OBJECTIVE: To examine prenatal diethylstilbestrol (DES) exposure in relation to male reproductive outcomes.
DESIGN: Prospective observational study.
SETTING: Participants were identified through record review, clinical trial participation, or an obstetrics clinic.
PATIENT(S): A total of 1,085 DES-exposed and 1,047 unexposed men.
INTERVENTION(S): Participants were exposed prenatally to DES through the mother’s obstetrics care or clinical trial participation.
MAIN OUTCOME MEASURE(S): Infertility; never fathering a pregnancy or live birth; number of pregnancies or live births fathered.
RESULT(S): We found little evidence that prenatal DES exposure affects the likelihood of never fathering a pregnancy or live birth, or influences the mean number of fathered pregnancies or live births. Our data suggest that DES-exposed men are slightly more likely to experience infertility (relative risk [RR] = 1.3, 95% confidence interval [CI] = 1.0-1.6). The DES dose and gestational timing did not influence infertility or the number of pregnancies or live births fathered, but results were inconsistent for dose effects on the likelihood of never fathering a pregnancy or a live birth.
CONCLUSION(S): Prenatal DES exposure may be associated with a slightly increased risk of having an infertility experience, but does not increase the likelihood of never fathering a pregnancy or a live birth, or the number of pregnancies or live births fathered.
Reproductive Outcomes in Men with prenatal Exposure to DiEthylStilbestrol, NCBI, Dr R Hoover, PMID:16359959, Dec 2005.
Testicular cancer may be elevated among DES-exposed men
2001 Study Abstract
BACKGROUND: An association between prenatal Diethylstilbestrol (DES) exposure and cancer in men, especially testicular cancer, has been suspected, but findings from case-control studies have been inconsistent. This study was conducted to investigate the association between prenatal DES exposure and cancer risk in men via prospective follow-up.
METHODS: A total of 3613 men whose prenatal DES exposure status was known were followed from 1978 through 1994. The overall and site-specific cancer incidence rates among the DES-exposed men were compared with those of the unexposed men in the study and with population-based rates. The relative rate (RR) was used to assess the strength of the association between prenatal DES exposure and cancer development. All statistical tests were two-sided.
RESULTS: Overall cancer rates among DES-exposed men were similar to those among unexposed men (RR = 1.07; 95% confidence interval [CI] = 0.58 to 1.96) and to national rates (RR = 0.99; 95% CI = 0.65 to 1.44). Testicular cancer may be elevated among DES-exposed men, since the RRs for testicular cancer were 3.05 (95% CI = 0.65 to 22.0) times those of unexposed men in the study and 2.04 (95% CI = 0.82 to 4.20) times those of males in the population-based rates. The higher rate of testicular cancer in the DES-exposed men is, however, also compatible with a chance observation.
CONCLUSIONS: To date, men exposed to DES in utero do not appear to have an increased risk of most cancers. It remains uncertain, however, whether prenatal DES exposure is associated with testicular cancer.
Cancer risk in men exposed in utero to diethylstilbestrol,NCBI, PMID: 11287449, 2001 Apr 4;93(7):545-51. Full text: Oxford Journals Medicine & Health International Journal of Epidemiology link.
DES-exposed women have a higher risk of infertility
2001 Study Abstract
Although it is well established that women exposed to diethylstilbestrol in utero have an increased risk of spontaneous abortion, ectopic pregnancy, and preterm delivery, it is not known whether they also have an increased risk of infertility. The authors assessed this question in data from a collaborative follow-up study of the offspring of women who took diethylstilbestrol during pregnancy. In 1994, 1,753 diethylstilbestrol-exposed and 1,050 unexposed women from an ongoing cohort study (National Cooperative Diethylstilbestrol Adenosis Study and Dieckmann cohorts) provided data on difficulties in conceiving and reasons for the difficulty. Age-adjusted relative risks were computed for the association of diethylstilbestrol exposure with specific types of infertility. A greater proportion of exposed than unexposed women were nulligravid (relative risk (RR) = 1.3, 95% confidence interval (CI): 1.1, 1.5), and a greater proportion had tried to become pregnant for at least 12 months without success (RR = 1.8, 95% CI: 1.6, 2.1). Diethylstilbestrol exposure was significantly associated with infertility due to uterine and tubal problems, with relative risks of 7.7 (95% CI: 2.3, 25) and 2.4 (95% CI: 1.2, 4.6), respectively. The present findings indicate that diethylstilbestrol-exposed women have a higher risk of infertility than do unexposed women and that the increased risk of infertility is primarily due to uterine or tubal problems.
Sadly for many DES daughters having their own children is not possible! Many of us who have experienced miscarriages, want to have kids but are struggling or unable to…
Infertility among women exposed prenatally to diethylstilbestrol,NCBI, PMID: 11495854, 2001 Aug 15;154(4):316-21. Full text: Oxford Journals Medicine & Health International Journal of Epidemiology link.
DES seems to have health effects across the lifespan, especially in the reproductive tract
DES Follow-up Study Summary
A recent analysis of data from questionnaires returned by the participants in the DES Follow-up Study suggests that exposed daughters tend to have a slightly earlier age at natural menopause than unexposed daughters (Hatch EE et al, Age at Natural Menopause in Women Exposed to Diethylstilbestrol in Utero, American Journal of Epidemiology, October 1, 2006). The researchers analyzed data on over 4210 exposed daughters and 1829 unexposed daughters, and accounted for other factors that could be related to the age at natural menopause, such as cigarette smoking, hormone use, pregnancy history, and the age of the mother’s menopause. The average age at menopause was 52.2 years in unexposed women and 51.5 years in DES-exposed women, equivalent to about a nine month earlier menopause. Women who had been exposed to higher cumulative doses of DES tended to have menopause even earlier than those who had lower doses. Although this relatively small difference in age at menopause should not be related to any major health problems among the DES daughters, it does highlight the fact that DES seems to have health effects across the lifespan, especially in the reproductive tract. In general, menopause is thought to occur when the number of ovarian follicles left in the ovaries reaches a ‘critical’ level, therefore it is possible that DES daughters may have been born with a smaller reserve of follicles than unexposed women.
2006 Study Abstract
BACKGROUND: Age at natural menopause is related to several health outcomes, including cardiovascular disease and overall mortality. Age at menopause may be influenced by the number of follicles formed during gestation, suggesting that prenatal factors could influence menopausal age. Diethylstilbestrol (DES), a nonsteroidal estrogen widely prescribed during the 1950s and 1960s, is related to reproductive tract abnormalities, infertility, and vaginal cancer in prenatally exposed daughters but has not been studied in relation to age at menopause. The authors used survival analyses to estimate the risk of natural menopause in 4,210 DES-exposed versus 1,829 unexposed US women based on responses to questionnaires mailed in 1994, 1997, and 2001. DES-exposed women were 50% more likely to experience natural menopause at any given age (hazard ratio = 1.49, 95% confidence interval: 1.28, 1.74). Among women for whom dose information was complete, there were dose-response effects, with a greater than twofold risk for those exposed to >10,000 mg. The causal mechanism for earlier menopause may be related to a smaller follicle pool, more rapid follicle depletion, or changes in hormone synthesis and metabolism in DES-exposed daughters. Age at menopause has been related, albeit inconsistently, to several exposures, but, to the authors’ knowledge, this is the first study to suggest that a prenatal exposure may influence reproductive lifespan.
Age at natural menopause in women exposed to diethylstilbestrol in utero,NCBI, PMID: 16887893, 2006 Oct 1;164(7):682-8. Epub 2006 Aug 3. Full text Oxford Journals Medicine & Health International Journal of Epidemiology link.
DES exposed daughters more likely to have begun menstruating at younger age
DES Follow-up Study Summary
Research has suggested that early life characteristics, such as size at birth and age at menarche, may be associated with health conditions later in life. For example, some studies have suggested that low birth weight babies tend to have a higher risk of cardiovascular disease later in life. Other studies have shown that women who begin having periods at a young age have a slightly higher risk of breast cancer than those who begin menstruation later.
Although there has been a great deal of research on health of the 2nd generation (DES daughters) later in life, little attention has been paid to whether they were similar in terms of birth weight and other early life factors. Results from one of the early clinical trials of DES suggested that it might be related to lower birth weight and a higher risk of preterm birth. We conducted a systematic evaluation of DES daughters participating in the NCI DES Follow-up Study to determine whether there were any differences in birth weight, length of gestation, and the average age of first menstruation in the DES-exposed compared to unexposed daughters.
We found that there was a 2 to 3 fold increase in risk of having been born prematurely (before 37 weeks gestational age) among the DES-exposed compared to unexposed daughters. On average, DES daughters tended to weigh slightly less at birth, and there was also a 60% higher risk of being born too small, or small for gestational age (SGA), defined as less than the 10th percentile of birth weight at each gestational age. We found stronger effects for birth weight, SGA, and preterm birth among women who were participants in the original DESAD study, as compared to those who were in the Dieckmann clinical trial, suggesting that part of the effect may have been due to the higher risk pregnancies among the exposed women and not solely to DES exposure.
When we evaluated the risk of having started menstruation before age 11, we found no difference between the DES exposed and unexposed daughters. However, DES daughters did have a small increased risk (40%) of starting menarche very young-at age 10 or less-but this was based on very small numbers of participants who had very early menstruation.
In summary, DES exposed daughters appeared to weigh slightly less and have a higher risk of being born prematurely than unexposed daughters. They also were somewhat more likely to have begun menstruating at age 10 or younger. These effects may have a small impact on the risk of some diseases occurring later in life.
2011 Study Abstract:
Diethylstilbestrol (DES), a synthetic estrogen used in pregnancy during the 1950s and 1960s, provides a model for potential health effects of endocrine disrupting compounds in the environment. We evaluated prenatal exposure to DES, based on medical record review, in relation to gestational length, fetal growth, and age at menarche in 4429 exposed and 1427 unexposed daughters. DES exposure was associated with an increase in preterm birth (odds ratio (OR)=2.97; 95% CI=2.27, 3.87), and a higher risk of small for gestational age (SGA) (OR=1.61; 95% CI=1.31, 1.98). The association between DES exposure and early menarche was borderline, with stronger effects when early menarche was defined as ≤ 10 years (OR=1.41 95% CI=0.97, 2.03) than defined as ≤ 11 years (OR=1.16; 95% CI=0.97, 1.39). This study provides evidence that prenatal DES exposure was associated with fetal growth and gestational length, which may mediate associations between DES and health outcomes in later life.
Preterm birth, fetal growth, and age at menarche among women exposed prenatally to diethylstilbestrol (DES),NCBI, PMID: 21130156, 2011 Feb;31(2):151-7. doi: 10.1016/j.reprotox.2010.11.006. Epub 2010 Dec 2. Full text link.
The 2001 stuy findings support an association between in-utero DES exposure and high-grade squamous neoplasia.
DES Follow-up Study Summary
Women exposed to Diethylstilbestrol (DES) before birth (in the womb), known as DES Daughters, are at increased risk for clear cell adenocarcinoma of the vagina and cervix, but the effect of in utero DES exposure on later development of squamous neoplasia in the cervix and vagina is uncertain. This combined follow-up study of 3,899 DES Daughters (median age 38) and 1,374 unexposed daughters (median age 39) was followed 1982-1995. Subjects were drawn from three previously studied cohorts (DESAD, Dieckmann, and Horne). The purpose was to examine the long-term risk of developing high-grade squamous intraepithelial neoplasia (HSIL) of the genital tract in DES Daughters compared with unexposed daughters.
The study found a small but significant increase in HSIL among DES Daughters in all age groups, including those over age 40. A total of 111 pathology-confirmed HSIL cases occurred, including five of the vagina, one of the vulva and two cases of invasive cervical cancer. The overall relative risk was 2.1 among DES-exposed versus unexposed. The relative risk among those whose mothers were prescribed DES within 7 weeks of the last menstrual period was 2.8 compared with 1.35 among women exposed for the first time at 15 weeks or later. Women with documented high-grade neoplasia before 1982 were excluded because prior treatment of the cervix may lower the subsequent finding of intraepithelial neoplasia. Researchers could not rule out that more frequent and intensive screening among DES-exposed women played a role in these findings.
Neoplasia is abnormal and uncontrolled cell growth; a neoplasm is new growth of benign or malignant tissue. Squamous cells are found in the tissue that forms the surface of the skin, the lining of the hollow organs of the body, and the passages of the respiratory and digestive tracts. These flat cells look like fish scales under a microscope. Squamous intraepithelial lesion (SIL) is a general term for the abnormal growth of squamous cells on the surface of the cervix. The changes in the cells are described as low grade or high grade, depending on how much of the cervix is affected and how abnormal the cells appear. Cervical intraepithelial neoplasia (CIN) is a general term for the growth of abnormal cells on the surface of the cervix. Numbers from 1 to 3 may be used to describe how much of the cervix contains abnormal cells. High-grade squamous intraepithelial lesion (HSIL) is a precancerous condition in which the cells of the uterine cervix are moderately or severely abnormal. In this study, grades 2 and 3 were considered high.
2001 Study Abstract
OBJECTIVES: Women exposed prenatally to Diethylstilbestrol (DES) have an excess risk of clear-cell adenocarcinoma of the vagina and cervix, but the effect on the incidence of squamous neoplasia is uncertain. The purpose of the current study was to evaluate the long-term risk of developing high-grade squamous neoplasia of the genital tract among women exposed prenatally to DES.
METHODS: A cohort comprising 3,899 DES-exposed and 1,374 unexposed daughters was followed for 13 years (1982 1995) for pathology-confirmed diagnoses of high-grade squamous intraepithelial neoplasia (HSIL) of the genital tract. Poisson regression analysis was used to compute relative risks (RR) and 95% confidence intervals (95% CI), adjusting for age, calendar year, and other covariates.
RESULTS: The RR (95% CI) among DES-exposed versus unexposed, based on 111 cases of high-grade disease, was 2.1 (1.2-3.8). Adjustment for screening history estimated by the number of years since the last Pap smear had little effect. Risk estimates were higher with earlier intrauterine exposure; the RR (95% CI) for exposure within 7 weeks of the last menstrual period was 2.8 (1.4-5.5). Only two cases of invasive squamous cervical cancer occurred in total, precluding separate analysis.
CONCLUSIONS: The findings support an association between in-utero DES exposure and high-grade squamous neoplasia, although a role for more intensive screening among DES-exposed women in the production of this excess could not be completely ruled out.
Incidence of squamous neoplasia of the cervix and vagina in women exposed prenatally to diethylstilbestrol (United States),NCBI, PMID: 11714112, 2001 Nov;12(9):837-45.
Women with prenatal exposure to DES have an increased risk of breast cancer after age 40 years
DES Follow-up Study Summary
One of the main purposes of our study is to examine whether prenatal Diethylstilbestrol (DES) exposure influences risk of breast cancer or other cancers in addition to cancers of the vagina and cervix. Results from our most recent analysis of prenatal DES exposure and breast cancer were published in the scientific journal Cancer Epidemiology Biomarkers and Prevention.
Questionnaire data collected in 2001, 1997, and 1994 were used to examine this issue among daughters participating in the study. 4,817 study participants whose mothers took DES while pregnant with them were compared with 2,073 participants who were unexposed. Medical records were obtained to confirm cancer diagnoses. A total of 102 participants were diagnosed with invasive breast cancer. Comparisons of exposed and unexposed women took into account differences in age and other factors such as number of births, age at first birth, and age at first menstruation that are related to breast cancer risk.
Before age 40, women exposed to DES prenatally were not at higher breast cancer risk compared to unexposed women. However, at ages 40 and older, DES-exposed women had two times the breast cancer risk of unexposed women. It appeared that the increase for exposed relative to unexposed women continued to rise with increasing age, but most study participants were still under 50 when the last questionnaire was completed and it is too early for definitive results. Data from the 2006 follow-up questionnaire will provide better information on this question. The association of DES exposure with breast cancer risk was present regardless of whether a participant had a family history of breast cancer or had used female hormone supplements.
Although breast cancer is the most common cancer in U.S. women, most women will never develop breast cancer. That is still the case for women exposed to DES prenatally – most will never develop breast cancer. Based on U.S. cancer registry data, for every 1,000 DES-exposed women aged 45-49, we would expect 4 new cases of breast cancer each year, compared to 2 new cases per year in 1,000 unexposed women.
Under American Cancer Society recommendations, all women who are 40 years or older are advised to undergo yearly mammograms to screen for early breast cancers. Women who were exposed to DES should follow this screening guideline if they are not already doing so.
2006 Study Abstract
It has been hypothesized that breast cancer risk is influenced by prenatal hormone levels. Diethylstilbestrol (DES), a synthetic estrogen, was widely used by pregnant women in the 1950s and 1960s. Women who took the drug have an increased risk of breast cancer, but whether risk is also increased in the daughters who were exposed in utero is less clear. We assessed the relation of prenatal DES exposure to risk of breast cancer in a cohort of DES-exposed and unexposed women followed since the 1970s by mailed questionnaires. Eighty percent of both exposed and unexposed women completed the most recent questionnaire. Self-reports of breast cancer were confirmed by pathology reports. Cox proportional hazards regression was used to compute incidence rate ratios (IRR) for prenatal DES exposure relative to no exposure. During follow-up, 102 incident cases of invasive breast cancer occurred, with 76 among DES-exposed women (98,591 person-years) and 26 among unexposed women (35,046 person-years). The overall age-adjusted IRR was 1.40 [95% confidence interval (95% CI), 0.89-2.22]. For breast cancer occurring at ages >or=40 years, the IRR was 1.91 (95% CI, 1.09-3.33) and for cancers occurring at ages >or=50 years, it was 3.00 (95% CI, 1.01-8.98). Control for calendar year, parity, age at first birth, and other factors did not alter the results. These results, from the first prospective study on the subject, suggest that women with prenatal exposure to DES have an increased risk of breast cancer after age 40 years. The findings support the hypothesis that prenatal hormone levels influence breast cancer risk.
Prenatal diethylstilbestrol exposure and risk of breast cancer,NCBI, PMID: 16896041, 2006 Aug;15(8):1509-14. Full text: Cancer Epidemiol Biomarkers Prevention link.
Greater mammary gland mass and increased risk of breast cancer for the DES-exposed
2013 Study Abstract:
PURPOSE: Prenatal DES exposure has been associated with increased risk of breast cancer, but the mechanisms are unknown. Larger bra cup size has also been associated with increased breast cancer risk, although not consistently. We investigated the relation of prenatal DES exposure to mammary gland mass, as estimated by bra cup size.
METHODS: In 2006, 3,222 DES-exposed and 1,463 unexposed women reported their bra cup size, band size (chest circumference), and weight at age 20. Prevalence ratios (PR) were calculated for DES exposure in relation to large bra cup size, with control for year of birth and study cohort. Primary analyses were carried out among women who reported a chest circumference of no more than 32 inches because their cup size would be less influenced by fat mass.
RESULTS: Within this group, DES-exposed women had an estimated 45 % increased prevalence (95 % CI 0.97-2.18) of large cup size (C or greater) relative to unexposed women. The PR was further increased among women in this group who had a body mass index of < 21 at age 20: PR = 1.83 (95 % CI 1.11-3.00). The PR for high-dose DES exposure relative to no exposure was 1.67, 95 % CI 1.02-2.73, whereas there was no association of bra cup size with low-dose exposure.
CONCLUSIONS: These results provide support for the hypothesis that in utero DES exposure may result in greater mammary gland mass. Taken together with previous research on bra size and breast cancer risk, these findings suggest a mechanism for a possible association of in utero DES exposure with increased risk of breast cancer.
Sources: Prenatal DES Exposure in Relation to Breast Size, NCBI, Dr R Hoover, PMID: 23775027, 2013 Sep;24(9):1757-61. doi: 10.1007/s10552-013-0248-3. Epub 2013 Jun 18. Full text link.
A total of 143 exposed women and 49 unexposed women in the DES Combined Cohort Follow-up Study were diagnosed with cancer as of 2001.
Compared with breast cancer rates in the general US population, there was no overall higher risk among DES exposed women. Comparing exposed with unexposed women within the study, there was about a 30% increase in cancer risk but this finding could be due to chance. As reported in a previous article (Palmer 2006), breast cancer risk was elevated but only among women over 40 years of age. Exposed women had a risk of CCA that was nearly 40% higher than the general population, however; the incidence of CCA decreased substantially after age 25 compared with women 20 to 24 years old. Excluding CCA and breast cancer, the higher risk of cancer among the DES exposed women was about 20%, a result that could be due to chance. DES was not associated with higher risks of either endometrial or ovarian cancer. These data suggest that the DES associated increase in CCA rates remains elevated through the reproductive years. There was no consistent evidence of a higher risk for cancers other than CCA, and breast in older women.
Given that the population is still young, continued follow-up is necessary to assess the overall cancer risk associated with prenatal DES exposure.
Cancer risk in women prenatally exposed to diethylstilbestrol,NCBI, PMID: 17390375, 2007 Jul 15;121(2):356-60.
In utero exposure of women to DES is associated with a high lifetime risk of a broad spectrum of adverse health outcomes
2011 Study Abstract:
BACKGROUND: Before 1971, several million women were exposed in utero to Diethylstilbestrol (DES) given to their mothers to prevent pregnancy complications. Several adverse outcomes have been linked to such exposure, but their cumulative effects are not well understood.
METHODS: We combined data from three studies initiated in the 1970s with continued long-term follow-up of 4653 women exposed in utero to DES and 1927 unexposed controls. We assessed the risks of 12 adverse outcomes linked to DES exposure, including cumulative risks to 45 years of age for reproductive outcomes and to 55 years of age for other outcomes, and their relationships to the baseline presence or absence of vaginal epithelial changes, which are correlated with a higher dose of, and earlier exposure to, DES in utero.
RESULTS: Cumulative risks in women exposed to DES, as compared with those not exposed, were as follows:
for infertility, 33.3% vs. 15.5% (hazard ratio, 2.37; 95% confidence interval [CI], 2.05 to 2.75)
spontaneous abortion, 50.3% vs. 38.6% (hazard ratio, 1.64; 95% CI, 1.42 to 1.88)
preterm delivery, 53.3% vs. 17.8% (hazard ratio, 4.68; 95% CI, 3.74 to 5.86)
loss of second-trimester pregnancy, 16.4% vs. 1.7% (hazard ratio, 3.77; 95% CI, 2.56 to 5.54)
ectopic pregnancy, 14.6% vs. 2.9% (hazard ratio, 3.72; 95% CI, 2.58 to 5.38)
preeclampsia, 26.4% vs. 13.7% (hazard ratio 1.42; 95% CI, 1.07 to 1.89)
stillbirth, 8.9% vs. 2.6% (hazard ratio, 2.45; 95% CI, 1.33 to 4.54)
early menopause, 5.1% vs. 1.7% (hazard ratio, 2.35; 95% CI, 1.67 to 3.31)
grade 2 or higher cervical intraepithelial neoplasia, 6.9% vs. 3.4% (hazard ratio, 2.28; 95% CI, 1.59 to 3.27)
breast cancer at 40 years of age or older, 3.9% vs. 2.2% (hazard ratio, 1.82; 95% CI, 1.04 to 3.18).
For most outcomes, the risks among exposed women were higher for those with vaginal epithelial changes than for those without such changes.
CONCLUSIONS: In utero exposure of women to DES is associated with a high lifetime risk of a broad spectrum of adverse health outcomes. (Funded by the National Cancer Institute).
Read: Adverse health outcomes in women exposed in utero to diethylstilbestrol, NCBI, PMID: 21991952, 2011 Oct 6;365(14):1304-14. doi: 10.1056/NEJMoa1013961.