaneous abortions were at increased risk for cancer for genetic reasons. The question is whether oncodevelopmental genes might be implicated in both spontaneous abortions and cancer. Dr. Bernheim thought that this cohort should be diagnosed and treated, as needed.

Janneke Verloop, M.Sc., Department of Epidemiology, Netherlands Cancer Institute, reported on a study that used the Netherlands DES Action Center to determine whether DES exposure in utero is associated with any cancers. In 1994, a questionnaire was mailed to 13,350 women; 5,421 responded (41 percent) with self-reports of various types of cancer. Sixty-five women reported cervical cancer, but when compared with medical files, only 14 cases were validated. Many of the women had reported in situ cancer as malignancy. Only a slight elevation in cervical cancer was found in DES-exposed women, compared with non-exposed women, and no association between DES exposure and other cancers was found. Because of problems of selectivity, the research team does not want to draw conclusions from these data.

The team is attempting to establish a new cohort and hopes to enroll 50,000 women using the DES Registry and the nationwide complete cancer registry in year 2000, provided adequate funding is available. Ms. Verloop hopes that they will be able to collaborate with U.S. cohort studies in the future.

Elizabeth Hatch, Ph.D., NCI, quickly reviewed some of the NCI studies presented during the poster sessions. Regarding DES-exposed daughters, the DCCS surveys have found an increased risk for CCAC but no increased risk for other cancers. Because most of the women in the study are under 50 years of age, Dr. Hatch emphasized the need for continued follow-up of this cohort. She noted that these findings are preliminary and based on self-reported data from mailed questionnaires and need to be confirmed by medical records. Other findings from the DCCS include:

Questions, answers, comments

The next part of this breakout session involved an open discussion that included a variety of questions, answers, and comments. Each comment or question is presented as its own paragraph.

Are there any studies that are looking at the infertility of DES-exposed sons?
Dr. Hatch responded that there was one comprehensive study in 1991, mentioned by Dr. Hoover, that did not find any difference in fertility of DES-exposed sons compared with unexposed. A question was included in the 1994 DCCS survey about the difficulty of fathering a child, and this question could be analyzed. It was noted that any available information would be welcome.

Is there a cohort of DES-exposed daughters of mothers with no history of spontaneous abortions who are being studied for the risks for any cancers?
Dr. Hatch said that about 30 percent of mothers had a history of spontaneous abortions. Dr. Helmrich asked Dr. Herbst to comment on the number of DES-exposed mothers in the Cancer Registry who had had prior spontaneous abortions compared with those who did not. Dr. Herbst noted that data are not recorded by this status; however, data from the registry show a statistically significant increase in the frequency of miscarriage among DES-exposed daughters who had clear cell cancer, when compared with those without clear cell cancer.

How were DES-exposed mothers selected for the DES studies?
Dr. Hatch recalled a mid-1970's DES mothers study in which subjects were identified through a review of prenatal medical records of mothers exposed to DES. The researchers searched the records at various clinics and then contacted women for permission to study them. This is a more valid method of obtaining subjects than relying on volunteers. In a follow-up question, an audience member asked if the doctors in this study were required to send in the names. Dr. Hatch responded that subjects were found in preselected medical centers, such as Dartmouth and the Mayo Clinic, for pregnancies that occurred between 1940 and 1960.

I am a DES-exposed mother; why didn't I know about these studies?
Dr. Helmrich explained that although these are large cohort studies at selected sites, they do not include all DES-exposed persons. She added that the NCI and the DES Cancer Network are interested in any concerns and issues from the workshop participants, such as lack of awareness of ongoing or new studies.

As a DES daughter, I am interested in any study of the effects of menopause and the contraindications of use of HRT. Is this being studied?
Dr. Hatch reported that questions about menopause and HRT are being investigated using the existing cohort. She noted that women in the 1997 survey are, on average, about 43 years old. Because of the relatively young average age of this cohort (relative to the average age of menopause among U.S. women, i.e., 52 years), however, data may not reveal any underlying associations that may exist. Despite this factor, the data need to be analyzed.

Is anyone looking at perimenopausal estrogen receptor blockade therapy in terms of DES-exposure? Is the question about DES exposure being asked in either the tamoxifen or the STAR (Study of Tamoxifen and Raloxifene) trial?
In response, it was noted that because the tamoxifen trial was started 7 years ago and the minimum age for enrollment was 35 years, it is doubtful that many of the DES-exposed daughters were eligible to enroll in that study. Dr. Helmrich commented that researchers need to contact those doing the surveys to ensure that questions about DES exposure are included in these trials. Dr. Hatch thought that there might be a problem with documenting DES-exposure status.

If one half of the DES-exposed mothers don't know they were exposed, don't we need better questions about whether they received the drug?
Yes.

A DES-exposed son inquired about research on age-related reproductive problems and prostate cancer.
Dr. Hatch reported that the DES-exposed sons cohort is being followed. Researchers collected additional information on cancers in the 1997 DCCS survey, including questions about prostate cancer; however, the sons' cohort is a little young for prostate cancer, which is most prevalent after age 60. Long-term follow-up is warranted. One of the key problems with sons' studies, however, is the low response rate from DES sons compared with daughters.

Could the sons' cohort be extended? Could the DES-exposed daughters be questioned as to whether they might have brothers who were exposed?
Dr. Hatch said there are 250 additional sons from the DES-exposed mothers study, but the sons' cohort is small. She did not know of any other cohorts that could be added to the study. She thought that this might be pursued through questions to the sisters.

A testicular cancer survivor and another DES son stated their frustrations at the lack of information available to sons and wanted to know how people can find out if they are exposed.
Dr. Helmrich responded that the DES Cancer Network receives these kinds of questions all the time. She noted that it is difficult to locate the mother's medical records because the mothers and their the doctors are often deceased. She suggested that individuals ask other relatives or search pharmaceutical records for information. She strongly emphasized the need to have absolute documentation of DES exposure for research findings to be valid.

Why are questions about DES exposure not asked routinely in all studies and by all doctors doing gynecological exams?
In brief, this question should probably be asked in all trials.

Why are there so few studies on reproductive abnormalities, such as T-shaped uteri and premature labor? Women who have a T-shaped uterus are not being counseled properly.
Dr. Hatch responded that Dr. Kaufman conducted a study about 15 years ago that showed a correlation between DES exposure and reproductive abnormalities. NCI is not collecting data on uterine malformations, however, but the DESAD data could be analyzed for such correlations. Confounding any such studies is that appropriate tests to detect uterine abnormalities may not have been done; further, most of the exposed women are beyond childbearing age.

Is anything else regarding DES mothers being studied?
Dr. Hatch said that recent analysis of the 1980's cohort of DES mothers showed a 30 percent increased risk of breast cancer in this cohort; this result confirmed the findings of other studies, such as the randomized trial in the Dieckmann cohort.

Why is information not getting out to us and why are doctors not informing patients of the problem?
Dr. Helmrich agreed that these issues are extremely important, should be addressed in the education session, and should be relayed to health educators and physicians. Often physicians mistakenly tell DES-exposed women that there is no longer a problem--thus underscoring the need for physician education.

The husband of a DES-exposed daughter who was not in any study wanted to know if women who knew their exposure status could volunteer for a study.
Dr. Hatch informed the group that these studies were based on defined populations where prenatal records were reviewed and that accepting volunteers might make the sample unrepresentative and invalidate the results. However, volunteers can help researchers design better research questions.

What information is available regarding how long, how many attempts, and in what ways DES-exposed daughters took to achieve conception?
Dr. Hatch noted that successes using different means of achieving pregnancy, including in vitro methods and artificial insemination, could be analyzed with current data. In fact, she noted, some smaller studies have looked at in vitro success rates. Dr. Herbst stated that earlier studies showing an 80 percent pregnancy success rate were done before in vitro methods were available. Findings will vary, of course, according to the age of individuals and whether the uterus is abnormal, making it difficult to obtain reliable information.

How many people are in the registry compared with the number of exposed persons?
The University of Chicago Registry currently includes 715 cases of clear cell adenoma of the cervix or vagina. Estimates of the total number of persons exposed in utero to DES also have been made based in part on cohort studies. The NCI Continuation of Follow-up Study includes 6,000 to 7,000 DES daughters and 2,500 DES sons. An audience member estimated the number of DES-exposed daughters to be 2.5 million. Another estimate similarly suggests that as many as 3 million women in the United States may have been exposed to DES in utero.8

Conclusions and Recommendations

The last task for the group involved reaching consensus on areas for future research and other issues. The following research needs and issues were identified:

The group was unable to reduce the list to the most important two and requested that all the above recommendations be reported during the co-chairs' discussion and/or in the final workshop report.

Co-chairs' report

The co-chairs of the epidemiology breakout group noted that a wide range of issues was covered during the small-group session and that participants found it difficult to limit their recommendations to just two points. The co-chairs thus grouped the issues discussed into three broad categories, as follows:

Education/Outreach Overview

Overview/presentation

Rounding out the presentations was Deborah Wingard, Ph.D., Professor of Preventive Medicine, University of California at San Diego, who provided highlights of the pilot National DES Education Program. This program, initially headed by Suzanne Haynes, Ph.D., Assistant Director for Science, US PHS OWH and currently directed by Sherry Mills, M.D., M.P.H., Chief, Applied Sociocultural Research Branch, Division of Cancer Control and Population Sciences, NCI, was a collaborative effort among five separate projects. The research teams consisted of scientists and advocacy groups that contributed to the design and implementation of the education programs.

The history of DES education and outreach through the NIH extends back to 1971, when the FDA issued a bulletin warning about the use of DES during pregnancy. By 1980, a provider booklet (the "brown book") was published describing DES-induced cancer, its diagnosis, and treatment. A second provider booklet was published in 1983, and in 1992, the first national DES conference, the predecessor of the current meeting, was held. In 1993, the National DES Education Program was launched. This year, the current NIH workshop was planned and held.

In parallel with the government's activities in this area, consumer groups have undertaken major education and outreach efforts. The year 1975 marks the founding year for establishment of several DES advocacy groups, including DES Action (1975), the DES Cancer Network (1982), DES Sons' Network (1985), and the DES Third Generation Network (1995). In addition, several DES international affiliates were established during the 1980's and 1990's. For example, the Australian, Netherlands, and Canadian affiliates were established in 1981, 1982, and 1983, respectively; affiliates in Ireland and Belgium were founded in 1990 and 1994, respectively. All of these groups are interested in educating the public and providers as well as offering support to DES-exposed individuals; this support occurs in person, over the phone, and through information dissemination. These groups also advocate continued DES research and funding for all aspects of research and education.

As part of the effort to define the extent of the need for DES education and outreach to the public, the California Behavioral Risk Factor Survey of 1994 included several DES questions.30 This survey is conducted annually in most states and identifies participants through a random-digit sampling of all telephone numbers within a state. This type of sampling allows for a relatively representative sampling of each state's population.

The DES questions in the 1994 California survey were targeted to those aged 23 years and over; the sample included 2,071 women and 1,625 men. Fewer than 50 percent of those in virtually every subgroup of this sample had ever heard of DES. The subgroups were divided by age, gender, racial or ethnic background, education level, and income. In all racial/ethnic groups (whites, blacks, Hispanics), more women than men were aware of DES. The highest level of awareness by racial/ethnic group was among whites, and the lowest level was among Hispanics. Although DES use was most common in whites, women in other groups were given the drug, so awareness across racial and ethnic groups is important. Knowledge of DES according to age, education, and income level among white women revealed that the greatest awareness, although still less than 50 percent, was for those between 39 and 53 years of age, those who had a college education, and those with a household income of at least $50,000. Similar trends were seen for the other racial/ethnic groups. Across all groups and subgroups, lower proportions were aware of the effects and consequences of DES exposure. The California survey also inquired about awareness regarding personal exposure. Within the population sampled, of the 50 percent of those who were aware of DES, only half reported having made an effort to determine whether they had ever taken DES or had been exposed to the drug in utero. Thus, only one quarter of the persons in the sample had investigated the possibility of their own DES exposure.

Given these findings, it became clear that increased DES education of and outreach to the general public was important. In response to this need, the National DES Education Program, funded jointly by the NCI and the National Institute of Child Health and Development, was begun in 1993 and continued through 1997. 31 It included five interactive projects, each of which shared four common goals:

At all five sites, the project began with a survey of the general public to assess general awareness and knowledge of DES. Participants were identified between 1994 and 1995 using random phone or mail sampling. The five geographic areas included in the project were Northern California, New York, Texas, Boston, and various Midwestern states. In this survey, the proportion of those who had heard of DES ranged from 31 to 58 percent, with the highest rates among those in California (58 percent) and Boston (47 percent). These higher rates may reflect the higher levels of activist and educational activities in those areas of the country compared with the other regions surveyed. The percent that attempted to confirm exposure was low, between 11 and 22 percent of all those sampled. Responses to questions about accuracy of knowledge of DES were similarly low.

The primary sources of information about DES were newspapers, magazines, television, or radio (58 to 61 percent of those who were aware of DES); health care providers were the least likely source of information about DES (only 7 to 24 percent reported this as a source). When asked whether their health care providers had ever inquired about exposure to DES, only 6 to 11 percent of the respondents reported that the provider asked about DES use during a past pregnancy, 18 to 31 percent inquired about in utero exposure, and 8 to 26 percent provided a health history form that asked about DES exposure. Further, very few respondents (3 to 5 percent) reported having specifically asked their providers about DES.

Essentially all the sites used media campaigns as their primary interventions to increase awareness of DES among the public. These campaigns used television, radio, and print media and included public service announcements. One site used an opinion leader training method, in which leaders in the DES field were chosen to disseminate the DES message using several aspects of the DES Action model. All sites helped develop booklets that could be used across the country and are still available. These books, which were tested using focus groups, have multiple targets (e.g., DES mothers, DES sons, DES daughters, plus more general topics) and try to present a positive message (i.e., with a focus on awareness and proper preventive care). Several sites also put together information/educational videos and films and some wrote and performed plays. In addition, all sites promoted the use of the toll-free phone number 1-800-DES-NEWS, which is still active and connects directly to DES Action offices.

Dr. Wingard explained that the opinion leader strategy for information dissemination is based on the belief that women rely on networks to learn about health and that unique individuals in the community can be used to exploit these networks. Using this approach, the California site trained five leaders who would each educate five individuals about DES; each of those five persons was then asked to educate an additional five persons. This strategy thus forms a tree or pyramid design. A complete training kit was designed to educate the leaders and assist them in their information dissemination efforts. The ultimate goal was to reach 50,000 persons starting with 100 trained opinion leaders. The impact of the opinion leader training was assessed using a random survey before and after the intervention. The assessment revealed that this technique increased the percent of DES discussions occurring in the community as well as the awareness of DES within the community. It also increased efforts to confirm exposure to DES.

Additional results taken across all sites showed that the media campaigns were moderately effective. The impact of these campaigns was related to the level of awareness or knowledge prior to implementation of the interventions. For example, in Massachusetts, where preintervention awareness was already relatively high, the media campaigns were less effective than in regions where prior DES knowledge was low (e.g., in the Midwest). However, the media interventions did not appear to change behaviors, such as attempts to confirm exposure. The media campaigns were most successful when combined with provider interventions.

Recommendations developed from results of the public interventions included:

A second barrier identified through this survey was a lack of knowledge about DES among health care providers. This lack of knowledge was apparent even when DES-exposed persons inquired about the effects of their exposure. To address this concern, the program conducted a series of interventions targeted toward health care providers. These interventions included a survey of providers to measure provider knowledge; information was obtained through responses to questionnaires mailed directly to physicians, through surveys of HMO's, and through a "convenience" sample of providers.

Results compared knowledge of primary care physicians with that of ob/gyns. Preliminary and subsequent analyses showed clear differences in the level of knowledge about DES between these two groups, which was expected, Dr. Wingard pointed out. Overall, awareness of DES was relatively high in both physician groups, with 80 to 90 percent of doctors in both groups familiar with DES. A higher percentage of ob/gyns (28 to 58 percent) reported being very familiar with DES, compared with the primary care physicians (7 to 13 percent were very familiar). However, less than half (20 to 47 percent) of the primary care providers had read the national DES guidelines for practice, in contrast with at least two thirds (70 to 91 percent) of the ob/gyns. For both groups, the proportion of physicians who routinely asked their patients about DES exposure was low, with only 7 to 20 percent of the primary care doctors and 24 to 72 percent of the ob/gyns falling into this category.

Providers were also asked about whether certain conditions are associated with DES exposure. The results were as follows. Both groups of doctors were aware of the most well-known conditions associated with DES exposure--vaginal cancer (86 to 100 percent of all doctors) and structural malformations of the reproductive tract of DES daughters (58 to 78 percent of primary care doctors and 96 to 97 percent of ob/gyns). A much lower proportion (10 to 31 percent of general practitioners, 47 to 58 percent of ob/gyns) were aware that DES daughters were at increased risk for ectopic pregnancies or miscarriages. Further, only 11 to 21 percent of ob/gyns and 8 to 17 percent of general practitioners knew that women given DES during pregnancy (DES mothers) are at increased risk for breast cancer. Fewer than half (14 to 27 percent of general practitioners, 6 to 39 percent of ob/gyns) were aware that DES sons were at risk of testicular lumps or epididymal cysts.

The providers' sources of DES information included the medical literature and/or professional lectures/seminars (59 to 89 percent), notices from professional societies or government agencies (22 to 62 percent), patients and their families (7 to 43 percent), and DES advocacy groups (2 to 18 percent). The latter two points suggest that the interaction between provider and patient can be an important mode for information exchange.

The provider intervention used most frequently across all sites was a technique known as academic detailing, in which physicians trained in DES issues took a DES "tool kit" containing posters, booklets, videos, slides, and other patient and physician educational materials, to other physicians' offices. Another intervention involved the development of algorithms for the treatment of DES mothers and children; in essence, these gave providers a boilerplate as to how to take a history of DES exposure and how to treat DES-exposed patients.

Results of the impact studies of the provider interventions revealed that printed materials, by themselves, were insufficient educational tools. Dr. Wingard and her colleagues also found that it was very difficult to get providers to attend seminars and other informational events. However, the intervention conducted in the HMO was more effective in reaching providers because the physicians were a "captive" audience in a system that already had in place mechanisms for education and outreach within the organization. The academic detailing, which was labor intensive and costly, proved to be successful; the level of familiarity with DES, as well as the number of physicians who read the DES guidelines and routinely asked their patients about exposure, increased through this intervention. However, this provider intervention alone did not markedly change patient behavior or knowledge.

In closing her presentation, Dr. Wingard outlined the most common questions and concerns raised by callers to the advocacy group, DES Action USA. These include questions and concerns about:

Resources for future DES education and outreach efforts include:

Breakout discussion summary (Co-chairs, Sherry Mills, Ph.D., Judith Helfand)

Participants in this breakout group considered a wide range of issues that touched on education and outreach to physicians, medical students, and other health care providers; patients; the general public; and insurers. Participants discussed the type of information that needs to be disseminated, vehicles for dissemination, and oversight of dissemination. They also discussed the issue of funding education and outreach efforts. Highlights of this discussion include:

Co-chairs' report

The co-chairs reported that those in this breakout group engaged in a lively discussion about how to expand the DES message to patients, the public, and health care providers and insurers. Highlights of that discussion included:

Next

Notes:

  1. Bell SE, Apfel RJ. Looking at bodies: Insights and inquiries about DES-related cancer. Qual Sociology 18:3-19, 1995

  2. (a) Taylor HS, Vanden Heuvel GB, Igarashi P. A conserved Hox axis in the mouse and human female reproductive system: Late establishment and persistent adult expression of the Hoxa cluster genes. Biol Reprod 57:1338-1345, 1997. (b) Ma L, Benson GV, Lim H, Dey SK, Maas RL. Abdominal B (AbdB) Hoxa genes: regulation in adult uterus by estrogen and progesterone and repression in Muellerian duct by the synthetic estrogen diethylstilbestrol (DES). Dev Biol197:141-154, 1998

  3. (a) Wingard DL, Turiel J. Long-term effects of exposure to diethylstilbestrol. West J Med 149:551-554, 1988. (b) Kalland T, Campbell T. Effects of diethylstilbestrol on human natural killer cells in vitro. Immunopharmacology 8:19-25, 1984. (c) Ablin RJ, Bartkus JM, Gonder MJ. In vitro effects of diethylstilbestrol and the LHRH analogue leuprolide on natural killer cell activity. Immunopharmacology 15:95-101, 1988. (d) Ways SC, Mortola JF, Zvaifler NJ, Weiss RJ, Yen SS. Alterations in immune responsiveness in women exposed to diethylstilbestrol in utero. Fertil Steril 48:193-197, 1987. (e) Holladay SD, Baylock BL, Comment CE, Heindel JJ, Fox WM, Korach KS, Luster MI. Selective prothymocyte targeting by prenatal diethylstilbestrol exposure. Cell Immunol 152:131-142, 1993

  4. Noller KL, Blair PB, O'Brien PC, Melton LJ III, Offord JR, Kaufman RH, Colton T. Increased occurrence of autoimmune disease among women exposed in utero to diethylstilbestrol. Fertil Steril 49:1080-1082, 1988

  5. Smith OW, Smith GV. The influence of diethylstilbestrol on the progress and outcome of pregnancy as based on a comparison of treated with untreated primagravidas. Am J Obstet Gynecol 56:994-1000,1948

  6. Merchant WJ, Gale J. Intestinal metaplasia in stilboestrol-induced vaginal adenosis.Histopathology 23:373-376, 1993

  7. Herbst AL, Anderson S, Hubby MM, Haenszel WM, Kaufman RH, Noller KL. Risk factors for the development of diethylstilbestrol-associated clear cell adenocarcinoma: A case-control study. Am J Obstet Gynecol 154:814-822, 1986 (Comment in Am J Obstet Gynecol 172:1651-1652, 1995)

  8. Waggoner SE, Mittendorf R, Biney N, Anderson D, Herbst AL. Influence of in utero diethylstilbestrol exposure on the prognosis and biologic behavior of vaginal clear-cell adenocarcinoma. Gynecol Oncol 55:238-44, 1994

  9. Macarthur C, Foran PJ, Bailar JC III. Qualitative assessment of studies included in a meta-analysis: DES and the risk of pregnancy loss. J Clin Epidemiol 48:739-747, 1995

  10. Robboy SJ, Noller KL, O'Brien, P, Kaufman RH, Townsend D, Barnes AB, Gundersen J, Lawrence D, Bergstrahl E, McGorray S, Tilley B, Anton J, Chazen G. Increased incidence of cervical and vaginal dysplasia in 3,980 diethylstilbestrol-exposed young women. Experience of the National Collaborative Diethylstilbestrol Adenosis Project. JAMA 252:2979-2983, 1984

  11. Kaufman RH, Adam E, Noller K, Irwin JF, Gray M. Upper genital tract changes and infertility in diethylstilbestrol-exposed women.Am J Obstet Gynecol 154:1312-1318, 1986

  12. Calle EE, Mervis CA, Thun MJ, Rodriguez C, Wingo PA, Heath CW Jr. Diethylstilbestrol and risk of fatal breast cancer in a prospective cohort of US women. Am J Epidemiol 144:645-652, 1996

  13. Hornsby PP, Wilcox AJ, Herbst AL. Onset of menopause in women exposed to diethylstilbestrol in utero. Am J Obstet Gynecol 172(1 Pt 1):92-95, 1995

  14. Melnick S, Cole P, Anderson D, Herbst AL. Rates and risks of diethylstilbestrol-related clear cell adenocarcinoma of the vagina and cervix. N Engl J Med 316:514-516, 1987

  15. Robboy SJ, Szyfelbein WM, Goellner JR, Kaufman RH, Taft PD, Richart RM, Gaffey TA, Prat J, Virata R, Hatab PA, McGorray SP, Noller KL, Townsend D, Labarthe D, Barnes AB. Dysplasia and cytologic findings in 4,589 young women enrolled in the Diethylstilbestrol-Adenosis (DESAD) Project. Am J Obstet Gynecol 140:579-586, 1981

  16. Wilcox AJ, Baird DD, Weinberg CR, Hornsby PP, Herbst AL. Fertility in men exposed prenatally to diethylstilbestrol. N Engl J Med 332:1411-1416, 1995

  17. Baird DD, Wilcox AJ, Herbst AL. Self-reported allergy, infection, and autoimmune diseases among men and women exposed in utero to diethylstilbestrol. J Clin Epidemiol 49:263-266, 1996

  18. Helmrich SP, Anderson DA, Palmer JR, Shena SA, Herbst AL. The DES Clear Cell Cancer Cohort described. Manuscript in preparation

  19. Palmer J, Anderson D, Helmrich S, Herbst, AL. Risk Factors for Diethylstillberstol-Associated Clear Cell Adenocarcinoma. Personal communication, Julie Palmer

  20. Wingard DL, Cohn BA, Helmrich SP, Edelstein SL. DES awareness and exposure: The 1994 California Behavioral Risk Factor Survey. Am J Prev Med 12:437-441, 1996

  21. National DES Educational Program for Health Professionals and the Public, (RFA CA-93-022), National Institutes of Health Guide, Volume 22, Number 15, April 16, 1993



Home Inroduction/Background Opening Remarks State of the Research Advocates' Remarks Recommendations and Findings Closing Remarks Appendices