Exogenous Estrogens and Breast Cancer : DES

Environmental endocrine modulators and human health: an assessment of the biological evidence, 1998


Maternal Exposure

Several studies have investigated breast cancer risk in women given DES or other exogenous estrogens during pregnancy. In a cohort study of 1531 women exposed to DES during pregnancy, the relative risk for breast cancer was 1.5 (CI 0.88 to 2.49).  Within the exposed group, there was also no evidence for a dose-response relationship with relative risks for breast cancer of 1.38, 1.46, and 1.29 for total DES doses of <1000 mg, 1000 to 4500 mg, and >4500 mg, respectively. The mean total DES dose in this study was 2100 mg. While there was a slight excess of breast cancer in the DES group (although not statistically significant), the authors note that this may have also been due to hormonally related reproductive difficulties in these women, which was why they were given DES.

In a study comparing the incidence of breast cancer in a cohort of 3033 women who had taken DES during pregnancy with an appropriate unexposed group, there was an increased relative risk of 1.46 (CI 1.1–1.9). Breast cancer mortality was slightly higher in the DES-exposed group (RR = 1.1), but this was not statistically significant. Because information on total DES doses used was not available, a dose-response relationship between DES and breast cancer could not be determined. The authors were unable to rule out whether the increased incidence of breast cancer was due solely to DES or some other characteristic of DES-exposed women (e.g., an underlying hormonal disorder that precipitated the use of DES). In a follow-up study of the same cohort, there was a modest, but statistically significant increase in breast cancer risk associated with exposure to DES during pregnancy (RR = 1.35). Because this follow-up study included 127 new breast cancer cases and 42,000 additional women-years of observation, in addition to controlling for previous miscarriage, the relative rate estimates are more precise than those in the earlier report. However, it did not appear that breast cancer risk associated with DES increased over time. Finally, in a study of 319 women who were part of a randomized clinical trial of DES, there was no difference in the incidence of breast cancer between DES exposed and unexposed. The mean total DES dose in this study was 11.5 g.

The data addressing increased breast cancer risk associated with DES exposure during pregnancy are equivocal. While the available data support a possible weak association between exposure to DES and increased risk of breast cancer, studies are limited by a lack of sufficient information on dose and duration and the inability to distinguish DES-induced effects from indicators for using DES (i.e., an underlying hormonal imbalance). Nevertheless, exposure to DES during pregnancy does not appear to appreciably increase the risk of breast cancer.

In Utero Exposure

It has also been hypothesized that increased maternal estrogen levels during pregnancy may be associated with an increased probability of breast cancer in daughters. However, there are limited empirical data to confirm this hypothesis. To date, there is no evidence of an association between in utero DES exposure and increased risk of breast cancer in adulthood because the relevant birth cohorts of DES offspring have not reached the age range at highest risk for breast cancer. Only indirect evidence has been used to suggest that intrauterine exposure to estrogens may be associated with subsequent increased risk of breast cancer. Correlations between endogenous serum estrogen levels during pregnancy in certain populations and breast cancer risk in the daughters may be useful in evaluating the potential association between in utero DES exposure and breast cancer. Significantly lower (i.e., 30%) serum estrogen levels in pregnancy have been reported in younger women (<20 years) compared with older women (20 to 29 years). These findings, together with evidence showing an association between later maternal age at birth and increased breast cancer risk in daughters have been used to suggest that in utero exposure to the potent, synthetic estrogen, DES, may be associated with increased breast cancer risk. However, this is entirely hypothetical and confirmation of this must await the results of studies now in progress, of women exposed in utero to DES as they reach the age of greatest breast cancer risk.


  • Environmental endocrine modulators and human health: an assessment of the biological evidence, Critical reviews in toxicology, NCBI PubMed, PMID: 9557209, 1998.
  • Featured image Samuel Zeller.

A randomized double-blind controlled trial of the value of stilboestrol therapy in pregnancy

Long-term follow-up of mothers and their offspring, 1983


In the early 1950s, a randomized, double-blind, controlled trial of the value of prophylactic stilboestrol therapy given antenatally to reduce the incidence of late pregnancy toxaemia and to improve perinatal mortality was conducted at University College Hospital, London.

Women expecting their first baby were allocated to one or other of two groups. Those in the stilboestrol group started treatment at the 12th week of pregnancy on average and received a mean dose of about 11.5 g of the drug while those in the control group received placebo tablets.

In spite of the fact that the original trial documentation was lost, it was possible to be fairly certain which was the treated group and follow-up data from 650 mothers and 660 offspring were obtained from death certificates, cancer registrations and questionnaires sent to general practitioners.

We found no indication of any harmful long-term effect of stilboestrol exposure during pregnancy on the mothers–in particular 10 out of 331 women in the untreated group and 9 out of 319 women in the treated group were found to have developed breast cancer.

Amongst the daughters, those in the treated group suffered an excess of minor benign lesions of the cervix uteri and an excess (not statistically significant) of unfavourable pregnancy outcomes. None of the daughters had developed clear cell adenocarcinoma of the vagina or cervix uteri.

Amongst the sons, we discovered no evidence of any significant excess of genital tract disorders or of impaired reproductive performance in the treated group but one son developed a (fatal) teratoma of the testis.

Unexpectedly, psychiatric disease (especially depression and anxiety) was reported by general practitioners about twice as often in the treated group offspring (sons and daughters) as in the untreated group. This result cannot be due to bias, and is unlikely to be due to confounding or chance, and may thus represent an adverse effect of exposure to stilboestrol in utero.


  • A randomized double-blind controlled trial of the value of stilboestrol therapy in pregnancy: long-term follow-up of mothers and their offspring, British journal of obstetrics and gynaecology, NCBI PubMed, PMID: 6357269, 1983.
  • University College Hospital, London featured image wellcomecollection.

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

An update, 1987


(DES Daughters) 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.


  • The effects in the human of diethylstilbestrol (DES) use during pregnancy, NCBI PubMed, PMID: 3506546, 1987.
  • Featured image Mathieu Bigard.

Diethylstilbestrol in pregnancy: an update

Canadian Medical Association journal, 1982


The problems associated with the use of diethylstilbestrol (DES) during pregnancy concern both female and male children exposed in utero and the mothers themselves.

Strong epidemiological evidence has linked clear-cell adenocarcinoma of the vagina in young women to maternal ingestion of DES during the 1st 18 weeks of pregnancy. Benign abnormalities of the genital tract have also occurred in daughters of women exposed during pregnancy.

3 data sources have been particularly important for continued assessment of DES:

  • the 1951 University of Chicago double-blind study following controls, treated women, and offspring;
  • the National Cooperative Diethylstilbestrol Adenosis (DESAD) project which collects information on thousands of women exposed in utero,
  • and the Registry of Clear-Cell Adenocarcinoma (Mesonephroma) of the Genital Tract in Young Females.

The risk of clear-cell adenocarcinoma of the vagina and cervix in this group for ages 14 through 24 is estimated to be .14-1.4/1000 females exposed in utero. The risk is highest when exposure was early in intrauterine life. Peak incidence of tumors is between 17-21 years, rarely appearing before the age of 14. Concern over an increase in squamous cell dysplasia was raised, however a Massachusetts General Hospital study showed the prevalence of dysplasia was 2.1% and the incidence .85/1000 women years of follow-up. Benign abnormalities of the genital tract are common among this group and include: vaginal adenosis and structural abnormalities such as cervical hoods, ridges, and T-shaped uterus. The structural abnormalites may predispose to problems with reproduction; the incidence of complications after the 20th week of pregnancy, premature delivery, and perinatal death were found to be significantly increased. Results are conflicting concerning the impact of DES exposure on fertility.

Males exposed to DES in utero may have an increased frequency of anatomic and functional changes including epididymal cyst, hypoplasia of the testes, induration of the testicular capsule and impairment of spermatogenesis, sperm maturation, and accessory gland secretion.

The data are inconclusive concerning the incidence of breast cancer for women who took DES during pregnancy.

The psychological impact on the mothers who took DES and on the exposed offspring is another important consideration.


  • Diethylstilbestrol in pregnancy: an update, Canadian Medical Association journal, NCBI PubMed, PMID: 7139494, 1982.
  • Featured image credit Daniil Kuželev.

Risks of malignant disease and congenital malformations, 1979

DES Sons : malignant lesions have not been reported.

1979 Abstract

The Department of National Health and Welfare’s special advisory committee are closely monitoring women, who used DES (diethylstilbestrol) for protection of pregnancy, and their offspring.

DES daughters have an increased risk of benign abnormalities of the genital tract and, infrequently, vaginal or cervical cancer.

Prenatal exposure of males to DES have shown a low frequency of epidiymal cysts, hypoplastic testes, induration of the testicular capsule, and impairment of spermatogenesis, sperm maturation, and accessory gland secretion.

Women who used DES during their pregnancy may possibly have an increased risk of breast cancer although the incidence is not statistically significant.

The advisory committee recommends that DES and other estrogenic drugs not be used during pregnancy for treatment of threatened abortion due to the possible abnormalities of the fetus. Instead the committee suggests that DES be used for patients with estrogen-responsive metastatic breast cancer or advanced prostate cancer.


  • Diethylstilbestrol: risks of malignant disease and congenital malformations, Canadian Medical Association journal, NCBI PubMed, PMID: 455196, 1979. Full text PDF.
  • Featured image credit wiki.

Dangers of diethylstilboestrol: Review of a 1953 paper

A subsequent reanalysis of [Does the administration of diethylstilbestrol during pregnancy have therapeutic value?] data revealed that DES increased the risk of spontaneous abortion, preterm birth, and neonatal death, 1978


Dieckmann’s report that DES had no effect on pregnancy was, in one sense wrong: the published data clearly show that DES significantly increased abortions, neonatal deaths, and premature births (see table).

Although the exact number of pregnant women treated with DES is unknown, it has been estimated to be as high as 2 million. A sizeable fraction of these exposures occurred between 1953, when the Dieckmann paper was published, and 1971, when Herbst’s article appeared.

This exposure might have been avoided if the Dieckmann data had been interpreted correctly to show that DES was harmful to the fetus and newborn.


  • Dangers of diethylstilboestrol: Review of a 1953 paper, Lancet, NCBI PubMed, PMID: 79882, 1978.

Postcoital Diethylstilbestrol

FDA Drug Bulletin, May 1973

IN AGREEMENT WITH ITS extragovernmental physician-advisers, FDA has approved, under restricted conditions, postcoital (contraceptive) use of diethylstilbestrol (DES), a synthetic estrogen.

Adequate evidence to support the use of any other estrogen for this purpose is not presently available.

The Agency considers the use of DES for this purpose to be safe only as an emergency measure (in situations such as rape, incest, or where, in the physician’s judgment, the patient’s physical or mental well-being is in jeopardy) and explicitly warns against its routine or frequent use as a contraceptive.

Physicians are urged, prior to prescribing DES for this purpose, to inform patients (or guardians) fully of the possible side effects of the drug, and of alternative measures available and their hazards, so that the patient may participate in an informed way in the decision to use the drug. Pregnancy should be ruled out by appropriate tests prior to instituting therapy, so that no unnecessary exposure of a fetus to DES occurs.

The efficacy of DES in preventing pregnancy depends upon the time-lapse after coitus and dosage of the drug. The currently recommended dosage is 25 mg twice a day for 5 continuous days beginning, preferably, within 24 hours and not later than 72 hours after exposure. When this dosage is given within the specified time interval after sexual intercourse, DES is highly effective in preventing conception. But the patient must be warned to take the full course of the drug in spite of the nausea which commonly occurs, if it is to be effective.

There is at present no positive evidence that the restricted postcoital use of DES carries a significant carcinogenic risk either to the mother or fetus. However, because existing data support the possibility of delayed appearance of carcinoma in females whose mothers have been given DES later in pregnancy, and because teratogenic and other adverse effects on the fetus with the very early administration recommended are ill understood, failure of postcoital treatment with DES deserves serious consideration of voluntary termination of pregnancy.

Before prescribing, the physician should be familiar with the complete FDA-approved labeling on products intended for this use.

More Information – Abstract from WikiVisually

  • In May 1973, in an attempt to restrict off-label use of DES as a postcoital contraceptive to emergency situations such as rape, a FDA Drug Bulletin was sent to all U.S. physicians and pharmacists that said the FDA had approved, under restricted conditions, postcoital contraceptive use of DES. (In February 1975, the FDA Commissioner testified that the only error in the May 1973 FDA Drug Bulletin was that the FDA had not approved postcoital contraceptive use of DES.)
  • In September 1973, the FDA published a proposed rule specifying patient labeling and special packaging requirements for any manufacturer seeking FDA approval to market DES as a postcoital contraceptive, inviting manufacturers to submit abbreviated new drug applications (ANDAs) for that indication, and notifying manufacturers that the FDA intended to order the withdrawal of DES 25 mg tablets (which were being used off-label as postcoital contraceptives).
  • In February 1975, the FDA said it had not yet approved DES as a postcoital contraceptive, but would after March 8, 1975 permit marketing of DES for that indication in emergency situations such as rape or incest if a manufacturer obtained an approved ANDA that provided patient labeling and special packaging as set out in a FDA final rule published in February 1975. To discourage off-label use of DES as a postcoital contraceptive, in February 1975 the FDA ordered DES 25 mg (and higher) tablets removed from the market and ordered the labeling of lower doses (5 mg and lower) of DES still approved for other indications be changed to state: “THIS DRUG PRODUCT SHOULD NOT BE USED AS A POSTCOITAL CONTRACEPTIVE” in block capital letters on the first line of the physician prescribing information package insert and in a prominent and conspicuous location of the container and carton label.
  • In March 1978, a FDA Drug Bulletin was sent to all U.S. physicians and pharmacists which said: “FDA has not yet given approval for any manufacturer to market DES as a postcoital contraceptive. The Agency, however, will approve this indication for emergency situations such as rape or incest if a manufacturer provides patient labeling and special packaging. To discourage ‘morning after’ use of DES without patient labeling, FDA has removed from the market the 25 mg tablets of DES, formerly used for this purpose“.


  • Selected Items, from the FDA Drug Bulletin, California Medicine, NCBI PubMed PMC1455105, May 1973.
  • Emergency contraception, DES, wikivisually.

Compounds interfering with ovum implantation and development – The role of estrogens

Though this study was not statistically significant, it represented the first time that prevention of implantation was demonstrated – with DES usage – in humans


“It has been known for many years that estrogens interfere with early pregnancy in the rabbit and other specics.”…

…”In spite of evidence that success in the macaque should be paralleled by success in man, initial human experimentation was undertaken with some trepidation.

The first cases were rape cases. All of the subjects received 50 mg. of stilbestrol for 4 to 6 days after exposure. The chance of pregnancy following rape is uncertain for many obvious reasons. Sometimes no sperm could be found in the cervix or vagina. In a few instances, temperature charts were started; if no rise occurred, no drug was given. In most of the cases accepted for treatment, exposure occurred near midcycle and fern crystallization of cervical mucus as well as presence of sperm were demonstrated. In this small series of patients, none has become pregnant so far. The subsequent menstruation was generally unremarkable, although in some instances it was either scantier or more profuse or prolonged than usual. Side effects, when they occurred, were those usually associated with administration of estrogen; they consisted of nausea and breast soreness, which ceased shortly after medication was stopped.

A limited number of courageous volunteers furnished an opportunity for further and more adequate observation. Coitus took place at midcycle near the time of the temperature rise. Fern crystallization and Huhner tests with motile sperm were obtained
in most instances.

The apparent effect of 5 to 50 mg. of stilbestrol or 0.5 mg. of ethinyl estradiol on the biphasic temperature curve chart is to counteract the thermogenic effect of progesterone or to shorten the luteal phase.

From these charts it was anticipated that the secretory changes in the endometrium might be altered. However, instead of a proliferative or hyperplastic endometrium, endometrial biopsies taken on postovulation days 5 to 7 and 10 to 12 showed a progestational effect with secretion in some instances on both sides of the nucleus, occasionally almost suggestive of an Arias-Stella reaction. The stroma was dense in some areas, markedly edematous in others. Basal vacuolization often persisted up to menstruation, sometirnes giving an early secretory appearance late in the cycle.

In these preliminary trials there have been no pregnancies. While of interest, these clinical studies are incomplete and have as yet no statistical significance.” …


  • Compounds interfering with ovum implantation and development. 3. The role of estrogens, American journal of obstetrics and gynecology, NCBI PubMed PMID: 4959099, 1966 Nov.
  • Image credit thinglink.

Association of DES use with increased B‐cell NHL risk

Pregnancy‐related factors and risk of B‐cell non‐Hodgkin lymphoma among women in Los Angeles

2018 Paper Abstracts

… “Pregnancy‐related factors evaluated included pregnancy history [ever (full‐term) pregnant, number of full‐term pregnancies], breast‐feeding (ever breast‐fed, duration, number of children breast‐fed), nausea during pregnancy that required treatment or hospitalization, diethylstilbestrol (DES) use during pregnancy and lactation suppressant use after full‐term pregnancy.” …

… “However, women who used DES during a pregnancy had two‐fold greater risk of B‐cell NHL overall than ever pregnant women who never used DES (OR = 2·37, 95% CI = 1·03–5·44). Notably, use of DES during pregnancy was associated with five‐fold greater risk of MZL (OR = 5·54, 95% CI = 1·76–17·45). This association is of potential interest as DES is known to alter immune function and is considered an oestrogenic endocrine disruptor.” …

… “In conclusion, our results provide evidence that increased parity, early age at first full‐term pregnancy, and breast‐feeding are associated with decreased risks of B‐cell NHL. These associations are also observed with breast cancer, and warrant further investigation to uncover whether similar anti‐carcinogenic mechanisms or specific hormone‐related immune alterations are responsible. Our report is the first suggesting the association of DES use with increased B‐cell NHL risk, particularly MZL, and warrants further investigation in collaborative efforts. Although no DES longer in use, should the association be replicated, it could provide important clues towards pinpointing biological mechanisms important for lymphomagenesis.” …


  • Pregnancy‐related factors and risk of B‐cell non‐Hodgkin lymphoma among women in Los Angeles, Wiley Online Library doi.org/10.1111/bjh.15699, 29 November 2018.
  • Featured image credit lymphoma-action.

Breast cancer risk for women exposed in utero and their offspring

Diethylstilbestrol: Potential health risks for women exposed in utero and their offspring

2017 Study Abstract

An increased risk of breast cancer has been well documented for women who took DES during pregnancy, and is estimated to be 30% greater than in unexposed women.

Long-term US studies of women exposed in utero reveal an increased risk of breast cancer in women age 40 years and older, with a hazard ratio of 1.82 (95% CI, 1.04-3.18) when compared with unexposed women. European follow-up studies do not support the finding of an increased breast cancer risk in women exposed to DES in utero. However, this may be due to the fact that the European cohort of women studied were 10 years younger than the American cohort and thus, at the time, included many women under age 40 years.

Animal studies suggest a transgenerational risk specifically for breast cancer in female offspring of women exposed to DES in utero, but this has not been supported by current patient data from United States or European follow-up studies.