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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Prenatal diethylstilbestrol exposure and human genital tract abnormalities

Herbst AL, Scully RE, Robboy SJ, DES research 1979

foetus image
Nonneoplastic abnormalities including vaginal adenosis, cervical eversion (ectropion), and transverse cervical and vaginal ridges are frequent in the DES-exposed population, particularly if the drug was administered early in pregnancy.

1979 Study Abstract

The incidence of clear cell adenocarcinoma of the vagina and cervix associated with intrauterine exposure to diethylstilbestrol DES and similar compounds during the first half of pregnancy has increased. Ninety percent of these cancers have occurred in patients 14 years of age or older.

Although these carcinomas are exceedingly rare, nonneoplastic abnormalities including vaginal adenosis, cervical eversion (ectropion), and transverse cervical and vaginal ridges are frequent in the exposed population, particularly if the drug was administered early in pregnancy. Current evidence favors a disturbance in development of the müllerian duct as the explanation of these changes.

Whether DES is only a teratogen or also a carcinogencerviccervi is unknown, as is the possible role of other factors in the development of cancer. An increased incidence of cancer among exposed males has not been documented.

Sources and more information
  • Prenatal diethylstilbestrol exposure and human genital tract abnormalities, Herbst AL, Scully RE, Robboy SJ. 1979 May;(51):25-35. NCBI PMID: 481577.
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Clear cell adenocarcinoma of the vagina and cervix secondary to intrauterine diethylstilbestrol exposure

Recurrent CCA has been observed as long as 20 years after primary therapy

image of CCAC
Factors that may increase the risk are maternal history of prior miscarriage, exposure to DES in early gestation, a fall season of birth, and prematurity. Recurrent CCA has been observed as long as 20 years after primary therapy emphasizing the importance of prolonged follow-up..

1990 Study Abstract

Intrauterine diethylstilbestrol (DES) exposure is associated with an increased risk for the development of clear cell adenocarcinoma (CCA) of the vagina and cervix.

The age of the DES-exposed patients has varied from 7 to 34 years with the highest frequency from 14 to 22 years. The risk among the exposed is small and is on the order of 1 per 1,000.

Factors that may increase the risk are maternal history of prior miscarriage, exposure to DES in early gestation, a fall season of birth, and prematurity. Pregnancy does not appear to influence adversely the tumor characteristics or prognosis of patients who have developed these malignancies.

Criteria for appropriate local therapy of small clear cell adenocarcinomas of the vagina are presented. Recurrent CCA has been observed as long as 20 years after primary therapy emphasizing the importance of prolonged follow-up..

Sources and more information
  • Clear cell adenocarcinoma of the vagina and cervix secondary to intrauterine exposure to diethylstilbestrol, Herbst AL, Anderson D, Semin Surg Oncol. 1990;6(6):343-6. NCBI PMID: 2263810.
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Cytology of 575 young women with prenatal exposure to diethylstilbestrol

Obstetrics and gynecology, Dr Arthur Herbst, 1976

cytology lab image
This 1976 study indicates that the presence of mucinous columnar or metaplastic squamous cells in vaginal scrapes is suggestive of vaginal adenosis but that vaginal cytology cannot be considered a uniformly reliable screening technic for detecting the presence of this disorder.

1976 Study Abstract

The vaginal and cervical cellular changes encountered in 575 postpubertal females exposed prenatally to diethylstilbestrol (DES) were compared with those of an unexposed population with particular reference to the role of cytology in the detection of vaginal adenosis and cervical ectropion (erosion).

Several methods of obtaining specimens were utilized, the most effcacious of which was scraping of the vagina, especially the fornices, and the portio vaginalis of the cervix.
With this technic, columnar cells of the mucinous type and metaplastic squamous cells were observed in 34% of the vaginal scrapes and 54% of the scrapes of the cervical portio.
A higher incidence was apparent among those patients in whom iodine staining of the vaginal mucosa was abnormal or vaginal adenosis was proven by biopsy.
Moderate to severe dysplasia of the squamous cells or atypical glandular cells were found in 1% of the exposed subjects.

This study indicates that the presence of mucinous columnar or metaplastic squamous cells in vaginal scrapes is suggestive of vaginal adenosis but that vaginal cytology cannot be considered a uniformly reliable screening technique for detecting the presence of this disorder.

Sources and more information
  • Cytology of 575 young women with prenatal exposure to diethylstilbestrol, Robboy SJ, Friedlander LM, Welch WR, Keh PC, Taft PD, Barnes AB, Scully RE, Herbst AL., Obstet Gynecol. 1976 Nov;48(5):511-5. NCBI PMID: 980279.
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Rates and risks of DES-related clear-cell adenocarcinoma of the vagina and cervix

CCAC update, Dr Arthur Herbst, 1987

clear_cell_carcinoma image
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.

1987 Study Abstract

We reviewed 519 cases of clear-cell adenocarcinoma of the vagina and cervix identified by the Registry for Research on Hormonal Transplacental Carcinogenesis of the University of Chicago through June 30, 1985. In 60 percent of all cases the patient’s mother had received diethylstilbestrol during pregnancy. An additional 12 percent of all mothers had been treated with another hormone or with an unidentified medication. Ninety-one percent of the cases in diethylstilbestrol-exposed women were diagnosed when the patient was between the ages of 15 and 27. The median age at diagnosis was 19.0 years. The risk that clear-cell adenocarcinoma will develop in an exposed female from birth through age 34 is 1 case per 1000 women. The temporal pattern of occurrence of clear-cell adenocarcinoma corresponds closely with that of the use of diethylstilbestrol for pregnancy support in the United States. The rarity of this tumor among exposed women suggests that diethylstilbestrol is not a complete carcinogen and that some other factor is also involved in the pathogenesis of clear-cell adenocarcinoma of the vagina and cervix.

Sources and more information
  • Rates and risks of diethylstilbestrol-related clear-cell adenocarcinoma of the vagina and cervix. An update., Melnick S, Cole P, Anderson D, Herbst A., N Engl J Med. 1987 Feb 26;316(9):514-6, NCBI Pubmed PMID: 3807995.
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Developmental effects of Diethylstilbestrol in pregnancy

Medical – Gynecology & Obstetrics and Urology, 1981

Developmental effects of diethylstilbestrol (DES) in pregnancy book cover image
Taken from DES books album on Flickr.

Unknown Binding: 203 pages

Publisher: Thieme-Stratton (1981)

Language: English

Written by Herbst, Arthur L,
and Bern, Howard A.

Check-out DES books album on Flickr.

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Prenatal diethylstilbestrol exposure and performance on college entrance examinations

DES exposure and written tests performance

writing-test
No differences in test performance were seen among exposed daughters. Among sons, test scores were marginally higher among the exposed, probably due to chance. Written test image by Melanie Holtsman.

1992 Study Abstract

The fetal rodent brain is permanently altered by exposure to sex hormones. Long-term effects of prenatal sex hormones on the human brain are far less clear.

In order to explore such effects, we studied a measure of cognitive function among young adults who had been exposed in utero to a powerful synthetic estrogen. In a randomized clinical trial conducted at the University of Chicago in 1950-1952, 1646 pregnant women were randomly assigned to receive either high doses of Diethylstilbestrol or placebo.

Women in this study gave birth to 1653 liveborn infants, of whom 1603 (820 sons and 783 daughters) survived to their fifteenth birthday. College entrance examination scores were obtained for 42% of these offspring. No differences in test performance were seen among exposed daughters. Among sons, test scores were marginally higher among the exposed, probably due to chance.

Sources
  • Prenatal diethylstilbestrol exposure and performance on college entrance examinations, Wilcox AJ, Maxey J, Herbst AL, NCBI PMID: 1398561, Horm Behav. 1992 Sep;26(3):433-9. Full study.
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Factors associated with a lack of pap smear utilisation in women exposed in utero to diethylstilbestrol

The higher risk group of DES-exposed women need early detection of cervical and vaginal adenocarcinomas

pap-smear-kit
DES exposure, not having a previous gynecologic dysplasia diagnosis, lack of insurance, originating cohort, increasing age, and previous screening behavior were all factors associated with not reporting a Pap smear examination in the 2006 questionnaire. Colposcopy equipment image by stacya.

2015 Study Abstract

BACKGROUND:
Women in the 1940s-1960s were prescribed Diethylstilbestrol (DES), a nonsteroidal estrogen, to prevent miscarriages, but the practice was terminated after it was discovered that the daughters so exposed in utero were at increased risk for developing clear cell adenocarcinoma (CCA) of the vagina or cervix at early ages. Pap smear screening is one of the principal methods used to identify tumor development and is necessary in this group of women to maintain their health. Currently, little is known about the factors associated with nonutilization of this screening tool in this high-risk population of women.

METHODS:
National cohort data from the National Cancer Institute (NCI) DES Combined Cohort Follow-up Study during 1994, 1997, 2001, and 2006 were used to determine which factors were associated with Pap smear screening nonutilization in 2006 among DES-exposed and unexposed women. Self-reported questionnaire data from 2,861 DES-exposed and 1,027 unexposed women were analyzed using binary logistic regression models.

RESULTS:
DES exposure, not having a previous gynecologic dysplasia diagnosis, lack of insurance, originating cohort, increasing age, and previous screening behavior were all factors associated with not reporting a Pap smear examination in the 2006 questionnaire, although college education reduced nonutilization.

CONCLUSIONS:
Understanding which factors are associated with not acquiring a screening exam can help clinicians better identify which DES-exposed women are at risk for nonutilization and possibly tailor their standard of care to aid in the early detection of cervical and vaginal adenocarcinomas in this high-risk group.

Sources
  • Factors associated with a lack of pap smear utilization in women exposed in utero to diethylstilbestrol, NCBI PMID: 25768943, J Womens Health (Larchmt). 2015 Apr;24(4):308-15. doi: 10.1089/jwh.2014.4930. Epub 2015 Mar 13.
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DES Researcher Doctor Arthur Herbst and DES Activists

Doctor Arthur Herbst, Frances K. Howell,
Kari Dordal Christianson and Susan Helmrich

Dr.-Arthur-Herbst image
Doctor Arthur Herbst, Frances K. Howell, Kari Dordal Christianson and Susan Helmrich.

Four decades ago the New England Journal of Medicine published Dr. Arthur Herbst’s article telling of an association between DES exposure and cancer. Today, Dr. Arthur Herbst key message is that DES research must continue!

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Incidence of squamous neoplasia of the cervix and vagina in DES-exposed daughters

Association between in utero DES exposure and high-grade squamous neoplasia

2000 Study Abstract

image of PubMed NCBI The Endocrine Society logo
The 2000 study findings support an association between in utero DES exposure and high-grade squamous neoplasia

PURPOSE:
Women exposed to diethylstibestrol (DES) in utero are known to have an excess risk of clear cell adenocarcinoma of the vagina and cervix, in addition to vaginal epithelial changes, but the effect on the incidence of squamous neoplasia is uncertain. This study evaluated the long-term risk of developing high-grade squamous neoplasia of the genital tract among women exposed prenatally to diethylstilbestrol.

METHODS:
A cohort comprising 3899 DES-exposed and 1374 unexposed daughters was followed for thirteen years (1982-1995) for pathology-confirmed diagnoses of high-grade squamous neoplasia. A pathologist blinded to exposure status reviewed seventy-seven percent of cases. Poisson regression analysis was used to compute relative risks (RR) and 95% confidence intervals (CI) controlling for age, calendar year, screening history and other covariates.

RESULTS:
The RR (95% CI) among DES-exposed versus unexposed, based on 111 cases of high-grade disease, was 2.12 (1.19-3.77). Adjustment for screening history had little effect, but when the analysis was restricted to a group highly screened before 1982, the risk was reduced. Risk estimates were higher among women exposed earlier in gestation; the RR (95% CI) for exposure within 7 weeks of the last menstrual period was 2.82 (1.43-5.53).

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 des-exposed daughters, NCBI, PMID: 11018391, Ann Epidemiol. 2000 Oct 1;10(7):467. Full text link.
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