Inositol and human reproduction

1. Dinicola S., UnferV., Facchinetti F., Soulage C.O., Greene N.D. et al. Inositols: from established knowledge to novel approaches. Int. J. Mol. Sci. 2021; 22(19): 10575. https://dx.doi.org/10.3390/ijms221910575.
2. Majunder A.L., Biswas B.B. Biology of inositols and phosphoinositides. Series: Subcellular Biochemistry. vol. 39. Springer; 2006 January. https://dx.doi.org/10.1007/0-387-27600-9.
3. Garzon S., Laganà A.S., 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.https://dx.doi.org/10.1080/17425255.2019.1651839.
4. Dinicola S., Minini M., Unfer V., Verna R., Cucina A., Bizzarri M. Nutritional and acquired deficiencies in inositol bioavailability. Correlations with metabolic disorders. Int. J. Mol. Sci. 2017; 18(10): 2187. https://dx.doi.org/10.3390/ijms18102187.
5. Ijuin T., Takenawa T. Regulation of insulin signaling and glucose transporter 4 (GLUT4) exocytosis by phosphatidylinositol 3,4,5-trisphosphate (PIP3) phosphatase, skeletal muscle, and kidney enriched inositol polyphosphate phosphatase (SKIP). J. Biol. Chem. 2012; 287(10): 6991-9. https://dx.doi.org/10.1074/jbc.M111.335539.
6. Bevilacqua A., Bizzarri M. Inositols in insulin signaling and glucose metabolism. Int. J. Endocrinol. 2018; 2018: 1968450. https://dx.doi.org/10.1155/2018/1968450.
7. Cabrera-Cruz H., Oróstica L., Plaza-Parrochia F., Torres-Pinto I., Romero C., Vega M. The insulin-sensitizing mechanism of myo-inositol is associated with AMPK activation and GLUT-4 expression in human endometrial cells exposed to a PCOS environment. Am. J. Physiol. Endocrinol. Metab. 2020; 318(2): E237-48. https://dx.doi.org/10.1152/ajpendo.00162.2019.
8. Nestler J.E., Unfer V. Reflections on inositol(s) for PCOS therapy: Steps toward success. Gynecol. Endocrinol. 2015; 31(7): 501-5. https://dx.doi.org/10.3109/09513590.2015.1054802.
9. Milewska E.M., Czyzyk A., Meczekalski B., Genazzani A.D. Inositol and human reproduction. From cellular metabolism to clinical use. Gynecol. Endocrinol. 2016; 32(9): 690-5. https://dx.doi.org/10.1080/09513590.2016.1188282.
10. Sacchi S., Marinaro F., Tondelli D., Lui J., Xella S., Marsella T. et al. Modulation of gonadotrophin induced steroidogenic enzymes in granulosa cells by d-chiroinositol. Reprod. Biol. Endocrinol. 2016; 14(1): 52. https://dx.doi.org/10.1186/s12958-016-0189-2.
11. Monastra G., Vucenik I., Harrath A.H., Alwasel S.H., Kamenov Z.A., Laganà A.S. et al. PCOS and inositols: controversial results and necessary clarifications. Basic differences between D-chiro and myo-inositol. Front. Endocrinol. 2021; 12: 660381.
12. Unfer V., Dinicola S., Laganà A.S., Bizzarri M. Altered ovarian inositol ratios may account for pathological steroidogenesisin PCOS. Int. J. Mol. Sci. 2020; 21(19): 7157. https://dx.doi.org/10.3390/ijms21197157.
13. Ravanos K., Monastra G., Pavlidou T., Goudakou M., Prapas N. Can high levels of D-chiro-inositol in follicular fluid exert detrimental effects on blastocyst quality? Eur. Rev. Med. Pharmacol. Sci. 2017; 21(23): 5491-8. https://dx.doi.org/10.26355/eurrev_201712_13940.
14. Facchinetti F., Bizzarri M., Benvenga S., D’Anna R., Lanzone A., Soulage C. et al. Results from the international consensus conference on myo-inositol and d-chiro-inositol in obstetrics and gynecology: The link between metabolic syndrome and PCOS. Eur. J. Obstet. Gynecol. Reprod. Biol. 2015;195: 72-6.
15. Unfer V., Carlomagno G., Papaleo E., Vailati S., Candiani M., Baillargeon J.P. Hyperinsulinemia alters myoinositol to d-chiroinositol ratio in the follicular fluid of patients with PCOS. Reprod. Sci. 2014; 21(7): 854-8. https://dx.doi.org/10.1177/1933719113518985.
16. Cheang K.I., Baillargeon J.P., Essah P.A., Ostlund R.E. Jr, Apridonize T., Islam L., Nestler J.E. Insulin-stimulated release of D-chiro-inositol-containing inositolphosphoglycan mediator correlates with insulin sensitivity in women with polycystic ovary syndrome. Metabolism. 2008; 57(10): 1390-7. https://dx.doi.org/10.1016/j.metabol.2008.05.008.
17. Bevilacqua A., Dragotto J., Lucarelli M., Di Emidio G., Monastra G., Tatone C. High doses of D-chiro-inositol alone induce a PCO-like syndrome and other alterations in mouse ovaries. Int. J. Mol. Sci. 2021; 22: 5691. https://dx.doi.org/10.3390/ijms22115691.
18. Unfer V., Facchinetti F., Orrù B., Giordani B., Nestler J. Myo-inositol effects in women with PCOS: A meta-analysis of randomized controlled trials. Endocr. Connect. 2017; 6(8): 647-58. https://dx.doi.org/10.1530/EC-17-0243.
19. Cantelmi T., Lambiase E., Unfer V.R., Gambioli R., Unfer V. Inositol treatment for psychological symptoms in polycystic ovary syndrome women. Eur. Rev. Med. Pharmacol. Sci. 2021; 25(5): 2383-9.
20. Facchinetti F., Appetecchia M., Aragona C., Bevilacqua A., Bezerra Espinola M.S., Bizzarri M. 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): 255-74. https://dx.doi.org/10.1080/17425255.2020.1737675.
21. Пустотина О.А. Инозитол и липоевая кислота в лечении инсулинорезистентности у женщин с синдромом поликистозных яичников. Акушерство и гинекология. 2020; 12: 209-16. [Pustotina O.A. Inositol and lipoic acid in the treatment of insulin resistance in women with polycystic ovary syndrome. Obstetrics and Gynecology. 2020; 12: 209-16. (in Russian)]. https://dx.doi.org/10.18565/aig.2020.12.209-216.
22. Пустотина О.А. Применение инозитолов при синдроме поликистозных яичников. Эффективная фармакотерапия. 2020; 16(28): 24-34. [Pustortina O.A. Use of inositols in polycystic ovary syndrome. Effective pharmacotherapy. 2020; 16(28): 24-34. (in Russian)]. https://dx.doi.org/10.33978/2307-3586-2020-16-28-24-34.
23. Nordio M., Basciani S., Camajani E. The 40:1 myo-inositol/D-chiro-inositol plasma ratio is able to restore ovulation in PCOS patients: comparison with other ratios. Eur. Rev. Med. Pharmacol. Sci. 2019; 23(12): 5512-21. https://dx.doi.org/10.26355/eurrev_201906_18223.
24. Thalamati S. A comparative study of combination of Myo-inositol and D-chiro-inositol versus Metformin in the management of polycystic ovary syndrome in obese women with infertility. Int. J. Reprod. Contracept. Obstet. Gynecol. 2019; 8(3): 825-9. https://dx.doi.org/10.18203/2320-1770.ijrcog20190498.
25. Bevilacqua A., Dragotto J., Giuliani A., Bizzarri M. 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): 9387-98. https://dx.doi.org/10.1002/jcp.27623.
26. Monastra G., Unfer V., Harrath A.H., Bizzarri M. 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. https://dx.doi.org/10.1080/09513590.2016.1247797.
27. Asimakopoulos G., Pergialiotis V., Anastasiou E., Antsaklis P., Theodora M., Vogiatzi E. et al. Effect of dietary myo-inositol supplementation on the insulin resistance and the prevention of gestational diabetes mellitus: Study protocol for a randomized controlled trial. Trials. 2020; 21(1): 633. https://dx.doi.org/10.1186/s13063-020-04561-2.
28. Vitale S.G., Corrado F., Caruso S., Di Benedetto A., Giunta L., Cianci A., D’Anna R. Myo-inositol supplementation to prevent gestational diabetes in overweight non-obese women: Bioelectrical impedance analysis, metabolic aspects, obstetric and neonatal outcomes - a randomized and open-label, placebo-controlled clinical trial. Int. J. Food Sci. Nutr. 2020; 72(5): 670-9. https://dx.doi.org/10.1080/09637486.2020.1852191.
29. D’Anna R., Corrado F., Loddo S., Gullo G., Giunta L., Di Benedetto A. Myoinositol plus α-lactalbumin supplementation, insulin resistance and birth outcomes in women with gestational diabetes mellitus: A randomized, controlled study. Sci. Rep. 2021; 11(1): 8866. https://dx.doi.org/10.1038/s41598-021-88329-x.
30. Facchinetti F., Cavalli P., Copp A.J., D’Anna R., Kandaraki E., Greene N.D.E., Unfer V.; 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: 1187-98. https://dx.doi.org/10.1080/17425255.2020.1828344.
31. Godfrey K.M., Barton S.J., El-Heis S., Kenealy T., Nield H., Baker P.N. et al. Myo-inositol, probiotics, and micronutrient supplementation from preconception for glycemia in pregnancy: NiPPeR International Multicenter Double-Blind Randomized Controlled Trial. Diabetes Care. 2021; 44(5): 1091-9. https://dx.doi.org/10.2337/dc20-2515.
32. Greene N.D., Leung K.Y., Copp A.J. Inositol, neural tube closure and the prevention of neural tube defects. Birth Defects Res. 2017; 109(2): 68-80. https://dx.doi.org/10.1002/bdra.23533.
33. Jauniaux E., Hempstock J., Teng C., Battaglia F.C., Burton G.J. Polyol concentrations in the fluid compartments of the human conceptus during the first trimester of pregnancy: Maintenance of redox potential in a low oxygen environment. J. Clin. Endocrinol. Metab. 2005; 90(2): 1171-5. https://dx.doi.org/10.1210/jc.2004-1513.
34. Rasmussen S.A., Chu S.Y., Kim S.Y., Schmid C.H., Lau J. Maternal obesity and risk of neural tube defects: A metaanalysis. Am. J. Obstet. Gynecol. 2008; 198(6): 611-9. https://dx.doi.org/10.1016/j.ajog.2008.04.021.
35. Hod M., Star S., Passonneau J., Unterman T.G., Freinkel N. Glucose induced dysmorphogenesis in the cultured rat conceptus: Prevention by supplementation with myo-inositol. Isr. J. Med. Sci. 1990; 26(10): 541-4.
36. Greene N.D., Leung K.Y., Gay V., Burren K., Mills K., Chitty L.S., Copp A.J. Inositol for the prevention of neural tube defects: A pilot randomised controlled trial. Br. J. Nutr. 2016; 115(6): 974-83.
37. De Luca M.N., Colone M., Gambioli R., Stringaro A., Unfer V. Oxidative stress and male fertility: role of antioxidants and inositols. Antioxidants. 2021; 10(8): 1283. https://dx.doi.org/10.3390/antiox10081283.
38. Yeung C.H., Anapolski M., Setiawan I., Lang F., Cooper T.G. Effects of putative epididymal osmolytes on sperm volume regulation of fertile and infertile c-ros transgenic Mice. J. Androl. 2004; 25(2): 216-23. https://dx.doi.org/10.1002/j.1939-4640.2004.tb02781.x.
39. Condorelli R.A., LaVignera S., Bellanca S., Vicari E., Calogero A.E. Myoinositol: does it improve sperm mitochondrial function and sperm motility? Urology. 2012; 79(6): 1290-5. https://dx.doi.org/10.1016/j.urology.2012.03.005.
40. Rubino P., Palini S., Chigioni S., Carlomagno G., Quagliariello A., DeStefani 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(3): 387-94. https://dx.doi.org/10.1007/s10815-014-0401-2.
41. Gulino F.A., Leonardi E., Marilli I., Musmeci G., Vitale S.G., Leanza V., Palumbo M.A. Effect of treatment with myo-inositol on semen parameters of patients undergoing an IVF cycle: In vivo study. Gynecol. Endocrinol. 2016; 32(1): 65-8. https://dx.doi.org/10.3109/09513590.2015.1080680.
42. Mohammadi F., Varanloo N., Heydari Nasrabadi M., Vatannejad A., Amjadi F.S., Javedani Masroor 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(1): 77-86. https://dx.doi.org/10.1007/s10561-018-9731-0.
43. Calogero A.E., Gullo G., La Vignera S., Condorelli R.A., Vaiarelli A. Myoinositol improves sperm parameters and serum reproductive hormones in patients with idiopathic infertility: A prospective double-blind randomized placebo-controlled study. Andrology. 2015; 3(3): 491-5. https://dx.doi.org/10.1111/andr.12025.
44. Santoro M., Aquila S., Russo G. Sperm performance in oligoasthenoteratozoospermic patients is induced by a nutraceuticals mix, containing mainly myo-inositol. Syst. Biol. Reprod. Med. 2021; 67(1): 50-63. https://dx.doi.org/10.1080/19396368.2020.1826067.
45. Montanino Oliva M., Minutolo E., Lippa A., Iaconianni P., Vaiarelli A. Effect of myoinositol and antioxidants on sperm quality in men with metabolic syndrome. Int. J. Endocrinol. 2016; 2016: 1674950. https://dx.doi.org/10.1155/2016/1674950.
46. Montanino Oliva M., Buonomo G., Carra M.C., Lippa A., Lisi F. Myo-inositol impact on sperm motility in vagina and evaluation of its effects on foetal development. Eur. Rev. Med. Pharmacol. Sci. 2020; 24(5): 2704-9. https://dx.doi.org/10.26355/eurrev_202003_20540.
47. Chiu T.T.Y., Rogers M.S., Law E.L.K., Briton-Jones C.M., Cheung L.P., Haines C.J. Follicular fluid and serum concentrations of myo-inositol in patients undergoing IVF: relationship with oocyte quality. Hum. Reprod. 2002; 17(6): 1591-6. https://dx.doi.org/10.1093/humrep/17.6.1591.
48. Özay Ö.E., Özay A.C., Çağlıyan E., Okyay R.E., Gülekli B. Myo-inositol administration positively effects ovulation induction and intrauterine insemination in patients with polycystic ovary syndrome: A prospective, controlled, randomized trial. Gynecol. Endocrinol. 2017; 33(7): 524-8. https://dx.doi.org/10.1080/09513590.2017.1296127.
49. Вартанян Э.В., Цатурова К.А., Девятова Е.А., Михайлюкова А.С., Левин В.А., Петухова Н.Л., Маркин А.В., Степцова Е.М. Резервы улучшения качества ооцитов при синдроме поликистозных яичников. Проблемы репродукции. 2017; 23(3): 50-4. [Vartanyan E.V., Tsaturova K.A., Devyatova E.A., Mikhaylyukova A.S., Levin V.A., Petuhova N.L., Markin A.V., Steptsova E.M. The reserves for improvement of quality of oocytes in polycystic ovarian syndrome. Russian Journal of Human Reproduction. 2017; 23(3): 50-4. (in Russian)]. https://dx.doi.org/10.17116/repro201723350-54.
50. Laganà A.S., Vitagliano A., Noventa M., Ambrosini G., D’Anna R. 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(4): 675-84. https//dx.doi.org/10.1007/s00404-018-4861-y.
51. Mohammadi S., Eini F., Bazarganipour F., Taghavi S.A., Kutenaee M.A. The effect of Myo-inositol on fertility rates in poor ovarian responder in women undergoing assisted reproductive technique: A randomized clinical trial. Reprod. Biol. Endocrinol. 2021; 19(1): 61. https://dx.doi.org/10.1186/s12958-021-00741-0.
52. Monastra G., Vazquez-Levin M., Bezerra Espinola M.S., Bilotta G., Laganà A.S., Unfer V. D-chiro-inositol, an aromatase down-modulator, increases androgens and reduces estrogens in male volunteers: A pilot study. Basic Clin. Androl. 2021; 31(1): 13. https://dx.doi.org/10.1186/s12610-021-00131-x.
53. Nordio M.K.P., Chiefari A., Puliani G. D-Chiro-inositol improves testosterone levels in hypogonadal males: A pilot study. Basic Clin. Androl. 2021; 31(1): 28.
54. Talaulikar V.S. Medical therapy for fibroids: An overview. Best Pract. Res. Clin. Obstet. Gynaecol. 2018; 46: 48-56. https://dx.doi.org/10.1016/j.bpobgyn.2017.09.007.
55. Bezerra Espinola M.S., Laganà A.S., Bilotta G., Gullo G., Aragona C., Unfer V. D-chiro-inositol induces ovulation in non-polycystic ovary syndrome (PCOS), non-insulin-resistant young women, likely by modulating aromatase expression: A Report of 2 Cases. Am. J. Case Rep. 2021; 22: e932722. https://dx.doi.org/10.12659/AJCR.932722.
56. Carlomagno G., De Grazia S., Unfer V., Manna F. Myo-inositol in a new pharmaceutical form: A step forward to abroader clinical use. Expert Opin. Drug Deliv. 2012; 9(3): 267-71. https://dx.doi.org/10.1517/17425247.2012.662953.
57. Leung K.-Y., Mills K., Burren K.A., Copp A.J., Greene N.D.E. Quantitative analysis of myo-inositol in urine, blood and nutritional supplements by high-performance liquid chromatography tandem mass spectrometry. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 2011; 879(26): 2759-63. https://dx.doi.org/10.1016/j.jchromb.2011.07.043.
58. Montanino Oliva M., Buonomo G., Calcagno M., Unfer V. Effects of myo-inositol plus alpha-lactalbumin in myo-inositol- resistant PCOS women. J. Ovarian Res. 2018; 11(1): 38. https://dx.doi.org/10.1186/s13048-018-0411-2.

Received 28.01.2022

Accepted 02.02.2022