**2.11 The brain has multiple targets for androgens**

3α-diol has novel mechanisms of action. T and DHT bind to androgen receptors (ARs), and some of the proliferative effects of androgens on the prostate may be through this mechanism. However, it seems that non-AR mechanisms of other T metabolites may be important for cognitive and/or affective behavior. 3α-diol has actions via ERβ and GABAA receptors [16–20] (**Figure 8**). E2 readily binds to cognate ERα and ERβ, and can enhance benign prostatic hyperplasia and adenocarcinoma, likely via actions at ERα, not ERβ, but this is not completely understood. Indeed, androgens' and estrogens' (anti)proliferative effects may depend in part upon tissue type and actions at ERs subtypes, ERα and ERβ, which are differentially distributed across the body and brain. In the prostate, ERβ is highly expressed in epithelial cells. Although ERα is localized in the stroma, ERα also has been found in premalignant and malignant epithelium of the prostate. In the brain, ERβ expression predominates in hippocampus and cortex, regions involved in cognition and affect. ERβ knockout mice have prostate hyperplasia in aging, suggesting a potential inhibitory role of ERβ for prostate growth [21, 22]. However, the stress reducing, cognitive and affective behavior enhancing effects likely occur through actions at ERβ as male mice or rats have greater responses to androgens that have actions at ERβ and ERβ knockout mice show reductions in these cognitive and affective responses [17]. Mice with the tfm mutation, rendering ARs non-functional, respond better than do wildtype mice to administration of 3α-diol for anti-depressive behavior in the forced swim test (**Figure 9**). Thus, trophic effects of androgens in the brain and body may be dissociable and involve different targets beyond the traditional target of androgens, the ARs.

#### **Figure 9.**

*Tfm and ER*β *knockout mice show more depressive-like behavior than do wildtype mice, an effect that can be reversed by administration of 3α-diol in the forced swim.*
