Abstract
This review aims to elucidate the possible effects of phosphodiesterase-5 (PDE5) inhibitors on sperm functions. PDEs hydrolyze cyclic nucleotides, and together with adenylyl and guanylyl cyclase, which catalyze the formation of cAMP and cGMP, regulate the levels of these second messengers in cells. cGMP-specific PDE5 is one of the PDEs that have been intensively studied because of its fundamental pharmacological relevance, as oral PDE5 inhibitors are used successfully in treating erectile dysfunction. In addition, they have shown diverse beneficial actions in different disease categories. Specific relevance of the cGMP system in reproductive functions has been recently proposed. Its use was shown to be devoid of effects on semen volume, concentration, sperm membrane integrity or sperm penetration assay. Most available studies demonstrated a significant increase in sperm motility and viability both in vivo and in vitro, which seems to be enhanced at low doses and reduced at high concentrations. Also, these molecules showed a role in capacitation and a debated one concerning acrosome reaction. However, due to the relative short period since the launching of oral PDE5 inhibitors, more investigations should be carried out in wider scales to assess their effect(s) on variant sperm function that could be beneficial as potential therapeutic approaches.
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References
Fawcett L, Baxendale R, Stacey P, McGrouther C, Harrow I, Soderling S et al. Molecular cloning and characterization of a distinct human phosphodiesterase gene family: PDE11A. Proc Natl Acad Sci USA 2000; 97: 3702–3707.
Zhang KY, Card GL, Suzuki Y, Artis DR, Fong D, Gillette S et al. A glutamine switch mechanism for nucleotide selectivity by phosphodiesterases. Mol Cell 2004; 15: 279–286.
Soderling SH, Beavo JA . Regulation of cAMP and cGMP signaling: new phosphodiesterases and new functions. Curr Opin Cell Biol 2000; 12: 174–179.
Blount MA, Beasley A, Zoraghi R, Sekhar KR, Bessay EP, Francis SH et al. Binding of tritiated sildenafil, tadalafil, or vardenafil to the phosphodiesterase-5 catalytic site displays potency, specificity, heterogeneity, and cGMP stimulation. Mol Pharmacol 2004; 66: 144–152.
Zoraghi R, Corbin JD, Francis SH . Properties and functions of GAF domains in cyclic nucleotide phosphodiesterases and other proteins. Mol Pharmacol 2004; 65: 267–278.
Sadovsky R, Miller T, Moskowitz M, Hackett G . Three-year update of sildenafil citrate (Viagra) efficacy and safety. Int J Clin Pract 2001; 55: 115–128.
Sommer F, Schulze W . Treating erectile dysfunction by endothelial rehabilitation with phosphodiesterase 5 inhibitors. World J Urol 2005; 23: 385–392.
Oudiz RJ, Roveran G, Hansen JE, Sun XG, Wasserman K . Effect of sildenafil on ventilatory efficiency and exercise tolerance in pulmonary hypertension. Eur J Heart Fail 2007; 9: 917–921.
Friedman EA, Harris PA, Wood AJ, Stein CM, Kurnik D . The effects of tadalafil on cold-induced vasoconstriction in patients with Raynaud's phenomenon. Clin Pharmacol Ther 2007; 81: 503–509.
Fox M, Sweis R, Wong T, Anggiansah A . Sildenafil relieves symptoms and normalizes motility in patients with oesophageal spasm: a report of two cases. Neurogastroenterol Motil 2007; 19: 798–803.
McVary KT, Roehrborn CG, Kaminetsky JC, Auerbach SM, Wachs B, Young JM et al. Tadalafil relieves lower urinary tract symptoms secondary to benign prostatic hyperplasia. J Urol 2007; 177: 1401–1407.
Middendorff R, Davidoff MS, Behrends S, Mewe M, Miethens A, Müller D . Multiple roles of the messenger molecule cGMP in testicular function. Andrologia 2000; 32: 55–59.
Bender AT, Beavo JA . Cyclic nucleotide phosphodiesterases: molecular regulation to clinical use. Pharmacol Rev 2006; 58: 488–520.
Fujishige K, Kotera J, Michibata H, Yuasa K, Takebayashi S, Okumura K et al. Cloning and characterization of a novel human phosphodiesterase that hydrolyzes both cAMP and cGMP (PDE10A). J Biol Chem 1999; 274: 18438–18445.
Scipioni A, Stefanini S, Santone R, Giorgi M . Immunohistochemical localisation of PDE5 in Leydig and myoid cells of prepubertal and adult rat testis. Histochem Cell Biol 2005; 124: 401–407.
Mewe M, Bauer CK, Müller D, Middendorff R . Regulation of spontaneous contractile activity in the bovine epididymal duct by cyclic GMP-dependent pathways. Endocrinology 2006; 147: 2051–2062.
Francis SH . Phosphodiesterase 11 (PDE11): is it a player in human testicular function? Int J Impot Res 2005; 17: 467–468.
Weeks JL, Zoraghi R, Beasley A, Sekhar KR, Francis SH, Corbin JD . High biochemical selectivity of tadalafil, sildenafil and vardenafil for human phosphodiesterase 5A1 (PDE5) over PDE11A4 suggests the absence of PDE11A4 cross-reaction in patients. Int J Impot Res 2005; 17: 5–9.
Dimitriadis F, Giannakis D, Pardalidis N, Zikopoulos K, Paraskevaidis E, Giotitsas N et al. Effects of phosphodiesterase-5 inhibitors on sperm parameters and fertilizing capacity. Asian J Androl 2008; 10: 115–133.
Fisch JD, Behr B, Conti M . Enhancement of motility and acrosome reaction in human spermatozoa: differential activation by type-specific phosphodiesterase inhibitors. Hum Reprod 1998; 13: 1248–1254.
Lefièvre L, de Lamirande E, Gagnon C . Presence of cyclic nucleotide phosphodiesterases PDE1A, existing as a stable complex with calmodulin, and PDE3A in human spermatozoa. Biol Reprod 2002; 67: 423–430.
Richter W, Dettmer D, Glander H . Detection of mRNA transcripts of cyclic nucleotide phosphodiesterase subtypes in ejaculated human spermatozoa. Mol Hum Reprod 1999; 5: 732–736.
Cheng CY, Boettcher B . Partial characterization of human spermatozoal phosphodiesterase and adenylate cyclase and the effect of steroids on their activities. Int J Androl 1982; 5: 253–266.
Aversa A, Mazzilli F, Rossi T, Delfino M, Isidori AM, Fabbri A . Effects of sildenafil (Viagra) administration on seminal parameters and post-ejaculatory refractory time in normal males. Hum Reprod 2000; 15: 131–134.
Purvis K, Muirhead GJ, Harness JA . The effects of sildenafil on human sperm function in healthy volunteers. Br J Clin Pharmacol 2002; 53 (Suppl 1): 53S–60S.
Jannini EA, Lombardo F, Salacone P, Gandini L, Lenzi A . Treatment of sexual dysfunctions secondary to male infertility with sildenafil citrate. Fertil Steril 2004; 81: 705–707.
du Plessis SS, de Jongh PS, Franken DR . Effect of acute in vivo sildenafil citrate and in vitro 8-bromo-cGMP treatments on semen parameters and sperm function. Fertil Steril 2004; 81: 1026–1033.
Hellstrom WJ, Overstreet JW, Yu A, Saikali K, Shen W, Beasley Jr CM et al. Tadalafil has no detrimental effect on human spermatogenesis or reproductive hormones. J Urol 2003; 170: 887–891.
Ali ST, Rakkah NI . Neurophysiological role of sildenafil citrate (Viagra) on seminal parameters in diabetic males with and without neuropathy. Pak J Pharm Sci 2007; 20: 36–42.
Grammeniatis E, Kanakas N, Tsounapi P, Baltogiannis D, Miyagawa I, Sofikitis N . Effects of vardenafil in sperm parameters and semen biochemistry. 32nd Annual Meeting of American Society of Andrology, 21–25 April, Tampa, USA. J Androl (Suppl) 2007; 28: 60.
Jarvi K, Dula E, Drehobl M, Pryor J, Shapiro J, Seger M . Daily vardenafil for 6 months has no detrimental effects on semen characteristics or reproductive hormones in men with normal baseline levels. J Urol 2008; 179: 1060–1065.
Tur-Kaspa I, Segal S, Moffa F, Massobrio M, Meltzer S . Viagra for temporary erectile dysfunction during treatments with assisted reproductive technologies. Hum Reprod 1999; 14: 1783–1784.
Kalsi JS, Bahadur G, Muneer A, Ozturk O, Christopher N, Ralph DJ et al. Novel PDE5 inhibitors for the treatment of male erectile dysfunction. Reprod Biomed Online 2003; 7: 456–461.
Kaplan B, Ben-Rafael Z, Peled Y, Bar-Hava I, Bar J, Orvieto R . Oral sildenafil may reverse secondary ejaculatory dysfunction during infertility treatment. Fertil Steril 1999; 72: 1144–1145.
Lenzi A, Lombardo F, Salacone P, Gandini L, Jannini EA . Stress, sexual dysfunctions, and male infertility. J Endocrinol Invest 2003; 26: 72–76.
Lanzafame F, Chapman MG, Guglielmino A, Gearon CM, Forman RG . Pharmacological stimulation of sperm motility. Hum Reprod 1994; 9: 192–199.
Nassar A, Morshedi M, Mahony M, Srisombut C, Lin MH, Oehninger S . Pentoxifylline stimulates various sperm motion parameters and cervical mucus penetrability in patients with asthenozoospermia. Andrologia 1999; 31: 9–15.
Bajpai M, Fiedler SE, Huang Z, Vijayaraghavan S, Olson GE, Livera G et al. AKAP3 selectively binds PDE4A isoforms in bovine spermatozoa. Biol Reprod 2006; 74: 109–118.
Cai ZM, Gui YT, Guo LD, Zhang LB, Zhang JR, Wang H et al. Functional expression of adenylyl cyclase and phosphodiesterase in ejaculated human spermatozoa. Zhonghua Nan Ke Xue 2006; 12: 195–198.
Yunes R, Fernández P, Doncel GF, Acosta AA . Cyclic nucleotide phosphodiesterase inhibition increases tyrosine phosphorylation and hyper motility in normal and pathological human spermatozoa. Biocell 2005; 29: 287–293.
Lefièvre L, De Lamirande E, Gagnon C . The cyclic GMP-specific phosphodiesterase inhibitor, sildenafil, stimulates human sperm motility and capacitation but not acrosome reaction. J Androl 2000; 21: 929–937.
Pomara G, Morelli G, Canale D, Turchi P, Caglieresi C, Moschini C et al. Alterations in sperm motility after acute oral administration of sildenafil or tadalafil in young, infertile men. Fertil Steril 2007; 88: 860–865.
Sofikitis N, Miyagawa I . Endocrinological, biophysical, and biochemical parameters of semen collected via masturbation versus sexual intercourse. J Androl 1993; 14: 366–373.
Andrade JR, Traboulsi A, Hussain A, Dubin NH . In vitro effects of sildenafil and phentolamine, drugs used for erectile dysfunction, on human sperm motility. Am J Obstet Gynecol 2000; 182: 1093–1095.
Cuadra DL, Chan PJ, Patton WC, Stewart SC, King A . Type 5 phosphodiesterase regulation of human sperm motility. Am J Obstet Gynecol 2000; 182: 1013–1015.
Glenn DR, McVicar CM, McClure N, Lewis SE . Sildenafil citrate improves sperm motility but causes a premature acrosome reaction in vitro. Fertil Steril 2007; 87: 1064–1070.
Burger M, Sikka SC, Bivalacqua TJ, Lamb DJ, Hellstrom WJ . The effect of sildenafil on human sperm motion and function from normal and infertile men. Int J Impot Res 2000; 12: 229–234.
Mostafa T . Tadalafil as an in vitro sperm motility stimulant. Andrologia 2007; 39: 12–15.
Mostafa T . In vitro sildenafil citrate use as a sperm motility stimulant. Fertil Steril 2007; 88: 994–996.
Carr DW, Fujita A, Stentz CL, Liberty GA, Olson GE, Narumiya S . Identification of sperm-specific proteins that interact with A-kinase anchoring proteins in a manner similar to the type II regulatory subunit of PK-A. J Biol Chem 2001; 276: 17332–17338.
Burton KA, Treash-Osio B, Muller CH, Dunphy EL, McKnight GS . Deletion of type IIa regulatory subunit delocalizes protein kinase A in mouse sperm without affecting motility or fertilization. J Biol Chem 1999; 274: 24131–24136.
Fournier V, Leclerc P, Cormier N, Bailey JL . Implication of calmodulin-dependent phosphodiesterase type 1 during bovine sperm capacitation. J Androl 2003; 24: 104–112.
Baxendale RW, Fraser LR . Mammalian sperm phosphodiesterases and their involvement in receptor-mediated cell signaling important for capacitation. Mol Reprod Dev 2005; 71: 495–508.
Lefièvre L, Jha KN, de Lamirande E, Visconti PE, Gagnon C . Activation of protein kinase A during human sperm capacitation and acrosome reaction. J Androl 2002; 23: 709–716.
Revelli A, Ghigo D, Moffa F, Massobrio M, Tur-Kaspa I . Guanylate cyclase activity and sperm function. Endocr Rev 2002; 23: 484–494.
Sofikitis N, Miyagawa I, Toda T, Terakawa N . Effects of an inhibitor of adenylate cyclase on acrosome reaction induced by protein kinase C activators. Arch Androl 1993; 30: 87–92.
Rosselli M, Dubey RK, Imthurn B, Macas E, Keller PJ . Effects of nitric oxide on human spermatozoa: evidence that nitric oxide decreases sperm motility and induces sperm toxicity. Hum Reprod 1995; 10: 1786–1790.
Nobunaga T, Tokugawa Y, Hashimoto K, Kubota Y, Sawai K, Kimura T et al. Elevated nitric oxide concentration in the seminal plasma of infertile males: nitric oxide inhibits sperm motility. Am J Reprod Immunol 1996; 36: 193–197.
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Mostafa, T. Oral phosphodiesterase-5 inhibitors and sperm functions. Int J Impot Res 20, 530–536 (2008). https://doi.org/10.1038/ijir.2008.29
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DOI: https://doi.org/10.1038/ijir.2008.29