New clinical targets of d-chiro-inositol: rationale and potential applications

References

• Unfer V, Facchinetti F. Editorial - Update on Inositol(s).. Eur Rev Med Pharmacol Sci. 2017;21(2 Suppl):1–3.
   Google Scholar
• Facchinetti F, Appetecchia M, Aragona C, et al. Experts’ opinion on inositols in treating polycystic ovary syndrome and non-insulin dependent diabetes mellitus: a further help for human reproduction and beyond. Expert Opin Drug Metab Toxicol. 2020;16(3):255–274.
   Google Scholar
• Papaleo E, Unfer V, Baillargeon JP, et al. Contribution of myo-inositol to reproduction. Eur J Obstet Gynecol Reprod Biol. 2009;147(2):120–123.
   Google Scholar
• Unfer V, Forte G. Does inositol ratio orchestrate the fate of ovarian follicles? Med Hypotheses. 2020;144:109983.
   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;293(3):1092–1098.
   Google Scholar
• Facchinetti F, Espinola MSB, Dewailly D, et al. Breakthroughs in the Use of Inositols for Assisted Reproductive Treatment (ART). Trends Endocrinol Metab. 2020. DOI:10.1016/j.tem.2020.04.003.
   Google Scholar
• Facchinetti F, Dante G, Neri I. The Ratio of MI to DCI and Its Impact in the Treatment of Polycystic Ovary Syndrome: Experimental and Literature Evidences. In: Genazzani A, Tarlatzis B, editors. Frontiers in Gynecological Endocrinology. ISGE series. Springer, Cham; 2016, pp 103-109.
   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(2):111–117.
   Google Scholar
• Unfer V, Carlomagno G, Papaleo E, et al. Hyperinsulinemia alters myoinositol to d-chiroinositol ratio in the follicular fluid of patients with PCOS. Reprod Sci. 2014;21(7):854–858.
   Google Scholar
• Bevilacqua A, Dragotto J, Giuliani A, et al. Myo-inositol and D-chiro-inositol (40:1) reverse histological and functional features of polycystic ovary syndrome in a mouse model. J Cell Physiol. 2019;234(6):9387–9398.
   Google Scholar
• Ravanos K, Monastra G, Pavlidou T, et al. Can high levels of D-chiro-inositol in follicular fluid exert detrimental effects on blastocyst quality? Eur Rev Med Pharmacol Sci. 2017;21(23):5491–5498.
   Google Scholar
• Nestler JE, Romero G, Huang LC, et al. Insulin mediators are the signal transduction system responsible for insulin’s actions on human placental steroidogenesis. Endocrinology. 1991;129(6):2951–2956.
   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(1):47–60.
   Google Scholar
• Nestler JE, Jakubowicz DJ, de Vargas AF, et al. Insulin stimulates testosterone biosynthesis by human thecal cells from women with polycystic ovary syndrome by activating its own receptor and using inositolglycan mediators as the signal transduction system. J Clin Endocrinol Metab. 1998;83(6):2001–2005.
   Google Scholar
• Nestler JE. Regulation of the aromatase activity of human placental cytotrophoblasts by insulin, insulin-like growth factor-I, and -II. TJ Steroid. Biochem Mol Biol. 1993;44(4–6):449–457.
   Google Scholar
• Cheang KI, Baillargeon JP, Essah PA, et al. Insulin-stimulated release of D-chiro-inositol-containing inositolphosphoglycan mediator correlates with insulin sensitivity in women with polycystic ovary syndrome. Metabolism. 2008;57(10):1390–1397.
   Google Scholar
• Sacchi S, Marinaro F, Tondelli D, et al. Modulation of gonadotrophin induced steroidogenic enzymes in granulosa cells by d-chiroinositol. Reprod Biol Endocrinol. 2016;14(1):52..
   Google Scholar
• Laganà AS, Unfer V. D-Chiro-Inositol’s action as aromatase inhibitor: rationale and potential clinical targets. Eur Rev Med Pharmacol Sci. 2019;23(24):10575–10576.
   Google Scholar
• Vestergaard P. Drugs Causing Bone Loss. Handb Exp Pharmacol. 2019. DOI:10.1007/164_2019_340
   Google Scholar
• Artini PG, Obino ME, Micelli E, et al. Effect of d-chiro-inositol and alpha-lipoic acid combination on COH outcomes in overweight/obese PCOS women. Gynecol Endocrinol. 2020. DOI:10.1080/09513590.2020.1737007.
   Google Scholar
• Laganà AS, Barbaro L, Pizzo A. Evaluation of ovarian function and metabolic factors in women affected by polycystic ovary syndrome after treatment with D-Chiro-Inositol. Arch Gynecol Obstet. 2015;291(5):1181–1186.
   Google Scholar
• Balen AH, Morley LC, Misso M, et al. The management of anovulatory infertility in women with polycystic ovary syndrome: an analysis of the evidence to support the development of global WHO guidance. Hum Reprod Update. 2016;22(6):687–708.
   Google Scholar
• Niethammer B, Körner C, Schmidmayr M, et al. Non-reproductive effects of anovulation: bone metabolism in the luteal phase of premenopausal women differs between ovulatory and anovulatory cycles. Geburtshilfe Frauenheilkd. 2015;75(12):1250–1257.
   Google Scholar
• Li D, Hitchcock CL, Barr SI, et al. Negative spinal bone mineral density changes and subclinical ovulatory disturbances–prospective data in healthy premenopausal women with regular menstrual cycles. Epidemiol Rev. 2014;36:137–147.
   Google Scholar
• Laganà AS, Rossetti P, Buscema M, et al. Metabolism and ovarian function in PCOS women: a therapeutic approach with inositols. Int J Endocrinol. 2016;2016:6306410.
   Google Scholar
• Shaw ND, Histed SN, Srouji SS, et al. Estrogen negative feedback on gonadotropin secretion: evidence for a direct pituitary effect in women. J Clin Endocrinol Metab. 2010;95(4):1955–1961.
   Google Scholar
• Nestler JE, Jakubowicz DJ, Reamer P, et al. Ovulatory and metabolic effects of D-chiro-inositol in the polycystic ovary syndrome. N Engl J Med. 1999;340(17):1314–1320.
   Google Scholar
• Nestler JE, Gunn R, Bates S, et al. D-chiro-inositol (INS-1) enhances ovulatory rate in hyperandrogenemic, oligomenorrheic women with the polycystic ovary syndrome. Fertil Steril. 2001;76(3):S110–S111.
   Google Scholar
• Laganà AS, Garzon S, Casarin J, et al. Inositol in Polycystic Ovary Syndrome: restoring Fertility through a Pathophysiology-Based Approach. Trends Endocrinol Metab. 2018;29(11):768–780.
   Google Scholar
• Iuorno MJ, Jakubowicz DJ, Baillargeon JP, et al. Effects of d-chiro-inositol in lean women with the polycystic ovary syndrome. Endocr Pract. 2002;8(6):417–423.
   Google Scholar
• Paul C, Laganà AS, Maniglio P, et al. Inositol’s and other nutraceuticals’ synergistic actions counteract insulin resistance in polycystic ovarian syndrome and metabolic syndrome: state-of-the-art and future perspectives. Gynecol Endocrinol. 2016;32(6):431–438.
   Google Scholar
• La Marca A, Morgante G, Palumbo M, et al. Insulin-lowering treatment reduces aromatase activity in response to follicle-stimulating hormone in women with polycystic ovary syndrome. Fertil Steril. 2002;78(6):1234–1239.
   Google Scholar
• De Leo V, la Marca A, Ditto A, et al. Effects of metformin on gonadotropin-induced ovulation in women with polycystic ovary syndrome. Fertil Steril. 1999;72(2):282–285.
   Google Scholar
• Sohrabvand F, Ansari S, Bagheri M. Efficacy of combined metformin–letrozole in comparison with metformin–clomiphene citrate in clomiphene-resistant infertile women with polycystic ovarian disease. Hum Reprod. 2006;21(6):1432–1435.
   Google Scholar
• Blumenfeld Z. The Ovarian Hyperstimulation Syndrome. Vitam Horm. 2018;107:423–451.
   Google Scholar
• Abramov Y, Barak V, Nisman B, et al. Vascular endothelial growth factor plasma levels correlate to the clinical picture in severe ovarian hyperstimulation syndrome. Fertil Steril. 1997;67(2):261–265.
   Google Scholar
• Jellad S, Haj Hassine A, Basly M, et al. Vascular endothelial growth factor antagonist reduces the early onset and the severity of ovarian hyperstimulation syndrome. J Gynecol Obstet Hum Reprod. 2017;46(1):87–91.
   Google Scholar
• Practice Committee of the American Society for Reproductive Medicine. Prevention and treatment of moderate and severe ovarian hyperstimulation syndrome: a guideline. Fertil Steril. 2016;106(7):1634–1647.
   Google Scholar
• Abramov Y, Elchalal U, Schenker JG. Obstetric outcome of in vitro fertilized pregnancies complicated by severe ovarian hyperstimulation syndrome: a multicenter study. Fertil Steril. 1998;70(6):1070–1076.
   Google Scholar
• Aboulghar M. Prediction of ovarian hyperstimulation syndrome (OHSS): estradiol level has an important role in the prediction of OHSS. Hum Reprod. 2003;18(6):1140–1141.
   Google Scholar
• Nelson SM. Prevention and management of ovarian hyperstimulation syndrome. Thromb Res. 2017;151(Suppl 1):S61–S64.
   Google Scholar
• Mai Q, Hu X, Yang G, et al. Effect of letrozole on moderate and severe early-onset ovarian hyperstimulation syndrome in high-risk women: a prospective randomized trial. Am J Obstet Gynecol. 2017;216(1):42.e1–42.e10.
   Google Scholar
• Khattab S, Fotouh IA, Mohesn IA, et al. Use of metformin for prevention of ovarian hyperstimulation syndrome: a novel approach. Reprod Biomed Online. 2006;13(2):194–197.
   Google Scholar
• Abushahin F, Goldman KN, Barbieri E, et al. Aromatase inhibition for refractory endometriosis-related chronic pelvic pain. Fertil Steril. 2011;96(4):939–942.
   Google Scholar
• Laganà AS, Vergara D, Favilli A, et al. Epigenetic and genetic landscape of uterine leiomyomas: a current view over a common gynecological disease. Arch Gynecol Obstet. 2017;296(5):855–867.
   Google Scholar
• Laganà AS, Alonso Pacheco L, Tinelli A, et al. Management of asymptomatic submucous myomas in women of reproductive age: a consensus statement from the global congress on hysteroscopy scientific committee. J Minim Invasive Gynecol. 2019;26(3):381–383.
   Google Scholar
• Vitale SG, Sapia F, Rapisarda AMC, et al. Hysteroscopic morcellation of submucous myomas: a systematic review. Biomed Res Int. 2017;2017:6848250.
   Google Scholar
• Bulun SE, Simpson ER, Word RA. Expression of the CYP19 gene and its product aromatase cytochrome P450 in human uterine leiomyoma tissues and cells in culture. J Clin Endocrinol Metab. 1994;78(3):736–743.
   Google Scholar
• Shozu M, Sumitani H, Segawa T, et al. Overexpression of aromatase P450 in leiomyoma tissue is driven primarily through promoter I.4 of the aromatase P450 gene (CYP19). J Clin Endocrinol Metab. 2002;87(6):2540–2548.
   Google Scholar
• Sinai Talaulikar V. Medical therapy for fibroids: an overview. Best Pract Res Clin Obstet Gynaecol. 2018;46:48–56.
   Google Scholar
• Giudice LC, Kao LC. Endometriosis. Lancet. 2004;364(9447):1789–1799.
   Google Scholar
• Noble LS, Simpson ER, Johns A, et al. Aromatase expression in endometriosis. J Clin Endocrinol Metab. 1996;81(1):174–179.
   Google Scholar
• Kitawaki J, Noguchi T, Amatsu T, et al. Expression of aromatase cytochrome P450 protein and messenger ribonucleic acid in human endometriotic and adenomyotic tissues but not in normal endometrium. Biol Reprod. 1997;57(3):514–519.
   Google Scholar
• Hudelist G, Czerwenka K, Keckstein J, et al. Expression of aromatase and estrogen sulfotransferase in eutopic and ectopic endometrium: evidence for unbalanced estradiol production in endometriosis. Reprod Sci. 2007;14(8):798–805.
   Google Scholar
• Vetvicka V, Laganà AS, Salmeri FM, et al. Regulation of apoptotic pathways during endometriosis: from the molecular basis to the future perspectives. Arch Gynecol Obstet. 2016;294(5):897–904.
   Google Scholar
• Laganà AS, Garzon S, Götte M, et al. the pathogenesis of endometriosis: molecular and cell biology insights. Int J Mol Sci. 2019;20(22):5615.
   Google Scholar
• Nothnick WB. The emerging use of aromatase inhibitors for endometriosis treatment. Reprod Biol Endocrinol. 2011;9:87.
   Google Scholar
• Mousa NA, Bedaiwy MA, Casper RF. Aromatase inhibitors in the treatment of severe endometriosis. Obstet Gynecol. 2007;109(6):1421–1423.
   Google Scholar
• Remorgida V, Abbamonte LH, Ragni N, et al. Letrozole and desogestrel-only contraceptive pill for the treatment of stage IV endometriosis. Aust N Z J Obstet Gynaecol. 2007;47(3):222–225.
   Google Scholar
• Bilotas M, Meresman G, Stella I, et al. Effect of aromatase inhibitors on ectopic endometrial growth and peritoneal environment in a mouse model of endometriosis. Fertil Steril. 2010;93(8):2513–2518.
   Google Scholar
• Ferrero S, Evangelisti G, Barra F. Current and emerging treatment options for endometriosis. Expert Opin Pharmacother. 2018;19(10):1109–1125.
   Google Scholar
• Oner G, Ozcelik B, Ozgun MT, et al. The effects of metformin and letrozole on endometriosis and comparison of the two treatment agents in a rat model. Hum Reprod. 2010;25(4):932–937.
   Google Scholar
• Yilmaz B, Sucak A, Kilic S, et al. Metformin regresses endometriotic implants in rats by improving implant levels of superoxide dismutase, vascular endothelial growth factor, tissue inhibitor of metalloproteinase-2, and matrix metalloproteinase-9. Am J Obstet Gynecol. 2010;202(4):368.e1–8.
   Google Scholar
• Huang B, Warner M, Gustafsson JA. Estrogen receptors in breast carcinogenesis and endocrine therapy. Mol Cell Endocrinol. 2015;418(Pt 3):240–244.
   Google Scholar
• Trabert B, Coburn SB, Falk RT, et al. Circulating estrogens and postmenopausal ovarian and endometrial cancer risk among current hormone users in the Women’s Health Initiative Observational Study. Cancer Causes Control. 2019;30(11):1201–1211.
   Google Scholar
• Tian W, Teng F, Zhao J, et al. Estrogen and insulin synergistically promote type 1 endometrial cancer progression. Cancer Biol Ther. 2017;18(12):1000–1010.
   Google Scholar
• Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials. Lancet. 2015;386(10001):1341–1352.
   Google Scholar
• Bhardwaj P, Au CC, Benito-Martin A, et al. Estrogens and breast cancer: mechanisms involved in obesity-related development, growth and progression. J Steroid Biochem Mol Biol. 2019;189:161–170.
   Google Scholar
• Genazzani AD. Inositol as putative integrative treatment for PCOS. Reprod Biomed Online. 2016;33(6):770–780.
   Google Scholar
• Genazzani AD, Prati A, Marchini F, et al. Differential insulin response to oral glucose tolerance test (OGTT) in overweight/obese polycystic ovary syndrome patients undergoing to myo-inositol (MYO), alpha lipoic acid (ALA), or combination of both. Gynecol Endocrinol. 2019;35(12):1088–1093.
   Google Scholar
• Carlomagno G, Unfer V, Roseff S. The D-chiro-inositol paradox in the ovary. Fertil Steril. 2011;95(8):2515–2516.
   Google Scholar
• Cadagan D, Khan R, Amer S. Thecal cell sensitivity to luteinizing hormone and insulin in polycystic ovarian syndrome. Reprod Biol. 2016;16(1):53–60.
   Google Scholar
• Azziz R, Carmina E, Chen Z, et al. Polycystic ovary syndrome. Nat Rev Dis Primers. 2016;2:16057.
   Google Scholar
• Unfer V, Carlomagno G, Papaleo E, et al. Hyperinsulinemia alters myoinositol to D-chiroinositol ratio in the follicular fluid of patients with PCOS. Reprod Sci. 2014;21(7):854–858.
   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):1–9.
   Google Scholar
• Unfer V, Porcaro G. Updates on the myo-inositol plus D-chiro-inositol combined therapy in polycystic ovary syndrome. Expert Rev Clin Pharmacol. 2014;7(5):623–631.
   Google Scholar
• Garzon S, Laganà AS, Monastra G. Risk of reduced intestinal absorption of myo-inositol caused by D-chiro-inositol or by glucose transporter inhibitors. Expert Opin Drug Metab Toxicol. 2019;15(9):697–703.
   Google Scholar
• Facchinetti F, Unfer V, Dewailly D, et al. Inositols in Polycystic ovary syndrome: an overview on the advances. Trends Endocrinol Metab. 2020;31(6):435–447.
   Google Scholar
• Rizk PJ, Kohn TP, Pastuszak AW, et al. Testosterone therapy improves erectile function and libido in hypogonadal men. Curr Opin Urol. 2017;27(6):511–515.
   Google Scholar
• Dudek P, Kozakowski J, Zgliczyński W. Late-onset hypogonadism. Prz Menopauzalny. 2017;16(2):66–69.
   Google Scholar
• Tan RBW, Guay AT, Hellstrom WJG. Clinical Use of Aromatase Inhibitors in Adult Males. Sex Med Rev. 2014;2(2):79–90.
   Google Scholar
• Fernandez CJ, Chacko EC, Pappachan JM. Male obesity-related secondary hypogonadism - pathophysiology, clinical implications and management. Eur Endocrinol. 2019;15(2):83–90.
   Google Scholar
• Rambhatla A, Mills JN, Rajfer J. The role of estrogen modulators in male hypogonadism and infertility. Rev Urol. 2016;18(2):66–72.
   Google Scholar
• Carrasquillo R, Chu K, Ramasamy R. Novel therapy for male hypogonadism. Curr Urol Rep. 2018;19(8):63.
   Google Scholar