Exposure to DES during pregnancy results in an increased risk for several male reproductive disorders
1996 Study Abstract
Male reproductive health has deteriorated in many countries during the last few decades. In the 1990s, declining semen quality has been reported from Belgium, Denmark, France, and Great Britain. The incidence of testicular cancer has increased during the same time incidences of hypospadias and cryptorchidism also appear to be increasing. Similar reproductive problems occur in many wildlife species. There are marked geographic differences in the prevalence of male reproductive disorders. While the reasons for these differences are currently unknown, both clinical and laboratory research suggest that the adverse changes may be inter-related and have a common origin in fetal life or childhood.
Exposure of the male fetus to supranormal levels of estrogens, such as diethlylstilbestrol, can result in the above-mentioned reproductive defects. The growing number of reports demonstrating that common environmental contaminants and natural factors possess estrogenic activity presents the working hypothesis that the adverse trends in male reproductive health may be, at least in part, associated with exposure to estrogenic or other hormonally active (e.g., antiandrogenic) environmental chemicals during fetal and childhood development. An extensive research program is needed to understand the extent of the problem, its underlying etiology, and the development of a strategy for prevention and intervention.
Occurrence of Abnormalities in the Reproductive System of the Sons of Women Exposed to Diethylstilbestrol during Pregnancy Exposure
Diethylstilbestrol (DES) was prescribed to more than five million pregnant women from the late 1940s to the early 1970s to prevent abortions and pregnancy complications. Dieckmann and co-workers performed a double-blind placebo-controlled study on the therapeutic value of DES during pregnancy in the early 1950s. DES was given to 840 pregnant women and placebo to 806 controls. Compliance was verified by a dye indicator in the urine during the whole study. The women entered the study between weeks 7 and 20 of pregnancy (the majority during weeks 10-12) and received increasing doses of DES until pregnancy week 35 (5-150 mg/day). This study clearly indicated that the medication was not efficacious in the indications for which it was used. Instead, in the reanalysis of the material of Dieckmann et al., DES was associated with significant increases in abortions, neonatal deaths, and premature births. When Herbst and co-workers reported the high incidence of a very rare cancer, clear cell adenocarcinoma of the vagina, in pubertal girls exposed to DES in utero, the U.S. Food and Drug Administration (FDA) banned the use of DES during pregnancy. Medical authorities in Europe that had allowed DES use for pregnant women soon followed FDA regulations. In Europe, approximately 200,000 French, more than 150,000 Dutch, 63,000 Czechoslovakian, and 7000 British women were exposed to DES, whereas in the United States 4.8 million women were prescribed DES during pregnancy. In addition, DES was used as an anabolic agent in livestock, and the general population that used dairy products and meat may have been exposed to the hormone via this route to an unknown, and probably variable, extent. Some of the DES-exposed daughters and sons have been followed since the 1970s and a significant number of abnormalities in the structure and function of reproductive organs have been described.
Structural anomalies of the reproductive organs that are significantly more frequent in DES-exposed male subjects than in controls include meatal stenosis (12.9 vs 1.8%); hypospadias (4.4 vs 0%); epididymal cysts (20.8 vs 4.9%); testicular abnormalities, including hypoplastic testis, cryptorchidism, and capsular induration (11.4 vs 2.9%); and microphallus (4 cases vs 0 cases) (172-174). The data of Bibbo and Gill and their co-workers are based on the follow-up studies of the offspring of mothers who took part in the double-blind study of the effects of DES on pregnancy in 1953, and therefore the studies can be considered prospective. There were 308 men exposed to DES and 307 men exposed to placebo included in the study; 31.5% of men exposed to DES had an abnormality of their reproductive tract, whereas only 7.8% of controls had an anomaly. In the recent follow-up study of these males, it was found that the men who were exposed to DES before week 11 of gestation had twice as high a frequency of genital anomalies than did those who were exposed only later. This finding indicates the importance of the timing of the exposure (time of organogenesis). In a small study comprising 17 DES-exposed men, 12 nonexposed volunteers, and 11 fertile control men, genital anomalies (varicocele, epididymal cysts, absent testes) were reported in 13 of the DES-exposed subjects, 4 of the volunteers and 4 of the fertile normal controls. Whitehead and Leiter reported genital abnormalities in 29 of 48 men exposed to DES. Hypertrophy and squamous metaplasia of the prostatic utricle was found more frequently in aborted male fetuses that had been exposed to DES than in nonexposed controls, suggesting that DES-exposed males may have an increased risk of prostatic hyperplasia and/or cancer when aging. The data connecting DES exposure to several structural abnormalities of the male reproductive tract are convincing and leave little space for speculation on confounding factors. However, no association was found between first-trimester exposure to sex hormones, other than DES, and external genital abnormalities in a recent metaanalysis of 14 studies. In a large cryptorchidism study, no association between the disorder and exposure to estrogens during the pregnancy could be found.
Gill et al. studied semen samples from 88 men exposed to DES and 85 men exposed to placebo, who were offspring of the mothers from the 1953 study performed by Dieckmann and co-workers. Sperm concentration of men exposed to DES was significantly lower than in the controls (83 million/ml vs 123 million/ml, p < 0.02). There was no difference in semen volume, whereas the total sperm count, sperm motility grade, the total number of motile sperm, the percentage of sperm with normal morphology, and the quality score were all statistically lower in men exposed to DES. Azoospermia was found only in men exposed to DES, and 20.5% compared to 3.5% of men who received placebo had a sperm concentration in semen of less than 20 million/ml. The groups did not differ in their testosterone, FSH, or LH levels. In a later study on the same men (20 controls declined to participate), sperm concentrations still differed significantly, whereas other semen characteristics were similar between the groups. Similar results were obtained in another study in which the mean sperm concentration of men exposed to DES was 66.4 million/ml compared to 101.7 million/ml in normal volunteers (p < 0.05). In this study, the zona-free hamster egg penetration assay was also performed: sperm from 14 of 17 men exposed to DES failed to penetrate more than 14% of the eggs (which is the reference value for the normal fertility range), suggesting infertility, whereas only 2 of 12 unexposed volunteers and none of 11 fertile normal controls had an abnormal test result. In the study performed by Whitehead and Leiter, only 33% of the men exposed to DES had normal semen quality. However, Andonian and Kessler found no difference in semen quality between 24 men exposed to DES and 24 age-matched control men. Again, the large 1953 study population that has been followed prospectively appears the most valid for evaluation of semen quality. On the basis of that finding, DES exposure resulted in a significant decrease in semen quality.
Semen quality and fertility are not in direct correlation. In the latest follow-up study of the Dieckmann cohort, no difference in the fertility between men exposed to DES and their controls were found. This is compatible with the earlier findings that the majority of the men exposed to DES had sperm concentrations well above the limit at which fertility is supposed to be disturbed (20 million/ml), although the mean sperm concentrations of exposed men were lower than those of controls.
Exposure to DES during pregnancy results in an increased risk for several male reproductive disorders, such as cryptorchidism, urethral abnormalities, epididymal cysts, and testicular hypoplasia. In addition, the semen quality of DES sons is worse than that of controls. Incidence of testicular cancer is approximately doubled among DES sons compared to the general population, but whether this represents a true increase of the cancer risk is equivocal.
- Full study (free access) : Male Reproductive Health and Environmental Xenoestrogens, Environmental health perspectives, NCBI PubMed, PMC1469672, 15 March 1996.