Current and emerging medical therapeutic agents for idiopathic male infertility

References

• Zegers-Hochschild F, Adamson GD, Dyer S, et al. The International glossary on infertility and fertility care, 2017. Hum Reprod. 2017;1(32):1786–1801.
   Google Scholar
• Vander Borght M, Wyns C. Fertility and infertility: definition and epidemiology. Clin Biochem. 2018. published online. 2018 Mar 16. DOI: 10.1016/j.clinbiochem.2018.03.012
   PubMed Web of Science ®Google Scholar
• Hamada AJ, Montgomery B, Agarwal A. Male infertility: a critical review of pharmacologic management. Expert Opin Pharmacother. 2012;13:2511–2531.
   PubMed Web of Science ®Google Scholar
• Tournaye H, Krausz C, Oates RD. Novel concepts in the aetiology of male reproductive impairment. Lancet Diabetes Endocrinol. 2017;5:544–553.
   PubMed Web of Science ®Google Scholar
• Cissen M, Bensdorp A, Cohlen BJ, et al. Assisted reproductive technologies for male subfertility. Cochrane Database Syst Rev. 2016;2:CD000360.
   PubMedGoogle Scholar
• Turner D, Turner EA, Aparicio NJ, et al. Response of luteinizing hormone and follicle-stimulating hormone to different doses of D-leucine-6-LH-RH ethylamide in oligospermic patients. Fertil Steril. 1976;27:545–548.
   PubMed Web of Science ®Google Scholar
• Chehval MJ, Mehan DJ. Chorionic gonadotropins in the treatment of the subfertile male. Fertil Steril. 1979;31:666–668.
   PubMed Web of Science ®Google Scholar
• Alexandre C. Study of 13 cases of ostensibly idiopathic male infertility treated successfully by HMG/HCG combination. Sem Hop. 1978;54:633–636.
   PubMedGoogle Scholar
• Pescosolido D, Curatola A, Gentili S, et al. A new gonadotropin treatment for idiopathic moderate oligoasthenospermia. Acta Eur Fertil. 1985;16:129–132.
   PubMedGoogle Scholar
• Iacono F, Barra S, Montano L, et al. Value of high-dose pure FSH in the treatment of idiopathic male infertility. J Urol. 1996;102:81–84.
   Google Scholar
• Foresta C, Bettella A, Merico M, et al. Use of recombinant human follicle-stimulating hormone in the treatment of male factor infertility. Fertil Steril. 2002;77:238–244.
   PubMed Web of Science ®Google Scholar
• Santi D, Simoni M. Biosimilar recombinant follicle stimulating hormones in infertility treatment. Expert Opin Biol Ther. 2014;14:1399–1409.
   PubMed Web of Science ®Google Scholar
• Chehab M, Madala A, Trussell JC. On-label and off-label drugs used in the treatment of male infertility. Fertil Steril. 2015;103:595–604.
   PubMed Web of Science ®Google Scholar
• de Kretser DM, Loveland KL, Meinhardt A, et al. Spermatogenesis. Hum Reprod. 1998;13(Suppl 1):1–8.
   PubMedGoogle Scholar
• Sluka P, O’Donnell L, Bartles JR, et al. FSH regulates the formation of adherens junctions and ectoplasmic specialisations between rat Sertoli cells in vitro and in vivo. J Endocrinol. 2006;189:381–395.
   PubMed Web of Science ®Google Scholar
• Dimitriadis F, Tsiampali C, Chaliasos N, et al. The Sertoli cell as the orchestra conductor of spermatogenesis: spermatogenic cells dance to the tune of testosterone. Hormones. 2015;14:479–503.
   PubMedGoogle Scholar
• Boehm U, Bouloux PM, Dattani MT, et al. Expert consensus document: European Consensus Statement on congenital hypogonadotropic hypogonadism–pathogenesis, diagnosis and treatment. Nat Rev Endocrinol. 2015;11:547–564.
   PubMed Web of Science ®Google Scholar
• Barbonetti A, Calogero AE, Balercia G, et al. The use of follicle stimulating hormone (FSH) for the treatment of the infertile man: position statement from the Italian Society of Andrology and Sexual Medicine (SIAMS). J Endocrinol Invest. 2018. published online 2018 Feb 1. DOI:10.1007/s40618-018-0843-y.
   Web of Science ®Google Scholar
• Attia AM, Abou-Setta AM, Al-Inany HG. Gonadotrophins for idiopathic male factor subfertility. Cochrane Database Syst Rev. 2013;23:CD005071.
   Google Scholar
• Santi D, Granata AR, Simoni M. FSH treatment of male idiopathic infertility improves pregnancy rate: a meta-analysis. Endocr Connect. 2015;4:R46–R58.
   PubMed Web of Science ®Google Scholar
• Garolla A, Ghezzi M, Cosci I, et al. FSH treatment in infertile males candidate to assisted reproduction improved sperm DNA fragmentation and pregnancy rate. Endocrine. 2017;56:416–425.
   PubMed Web of Science ®Google Scholar
• Casamonti E, Vinci S, Serra E, et al. Short-term FSH treatment and sperm maturation: a prospective study in idiopathic infertile men. Andrology. 2017;5:414–422.
   PubMed Web of Science ®Google Scholar
• Barbotin AL, Ballot C, Sigala J, et al. Pregnancy after intracytoplasmic sperm injection following extended sperm preparation and hormone therapy in an azoospermic man with maturation arrest and microlithiasis: a case report and literature review. Andrologia 2017;49
   Google Scholar
• Cocci A, Cito G, Russo GI, et al. Effectiveness of highly purified urofollitropin treatment in patients with idiopathic azoospermia before testicular sperm extraction. Urologia. 2018;85:19–21.
   PubMed Web of Science ®Google Scholar
• Colacurci N, Monti MG, Fornaro F, et al. Recombinant human FSH reduces sperm DNA fragmentation in men with idiopathic oligoasthenoteratozoospermia. J Androl. 2012;33:588–593.
   PubMedGoogle Scholar
• Simoni M, Santi D, Negri L, et al. Treatment with human, recombinant FSH improves sperm DNA fragmentation in idiopathic infertile men depending on the FSH receptor polymorphism p.N680S: a pharmacogenetic study. Hum Reprod. 2016;31:1960–1969.
   PubMed Web of Science ®Google Scholar
• Zwart-van Rijkom JE, Broekmans FJ, Leufkens HG. From HMG through purified urinary FSH preparations to recombinant FSH: a substitution study. Hum Reprod. 2002;17:857–865.
   PubMed Web of Science ®Google Scholar
• Ym D, Xj Z, Jp L, et al. Treatment of idiopathic oligozoospermia with recombinant human follicle-stimulating hormone: a prospective, randomized, double-blind, placebo-controlled clinical study in Chinese population. Clin Endocrinol. 2015;83:866–871.
   PubMed Web of Science ®Google Scholar
• Mastrangeli R, Satwekar A, Cutillo F, et al. In-vivo biological activity and glycosylation analysis of a biosimilar recombinant human follicle-stimulating hormone product (Bemfola) compared with its reference medicinal product (GONAL-f). PLoS One. 2017;12:e0184139.
   PubMed Web of Science ®Google Scholar
• Valenti D, La Vignera S, Condorelli RA, et al. Follicle-stimulating hormone treatment in normogonadotropic infertile men. Nat Rev Urol. 2013;10:55–62.
   PubMed Web of Science ®Google Scholar
• Simoni M, Gromoll J, Hoppner W, et al. Mutational analysis of the follicle-stimulating hormone (FSH) receptor in normal and infertile men: identification and characterization of two discrete FSH receptor isoforms. J Clin Endocrinol Metab. 1999;84:751–755.
   PubMed Web of Science ®Google Scholar
• Selice R, Garolla A, Pengo M, et al. The response to FSH treatment in oligozoospermic men depends on FSH receptor gene polymorphisms. Int J Androl. 2011;34:306–312.
   PubMedGoogle Scholar
• Grigorova M, Punab M, Ausmees K, et al. FSHB promoter polymorphism within evolutionary conserved element is associated with serum FSH level in men. Hum Reprod. 2008;23:2160–2166.
   PubMed Web of Science ®Google Scholar
• Ferlin A, Vinanzi C, Selice R, et al. Toward a pharmacogenetic approach to male infertility: polymorphism of follicle-stimulating hormone beta-subunit promoter. Fertil Steril. 2011;96:1344–1349.
   PubMed Web of Science ®Google Scholar
• Condorelli RA, Cannarella R, Calogero AE, et al. Evaluation of testicular function in prepubertal children. Endocrine. [ published on line 2018 Jul 7]. DOI:10.1007/s12020-018-1670-9
   PubMed Web of Science ®Google Scholar
• Rey RA, Musse M, Venara M, et al. Ontogeny of the androgen receptor expression in the fetal and postnatal testis: its relevance on Sertoli cell maturation and the onset of adult spermatogenesis. Microsc Res Tech. 2009;72:787–795.
   PubMed Web of Science ®Google Scholar
• Lee JA, Ramasamy R. Indications for the use of human chorionic gonadotropic hormone for the management of infertility in hypogonadal men. Transl Androl Urol. 2018;7:S348–S352.
   PubMed Web of Science ®Google Scholar
• Schaison G, Young J, Pholsena M, et al. Failure of combined follicle-stimulating hormone-testosterone administration to initiate and/or maintain spermatogenesis in men with hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 1993;77:1545–1549.
   PubMed Web of Science ®Google Scholar
• Vicari E, Mongioì A, Calogero AE, et al. Therapy with human chorionic gonadotrophin alone induces spermatogenesis in men with isolated hypogonadotrophic hypogonadism-long-term follow-up. Int J Androl. 1992;15:320–329.
   PubMed Web of Science ®Google Scholar
• La Vignera S, Condorelli RA, Cimino L, et al. Late-onset hypogonadism: the advantages of treatment with human chorionic gonadotropin rather than testosterone. Aging Male. 2016;19:34–39.
   PubMed Web of Science ®Google Scholar
• Coviello AD, Matsumoto AM, Bremner WJ, et al. Low-dose human chorionic gonadotropin maintains intratesticular testosterone in normal men with testosterone-induced gonadotropin suppression. J Clin Endocrinol Metab. 2005;90:2595–2602.
   PubMed Web of Science ®Google Scholar
• Hsieh TC, Pastuszak AW, Hwang K, et al. Concomitant intramuscular human chorionic gonadotropin preserves spermatogenesis in men undergoing testosterone replacement therapy. J Urol. 2013;189:647–650.
   PubMed Web of Science ®Google Scholar
• Krause W. The effect of intravenously administered human chorionic gonadotrophin on plasma testosterone in patients with sexual impotence and oligozoospermia. Int J Androl. 1980;3:251–255.
   PubMedGoogle Scholar
• Schill WB, Jüngst D, Unterburger P, et al. Combined hMG/hCG treatment in subfertile men with idiopathic normogonadotrophic oligozoospermia. Int J Androl. 1982;5:467–477.
   PubMedGoogle Scholar
• Mizutani M, Moriyama H, Sanda N, et al. Combined administration of human chorionic gonadotropin and human menopausal gonadotropin in idiopathic male infertility. Hinyokika Kiyo. 1987;33:51–54.
   PubMedGoogle Scholar
• Okuyama A, Nonomura N, Nakamura M, et al. Effectiveness of hMG-hCG treatment for DNA/RNA syntheses in subfertile human testis in vitro. Arch Androl. 1989;22: 167–7.
   Google Scholar
• Knuth UA, Hönigl W, Bals-Pratsch M, et al. Treatment of severe oligospermia with human chorionic gonadotropin/human menopausal gonadotropin: a placebo-controlled, double blind trial. J Clin Endocrinol Metab. 1987;65:1081–1087.
   PubMed Web of Science ®Google Scholar
• Shoshany O, Abhyankar N, Mufarreh N, et al. Outcomes of anastrozole in oligozoospermic hypoandrogenic subfertile men. Fertil Steril. 2017;107:589–594.
   PubMed Web of Science ®Google Scholar
• Tadros NN, Sabanegh ES. Empiric medical therapy with hormonal agents for idiopathic male infertility. Indian J Urol. 2017;33:194–198.
   PubMed Web of Science ®Google Scholar
• Cp P, King P, Goldstein M, et al. Evidence of a treatable endocrinopathy in infertile men. J Urol. 2001;165:837–841.
   PubMed Web of Science ®Google Scholar
• Saylam B, Efesoy O, Cayan S. The effect of aromatase inhibitor letrozole on body mass index, serum hormones, and sperm parameters in infertile men. Fertil Steril. 2011;95:809–811.
   PubMed Web of Science ®Google Scholar
• Gregoriou O, Bakas P, Grigoriadis C, et al. Changes in hormonal profile and seminal parameters with use of aromatase inhibitors in management of infertile men with low testosterone to estradiol ratios. Fertil Steril. 2012;98:48–51.
   PubMed Web of Science ®Google Scholar
• Cavallini G, Biagiotti G, Bolzon E. Multivariate analysis to predict letrozole efficacy in improving sperm count of non-obstructive azoospermic and cryptozoospermic patients: a pilot study. Asian J Androl. 2013;15:806–811.
   PubMed Web of Science ®Google Scholar
• Ribeiro MA, Gameiro LF, Scarano WR, et al. Aromatase inhibitors in the treatment of oligozoospermic or azoospermic men: a systematic review of randomized controlled trials. JBRA Assist Reprod. 2016;20:82–88.
   PubMed Web of Science ®Google Scholar
• Helo S, Wynia B, McCullough A. “Cherchez La Femme”: modulation of estrogen receptor function with selective modulators: clinical implications in the field of urology. Sex Med Rev. 2017;5:365–386.
   PubMedGoogle Scholar
• Patankar SS, Kaore SB, Sawane MV, et al. Effect of clomiphene citrate on sperm density in male partners of infertile couples. Indian J Physiol Pharmacol. 2007;51:195–198.
   PubMedGoogle Scholar
• Ko EY, Siddiqi K, Brannigan RE, et al. Empirical medical therapy for idiopathic male infertility: a survey of the American Urological Association. J Urol. 2012;187:973–978.
   PubMed Web of Science ®Google Scholar
• Schlegel PN. Aromatase inhibitors for male infertility. Fertil Steril. 2012;98:1359–1362.
   PubMed Web of Science ®Google Scholar
• Siddiq FM, Sigman M. A new look at the medical management of infertility. Urol Clin North Am. 2002;29:949–963.
   PubMed Web of Science ®Google Scholar
• Kamischke A, Nieschlag E. Analysis of medical treatment of male infertility. Hum Reprod. 1999;14:1–23.
   PubMed Web of Science ®Google Scholar
• Vandekerckhove P, Lilford R, Vail A, et al. Clomiphene or tamoxifen for idiopathic oligo/asthenospermia. Cochrane Database Syst Rev. 2000;2:CD000151.
   Google Scholar
• Chua ME, Escusa KG, Luna S, et al. Revisiting oestrogen antagonists (clomiphene or tamoxifen) as medical empiric therapy for idiopathic male infertility: a meta-analysis. Andrology. 2013;1:749–757.
   PubMed Web of Science ®Google Scholar
• Ghanem H, Shaeer O, El-Segini A. Combination clomiphene citrate and antioxidant therapy for idiopathic male infertility: a randomized controlled trial. Fertil Steril. 2010;93:2232–2235.
   PubMed Web of Science ®Google Scholar
• ElSheikh MG, Hosny MB, Elshenoufy A, et al. Combination of vitamin E and clomiphene citrate in treating patients with idiopathic oligoasthenozoospermia: a prospective, randomized trial. Andrology. 2015;3:864–867.
   PubMed Web of Science ®Google Scholar
• Bozhedomov VA, Lipatova NA, Bozhedomova GE, et al. Using L- and acetyl-L-carnintines in combination with clomiphene citrate and antioxidant complex for treating idiopathic male infertility: a prospective randomized trial. Urologiia. 2017;3:22–32.
   Google Scholar
• Guo L, Jing J, Feng YM, et al. Tamoxifen is a potent antioxidant modulator for sperm quality in patients with idiopathic oligoasthenospermia. Int Urol Nephrol. 2015;47:1463–1469.
   PubMed Web of Science ®Google Scholar
• Hussein A, Ozgok Y, Ross L, et al. Clomiphene administration for cases of nonobstructive azoospermia: a multicenter study. J Androl. 2005;26:787–791.
   PubMedGoogle Scholar
• Moein MR, Tabibnejad N, Ghasemzadeh J. Beneficial effect of tamoxifen on sperm recovery in infertile men with nonobstructive azoospermia. Andrologia. 2012;44(Suppl 1):194–198.
   PubMedGoogle Scholar
• Kumar N, Singh AK. Reactive oxygen species in seminal plasma as a cause of male infertility. J Gynecol Obstet Hum Reprod. published on line. 2018 Jul 16. DOI:10.1016/j.jogoh.2018.06.008
   PubMedGoogle Scholar
• Conrad M, Ingold I, Buday K, et al. ROS, thiols and thiol-regulating systems in male gametogenesis. Biochim Biophys Acta. 2015;1850:1566–1574.
   PubMed Web of Science ®Google Scholar
• Morimoto H, Iwata K, Ogonuki N, et al. ROS are required for mouse spermatogonial stem cell self-renewal. Cell Stem Cell. 2013;12:774–786.
   PubMed Web of Science ®Google Scholar
• Aitken RJ, Clarkson JS, Fishel S. Generation of reactive oxygen species, lipid peroxidation, and human sperm function. Biol Reprod. 1989;41:183–197.
   PubMed Web of Science ®Google Scholar
• Lanzafame FM, La Vignera S, Vicari E, et al. Oxidative stress and medical antioxidant treatment in male infertility. Reprod Biomed Online. 2009;19:638–659.
   PubMed Web of Science ®Google Scholar
• La Vignera S, Condorelli RA, Vicari E, et al. Markers of semen inflammation: supplementary semen analysis? J Reprod Immunol. 2013;100:2–10.
   PubMed Web of Science ®Google Scholar
• Agarwal A, Sharma RK, Nallella KP, et al. Reactive oxygen species as an independent marker of male factor infertility. Fertil Steril. 2006;86:878–885.
   PubMed Web of Science ®Google Scholar
• Condorelli RA, La Vignera S, Mongioì LM, et al. Myo-inositol as a male fertility molecule: speed them up! Eur Rev Med Pharmacol Sci. 2017;21:30–35.
   PubMed Web of Science ®Google Scholar
• Calogero AE, Condorelli RA, Russo GI, et al. Conservative nonhormonal options for the treatment of male infertility: antibiotics, anti-inflammatory drugs, and antioxidants. Biomed Res Int. 2017;2017:4650182.
   PubMed Web of Science ®Google Scholar
• Paoli D, Gallo M, Rizzo F, et al. Mitochondrial membrane potential profile and its correlation with increasing sperm motility. Fertil Steril. 2011;95:2315–2319.
   PubMed Web of Science ®Google Scholar
• Wang X, Sharma RK, Gupta A, et al. Alterations in mitochondria membrane potential and oxidative stress in infertile men: a prospective observational study. Fertil Steril. 2003;80 Suppl 2:844–850.
   PubMed Web of Science ®Google Scholar
• Lewis SE, John Aitken R, Conner SJ, et al. The impact of sperm DNA damage in assisted conception and beyond: recent advances in diagnosis and treatment. Reprod Biomed Online. 2013;27:325–337.
   PubMed Web of Science ®Google Scholar
• Simon L, Lutton D, McManus, et al. Sperm DNA damage measured by the alkaline Comet assay as an independent predictor of male infertility and in vitro fertilization success. Fertil Steril. 2011;95:652–657.
   PubMed Web of Science ®Google Scholar
• Simon L, Proutski I, Stevenson, et al. Sperm DNA damage has negative association with live birth rates after IVF. Reprod Biomed. 2013;26:68–78. Online.
   PubMed Web of Science ®Google Scholar
• Majzoub A, Agarwal A. Antioxidant therapy in idiopathic oligoasthenoteratozoospermia. Indian J Urol. 2017;33:207–214.
   PubMed Web of Science ®Google Scholar
• Gharagozloo P, Aitken RJ. The role of sperm oxidative stress in male infertility and the significance of oral antioxidant therapy. Hum Reprod. 2011;26:1628–1640.
   PubMed Web of Science ®Google Scholar
• Ng CM, Blackman MR, Wang C, et al. The role of carnitine in the male reproductive system. Ann N Y Acad Sci. 2004;1033:177–188.
   PubMed Web of Science ®Google Scholar
• Mongioi L, Calogero AE, Vicari E, et al. The role of carnitine in male infertility. Andrology. 2016;4:800–807.
   PubMed Web of Science ®Google Scholar
• Cooper TG, Weidner W, Nieschlag E. The influence of inflammation of the human male genital tract on secretion of the seminal markers alpha-glucosidase, glycerophosphocholine, carnitine, fructose and citric acid. Int J Androl. 1990;13:329–336.
   PubMedGoogle Scholar
• Vicari E, Rubino C, De Palma A, et al. Antioxidant therapeutic efficiency after the use of carnitine in infertile patients with bacterial or non bacterial prostato-vesiculo-epididymitis. Arch Ital Urol Androl. 2001;73:15–25.
   PubMedGoogle Scholar
• Vicari E, Calogero AE. Effects of treatment with carnitines in infertile patients with prostato-vesiculo-epididymitis. Hum Reprod. 2001. Vol. 16. 2338–2342.
   PubMed Web of Science ®Google Scholar
• Vicari E, La Vignera S, Calogero AE. Antioxidant treatment with carnitines is effective in infertile patients with prostatovesiculoepididymitis and elevated seminal leukocyte concentrations after treatment with nonsteroidal anti-inflammatory compounds. Fertil Steril. 2002;78:1203–1208.
   PubMed Web of Science ®Google Scholar
• Banihani S, Agarwal A, Sharma R, et al. Cryoprotective effect of L-carnitine on motility, vitality and DNA oxidation of human spermatozoa. Andrologia. 2014;46:637–641.
   PubMed Web of Science ®Google Scholar
• Bornman MS, du Toit D, Otto B, et al. . Seminal carnitine, epididymal function and spermatozoal motility. S Afr Med J. 1989;75:20–21.
   PubMed Web of Science ®Google Scholar
• Sigman M, Glass S, Campagnone J, et al. Carnitine for the treatment of idiopathic asthenospermia: a randomized, double-blind, placebo-controlled trial. Fertil Steril. 2006;85:1409–1414.
   PubMed Web of Science ®Google Scholar
• Moncada ML, Vicari E, Cimino C, et al. Effect of acetylcarnitine treatment in oligoasthenospermic patients. Acta Eur Fertil. 1992;23:221–224.
   PubMedGoogle Scholar
• Costa M, Canale D, Filicori M, et al. L-carnitine in idiopathic asthenozoospermia: a multicenter study. Italian Study Group on Carnitine and Male Infertility. Andrologia. 1994;26:155–159.
   Google Scholar
• Vitali G, Parente R, Melotti C. Carnitine supplementation in human idiopathic asthenospermia: clinical results. Drugs Exp Clin Res. 1995;21:157–159.
   PubMedGoogle Scholar
• Lenzi A, Sgrò P, Salacone P, et al. A placebo-controlled double-blind randomized trial of the use of combined l-carnitine and l-acetyl-carnitine treatment in men with asthenozoospermia. Fertil Steril. 2004;81:1578–1584.
   PubMed Web of Science ®Google Scholar
• Cavallini G, Ferraretti AP, Gianaroli L, et al. Cinnoxicam and L-carnitine/acetyl-L-carnitine treatment for idiopathic and varicocele-associated oligoasthenospermia. J Androl. 2004;25:761–772.
   PubMedGoogle Scholar
• Balercia G, Regoli F, Armeni T, et al. Placebo-controlled double-blind randomized trial on the use of L-carnitine, L-acetylcarnitine, or combined L-carnitine and L-acetylcarnitine in men with idiopathic asthenozoospermia. Fertil Steril. 2005;84:662–671.
   PubMed Web of Science ®Google Scholar
• Gvozdjáková A, Kucharská J, Dubravicky J, et al. Coenzyme Q₁₀, α-tocopherol, and oxidative stress could be important metabolic biomarkers of male infertility. Dis Markers. 2015;2015:827941.
   PubMed Web of Science ®Google Scholar
• Alleva R, Scararmucci A, Mantero F, et al. The protective role of ubiquinol-10 against formation of lipid hydroperoxides in human seminal fluid. Mol Aspects Med. 1997;18:S221–228.
   PubMed Web of Science ®Google Scholar
• Giacone F, Condorelli RA, Mongioì LM, et al. In vitro effects of zinc, D-aspartic acid, and coenzyme-Q10 on sperm function. Endocrine. 2017;56:408–415.
   PubMed Web of Science ®Google Scholar
• Balercia G, Buldreghini E, Vignini A, et al. Coenzyme Q10 treatment in infertile men with idiopathic asthenozoospermia: a placebo-controlled, double-blind randomized trial. Fertil Steril. 2009;91:1785–1792.
   PubMed Web of Science ®Google Scholar
• Safarinejad MR. Efficacy of coenzyme Q10 on semen parameters, sperm function and reproductive hormones in infertile men. J Urol. 2009;182:237–248.
   PubMed Web of Science ®Google Scholar
• Nadjarzadeh A, Shidfar F, Amirjannati N, et al. Effect of coenzyme Q10 supplementation on antioxidant enzymes activity and oxidative stress of seminal plasma: a double-blind randomised clinical trial. Andrologia. 2014;46:177–183.
   PubMed Web of Science ®Google Scholar
• Safarinejad MR. The effect of coenzyme Q₁₀ supplementation on partner pregnancy rate in infertile men with idiopathic oligoasthenoteratozoospermia: an open-label prospective study. Int Urol Nephrol. 2012;44:689–700.
   PubMed Web of Science ®Google Scholar
• Nadjarzadeh A, Sadeghi MR, Amirjannati N, et al. Coenzyme Q10 improves seminal oxidative defense but does not affect on semen parameters in idiopathic oligoasthenoteratozoospermia: a randomized double-blind, placebo controlled trial. J Endocrinol Invest. 2011;34:e224–e228.
   PubMed Web of Science ®Google Scholar
• Lafuente R, González-Comadrán M, Solà I, et al. Coenzyme Q10 and male infertility: a meta-analysis. J Assist Reprod Genet. 2013;30:1147–1156.
   PubMed Web of Science ®Google Scholar
• Yeung CH, Anapolski M, Setiawan I, et al. Effects of putative epididymal osmolytes on sperm volume regulation of fertile and infertile c-ros transgenic Mice. J Androl. 2004;25:216–223.
   PubMedGoogle Scholar
• Bahat A, Eisenbach M. Human sperm thermotaxis is mediated by phospholipase C and inositol trisphosphate receptor Ca2+ channel. Biol Reprod. 2010;82:606–616.
   PubMed Web of Science ®Google Scholar
• Dragileva E, Rubinstein S, Breitbart H. Intracellular Ca(2+)-Mg(2+)-ATPase regulates calcium influx and acrosomal exocytosis in bull and ram spermatozoa. Biol Reprod. 1999;61:1226–1234.
   PubMed Web of Science ®Google Scholar
• Ho HC, Suarez SS. Characterization of the intracellular calcium store at the base of the sperm flagellum that regulates hyperactivated motility. Biol Reprod. 2003;68:1590–1596.
   PubMed Web of Science ®Google Scholar
• Condorelli RA, La Vignera S, Di Bari F, et al. Effects of myoinositol on sperm mitochondrial function in-vitro. Eur Rev Med Pharmacol Sci. 2011;15:129–1347.
   PubMed Web of Science ®Google Scholar
• Palmieri M, Papale P, Della Ragione A, et al. In vitro antioxidant treatment of semen samples in assisted reproductive technology: effects of myo-inositol on nemaspermic parameters. Int J Endocrinol. 2016;2016:1–5.
   PubMedGoogle Scholar
• Condorelli RA, La Vignera S, Bellanca S, et al. Myoinositol: does it improve sperm mitochondrial function and sperm motility? Urology. 2012;79:1290–1295.
   PubMed Web of Science ®Google Scholar
• Rubino P, Palini S, Chigioni S, et al. Improving fertilization rate in ICSI cycles by adding myoinositol to the semen preparation procedures: a prospective, bicentric, randomized trial on sibling oocytes. J Assist Reprod Genet. 2015;32:387–394.
   PubMed Web of Science ®Google Scholar
• Calogero AE, Gullo G, La Vignera S, et al. Myoinositol improves sperm parameters and serum reproductive hormones in patients with idiopathic infertility: a prospective double-blind randomized placebo-controlled study. Andrology. 2015;3:491–495.
   PubMed Web of Science ®Google Scholar
• Gulino FA, Leonardi E, Marilli I, et al. Effect of treatment with myo-inositol on semen parameters of patients undergoing an IVF cycle: in vivo study. Gynecol Endocrinol. 2016;32:65–68.
   PubMed Web of Science ®Google Scholar
• Montanino Oliva M, Minutolo E, Lippa A, et al. Effect of myoinositol and antioxidants on sperm quality in men with metabolic syndrome. Int J Endocrinol. 2016;2016:1674950.
   PubMed Web of Science ®Google Scholar
• Dinkova A, Martinov D, Konova E. Efficacy of myo-inositol in the clinical management of patients with asthenozoospermia. Eur Rev Med Pharmacol Sci. 2017;21:62–65.
   PubMed Web of Science ®Google Scholar
• Walczak-Jedrzejowska R, Wolski JK, Slowikowska-Hilczer J. The role of oxidative stress and antioxidants in male fertility. Cent European J Urol. 2013;66:60–67.
   PubMedGoogle Scholar
• Dawson EB, Harris WA, Teter MC, et al. Effect of ascorbic acid supplementation on the sperm quality of smokers. Fertil Steril. 1992;58:1034–1039.
   PubMed Web of Science ®Google Scholar
• Thérond P, Auger J, Legrand A, et al. Alpha-Tocopherol in human spermatozoa and seminal plasma: relationships with motility, antioxidant enzymes and leukocytes. Mol Hum Reprod. 1996;2:739–744.
   PubMed Web of Science ®Google Scholar
• Omu AE, Fatinikun T, Mannazhath N, et al. Significance of simultaneous determination of serum and seminal plasma alpha-tocopherol and retinol in infertile men by high-performance liquid chromatography. Andrologia. 1999;31:347–354.
   PubMed Web of Science ®Google Scholar
• Thiele JJ, Friesleben HJ, Fuchs J, et al. Ascorbic acid and urate in human seminal plasma: determination and interrelationships with chemiluminescence in washed semen. Hum Reprod. 1995;10:110–115.
   PubMed Web of Science ®Google Scholar
• Song GJ, Norkus EP, Lewis V. Relationship between seminal ascorbic acid and sperm DNA integrity in infertile men. Int J Androl. 2006;29:569–575.
   PubMedGoogle Scholar
• Baker HW, Brindle J, Irvine DS, et al. Protective effect of antioxidants on the impairment of sperm motility by activated polymorphonuclear leukocytes. Fertil Steril. 1996;65:411–419.
   PubMed Web of Science ®Google Scholar
• Moilanen J, Hovatta O. Excretion of alpha-tocopherol into human seminal plasma after oral administration. Andrologia. 1995;27:133–136.
   PubMed Web of Science ®Google Scholar
• Kessopoulou E, Powers HJ, Sharma KK, et al. A double-blind randomized placebo cross-over controlled trial using the antioxidant vitamin E to treat reactive oxygen species associated male infertility. Fertil Steril. 1995;64:825–831.
   PubMed Web of Science ®Google Scholar
• Suleiman SA, Ali ME, Zaki ZM, et al. Lipid peroxidation and human sperm motility: protective role of vitamin E. J Androl. 1996;17:530–537.
   PubMed Web of Science ®Google Scholar
• Cyrus A, Kabir A, Goodarzi D, et al. The effect of adjuvant vitamin C after varicocele surgery on sperm quality and quantity in infertile men: a double blind placebo controlled clinical trial. Int Braz J Urol. 2015;41:230–238.
   PubMed Web of Science ®Google Scholar
• Rolf C, Cooper TG, Yeung CH, et al. Antioxidant treatment of patients with asthenozoospermia or moderate oligoasthenozoospermia with high-dose vitamin C and vitamin E: a randomized, placebo-controlled, double-blind study. Hum Reprod. 1999;14:1028–1033.
   PubMed Web of Science ®Google Scholar
• Comhaire FH, Christophe AB, Zalata AA, et al. The effects of combined conventional treatment, oral antioxidants and essential fatty acids on sperm biology in subfertile men. Prostaglandins Leukot Essent Fatty Acids. 2000;63:159–165.
   PubMed Web of Science ®Google Scholar
• Keskes-Ammar L, Feki-Chakroun N, Rebai T, et al. Sperm oxidative stress and the effect of an oral Vitamin E and selenium supplement on semen quality in infertile men. Arch Androl. 2003;49:83–94.
   PubMedGoogle Scholar
• Greco E, Iacobelli M, Rienzi L, et al. Reduction of the incidence of sperm DNA fragmentation by oral antioxidant treatment. J Androl. 2005;26:349–353.
   PubMed Web of Science ®Google Scholar
• Moslemi MK, Tavanbakhsh S. Selenium-vitamin E supplementation in infertile men: effects on semen parameters and pregnancy rate. Int J Gen Med. 2011;4:99–104.
   PubMedGoogle Scholar
• Kelkel M, Schumacher M, Dicato M, et al. Antioxidant and anti-proliferative properties of lycopene. Free Radic Res. 2011;45:925–940.
   PubMed Web of Science ®Google Scholar
• Liang ZW, Guo KM, Dai XF, et al. Protective effect of lycopene on human spermatozoa during cryopreservation and its mechanism. Zhonghua Nan Ke Xue. 2015;21:521–526.
   PubMedGoogle Scholar
• Mohanty NK, Kumar S, Jha AK, et al. Management of idiopathic oligoasthenospermia with lycopene. Indian J Urol. 2001;18:57–61.
   Google Scholar
• Gupta NP, Kumar R. Lycopene therapy in idiopathic male infertility – A preliminary report. Int Urol Nephrol. 2002;34:369–372.
   PubMedGoogle Scholar
• Yamamoto Y, Aizawa K, Mieno M, et al. The effects of tomato juice on male infertility. Asia Pac J Clin Nutr. 2017;26:65–71.
   PubMed Web of Science ®Google Scholar
• Ahsan U, Kamran Z, Raza I, et al. Role of selenium in male reproduction - a review. Anim Reprod Sci. 2014;146:55–62.
   PubMed Web of Science ®Google Scholar
• Noack-Füller G, De Beer C, Seibert H. Cadmium, lead, selenium, and zinc in semen of occupationally unexposed men. Andrologia. 1993;25:7–12.
   PubMed Web of Science ®Google Scholar
• Ursini F, Heim S, Kiess M, et al. Dual function of the selenoprotein PHGPx during sperm maturation. Science. 1999;285:1393–1396.
   PubMed Web of Science ®Google Scholar
• Chia SE, Ong CN, Chua LH, et al. Comparison of zinc concentrations in blood and seminal plasma and the various sperm parameters between fertile and infertile men. J Androl. 2000;21:53–57.
   PubMed Web of Science ®Google Scholar
• Ghafarizadeh AA, Vaezi G, Shariatzadeh MA, et al. Effect of in vitro selenium supplementation on sperm quality in asthenoteratozoospermic men. Andrologia. published online. 2017 August 6. DOI:10.1111/and.12869
   PubMed Web of Science ®Google Scholar
• Safarinejad MR, Safarinejad S. Efficacy of selenium and/or N-acetyl-cysteine for improving semen parameters in infertile men: a double-blind, placebo controlled, randomized study. Urol. 2009;181:741–751.
   Google Scholar
• Iwanier K, Zachara BA. Selenium supplementation enhances the element concentration in blood and seminal fluid but does not change the spermatozoal quality characteristics in subfertile men. J Androl. 1995;16:441–447.
   PubMedGoogle Scholar
• Hawkes WC, Alkan Z, Wong K. Selenium supplementation does not affect testicular selenium status or semen quality in North American men. J Androl. 2009;30:525–533.
   PubMedGoogle Scholar
• Vézina D, Mauffette F, Roberts KD, et al. Selenium-vitamin E supplementation in infertile men. Effects on Semen Parameters and Micronutrient Levels and Distribution. Biol Trace Elem Res. 1996;53:65–83.
   PubMed Web of Science ®Google Scholar
• Tikkiwal M, Ajmera RL, Mathur NK. Effect of zinc administration on seminal zinc and fertility of oligospermic males. Indian J Physiol Pharmacol. 1987;31:30–34.
   PubMedGoogle Scholar
• Omu AE, Dashti H, Al-Othman S. Treatment of asthenozoospermia with zinc sulphate: andrological, immunological and obstetric outcome. Eur J Obstet Gynecol Reprod Biol. 1998;79:179–184.
   PubMed Web of Science ®Google Scholar
• Omu AE, Al-Azemi MK, Kehinde EO, et al. Indications of the mechanisms involved in improved sperm parameters by zinc therapy. Med Princ Pract. 2008;17:108–116.
   PubMed Web of Science ®Google Scholar
• Azizollahi G, Azizollahi S, Babaei H, et al. Effects of supplement therapy on sperm parameters, protamine content and acrosomal integrity of varicocelectomized subjects. J Assist Reprod Genet. 2013;30:593–599.
   PubMed Web of Science ®Google Scholar
• Hadwan MH, Almashhedy LA, Alsalman AR. Oral zinc supplementation restores superoxide radical scavengers to normal levels in spermatozoa of Iraqi asthenospermic patients. Int J Vitam Nutr Res. 2015;85:165–173.
   PubMed Web of Science ®Google Scholar
• Raigani M, Yaghmaei B, Amirjannti N, et al. The micronutrient supplements, zinc sulphate and folic acid, did not ameliorate sperm functional parameters in oligoasthenoteratozoospermic men. Andrologia. 2014;46:956–962.
   PubMed Web of Science ®Google Scholar
• Sommer F, Bäckhed F. The gut microbiota — masters of host development and physiology. Nat Rev Microbiol. 2013;11:227–238.
   PubMed Web of Science ®Google Scholar
• Baker JM, Al-Nakkash L, Herbst-Kralovetz MM. Estrogen-gut microbiome axis: physiological and clinical implications. Maturitas. 2017;103:45–53.
   PubMed Web of Science ®Google Scholar
• Maretti C, Cavallini G. The association of a probiotic with a prebiotic (Flortec, Bracco) to improve the quality/quantity of spermatozoa in infertile patients with idiopathic oligoasthenoteratospermia: a pilot study. Andrology. 2017;5:439–444.
   PubMed Web of Science ®Google Scholar
• Du Plessis SS, Gokul S, Agarwal A. Semen hyperviscosity: causes, consequences, and cures. Front Biosci (Elite Ed). 2013;5:224–231.
   PubMedGoogle Scholar
• La Vignera S, Vicari E, Condorelli RA, et al. Prevalence of human papilloma virus infection in patients with male accessory gland infection. Reprod Biomed Online. 2015;30:385–391.
   PubMed Web of Science ®Google Scholar
• Calogero AE, Duca Y, Condorelli RA, et al. Male accessory gland inflammation, infertility, and sexual dysfunctions: a practical approach to diagnosis and therapy. Andrology. 2017;5:1064–1072(b).
   PubMed Web of Science ®Google Scholar
• Garolla A, De Toni L, Bottacin A, et al. Human Papillomavirus Prophylactic Vaccination improves reproductive outcome in infertile patients with HPV semen infection: a retrospective study. Sci Rep. 2018;8:912.
   PubMed Web of Science ®Google Scholar
• Foresta C, Noventa M, De Toni L, et al. HPV-DNA sperm infection and infertility: from a systematic literature review to a possible clinical management proposal. Andrology. 2015;3:163–173.
   PubMed Web of Science ®Google Scholar