Inhibition of
phosphodiesterase-5 (PDE5) is a well-known mechanism for the effective treatment of
erectile dysfunction (ED).
Androgen supplementation has also been prescribed for treating ED. However, it has been widely accepted that
androgen can upregulate PDE5 expression, and thus creating a paradox in which a positive regulator of erectile function (
androgen) could possibly increase the level of a negative regulator (PDE5). To solve this paradox, we conducted a systematic search of the PubMed and a non-systematic search of the Internet using PDE5, erectile, penis,
testosterone and
androgen as keywords. The retrieved papers were analyzed for data concerning the expression and regulation of PDE5 by
androgens. Human and rat PDE5A gene sequences were retrieved from GenBank and computer-analyzed. The results showed that a putative
androgen-response element (ARE) was reported in a study of human PDE5A gene promoter, and this prompted a separate study on whether
androgen regulates PDE5 expression. The positive outcome in the latter study has since been cited in 17 review and editorial articles as the underlying mechanism for
androgen's
therapeutic effects on ED. In addition, five other research studies also reached the same conclusion. On the other hand, two independent studies on the genome-wide searches for
androgen-regulated genes did not find PDE5A as a candidate. Sequence analysis conducted in this study also failed to find ARE in rat PDE5A gene. Two independent studies on Leydig cells also failed to find positive regulation of PDE5 expression by
androgen. Two other studies found concomitant reduction of cavernous smooth muscle and PDE5 expression in castrated rats. One of these studies also found no effect of
androgen on PDE5 expression in cultured cavernous smooth muscle cells. Thus, it appears that reduced PDE5 expression in castrated animals is due to reduced smooth muscle content and that PDE5A gene is not directly regulated by
androgens.