Menstrual History of Young DES Daughters

Is oligomenorrhea associated with DES exposure ?

1979 Study Abstract

The menstrual histories of 218 patients exposed in utero to diethylstilbestrol (DES) were compared with those of 158 control subjects.

  • No significant differences were revealed in the complaint of menstrual irregularities at either the initial or follow-up examination.
  • Age at menarche was the same in both groups, and was the same as found in the United States as a whole.

These findings differ from the report of a controlled trial in Chicago which suggests that there is a specific pattern of oligomenorrhea associated with DES exposure.

References

  • Menstrual history of young women exposed in utero to diethylstilbestrol, Fertility and sterility, NCBI PubMed PMID: 467695, 1979.
  • Featured image Annie Spratt.
DES DIETHYLSTILBESTROL RESOURCES

Prenatal Diethylstilbestrol Exposure and Risk of Depression in Women and Men

Prenatal exposure to diethylstilbestrol (DES), an endocrine disrupting chemical, may be associated with depression in adulthood, but previous findings are inconsistent

2019 Study Abstract

METHODS
Women (3,888 DES exposed, 1,729 unexposed) and men (1,021 DES exposed, 1,042 unexposed) participating in the National Cancer Institute (NCI) DES Combined Cohort Follow-up Study were queried in 2011 for any history of depression diagnosis or treatment. Hazard ratios (HR; 95% confidence intervals (CI)) estimated the associations between prenatal DES exposure and depression risk.

RESULTS
Depression was reported by 993 (26%) exposed and 405 (23%) unexposed women, and 177 (17%) exposed and 181 (17%) unexposed men. Compared with the unexposed, HRs for DES and depression were 1.1 (95% CI: 0.9, 1.2) in women and 1.0 (95% CI: 0.8, 1.2) in men. For medication-treated depression, the HRs (CIs) were 1.1 (0.9, 1.2) in women and 0.9 (0.7, 1.2) in men. In women, the HR (CI) for exposure to a low cumulative DES dose was 1.2 (1.0, 1.4), and for DES exposure before 8 weeks’ gestation was 1.2 (1.0-1.4). In men, the HR for low dose was 1.2 (95% CI 0.9,1.6) and there was no association with timing. In women, associations were uninfluenced by the presence of DES-related vaginal epithelial changes or a prior diagnosis of DES-related adverse outcomes.

CONCLUSIONS
Prenatal DES exposure was not associated overall with risk of depression in women or men. In women, exposure in early gestation or to a low cumulative dose may be weakly associated with an increased depression risk.

References

DES DIETHYLSTILBESTROL RESOURCES

Immunological Effects Following In Utero Exposure to DES

Environmental endocrine modulators and human health: an assessment of the biological evidence, 1998

Abstract

Human Data

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.

Anima Data

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.

References

  • Environmental endocrine modulators and human health: an assessment of the biological evidence, Critical reviews in toxicology, NCBI PubMed, PMID: 9557209, 1998.
  • Featured image wikipedia.
DES DIETHYLSTILBESTROL RESOURCES

Alterations of sexual behavior – Human DES data

Environmental endocrine modulators and human health: an assessment of the biological evidence, 1998

Abstract

Several studies have addressed the potential effects of prenatal DES exposure on sexual behavior in adult human males and females. Due to the inherent complexity of human sexuality, the results of these studies are difficult to interpret; however, they do not appear to corroborate the findings observed in rats following in utero exposure to TCDD. Unfortunately, many of the studies investigating potential DES effects on human sexual behavior do not describe maternal DES dosages. While some subtle effects on sexual behavior of male and female offspring exposed to DES in utero have been observed, limited dose-response data suggest that these are likely associated with high total maternal DES doses and durations of exposure.

Psychosexual behavior was investigated in 62 adult males following in utero exposure to DES (n = 17), DES + natural progesterone (n = 22), natural progesterone only (n = 10), or synthetic progesterone (n = 13). DES dosages ranged from 50 to 14,000 mg with a mean of 3979 mg; duration of administration was from 0.5 to 29 weeks with a mean of 13.5 weeks. A large number of psychological tests were administered to subjects exposed and unexposed; sexual fantasies and behavior were also assessed. Comparison with matched unexposed men revealed a few subtle differences of unknown importance. Relative to the unexposed men, the DES-exposed group showed higher scores on the feminine scale of a sex role inventory, but also showed a greater interest in sports. With respect to adult sexual orientation, there were no differences between DES-exposed men and unexposed in either homosexual fantasies or behavior.

The relation between prenatal hormone exposure and sexual behavior in both men and women was evaluated in an extensive review of 19 relevant studies. Total mean DES doses in the few studies that reported such data averaged approximately 2500 mg administered for an average (mean) of 14 weeks during pregnancy. Findings from the 19 studies reviewed were classified into eight behavioral categories: play and recreation interests, peer relations, aggression/assertion, interest in marriage and maternalism, gender identity/role and personality, sexual maturation and behavior, cognitive abilities and academic achievement, and athletic ability/physical coordination. Compared with unexposed males, DES-exposed males were significantly less likely to categorize themselves as “likes to fight” (aggression/assertion) and somewhat less likely to report “usually wins fights”, responses that were considered “feminized”. Overall, there was a non significant tendency toward feminization on the aggregate aggression score. In another study of males exposed in utero to DES, in the category of vocational interest, DES-exposed males, relative to unexposed males, reported an increased interest in social services and in writing (although the latter was non significant). Although these traits were characterized as “feminized”, DES-exposed males were (non significantly) more likely relative to unexposed males, to have an increased number of male friends and elevated interest in sports and in TV shows with aggressive themes (“masculinized” characteristics). With respect to sexual orientation there were no differences between DES exposed and unexposed men. For women exposed in utero to DES, one initial study suggested a tendency toward bisexual or homosexual ratings on a number of measurement scales. However, in a larger follow-up study, DES-exposed women were not different from unexposed women on the same measurement tests employed in the initial study. In their discussion of the potential effects of prenatal hormone exposure on sexual behavior, Reinisch et al. noted that the behavioral repertoires of males and females overlap to a large extent; thus, no particular behavior is exclusively male or female. In addition, individuals can exhibit high frequencies of both masculine and feminine behavior (androgynous), low levels of both kinds of behavior (undifferentiated), or high levels of one type of behavior and low levels of the other (masculine or feminine).

Another extensive review of studies addressing gender-related behavior in women exposed in utero to DES concluded that there was no clear-cut difference between unexposed and DES-exposed women. In all seven studies reviewed there were more behavior trait similarities between DES-exposed and unexposed women than differences. This finding was considered striking by the investigators considering that the bias of their studies was that there would be differences between groups because the experimental protocols employed were specifically designed to detect differences and not similarities. Consideration of pre- and postnatal influences, including social, economic, and environmental factors suggests that unexplained individual variation appears more important than in utero exposure to DES.

A recent, extensive study investigated the effects of prenatal exposure to DES and sexual orientation in three groups of DES-exposed women (DES1, DES2, and DES3).The DES1 and DES2 groups had a high prevalence of DES-related vaginal or cervical abnormalities (90% and 97%, respectively).
In 13 of the 30 DES1 women with sufficient exposure information, total maternal DES dosage ranged from 210 to 10,475 mg with a median of 1800 mg. In 5 of 30 DES2 women with sufficient data, total maternal DES dosage ranged from 252 to 19,800 with a median of 3600 mg. While the precise maternal dosages in the DES3 group were unknown, vaginal epithelial changes associated with DES were present in 50% of the woman, and the available records suggested that total maternal DES dosages were lower than the recommended regimens of the time.
This study demonstrated that more DES-exposed than unexposed women were rated as bisexual or homosexual. Although the DES-exposed women were significantly more likely than the unexposed women to report bisexuality and homosexuality, the actual differences between the two groups were modest; a predominantly homosexual orientation was reported as lifelong by only 4 of 96 DES-exposed women, while only six women reported current homosexual orientation. Most of the differences between DES-exposed and unexposed women were limited to degrees of bisexuality, and for many, bisexuality was confined to imagery and not behaviorally expressed. Of interest is the fact that most of the differences were observed when the DES1 and DES2 groups were compared with unexposed women; only one difference was noted when the DES3 group was compared with unexposed women. While there were significant overall differences between DES-exposed and unexposed women, the relative absence of effects for the DES3 group suggests a dose-related effect on sexual orientation. It is also worth noting that, even though this was a study that focused predominantly on women, potential effects in men in the same cohort were also evaluated with the same set of questions. In men, there was no apparent relation between in utero DES exposure and alterations in sexual behavior.

References

  • Environmental endocrine modulators and human health: an assessment of the biological evidence, Critical reviews in toxicology, NCBI PubMed, PMID: 9557209, 1998.
DES DIETHYLSTILBESTROL RESOURCES

Exogenous Estrogens and Breast Cancer : DES

Environmental endocrine modulators and human health: an assessment of the biological evidence, 1998

Abstract

Maternal Exposure

Several studies have investigated breast cancer risk in women given DES or other exogenous estrogens during pregnancy. In a cohort study of 1531 women exposed to DES during pregnancy, the relative risk for breast cancer was 1.5 (CI 0.88 to 2.49).  Within the exposed group, there was also no evidence for a dose-response relationship with relative risks for breast cancer of 1.38, 1.46, and 1.29 for total DES doses of <1000 mg, 1000 to 4500 mg, and >4500 mg, respectively. The mean total DES dose in this study was 2100 mg. While there was a slight excess of breast cancer in the DES group (although not statistically significant), the authors note that this may have also been due to hormonally related reproductive difficulties in these women, which was why they were given DES.

In a study comparing the incidence of breast cancer in a cohort of 3033 women who had taken DES during pregnancy with an appropriate unexposed group, there was an increased relative risk of 1.46 (CI 1.1–1.9). Breast cancer mortality was slightly higher in the DES-exposed group (RR = 1.1), but this was not statistically significant. Because information on total DES doses used was not available, a dose-response relationship between DES and breast cancer could not be determined. The authors were unable to rule out whether the increased incidence of breast cancer was due solely to DES or some other characteristic of DES-exposed women (e.g., an underlying hormonal disorder that precipitated the use of DES). In a follow-up study of the same cohort, there was a modest, but statistically significant increase in breast cancer risk associated with exposure to DES during pregnancy (RR = 1.35). Because this follow-up study included 127 new breast cancer cases and 42,000 additional women-years of observation, in addition to controlling for previous miscarriage, the relative rate estimates are more precise than those in the earlier report. However, it did not appear that breast cancer risk associated with DES increased over time. Finally, in a study of 319 women who were part of a randomized clinical trial of DES, there was no difference in the incidence of breast cancer between DES exposed and unexposed. The mean total DES dose in this study was 11.5 g.

The data addressing increased breast cancer risk associated with DES exposure during pregnancy are equivocal. While the available data support a possible weak association between exposure to DES and increased risk of breast cancer, studies are limited by a lack of sufficient information on dose and duration and the inability to distinguish DES-induced effects from indicators for using DES (i.e., an underlying hormonal imbalance). Nevertheless, exposure to DES during pregnancy does not appear to appreciably increase the risk of breast cancer.

In Utero Exposure

It has also been hypothesized that increased maternal estrogen levels during pregnancy may be associated with an increased probability of breast cancer in daughters. However, there are limited empirical data to confirm this hypothesis. To date, there is no evidence of an association between in utero DES exposure and increased risk of breast cancer in adulthood because the relevant birth cohorts of DES offspring have not reached the age range at highest risk for breast cancer. Only indirect evidence has been used to suggest that intrauterine exposure to estrogens may be associated with subsequent increased risk of breast cancer. Correlations between endogenous serum estrogen levels during pregnancy in certain populations and breast cancer risk in the daughters may be useful in evaluating the potential association between in utero DES exposure and breast cancer. Significantly lower (i.e., 30%) serum estrogen levels in pregnancy have been reported in younger women (<20 years) compared with older women (20 to 29 years). These findings, together with evidence showing an association between later maternal age at birth and increased breast cancer risk in daughters have been used to suggest that in utero exposure to the potent, synthetic estrogen, DES, may be associated with increased breast cancer risk. However, this is entirely hypothetical and confirmation of this must await the results of studies now in progress, of women exposed in utero to DES as they reach the age of greatest breast cancer risk.

References

  • Environmental endocrine modulators and human health: an assessment of the biological evidence, Critical reviews in toxicology, NCBI PubMed, PMID: 9557209, 1998.
  • Featured image Samuel Zeller.
DES DIETHYLSTILBESTROL RESOURCES

Intrauterine exposure to diethylstilbestrol: long-term effects in humans

APMIS : acta pathologica, microbiologica, et immunologica Scandinavica, 2000

Abstracts

DES is the most carefully scrutinized EDC and its history provides valuable insights into the current evaluation of less well-studied EDCs. This review summarizes the health effects of prenatal exposure to diethylstilbestrol (DES) and emphasizes the role of DES as the first endocrine disrupting chemical (EDC).

Daughters

Vaginal clear cell adenocarcinoma (CCAC), the most severe consequence of prenatal exposure to DES, affected only 0.1% of exposed females, while the far more prevalent teratogenic and reproductive effects of DES were only discovered when DES daughter were screened for CCAC. Initial studies, conducted before most DES daughters had tried to conceive, examined vaginal cancer and vaginal, cervical and uterine abnormalities. Subsequently, several controlled studies demonstrated the increased risk of adverse reproductive outcomes in DES daughters. While most DES daughters can eventually experience a live birth, this is less likely in women with genital tract abnormalities, in whom there is a two-thirds chance that each pregnancy will be unsuccessful.

Sons

In DES sons, who have been far less studied, results suggest male reproductive toxicity, but are less consistent. The importance of dose and gestational age at initial exposure are discussed, and the implications of DES findings for the evaluation of risks from current EDCs emphasized.

Because of the dramatic development of vaginal/cervical clear cell adenocarcinoma in DES daughters, an increased risk of testicular cancer in DES sons has long been postulated. However, studying this association is difficult since both the disease and the exposure are uncommon. Only two cohort studies have examined testicular cancer, one reporting a testicular teratoma and the other two germ cell cancers in the exposed and none in the unexposed. In the six case-control studies published, exposure was broadly defined, and none studied DES specifically. These studies examined testicular cancer in relation to a maternal history of any hormone medication during the pregnancy, or any drug for bleeding, spotting or threatened abortion or prevention of miscarriage. The strongest association was seen in the one study that restricted exposure to the first trimester, which reported a relative risk estimate of 8.0 (p=0.02). These case-control studies were all of low statistical power. One of the largest, with 225 cases, did not have the power to rule out a relative risk of 7.0 (assuming alpha=0.05 and beta=0.80 and a 1% exposure to DES). Thus, while no consistent pattern of testicular cancer risk is seen for prenatal hormone exposure (featured image), an increased risk of testicular cancer in association with prenatal hormone use cannot be ruled out. Prenatal exposure to DES, specifically, is currently being examined in the DES Combined Cohort Studies (DCCS), a cohort study that includes 2,000 DES sons and 2,000 controls. However, it should be remembered that CCAC occurred in only one DES-daughter per thousand. If DES caused an equally rare form of genital tract cancer in DES sons, it is unlikely to be detected in this cohort study.

Several authors have reported increased urogenital tract abnormalities in males exposed in utero to DES. In Depue, an analysis of birth outcomes from the Collaborative Perinatal Project, the (matched) relative risk for cryptorchidism and mother’s use of estrogen (estradiol or DES) was 2.80 (p=0.06). Genital tract abnormalities were studied in the Dieckmann cohort by Bibbo, Gill and and Wilcox.

Several other authors studied cohorts identified in a single hospital or city. Most of these studies found a significant excess of one or more genital tract abnormalities, including epididymal cysts, hypertrophic or undescended testis, capsular induration, hypoplastic penis or hypospadias.

In addition, several studies examined the relationship between prenatal DES exposure and semen quality. The findings were mixed, with some studies finding significantly impaired semen quality in exposed males, and others finding little or no association. Leary and colleagues examined 265 exposed and 274 unexposed men born at the Mayo Clinic. They did not find increases of genitourinary abnormalities or infertility. As noted above, the median total dose their mothers received was only 720 gms. This should be compared to median doses of 11,025 and 2,530 gms for DESAD participants with and without structural anomalies.

The data on infertility in DES sons are quite limited. Wilcox and colleagues found no impairment of fertility in their follow-up of the Dieckmann cohort. In particular, the probability of conception in 119 couples in which the man was DES-exposed did not differ from 104 couples in which the man was unexposed. While a greater excess of genital abnormalities was reported in this study for men exposed prior to week 11, fertility did not differ by week of exposure. However, as noted above, the proportion of men in the Dieckmann cohort who were exposed in very early pregnancy is quite low.

In 1980 Driscoll conducted a controlled study of perinates identified from autopsy records, using a study design similar to that used by Johnson in examining female abortuses and stillbirths with respect to adenosis (discussed above). Blinded to exposure status, Driscoll examined prostate sections from 31 exposed and 62 unexposed pregnancies. Significantly higher rates of prostate abnormalities (abnormalities of the utricle and dilated ducts) were seen in the exposed. The highest rates were in those nine perinates exposed to DES alone; 100% had both a prostatic utricle and dilated ducts with squamous metaplasia. While there have been no reports of prostate abnormalities in adults exposed to DES during fetal life, most DES sons are not yet 50 years old. Since few of these men have reached the age at which benign prostatic hyperplasia (BPH) or prostate cancer increases in frequency, prostate abnormalities in DES sons have not yet been studied and it is important that this cohort be monitored for these endpoints.

A limited number of studies have examined the hypothesis that the development of hemispheric organization and cognitive abilities in humans is influenced by prenatal hormones, and DES in particular. Reinish conducted a double blind study of ten pairs of male siblings. One was exposed to a DES dose exceeding 1000 mg and early exposure (eight of ten were exposed by gestational week ten), while the other was unexposed to any exogenous hormone. This study reported DES exposure significantly associated with reduced hemispheric laterality and lowered spatial ability.

References

  • Intrauterine exposure to diethylstilbestrol: long-term effects in humans, APMIS : acta pathologica, microbiologica, et immunologica Scandinavica, NCBI PubMed PMID: 11252812, 2000.
  • Featured image credit mmcapital.
DES DIETHYLSTILBESTROL RESOURCES

A randomized double-blind controlled trial of the value of stilboestrol therapy in pregnancy

Long-term follow-up of mothers and their offspring, 1983

Abstract

In the early 1950s, a randomized, double-blind, controlled trial of the value of prophylactic stilboestrol therapy given antenatally to reduce the incidence of late pregnancy toxaemia and to improve perinatal mortality was conducted at University College Hospital, London.

Women expecting their first baby were allocated to one or other of two groups. Those in the stilboestrol group started treatment at the 12th week of pregnancy on average and received a mean dose of about 11.5 g of the drug while those in the control group received placebo tablets.

In spite of the fact that the original trial documentation was lost, it was possible to be fairly certain which was the treated group and follow-up data from 650 mothers and 660 offspring were obtained from death certificates, cancer registrations and questionnaires sent to general practitioners.

We found no indication of any harmful long-term effect of stilboestrol exposure during pregnancy on the mothers–in particular 10 out of 331 women in the untreated group and 9 out of 319 women in the treated group were found to have developed breast cancer.

Amongst the daughters, those in the treated group suffered an excess of minor benign lesions of the cervix uteri and an excess (not statistically significant) of unfavourable pregnancy outcomes. None of the daughters had developed clear cell adenocarcinoma of the vagina or cervix uteri.

Amongst the sons, we discovered no evidence of any significant excess of genital tract disorders or of impaired reproductive performance in the treated group but one son developed a (fatal) teratoma of the testis.

Unexpectedly, psychiatric disease (especially depression and anxiety) was reported by general practitioners about twice as often in the treated group offspring (sons and daughters) as in the untreated group. This result cannot be due to bias, and is unlikely to be due to confounding or chance, and may thus represent an adverse effect of exposure to stilboestrol in utero.

References

  • A randomized double-blind controlled trial of the value of stilboestrol therapy in pregnancy: long-term follow-up of mothers and their offspring, British journal of obstetrics and gynaecology, NCBI PubMed, PMID: 6357269, 1983.
  • University College Hospital, London featured image wellcomecollection.
DES DIETHYLSTILBESTROL RESOURCES

Epidemiological studies of the effects of diethylstilboestrol

International Agency for Research on Cancer scientific publications, 1989

Study Abstract

Herbst and his colleagues first showed in 1971 that girls born to mothers who had taken diethylstilboestrol (DES) during pregnancy were at an increased risk of clear-cell adenocarcinoma of the vagina and cervix. At first it was feared that these girls would have a high probability of developing clear-cell carcinomas, but the latest report from the Registry for Research on Hormonal Transplacental Carcinogenesis of the University of Chicago puts the risk at only 1 per 1000 of those exposed, from birth through to age 34. On this basis, Herbst and his colleagues have suggested that DES is not a complete carcinogen, but that some other factor is involved in the pathogenesis of clear-cell carcinoma of the vagina and cervix. Women exposed in utero to DES have a high prevalence of vaginal adenosis and tend, therefore, to have an extensive transformation zone on the cervix and in the vagina. There is considerable controversy as to whether or not such women are at increased risk for vaginal and cervical intraepithelial neoplasia. The latest findings from the Study of the Incidence and Natural History of Genital Tract Anomalies and Cancer in Offspring Exposed in Utero to Synthetic Estrogens (the DESAD project) are, however, worrying; during follow-up, vaginal and cervical intraepithelial neoplasia occurred at a rate of 15.7/1000 woman-years in the exposed and at a rate of 7.9/1000 woman-years in the controls (p = 0.01).

There is some evidence that exposure in utero to exogenous oestrogens increases the risk of testicular cancer in males. The findings, however, are not conclusive, and the effect does not seem to be specific to DES and related nonsteroidal oestrogens.

References

  • Lesions of testis and epididymis associated with prenatal diethylstilbestrol exposure, Environmental Health Perspectives, NCBI PubMed, PMC1474522, 1988 Apr.
  • Featured image @IARCWHO.
DES DIETHYLSTILBESTROL RESOURCES

The effects in the human of diethylstilbestrol (DES) use during pregnancy

An update, 1987

Abstract

(DES Daughters) Intrauterine diethylstilbestrol (DES) exposure is associated with an increased risk for the development of clear cell adenocarcinoma (CCA) of the vagina and cervix. The age of the patients at diagnosis has varied from 7-35 years with the highest frequency from 14-22 years. The risk among the exposed, however, is small and is of the order of 1 per 1,000. Almost all of the cases occur in postmenarchal females. Other factors that may increase the risk are maternal history of prior miscarriage, exposure to DES in early gestation, a fall season of birth and prematurity. The occurrence of CCA has paralleled the sales of DES for pregnancy support in the U.S. Both vaginal adenosis (benign glands in the vagina) and CCA are more frequent among those whose mothers began DES in early pregnancy. An increased risk of squamous cell neoplasia has been hypothesized but not proven. The changes that occur in the female genital tract of the DES exposed appear to result from alterations in the development of the mullerian ducts.

Currently there is not definitive evidence for an elevated risk of cancer among DES mothers or DES sons but studies have suggested a possible increase of breast cancer in the former group and testicular cancer in the latter group; a valid association has not been established in either.

References

  • The effects in the human of diethylstilbestrol (DES) use during pregnancy, NCBI PubMed, PMID: 3506546, 1987.
  • Featured image Mathieu Bigard.
DES DIETHYLSTILBESTROL RESOURCES

Diethylstilbestrol in pregnancy: an update

Canadian Medical Association journal, 1982

Abstract

The problems associated with the use of diethylstilbestrol (DES) during pregnancy concern both female and male children exposed in utero and the mothers themselves.

Strong epidemiological evidence has linked clear-cell adenocarcinoma of the vagina in young women to maternal ingestion of DES during the 1st 18 weeks of pregnancy. Benign abnormalities of the genital tract have also occurred in daughters of women exposed during pregnancy.

3 data sources have been particularly important for continued assessment of DES:

  • the 1951 University of Chicago double-blind study following controls, treated women, and offspring;
  • the National Cooperative Diethylstilbestrol Adenosis (DESAD) project which collects information on thousands of women exposed in utero,
  • and the Registry of Clear-Cell Adenocarcinoma (Mesonephroma) of the Genital Tract in Young Females.

The risk of clear-cell adenocarcinoma of the vagina and cervix in this group for ages 14 through 24 is estimated to be .14-1.4/1000 females exposed in utero. The risk is highest when exposure was early in intrauterine life. Peak incidence of tumors is between 17-21 years, rarely appearing before the age of 14. Concern over an increase in squamous cell dysplasia was raised, however a Massachusetts General Hospital study showed the prevalence of dysplasia was 2.1% and the incidence .85/1000 women years of follow-up. Benign abnormalities of the genital tract are common among this group and include: vaginal adenosis and structural abnormalities such as cervical hoods, ridges, and T-shaped uterus. The structural abnormalites may predispose to problems with reproduction; the incidence of complications after the 20th week of pregnancy, premature delivery, and perinatal death were found to be significantly increased. Results are conflicting concerning the impact of DES exposure on fertility.

Males exposed to DES in utero may have an increased frequency of anatomic and functional changes including epididymal cyst, hypoplasia of the testes, induration of the testicular capsule and impairment of spermatogenesis, sperm maturation, and accessory gland secretion.

The data are inconclusive concerning the incidence of breast cancer for women who took DES during pregnancy.

The psychological impact on the mothers who took DES and on the exposed offspring is another important consideration.

References

  • Diethylstilbestrol in pregnancy: an update, Canadian Medical Association journal, NCBI PubMed, PMID: 7139494, 1982.
  • Featured image credit Daniil Kuželev.
DES DIETHYLSTILBESTROL RESOURCES