Design and preliminary observations of the National Cooperative Diethylstilbestrol Adenosis Project

Obstetrics and Gynecology, DESAD Project, 1978

DESAD-Project logo
Aims of the 1978 DESAD Project: to fill urgent needs for information on the prevalence and incidence of structural and epithelial abnormalities or neoplastic changes and their complications in DES Daughters.

1978 Paper Abstract

The National Cooperative Diethylstilbestrol Adenosis (DESAD) Project has completed the major portion of its enrollment phase with the examination of more than 3000 daughters of women taking synthetic nonsteroidal estrogens (denoted diethylstilbestrol DES) during pregnancies occurring from the early 1940s to the mid-1960s.

The aims of the Project are to fill urgent needs for information on the prevalence and incidence of structural and epithelial abnormalities or neoplastic changes and their complications in these young women.

Participants are grouped by mode of entry as identified by prenatal record review (40.1%), documented as DES-exposed but walking in (25.1%), or referred (22.8%) to the DESAD Project for examination, and not documented as exposed but having gynecologic abnormalities typical of those associated with DES exposure (12.0%).

This study cohort, in part having paired controls, will be examined annually for at least 5 years. Details of the design and selected preliminary findings are reported.

Sources and more information
  • Design and preliminary observations of National Cooperative Diethylstilbestrol Adenosis (DESAD) Project, Obstetrics and Gynecology 1978 Apr;51(4):453-8, NCBI PMID: 662228.
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Epidemiological studies of the effects of diethylstilbestrol

Vessey MP, National Center for Biotechnology Information, 1989

Epidemiological-studies graphic
Herbst and his colleagues have suggested that DES is not a complete carcinogen, but that some other factor is involved in the pathogenesis of clear-cell carcinoma of the vagina and cervix.

1989 Study Abstract

Herbst and his colleagues first showed in 1971 that girls born to mothers who had taken diethylstilbestrol (DES) during pregnancy were at an increased risk of clear-cell adenocarcinoma of the vagina and cervix. At first it was feared that these girls would have a high probability of developing clear-cell carcinomas, but the latest report from the Registry for Research on Hormonal Transplacental Carcinogenesis of the University of Chicago puts the risk at only 1 per 1000 of those exposed, from birth through to age 34.

On this basis, Herbst and his colleagues have suggested that DES is not a complete carcinogen, but that some other factor is involved in the pathogenesis of clear-cell carcinoma of the vagina and cervix.

Women exposed in utero to DES have a high prevalence of vaginal adenosis and tend, therefore, to have an extensive transformation zone on the cervix and in the vagina. There is considerable controversy as to whether or not such women are at increased risk for vaginal and cervical intraepithelial neoplasia.

The latest findings from the Study of the Incidence and Natural History of Genital Tract Anomalies and Cancer in Offspring Exposed in Utero to Synthetic Estrogens (the DESAD project) are, however, worrying; during follow-up, vaginal and cervical intraepithelial neoplasia occurred at a rate of 15.7/1000 woman-years in the exposed and at a rate of 7.9/1000 woman-years in the controls (p = 0.01).

There is some evidence that exposure in utero to exogenous oestrogens increases the risk of testicular cancer in males. The findings, however, are not conclusive, and the effect does not seem to be specific to DES and related nonsteroidal oestrogens.

Sources and more information
  • Epidemiological studies of the effects of diethylstilboestrol, IARC Sci Publ. 1989;(96):335-48. NCBI PMID: 2680951.
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Structural anomalies of the cervix and vagina in women enrolled in the Diethylstilbestrol Adenosis Project

Prevalence rate of the anomalies lower among subjects who had been pregnant, and higher among those with later age at menarche

woman-thinking
DiEthylStilbestrol usage review buttress the need for adequate and rigorous research into the use of drugs in pregnancy and ensure that they do more good than harm before being introduced for consumption. Contemplation by Rennett Stowe.

1984 Study Abstract

Among women exposed in utero to diethylstilbestrol (DES) and enrolled in the Diethylstilbestrol Adenosis (DESAD) Project, structural anomalies of the cervix or vagina were found in 25% of the 1,655 subjects identified by review of prenatal records, 43% of the 800 who themselves requested entry into the project, and 49% of the 1,089 referred by physicians but in only 2% of the 963 control subjects. Among the 367 cases found by record review to have complete information on the DES exposure, multivariate analysis indicated close association of the anomalies with the gestational week of first exposure and the total dose. Also, the prevalence rate of the anomalies was lower among subjects who had been pregnant and higher among those with later age at menarche.

Sources and more information
  • Structural anomalies of the cervix and vagina in women enrolled in the Diethylstilbestrol Adenosis (DESAD) Project, Am J Obstet Gynecol, NCBI PMID: 6691382, 1984 Jan 1;148(1):59-66.
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In-Utero DES Exposure associated with a Higher Rate of Herpes and HPV infections

Development of cervical and vaginal squamous cell neoplasia as a late consequence of in utero exposure to diethylstilbestrol

herpes-simplex-virus
In 1984, the DES-Adenosis (DESAD) Project found that DES-exposed daughters are associated with a higher rate of herpes simplex virus and human papillomavirus infections.

1988 Study Abstract

During the last 14 years, several articles have given contradictory reports on prevalence rates of squamous cell neoplasia of the cervix and vagina in diethylstilbestrol (DES)-exposed progeny.

In 1984, the DES-Adenosis (DESAD) Project found that the incidence of cervical and vaginal intraepithelial neoplasia in DES-exposed daughters was twice as high as in a comparison group of unexposed women.

This was also associated with a higher rate of herpes simplex virus and human papillomavirus infections. Possible hypotheses on the etiology of the increased incidence of squamous neoplasia are discussed.

Sources and more information
  • Development of cervical and vaginal squamous cell neoplasia as a late consequence of in utero exposure to diethylstilbestrol,
    NCBI PMID: 2829071, Obstet Gynecol Surv. 1988 Jan;43(1):15-21.
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The association between in utero cigarette smoke exposure and age at menopause

Prenatal exposure to maternal cigarette smoke may play a role in programming age at menopause

cigarette-and-pregancy image
In this cohort of participants predominantly exposed to diethylstilbestrol, results suggest that prenatal exposure to maternal cigarette smoke may play a role in programming age at menopause.

2008 Study Abstract

Menopause onset, on average, occurs earlier among women who smoke cigarettes than among women who do not smoke. Prenatal smoke exposure may also influence age at menopause through possible effects on follicle production in utero.

Smoking information was obtained from the mothers of 4,025 participants in the National Cooperative Diethylstilbestrol Adenosis (DESAD) Project, a US study begun in 1975 to examine the health effects of prenatal diethylstilbestrol exposure. Between 1994 and 2001, participants provided information on menopausal status. Cox proportional hazards modeling compared the probability of menopause among participants who were and were not prenatally exposed to maternal cigarette smoke.

Participants prenatally exposed to maternal cigarette smoke were more likely than those unexposed to be postmenopause (hazard ratio = 1.21, 95% confidence interval: 1.02, 1.43). The association was present among only those participants who themselves had never smoked cigarettes (hazard ratio = 1.38, 95% confidence interval: 1.10, 1.74) and was absent among active smokers (hazard ratio = 1.03, 95% confidence interval: 0.81, 1.31).

In this cohort of participants predominantly exposed to Diethylstilbestrol (DES) , results suggest that prenatal exposure to maternal cigarette smoke may play a role in programming age at menopause. The possibility that active cigarette smoking modifies this effect is also suggested.

Sources
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Breast cancer incidence in women prenatally exposed to maternal cigarette smoke

Prenatal hormone exposure may affect future breast cancer risk

DES Follow-up Study Summary

National Cancer Inst logo image
These 2005 study results provide further evidence supporting the hypothesis that prenatal hormone exposure may affect future breast cancer risk.

Fetal exposure to maternal pregnancy hormones may influence future breast cancer risk and cigarette smoking is among the factors believed to alter pregnancy hormone levels. Specifically, total pregnancy estrogen levels are slightly decreased among pregnant women who smoke relative to women who do not. More pronounced reductions of pregnancy estiol (E3) and estradiol (E2) were observed among smoking women. Possibly, women prenatally exposed to maternal cigarette smoke may have reduced breast cancer risk as an adult. The National Cooperative DES Adenosis (DESAD) Project was a prospective study of the effects of prenatal Diethylstilbestrol (DES) exposure. When women were enrolled in the study from 1975 through 1981, their mothers were questioned about their health habits including cigarette smoking during their pregnancy with the study participant. Using responses to this question provided by the mothers at the start of the study, investigators were able to compare the breast cancer rates among women who were and were not prenatally exposed to maternal cigarette smoke. Investigators observed a 51% decrease in breast cancer rates among women whose mothers smoked while pregnant with them compared to women who were not prenatally exposed to maternal cigarette smoke. Daughters of women who smoked 15 or fewer cigarettes per day during the pregnancy appeared to have a 65% reduction in breast cancer rates compared to women whose mothers did not smoke during pregancy. The adverse effects of prenatal cigarette smoke exposure far outweigh any benefit from possible reduction of breast cancer risk. These study results do, however, provide further evidence supporting the hypothesis that prenatal hormone exposure may affect future breast cancer risk.

2005 Study Abstract

BACKGROUND:
Clinical studies show that maternal cigarette smoking reduces pregnancy estrogen levels. Women prenatally exposed to maternal cigarette smoke may, therefore, have a lower breast cancer risk because the fetal mammary gland’s exposure to maternal estrogen is decreased. Associations between prenatal maternal cigarette smoke exposure and breast cancer, however, have not been observed in previous case-control studies that relied on exposure assessment after the onset of cancer. At the start of this study, cigarette smoking history was obtained directly from the mother.

METHODS:
The National Cooperative DES Adenosis project was a follow-up study of health outcomes in women prenatally exposed to diethylstilbestrol (DES). At the start of the study, women’s mothers provided information about cigarette smoking habits during the time they were pregnant with the study participant. In the current study, the breast cancer rates are compared among 4031 women who were or were not prenatally exposed to maternal cigarette smoke. The resultant relative rate (RR) is adjusted for potential confounding by other breast cancer risk factors using Poisson regression modeling.

RESULTS:
Fetal exposure to maternal cigarette smoke appeared to be inversely associated with breast cancer incidence (RR = 0.49; 95% confidence interval [CI] = 0.24-1.03). The inverse association was more apparent among women whose mothers smoked 15 cigarettes or fewer per day than among daughters of heavier smokers. There were, however, too few cases to precisely estimate a possible dose-response relationship.

CONCLUSION:
These results support the hypothesis that in utero exposure to maternal cigarette smoke reduces breast cancer incidence.

Sources

  • Breast cancer incidence in women prenatally exposed to maternal cigarette smokeNCBI, PMID: 15824550, 2005 May;16(3):342-5.
  • NCI, DES Follow-up Study Published Papers.
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Dysplasia and Cytologic Findings in 4589 Young Women enrolled in DiEthylStilbestrol-Adenosis Project

DiEthylStilbestrol usage review buttress the need for adequate and rigorous research into the use of drugs in pregnancy and ensure that they do more good than harm before being introduced

Abstract

image of PubMed NCBI The Endocrine Society logo
DiEthylStilbestrol usage review buttress the need for adequate and rigorous research into the use of drugs in pregnancy and ensure that they do more good than harm before being introduced.

This report presents the cytologic findings and the rates of dysplasia for 4,589 young women enrolled in the National Cooperative Diethylstilbestrol-Adenosis (DESAD) Project. Mucinous columnar cells and/or metaplastic squamous cells with or without mucinous droplets were encountered in 22% of vaginal scrape smears from all diethylstilbestrol (DES)-exposed participants identified by review of prenatal records and in 43% of women in whom vaginal epithelial changes (VEC) were observed by colposcopy or by iodine staining. The frequency of cellular findings in the vaginal scrape smears was closely related to the timing of the administration of the DES to the mother. With increasing age of the daughters, the overall frequencies of both the mucinous and metaplastic cells decreased; relative to each other, an increasing proportion was metaplastic squamous cells. These data suggest that, as the women grow older, vaginal adenosis regresses by the process of squamous metaplasia. Endometrial type cells were found in 2% of vaginal scrape smears. Their cyclical occurrence during the menstrual cycle and lack of correlation with the presence of VEC indicated an origin from the uterine corpus rather than the tuboendometrial type of adenosis. Squamous cell dysplasia of the vagina and cervix was detected by biopsy or scrape smear specimens in 1.8% of DES-exposed women in the record review group. The rate of unexposed women was twice as high. In general, the rates of dysplasia were higher in the cervix than vagina, and the more severe degrees of dysplasia were encountered only in those women who were referred to the DESAD Project or who themselves requested entry. Four patients who were referred or who themselves requested entry were found to have clear cell adenocarcinoma of the vagina. The vaginal smear provided the first clue to the presence of an abnormality in three of them.

Sources

  • Dysplasia and cytologic findings in 4,589 young women enrolled in diethylstilbestrol-adenosis (DESAD) project, NCBI, PMID: 7195652, Am J Obstet Gynecol. 1981 Jul 1;140(5):579-86.
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Preterm Birth, Fetal Growth, Age at Menarche among Women exposed prenatally to DiEthylStilbestrol

DES exposed daughters more likely to have begun menstruating at younger age

DES Follow-up Study Summary

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DES exposed daughters appeared to weigh slightly less and have a higher risk of being born prematurely than unexposed daughters. They also were somewhat more likely to have begun menstruating at age 10 or younger.

Research has suggested that early life characteristics, such as size at birth and age at menarche, may be associated with health conditions later in life. For example, some studies have suggested that low birth weight babies tend to have a higher risk of cardiovascular disease later in life. Other studies have shown that women who begin having periods at a young age have a slightly higher risk of breast cancer than those who begin menstruation later.

Although there has been a great deal of research on health of the 2nd generation (DES daughters) later in life, little attention has been paid to whether they were similar in terms of birth weight and other early life factors. Results from one of the early clinical trials of DES suggested that it might be related to lower birth weight and a higher risk of preterm birth. We conducted a systematic evaluation of DES daughters participating in the NCI DES Follow-up Study to determine whether there were any differences in birth weight, length of gestation, and the average age of first menstruation in the DES-exposed compared to unexposed daughters.

We found that there was a 2 to 3 fold increase in risk of having been born prematurely (before 37 weeks gestational age) among the DES-exposed compared to unexposed daughters. On average, DES daughters tended to weigh slightly less at birth, and there was also a 60% higher risk of being born too small, or small for gestational age (SGA), defined as less than the 10th percentile of birth weight at each gestational age. We found stronger effects for birth weight, SGA, and preterm birth among women who were participants in the original DESAD study, as compared to those who were in the Dieckmann clinical trial, suggesting that part of the effect may have been due to the higher risk pregnancies among the exposed women and not solely to DES exposure.

When we evaluated the risk of having started menstruation before age 11, we found no difference between the DES exposed and unexposed daughters. However, DES daughters did have a small increased risk (40%) of starting menarche very young-at age 10 or less-but this was based on very small numbers of participants who had very early menstruation.

In summary, DES exposed daughters appeared to weigh slightly less and have a higher risk of being born prematurely than unexposed daughters. They also were somewhat more likely to have begun menstruating at age 10 or younger. These effects may have a small impact on the risk of some diseases occurring later in life.

2011 Study Abstract:

Diethylstilbestrol (DES), a synthetic estrogen used in pregnancy during the 1950s and 1960s, provides a model for potential health effects of endocrine disrupting compounds in the environment. We evaluated prenatal exposure to DES, based on medical record review, in relation to gestational length, fetal growth, and age at menarche in 4429 exposed and 1427 unexposed daughters. DES exposure was associated with an increase in preterm birth (odds ratio (OR)=2.97; 95% CI=2.27, 3.87), and a higher risk of small for gestational age (SGA) (OR=1.61; 95% CI=1.31, 1.98). The association between DES exposure and early menarche was borderline, with stronger effects when early menarche was defined as ≤ 10 years (OR=1.41 95% CI=0.97, 2.03) than defined as ≤ 11 years (OR=1.16; 95% CI=0.97, 1.39). This study provides evidence that prenatal DES exposure was associated with fetal growth and gestational length, which may mediate associations between DES and health outcomes in later life.

Sources:

  • Preterm birth, fetal growth, and age at menarche among women exposed prenatally to diethylstilbestrol (DES),NCBI, PMID: 21130156, 2011 Feb;31(2):151-7. doi: 10.1016/j.reprotox.2010.11.006. Epub 2010 Dec 2. Full text link.
  • NCI, DES Follow-up Study Published Papers.
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Incidence of Squamous Neoplasia of the Cervix and Vagina in Women exposed prenatally to DES

The 2001 stuy findings support an association between in-utero DES exposure and high-grade squamous neoplasia.

DES Follow-up Study Summary

National Cancer Inst logo image
The 2001 stuy findings support an association between in-utero DES exposure and high-grade squamous neoplasia.

Women exposed to Diethylstilbestrol (DES) before birth (in the womb), known as DES Daughters, are at increased risk for clear cell adenocarcinoma of the vagina and cervix, but the effect of in utero DES exposure on later development of squamous neoplasia in the cervix and vagina is uncertain. This combined follow-up study of 3,899 DES Daughters (median age 38) and 1,374 unexposed daughters (median age 39) was followed 1982-1995. Subjects were drawn from three previously studied cohorts (DESAD, Dieckmann, and Horne). The purpose was to examine the long-term risk of developing high-grade squamous intraepithelial neoplasia (HSIL) of the genital tract in DES Daughters compared with unexposed daughters.

The study found a small but significant increase in HSIL among DES Daughters in all age groups, including those over age 40. A total of 111 pathology-confirmed HSIL cases occurred, including five of the vagina, one of the vulva and two cases of invasive cervical cancer. The overall relative risk was 2.1 among DES-exposed versus unexposed. The relative risk among those whose mothers were prescribed DES within 7 weeks of the last menstrual period was 2.8 compared with 1.35 among women exposed for the first time at 15 weeks or later. Women with documented high-grade neoplasia before 1982 were excluded because prior treatment of the cervix may lower the subsequent finding of intraepithelial neoplasia. Researchers could not rule out that more frequent and intensive screening among DES-exposed women played a role in these findings.

Neoplasia is abnormal and uncontrolled cell growth; a neoplasm is new growth of benign or malignant tissue. Squamous cells are found in the tissue that forms the surface of the skin, the lining of the hollow organs of the body, and the passages of the respiratory and digestive tracts. These flat cells look like fish scales under a microscope. Squamous intraepithelial lesion (SIL) is a general term for the abnormal growth of squamous cells on the surface of the cervix. The changes in the cells are described as low grade or high grade, depending on how much of the cervix is affected and how abnormal the cells appear. Cervical intraepithelial neoplasia (CIN) is a general term for the growth of abnormal cells on the surface of the cervix. Numbers from 1 to 3 may be used to describe how much of the cervix contains abnormal cells. High-grade squamous intraepithelial lesion (HSIL) is a precancerous condition in which the cells of the uterine cervix are moderately or severely abnormal. In this study, grades 2 and 3 were considered high.

2001 Study Abstract

OBJECTIVES:
Women exposed prenatally to Diethylstilbestrol (DES) have an excess risk of clear-cell adenocarcinoma of the vagina and cervix, but the effect on the incidence of squamous neoplasia is uncertain. The purpose of the current study was to evaluate the long-term risk of developing high-grade squamous neoplasia of the genital tract among women exposed prenatally to DES.

METHODS:
A cohort comprising 3,899 DES-exposed and 1,374 unexposed daughters was followed for 13 years (1982 1995) for pathology-confirmed diagnoses of high-grade squamous intraepithelial neoplasia (HSIL) of the genital tract. Poisson regression analysis was used to compute relative risks (RR) and 95% confidence intervals (95% CI), adjusting for age, calendar year, and other covariates.

RESULTS:
The RR (95% CI) among DES-exposed versus unexposed, based on 111 cases of high-grade disease, was 2.1 (1.2-3.8). Adjustment for screening history estimated by the number of years since the last Pap smear had little effect. Risk estimates were higher with earlier intrauterine exposure; the RR (95% CI) for exposure within 7 weeks of the last menstrual period was 2.8 (1.4-5.5). Only two cases of invasive squamous cervical cancer occurred in total, precluding separate analysis.

CONCLUSIONS:
The findings support an association between in-utero DES exposure and high-grade squamous neoplasia, although a role for more intensive screening among DES-exposed women in the production of this excess could not be completely ruled out.

Sources

  • Incidence of squamous neoplasia of the cervix and vagina in women exposed prenatally to diethylstilbestrol (United States),NCBI, PMID: 11714112, 2001 Nov;12(9):837-45.
  • NCI, DES Follow-up Study Published Papers.
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Breast Cancer Screening in Women exposed in Utero to DiEthylStilbestrol

The majority of DES-exposed women do not perform monthly breast-self examinations

DES Follow-up Study Summary

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The majority of DES-exposed women do not perform monthly breast-self examinations.

The purpose of this paper was to determine if women exposed in utero to Diethylstilbestrol (DES) are more likely than unexposed women to receive recommended or additional breast cancer screening examinations.

Data from the study cohort were used to assess the degree of recommended compliance of breast cancer screenings was found in 3,140 DES exposed and 826 unexposed women. Participants were enrolled at four sites: Houston, Boston, Rochester, and Los Angeles. The data from the mailed questionnaires that included the reported frequency from 1990 through 1994 of breast-self examinations (BSEs), clinical breast examinations (CBEs), and mammograms was analyzed.

The results showed that the DES-exposed women exceeded annual recommendations for CBEs among women without a history of benign breast disease compared with unexposed women. There were no other statistically significant differences between exposed and unexposed women who reported performing BSEs, CBEs (less than 40 years of age), and mammographies, regardless of benign breast disease history.

Although this study showed that the majority of DES-exposed women receive breast cancer screenings at least at recommended intervals, it also showed that over two thirds do not perform monthly BSEs. It is recommended that Future efforts should be focused on further educating this and other at-risk populations through mailed reminders and during patient consultations on the benefits of screening examinations.

2009 Study Abstract

Purpose:
To determine if women exposed in utero to diethylstilbestrol (DES) are more likely than unexposed women to receive recommended or additional breast cancer screening examinations.

Methods:
1994 Diethylstilbestrol-Adenosis (DESAD) cohort data are used to assess the degree of recommended compliance of breast cancer screenings found in 3140 DES-exposed and 826 unexposed women. Participants were enrolled at four sites: Houston, Boston, Rochester, and Los Angeles. Logistic regression modeling was used to analyze mailed questionnaire data that included reported frequency over the preceding 5 years (1990-1994) of breast-self examinations (BSEs), clinical breast examinations (CBEs), and mammograms.

Results:
DES-exposed women exceeded annual recommendations for CBEs (aOR 2.20, 95% CI, 1.04-4.67) among women without a history of benign breast disease (BBD) compared with unexposed women. There were no other statistically significant differences between exposed and unexposed women who reported performing BSEs, CBEs (<40 years of age), and mammographies, regardless of BBD history.

Conclusions:
The majority of DES-exposed women receive breast cancer screenings at least at recommended intervals, but over two thirds do not perform monthly BSEs. Future efforts should be focused on further educating this and other at-risk populations through mailed reminders and during patient consultations on the benefits of screening examinations.

Sources

  • Breast cancer screening in women exposed in utero to diethylstilbestrol,NCBI, PMID: 19361323, 2009 Apr;18(4):547-52. doi: 10.1089/jwh.2007.0580. Full text PMC2857514.
  • NCI, DES Follow-up Study Published Papers.
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