Top Line: Can exogenous estrogen be used to treat prostate cancer?
The Study: In the 1960’s both orchiectomy and exogenous estrogen were used to treat advanced disease. Exogenous estrogens feedback inhibit LHRH production and result in castrate testosterone levels. When ADT is used, though, testosterone depletion also results in estrogen depletion. And it’s that estrogen depletion that’s thought to contribute to skeletal and cardiovascular side effects of ADT. So, why don’t we use estrogens much today? A VA trial in the 1960’s found that treatment with 5mg daily diethylstilbestrol (DES) significantly increased cardiovascular mortality and the risk of thromboembolism. That and the development of effective forms of chemical castration is the reason we don’t see much estrogen therapy today. Didn’t we say estrogen depletion contributed to cardiovascular toxicity from ADT? Yes, but oral estrogens cause adverse cardiovascular and prothrombotic effects because they take a first-pass through the liver and can have major effects on hepatic protein synthesis. The UK PATCH trial compares exogenous estrogen therapy (using a transdermal estradiol patch to bypass first-pass hepatic metabolism) to ADT with a LHRH agonist. Earlier results showed no difference in castrate testosterone levels at 3 months (93%). This long-term report of cardiovascular outcomes shows there is no difference in the time to first cardiovascular event or the rate of cardiovascular mortality. Of note, though, a third of CV events in the estradiol arm occurred after it was stopped or changed to a LHRH agonist. Gynecomastia was more frequent with estradiol (86 vs 38%) while hot flashes were more frequent with LHRH agonists (86 vs 35%). A final remaining question in using transdermal estradiol as an alternative form of ADT is whether survival and prostate cancer outcomes are similar with transdermal estrogen.
TBL: Transdermal estradiol does not increase cardiovascular morbidity or mortality (although it didn’t decrease it, either) compared to LHRH agonists in men with advanced prostate cancer. | Langley, Lancet 2021