25 years of ERβ: a personal journey.

After the discovery of ERβ, a novel role for DHT in estrogen signaling was revealed. Instead of just being a better androgen, DHT was found to be a precursor of the ERβ agonist 5α-androstane-3β, 17β-diol (3βAdiol), the second estrogen in the body which did not require aromatase for its synthesis. ERβ was found to oppose androgen signaling and thus a potential target for treatment of prostate cancer. ERβ was also found to have effects that were independent of androgen signaling, particularly in the CNS. Although in rodent models of neurodegenerative diseases, ERβ agonists are very effective, this has not proven to be the case in humans. In this review we will focus on the main differences in ERβ signaling between rodents and humans and will make the point that the difference is in the splice variants which are expressed in humans and not rodents. The main conclusion is that before we think of using ERβ agonists clinically, much more work on ERβ signaling in the primate brain is needed.