Menstrual history and fecundity of DES-exposed women (in utero)

The Journal of reproductive medicine, 1984

Abstract

Sequential examination and interview of 349 women exposed to diethylstilbestrol (DES) and 375 women unexposed to the drug verified that DES exposure has no effect on age at menarche and indicated no differences in the age at 1st coitus, pregnancy, and live birth.

Records of the women in the DES Adenosis project were studied to determine DES dosage and timing, but starting date and total amount prescribed could not always be determined accurately.

Estimates indicate that about 1-2% of pregnant patients in the late 1950s and 1960s were exposed to the drug. As many as 30% of mothers were unaware that DES was given to them during pregnancy. The women were asked about marital status, age at menarche, menstrual history, pelvic inflammatory disease (PID), operations, birth control, and pregnancy experience.

Analysis of variance indicated that there is an age-related increase in oligomenorrhea in DES-exposed women as compared to unexposed women that disappears as the patients reach their late 20s.

Of 133 exposed women, 59 (44%) had induced abortions, and of 162 unexposed women 93 (57%) had induced abortions. DES-exposed women used oral contraceptives (OCs) but not as frequently or extensively as their unexposed counterparts.

Age at first coitus was 19.33 +or-2.95 years for the exposed and 18.89 +or-2.62 years for the unexposed, showing no significant difference.

In a higher percentage of DES-exposed women the cause of the couple’s infertility was undetermined. 44 (12.6%) of the exposed and 42 (11.2%) of the unexposed women had dilatation and curettage (D and C) for some reason other than abortion.

There appears to be no substantial effect of in utero exposure to DES on women’s ability to conceive. Whether or not exposure to DES has specific physiological effects on reproductive function, exposed women may alter their sexual and reproductive behavior in anticipation of those effects as well as experiencing them.

Sources

DES DIETHYLSTILBESTROL RESOURCES

Reproductive performance among DES exposed daughters compared with that of their mothers

The Ohio State medical journal, 1983

Abstract

The study was undertaken to determine what the experience of 158 diethylstilbestrol (DES) exposed daughters in the Toledo area has been and whether the rate of pregnancy loss is related to a similar rate in their mothers, indicating a familial factor in the etiology.

45 patients could produce written, documented evidence through their mothers’ prenatal records of having been exposed to DES. In these, not only the drug, but also the dose, stage of gestation, and duration were known. In 37 of these (82.2%), definite, benign DES related changes were found in the vagina and cervix. In another 49 patients documented evidence was not available, but all demonstrated the same gross and/or colposcopic changes, thereby giving presumptive evidence of DES exposure. These 94 patients make up Group A.

In 64 patients, no documented evidence of DES exposure was obtainable, since their mothers’ prenatal records had been lost or destroyed. The mothers themselves recalled using the drug with varying degrees of knowledge about the specifics of dose or duration. None of these daughters had objective findings, by gross or colposcopic examination, suggestive of DES effect. In 20 of them there was some evidence consistent with exposure. These were designated “equivocal findings” and included with the Group B patients.

In the group of 94 women who satisfied the criteria of DES exposure by documented history and/or characteristic physical findings (Group A), there were 39 who were sexually active without contraception. The remaining either denied coitus or were regular contraceptive users. 10 patients attempted to conceive for more than 1 year without success, for a primary infertility rate of 25.6%. 29 achieved a total of 46 pregnancies; 22 were delivered at term, and 24 aborted spontaneously, for a pregnancy failure rate of 52.2%.

Of the 64 patients with histories of DES exposure but no documented evidence (Group B), there were 24 sexually active without contraceptive use. In these 24 there were 3 who complained of primary infertility, which was defined as regular coitus without contraception for a period of at least 1 year, for a primary infertility rate of 12.5%. The remaining 21 patients had a total of 41 pregnancies. 31 of these resulted in full term live infants. 2 were electively aborted, and 8 were aborted spontaneously.

Reproductive histories were available in 105 of the mothers of these daughters. The mothers of the women in both groups had poor reproductive histories. The reproductive performance of Group B daughters was better than that of their mothers and closely approximated that usually quoted for the general population.

The performance of group A mothers was significantly worse than that of their mothers, in whom the pregnancy failure rate already was high.

The data indicate that the DES exposed daughters have a higher reproductive failure rate than their mothers, while that of DES unexposed daughters is lower. The existence of a familial factor is not supported.

Sources

  • Reproductive performance among DES exposed daughters compared with that of their mothers, The Ohio State medical journal, NCBI PubMed, PMID: 6646562, 1983 Nov.
  • Image credit sagepub
DES DIETHYLSTILBESTROL RESOURCES

Estrogen Metabolism in Postmenopausal Women Exposed In Utero to Diethylstilbestrol

Increased postmenopausal breast cancer risk in DES Daughters

2018 Study Abstract

Background
Prenatal diethylstilbestrol (DES) exposure is associated with adverse reproductive outcomes and cancer of the breast and vagina/cervix in adult women. DES effects on estrogen metabolism have been hypothesized, but reproductive hormone concentrations and metabolic pathways have not been comprehensively described.

Methods
Blood samples were provided by 60 postmenopausal women (40 exposed and 20 unexposed) who were participants in the NCI Combined DES Cohort Study, had never used hormone supplements or been diagnosed with cancer, had responded to the most recent cohort study questionnaire, and lived within driving distance of Boston University Medical School (Boston, MA). Parent estrogens and their metabolites were measured by high-performance liquid chromatography-tandem mass spectrometry. Age-adjusted percent changes in geometric means and associated 95% confidence intervals (CIs) between the exposed and unexposed were calculated.

Results

  • Concentrations of total estrogens (15.3%; CI, -4.1-38.5) and parent estrogens (27.1%; CI, -8.2-76.1) were slightly higher in the DES-exposed than unexposed.
  • Ratios of path2:parent estrogens (-36.5%; CI, -53.0 to -14.3) and path2:path16 (-28.8%; CI, -47.3-3.7) were lower in the DES exposed.
  • These associations persisted with adjustment for total estrogen, years since menopause, body mass index, parity, and recent alcohol intake.

Conclusions
These preliminary data suggest that postmenopausal women who were prenatally DES exposed may have relatively less 2 than 16 pathway estrogen metabolism compared with unexposed women.

Impact
Lower 2 pathway metabolism has been associated with increased postmenopausal breast cancer risk and could potentially offer a partial explanation for the modest increased risk observed for prenatally DES-exposed women.

Sources

  • Estrogen Metabolism in Postmenopausal Women Exposed In Utero to Diethylstilbestrol, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, NCBI PubMed PMID: 30049842, 2018 Oct;27.
  • Featured image credit aacrjournals.
DES DIETHYLSTILBESTROL RESOURCES

Prenatal diethylstilbestrol exposure and mammographic density

No association found between prenatal DES exposure and high breast density

2018 Study Abstract

In a prospective cohort study of the health effects associated with prenatal Diethylstilbestrol (DES) exposure, DES was associated with an increased breast cancer risk after 40 years of age. It is unknown whether it is associated with greater mammographic density, which strongly predicts breast cancer risk.

A cohort of DES-exposed and unexposed women was assembled at the Mayo Clinic in 1975, and followed through 2012 as part of the National Cancer Institute’s DES follow-up study. Mammographic density from 3,637 mammograms for 332 (222 DES-exposed, 110 unexposed) women in this cohort screened at the Mayo Clinic, Rochester between 1996 and 2015 was determined clinically using the Breast Imaging Reporting and Data System (BI-RADS). Any effect of prenatal DES exposure on mammographic density was estimated using repeated measures logistic regression.

There was no association between prenatal DES exposure and high mammographic density for either premenopausal [Odds ratios (OR) = 0.92 (95% Confidence Interval (CI): 0.50, 1.7] or postmenopausal women (OR = 0.90; 95% CI: 0.54, 1.5). Among premenopausal women, associations differed by body mass index (BMI), with ORs of 1.47 (0.70, 3.1) for women with BMI above the median and 0.53 (0.23, 1.3) for those with BMI below the median (pinteraction  = 0.05). Overall, however, prenatal DES exposure was not associated with high mammographic density in this sample of DES Study participants.

Consequently, this study does not provide evidence that high mammographic density is involved with the influence of DES on breast cancer.

Sources

  • Prenatal diethylstilbestrol exposure and mammographic density, International journal of cancer, NCBI PubMed PMID: 29658110, 2018 Sep 15.
  • Featured image credit medicalxpress.
DES DIETHYLSTILBESTROL RESOURCES

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

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.

Sources

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