Developmental origins of health and disease

Prenatal exposure to diethylstilbestrol and long-term impact on the breast and reproductive tract in humans and mice

2012 Study Abstract

The term ‘developmental origins of health and disease‘ (DOHaD) originally referred to delayed effects of altered maternal factors (e.g. smoking or poor nutrition) on the developing offspring, but it now also encompasses early life exposure to environmental chemicals, which can cause an unhealthy prenatal environment that endangers the fetus and increases its susceptibility to disease later in life.

Prenatal exposure to the pharmaceutical diethylstilbestrol (DES) is a well-known DOHaD example as it was associated in the 1970s with vaginal cancer in daughters who were exposed to this potent synthetic estrogen before birth. Subsequently, numerous long-term effects have been described in breast and reproductive tissues of DES-exposed humans and experimental animals.

Data reviewed suggest that the prenatal DES-exposed population should continue to be monitored for potential-increased disease risks as they age. Knowledge of sensitive developmental periods, and the mechanisms of DES-induced toxicities, provides useful information in predicting potential adverse effects of other environmental estrogens.


  • Prenatal exposure to diethylstilbestrol and long-term impact on the breast and reproductive tract in humans and mice, Journal of developmental origins of health and disease, NCBI PubMed PMID: 25101917, 2012 Apr 3.
  • Featured image credit Tanja Heffner.

Prenatal exposure to DES alter mammary cancer susceptibility

Endocrine-active chemicals in mammary cancer causation and prevention

2012 Study Abstract

Endocrine-active chemicals alter or mimic physiological hormones. These compounds are reported to originate from a wide variety of sources, and recent studies have shown widespread human exposure to several of these compounds.

Given the role of the sex steroid hormone, estradiol, in human breast cancer causation, endocrine-active chemicals which interfere with estrogen signaling constitute one potential factor contributing to the high incidence of breast cancer.

Thus, the aim of this review is to examine several common endocrine-active chemicals and their respective roles in breast cancer causation or prevention.

  • The plastic component, bisphenol A (BPA),
  • the synthetic estrogen, diethylstilbestrol (DES),
  • the by-product of organic combustion, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD),
  • the soy component, genistein,
  • and the red grape phytoalexin, resveratrol,

have some degree of structural similarities to each other and estradiol.

However, despite these structural similarities, the in vitro and in vivo properties of each of these chemicals vary greatly in terms of breast cancer causation and prevention.

Early life exposure to BPA and DES increases rodent susceptibility to chemically induced mammary carcinogenesis, presumably through retardation of normal mammary gland maturation and/or disrupting the ratio of cell proliferation and apoptosis in the mammary gland.

A recent study showed that in utero DES-exposed women greater than 40 years of age exhibited a statistically significant increase in the relative risk of developing breast cancer. This increase in risk was even more pronounced in DES-exposed women older than 50, though small samples size limited statistical significance. Also,there appears to be an increased risk of developing breast cancer associated with the mothers exposed to DES during pregnancy, though this appears to be a modest increase which does not manifest until decades after DES administration.

On the other hand, early exposures to genistein and resveratrol protect rodents against chemically induced and spontaneous mammary cancers. This is reported to occur through the ability of genistein and resveratrol to accelerate mammary gland maturation.

Interestingly, TCDD, which is the most structurally dissimilar to the above chemicals and functions as an anti-estrogen, also increases chemically induced mammary carcinogenesis through retardation of mammary gland maturation.

This article is part of a Special Issue entitled ‘Endocrine disruptors’.


  • Endocrine-active chemicals in mammary cancer causation and prevention, The Journal of steroid biochemistry and molecular biology, NCBI PubMed PMID: 21729753, 2012 Apr.
  • Featured image credit Embarazo-feliz.

Mammography screening behaviors of women exposed prenatally to diethylstilbestrol

Continued monitoring is recommended for DES Daughters

2012 Study Abstract

In utero diethylstilbestrol (DES) exposure is a risk factor for rare development of vaginal and cervical cancer and may potentially be a risk factor for breast cancer. Mammography use in this population is relatively unknown; therefore, this study aims to determine if in utero DES exposure is associated with the frequency of mammography screening examinations while considering demographic and clinical factors.

Using combined DES cohort questionnaire data, self-reported mammography screening over the past 5 years (2001-2006) was analyzed in women aged ≥45 years. Binary logistic regression assessed if DES exposure was associated with mammography use after adjustment for benign breast disease (BBD), previous cancer diagnosis, and whether insurance access influenced screening use.

Overall, the frequency of mammography examinations was similar for both DES-exposed and unexposed women. DES-exposed (n=2986) and unexposed women (n=1397) over the age of 44 reported receiving ≥3 mammography examinations in the past 5 years (73.8% and 74.0%, respectively). After adjustment, DES exposure was not associated with ≥3 mammograms in the past 5 years compared to ≤2 examinations (odds ratio [OR] 1.00, 95% confidence interval [CI] 0.86-1.17), p=0.99).

In utero DES exposure was not associated with mammography use, nor was health insurance status or a BBD or cancer diagnosis. Because of the potential elevated risk for breast cancer in women exposed prenatally to DES, continued monitoring of standard mammography recommendations is recommended for this group, which is predominantly over the age of 45.


  • Mammography screening behaviors of women exposed prenatally to diethylstilbestrol, Journal of women’s health, NCBI PubMed PMID: 22150213, 2012 Feb 21.
  • Featured image credit Janko Ferlič.

Breast cancer following diethylstilbestrol exposure in utero

Insights from a tragedy, European journal of epidemiology, 2012


Recent evidence indicates that in utero exposure to DES is also linked to breast cancer in women over the age of 40 years. This evidence provides support to the hypothesis that in utero exposures may affect breast cancer risk in adult life.

Women were exposed during a well-defined and vulnerable intra-uterine period to a potent synthetic estrogen, which crosses the placenta and was often given in high doses escalating from the 7th to the 35th week of pregnancy according to a fixed regimen.

A wealth of experimental data illustrates numerous conceivable mechanisms whereby DES could interfere with cellular processes and disrupt normal breast development. Hence, the landmark NCI study – see here and here provides the first direct evidence that breast cancer risk in adulthood is indeed influenced by an exposure entirely confined to the intra-uterine period.


  • Breast cancer following diethylstilbestrol exposure in utero: insights from a tragedy, European journal of epidemiology, NCBI PubMed PMID: 22286719, 2012 Jan.
  • Featured image credit 
    Janko Ferlič

Risk factors for breast cancer, including occupational exposures

Lifestyle-Related Risk Factors for Breast Cancer

Use of exogenous hormones

According to the International Agency for Research on Cancer (IARC), in-utero exposure to diethylstilbestrol, i.e., when a pregnant woman uses the drug, increases a female child’s risk of developing breast cancer.


The knowledge on the etiology of breast cancer has advanced substantially in recent years, and several etiological factors are now firmly established. However, very few new discoveries have been made in relation to occupational risk factors. The International Agency for Research on Cancer has evaluated over 900 different exposures or agents to-date to determine whether they are carcinogenic to humans. These evaluations are published as a series of Monographs.

For breast cancer the following substances have been classified as “carcinogenic to humans” (Group 1): alcoholic beverages, exposure to diethylstilbestrol, estrogen-progestogen contraceptives, estrogen-progestogen hormone replacement therapy and exposure to X-radiation and gamma-radiation (in special populations such as atomic bomb survivors, medical patients, and in-utero exposure). Ethylene oxide is also classified as a Group 1 carcinogen, although the evidence for carcinogenicity in epidemiologic studies, and specifically for the human breast, is limited.

The classification “probably carcinogenic to humans” (Group 2A) includes estrogen hormone replacement therapy, tobacco smoking, and shift work involving circadian disruption, including work as a flight attendant. If the association between shift work and breast cancer, the most common female cancer, is confirmed, shift work could become the leading cause of occupational cancer in women.


  • Full study (free access) : Risk Factors for Breast Cancer, Including Occupational Exposures, Saf Health Work, NCBI PubMed PMC3431884, 2011 Mar.
  • Featured image credit cipherpharma.

Intrauterine factors and risk of breast cancer

Systematic review and meta-analysis of current evidence, 2007


Emerging evidence suggests an association between female prenatal experience and her subsequent risk of developing breast cancer. Potential underlying mechanisms include variation in amounts of maternal endogenous sex hormones and growth hormones, germ-cell mutations, formation of cancer stem-cells, and other genetic or epigenetic events. We reviewed and summarised quantitatively the available data on intrauterine exposures and risk of breast cancer.

We systematically searched for studies that assessed association between perinatal factors and risk of breast cancer. We reviewed separately each of the perinatal factors, including birthweight, birth length, parental age at delivery, gestational age, intrauterine exposure to diethylstilbestrol, twin membership, maternal pre-eclampsia or eclampsia, and other factors.

We identified 57 studies published between Oct 1, 1980, and June 21, 2007. Increased risk of breast cancer was noted with increased birthweight (relative risk [RR] 1.15 [95% CI 1.09-1.21]), birth length (1.28 [1.11-1.48]), higher maternal age (1.13 [1.02-1.25]), and paternal age (1.12 [1.05-1.19]). Decreased risk of breast cancer was noted for maternal pre-eclampsia and eclampsia (0.48 [0.30-0.78]) and twin membership (0.93 [0.87-1.00]). No association was noted between risk of breast cancer and gestational age at birth (0.95 [0.71-1.26]) or maternal diethylstilbestrol treatment (1.40 [0.86-2.28]).

The intrauterine environment contributes to the predisposition of women to breast cancer in adulthood. The in-utero mechanisms responsible for such predisposition need to be elucidated.


  • Intrauterine factors and risk of breast cancer: a systematic review and meta-analysis of current evidence, The Lancet Oncology, NCBI PubMed PMID: 18054879, 2007 Dec.
  • Image credit swissfetus.

Intrauterine factors and breast cancer risk

Breast cancer increased risk in DES offspring


“Suggestions that risk of breast cancer in human beings might be affected by early-life exposures, or even intrauterine events and conditions, have been reported in published studies in the past four decades, …

… More direct evidence in support of a role of pregnancy oestrogens has been provided by the results from a unique cohort of women in utero exposed to diethylstilbestrol, a synthetic oestrogen. These women were found to be at increased risk for breast cancer after the age of 40 years, when familial breast cancer becomes rare.”



Breast cancer risk in DES offspring

Intrauterine exposures, pregnancy estrogens and breast cancer risk: where do we currently stand?

2006 Study Abstracts

Since 1990, when a hypothesis on intrauterine influences on breast cancer risk was published, several studies have provided supportive, indirect evidence by documenting associations of birth weight and other correlates of the prenatal environment with breast cancer risk in offspring. Recent results from a unique cohort of women with documented exposure to diethylstilbestrol in utero have provided direct evidence in support of a potential role of pregnancy oestrogens on breast cancer risk in offspring.

Since 1992, all US cohorts of DES-exposed persons for whom there was an appropriate comparison group of unexposed persons and for whom there was medical record documentation of exposure (or not) to this substance are being followed in a study supported by the US National Cancer Institute. Slightly more than 4800 women exposed in utero to DES and approximately 2070 unexposed women are included in this cohort. Results concerning breast cancer in offspring have been reported in three reports. The risk for developing breast cancer in the earliest report, when women exposed to DES in utero were still very young (38 years on the average), was barely 18% higher in exposed to nonexposed women. However, the increase became progressively greater with longer follow up.

In the most recent report, for breast cancer occurring at age 40 years or older the risk was significantly higher, by 91%, in women exposed to DES in utero than in those who were not exposed. For breast cancer at age 50 years or older the corresponding excess was 200%, which again was significant but with a wide confidence interval. The overall pattern does not come as a surprise because breast cancer among young women is known frequently to have genetic roots, so an excess risk on account of intrauterine exposure to oestrogens is likely to become more evident with advancing age.


  • Full paper (free access) : Intrauterine exposures, pregnancy estrogens and breast cancer risk: where do we currently stand?, Breast Cancer Research, NCBI PubMed PMC1797035, 2006.
  • Image credit boram kim.

DES exposure and the aging woman: mothers and daughters

DES mothers have a 30% higher risk of breast cancer

2002 Study Abstract

Diethylstilbestrol (DES), the first orally active artificial estrogen ever developed, was prescribed to several million pregnant women during the 1940s through the 1960s in the mistaken belief that it reduced the risk of miscarriage.

In 1971, the US Food and Drug Administration contraindicated its use in pregnancy when DES was associated with the development of vaginal clear cell adenocarcinoma (CCA) in daughters exposed in utero.

In daughters whose mothers took DES during pregnancy, the drug has been associated with congenital malformations of the reproductive tract, fertility problems, a possible increased risk of cervical carcinoma in situ, and a presumed lifetime risk of vaginal and cervical CCA.

DES mothers have an increased risk of breast cancer (RR = 1.3).

DES sons have an increased prevalence of urogenital anomalies, and a possible increased risk of testicular cancer.



DES Research Heats Up Again After Breast Cancer Finding

Journal of the National Cancer Institute, August 1999

“Based on continued cohort studies, we are now fairly sure that DES women face a 20% to 30% excess risk for breast cancer,”

Robert Hoover, M.D., director of the Epidemiology and Biostatistics Program at the National Cancer Institute

“DES could serve the study of other potential estrogenic cancer-causing compounds and environmental estrogens — none are as potent as DES and it would make an excellent model,”

Retha Newbold, head of the Developmental Endocrinology Section at the National Institute of Environmental Health Sciences, Research Triangle Park, N.C.

Another recommendation from the group was that researchers start to examine grandchildren of DES-exposed women, as they too may have a potential for DES cancers.

Read the full paper DES Research Heats Up Again After Breast Cancer Finding on Oxford University Press, 18 August 1999.