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

Abstract

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 10(7) molecules/microg 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 IC(50) for sildenafil (IC(50) = 2.16 +/- 0.62 nm). In control CC strips, sildenafil dose-dependently increased relaxation induced by electrical field stimulation, with EC(50) = 3.42 +/- 1.7 nm. Hypogonadism reduced, and T increased, sildenafil effect on electrical field stimulation, again without changing their relative EC(50) 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.

Influence of serum testosterone on urinary continence and sexual activity in patients undergoing radical prostatectomy for clinically localized prostate cancer

“…24,25 As T positively controls both the initiation (nitric oxide synthase) and the end (PDE5) of the erectile process, its net effect on erection is modest. Hence, erections are still possible in hypogonadal conditions, in which a decreased cyclic guanosine monophosphate formation, owing to impaired nitric oxide production, is most probably counterbalanced by a reduced PDE5 activity and cyclic guanosine monophosphate hydrolysis.…”

“…14 IIEF was used to better define the erectile function. The possible scores for the IIEF-5 range from 5 to 25, and ED was classified into five categories based on the scores: severe (5-7), moderate (8)(9)(10)(11), mild to moderate (12)(13)(14)(15)(16), mild (17)(18)(19)(20)(21) and no ED (22)(23)(24)(25). 15 …”

The Princeton III Consensus Recommendations for the Management of Erectile Dysfunction and Cardiovascular Disease

“…41 Testosterone is a key central and peripheral modulator of erectile function in animal studies. [42][43][44][45] Consistent with these observations, a single-center study of 1050 men seeking new consultation for sexual dysfunction found that 36% had hypogonadism. 46 Buvat and Bou Jaoude, 47 in a compilation of data from 7000 men with ED in 9 large series, reported serum testosterone levels less than 300 ng/dL (to convert to nmol/L, multiply by 0.0347) in 12%, including 4% before and 15% after age 50 years.…”

Effect of sildenafil administration on penile hypoxia induced by cavernous neurotomy in the rat

“…Sildenafil is a well-known inhibitor of PDE5, the major enzymes involved in cyclic guanosine monophosphate (cGMP) breakdown in the penis. 37 Its ability in limiting in a very short time frame BCN-induced penile hypoxia might be related to its effect on PDE5, although other mechanisms of action, independent from PDE5 inhibition, cannot be ruled out. It is interesting to note that similar results on penile oxygenation were previously obtained with a prolonged and continuous exposure to another chemically unrelated PDE5i, tadalafil.…”