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Androgens Regulate Phosphodiesterase Type 5 Expression and Functional Activity in Corpora Cavernosa

Andrology Unit (A.M., S.F., R.M., M.L., L.V., G.F., Ma.M.) and Clinical Biochemistry (C.O.), Department of Clinical Physiopathology, Department of Anatomy, Histology and Forensic Medicine (Mi.M., G.B.V.), Department of Urology (A.N.), Department of Pharmacology (F.L.), University of Florence, Florence 50139, Italy; Chair of Internal Medicine III (A.A.), Department of Physiopathology, University of Rome "La Sapienza," Rome 00100, Italy; and Department of Experimental Medicine (M.G., E.A.J.), University of L’Aquila, 67100 L’Aquila, Italy

Address all correspondence and requests for reprints to: Mario Maggi, M.D., Andrology Unit, Department of Clinical Physiopathology, University of Florence, V.le G. Pieraccini, 6, 50139 Florence, Italy. E-mail: m.maggi{at}dfc.unifi.it.

By real-time RT-PCR and Western blot analysis, we found that phosphodiesterase type 5 (PDE5) mRNA and protein abundance was several fold higher in human male than in female reproductive tracts. The highest mRNA level (>1 x 10⁷ molecules/µg total RNA) was detected in human corpora cavernosa (CC), where PDE5 protein was immunolocalized in both muscular and endothelial compartment. The possible role of androgens in regulating PDE5 expression was studied using a previously established rabbit model of hypogonadotropic hypogonadism. In this model, hypogonadism reduced, and testosterone (T) supplementation restored, CC PDE5 gene and protein expression. In addition, T supplementation completely rescued and even enhanced cyclic GMP conversion to metabolites, without changing IC₅₀ for sildenafil (IC₅₀ = 2.16 ± 0.62 nM). In control CC strips, sildenafil dose-dependently increased relaxation induced by electrical field stimulation, with EC₅₀ = 3.42 ± 1.7 nM. Hypogonadism reduced, and T increased, sildenafil effect on electrical field stimulation, again without changing their relative EC₅₀ values. CC sensitivity to the NO-donor NCX4040 was greater in hypogonadal rabbit strips than in control or T-treated counterparts. Moreover, sildenafil enhanced NCX4040 effect in eugonadal rabbit strips but not in hypogonadal ones. This suggests that androgens up-regulate PDE5 in rabbit penis. We also measured PDE5 gene expression and metabolic activity in human CC from male-to-female transsexual individuals, chronically treated with estrogens and cyproterone acetate. Comparing the observed values vs. eugonadal controls, PDE5 mRNA, protein, and functional activity were significantly reduced. In conclusion, we demonstrated, for the first time, that androgens positively regulate PDE5, thus providing a possible explanation about the highest abundance of this enzyme in male genital tract.

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