Age-incidence and risk of diethylstilbestrol-related clear cell adenocarcinoma of the vagina and cervix
This study was based on cases accessioned in the Registry of Clear Cell Adenocarcinoma of the Genital Tract in Young Females to ascertain the incidence of diethylstilbestrol (DES)-related cancers by age and year of birth. For accuracy in estimating the size of the reference population for the incidence rates, calculations were restricted to 127 white residents of the United States who were exposed prenatally to DES or other nonsteroidal synthetic estrogens. The disease is exceedingly rare prior to age 14 when the incidence rate begins to rise rapidly. The incidence peaks at age 19 (median 19.2 years) and then drops precipitately. Thus, DES-related clear cell adenocarcinoma is unusual in that nearly all cancers have been diagnosed in a narrow age range of 10 years (14 to 23 years). Women born in 1951 to 1953 have higher incidence rates than those born in the previous or subsequent three-year period. This suggests that the prevalence of pregnancy-related use of DES was at a peak in the early 1950’s. The cumulative risk of this type of genital cancer, through age 24, for DES-exposed female subjects is estimated to be in the range of 0.14 to 1.4 per thousand. The wide limits are due to the fact that the number of young women exposed is not known precisly. The low risk of disease and the narrow age range of the cases, relative to the long latency period, suggest that DES is an incomplete carcinogen. Other factors, possibly related to puberty, may be involved in the causation of this disease.
American journal of obstetrics and gynecology, 1981
Information on reproductive history, gynecologic operations, and examinations was analyzed for 338 diethylstilbestrol (DES)-exposed and 298 unexposed women whose mothers participated in an evaluation of DES use in pregnancy 28 years ago. A history of infrequent menses (less often than every 36 days) was reported more commonly by the exposed women (32%) than by the unexposed women (15%) and the mean duration of menstrual flow was also less. A greater number of exposed women than unexposed women experienced primary infertility (53 versus 19). The reasons for these differences are not currently known. Comparison of the outcomes of first pregnancies showed a higher proportion of premature births, spontaneous abortions, and ectopic pregnancies in the exposed women (P less than 0.001). The difference in the occurrence of ectopic pregnancies was statistically significant (8 versus 0; P less than 0.005). An adverse pregnancy outcome was more likely in DES-exposed women with cervicovaginal ridges. However, when the outcome of all pregnancies were considered, 81% of the exposed women had at least one living child. More exposed women than unexposed women had gynecologic surgical procedures, which may, in part, be due to the increased medical surveillance of the exposed group. The spectrum of diseases at operation in both groups was similar. Adnexal masses and pelvic inflammatory disease were more commonly reported among the exposed women while the occurrence of endometriosis in both groups was similar. For the exposed women who had been examined at the Chicago Lying-In Hospital over a 4-year period, epithelial changes in the vagina had disappeared in 32% and cervicovaginal ridges had disappeared in 57%.
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:
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.
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.
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.
Transgenerational effects of Diethylstilbestrol (DES) have been reported in animals, but effects in human beings are unknown. Alerted by two case reports, we aimed to establish the risk of hypospadias in the sons of women who were exposed to DES in utero.
We did a cohort study of all sons of a Dutch cohort of 16284 women with a diagnosis of fertility problems. We used a mailed questionnaire assessing late effects of fertility treatment to identify boys with hypospadias. We compared the prevalence rate of hypospadias between boys with and without maternal DES exposure in utero.
16284 mothers (response rate 67%) reported 8934 sons. The mothers of 205 boys reported DES exposure in utero. Four of these children were reported to have hypospadias. In the remaining 8729 children, only eight cases of hypospadias were reported (prevalence ratio 21.3 [95% CI 6.5-70.1]). All cases of hypospadias were medically confirmed. Maternal age or fertility treatment did not affect the risk of hypospadias. Children conceived after assisted reproductive techniques such as in-vitro fertilisation were not at increased risk of hypospadias compared with children conceived naturally (1.8, 0.6-5.7).
Our findings suggest an increased risk of hypospadias in the sons of women exposed to DES in utero. Although the absolute risk of this anomaly is small, this transgenerational effect of DES warrants additional studies.
The overall 40% excess risk in DES Daughters, arising exclusively from the subset of estrogen receptor-positive cases, raises a concern calling for continued investigation
DES Follow-up Study Summary
The question of whether daughters of women who took Diethylstilbestrol (DES) while pregnant with them will have a greater chance of getting breast cancer has been of great interest to both the DES population and researchers. Questionnaire data collected in 1994 and 1997 from participants in the combined follow-up study were used to investigate this question. 4821 exposed and 2095 unexposed women completed one or both of the follow-up questionnaires, answering questions on reproductive factors, health habits, and disease outcomes. Reports of breast cancer were confirmed by checking medical records or death certificates. There were 43 cases of breast cancer among the DES-exposed and 15 among the unexposed women.
Overall, exposed daughters did not have a statistically significant increase in the risk of breast cancer. Although the relative risk was 1.4, this elevation could have been a chance finding due to the small number of breast cancer cases. However, among the subgroup of women aged 40 and older, those exposed to DES were estimated to have 2.5 times the risk of breast cancer, and this result was statistically significant. Follow-up in the study has continued, and a new analysis that includes additional cases diagnosed since 1997 has begun. The new analysis will likely provide more definitive results.
2002 Study Abstract
A synthetic estrogen, Diethylstilbestrol (DES), was widely prescribed to pregnant women during the 1950s and 1960s but was later discovered to be associated with an increased risk of clear-cell carcinoma of the vagina and cervix in female offspring. DES has not been linked to other cancers in female offspring, but studies of other prenatal factors such as twin gestation and pre-eclampsia have indicated that in-utero estrogen levels may influence breast cancer risk. We evaluated the relation of in-utero DES exposure to the risk of adult breast cancer.
A cohort of 4821 exposed women and 2095 unexposed women, most of whom were first identified in the mid-1970s, were followed by mailed questionnaires for an average of 19 years. Reported cancer outcomes were validated by medical record review. Breast cancer incidence in DES-exposed daughters was compared with cancer incidence in unexposed daughters with use of Poisson regression analysis, adjusting for year of birth, age at menarche, age at first birth, and number of births.
The rate ratio for incidence of invasive breast cancer in exposed versus unexposed women was 1.4 (95% confidence interval (CI) = 0.7-2.6). DES exposure was not associated with an increased risk of breast cancer in women under 40 years, but among women aged 40 and older the rate ratio was 2.5 (95% CI = 1.0-6.3). The rate ratio for the association of DES exposure with estrogen receptor-positive tumors was 1.9 (95% CI = 0.8-4.5).
While not statistically significant, the overall 40% excess risk, arising exclusively from the subset of estrogen receptor-positive cases, raises a concern calling for continued investigation.
Risk of breast cancer in women exposed to diethylstilbestrol in utero: prelimiinary results (United States),NCBI, PMID: 12420954, 2002 Oct;13(8):753-8.
Prenatal exposure to DES increases risk of male urogenital abnormalities
DES Follow-up Study Summary
One of the most frequently asked questions from DES exposed families is whether the sons have had any adverse health effects. For that reason, our collaborative follow-up has included over 1,000 DES-exposed sons and over 1,000 other men of the same ages who were never exposed to DES. These men have been completing mailed questionnaires on the same schedule as women in the study, in 1994, 1997, 2001, and 2006. Some of the questions are the same and some are different. The men were asked whether they had ever been diagnosed with any of a list of urogenital abnormalities. These abnormalities were studied more than 20 years ago in both the offspring of mothers from the University of Chicago DES clinical trial and in a group of sons born to mothers at the Mayo Clinic. The two studies reported different findings, with the University of Chicago follow-up finding a higher prevalence of abnormalities in the DES-exposed sons and the Mayo Clinic study finding no difference between DES-exposed and unexposed sons. We thought we might be able to clarify this question with data from the entire collaborative cohort – including the Mayo sons, the Chicago sons, and additional sons from women who gave birth in Massachusetts.
We found that urogenital abnormalities were fairly rare among DES-exposed sons, as is true for the general U.S. population. However, DES-exposed sons did have a higher prevalence of both undescended testicle and epididymal cyst. They were two times as likely to have had one of those conditions as were unexposed men. For both of these conditions, the prevalence was highest if son was exposed during the first 10 weeks of gestation. In men born at the Mayo clinic, DES exposure was not significantly associated with these conditions overall, but there was a significant association with undescended testicle and epididymal cyst for sons exposed early in gestation. In the University of Chicago clinical trial, the protocol was to give DES as soon as a pregnancy was identified and for use to continue until the last weeks of pregnancy. This same protocol was typical in Boston and in some other regions of the U.S. It was not the usual protocol at the Mayo Clinic, however, where women usually began DES later in pregnancy and took it for only a few months. Differences in patterns of use may explain the conflicting findings in earlier studies of urogenital abnormalities in sons. Our conclusion is that DES-exposed sons do indeed have a higher risk of certain urogenital abnormalities particularly if they were exposed in the early months of fetal development. Fortunately, we and others have already shown that prenatal DES exposure does not affect fertility in men, even in those men with these urogenital abnormalities.
Because the sons are now adults, they were also asked if they had ever been diagnosed with infection or inflammation of the urogenital organs. Prenatal DES exposure was not associated with occurrence of infection or inflammation of the prostate, urethra, or epididymus, or with benign prostatic hypertrophy (enlarged prostate). DES-exposed sons were approximately two and a half times more likely to have had an infection or inflammation of the testes. We do not know the reasons for such an increase. It is possible that minimal structural abnormalities, such as minor obstructions, could explain the increase in infection and inflammation. We will continue to investigate these conditions, especially benign prostatic hypertrophy, as men in the study grow older.
2009 Study Abstract:
BACKGROUND: Diethylstilbestrol (DES), a synthetic estrogen widely prescribed to pregnant women during the 1940s70s, has been shown to cause reproductive problems in the daughters. Studies of prenatally-exposed males have yielded conflicting results.
In data from a collaborative follow-up of three U.S. cohorts of DES-exposed sons, we examined the relation of prenatal DES exposure to occurrence of male urogenital abnormalities. Exposure status was determined through review of prenatal records. Mailed questionnaires (1994, 1997, 2001) asked about specified abnormalities of the urogenital tract. Risk ratios (RR) were estimated by Cox regression with constant time at risk and control for year of birth.
Prenatal DES exposure was not associated with varicocele, structural abnormalities of the penis, urethral stenosis, benign prostatic hypertrophy, or inflammation/infection of the prostate, urethra, or epididymus. However, RRs were 1.9 (95% confidence interval 1.13.4) for cryptorchidism, 2.5 (1.54.3) for epididymal cyst, and 2.4 (1.54.4) for testicular inflammation/infection. Stronger associations were observed for DES exposure that began before the 11th week of pregnancy: RRs were 2.9 (1.65.2) for cryptorchidism, 3.5 (2.06.0) for epididymal cyst, and 3.0 (1.75.4) for inflammation/infection of testes.
These results indicate that prenatal exposure to DES increases risk of male urogenital abnormalities and that the association is strongest for exposure that occurs early in gestation. The findings support the hypothesis that endocrine disrupting chemicals may be a cause of the increased prevalence of cryptorchidism that has been seen in recent years.
Urogenital abnormalities in men exposed to diethylstilbestrol in utero: a cohort study,NCBI, PMID: 19689815, 2009 Aug 18;8:37. doi: 10.1186/1476-069X-8-37. Full text PMC2739506.
Concern about the possible impact of estrogen-like substances found in the environment on a range of health conditions has spurred research in this area. Diethylstilbestrol (DES) is an example of an endocrine-disruptor i.e., chemicals that interfere with the body’s hormone system. While prenatal exposure to DES is known to increase risks of vaginal or cervical cancer and poor reproductive outcomes in women, and abnormalities in the urinary and genital tracts in men information on non-reproductive medical conditions are lacking.
We studied the associations between prenatal DES exposure and the occurrence of cardiovascular disease, diabetes, osteoporosis and related conditions among 5,590 exposed and unexposed daughters and 2,657 exposed and unexposed sons in the NCI Combined DES Follow-up Study. The associations took into account the participants’ birth year, sex, weight adjusted for height, smoking status, alcohol use, educational status, number of general physical examinations in the past 5 years, and study site.
Comparing participants exposed prenatally to DES with those who were not exposed, there were increases in the risk of developing cardiovascular disease (27%), heart attacks (28%), hypertension (14%), and high cholesterol (12%). In addition, the risks of developing diabetes, coronary artery disease, osteoporosis and fractures were elevated, but these findings were possibly due to chance. The associations of DES and the medical conditions did not differ by dose and timing of DES exposure, nor, in the women, by presence or absence of vaginal epithelial changes (a marker of DES host susceptibility).
This study raises the possibility that prenatal DES exposure is associated with several common medical conditions in adulthood, although there is the possibility that our results are explained by differences in the reporting of conditions by the exposed and unexposed participants, or by other factors related to both the conditions and DES exposure status that were not accounted for in the study, such as dietary intake and physical activity. We plan to continue to study these associations by obtaining medical records to confirm the diagnoses in the current round of the study.
DES Info commented: ” DES Exposure estimated hazard ratios and their associated 95% confidence intervals for the associations between prenatal DES exposure and the occurrence of cardiovascular disease, diabetes, osteoporosis, and related conditions among 5590 female and 2657 male offspring followed from 1994 through 2006, adjusted for birth year, cohort, sex, body mass index, smoking status, alcohol use, education, and number of general physical examinations in the past 5 years “.
2013 Study Abstract:
BACKGROUND: Diethylstilbestrol (DES), a synthetic estrogen that was used in pregnancy, is a prototype endocrine-disrupting chemical. Although prenatal exposure to DES is known to increase risks of vaginal/cervical adenocarcinoma and adverse reproductive outcomes in women, and urogenital anomalies in men, data on nonreproductive medical conditions are lacking.
We estimated hazard ratios and their associated 95% confidence intervals for the associations between prenatal DES exposure and the occurrence of cardiovascular disease, diabetes, osteoporosis, and related conditions among 5590 female and 2657 male offspring followed from 1994 through 2006, adjusted for birth year, cohort, sex, body mass index, smoking status, alcohol use, education, and number of general physical examinations in the past 5 years.
Comparing persons exposed prenatally to DES with those who were not exposed, the hazard ratios were 1.21 (95% confidence interval = 0.96-1.54) for diabetes, 1.27 (1.00-1.62) for all cardiovascular disease, 1.18 (0.88-1.59) for coronary artery disease, 1.28 (0.88-1.86) for myocardial infarction, 1.12 (1.02-1.22) for high cholesterol, 1.14 (1.02-1.28) for hypertension, 1.24 (0.99-1.54) for osteoporosis, and 1.30 (0.95-1.79) for fractures. The associations did not differ by dose and timing of DES exposure, nor, in the women, by the presence or absence of vaginal epithelial changes (a marker of DES host susceptibility).
These data raise the possibility that prenatal exposure to DES is associated with several common medical conditions in adulthood, although differential reporting by DES status and residual confounding cannot be ruled out. Further follow-up should assess these findings with validated outcomes and seek to understand the biological mechanisms.
Medical conditions among adult offspring prenatally exposed to diethylstilbestrol,NCBI, PMID: 23474687, 2013 May;24(3):430-8. doi: 10.1097/EDE.0b013e318289bdf7. Full text link.
Third-generation of DES-exposed women: menstrual irregularity and possible infertility
DES Follow-up Study Summary
We examined menstrual and reproductive characteristics in a unique cohort consisting of the daughters of women prenatally exposed (or not) to Diethylstilbestrol DES (i.e., the third generation). The menstrual and reproductive characteristics of 793 third generation women were assessed by mailed questionnaires. The study showed a comparable average age of menarche (12.6 years) in the daughters of prenatally DES-exposed and unexposed women. The daughters of the exposed women reached menstrual regularity later compared to the daughters of the unexposed, and were more likely to report irregular menstrual periods, odds ratio. A possible association between mothers’ DES exposure and daughters’ infertility was compatible with chance. For the most part, daughters of the prenatally DES-exposed and unexposed had similar reproductive outcomes, but daughters of exposed women had fewer live births than the unexposed. The high risk of reproductive problems seen in women exposed prenatally to DES was not observed in their daughters, but most third generation women have not yet attempted to start their families. Consequently, further follow-up is needed to assess their reproductive health.
2006 Study Abstract
In women, prenatal exposure to diethylstilbestrol (DES) is associated with adult reproductive dysfunction. The mouse model, which replicates many DES outcomes, suggests DES causes epigenetic alterations, which are transmissable to daughters of prenatally exposed animals. We report menstrual and reproductive characteristics in a unique cohort comprising daughters of women exposed prenatally to DES.
Menstrual and reproductive outcomes and baseline characteristics were assessed by mailed questionnaire in 793 women whose mothers had documented information regarding in utero DES exposure.
Mean age at menarche was 12.6 years in both groups, but daughters of the exposed women attained menstrual regularization later (mean age of 16.2 years vs. 15.8 years; P = 0.05), and were more likely to report irregular menstrual periods, odds ratio (OR) = 1.54 [95% confidence interval (95% CI 1.02-2.32)]. A possible association between mothers’ DES exposure and daughters’ infertility was compatible with chance, age, and cohort adjusted OR = 2.19 (95% CI 0.95-5.07). We found limited evidence that daughters of the exposed had more adverse reproductive outcomes, but daughters of exposed women had fewer live births (1.6) than the unexposed (1.9) (P = 0.005).
The high risk of reproductive dysfunction seen in women exposed to DES in utero was not observed in their daughters, but most women in our cohort have not yet attempted to start their families, and further follow-up is needed to assess their reproductive health. Our findings of menstrual irregularity and possible infertility in third-generation women are preliminary but compatible with speculation regarding transgenerational transmission of DES-related epigenetic alterations in humans.
Menstrual and reproductive characteristics of women whose mothers were exposed in utero to diethylstilbestrol (DES),NCBI, PMID: 16723367, 2006 Aug;35(4):862-8. Epub 2006 May 24. Full text Oxford Journals Medicine & Health International Journal of Epidemiology link.
” Exposure to estrogens during various stages of development has been shown to irreversibly influence responsive target organs. The recent finding of the presence of estrogen receptor in both osteoblasts and osteoclasts has suggested a direct role of steroid hormones on bone tissue. Furthermore, estrogens have important effects on bone turnover in both humans and experimental animal models. Thus, this tissue is now regarded as a specific estrogen target tissue. To investigate whether a short-term developmental exposure to estrogens can influence bone tissue, we have injected female mice with diethylstilbestrol (DES) from day 1 through day 5 of life. Additionally, a group of pregnant female mice were injected with different doses of DES from day 9 through 16 of pregnancy. Mice were then weaned at 21 days of age, and effects on bone tissue of the female mice were evaluated in adulthood (7-12 months of age). These short-term treatments did not affect body weight of exposed mice. However, a dose-dependent increase in bone mass, both in the trabecular and compact compartments, was observed in the DES-exposed female offspring. Furthermore, femurs from DES-exposed females were shorter than femurs from controls. A normal skeletal mineralization accompanied these changes in the bone tissue. In fact, a parallel increase in total calcium content of the skeleton was found in concomitance with the increase in bone mass. Estrogen treatment induced an increase in the amount of mineralized skeleton when compared to untreated controls. In summary, this report shows that alterations of estrogen levels during development can influence the early phases of bone tissue development inducing permanent changes in the skeleton. These changes appear to be related to bone cell programming in early phases of life. ”