Over 50 years later, DES’ adverse effects continue

Women Exposed to DiEthylStilbestrol In Utero Face Ongoing Risks for Adverse Health Outcomes

October 8th, 2011, NEJM Journal Watch talked with two authors of the reportAdverse Health Outcomes in Women Exposed In Utero to Diethylstilbestrol“.

Press Play > to listen to the recording.

Sources and more information

Our SoundCloud Playlists
More DES DiEthylStilbestrol Resources

Environmental signaling: from environmental estrogens to endocrine-disrupting chemicals and beyond

Environmental chemicals mimic hormones or other metabolic signaling molecules and behavioral experience can be transduced into chemical signals that also modify gene expression

Abstract

The landmark report (Herbst et al. 1971) linking prenatal treatment with a synthetic estrogen, diethylstilbestrol (DES), to cancer at puberty in women whose mothers took the drug while pregnant ushered in an era of research on delayed effects of such exposures on functional outcomes in offspring.

An animal model developed in our laboratory at the National Institute of Environmental Health Sciences confirmed that DES was the carcinogen and exposure to DES caused, as well, functional alterations in the reproductive, endocrine, and immune systems of male and female mice treated in utero.

American Society of Andrology and European Academy of Andrology, NCBI PubMed PMID: 27230799, 2016 May 27.

Lighthouse at sunset, Aaron.

DES was also being used in agriculture and we discovered, at the first meeting on Estrogens in the Environment in 1979 (Estrogens in the Environment, 1980), that many environmental contaminants were also estrogenic.

Many laboratories sought to discern the basis for estrogenicity in environmental chemicals and to discover other hormonally active xenobiotics. Our laboratory elucidated how DES and other estrogenic compounds worked by altering differentiation through epigenetic gene imprinting, helping explain the transgenerational effects found in mice and humans.

At the Wingspread Conference on the Human-Wildlife Connection in 1991 (Advances in Modern Environmental Toxicology, 1992), we learned that environmental disruption of the endocrine system occurred in many species and phyla, and the term endocrine disruption was introduced.

Further findings of transgenerational effects of environmental agents that mimicked or blocked various reproductive hormones and the ubiquity of environmental signals, such as Bisphenol-A increased concern for human and ecological health.

Scientists began to look at other endocrine system aspects, such as cardiovascular and immune function, and other nuclear receptors, with important observations regarding obesity and metabolism. Laboratories, such as ours, are now using stem cells to try to understand the mechanisms by which various environmental signals alter cell differentiation.

Since 2010, research has shown that trauma and other behavioral inputs can function as ‘environmental signals,’ can be encoded in gene regulation networks in a variety of cells and organs, and can be passed on to subsequent generations. So now we come full circle: environmental chemicals mimic hormones or other metabolic signaling molecules and now behavioral experience can be transduced into chemical signals that also modify gene expression.

More DES DiEthylStilbestrol Resources

DiEthylStilbestrol Resources: Epigenetics and Transgenerational Effects

NCBI advances science & health by providing access to biological information

Epigenetics

image of PubMed logo
NCBI PubMed DiEthylStilbestrol Resources: Epigenetics and Transgenerational Effects.

DES Transgenerational Effects

More DES DiEthylStilbestrol Resources

Management of females exposed to DES-type drugs ; 1977 recommendations

Vaginal and cervical cancers and other abnormalities associated with exposure in utero to diethylstilbestrol and related synthetic hormones

woman-at-hospital
1977 study and recommendations about vaginal and cervical cancers and other abnormalities associated with exposure in utero to diethylstilbestrol and related synthetic hormones. all you’ve been through.

1977 Study Abstract

All asymptomatic girls who wore exposed to diethylstilbestrol in utero should receive a thorough pelvic examination at menarche or if they have reached 14 years of age. Younger girls should be examined if they develop abnormal bleeding or discharge. Whenever prenatal exposure is probable and theme are symptoms of discharge, further investigation is imperative, regardless of the patient’s age. This investigation should not be concluded until it is certain that no lesion is present.

Before the examination is undertaken, the entire procedure should be thoroughly discussed with the patient (and her mother on father if she is a minor).

The examination should include inspection and palpation, Papanicolaou smear (cervix and vagina), and an iodine staining test of the entire cervix and vagina. Abnormal areas, including those that do not stain with iodine, should be biopsied.  This procedure can be performed in the physician’s office with small biopsy instruments and without significant discomfort.

For the very young patient who has symptoms that require investigation, anesthesia may occasionally be required be fore an examination. A small speculum permits adequate visualization of the vagina without undue discomfort in younger patients.

With asymptomatic females, if adequate examination is not possible at the initial visit, vaginal tampons should be used for a few months to allow an adequate examination later without discomfort. Colposcopy is a useful adjunct to this examination, but it is not essential. Utilizing its low power magnification to examine the vagina and cervix, the physician can identify areas of glandular tissue (adenosis) in the vagina on on the cervix. This identification permits directed rather than “blind” biopsies. When used in con junction with the iodine staining test and selected biopsy, colposcopy permits precise recording of observed abnormalities and their appraisal at fixed intervals.

The patient exposed to DES-type drugs should be followed on a regular basis. After a normal initial examination, annual pelvic examinations with cervical and vaginal cytology and iodine staining are probably adequate. If any abnormalities are noted during the initial evaluation, more frequent follow-up examinations are suggested (every 3 to 6 months, depending on the severity of the findings).

Locally destructive measures such as cauterization, cryosurgery, or excision can be utilized if atypical changes such as marked squamous dysplasia on carcinoma in situ of the vagina or cervix are found on biopsy.

Sources and more information
  • Vaginal and cervical cancers and other abnormalities associated with exposure in utero to diethylstilbestrol and related synthetic hormones, Cancer Research, 1977 Apr.
More DES DiEthylStilbestrol Resources

Age at menarche among diethylstilbestrol granddaughters

Age at menarche for DES granddaughters seemed to be unaffected by mother’s prenatal DES exposure

girl-ocean-sskennel-text
In this 1995 study, age at menarche for DES granddaughters seemed to be unaffected by mother’s prenatal diethylstilbestrol exposure. However the 2011 study showed DES-exposed girls were somewhat more likely to have begun menstruating at age 10 or younger.

1995 Study Abstract

American journal of obstetrics and gynecology, NCBI PMID: 7573253, 1995 Sep.

We interviewed 542 women whose mothers were in a randomized trial of diethylstilbestrol. Effects of diethylstilbestrol on the third generation were explored by ascertaining age at menarche for the women’s daughters. A total of 123 daughters were > or = 10 years old (52 exposed and 71 unexposed). Age at menarche was unaffected by mother’s prenatal diethylstilbestrol exposure.

Sources and more information
More DES DiEthylStilbestrol Resources

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.
More DES DiEthylStilbestrol Resources

Epidemiology of vaginal adenosis and adenocarcinoma associated with exposure to stilbestrol in utero

US National Library of Medicine National Institutes of Health, 1977

image of woman thinking
While the risk of developing adenocarcinoma appears to be very low, a majority of exposed females do have other abnormalities of the lower genital tract. Almost sad – m00by by M.E. Aguila.

1977 Study Abstract

Following the observation that maternal ingestion of diethylstilbestrol was associated with the development of adenocarcinoma of the vagina in young women, analysis of 170 cases of the disease, collected over a two-year period, was undertaken. Details of history of non-steroidal estrogenic intake during pregnancy, its dosage and duration of intake and prevalence of concomitant abnormalities of the vagina and cervix were recorded.

This analysis disclosed that dosage and duration of intake do not appear to be vital factors in contributing to the development of carcinoma. A controlled, prospective investigation of prenatal exposure to stilbestrol was also carried out. Vaginal and cervical abnormalities were common among 110 young women exposed to stilbestrol in utero. Biopsy-proved vaginal adenosis was present in 35% of the exposed population as compared with only 1% of the control subjects. Fibrous ridges of the vagina and cervix and failure of the vaginal mucosa and portions of the cervix to stain with iodine were also more frequently observed in the exposed population.

While the risk of developing adenocarcinoma appears to be very low, a majority of exposed females do have other abnormalities of the lower genital tract. While some investigators believe that adenosis is a premalignant lesion, at present there is no clear-cut evidence of transition from adenosis to adenocarcinoma.

Sources and more information
  • Epidemiology of vaginal adenosis and adenocarcinoma associated with exposure to stilbestrol in utero, Cancer. ;39(4 Suppl):1892-5., Poskanzer DC, Herbst AL., NCBI PMID: 856457, 1977 Apr.
  • Full study, Volume 39, Issue Supplement S4, PDF, Article first published online: 27 JUN 2006
More DES DiEthylStilbestrol Resources

The effects in the human of DiEthylStilbestrol (DES) use during pregnancy

US National Library of Medicine National Institutes of Health, 1987

Diethylstilbestrol advert 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

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 patients at diagnosis has varied from 7-35 years with the highest frequency from 14-22 years. The risk among the exposed, however, is small and is of the order of 1 per 1,000.

Almost all of the cases occur in postmenarchal females. Other 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.

The occurrence of CCA has paralleled the sales of DES for pregnancy support in the U.S. Both vaginal adenosis (benign glands in the vagina) and CCA are more frequent among those whose mothers began DES in early pregnancy.

An increased risk of squamous cell neoplasia has been hypothesized but not proven. The changes that occur in the female genital tract of the DES exposed appear to result from alterations in the development of the mullerian ducts.

Currently there is not definitive evidence for an elevated risk of cancer among DES mothers or DES sons but studies have suggested a possible increase of breast cancer in the former group and testicular cancer in the latter group; a valid association has not been established in either.

Sources and more information
  • The effects in the human of diethylstilbestrol (DES) use during pregnancy, Princess Takamatsu Symposia 1987;18:67-75., NCBI PMID: 3506546.
More DES DiEthylStilbestrol Resources

Epidemiologic aspects and factors related to survival in DES-associated cases of CCAC cancer

American Journal of Obstetrics and Gynecology, 1979

CCAC painting
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.

1979 Study Abstract

Three hundred and eighty-four cases of clear cell adenocarcinoma of the vagina and cervix accessioned in the Registry as of December 31, 1978, have been analyzed.

The annual incidence of these tumors has been found to correspond closely to the estimated usage of diethylstilbestrol (DES) for pregnancy support in the United States. The annual incidence of the DES-associated cases appears to have dropped in the United States in the past 2 years in comparison to 1973 to 1975.

The risk of tumor development appears to be higher in young women exposed to DES early in intrauterine life than in those exposed later. The carcinomas are rare before the age of 14 years and an irregular peak in the age-incidence curve appears between 17 and 21 years followed by a decline.

The 5-year survival rate is better for women over the age of 19 years than for younger patients, and a higher frequency oral contraceptive usage did not appear to influence the behavior of the tumor and the improved survival in those using this medication appears to be related to greater medical surveillance.

Sources and more information
  • Epidemiologic aspects and factors related to survival in 384 Registry cases of clear cell adenocarcinoma of the vagina and cervix, American Journal of Obstetrics and Gynecology 1979 Dec 1;135(7):876-86, NCBI PMID: 507130.
More DES DiEthylStilbestrol Resources

Atypical vaginal adenosis and cervical ectropion, Association with CCAC in DES-exposed offspring

Atypical vaginal adenosis and atypical cervical ectropion of the tuboendometrial type are precursors of clear cell adenocarcinoma

Cervical-Ectropion-Analysis image
The frequency with which atypical tuboendometrial glands in the vagina and cervix were associated with the carcinomas and the proximity of the former to the latter provide strong evidence that atypical vaginal adenosis and atypical cervical ectropion of the tuboendometrial type are precursors of clear cell adenocarcinoma.

1984 Study Abstract

Knowledge of the evolution of clear cell adenocarcinomas of the vagina and cervix in diethylstilbestrol-exposed progeny has remained elusive despite the known topographical association of these tumors with the tuboendometrial form of vaginal adenosis and cervical ectropion.

Twenty radical hysterectomy or radical hysterectomy and vaginectomy specimens of clear cell adenocarcinoma of the vagina or cervix were serially blocked in toto;

  • tuboendometrial epithelium was found in the vagina in 19 (95%) of the cases, usually in greatest concentration at the margin of the tumor, particularly inferiorly.
  • Foci of atypical tuboendometrial epithelium were identified in 16 (80%) of the cases, almost always immediately adjacent to the tumor.

Twenty-five of a second group of 47 specimens in which only substantial portions of the vagina or cervix adjacent to a clear cell adenocarcinoma were available for examination also had foci of atypical tuboendometrial epithelium.

The frequency with which atypical tuboendometrial glands in the vagina and cervix were associated with the carcinomas and the proximity of the former to the latter provide strong evidence that atypical vaginal adenosis and atypical cervical ectropion of the tuboendometrial type are precursors of clear cell adenocarcinoma.

Sources and more information
  • Atypical vaginal adenosis and cervical ectropion. Association with clear cell adenocarcinoma in diethylstilbestrol-exposed offspring, Cancer. 1984, Sep 1, ;54(5):869-75. Robboy SJ, Young RH, Welch WR, Truslow GY, Prat J, Herbst AL, Scully RE, NCBI PMID: 6537153.
  • Full paper: Cancer Volume 54, Issue 5, Article first published online: 29 JUN 2006, PDF.
More DES DiEthylStilbestrol Resources