Diethylstilbestrol: risks of malignant disease and congenital malformations

US National Library of Medicine, Canadian Medical Association, 1979

image of malignant-disease
DiEthylStilbestrol usage review buttress the need for adequate and rigorous research into the use of drugs in pregnancy and ensure that they do more good than harm before being introduced for consumption.

1979 Study Abstract

In 1951 a prospective double-blind study was begun at the University of Chicago to evaluate the usefulness of diethylstilbestrol in the protection of pregnancy. The women involved, the controls and all the offspring are being carefully followed up. Preliminary long-term follow-up data, collected to the end of 1977, have been reviewed by a task force of the Department of National Health and Welfare’s special advisory committee on reproductive physiology.

The Chicago study and others have demonstrated that the female offspring of women given diethylstilbestrol during pregnancy are at an increased risk for a variety of benign abnormalities of the genital tract. In addition, the very infrequent occurrence of carcinoma of the vagina or cervix in such individuals is well documented.

It is now also evident that prenatal exposure of males to diethylstilbestrol is associated with a low frequency of various detectable anatomic and functional changes in the reproductive tract. The abnormalities observed include epididymal cysts, hypoplastic testes, induration of the testicular capsule, and some impairment of spermatogenesis, sperm maturation and accessory gland secretion; malignant lesions have not been reported.

Sources and more information
  • Diethylstilbestrol: risks of malignant disease and congenital malformations, Canadian Medical Association, NCBI PMCID: PMC1704227, 1979 Jun 23.
  • Full text PDF, CMA JOURNAL/JUNE 23, 1979/VOL. 120.
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Epidemiologic aspects and factors related to survival in DES-associated cases of CCAC cancer

American Journal of Obstetrics and Gynecology, 1979

CCAC painting
DiEthylStilbestrol usage review buttress the need for adequate and rigorous research into the use of drugs in pregnancy and ensure that they do more good than harm before being introduced for consumption.

1979 Study Abstract

Three hundred and eighty-four cases of clear cell adenocarcinoma of the vagina and cervix accessioned in the Registry as of December 31, 1978, have been analyzed.

The annual incidence of these tumors has been found to correspond closely to the estimated usage of diethylstilbestrol (DES) for pregnancy support in the United States. The annual incidence of the DES-associated cases appears to have dropped in the United States in the past 2 years in comparison to 1973 to 1975.

The risk of tumor development appears to be higher in young women exposed to DES early in intrauterine life than in those exposed later. The carcinomas are rare before the age of 14 years and an irregular peak in the age-incidence curve appears between 17 and 21 years followed by a decline.

The 5-year survival rate is better for women over the age of 19 years than for younger patients, and a higher frequency oral contraceptive usage did not appear to influence the behavior of the tumor and the improved survival in those using this medication appears to be related to greater medical surveillance.

Sources and more information
  • Epidemiologic aspects and factors related to survival in 384 Registry cases of clear cell adenocarcinoma of the vagina and cervix, American Journal of Obstetrics and Gynecology 1979 Dec 1;135(7):876-86, NCBI PMID: 507130.
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Development of DES-associated clear-cell carcinoma: the importance of regular screening

Regular and frequent PAP smears are needed for DES-affected women

pap-smear image
This 1979 study underscores the necessity for frequent vaginal cytologic smears and pelvic examinations at intervals no greater than 6 months for the DES-affected women.

1979 Study Abstract

Because the rate of malignancies in young women exposed in utero to diethylstilbestrol (DES) is low, appropriate population screening methods have not been established. A case is presented that is believed to represent the first reported instance of a DES-exposed daughter who developed clear cell adenocarcinoma of the vagina after initially negative examinations. The patient was followed with Papanicolaou smears, pelvic examinations, and colposcopy every 6 months for 2 years prior to the discovery of malignancy. Initially negative, Papanicolaou smears successfully predicted the presence of an early adenocarcinoma. Palpation aided by colposcopy allowed directed biopsy of the small asymptomatic lesion.

This case underscores the necessity for frequent vaginal cytologic smears and pelvic examinations at intervals no greater than 6 months. Colposcopy is indicated to direct biopsies when an abnormal cytologic smears is reported or when abnormal bleeding or discharge occurs. Biopsy of any palpable lesion is mandatory.

Sources and more information
  • Development of DES-associated clear-cell carcinoma: the importance of regular screening, Obstetrics and Gynecology 1979 Mar;53(3):293-9, NCBI PMID: 424100.
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Prenatal diethylstilbestrol exposure and human genital tract abnormalities

Herbst AL, Scully RE, Robboy SJ, DES research 1979

foetus image
Nonneoplastic abnormalities including vaginal adenosis, cervical eversion (ectropion), and transverse cervical and vaginal ridges are frequent in the DES-exposed population, particularly if the drug was administered early in pregnancy.

1979 Study Abstract

The incidence of clear cell adenocarcinoma of the vagina and cervix associated with intrauterine exposure to diethylstilbestrol DES and similar compounds during the first half of pregnancy has increased. Ninety percent of these cancers have occurred in patients 14 years of age or older.

Although these carcinomas are exceedingly rare, nonneoplastic abnormalities including vaginal adenosis, cervical eversion (ectropion), and transverse cervical and vaginal ridges are frequent in the exposed population, particularly if the drug was administered early in pregnancy. Current evidence favors a disturbance in development of the müllerian duct as the explanation of these changes.

Whether DES is only a teratogen or also a carcinogencerviccervi is unknown, as is the possible role of other factors in the development of cancer. An increased incidence of cancer among exposed males has not been documented.

Sources and more information
  • Prenatal diethylstilbestrol exposure and human genital tract abnormalities, Herbst AL, Scully RE, Robboy SJ. 1979 May;(51):25-35. NCBI PMID: 481577.
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Vaginal cancer: six years’ experience with screening of a diethylstilbestrol-exposed population

During the 6 years from the initial survey, 830 young women exposed to DES in utero were periodically screened.

Of these 830 patients who responded to the questionnaire,in 1979, 61.7% were found to have cervicovaginal abnormalities, and 65.9% of the patients showed either adenosis or evidence of the prior existence of vaginal adenosis. Screening survey image via SelectScience.

1979 Study Abstract

The physician population delivering obstetric care in Philadelphia between 1950 and 1970 was contacted to ascertain their use of diethylstilbestrol (DES) during pregnancy. Of the 31.8% of the physicians who responded to the questionnaire, 71.8% used DES during pregnancy and 12.7% desired assistance in review of their records.

During the 6 years from the initial survey, 830 young women exposed to DES in utero were periodically screened for cervicovaginal abnormalities and clear cell adenocarcinoma. Of these 830 patients 61.7% were found to have cervicovaginal abnormalities, and 65.9% of the patients showed either adenosis or evidence of the prior existence of vaginal adenosis. Eight patients were treated for clear cell adenocarcinoma. Two cases were detected while asymptomatic. Seven of the patients are living with no evidence of cancer, and two of these have survived over 5 years.

Sources and more information
  • Six years’ experience with screening of a diethylstilbestrol-exposed population, NCBI PMID: 463989, Am J Obstet Gynecol. 1979 Aug 15;134(8):860-5.
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Effect of DiEthylStilboestrol on Gonad Development

Gonadal feminization and feminization of the quail following DES exposure

1st Abstract – 1979

image of PubMed NCBI The Endocrine Society logo
The effect of diethylstilboestrol on gonad development in quail embryos has been quantitatively analysed.

Early treatment of Quail eggs by DES promotes a transient feminization of the gonads in genetic males and a strong stimulation of the Müllerian ducts. The left ovotestis results from the juxtaposition of a testicular medulla and an induced female-type cortex, which develops follicles and a characteristic 17 beta-HSD activity. The right testis is reduced but keeps a consistent structure. The medulla of the treated gonads shows, in both sexes, an inhibition of delta 5-3 beta HSD activity during embryonic development. After hatching, this specific enzyme then develops in the steroidogenic cells. These results are compared with others obtained with estradiol and also in chick. The discussion deals also with the effects of these estrogens on the endogenous abilities and specific responses of the gonads in relation to sex differentiation factors.

2nd Abstract – 1995

The effect of diethylstilboestrol on gonad development in quail embryos has been quantitatively analysed. Quail embryos at 4 days of incubation were treated with diethylstilboestrol (DES), using the egg dipping method. At 10 days of incubation, embryos were removed and killed by decapitation. Tissues were prepared for chromosome analysis, and the parts of the abdomen containing the gonads were prepared for serial sectioning and quantitative assessment. Left gonads of DES-treated male embryos resembled ovaries histologically, while their right gonads were markedly reduced in size. Right gonads of DES-treated female embryos were also further reduced by treatment with DES. There was no statistically significant effect by DES treatment on the size of left gonads, although the ratio of left compared with right gonadal volumes was highly significant. Since, in birds, the left embryonic gonad has ambisexual potential, while the potential of the right gonad is exclusively masculine, these results exemplify the adverse effect exerted by oestrogen on male sexual development in vertebrates.

Sources
  • Feminization of the quail by early diethylstilbestrol treatment: histoenzymological investigations on steroid dehydrogenases in the gonadsNCBI, PMID: 294849, 1979;68(2):85-98.
  • A quantitative investigation of gonadal feminization by diethylstilboestrol of genetically male embryos of the quail Coturnix coturnix japonicaNCBI, PMID: 7616493, 1995 Mar;103(2):223-6.
  • Full text: Journal of Reproduction and Fertility, doi: 10.1530/jrf.0.1030223
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