[Frontiers in Bioscience 1, d59-71, March 1, 1996]


Evan T. Keller, William B. Ershler, and Chawnshang Chang

The Institute on Aging and the Department of Human Oncology, University of Wisconsin, Madison, WI 53706, USA.

Received 01/16/96; Accepted 02/22/96; On-line 03/01/96

5. Why are there two androgens (Testosterone and Dihydrotestosterone) active on one androgen receptor?

T and DHT mediate their effects by altering gene expression in target tissues via a single receptor, the AR. Despite the binding of T and DHT to a single receptor, the effect of these hormones on a single gene may be quite distinct. For example, differential regulatory effects of T and DHT on expression of several genes including Far-17a (84), and the cytokines interleukin-4 (IL-4), IL-5 and g-interferon (gIFN) has been reported (85). The observation that both T and DHT can differentially regulate the expression of the androgen responsive genes has led to the controversial idea that more than one AR may exist. This hypothesis is supported by the following observations (reviewed in (86)) : (1) (3H)T, when injected into rats, concentrates in the hypothalamic nuclei and 100x unlabeled DHT does not inhibit this localization; (2) hypothalamic localization is not observed after injection of (3H)DHT; and (3) the ability of T, but not DHT to induce neuronal proliferation or male sexual behavior in castrated male rats. These data are consistent with two different possibilities. One possibility is that two different androgen receptors indeed exist. On the other hand, these data may be due to different metabolic interactions of the androgens on a single androgen receptor. As discussed above, T dissociates from the AR 3 times faster than DHT and is less effective in stabilizing the AR (74). This difference in the dissociation rate has been directly related to the androgens' ability to stimulate transcription of an androgen responsive gene (87). These observations could account for the differential effects of these androgens mediated by one receptor.

Perhaps the strongest evidence for the presence of one androgen receptor is derived from the observation that genotypic XY mice and rats with testicular feminization syndrome (Tfm) do not have a fully functional AR (87-90) and even though they express both T and DHT they develop into phenotypic females. This experiment of nature demonstrates that loss of one AR can result in loss of action of both androgens.

The presence of two androgens acting on one receptor may serve several possible functions. Cells which contain steroid 5a-reductase can convert T into DHT. Thus, the overall effect of this system may be to amplify the action of T via conversion to DHT within these cells, thus providing a mechanism of local regulation.

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