What is Diethylstilbestrol (DES)?
Diethylstilbestrol (DES) is a synthetic nonsteroidal estrogen that was prescribed to pregnant women from 1938-1971 in the United States to prevent miscarriage and pregnancy complications, but was discontinued after being linked to serious adverse health outcomes in exposed offspring, particularly vaginal clear cell adenocarcinoma in daughters. 1
Historical Context and Clinical Use
DES was the first orally active artificial estrogen developed and was given to several million pregnant women during the 1940s through 1960s based on the mistaken belief that it reduced miscarriage risk 2. The drug was used in the United States until 1971 and continued into the 1980s in other countries 3. In 1971, the U.S. Food and Drug Administration issued a contraindication for its use during pregnancy after establishing the relationship between prenatal DES exposure and clear cell adenocarcinoma of the vagina and cervix in young women 1.
Mechanism of Action in Prostate Cancer
Beyond its historical use in pregnancy, DES has been studied as a hormonal therapy for prostate cancer. At a dose of 3 mg daily, DES achieves castrate levels of testosterone within 1-2 weeks by inhibiting LHRH production from the hypothalamus 4. The drug also demonstrates a direct cellular cytotoxic effect through an apoptotic mechanism in hormone-refractory cell lines 4.
In androgen-independent prostate cancer, DES at 3 mg daily produced PSA declines ≥50% in 24% of patients, with a median response duration of 3.8 months 4.
Serious Health Risks and Adverse Effects
In DES-Exposed Mothers
- Modestly increased breast cancer risk (RR = 1.27,95% CI 1.07-1.52) in women who took DES during pregnancy 5
- This increased risk is not exacerbated by family history of breast cancer or use of oral contraceptives/hormone replacement therapy 5
- No evidence of increased risk for ovarian, endometrial, or other cancers 5
In DES-Exposed Daughters (In Utero Exposure)
- Increased risk of vaginal and cervical clear cell adenocarcinoma, with a presumed lifetime risk [2, @33@]
- Structural reproductive tract anomalies including T-shaped uterus, constriction rings, and hypoplastic uterus 6
- Increased infertility rates and poor pregnancy outcomes including spontaneous abortion, ectopic pregnancy, and preterm delivery 1
- Possible increased risk of cervical carcinoma in situ 2
- Early menopause 3
- Increased mammographic breast density 4
In DES-Exposed Sons
- Increased prevalence of urogenital anomalies 2
- Possibly increased risk of testicular and prostate cancer 1, 2
Cardiovascular and Thrombotic Complications
DES is associated with significant cardiovascular toxicities including myocardial infarction, stroke, and pulmonary embolism, especially at moderate to high doses 4. Even at the lower 1 mg daily dose, 13% of patients in the EORTC study discontinued DES due to complications 4. Historical trials reported cardiovascular events in more than 30% of subjects 4. Prophylactic low-dose warfarin does not prevent venous thrombosis 4.
Other Adverse Effects
- Gynecomastia (common, may be reduced by prophylactic breast irradiation) 4
- Edema, cramps, and dyspnea 4
- Mild fatigue and mastodynia 4
Current Clinical Status
DES is no longer commercially available in North America and should not be considered as a standard first-line treatment option 4. The American Society of Clinical Oncology guidelines explicitly state that DES should not be considered for initial hormonal management of prostate cancer due to its significant cardiovascular and thrombotic risks 4.
Surveillance Recommendations for Exposed Individuals
For DES Daughters
- Annual cervical and vaginal cytology 1
- Vaginal and cervical digital palpation at gynecologic examinations (may provide the only evidence of clear cell adenocarcinoma) 1
- Initial colposcopic examination should be considered; if abnormal, repeat annually 1
- Obstetric consultation for pregnant women with in utero DES exposure due to higher risks of spontaneous abortion, ectopic pregnancy, and preterm delivery 1
For DES Mothers
- Regular mammography given slightly higher breast cancer risk 1