25 years of ER beta: a personal journey

After the discovery of ER beta, a novel role for dihydrotestosterone (DHT) in estrogen signaling was revealed. Instead of just being a better androgen, DHT was found to be a precursor of the ER beta agonist 5 alpha -androstane-3 beta, 17 beta -diol (3 beta Adiol), an estrogen which does not require aromatase for its synthesis. ER beta was found to oppose androgen signaling and thus is a potential target for treatment of prostate cancer. ER beta was also found to have effects that were independent of androgen signaling, particularly in the CNS. Although in rodent models of neurodegenerative diseases (Parkinson's disease, multiple sclerosis, and Alzheimer's disease), ER beta agonists are very effective in relieving symptoms and improving pathologies, this has not proven to be the case in humans. In this review we will focus on the main differences in ER beta signaling between rodents and humans and will make the point that a very important difference between the two species is in the splice variants which are expressed in humans and not rodents. The main conclusion at this point is that before we think of using ER beta agonists clinically, much more work on ER beta signaling in the human or in primates needs to be done.