There are three common estrogens in humans conveniently numbered 1, 2, and 3. The most common bioactive one is estradiol, abbreviated E2. But it turns out there is a fourth estrogen, which one does not hear about often because it primarily shows up in the liver or the foetus. It is estetrol, i.e., E4.
A new study shows that E4 can limit some of the more bothersome side effects of estrogen deprivation that come with androgen suppression. This is a small study sponsored by a drug company in the Netherlands. It was a double-blind, randomized trial which involved patients on standard ADT plus either a placebo (N= 21) or a daily oral E4 (N=41). The sample size was small, and the study only ran for 24 weeks, however, the findings are significant in several regards. There was no elevation of blood clots in the experimental arm. And the incidence of hot flashes was profoundly reduced. The patients also showed some sign of better quality of life overall. Similar to other estrogens, there was nipple sensitivity and some breast development reported by the men on E4.
What is particularly interesting about this study is that it is the first one sponsored by a drug company looking at giving men an estrogen to relieve the side effects of ADT. Clearly the company sponsored this research with hopes of bringing their product to market. Currently, patients in the western world, who use an estrogen product to manage ADT side effects, have to do it “off label” because there are no products specifically licensed for this purpose. E4 is now being evaluated specifically for this purpose. A larger, phase 3 trial is necessary before we can expect to see estetrol licensed and prescribed by MD’s to reduce ADT side effects. If estetrol proves safe and effective in controlling ADT side effects, it will still be a few years before we can expect to see it on the market. If that happens, the next question is: “Will it be priced low enough so most patients on ADT can afford it?
We shall wait and see.
To read the full paper, see: https://www.sciencedirect.com/science/article/pii/S2666168322019061
Reference:
Zimmerman, Y., Frydenberg, M., van Poppel, H., van Moorselaar, R. J. A., Roos, E. P., Somford, D. M., ... & Bennink, H. J. C. (2022). Estetrol Prevents Hot Flushes and Improves Quality of Life in Patients with Advanced Prostate Cancer Treated with Androgen Deprivation Therapy: The PCombi Study. European Urology Open Science, 45, 59-67. https://doi.org/10.1016/j.euros.2022.09.006