DES side effects in the third generation, known in 2005

The history of DES, lessons to be learned

“Health care professionals have to know the (full) history of DES to prevent future disasters with drugs prescribed.”

Abstract – 2005

At this moment, little is known about the implications of DES exposure for the third generation. Research has been done in mice to investigate the possibility of negative effects of DES on the male offspring of in utero exposed mice. The fertility of these males appeared to be the same as the fertility of the reference group. However, an increase in lesions of the testis and in tumours of the reproductive tract was reported, thereby providing the suggestion that effects of DES exposure can be transmitted to the third generation in mice.

Female offspring of mice exposed to DES in utero was also examined. In a group of 40 third generation mice ten uterine adenocarcinomas and five ovarian cystadenocarcinomas were seen, while tumours were absent in the control group. The development of these forms of cancer seemed to be age-dependent.

To find out whether these results would also be seen in humans, a group of 28 third-generation daughters was observed. While 61.5% of their mothers demonstrated cervical or vaginal changes associated with DES exposure in utero, none of these daughters showed any abnormality in the lower genital tract. However, this study is too small to draw conclusions but it seems that the carryover of DES effects in the female third generation is not of great significance.

Because the effects of DES in the third generation might be caused by biologic mechanisms, a study focused on the age at menarche in DES granddaughters. Fifty-two girls of mothers exposed to DES in utero were compared with 71 girls of unexposed mothers. The age at menarche was unaffected by DES administration to the grandmothers of these girls.

Next to the consequences in DES granddaughters, DES effects on the third-generation sons were also examined. As a result of two cases of hypospadia in sons of women that were exposed to DES in utero, a cohort study was done to find out whether an association between hypospadia in third generation males and DES exists. Hypospadia is a defect of the urogenital system in which the urethral opening is located on the ventral surface of the penis or on the scrotum. Sons of women with fertility problems (N ¼ 8934) were included in this study; 205 boys were sons of women exposed to DES in utero and the mothers of the remaining 8729 were unexposed. Four cases of hypospadia were reported in sons of exposed women compared with eight in the sons of unexposed. The prevalence rate ratio for hypospadia following from these results is 21.3, thereby suggesting an association between the administration of DES and the risk of hypospadia in the male third generation.

These outcomes suggest that there are no effects of DES exposure in females of the third generation, but that an increased risk of hypospadias exists for male offspring of women exposed to DES in utero. However, these results are obtained from small studies, so more research has to be carried out to obtain more reliable information.


  • The history of DES, lessons to be learned, Pharmacy world & science : PWS, PMID: 16096877, 2005 Jun.
  • Image credit rawdonfox.

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