Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, San Francisco, CA94143-0738, USA.
Int J Impot Res. 2013 May;25(3):81-5. doi: 10.1038/ijir.2013.11. Epub 2013 Mar 14.
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.
磷酸二酯酶-5（PDE5）的抑制作用是治疗勃起功能障碍（ED）的有效机制。雄激素补充疗法也被用于治疗 ED。然而，人们广泛认为雄激素可以上调 PDE5 的表达，从而产生了一个悖论，即勃起功能的正调节剂（雄激素）可能会增加负调节剂（PDE5）的水平。为了解决这个悖论，我们系统地检索了 PubMed，并在互联网上进行了非系统性检索，使用 PDE5、勃起、阴茎、睾丸酮和雄激素作为关键词。检索到的论文分析了雄激素对 PDE5 表达和调节的数据。从 GenBank 中检索到人和大鼠 PDE5A 基因序列，并进行计算机分析。结果表明，在一项人类 PDE5A 基因启动子研究中报道了一个假定的雄激素反应元件（ARE），这促使人们对雄激素是否调节 PDE5 表达进行了单独研究。后者的阳性结果此后被 17 篇综述和社论文章引用为雄激素治疗 ED 作用的潜在机制。此外，另外 5 项研究也得出了相同的结论。另一方面，两项关于雄激素调节基因的全基因组搜索的独立研究没有发现 PDE5A 是候选基因。本研究进行的序列分析也未能在大鼠 PDE5A 基因中发现 ARE。两项关于间质细胞的独立研究也未能发现雄激素对 PDE5 表达的正向调节。另外两项研究发现去势大鼠海绵体平滑肌和 PDE5 表达同时减少。其中一项研究还发现雄激素对培养的海绵体平滑肌细胞中 PDE5 的表达没有影响。因此，去势动物中 PDE5 表达减少似乎是由于平滑肌含量减少所致，并且 PDE5A 基因不是直接受雄激素调节的。
