Reproductive performance of DES-exposed-female progeny

Consequences of diethylstilbestrol in women whose mothers ingested the substance during pregnancy

Abstract

Between October 1973-October 1979, 613 women who had been exposed to diethylstilbestrol (DES) in utero were observed at the Brookdale Medical Center;

106 of these patients were observed for problems related to pregnancy. Most patients were between 17-27 years of age, and 39% were unmarried; 70 were in their 1st pregnancy.

Results of the 1st pregnancy were

  • 52 induced abortions,
  • 3 pregnancies still ongoing at the time of the study;

of the remaining 51 pregnancies,

  • 32 terminated in delivery;
  • there was a 37% of fetal wastage, mostly due to early delivery.

36 of the original 106 patients had a 2nd pregnancy;

  • in this group there were 7 abortions
  • and only 22 deliveries.

11 patients had a 3rd pregnancy, and 5 a 4th pregnancythese patients were able to bring their pregnancy to term.

In total there were 159 pregnancies, and a high percentage of fetal loss, mostly between the 13th and 28th week of pregnancy.

It is well known that many women who have been exposed to DES in utero present modifications of the aspect, shape, and size of the uterine cavity, which causes difficulties in bringing a pregnancy to term.

The article reviews the published literature on the subject.

Sources

  • Reproductive performance of DES-exposed-female progeny. Consequences of diethylstilbestrol in women whose mothers ingested the substance during pregnancy, Contraception, fertilite, sexualite, NCBI PubMed, PMID: 12338184, 1982 May.
  • Image credit watermark.silverchair.
DES DIETHYLSTILBESTROL RESOURCES

Breast Cysts and Lesions following Estrogen Replacement Therapy in the DES-Exposed

Perinatal Exposure to Bisphenol A or Diethylstilbestrol Increases the Susceptibility to Develop Mammary Gland Lesions After Estrogen Replacement Therapy in Middle-Aged Rats

2017 Study Abstract

The development of the mammary gland is a hormone-regulated event. Several factors can dysregulate its growth and make the gland more susceptible to cellular transformation. Among these factors, perinatal exposure to xenoestrogens and hormone replacement therapy has been associated with increased risk of developing breast cancer.

Here, we assessed the effects induced by estrogen replacement therapy (ERT) in ovariectomized (OVX) middle-aged rats and whether perinatal exposure to diethylstilbestrol (DES) or bisphenol A (BPA) modified these effects in the mammary gland.

Pregnant rats were orally exposed to vehicle, 5 μg DES/kg/day, or 0.5 or 50 μg BPA/kg/day from gestational day 9 until weaning. Then, 12-month-old offspring were OVX and treated with 17β-estradiol for 3 months. Morphological changes and the percentage of epithelial cells that proliferated or expressed estrogen receptor alpha (ESR1) and progesterone receptor (PR) were analyzed in mammary gland samples of 15-month-old animals. ERT induced lobuloalveolar hyperplasia and ductal cysts in the mammary gland of middle-aged rats, associated with a higher proliferation index of epithelial cells. Perinatal exposure to DES followed by ERT increased the number of cysts and induced the formation of fibroadenoma and ductal carcinoma in situ, without modifying the expression of ESR1 or PR. Also, after 3 months of ERT, BPA-exposed rats had a higher incidence of ductal hyperplasia and atypical lobular hyperplasia than animals under ERT alone.

In conclusion, perinatal exposure to xenoestrogens increases the susceptibility of the mammary gland to develop cysts and hyperplastic lesions when confronted with ERT later in life.

Sources

  • Perinatal Exposure to Bisphenol A or Diethylstilbestrol Increases the Susceptibility to Develop Mammary Gland Lesions After Estrogen Replacement Therapy in Middle-Aged Rats, Hormones & Cancer, NCBI PubMed PMID: 28078498, 2017 Apr.
  • Featured image credit everydayhealth.
DES DIETHYLSTILBESTROL RESOURCES

Prenatal DES exposure and breast cancer

Risk of breast cancer in women prenatally exposed to diethylstilbestrol

2012 Study Abstract

Diethylstilbestrol (DES) is a synthetic estrogen prescribed to prevent miscarriages until 1977.

Its role in the development of vaginal adenocarcinoma and cervical dysplasia is known and screening codified.

Recent cohort studies show that exposure to DES in utero increases breast cancer risk especially after 40 years.

This article reports the observation of a breast cancer of exceptional gravity in a patient exposed to DES in utero. It details the risk of breast cancer for “DES daughters” and support possible screening modalities.

Sources

  • Prenatal diethylstilbestrol exposure and breast cancer, Gynécologie, obstétrique & fertilité, NCBI PubMed PMID: 23102737, 2012 Dec.
  • Featured image credit artranked.
DES DIETHYLSTILBESTROL RESOURCES

Breast cancer following diethylstilbestrol exposure in utero : a tragedy ?

Breast cancer following diethylstilbestrol exposure in utero: insights from a tragedyauthor reply to Dr. Bluming, who has been compensated on an hourly basis for testimony as an expert witness on behalf of defendant, Pfizer Pharmaceuticals, in DES litigation.

We thank Dr. Tournaire and his colleagues for sharing data on diethylstilbestrol (DES) doses prescribed in France. This information supports the notion that DES was prescribed in lower doses and for shorter periods during pregnancy in Europe than in the US. It would be particularly interesting to know whether any women in the French cohort developed vaginal epithelial changes as a marker of high-dose exposure. And it is unfortunate that the small size of the French cohort (110 women) does not allow an informative analysis of breast cancer risk.

Although we realize that our opinion may not be appreciated in some quarters, Dr. Bluming’s denial of the indicated statistical significance in the NCI cohort is strange. We can only encourage readers to scrutinize the two most informative studies and develop their own opinion. Exclusion of one component cohort in the most recent study, due to lack of information on vaginal epithelial changes as a marker of high exposure, reduces statistical power but does not compromise the validity of the study. Although we are fortunate to have one high quality, competently analyzed prospective study, causal inference is challenging as discussed in our Commentary.

Definition of a tragedy is obviously a subjective process. We doubt, however, that the millions of women who were prescribed a useless drug with several harmful effects would disagree with our judgment.

Dr. Adami, consultant in litigation on behalf of DES daughters claiming breast cancer injury due to DES exposure.

Sources

  • Breast cancer following diethylstilbestrol exposure in utero: a tragedy?, NCBI PubMed, European journal of epidemiology PMID: 22860252, 2012 Apr.
  • Featured image credit gofundme.
DES DIETHYLSTILBESTROL RESOURCES

Breast cancer following DES exposure in utero

Diethylstilbestrol exposure: evaluation of the doses received in France, 2012

Abstract

In an analysis of two prospective studies on the relationship between DES exposure in utero and breast cancer, Adami et al. oppose a dose dependent excess risk after the age of 40 years and the absence of evidence of such an excess risk. Indeed, the American study suggested an excess risk of breast cancer for women exposed in utero aged 40 years or more. The Incidence Rate Ratio (IRR) was 1.91 (95 % CI 1.09–3.33) relative to unexposed cohorts. Nevertheless, IRR was significant for high dose exposure (IRR = 2.16, 95 % CI, 1.18–3.96) but not for low-dose exposure (IRR = 1.63, 95 % CI, 0.87–3.08) relative to unexposed cohort. The Dutch study by contrast revealed no increase of breast cancer for DES-exposed daughters.

One hypothesis that may explain these discordant results, besides possible differences in age of the cohorts and methods, concerns the differences in doses of DES given in the United States and in the Netherlands. This could stimulate a renewed interest in prescribed doses of DES, especially in Europe. Adami et al. observed that additional informative studies seem unfeasible since the use of DES ended four decades ago. However, we would like to focus on information obtained 2 or 3 decades ago on the DES doses used in France since our results seem relevant.

Sources

DES DIETHYLSTILBESTROL RESOURCES

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.

Sources

  • 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.
DES DIETHYLSTILBESTROL RESOURCES

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’.

Sources

  • 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.
DES DIETHYLSTILBESTROL RESOURCES

Mammography screening behaviors of women exposed prenatally to diethylstilbestrol

Continued monitoring is recommended for DES Daughters

2012 Study Abstract

BACKGROUND
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.

METHODS
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.

RESULTS
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).

CONCLUSIONS
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.

Sources

  • 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.
DES DIETHYLSTILBESTROL RESOURCES

Breast cancer following diethylstilbestrol exposure in utero

Insights from a tragedy, European journal of epidemiology, 2012

Abstracts

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.

Sources

  • 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
    .
DES DIETHYLSTILBESTROL RESOURCES

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.

Summary

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.

Sources

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