Females whose mothers were prescribed DES while pregnant with them.
Much of the information regarding the medical conditions of DES Daughters reported here comes from an article published in the New England Journal of Medicine, “Adverse Health Outcomes in Women Exposed in Utero to Diethylstilbestrol,” Robert N. Hoover et al., October 6, 2011. The abstract is available online, but only NEJM subscribers have access to the full text. A review of the important NEJM article was done by Medpage Today, an online publication written for healthcare providers. DES Daughters may find it useful to print and share with their doctors.
Respected researchers with the National Cancer Institute (NCI) DES Follow-up Study developed the information in the NEJM article. They identified twelve adverse health outcomes for women exposed to DES before birth. A layman’s explanation of the research can be found in the DES Action VOICE newsletter review of the study.
An article entitled, Prenatal Diethylstilbestrol Exposure and Cancer Risk in Women by Rebecca Troisi et al. of the NCI DES Follow-up Study, which appeared in Environmental and Molecular Mutagenesis in 2017, stated: “Taken together, it appears that in-utero exposure to DES is associated with increased risk of malignancy for virtually all of the female lower genital tract, with a relatively small absolute risk that nonetheless, appears to last throughout life.”
***Unless otherwise stipulated, statistics regarding risk factors listed on this page come from this NCI DES Follow-up Study peer-reviewed research.***
Clear Cell Adenocarcinoma (CCA) of the Vagina and Cervix
Various types of cancers affect the vagina and cervix, but only one specific kind is associated with prenatal DES exposure. Clear Cell Adenocarcinoma (CCA) of the vagina/cervix is a rare cancer, even for DES Daughters. The risk is estimated to be approximately 1 in 1,000 DES Daughters.
Years ago, there was a mistaken belief that DES Daughters over age 30 were out of danger. However, a 2012 population-based analysis by the Centers for Disease Control and Prevention (CDC) suggests otherwise. It raises the specter that this cancer has no upper age limit for DES Daughters. Cases have been reported in exposed women older than age 50, so researchers are watching for a possible spike in CCA cases among post-menopausal DES Daughters.
A study published in June 2022 (DOI: 10.1007/s10552-022-01598-3) investigated the risk of CCA as DES Daughters age. However, this study took a different approach to studying CCA than previous DES-related studies. Instead of comparing a group of known DES Daughters to known unexposed women, these researchers, led by Mary C. White at the CDC, focused on the eras when women were born. The researchers compared CCA rates among women born between 1947 and 1971 – the “DES era” – to women born before 1947. The drawback of this approach is that it is impossible to be sure how many women in the 1947-1971 cohort were exposed to DES. But, in a way, that is also the study’s strength. Since so many women never learned of their DES exposure, a study like this can capture the impact of the drug’s effects even among women who never knew – and still perhaps do not know – they were DES Daughters.
The authors concluded that the results of their study are consistent with prior research and suggest an elevated risk of CCA in midlife and at older ages among women exposed in utero to DES. These results highlight unresolved issues regarding cancer risk among aging DES daughters and appropriate screening guidance. Examining population-based cancer surveillance data may help monitor trends in the incidence of other rare cancers over time among specific birth cohorts.
Arthur L. Herbst, MD, Director – University of Chicago CCA Study, who first discovered the link between prenatal DES exposure and vaginal or cervical clear cell adenocarcinoma, recommends: “Even in the absence of a pap smear, the DES-exposed woman should have an annual pelvic exam where her physician fully views the vagina and cervix.” Even if the pap smear is not done annually, it is important that they have annual pelvic exams. Additionally, he says, “we do not have enough data to definitively say or support that there is no upper age limit on CCA diagnoses. Since it is not known yet, this should lead to the continuation of annual exams.”
If you or someone you know has been diagnosed with clear cell adenocarcinoma (CCA) of the vagina or cervix, you are asked to contact the University of Chicago Registry for Research on Hormonal Transplacental Carcinogenesis, the so-called DES Cancer Registry. Researchers appreciate your help in reporting as they keep track of the CCA vagina/cervix numbers in DES Daughters or suspected DES Daughters.
- DES DAUGHTER PAP/PELVIC EXAM
The screening exam for DES Daughters is similar to a routine one for unexposed women, but it is more comprehensive. Print the directions for the DES Daughter Annual Exam to bring with you when you go for your appointment. Your healthcare provider can follow them, and you will be reassured your exam is done properly. Here is a Pap screening fact sheet specifically for DES Daughters.
After a hysterectomy, DES Daughters should continue having annual Pap/pelvic exams. Even though the cervix was removed during surgery, DES Daughters remain at risk for CCA of the vagina and should be screened for it every year. DES Daughter Annual Exam directions should be shared with the doctor, who will focus on checking the vagina for cancer.
Cervical cancer screening guidelines are evolving, with the latest recommendation (8/2018) from the U.S. Preventive Services Task Force (USPSTF) suggesting that many women can skip years between Pap exams. However, the USPSTF explicitly states this guideline does NOT apply to DES Daughters. See Final Recommendation Statement, Cervical Cancer Screening. These recommendations also do not apply to individuals with in-utero exposure to diethylstilbestrol or those who have a compromised immune system (e.g, women living with HIV). DES Daughters can print the guidelines and highlight the exclusion to show their healthcare providers. Pointing it out should help in advocating for yearly Pap/pelvic exams.
While the need for annual Pap smears for cervical cancer screening is under discussion, the yearly pelvic part of the exam is also being questioned for all women. However, special consideration should be given to the needs of DES Daughters, and some might say the pelvic portion of the Pap/pelvic exam is the most essential part of the screening for CCA of the vagina and cervix. Annual pelvic exams may be questioned for some women but not for DES Daughters.
For some DES Daughters, being told a Pap smear is abnormal became a common occurrence, but by around age 40 many DES Daughters report their Pap results started coming back as normal. However, no matter what the age, there should be a follow-up appointment with a doctor after every abnormal pap.
For DES Daughters who live in countries without specific guidelines on pelvic and pap smear exam frequency, we suggest giving the US National Institutes of Health (NIH) guidelines to your doctor and asking your medical professionals to use them to guide your treatment. Access the US guidelines easily by printing the “Print and Take to Your Gynecologist” resource for professionals.
Breast Cancer
- Risk
Breast cancer has many risk factors, and DES exposure is one of them. Previous studies have shown a slight increase in risk among DES Daughters throughout their lifetime. However, in the latest analysis by the National Cancer Institute, there was up to a 30% increase in breast cancer risk in DES Daughters in their 40s.To put this in context, the NCI’s Surveillance, Epidemiology, and End Results (SEER) Program estimates the risk of breast cancer as 1.5% at age 40 to 2.4% at age 50. A 30% increased risk for the DES-exposed means approximately 2% to 3.1% from age 40 to 50. Much of the increase in risk appears to be caused by the effects of DES on fertility, mainly later age at first childbirth. More research is being done to study how DES Daughters metabolize estrogen and whether this relates to the excess breast cancer risk. The extra risk appears to begin lessening after age 50, even though breast cancer risk in general – independent of DES exposure – tends to increase with age. Please see the most recent study and login to see the report on this study in the Winter Voice 2018, #155. - Breast Cancer Screening
DES Action encourages all DES Daughters to remind their healthcare providers of their increased breast cancer risk and discuss an appropriate screening protocol, which likely will include annual breast screenings and yearly clinical breast exams. DES Daughters should also pay attention to the appearance and feel of their breasts and notable report any changes to their doctors. Any woman with dense breast tissue (DES-exposed or not) is at higher risk for breast cancer and needs a 3D mammogram, which looks through layers of breast tissue. This should be followed six months later by either a breast ultrasound or a breast MRI. If you have dense breast tissue, please discuss the appropriate screening with your doctor. (Members login to see this discussion in our video interview with Dr. Gary Levine, Radiologist and Breast Screening Specialist-Memorial Care Breast Centers, CA). - Breast Cancer Type
There is no specific malignant tumor type of breast cancer associated with the increased risk for breast cancer among DES Daughters over the age of forty. Instead, prenatal DES exposure may increase the growth of any cells that develop into breast cancer—this potential for a more rapid growth rate results in an increased risk for DES Daughters.
Once diagnosed with breast cancer, the treatment for DES Daughters is the same as that for unexposed women. - How DES Causes Harm
A study by Yale University researchers found that DES does not mutate a DES Daughter’s DNA sequence. Instead, prenatal DES exposure appears to alter the regulating system that influences how genes operate by turning on and off. It is believed DES may cause changes in the operation of tumor-suppressing genes that can lead to breast cancer formation. Additionally, a recent study in the medical journal Cancer Epidemiology, Biomarkers and Prevention on endocrine-disrupting chemicals similar to DES demonstrated that exposure significantly increased the likelihood of early menstruation, a common risk factor for breast cancer.
Structural Changes of the Reproductive Tract
DES Daughters have an increased incidence of structural changes in their reproductive organs, including a T-shaped uterus (See illustration below). The uterine lining of a T-shaped uterus appears to be the same as for an unexposed woman, so researchers suggest the fundamental difference (except for the shape) is in the underlying structure of the fibromusculature. Of note is that pregnant DES Daughters with a T-shaped uterus and those with a normally shaped uterus are both at increased risk for premature delivery. Prenatal DES exposure can adversely affect the shape and functioning of virtually the entire reproductive tract, including the vagina, cervix, uterus, fallopian tubes, and ovaries. Some DES Daughters report having an incompetent cervix, which can be the cause of some second-trimester pregnancy losses.
A 2019 study published in the Journal of Human Reproductive Sciences suggests that a procedure called hysteroscopic metroplasty may improve pregnancy rates and live births among patients with T-shaped uterus. The study’s authors concluded that “hysteroscopic metroplasty is a simple procedure which can potentially improve outcomes in sub-fertile women, but the data is not robust. There is a need for a centralized database for registration of women with T-shaped uterine anomalies, which will help in defining clear diagnostic criteria, surgical indication & technique, and follow up of reproductive outcomes after the procedure.”
Illustration: cdc.gov
Infertility
DES Daughters have an increased risk for infertility, with studies showing DES Daughters dealing with infertility at a rate 2.4 times higher than unexposed women. Of note is that for DES Daughters exposed before 9 weeks of pregnancy, the never achieved-pregnancy rate was 30.2% compared with a rate of 20.5% among DES Daughters whose exposure occurred later than 13 weeks into gestation. This is not unexpected, given that the reproductive tract develops during the early stages of fetal life. This NCI research into reasons for infertility among DES Daughters is interesting for those who have dealt with the condition and those just embarking on their family planning journey.
- Treatment
In general, infertility treatments for DES Daughters are the same as for other women. Working with a doctor you like and trust is essential. - Clomid and Uterine Cancer
Widely used for women undergoing infertility treatments, clomiphene citrate (also known as Clomid or Serophene) is implicated in an increased risk for uterine cancer. The study was not DES specific; however, its finding suggests all women should have a conversation with their doctors before taking it. Clomid is often prescribed early in treatment protocols, meaning many DES Daughters have been prescribed the drug through the years.
Notably, the uterine cancer risk increased with total Clomid dose and was highest among women who never became pregnant. If applicable, it may be worth having Clomid use noted on your patient history so that healthcare providers can be alert for the possibility of uterine cancer.
Ectopic Pregnancy
DES Daughters should get early confirmation of pregnancy to ensure the fetus is not developing outside of the uterus, which could cause serious complications. A NCI DES Follow-up Study found that ectopic (or tubal) pregnancy rates for DES Daughters were 14.6% compared with only 2.9% in the unexposed population.
Miscarriage, Stillbirth, and Preterm Labor
Because of their increased risks for miscarriage, stillbirth, and preterm labor, all DES Daughters, even if they have had previous normal pregnancies, should be given high-risk obstetric care starting at the earliest stage of pregnancy. Sadly, most early miscarriages are not preventable; however, careful monitoring of the cervix is warranted.
Several of the twelve adverse health impacts identified by NCI researchers involve DES Daughters having higher rates of complications during pregnancy compared with unexposed women. The NCI researchers found the incidence of preterm delivery at 53.3% in DES Daughters, as opposed to 17.8% in unexposed women. Miscarriage figures among DES Daughters compared to unexposed women are 50.3% versus 38.6%. Stillbirth numbers in DES Daughters are also higher, pegged at 8.9% compared with 2.6% in women not exposed to DES.
Understanding the cause of a threatened second-trimester pregnancy loss is important. Some second-trimester losses may occur in DES-exposed women because of incompetent cervices, while others result from premature labor. This is an important distinction since treatments used in these conditions are different. A cerclage (stitch) may be inserted to keep the cervix closed if an incompetent cervix is the problem. In the case of premature labor, a cerclage would be of little use, and after careful consideration, the doctor may recommend bed rest, drugs, or both to suppress labor.
Preeclampsia
DES Daughters have a 1.4 times higher risk for this pregnancy complication involving a form of high blood pressure and edema (fluid retention) than unexposed women. That translates into 26.4% of DES Daughters dealing with preeclampsia during their pregnancies compared with 13.7% of unexposed women. This represents yet another reason why pregnant DES Daughters should be carefully monitored as high-risk obstetric patients, even after a previous successful birth.
Endometriosis
DES Daughters are at increased risk for this painful chronic disease in which endometrial tissue is found outside the uterus in the pelvic cavity. Data from the Nurses’ Health Study II shows a staggering 80% higher endometriosis incidence in DES Daughters than in unexposed women. The numbers were even greater among DES Daughters who reported dealing with infertility.
A meta-analysis report (DOI: 10.1016/j.rbmo.2020.04.005) showed similar results by comparing multiple studies. When the studies’ results were combined and analyzed, the researchers found that DES Daughters had a 65% increased relative risk of developing endometriosis. That means for every 100 non-DES-exposed women with endometriosis, there are 165 DES Daughters with endometriosis.
DES Daughters often have anatomical complications such as cervical stenosis (narrowing of the cervical canal, sometimes to the point of closure) that may increase the likelihood of retrograde menstruation. Other anatomical malformations common to DES Daughters may also increase the endometriosis risk. A review of this study, including additional information, can be read in the DES Action VOICE newsletter.
The good news is that for most women, including DES Daughters, the pain of endometriosis disappears after menopause.
Uterine Fibroids
These benign tumors (officially called leiomyomata) can cause pain, bleeding, infertility, and pregnancy complications. They are the leading cause of hysterectomies nationwide. When responses to the Nurses’ Health Study II were analyzed, the results showed DES Daughters had a 12% increased incidence of uterine fibroids, with the strongest correlation occurring in those exposed to DES during the first three months of gestation. An article about this study ran in the Summer 2014 DES Action VOICE newsletter.
Investigations into the possible link between DES exposure and uterine fibroids are ongoing because other studies have shown conflicting results. One done by the NCI DES Follow-up Study did not find an increased incidence of uterine fibroids. At the same time, research conducted by the National Institute of Environmental Health Sciences (NIEHS) Sister Study did show a DES link, with larger fibroids reported by DES Daughters than women who were not exposed. That has led to the speculation that in DES Daughters, the benign tumors may have either started at an earlier age, grown faster, or both. As with endometriosis, for many women, uterine fibroids regress after menopause.
Paraovarian Cysts
Prenatal DES exposure is associated with an increased risk for these benign gynecologic tumors or non-cancerous fluid-filled sacs adjacent to the ovaries. Researchers with the NCI DES Follow-up Study worked with data generated in the 1990s. They pointed out that while the risk for paraovarian cysts in DES Daughters is increased, they found no heightened risk for ovarian cysts among DES Daughters. But studies are continuing.
Paraovarian cysts are common among all women in the U.S., and treatment generally includes surgery, depending on the symptoms of discomfort experienced. Details about this study can be viewed in the DES Action VOICE newsletter.
Adenosis
Vaginal adenosis is a condition found primarily in DES Daughters when a type of tissue develops on the surface of the vagina that is not generally found there in unexposed women. Because these cells can be (but usually are not) a precursor to cancer, they should be carefully monitored. A layer of flat cells called squamous cells normally lines the vagina. However, DES Daughters often have sections of the vagina lined with glandular cells, most often found lining the uterus, fallopian tubes, and cervix. When these glandular cells are located in the vagina, they are called adenosis. While this tissue can normally be found in the body, in cases of adenosis, it is in the wrong place.
These extra glandular cells are to blame for secreting the profuse vaginal discharge many DES Daughters have experienced. According to the latest research, there appears to be a dose-response relationship regarding adenosis. Adenosis, often exhibited by excessive amounts of mucous discharge, indicates the prenatal DES dose was high and early in the pregnancy. Many DES Daughters experience a lessening of vaginal discharge as they age.
Menopause
- Early Menopause
DES Daughters, as a group, tend to begin menopause slightly earlier than unexposed women, with the earliest being in those exposed to the highest cumulative doses of DES in the womb. However, it appears the experience of menopause for DES Daughters is no different from that of women who were not exposed to DES. A review of this study in the DES Action VOICE newsletter has a thorough explanation. - DES Daughters and HRT
Studies have not been done specifically concerning DES exposure and hormone replacement therapy (HRT) use. However, since DES Daughters were exposed, in many cases, to a high level of a synthetic hormone before birth, the precautionary principle suggests DES Daughters should avoid extra hormonal exposures. Writing in the DES Action VOICE newsletter, DES Daughter Carol O’Leary shared her tips for surviving menopause without HRT. Menopause can be debilitating for some women whose quality of life is seriously diminished by the symptoms. In that case, if HRT is absolutely necessary, and only then should they consider using the lowest HRT dose possible for the shortest length of time. But caution is advised. This should be discussed with a healthcare provider to determine the safest and best course of action.
Autoimmune Disease – No DES Link Except For Rheumatoid Arthritis
Despite animal research in the 1990s that found an association between DES and autoimmune issues, there has been no confirmation of that finding in human studies, with the exception of Rheumatoid Arthritis (RA). This is vexing because DES mouse studies are usually a good predictor of the human experience.
Researchers speculate that perhaps the human cohort (group) was not large enough to tease out additional autoimmune diseases. Another theory is that those exposed to DES may develop autoimmune disorders at earlier ages than the general population. Still, the overall rate of autoimmune disease may be the same among the DES-exposed and unexposed. Read more in an article from the DES Action VOICE newsletter.
Depression
DES exposure before birth may be linked to an increased risk for adult depression and anxiety. Results from the Nurses’ Health Study II published in the American Journal of Epidemiology in 2010 (with more than 76,000 participants) indicate a history of depression reported by 19.7% of DES Daughters compared with 15.9% of unexposed women. The study was reviewed in the DES Action VOICE newsletter.
Since that review, a September 2019 study in the journal Epidemiology surveyed nearly 5,000 DES-exposed and over 2,700 unexposed participants in the NCI’s DES Combined Cohort Follow-up Study (DOI: 10.1097/EDE.0000000000001048). Among women, 26% of DES Daughters and 23% of unexposed women reported depression, and 17% of both DES Sons and unexposed men reported depression. The researchers found no statistically significant increased risk of depression in DES Children, even when limited to those taking antidepressants. They controlled for various factors, including physical health problems, but not a family history of depression. However, the authors did find a weak association between DES and depression for only DES Daughters with a low exposure dose or exposure before 8 weeks gestation: They were 1.2 times more likely to have depression than unexposed women. The depression diagnoses weren’t related to whether the DES Daughters had abnormal findings in the vaginal lining or any other DES-related problems. The researchers concluded, “We found a potentially slightly increased risk of depression in women who were exposed very early in gestation. Also noted was a weak link in women and men exposed to a low cumulative prenatal dose of DES, but among men, this was apparent only after accounting for other factors.” Together, this research shows that a link between DES exposure and depression cannot be completely ruled out. Still, there is not enough evidence to suggest depression is any more likely in DES Daughters and Sons than in the general population.
Cardiovascular Disease, Diabetes and Osteoporosis
DES studies continue with additional medical issues now possibly linked to exposure. These conditions have been found to occur at higher rates for DES Daughters and DES Sons than for individuals who were not exposed.
- diabetes
- high cholesterol
- hypertension
- cardiovascular disease (coronary artery disease and myocardial infarction)
- osteoporosis.
Specifics on the NCI DES Follow-up Study research findings are in a DES Action VOICE newsletter article.
Scientists have been seeing mounting evidence that endocrine disruptors, of which DES is one, are implicated in increased risks for cardiovascular disease. Therefore, the results of this study were not unexpected.
These results were reconfirmed in a study published in October 2017. No special screenings or treatments have been identified, but DES Daughters should stay aware of potential increased risks.
Sex, Sexuality and Gender
Endocrine-disrupting compounds are being examined in gender identity studies, but DES research has not found a conclusive DES link. One confounding thought now under investigation regards the layering of endocrine disruptive exposures, both prenatally and perinatally. Researchers want to understand if there is an association and whether DES exposure might be a cause or, perhaps combined with other exposures, be a trigger for variations.
Questions have been routinely raised in the DES community regarding the possibility that prenatal DES exposure may be linked to increased rates of homosexuality, transgender, and transsexual conditions. Animal studies point in that direction, yet no evidence-based research in human populations has been able to confirm it. An article from 2003 on DES and sexuality ran in the DES Action VOICE newsletter describes what researchers saw in human studies. However, a new research study from the National Institute of Health DES cohort study titled Gender Identity and Sexual Orientation Identity in Women and Men Prenatally Exposed to Diethylstilbestrol appeared in the Archives of Sexual Behavior in January 2020. Until now, no credible studies have attempted to quantify the DES LGBTQ+ community compared to those unexposed. This study sheds a bit more information on this topic. This new study was covered in our Spring Voice 2020. Members may log in and find it in the Archived Voices section. For more discussion on this study, DES exposure, and human sexuality, sex, and gender studies, click here.
To understand the struggles faced by transgender individuals, read a letter that was sent to DES Action. But note that some statements may not hold up to scientific scrutiny.
Emotional Impacts
DES creates emotional trauma for all who come in contact with it: DES Mothers (and Fathers), DES Daughters, DES Sons, and DES Grandchildren and beyond. It is truly a family issue.
Upon first learning of exposure, some DES Daughters react with shock, disbelief, and even a sense of betrayal. It can strain the mother-daughter relationship even though both parties involved are victims.
Some DES Daughters want to brush off the known risks as “not a concern” to them, only to grow more interested when/if DES health problems develop. Meanwhile, others investigate all possible consequences as soon as they learn of their exposure. Other responses reported by DES Daughters are fear and anxiety when new health problems are identified.
Then there are anger issues. Sadly, some DES Mothers feel the brunt of that emotion from their daughters. However, the anger is more commonly directed against doctors, drug companies, and the world in general.
Experience shows that keeping lines of communication open can be helpful. Staying current on the latest DES findings and health screening recommendations can open discussions with family members. Taking action, including being vigilant in getting proper medical care, can also reduce feelings of helplessness. Climbing on our soapbox now – joining DES Action can be another step toward healing. Members get new information throughout the year and feel good about doing something positive by supporting an organization actively pushing for more DES research.
DES As An Endocrine Disruptor
It is worth noting that DES is an endocrine-disrupting chemical. The DES community is described as the “poster population” for what can happen when individuals are exposed to these chemicals before birth. The DES experience triggered research into endocrine disruptors and how hormonally active substances interfere with prenatal development and can cause adverse health outcomes later in life.
Another such chemical is bisphenol A (BPA), a synthetic estrogen with a very similar chemical structure to that of DES. Health impacts linked to BPA are remarkably familiar to those known to be associated with DES exposure but occur at much lower doses.
This is an essential distinction between the two that must be considered: Pay attention to the exposure dose. Here is an explanation of the similarities and differences between the two endocrine disruptors: DES and BPA.
Also, because many of these exposures are common in our environment, rather than exposure through a drug like DES, identifying and eliminating the exposure potential can be challenging. Here’s a link with ways to reduce environmental exposures in our daily lives.
