Advances in non-hormonal pharmacotherapy for the treatment of male infertility: the role of inositols

References

• World Health Organization. Report of the meeting on the prevention of infertility at the primary health care levels (WHO, Geneva, 1983).
   Google Scholar
• Agarwal A, Mulgund A, Hamada A, et al. A unique view on male infertility around the globe. Reprod Biol Endocrinol. 2015 26;13:37.
   PubMed Web of Science ®Google Scholar
• Agarwal A, Parekh N, Panner Selvam MK, et al. Male Oxidative Stress Infertility (MOSI): proposed Terminology and clinical practice guidelines for management of Idiopathic male Infertility. World J Mens Health. 2019;37:296–312.
   PubMedGoogle Scholar
• Sakkas D, Mariethoz E, Manicardi G, et al. Origin of DNA damage in ejaculated human spermatozoa. Rev Reprod. 1999Jan;41:31–37. PMID: 10051100
   PubMedGoogle Scholar
• Kemal Duru N, Morshedi M, Oehninger S. Effects of hydrogen peroxide on DNA and plasma membrane integrity of human spermatozoa. Fertil Steril. 2000Dec;74(6):1200–1207. PMID: 11119751.
   PubMed Web of Science ®Google Scholar
• Aitken RJ, Krausz C. Oxidative stress, DNA damage and the Y chromosome. Reproduction. 2001Oct;122(4):497–506. PMID: 11570956.
   PubMed Web of Science ®Google Scholar
• Spiropoulos J, Turnbull DM, Chinnery PF. Can mitochondrial DNA mutations cause sperm dysfunction? Mol Hum Reprod. 2002Aug;8(8):719–721. PMID: 12149402.
   PubMed Web of Science ®Google Scholar
• Sharma RK, Agarwal A. Role of reactive oxygen species in gynecologic diseases. Reprod Med Biol. 2004 Dec 3;3(4):177–199. PMID: 29699197; PMCID: PMC5904640.
   PubMedGoogle Scholar
• Calogero AE, Aversa A, La Vignera S, et al. The use of nutraceuticals in male sexual and reproductive disturbances: position statement from the Italian society of andrology and sexual medicine (SIAMS). J Endocrinol Invest. 2017Dec;40(12):1389–1397. Epub 2017 Jun 6. PMID: 28589384
   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
• Cannarella R, Calogero AE, Condorelli RA, et al. Non-hormonal treatment for male infertility: the potential role of Serenoa repens, selenium and lycopene. Eur Rev Med Pharmacol Sci. 2019;23(7):3112–3120.
   PubMed Web of Science ®Google Scholar
• Artini PG, Casarosa E, Carletti E, et al. In vitro effect of myo-inositol on sperm motility in normal and oligoasthenospermia patients undergoing in vitro fertilization. Gynecol Endocrinol. 2017;33:109–112.
   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
• Canepa P, Dal Lago A, De Leo C, et al. Combined treatment with myo-inositol, alpha-lipoic acid, folic acid and vitamins significantly improves sperm parameters of sub-fertile men: a multi-centric study. Eur Rev Med Pharmacol Sci. 2018;22:7078–7085.
   PubMed Web of Science ®Google Scholar
• Michell RH. Inositol derivatives: evolution and functions. Nat Rev Mol Cell Biol. 2008;9:151–161.
   PubMed Web of Science ®Google Scholar
• Barrese V, Stott JB, Baldwin SN, et al. SMIT (Sodium-Myo-Inositol Transporter) 1 regulates arterial contractility through the modulation of vascular Kv7 channels. Arterioscler Thromb Vasc Biol. 2020Oct;40(10):2468–2480. Epub 2020 Aug 13. PMID: 32787517; PMCID: PMC7505149
   PubMed Web of Science ®Google Scholar
• Croze ML, Soulage CO. Potential role and therapeutic interests of myo-inositol in metabolic diseases. Biochimie. 2013Oct;95(10):1811–1827. Epub 2013 Jun 10. PMID: 23764390.
   PubMed Web of Science ®Google Scholar
• Westfall SD, Hendry IR, Obholz KL, et al. Putative role of the phosphatidylinositol 3-kinase-Akt signaling pathway in the survival of granulosa cells. Endocrine. 2000Jun;123:315–321. PMID: 10963053
   PubMed Web of Science ®Google Scholar
• Facchinetti F, Unfer V, Dewailly D, et al.; Group of ‘Inositol in PCOS and Reproduction.’ Inositols in Polycystic Ovary Syndrome: an Overview on the Advances. Trends Endocrinol Metab. 2020;31:435–447.
   PubMed Web of Science ®Google Scholar
• Monastra G, Unfer V, Harrath AH, et al. Combining treatment with myo-inositol and D-chiro-inositol (40:1) is effective in restoring ovary function and metabolic balance in PCOS patients. Gynecol Endocrinol. 2017;33:1–9.
   PubMed Web of Science ®Google Scholar
• Dinicola S, Chiu TT, Unfer V, et al. The rationale of the myo-inositol and D-chiro-inositol combined treatment for polycystic ovary syndrome. J Clin Pharmacol. 2014 Oct;54(10):1079–1092.
   PubMed Web of Science ®Google Scholar
• Gambioli R, Forte G, Aragona C, et al. The use of D-chiro-Inositol in clinical practice. Eur Rev Med Pharmacol Sci. 2021 Jan;25(1):438–446.
   PubMed Web of Science ®Google Scholar
• Zhang X, Huang R, Zhou Y, et al. IP3R Channels in Male Reproduction. Int J Mol Sci. 2020 Dec 2;21(23):9179. PMID: 33276427; PMCID: PMC7730405.
   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;15:129–134.
   PubMed Web of Science ®Google Scholar
• Pundir J, Psaroudakis D, Savnur P, et al. Inositol treatment of anovulation in women with polycystic ovary syndrome: a meta-analysis of randomised trials. Bjog. 2018;125:299–308.
   PubMedGoogle Scholar
• Facchinetti F, Cavalli P, Copp AJ, et al.; Experts Group on Inositol in Basic and Clinical Research. An update on the use of inositols in preventing gestational diabetes mellitus (GDM) and neural tube defects (NTDs). Expert Opin Drug Metab Toxicol. 2020;16:1187–1198.
   PubMed Web of Science ®Google Scholar
• Laganà AS, Vitagliano A, Noventa M, et al. Myo-inositol supplementation reduces the amount of gonadotropins and length of ovarian stimulation in women undergoing IVF: a systematic review and meta-analysis of randomized controlled trials. Arch Gynecol Obstet. 2018;298:675–684. E.
   PubMed Web of Science ®Google Scholar
• Colazingari S, Treglia M, Najjar R, et al. The combined therapy myo-inositol plus D-chiro-inositol, rather than D-chiro-inositol, is able to improve IVF outcomes: results from a randomized controlled trial. Arch Gynecol Obs. 2013; 288: 1405–1411.
   PubMed Web of Science ®Google Scholar
• Colone M, Marelli G, Unfer V, et al. Inositol activity in oligoasthenoteratospermia–an in vitro study. Eur Rev Med Pharmacol Sci. 2010;14:891–896.
   PubMed Web of Science ®Google 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
• Scarselli F, Lobascio AM, Terribile M, et al. Analysis of MYO-Inositol effect on spermatozoa motility, in hyper viscous ejaculates and in patients with grades II and III varicocele. Arch Ital Urol Androl. 2016;88:279–283.
   PubMedGoogle 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;2016:2839041.
   PubMed Web of Science ®Google Scholar
• Mohammadi F, Varanloo N, Heydari Nasrabadi M, et al. Supplementation of sperm freezing medium with myoinositol improve human sperm parameters and protects it against DNA fragmentation and apoptosis. Cell Tissue Bank. 2019;20:77–86.
   PubMed Web of Science ®Google Scholar
• Saleh R, Assaf H, Abd El Maged WM, et al. Increased cryo-survival rate in ejaculated human sperm from infertile men following pre-freeze in vitro myo-inositol supplementation. Clin Exp Reprod Med. 2018;45:177–182.
   PubMedGoogle Scholar
• Pallotti F, Cargnelutti F, Senofonte G, et al. In vitro effects of myo-inositol on normokinetic human semen samples with nonlinear motility. Eur Rev Med Pharmacol Sci. 2019Dec;2323:10557–10563. PMID: 31841212
   PubMed Web of Science ®Google Scholar
• Governini L, Ponchia R, Artini PG, et al. Respiratory mitochondrial efficiency and DNA oxidation in human sperm after in vitro Myo-Inositol treatment. J Clin Med. 2020;9:1638.
   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, Buonomo G, Carra MC, et al. Myo-inositol impact on sperm motility in vagina and evaluation of its effects on foetal development. Eur Rev Med Pharmacol Sci. 2020 Mar;24(5):2704–2709.
   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
• Capece M, Romeo G, Ruffo A, et al. A phytotherapic approach to reduce sperm DNA fragmentation in patients with male infertility. Urologia. 2017;84:79–82.
   PubMed Web of Science ®Google Scholar
• Scaruffi P, Licata E, Maccarini E, et al. Oral antioxidant treatment of men significantly improves the reproductive outcome of IVF cycles. J Clin Med. 2021;10:3254.
   PubMed Web of Science ®Google Scholar
• De Luca MN, Colone M, Gambioli R, et al. Oxidative stress and male fertility: role of antioxidants and inositols. Antioxidants (Basel). 2021;10:1283.
   PubMedGoogle Scholar
• Vazquez-Levin MH, Verón GL. Myo-inositol in health and disease: its impact on semen parameters and male fertility. Andrology. 2020;8(2):277–298.
   PubMed Web of Science ®Google Scholar
• Delbarba A, Arrighi N, Facondo P, et al. Positive effect of nutraceuticals on sperm DNA damage in selected infertile patients with idiopathic high sperm DNA fragmentation. Minerva Endocrinol. 2020;45:89–96.
   PubMed Web of Science ®Google Scholar
• Sun TH, Heimark DB, Nguygen T, et al. Both myo-inositol to chiro-inositol epimerase activities and chiro-inositol to myo-inositol ratios are decreased in tissues of GK type 2 diabetic rats compared to wistar controls. Biochem Biophys Res Commun. 2002 May 10 293(3):1092–1098.
   PubMed Web of Science ®Google Scholar
• Larner J. D-chiro-inositol in insulin action and insulin resistance-old-fashioned biochemistry still at work. IUBMB Life. 2001Mar;51(3):139–148. PMID: 11547915.
   PubMed Web of Science ®Google Scholar
• Munir I, Yen HW, Geller DH, et al. Insulin augmentation of 17alpha-hydroxylase activity is mediated by phosphatidyl inositol 3-kinase but not extracellular signal-regulated kinase-1/2 in human ovarian theca cells. Endocrinology. 2004 Jan;145(1):175–183.
   PubMed Web of Science ®Google Scholar
• Ueshiba H, Shimizu Y, Hiroi N, et al. Decreased steroidogenic enzyme 17,20-lyase and increased 17-hydroxylase activities in type 2 diabetes mellitus. Eur J Endocrinol. 2002 Mar;146(3):375–380.
   PubMed Web of Science ®Google Scholar
• Larner J. D-chiro-inositol–its functional role in insulin action and its deficit in insulin resistance. Int J Exp Diabetes Res. 2002;3:47–60.
   PubMedGoogle Scholar
• Gambioli R, Montanino Oliva M, Nordio M, et al. New Insights into the Activities of D-Chiro-Inositol: a narrative review. Biomedicines. 2021 Oct 2;9(10):1378. PMID: 34680494; PMCID: PMC8533370.
   PubMed Web of Science ®Google Scholar
• Genazzani AD, Santagni S, Rattighieri E, et al. Modulatory role of D-chiro-inositol (DCI) on LH and insulin secretion in obese PCOS patients. Gynecol Endocrinol. 2014;30:438–443.
   PubMed Web of Science ®Google Scholar
• Bucci D, Rodriguez-Gil JE, Vallorani C, et al. GLUTs and mammalian sperm metabolism. J Androl. 2011Jul-Aug;324:348–355. Epub 2010 Nov 18. PMID: 21088231
   PubMedGoogle Scholar
• Condorelli RA, Barbagallo F, Calogero AE, et al. D-Chiro-Inositol improves sperm mitochondrial membrane potential: in vitro evidence. J Clin Med. 2020;9:1373.
   Web of Science ®Google Scholar
• Formuso C, Stracquadanio M, Ciotta L. Myo-inositol vs. D-chiro inositol in PCOS treatment. Minerva Ginecol. 2015;67:321–325.
   PubMed Web of Science ®Google Scholar
• Barbagallo F, Condorelli RA, Mongioì LM, et al. Molecular mechanisms underlying the relationship between obesity and male infertility. Metabolites. 2021 Dec 4;11(12):840. PMID: 34940598; PMCID: PMC8706114.
   PubMed Web of Science ®Google Scholar
• Monastra G, Vazquez-Levin M, Bezerra Espinola MS, et al. D-chiro-inositol, an aromatase down-modulator, increases androgens and reduces estrogens in male volunteers: a pilot study. Basic Clin Androl. 2021; 31: 13.
   PubMed Web of Science ®Google Scholar
• Nordio M, Kumanov P, Chiefari A, et al. D-Chiro-Inositol improves testosterone levels in older hypogonadal men with low-normal testosterone: a pilot study. Basic Clin Androl. 2021; 31: 28.
   PubMed Web of Science ®Google Scholar
• Ohlander SJ, Lindgren MC, Lipshultz LI. Testosterone and Male Infertility. Urol Clin North Am. 2016;43:195–202.
   PubMed Web of Science ®Google Scholar
• Del Giudice F, Busetto GM, De Berardinis E, et al. A systematic review and meta-analysis of clinical trials implementing aromatase inhibitors to treat male infertility. Asian J Androl. 2020;22:360–367.
   PubMed Web of Science ®Google Scholar
• Chainy GBN, Sahoo DK. Hormones and oxidative stress: an overview. Free Radic Res. 2020;54:1–26.
   PubMed Web of Science ®Google Scholar
• Condorelli RA, Calogero AE, La Vignera S. Hyperestrogenism and low serum testosterone-17beta-estradiol ratio are associated with non-bacterial male accessory gland inflammation. Int J Immunopathol Pharmacol. 2016;29:488–493.
   PubMed Web of Science ®Google Scholar
• La Vignera S, Crafa A, Condorelli RA, et al. Ultrasound evaluation of patients with male accessory gland inflammation: a pictorial review. Andrology. 2021; https://doi.org/10.1111/andr.13011.
   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
• Condorelli RA, Russo GI, Calogero AE, et al. Chronic prostatitis and its detrimental impact on sperm parameters: a systematic review and meta-analysis. J Endocrinol Invest. 2017;40:1209–1218.
   PubMed Web of Science ®Google Scholar
• Chauvin TR, Griswold MD. Characterization of the expression and regulation of genes necessary for myo-inositol biosynthesis and transport in the seminiferous epithelium. Biol Reprod. 2004;7:744–751. Epub 2003 Nov 12. PMID: 14613899.
   Google Scholar
• Cannarella R, Condorelli RA, La Vignera S, et al. Commentary: molecular mechanisms of action of FSH. Front Endocrinol (Lausanne). 2019;10:593.
   PubMed Web of Science ®Google Scholar
• Heimark D, McAllister J, Larner J. Decreased myo-inositol to chiro-inositol (M/C) ratios and increased M/C epimerase activity in PCOS theca cells demonstrate increased insulin sensitivity compared to controls. Endocr J. 2014;61:111–117.
   PubMed Web of Science ®Google Scholar
• Minhas S, Bettocchi C, Boeri L, et al. EAU working group on male sexual and reproductive health. European association of urology guidelines on male sexual and reproductive health. Update on Male Infertility Eur Urol. 2021;S0302-2838(21)01982–5. https://doi.org/10.1016/j.eururo.2021.08.014
   Google Scholar
• Smits RM, Mackenzie-Proctor R, Yazdani A, et al. Antioxidants for male subfertility. Cochrane Database Syst Rev. 2019;3. https://doi.org/10.1002/14651858.CD007411.pub4. CD007411.
   Google Scholar
• La Vignera S, Condorelli RA, Duca Y, et al. FSH treatment for normogonadotropic male infertility: a synergistic role for metformin? Eur Rev Med Pharmacol Sci. 2019;23:5994–5998.
   PubMed Web of Science ®Google Scholar
• Cannarella R, Condorelli RA, La Vignera S, et al. Effects of the insulin-like growth factor system on testicular differentiation and function: a review of the literature. Andrology. 2018Jan;61:3–9. Epub 2017 Dec 1. PMID: 29195026
   PubMed Web of Science ®Google Scholar