Effects in Men of Intra-Uterine Exposure to DES

1998 Study Abstract

The reasons for increased incidence of cryptorchidism, hypospadias and testicular cancer are unknown, but experimental data demonstrating the important role of sex steroids in the physiology of testicular descent and urethral development point to the possibility that environmental factors could cause the problem by interfering with the sex steroids. The best example of such an influence is diethylstilbestrol (DES), which has been studied extensively in both humans and experimental animals.

Millions of pregnant women in the USA and Europe were treated with DES between the late 1940s and early 1970s to prevent abortion, pre-eclampsia and other complications of pregnancy. Doubleblind, placebo-controlled trials had already demonstrated in the 1950s that the treatment was not efficacious, but despite that it was used until the 1970s when the US Food and Drug Administration banned its use during pregnancy after it had become evident that the daughters of DES-treated women had an increased risk of developing clear cell adenocarcinoma of the vagina.

Thereafter, several studies on the effects of DES on the children of exposed mothers were published. Many of the papers are based on the socalled Dieckmann cohort comprising more than 1600 pregnant women who were treated with increasing doses of DES or placebo from gestational weeks 7-20 to week 35 . The use of the medication was verified by a dye indicator in the urine. Children from these pregnancies have been followed since the 1970s, and a large number of structural and functional abnormalities in their reproductive organs have been found. For example, 20.8% of 308 men exposed to DES in utero had epididymal cysts, compared with 4.9% of 307 placebo-exposed controls. There were other structural anomalies in reproductive organs that were more frequent in DES-exposed male subjects than in controls, for example meatal stenosis (12.9% versus 1.8%), hypospadias (4.4% versus 0%), testicular abnormalities, including hypoplastic testis, cryptorchidism and capsular induration (11.4% versus 2.9%), and microphallus (4 cases versus 0 cases). The frequency of anomalies was dependent on the timing of exposure, so that the men who were exposed to DES before week 11 of gestation had a significantly higher prevalence of anomalies than those who were exposed only later, emphasizing the sensitivity of organogenesis to external disturbance. In these cohort studies, cryptorchidism was significantly more frequent in DES-exposed men than in controls, but in retrospective case-control studies, maternal oestrogen exposure was not associated with an increased incidence of cryptorchidism in the offspring. The strength of a retrospective case-control study, however, is not as good as that of a prospective cohort study, and DES can therefore be considered to be a risk factor for cryptorchidism. In a metaanalysis of 14 studies, no association was found between first-trimester exposure to sex hormones other than DES, and external genital abnormalities.

Several reports have demonstrated that the semen quality of men exposed to DES in utero is significantly worse than in placebo-exposed controls. However, the sperm concentrations of most of the DES-exposed men were well above the limit at which subfertility occurs, and it is therefore not surprising that the fertility of these men was reported to be normal.

The risk of testicular cancer among men exposed to DES in utero has been a controversial issue, and one can often read in the literature claims that the risk is not increased. This does not seem to be true. On the basis of a meta-analysis of six case-control studies, Mantel-Haenszel estimate of the odds ratio was 2.6, with 95% confidence limits of 1.1-6.1. However, more direct evidence would be necessary to assess the risk. Thus far, no data have been available for testicular cancer in the known DES-exposed cohorts.



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