International Journal of Impotence Research (2005) 17, 385–386 & 2005 Nature Publishing Group All rights reserved 0955-9930/05 $30.00 www.nature.com/ijir Letter to the Editor Inhibition of phosphodiesterase 11 (PDE11) impacts on sperm quality Comment on ‘High biochemical selectivity of tadalafil, sildenafil and vardenafil for human phosphodies- terase 5A1 (PDE5) over PDE11A4 suggests the absence of PDE11A4 cross-reaction in patients.’ by Weeks JL, Zoraghi R, Beasley A, Sekhar KR, Francis SH, Corbin JD. (Int J Impot Res 2004 Nov 11 [Epub ahead of print]). G Pomara1* and G Morelli1 1Section of Urology, Department of Surgery, S Chiara Hospital, Pisa University, Italy International Journal of Impotence Research (2005) 17, 385–386. doi:10.1038/sj.ijir.3901304 There is a growing interest worldwide in under- tadalafil is a nonspecific PDE11A4 inhibitor, we believe standing potential crossreaction of PDE5 inhibitors that for safety purpose we should consider the possible with other proteins and we agree with the authors crossreaction with all the four human PDE11 variants. that PDE11 is one of the obvious candidates, since it This global evaluation may provide the highest thera- is closely related to the PDE5. Weeks et al should be peutic benefits/undesirable side effects ratio. For these congratulated because, comparing the potencies of reasons, we do not believe that all safety issues on tadalafil, vardenafil and sildenafil for PDE11A4 and tadalafil crossreaction with PDE11 are satisfied. the fold selectivity of these inhibitors for PDE5A1 Within human PDE11A family, the alternatively over PDE11A4, they provide several important spliced isoforms display unique tissue expression information for safety issues. and specificity.3 We focused our attention on the conclusions of PDE11A4 is expressed in the prostate gland and the authors. Whereas we perfectly agree that ‘the unlikely it could be related to the tadalafil-related fold selectivity for PDE5 over PDE11A4 for sildenafil side effects, back-pain and alteration of sperm quality. (1000-fold selectivity) and vardenafil (9000-fold PDE11A1 is predominantly present in skeletal selectivity) reveals that these drugs are very unlikely muscle and, as the authors remember, there are to crossreact with PDE11A4 in patients treated with studies reporting a low selectivity (five-fold) of these medications’,1 on the contrary, we would tadalafil for PDE5 over PDE11A1.2 This enzyme suggest caution concerning the newest PDE-5 in- and its inhibition could account for the back pain, hibitor tadalafil. In fact, the 40-fold selectivity ratio reported by some men taking tadalafil. In our of tadalafil for PDE5 over PDE11A4, found in this opinion, the ‘back-pain’, ‘specific pain felt in the study, significantly lower than those reported with low or upper back’, should be considered a tadalafil- the other two drugs, is nearly the same of that specific-side effect, more than ‘myalgia’, ‘pain in a reported for sildenafil over PDE1 (41-fold). In this nonspecific muscle’, which has been reported even case, it has been suggested that the 41-fold selectiv- with sildenafil or vardenafil. ity of sildenafil for PDE5 over PDE1 may induce We have not many information on PDE11A2, but vasodilatation, flushing and tachycardia.2 its transcripts were detected in various tissues Moreover, Weeks et al studied and gave informa- including brain, lung, skeletal muscle, spleen, testis tion only on PDE11A4, which is one among four of and prostate.3 the identified human PDE11A splice variants. PDE11A3 is present predominantly in the testes Probably ‘PDE11A4, containing the most extensive and its inhibition could produce alteration in the regulatory domain structure, is highly regulated and quality of sperm of some patients taking tadalafil. plays an important physiological role’,1 but, since This hypothesis is consistent with the results of our preliminary report, which investigate for the first time the effect of tadalafil administration on men with fertility problems. Tadalafil, compared to the *Correspondence: G Pomara, Section of Urology, Depart- baseline, caused a statistically significant decrease ment of Surgery, S Chiara Hospital, Via Cervino, 6, 56100 of spermatozoa with rapid progressive motility 4 Pisa University, Italy. (12.3%72.2 vs 9%71.9 (Po0.05)). Moreover, E-mail: [email protected] surprisingly our results are comparable with those Letter to the Editor 386 reported in mice knock out for the PDE11. ‘Ejaculated (PDE5) over PDE11A4 suggests the absence of PDE11A4 cross- sperm from PDE11KO mice had a reduced rate of for- reaction in patients. Int J Impot Res 2004 Nov 11 [Epub ahead ward progression compared with WT mice (range ¼ 1 of print]. 7 7 5 2 Bischoff E. Potency, selectivity, and consequences of non- (low) to 4 (high); 2.2 0.2 vs 2.9 0.1, Po0.05),’. selectivity of PDE inhibition. Int J Impot Res. 2004; 16(Suppl 1): In light of these findings, we believe that PDE11 S11–S14. inhibition impacts on sperm quality. Reasonable 3 Yuasa K et al. Identification of rat cyclic nucleotide phospho- caution should be suggested in patients taking the diesterase 11A (PDE11A). Comparison of rat and human PDE11A splicing variants. Eur J Biochem 2001; 268: prescribed dosages of tadalafil, the only PDE5 4440–4448. inhibitor to date which could crossreact with human 4 Pomara G et al. Effect of acute in vivo sildenafil or tadalafil PDE11A splicing variants. treatments on semen parameters in patients with fertility problem, a randomized, double-blind, crossover study. Oral Communication. 7th Congress of the European Society for References Sexual Medicine. London, December 2004. 5 Wayman C et al. Ablation of phosphodiesterase 11 (PDE11) impacts sperm physiology. Oral Communication. 7th Congress 1 Weeks JL et al. High biochemical selectivity of tadalafil, of the European Society for Sexual Medicine. London, sildenafil and vardenafil for human phosphodiesterase 5A1 December 2004. International Journal of Impotence Research.