The DCEG’s coprincipal investigators of the 1992 DES Follow-Up cohort study
Recognizing the need to continue observing DES-exposed mothers and their offspring, Dr. Robert N. Hoover reached out to several principal investigators at the various study centers and suggested reviving the cohorts and pooling the data to better answer the many questions that remained.
Dr. Hoover and Rebecca Troisi, Sc.D., a staff scientist in EBP, have been DCEG’s coprincipal investigators of the 1992 DES Follow-Up Study cohort study.
Consequences of in utero DES exposure on the breast may be mediated by proliferative effects of estrogen
In 1992, the National Cancer Institute (NCI) established the Continuation of Follow-Up of DES-Exposed Cohorts to study the long-term health effects of exposure to Diethylstilbestrol (DES) . Genetic effects on human breast tissue have not been examined. The authors investigated whether breast tissue of women exposed in utero to DES might exhibit the genetic abnormalities that characterize other DES-associated tumors.
Subjects enrolled in the NCI Cohort were queried about breast biopsies or breast cancer diagnoses. Available tissue blocks were obtained for invasive cancers (IC), in situ cancers (CIS), or atypical hyperplasia (AH). Exposure status was blinded, lesions were microdissected, and their DNA was analyzed for microsatellite instability (MI) and loss of heterozygosity (LOH), or allele imbalance (AI), at 20 markers on 9 chromosome arms.
From 31 subjects (22 exposed, 9 unexposed), 273 samples were analyzed (167 normal epithelium, 16 AH, 30 CIS, 60 IC). Exposed and unexposed subjects exhibited no differences in breast cancer risk factors or demographic characteristics, except for age at diagnosis (exposed vs. unexposed: 43.2 vs. 48.8 years of age, P = .02). The authors found that MI was rare and that AI was common, with frequencies consistent with previous reports. The global age-adjusted relative rate (RR) of AI was 1.3, 95% CI = 0.8-2.4. No statistically significant associations were observed after adjustment for risk factors or after stratification by histology or by chromosome arm.
In utero DES exposure does not appear to significantly increase genomic instability in breast epithelium, as measured by MI and AI. Breast tissue may respond differently from that of the reproductive tract to in utero DES exposure. Consequences of in utero DES exposure on the breast may be mediated by proliferative effects of estrogen.
Sources and full study
In utero exposure to diethylstilbestrol (DES) does not increase genomic instability in normal or neoplastic breast epithelium, NCBIPMID: 16998936, Cancer. 2006 Nov 1;107(9):2122-6.
DES daughters haved 2-3 times the risk of being diagnosed with paraovarian cysts
DES Follow-up Study Summary
We investigated the association between prenatal Diethylstilbestrol DES exposure and benign gynecologic tumors among women participating in the DES collaborative follow-up study. A total of 85 cases of uterine fibroids and 168 cases of ovarian or paraovarian cysts were confirmed by medical records. After adjustment for age, no association was found between prenatal DES exposure and ovarian cysts or uterine fibroids. DES daughters had 2-3 times the risk of being diagnosed with paraovarian cysts, which are cysts that originate from remnants of the Mullerian ducts and are located near the ovary and fallopian tubes. Paraovarian cysts are not known to cause any health problems.
We recommend caution when interpreting the results for paraovarian cysts. First, the pathologist making the initial diagnosis was not blinded as to the patient’s exposure status. Therefore, the pathologist’s knowledge of a patient’s DES status may have influenced the recording of cysts, particularly those that have little clinical significance (e.g., paraovarian cysts), which in the absence of such exposure history were often not recorded. Second, the lining of the Mullerian duct derives from coelomic epithelium, as does the covering of the ovary from which epithelial cysts arise. It is unlikely that DES exposure would be associated with an increase in cysts of Mullerian origin (e.g., paraovarian), but not of ovarian epithelial origin (e.g., cystadenomas). Thus, greater incidental detection of paraovarian cysts among DES daughters, or more likely the absence of recording in non-exposed daughters, could have produced the positive association observed in our study.
2005 Study Abstract
To investigate the association between prenatal diethylstilbestrol (DES) exposure and risk of benign gynecologic tumors.
We conducted a collaborative follow-up study of women with and without documented intrauterine exposure to DES. We compared the incidence of self-reported ovarian cysts, paraovarian cysts, and uterine leiomyomata confirmed by medical record in DES-exposed and unexposed women.
A total of 85 cases of uterine leiomyomata and 168 cases of ovarian or paraovarian cysts were confirmed histologically. After adjustment for age, no association was found between prenatal DES exposure and ovarian cysts or uterine leiomyomata. Prenatal DES exposure was positively associated with paraovarian cysts.
The present results do not support the hypothesis that prenatal DES exposure increases risk of uterine leiomyomata or ovarian cysts. Prenatal DES exposure was associated with an increased risk of paraovarian cysts, but detection bias cannot be ruled out as an explanation of this finding.
Risk of benign gynecologic tumors in relation to prenatal diethylstilbestrol exposure,NCBI, PMID: 15625159, Obstet Gynecol. 2005 Jan;105(1):167-73.
DES exposure possible effects on psychosexual characteristics remain largely unknown
DES Follow-up Study Summary
Animal studies suggest that estrogen affects the developing brain, including the part that governs sexual behavior and right and left dominance. We examined the potential impact of prenatal Diethylstilbestrol (DES) exposure on these characteristics in 2,684 men and 5,686 women participating in the NCI DES Follow-up Study.
Information on marital status, sexual behavior, and handedness was reported by subjects on a questionnaire. Responses indicated that DES neither influenced sexual behavior nor resulted in an increased likelihood of homosexual contact. In sons, DES was unrelated to the likelihood of ever having been married or of having a same-sex sexual partner in adulthood, age at first intercourse and number of sexual partners. DES Daughters were slightly more likely than unexposed women to have ever been married but were less likely to report having had a same-sex sexual partner, having had their first sexual intercourse before age 17 and to having had more than one sexual partner.
DES Daughters were just as likely as unexposed women to be left-handed. DES Sons were slightly more likely to be left-handed than unexposed men. Overall, about 17% of women reported a mental illness, but we found no evidence that it was more frequent in the exposed than the unexposed women. Mental illness was not assessed in the men.
2003 Study Abstract
Between 1939 and the 1960s, the synthetic estrogen diethylstilbestrol (DES) was given to millions of pregnant women to prevent pregnancy complications and losses. The adverse effects of prenatal exposure on the genitourinary tract in men and the reproductive tract in women are well established, but the possible effects on psychosexual characteristics remain largely unknown.
We evaluated DES exposure in relation to psychosexual outcomes in a cohort of 2,684 men and 5,686 women with documented exposure status.
In men, DES was unrelated to the likelihood of ever having been married, age at first intercourse, number of sexual partners, and having had a same-sex sexual partner in adulthood. DES-exposed women, compared with the unexposed, were slightly more likely to have ever married (odds ratio [OR] = 1.1; confidence interval [CI] = 1.0-1.4) and less likely to report having had a same-sex sexual partner (OR = 0.7; CI = 0.5-1.0). The DES-exposed women were less likely to have had first sexual intercourse before age 17 (OR = 0.7; CI = 0.6-0.9) or to have had more than one sexual partner (OR = 0.8; CI = 0.7-0.9). There was an excess of left-handedness in DES-exposed men (OR = 1.4; CI = 1.1-1.7) but not in DES-exposed women. DES exposure was unrelated to self-reported history of mental illness in women.
Overall, our findings provide little support for the hypothesis that prenatal exposure to DES influences the psychosexual characteristics of adult men and women.
Psychosexual characteristics of men and women exposed prenatally to diethylstilbestrol,NCBI, PMID: 12606880, Epidemiology. 2003 Mar;14(2):155-60.
Prenatal hormone exposure may affect future breast cancer risk
DES Follow-up Study Summary
Fetal exposure to maternal pregnancy hormones may influence future breast cancer risk and cigarette smoking is among the factors believed to alter pregnancy hormone levels. Specifically, total pregnancy estrogen levels are slightly decreased among pregnant women who smoke relative to women who do not. More pronounced reductions of pregnancy estiol (E3) and estradiol (E2) were observed among smoking women. Possibly, women prenatally exposed to maternal cigarette smoke may have reduced breast cancer risk as an adult. The National Cooperative DES Adenosis (DESAD) Project was a prospective study of the effects of prenatal Diethylstilbestrol (DES) exposure. When women were enrolled in the study from 1975 through 1981, their mothers were questioned about their health habits including cigarette smoking during their pregnancy with the study participant. Using responses to this question provided by the mothers at the start of the study, investigators were able to compare the breast cancer rates among women who were and were not prenatally exposed to maternal cigarette smoke. Investigators observed a 51% decrease in breast cancer rates among women whose mothers smoked while pregnant with them compared to women who were not prenatally exposed to maternal cigarette smoke. Daughters of women who smoked 15 or fewer cigarettes per day during the pregnancy appeared to have a 65% reduction in breast cancer rates compared to women whose mothers did not smoke during pregancy. The adverse effects of prenatal cigarette smoke exposure far outweigh any benefit from possible reduction of breast cancer risk. These study results do, however, provide further evidence supporting the hypothesis that prenatal hormone exposure may affect future breast cancer risk.
2005 Study Abstract
Clinical studies show that maternal cigarette smoking reduces pregnancy estrogen levels. Women prenatally exposed to maternal cigarette smoke may, therefore, have a lower breast cancer risk because the fetal mammary gland’s exposure to maternal estrogen is decreased. Associations between prenatal maternal cigarette smoke exposure and breast cancer, however, have not been observed in previous case-control studies that relied on exposure assessment after the onset of cancer. At the start of this study, cigarette smoking history was obtained directly from the mother.
The National Cooperative DES Adenosis project was a follow-up study of health outcomes in women prenatally exposed to diethylstilbestrol (DES). At the start of the study, women’s mothers provided information about cigarette smoking habits during the time they were pregnant with the study participant. In the current study, the breast cancer rates are compared among 4031 women who were or were not prenatally exposed to maternal cigarette smoke. The resultant relative rate (RR) is adjusted for potential confounding by other breast cancer risk factors using Poisson regression modeling.
Fetal exposure to maternal cigarette smoke appeared to be inversely associated with breast cancer incidence (RR = 0.49; 95% confidence interval [CI] = 0.24-1.03). The inverse association was more apparent among women whose mothers smoked 15 cigarettes or fewer per day than among daughters of heavier smokers. There were, however, too few cases to precisely estimate a possible dose-response relationship.
These results support the hypothesis that in utero exposure to maternal cigarette smoke reduces breast cancer incidence.
Breast cancer incidence in women prenatally exposed to maternal cigarette smoke, NCBI, PMID: 15824550, 2005 May;16(3):342-5.
Small devices such as nanowire sensors that could detect cancer
In this diagram, nano sized sensing wires are laid down across a microfluidic channel. These nanowires by nature have incredible properties of selectivity and specificity. As particles flow through the microfluidic channel, the nanowire sensors pick up the molecular signatures of these particles and can immediately relay this information through a connection of electrodes to the outside world.
These nanodevices are man-made constructs made with carbon, silicon and other materials that have the capability to monitor the complexity of biological phenomenon and relay the information, as it is monitored, to the medical care provider.
They can detect the presence of altered genes associated with cancer and may help researchers pinpoint the exact location of those changes.
This 2010 study provides little support for an association between prenatal DES exposure and development of autoimmune disease
DES Follow-up Study Summary
Data shows no difference between rates of autoimmune diseases among the DES exposed and unexposed women.
Autoimmune disease is a class of diseases where antibodies usually meant to recognize foreign organisms instead react to a person’s own cells and tissues. We studied four specific types of autoimmune disease to investigate whether prenatal Diethylstilbestrol (DES) exposure affects the occurrence of these diseases. Systemic Lupus Erythematosus, or lupus, is an inflammatory disease resulting from an antibody attack on tissues and organs resulting in skin rashes, arthritis (chronic joint swelling), renal failure, or nervous system disorders. Rheumatoid arthritis (RA), not to be confused with commonly occurring osteoarthritis, is a disorder resulting from an immune response to an individual’s own connective tissue. The disease results in joint swelling and stiffness. Optic neuritis (ON) is a swelling of the optic nerve due to immune response resulting in vision loss in one eye, painful eye movement, and loss of color vision. Idiopathic Thrombocytopenia Purpura (ITP) is an unexplained decrease in the amount of platelets, cells designed to aid in blood clotting.
The rates of these diseases were compared among women who were and were not prenatally exposed to DES. Women who reported a diagnosis of any of these four diseases on the questionnaires sent in 1994, 1998, or 2001 were asked for permission to contact their doctors to verify the diagnosis. Considering all verified reports, there was no difference between the combined rates of these autoimmune diseases among the DES-exposed and unexposed women. Individually, there was also no difference in the rates of lupus and ON in these two groups. While there was no overall difference in RA between the two groups, there did appear to be a higher rate of RA among exposed women under the age of 45 compared to unexposed women of the same age. This difference however was based on a small number of cases (17 DES-exposed and 2 unexposed) and as a result there is some uncertainty as to the magnitude of this increase. Also there was no increase in RA among DES-exposed women 45 years and older compared with unexposed women of the same age. There were too few ITP cases to conclude whether or not there was a difference in the rate of this disease in the two groups.
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.
2010 Study Abstract
Animal studies have suggested that prenatal diethylstilbestrol (DES) exposure may alter immune system development and function including antigen self-recognition. A cohort study was conducted to investigate whether prenatal DES exposure might influence the incidence of at least some specific autoimmune diseases in women.
A group of women who were and were not prenatally exposed to DES have been followed for more than 25 years for numerous health outcomes including autoimmune disease. To verify diagnoses, medical records or physician abstracts were requested for all women who reported a diagnosis of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), optic neuritis (ON), and idiopathic thrombocytopenic purpura (ITP). Incidence rates of these autoimmune diseases were compared between women who were and who were not prenatally DES-exposed.
Overall, there was no increase in verified autoimmune disease among DES-exposed women relative to those who were not exposed (RR 1.2; 95% CI 0.7, 2.1). There was, however, a positive association between prenatal DES exposure and RA among women younger than 45 years (RR 4.9; 95% CI 1.1, 21.6) and an inverse association among women who were 45 years and older (RR 0.1; 95% CI 0.01, 0.7).
Overall, these data provide little support for an association between prenatal DES exposure and development of autoimmune disease. The implication that such exposure may be related to RA in an unusual age-related manner is based on small numbers of cases and warrants further study.
Autoimmune disease incidence among women prenatally exposed to diethylstilbestrol,NCBI, PMID: 20634240, 2010 Oct;37(10):2167-73. doi: 10.3899/jrheum.091092. Epub 2010 Jul 15. Full text link.