Benign and Malignant Outcomes in the Offspring of Females Exposed In Utero to Diethylstilbestrol (DES): An Update from the NCI Third Generation Study

Linda Titus; Elizabeth E Hatch; Kimberly A Bertrand; Julie R Palmer; William C Strohsnitter; Dezheng Huo; Michael Curry; Marianne Hyer; Kjersti Aagaard; Gretchen L Gierach; Rebecca Troisi

doi:10.3390/cancers16142575

Benign and Malignant Outcomes in the Offspring of Females Exposed In Utero to Diethylstilbestrol (DES): An Update from the NCI Third Generation Study

Cancers (Basel). 2024 Jul 18;16(14):2575. doi: 10.3390/cancers16142575.

Authors

Affiliations

¹ Department of Pediatrics, Geisel School of Medicine at Dartmouth, and the Norris Cotton Cancer Center, Lebanon, NH 03756, USA.
² Department of Epidemiology and Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA.
³ Boston University Chobanian & Avedisian School of Medicine and Slone Epidemiology Center, Boston University, Boston, MA 02118, USA.
⁴ Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
⁵ Department of Public Health Sciences, University of Chicago, Chicago, IL 60637, USA.
⁶ Information Management Services, Rockville, MD 20852, USA.
⁷ Department of Obstetrics & Gynecology, Division of Maternal-Fetal Medicine, Baylor College of Medicine and Texas Children's Hospital, Houston, TX 77401, USA.
⁸ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA.

Abstract

Background: Females exposed prenatally to diethylstilbestrol (DES) have an elevated risk of cervical dysplasia, breast cancer, and clear cell adenocarcinoma (CCA) of the cervix/vagina. Testicular cancer risk is increased in prenatally exposed males. Epigenetic changes may mediate the transmission of DES effects to the next ("third") generation of offspring.

Methods: Using data self-reported by third-generation females, we assessed DES in relation to the risk of cancer and benign breast and reproductive tract conditions. Using data from prenatally DES-exposed and unexposed mothers, we assessed DES in relation to cancer risk in their female and male offspring. Cancer risk was assessed by standardized incidence ratios (SIR) and 95% confidence intervals (CI); the risks of benign and malignant diagnoses were assessed by hazard ratios (HR) and 95% CI.

Results: In self-reported data, DES exposure was not associated with an increased risk of overall cancer (HR 0.83; CI 0.36-1.90), breast cancer, or severe cervical dysplasia. No females reported CCA. The risk of borderline ovarian cancer appeared elevated, but the HR was imprecise (3.46; CI 0.37-32.42). Based on mothers' reports, DES exposure did not increase the risk of overall cancer (HR 0.80; CI 0.49-1.32) or of other cancers in third-generation females. Overall cancer risk in exposed males appeared elevated (HR 1.41; CI 0.70-2.86), but the CI was wide. The risk of testicular cancer was not elevated in exposed males; no cases of prostate cancer were reported.

Conclusions: To date, there is little evidence that DES is associated with cancer risk in third-generation females or males, but these individuals are relatively young, and further follow-up is needed.

Keywords: cancer; diethylstilbestrol; endocrine disruptor; in utero; prenatal exposure; third generation.

Grants and funding

This project has been supported with federal funds from the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health.