In November 1971 the health protection branch of the Department of National Health and Welfare announced, on the basis of data reported from the United States, an association of the use of diethylstilbestrol during pregnancy with the later development of adenocarcinoma of the vagina in exposed offspring.’ The health protection branch has since required the manufacturers of DES and other estrogenic drugs to include in their product literature a contraindication to the use of all estrogens during pregnancy. Similar warnings and reminders followed in subsequent issues of Rx Bulletin.
For the past decade the indications for the use of DES in Canada have been limited to the palliation of estrogen-responsive metastatic carcinoma of the breast and advanced carcinoma of the prostate.
In 1979 Canadian physicians were advised by the health protection branch’s special advisory committee on reproductive physiology, a group of nongovernment consultants, of the risks of congenital malformations and malignant disease in the offspring of women exposed to DES during pregnancy. While DES is no longer recommended for use during pregnancy, it is probably still being given for other purposes, such as postpartum suppression of lactation and postcoital contraception. These indications have not been approved by the health protection branch, and our committee does not recommend the use of DES for these purposes.
The problems associated with the use of DES during pregnancy concern both female and male offspring exposed in utero and the mothers themselves. While available evidence indicates that the magnitude of the DES problem in Canada is low we thought it advisable to summarize the current knowledge in this area for Canadian physicians.
Sources and more information
Diethylstilbestrol in pregnancy: an update, Canadian Medical Association Journal, 1982 Nov 1; 127(9): 812–813., NCBI PMID: PMC1862229.
Genital tract abnormalities that are both structural and functional are common in DES-exposed males
Various complications of pregnancy, notably threatened abortion, were commonly treated with diethylstilboestrol (DES) during the 1940’s through the 1960’s. Prenatal exposure to DES became a cause for concern in 1971 when accumulated evidence linked clear-cell adenocarcinoma of the vagina and vaginal adenosis with the administration of DES during pregnancy to the mothers of the affected young women.
Later, concern arose regarding hazards of transplacental DES on the developing male fetus. Follow-up comparison 25 years or later on subjects involved in a double-blind study of the efficacy of DES in preventing untoward effects of pregnancy showed DES-exposed males to have a greater prevalence of epididymal cysts, hypoplastic testes or both. Of 308 males exposed to DES, 31.5 percent had epididymal cysts, hypoplastic testes or both, as compared with 7.8 percent of 307 placebo-exposed controls. Of 26 DES-exposed males with testicular hypoplasia, 17 had a history of cryptorchidism, while only 1 of 6 placebo-exposed males with testicular hypoplasia had a history of testicular maldescent. Analysis of semen of 134 males exposed to DES showed severe pathologic changes in 18 percent compared with 8 percent of 87 male controls. This finding suggests that DES exposure in utero may have an effect on male fertility.
Although there is no control study showing an increased incidence of malignant tumors among DES-exposed men,one must keep in mind the increased risk of testicular carcinoma in testes that are or were cryptorchid. Testicular carcinoma has been reported in three men who had a history of exposure to DES in utero and of cryptorchidism. There has as yet been no report of carcinoma of the prostatic utricle in men exposed to DES in utero. The prostatic utricle, the miillerian duct remnant that is homologous to the female vagina, has been found to be the site of carcinoma in older men.
In summary, administration of DES during pregnancy appears to be followed by male genital tract abnormalities that are both structural (epididymal cysts, hypoplastic testes and cryptorchidism) and functional (abnormal semen). Due to prolonged latency in expression of DES effects, it will probably be another decade or more before the question of potential malignancy in men exposed to DES in utero is answered. Additional follow-up will also give insight into the probability of sub-normal fertility in males exposed to DES in utero.
THE WESTERN JOURNAL OF MEDICINE, EPITOMES-PEDIATRICS, ROBERT PENNY MD, APRIL 1982
Pediatrics-epitomes of progress: the effect of des on male offspring, NCBI, PMID 18749074 PMCID: PMC1273720, West J Med. 1982 Apr;136(4):329-30.
The stage of cellular differentiation at the time of DES exposure may be critical in the final expression of these abnormalities
The association of intrauterine exposure to diethylstilbestrol (DES) and the subsequent development of reproductive tract abnormalities in young women has been well documented. Although the incidence of vaginal adenocarcinoma was low in the exposed population, vaginal adenosis, a nonmalignant abnormality, was quite common. In order to study the pathogenesis of adenocarcinoma and to determine the frequency of adenosis following prenatal exposure to DES, timed pregnant CD-1 mice were treated s.c. with DES (dose range, 5 to 100 micrograms/kg/day) on Days 9 though 16 of gestation. This period corresponds to major organogenesis of the reproductive tract in the mouse. Female offspring were sacrificed between 1 and 18 months of age. In addition to nonmalignant abnormalities, some of which have been described in women exposed prenatally to DES, two cases of vaginal adenocarcinoma (2%) were observed in 91 prenatally DES-treated animals. No comparable epithelial lesions were seen in 158 control female mice. One other case of adenocarcinoma of the vagina was reported previously by this laboratory using the prenatally exposed animal model. In another series of mice treated prenatally with DES, 100 micrograms/kg/day, 3 of 20 (15%) 1-month-old animals and one of 10 (10%) 18-month-old treated offspring had glandular epithelium abnormally located in the vaginal fornices (adenosis). Other cervicovaginal abnormalities observed after prenatal DES exposure included structural alterations, cervical enlargement, squamous metaplasia in the endocervical canal, excess keratinization of the ectocervix and vagina, transverse folds and basal cell hyperplasia in the upper vagina, and prominent Wolffian duct remnants. Thus, vaginal adenosis in the mouse does not appear to be a common abnormality following treatment with DES in utero. Neonatal exposure to DES on Days 1 to 5, on the other hand, resulted in six of eight (75%) animals with adenosis at 35 days of age. Since perinatal mouse studies have reported high incidences of vaginal adenosis, but, to our knowledge, no cases of vaginal adenocarcinoma, the results presented in this report suggest that the stage of cellular differentiation at the time of DES exposure may be critical in the final expression of these abnormalities.