Trial Information

Continuation of Follow-up of DES-Exposed Cohorts

Diethylstilbestrol (DES), a drug first synthesized in 1938, was administered to several
million pregnant women in the U.S. and Europe for the prevention of spontaneous abortion and
premature delivery. In 1971, Herbst reported a strong association between DES use in
pregnancy and the occurrence of vaginal clear cell adenocarcinoma (CCA) in exposed female
offspring. Animal models have demonstrated a range of DES effects on offspring exposed in
utero, including reproductive dysfunction, immune system changes, behavioral and sexual
abnormalities, and increases in various reproductive cancers in males and females. In the
mid-1970's, several separate cohorts of DES-exposed daughters and unexposed comparison
groups were followed for the occurrence of cancer, precursor lesions, and reproductive
effects, but systematic follow-up of these cohorts had ceased by 1990. In 1992, Congress
passed a bill (H;.R. 4178) mandating the continued follow-up of DES-exposed cohorts of
mothers, daughters, sons and grandchildren. The National Cancer Institute, in collaboration
with five field centers, reassembled previously studied cohorts of DES-exposed and unexposed
mothers, daughters and sons, and identified subjects with documented exposure status who had
not been studied previously, through familial links within the cohorts. Standardized
baseline questionnaires were mailed to cohort members to ascertain the risk of cancer and
other disorders. Pathology reports were collected for reported cancers and preneoplastic
conditions. Three separate phases of follow up have been conducted. Patients from the
Registry for Research on Hormonal Transplacental Carcinogenesis at the University of Chicago
will be added to the follow-up effort and mailed the questionaire used in the third phase of
follow-up. A cohort of daughters of women exposed and not exposed to DES in utero have been
added to the study to assess the effects of DES on third generation women.

The purpose of this study as a whole is to continue the follow-up, by means of mailed
questionnaires and medical record collection, which was begun during the first phase of the
study. Concern has arisen that DES-exposed daughters may be at higher risk of breast
cancer. Exposure to high levels of endogenous estrogen in utero has been hypothesized to
increase the risk of breast cancer and DES is a potent estrogen. Cancer risk in the sons
will also continue to be assessed, especially for increased risks of prostate cancer. Since
the offspring who were exposed to DES in utero are currently reaching their late forties,
when cancer rates begin to rise, it is important to continue the follow-up of these cohorts
to determine if there are long-term increases in cancer risk.