In this prospective study, we found a higher risk of depression among middle-aged women exposed to DES and/or other hormones in utero. The findings persisted 10 years after women reported their exposure. The strengths of our study include the partially prospective cohort design, large sample size, and long follow-up. However, information on depression was based on self-reported use of antidepressants and symptoms of depression, rather than a physician diagnosis of depression following criteria from the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders. DES exposure was also self-reported by participants, but among those whose mothers also reported DES exposure, agreement was good. We cannot rule that some mothers, and thus participants, are unaware that they were prescribed DES, but this would not explain our findings.
An association between DES exposure and increased psychiatric and anxiety disorders was first reported by Vessey et al. (5
) in 1983. In this study, general practitioners were contacted directly for the medical history of offspring of women randomized to placebo or DES in a double-blind controlled trial conducted in London during the 1950s. DES was started at 5 mg/day as close to the sixth week of pregnancy as possible, but not after the 16th week, and continued until the 35th week when the dose had incrementally reached 125 mg/day. Although study documentation from the original trial was lost, and it was only known if women had been assigned to group A or group B, the authors wrote that they were fairly certain which group was in fact the exposed group. Offspring of the exposed group had twice as many reports of psychiatric disorders, including depression and anxiety, as the unexposed group (15.1% in the exposed, 7.4% in the unexposed). These findings cannot be attributed to distress at learning of DES exposure because that was unknown at the time of the Vessey study, or to confounding by indication because of the randomized design. Further, the reports of illnesses of the breast and urogenital system were similar in both groups, and therefore the somatic effects of DES were unlikely to be the cause of the increased incidence of psychiatric conditions. Two small case-control studies were published thereafter. Lifetime occurrence of major depressive disorder was similar among 30 DES-exposed women and 30 women with abnormal Papanicolaou smears (7
). Fifty DES-exposed women had significantly higher odds of major depressive disorder and recurrent major depression (based on criteria from the third edition of the Diagnostic and Statistical Manual of Mental Disorders
assessed with the Diagnostic Interview Schedule) and of amphetamine abuse when compared with their control sister, whereas no difference was found when they were compared with controls with abnormal Papanicolaou smears (6
). In both studies, the authors concluded that an increase in major depressive disorder was a result of concern about gynecologic problems. However, recently a large study comprising 4 cohorts assembled retrospectively, including 8,000 men and women who had documented DES exposure in utero, found similar proportions of self-reported diagnosis and treatment for mental illness across exposure status (14
). Finally, one partially prospective study of offspring exposed to DES found no association between prenatal DES exposure and serious psychiatric outcomes (suicide or hospitalization) or serious psychiatric outcomes plus psychiatric/psychological consultation, as reported by their mother (15
). We had insufficient suicides to examine the association in the current analysis.
It is possible that the increased initiation of antidepressants and depressive symptoms among the DES-exposed women in our study results from their knowledge of the long-term adverse reproductive effects of exposure in utero, but this interpretation would not explain the results of Vessey et al. (5
) reported above. The weaker association found in our study as compared with the study by Vessey et al. may be explained by lower doses and shorter duration of DES exposure among women in our cohort. Although we do not have direct information on dose, the dose and early administration of DES were likely to have been more consistent among women in a randomized trial.
Two recent reports summarize the neural and behavioral effects of BPA when administered to experimental animals in doses considered safe in humans (12
), including reduced novelty-seeking (16
), increased anxiety (17
), and “depression-like” behavior (19
). BPA is an estrogenic compound, similar to DES, used in polycarbonate plastic bottles, dental sealants, and epoxy resin in the lining of food cans. It has been detected in the urine at levels of 0.1 μg/L in 95% of the adults and 92.6% of the participants aged 6 years or more in US reference populations (20
). Children had higher concentrations than adolescents who had higher concentrations than adults.
Recent research implicates endocrine disruptors and DNA methylation in the etiology of psychiatric disorders (22
). In animal models, exposure to DES, BPA, and other estrogenic compounds during development and early life results in altered methylation patterns in CpG islands (in promoter genes, thus changing tissue-specific gene expression) (24
). For example, it has been shown that estradiol lowered catechol-O
-methyl transferase (COMT) transcription (25
is one of a number of genes associated with bipolar disorder and schizophrenia when its promoter region is hypomethylated (22
). In mice experiments, the hypomethylating effects of exposure to BPA were negated by dietary supplementation with folate, which is a coenzyme in the methylation reactions (27
In summary, we found that women who were exposed to DES in utero had a higher risk of depressive symptoms and use of antidepressants, and that this increase in risk extended into their middle age. Although the possibility that some women became depressed because of awareness of their exposure status cannot be ruled out, these results are consistent with the hypothesis that the physiologic effects of in utero exposure to DES lead to higher rates of depression during adult life. It remains to be established whether prenatal exposures to ubiquitous environmental chemicals that are structurally similar to DES and have similar estrogenic effects also increase the risk of depression.