Abstract This study evaluated the effect of a selective estrogen receptor beta (ERβ) agonist in the prostate of the aging Mongolian gerbil. The gerbil is a rodent known for spontaneous development of prostatic lesions such as prostatic intraepithelial neoplasias (PIN), adenocarcinomas and micro invasive carcinomas as they become old. This representative feature makes the gerbil interesting for testing the role of novel targets to prevent or treat prostate cancer. ERβ is known to have anti-proliferative and pro-apoptotic effects in the prostate epithelium, and therefore is a potential target for treatment of prostatic disorders. ERβ agonist and vehicle pellets were implanted subcutaneously in 12-month-old male gerbils (n=5) and the ventral prostates were harvested after 3 and 7 consecutive days of treatment. The tissue was processed for light microscopy and stained for H&E for morphological analysis. Expression of the nuclear receptors AR, ERα and ERβ, as well as markers of proliferation and apoptosis were examined by immunohistochemistry. Anatomically, the prostates of gerbils treated with vehicle pellets were smaller and more compact than those treated for 3 days with the ERβ agonist. The change was due to increased volume of the ducts and return of the ductal epithelium to a single organized layer. Histologically, the slides stained with H&E showed a hyperplastic and inflamed epithelium with a dense stroma in the vehicle treated groups, as typical of senile gerbil prostates. However, the treatment with the ERβ agonist promoted a reorganization of the prostatic epithelium. Ducts became lined in single layer of cubic/columnar cells, with enlarged lumen, full of secretion. The hyperplastic phenotype had normalized. These effects were more prominent after 3 days than after 7 days and were confirmed by a decreased expression of the proliferation marker ki67. In addition, ERβ expression, which is usually very weak or undetectable in the prostate of 12-month-old gerbils, was fully recovered after 3 days of treatment while expression of ERα and AR remained the same, indicating the effects occurred via ERβ signaling exclusively. Upon 7 days of continuous exposure to the ERβ agonist, ERβ expression was down-regulated. Therefore, the results found so far are promising as they indicate the ERβ as a novel and effective target for the treatment of prostatic disorders. However, the route and regimen of drug delivery remains to be carefully worked out. Citation Format: Sabrina S. Rochel-Maia, Sebastião R. Taboga, Margaret Warner, Jan-Åke Gustafsson. Effect of an ERβ agonist in the gerbil senile prostate: Novel treatment for age related disorders? [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr A53.