APMIS : acta pathologica, microbiologica, et immunologica Scandinavica, 2000
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).
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.
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.
- 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.