Diethylstilbestrol

Cardiovascular

The effect of diethylstilbestrol in prostate cancer has been studied in 29 patients, who were given diethylstilbestrol 1 mg/day and 5 mg on the day before docetaxel, then docetaxel 36 mg/m ² intravenously weekly for 3 weeks of a 4-week cycle [ ]. The median number of cycles was six. Prophylactic anticoagulation was used in all cases. The combination of diethylstilbestrol and docetaxel produced a significant fall in prostate-specific antigen (PSA) and a measurable disease response rate. However, 15 patients had grade 3/4 adverse effects, two died of causes unrelated to therapy, and another died from a glucocorticoid-induced ulcer; six patients developed thrombosis, and of those tested 75% had factor V mutations. The adverse effects pattern was similar to that seen without diethylstilbestrol, except for venous thrombosis.

In a randomized study of men treated hormonally for prostatic cancer [ ], cardiovascular adverse effects were reported more often in patients treated with diethylstilbestrol than in those treated with cyproterone acetate. The risk was highest during the first 6 months of treatment.

Mineral balance

Profound hypocalcemia occurred in a patient with osteoblastic metastatic carcinoma of the prostate after treatment with diethylstilbestrol 15 mg/day for 7 days [ ].

Hematologic

The risk of thromboembolic complications when diethylstilbestrol is used in treating prostatic cancer is well documented, but there has been some doubt as to the mechanisms involved. Oral diethylstilbestrol diphosphate 300 mg/day has been compared with LHRH agonist therapy or no treatment in 35 patients with prostatic cancer [ ]. Diethylstilbestrol reduced the concentrations of protein S to below the lower limit of normal in 24 of the 35 cases. There was also some reduction in antithrombin III concentrations. These results were consistently confirmed in a follow-up group of eight further patients who took diethylstilbestrol. Since these very low concentrations of protein S are virtually the same as those found in congenital deficiency, it seems likely that this plays a role in the development of cardiovascular complications during diethylstilbestrol treatment.

Liver

Liver damage is occasionally attributed to diethylstilbestrol [ ].

• A 65-year-old man started to take diethylstilbestrol 1 mg bd for prostatic cancer (Gleason grade 3) [ ]. After 11 years of treatment without metastasis he was switched to treatment with an LH-RH analogue, which was regarded as safer, but at this time his liver function tests were found to be seriously deranged. Biopsy showed established cirrhosis with steatohepatitis. He had no history of excessive alcohol intake, and it seemed likely that the diethylstilbestrol was the cause of the liver disorder.

Non-alcoholic steatohepatitis was also discovered at postmortem in six patients who had taken diethylstilbestrol for prostate cancer [ ].

Immunologic

In 13 women exposed to diethylstilbestrol in utero compared with similar control subjects with respect to the in vitro T cell response to the mitogens phytohemagglutinin, concanavalin A, and interleukin-2, incorporation of tritiated thymidine into T cells from diethylstilbestrol-exposed women was increased threefold over a range of concentrations in response to concanavalin A, increased by 50% over a range of concentrations in response to phytohemagglutinin, and increased twofold in response to the endogenous mitogen interleukin-2 [ ]. This in vitro evidence of a change in T cell-mediated immunity clearly raises questions about the clinical consequences.

Tumorigenicity

Exposure to diethylstilbestrol during pregnancy in 4836 women has been reported to carry a relative risk of 1.27 of breast cancer later in life. However, the authors found no evidence to support the link between diethylstilbestrol exposure and ovarian, endometrial, or other cancers.

In a 25-year follow-up study there were very slightly more breast tumors in women using diethylstilbestrol in pregnancy and significantly more cancer deaths [ ].

In one study there was a sixfold risk of endometrial cancer among estrogen users compared with non-users; long-term users (over 5 years) had a 15-fold risk; there were excess risks for both diethylstilbestrol and conjugated estrogens [ ].

Diethylstilbestrol can cause hepatic adenomas and carcinomas in experimental animals [ ], and hepatocellular carcinoma has been reported in a man who took a total of 668 g over 12 years for suspected carcinoma of the prostate [ ].