Environmental endocrine modulators and human health: an assessment of the biological evidence, 1998
There are limited human data on long term immunological effects subsequent to in utero exposure to DES.
Two small studies of immune response in women exposed in utero to DES have produced conflicting results. Evidence of hyperreactive immune systems, as measured by heightened lymphocyte responses to PHA and PWM, was noted in eight women exposed in utero to DES, all of whom had reproductive tract abnormalities and evidence of cervical and/or vaginal adenosis. In contrast, there were no effects on NK activity among 12 women exposed in utero to DES prior to the 18th week of gestation, all of whom had anatomical reproductive tract changes consistent with such exposures. The maternal DES dosages to which these women were exposed in utero were not available, but it appears that DES dosages were sufficient to cause reproductive tract abnormalities in both groups. The fact that different measures of immune function were used in each study also makes it difficult to compare results.
Two large DES-exposed cohorts have been studied to determine the potential immunologic consequences of in utero exposure to DES. General immune status and autoimmune conditions among DES-exposed persons (i.e., mothers, daughters, and sons) has been evaluated in the DESAD project (DES Adenosis), a multicenter epidemiological study of cohorts identified through the Mayo Foundation, University of California, Baylor College of Medicine, and Boston University. DES exposure of the DESAD cohort was confirmed between 1972 and 1983 by record review, and various health outcomes have been assessed annually thereafter by questionnaire. The other cohort is part of the DES Action USA Registry and involves periodic surveys of DES-exposed mothers and their offspring. While the majority of this cohort reports DES exposure, only about 30% have records documenting exposure.
In response to the 1985 questionnaire, 520 mothers, 1079 daughters, and 94 sons participating in a DES Action survey provided information about general immune statue, as well as possible autoimmune conditions. DES-exposed sons had significantly higher self-reported frequencies of asthma, arthritis, diabetes, and prostate problems relative to men surveyed in the 1985 National Health Interview Survey. All three DES-exposed groups reported higher rates of respiratory tract conditions; overall rates were two to three times higher than controls. The investigators had anticipated increased frequencies of diabetes in the DES-exposed groups, because DES was often prescribed for high-risk diabetic mothers and has also has a strong familial component. The same survey also reported an increased prevalence of the autoimmune diseases asthma, arthritis, and lupus in DES-exposed respondees.
In a survey of the DESAD cohort, one autoimmune disease, Hashimoto’s thyroiditis, occurred significantly more often in exposed women (5.8 per 1000) than unexposed (1.1 per 1000).408 For any self-reported autoimmune disease, the overall frequency among women exposed to DES in utero was 28.6 per 1000 vs. 16.3 per 1000 in unexposed women. Women with vaginal epithelial changes had almost 50% more autoimmune disease than women without such changes. Because DES-exposed subjects might be more inclined to report medical conditions, the validity of self-reported data is uncertain. Despite confirmation of DES exposure, maternal DES doses were not known for any study participants and typical maternal dosing regimens varied among study centers.
A second questionnaire-based study of the DESAD cohort found no evidence that DES-exposed persons differed from unexposed persons with regard to measures of general immune status, that is, lifetime history of common childhood diseases (i.e., measles, mumps, rubella, chickenpox, and strep throat) were similar for both groups. Prevalence rates of less common diseases (i.e., mononucleosis, oral herpes, pneumonia, appendicitis, and hepatitis) were also similar in both groups. There was a significant increase in the prevalence of rheumatic fever in the DES-exposed individuals compared with unexposed individuals. This finding was based on few cases so the significance is uncertain, particularly because the prevalence of strep throat, which often precedes rheumatic fever, was the same in both groups. In a smaller subset of women (33 DES exposed and 21 unexposed) serum antibody titers to six human viral diseases (measles, varicella-zoster, rubella, cytomegalovirus, influenza A, and herpes simplex) were determined, but no significant differences between DES exposed and unexposed persons were detected. Additional research of these issues is required, particularly functional immune testing in individuals with different in utero exposures to DES, to determine the ultimate validity of the findings and possible associations with maternal DES doses. This will be particularly important as the DES-exposed cohort ages and the expectation of normal age-related declines in immune function occur.
There are limited data on the immunological consequences of adult exposure to exogenous estrogens. Estrogen replacement therapy has been reported to cause decreases in the mixed lymphocyte reaction and increased levels of serum total cortisol. These changes were not correlated and are of unknown clinical significance but suggest that additional research is needed to evaluate the potential immunological consequences of adult exposure to exogenous estrogenic substances.
The immunological effects reported in humans exposed in utero to DES are generally consistent with data from rodents treated neonatally with DES. Neonatally DES-exposed female mice have decreased T-cell populations, decreased response to T-cell independent antigens (i.e., LPS), and impaired NK cell function (not observed in humans) with an increased susceptibility to transplanted and primary carcinogen-induced tumors.
Other studies demonstrate that in utero exposure of male and female mice to DES resulted in enhanced humoral immune function in males and either no effect or a slight suppression in females. In contrast, mice exposed to DES in utero show defects in T-cell, B-cell, and NK cell function, but some of these impairments become detectable only as the animals age. Spleen cell responses to mitogen stimulation showed diminished responses to PHA and LPS, as well as reductions in a mixed lymphocyte culture and graft vs. host response in mice exposed in utero to DES. These reductions generally followed a pattern of initial hyperstimulation of spleen cell response in 1-month-old mice followed by a gradual decline in immune responsiveness at about 2 to 9 months of age. Because the dose of DES used in this study (1 µg/d) is about 10 times the amount needed to produce the same genital tract alterations as 20 µg of 17β-estradiol, the authors speculate whether lower DES doses would still produce immunosuppression. Studies on the immune effects of neonatal estrogen exposure in mice demonstrate that DES is more potent than 17β-estradiol in producing such effects, but there are also DES dose levels at which no effects occur. Following five daily doses of DES (0.01, 0.1, 1, or 5 µg) only the 5 µg dose resulted in a persistent reduction of in vitro mitogen response to Con A or LPS.
Overall, a substantial amount of animal data demonstrate numerous immunological effects following in utero exposure to DES, including abnormal B-cell and T-cell responses and diminished NK activity. Most of these effects persist for the lifetime of the animal and some may even become more severe with age. The relationship between these effects and neoplasia in rodents is unknown, as is the relevance of these findings to possible health consequences in humans.
While in utero exposure to estradiol has also been reported to result in some immunological impairment, it is not as severe as that produced by DES. The data on DES and estradiol demonstrate that dose-response relationships for possible immunological effects from in utero or neonatal exposures may be important. The fact that estradiol might have immunological consequences less than DES highlights the need to understand the comparative potency aspects of this phenomenon. Finally, the observation that some adverse immunological effects become more severe with age suggests that continuing surveillance of men and women exposed in utero to DES is warranted.
- Environmental endocrine modulators and human health: an assessment of the biological evidence, Critical reviews in toxicology, NCBI PubMed, PMID: 9557209, 1998.
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