Dihydrotestosterone may inhibit hypothalamo-pituitary-adrenal activity by acting through estrogen receptor in the male mouse

The corticosterone (CORT) response to environmental perturbation has been shown to be enhanced by estrogen but inhibited by the androgen dihydrotestosterone (DHT). However, the mechanism of androgen's action has not been identified. This study examined the effects of estradiol benzoate (EB), the non-aromatizable androgen DHT, and the DHT metabolite 5α-androstan- 3β, 17β-diol (3β-diol) on the corticosterone response to stress. Adult male CBB6/F1 mice were gonadectomized and injected subcutaneously (once a day for 4 days) with the above compounds (controls received oil vehicle injections). Animals (within treatments) were randomly assigned to stress or non-stress conditions. The non-stress animals were taken directly from their home cages and killed. Animals were stressed by a 30 min restraint prior to being killed. Hormone levels were determined in plasma via radioimmunoassay. In agreement with previous studies, the CORT response to immobilization was enhanced by EB and inhibited by DHT. Surprisingly, 3β-diol inhibited the CORT response similar to the effect of DHT. In a second study, concomitant injections of the androgen receptor antagonist flutamide only partially blocked DHT's, but had no effect on 3β-diol's, inhibitory action. In contrast, injections with the estrogen receptor antagonist tamoxifen completely blocked the effects of 3β-diol and partially blocked DHT's effect. Taken together these studies suggest that DHT's inhibitory effects may be, at least in part, via the estrogen receptor, through its conversion to 3β-diol. These studies also suggest that the DHT metabolites may be functionally relevant when considering hormonal responses to stress.