Inositols in reproductive medicine
Keywords:reproductive system, inositol, myo-inositol, polycystic ovary syndrome, D-chiro-inositol paradox, female and male reproduction, preconception preparation, gestational complications
The article presents literature data on the role of inositol and its derivatives in human body, results of the myo-inositol (MI) use in gynecological diseases, treatment of female and male infertility, including in cycles of assisted reproductive technologies, in the prevention of gestational and perinatal complications. It has been shown that the inability to adequately synthesize or metabolize inositol can contribute to disturbances in the transmission of intracellular signals, disturbances in the activity of insulin signaling cascades, development of insulin resistance and hyperinsulinemia, which cause abnormal steroidogenesis in the gonads and metabolic disorders.
The concept of “D-chiro-inositol paradox” is highlighted, according to which women with polycystic ovary syndrome are characterized by increased epimerization of MI to D-chiro-inositol, depletion of MI reserves and low oocyte quality. Prescribing biologically active supplements with MI and folic acid for pregnant women reduces the likelihood of threatened abortion, preeclampsia, placental dysfunction, gestational diabetes mellitus, diabetic fetopathy, malformations, oxidative stress in the fetus.
Experience has also been accumulated about myo-inositol use in andrology: it plays a decisive role in osmoregulation of seminal fluid and, as a consequence, increasing the progressive sperm motility and speed, increasing the mitochondrial sperm potential, improves libido and potency, helps to increase the endogenous testosterone, and normalizes the men’s hormonal balance. Inositol is a synergist of folates and other B vitamins and significantly potentiates their effect on the human body; it is the basis for the advantages of using combined biological supplements such as Miofolic® and Miofolic® MEN in the clinic for female and male reproduction. Harmonious use of all possible reserves of micronutrient support for the preconception and gestational period with the use of biologically active supplements of MI in combination with folic acid and vitamin B12 is a promising preventive and therapeutic agent in supporting of reproductive system, embryo development, neuroprotection of the fetal brain, ensuring the activity of signaling cascades insulin.
Gromova, O.A., Torshin, I.Y., Tetruashvili, N.K. “The role of myo-inositol in maintaining a woman's reproductive health. Improving the efficiency of in vitro fertilization technologies.” Russian Medical Journal 1 (2018): 88–95. DOI: 10.32364/2618-8430-2018-1-1-88-95
Limanova, O.A., Gromova, O.A., Torshin, I.Y., et al. “Systematic analysis of the molecular physiological effects of myo-inositol: evidence from molecular biology, experimental and clinical medicine.” Effective pharmacotherapy 28 (2013): 32–57.
Abdali, D., Samson, S.E., Grover, A.K. “How effective are antioxidant supplements in obesity and diabetes?” Med Princ Pract 24.3 (2015): 201–15. DOI: 10.1159/000375305
Aboulghar, M. “Symposium: Update on prediction and management of OHSS. Prevention of OHSS.” Reprod Biomed Online 19.1 (2009): 33-42. DOI: 10.1016/s1472-6483(10)60043–0
Bizzarri, M., Dinicola, S., Bevilacqua, A., Cucina, A. “Broad Spectrum Anticancer Activity of Myo-Inositol and Inositol Hexakisphosphate.” Int J Endocrinol 2016 (2016): 5616807. DOI: 10.1155/2016/5616807
Calogero, A.E., Gullo, G., La Vignera, S., et al. “Myo-inositol improves sperm parameters and serum reproductive hormones in patients with idiopathic infertility: a prospective double-blind randomized placebo- controlled study.” Andrology 3.3 (2015): 491–5. DOI: 10.1111/andr.12025
Carlomagno, G., Unfer, V., Roseff, S. “The D-chiro-inositol paradox in the ovary.” Fertil Steril 95.8 (2011): 2515–6. DOI: 10.1016/j.fertnstert.2011.05.027
Chatree, S., Thongmaen, N., Tantivejkul, K., et al. “Role of Inositols and Inositol Phosphates in Energy Metabolism.” Molecules 25.21 (2020): 5079. DOI: 10.3390/molecules25215079
Chauvin, T.R., Griswold, M.D. “Characterization of the expression and regulation of genes necessary for myo- inositol biosynthesis and transport in the seminiferous epithelium.” Biol Reprod 70.3 (2004): 744–51. DOI: 10.1095/biolreprod.103.022731
Chu, A.H.Y., Tint, M.T., Chang, H.F., et al. “High placental inositol content associated with suppressed pro-adipogenic effects of maternal glycaemia in offspring: the GUSTO cohort.” Int J Obes (Lond) (2020). DOI: 10.1038/s41366-020-0596-5
Ciotta, L., Stracquadanio, M., Pagano, I., et al. “Effects of myo-inositol supplementation on oocyte's quality in PCOS patients: a double-blind trial.” Eur Rev Med Pharmacol Sci 15.5 (2011): 509–14.
Colazingari, S., Treglia, M., Najjar, R., Bevilacqua, A. “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 Obstet 288.6 (2013): 1405–11. DOI: 10.1007/s00404-013-2855-3
Colone, M., Marelli, G., Unfer, V., et al. “Inositol activity in oligoasthenoteratospermia – an in vitro study.” Eur Rev Med Pharmacol Sci 14.10 (2010): 891–6.
Condorelli, R.A., La Vignera, S., Di Bari, F., et al. “Effects of myo-inositol on sperm mitochondrial function in-vitro.” Eur Rev Med Pharmacol Sci 15.2 (2011): 129–34.
Costantino, D., Minozzi, G., Minozzi, E., Guaraldi, C. “Metabolic and hormonal effects of myo-inositol in women with polycystic ovary syndrome: a double-blind trial.” Eur Rev Med Pharmacol Sci 13.2 (2009): 105–10.
D'Anna, R., Di Benedetto, A., Scilipoti, A., et al. “Myo-inositol Supplementation for Prevention of Gestational Diabetes in Obese Pregnant Women: A Randomized Controlled Trial.” Obstet Gynecol 126.2 (2015): 310–5. DOI: 10.1097/AOG.0000000000000958
D'Anna, R., Di Benedetto, V., Rizzo, P., et al. “Myo-inositol may prevent gestational diabetes in PCOS women.” Gynecol Endocrinol 28.6 (2012): 440–2. DOI: 10.3109/09513590.2011.633665
D'Anna, R., Scilipoti, A., Giordano, D., et al. “Myo-inositol supplementation and onset of gestational diabetes mellitus in pregnant women with a family history of type 2 diabetes: a prospective, randomized, placebo-controlled study.” Diabetes Care 36.4 (2013): 854–7. DOI: 10.2337/dc12-1371
Dinkova, A., Martinov, D., Konova, E. “Efficacy of myo-inositol in the clinical management of patients with asthenozoospermia.” Eur Rev Med Pharmacol Sci 21 Suppl. 2 (2017): 62–5.
Fangxian, L., Alrais, M., Ontiveros, A.E., et al. “Effect of inositol supplementation during pregnancy on neurobehavioral outcome of offspring born to pregnant dams with metabolic syndrome.” American Journal of Obstetrics & Gynecology P852 (2017): 488.
Ferraretti, A.P., La Marca, A., Fauser, B.C., et al. “ESHRE consensus on the definition of 'poor response' to ovarian stimulation for in vitro fertilization: the Bologna criteria.” Hum Reprod 26.7 (2011): 1616–24. DOI: 10.1093/humrep/der092
Galletta, M., Grasso, S., Vaiarelli, A., Roseff, S.J. “Bye-bye chiro-inositol – myo-inositol: true progress in the treatment of polycystic ovary syndrome and ovulation induction.” Eur Rev Med Pharmacol Sci 15/10 (2011): 1212–4.
Garg, D., Tal, R. “Inositol Treatment and ART Outcomes in Women with PCOS.” Int J Endocrinol 2016 (2016): 1979654. DOI: 10.1155/2016/1979654
Genazzani, A.D., Lanzoni, C., Ricchieri, F., Jasonni, V.M. “Myo-inositol administration positively affects hyperinsulinemia and hormonal parameters in overweight patients with polycystic ovary syndrome.” Gynecol Endocrinol 24.3 (2008): 139–44. DOI: 10.1080/09513590801893232
Gerli, S., Mignosa, M., Di Renzo, G.C. “Effects of inositol on ovarian function and metabolic factors in women with PCOS: a randomized double blind placebo-controlled trial.” Eur Rev Med Pharmacol Sci 7.6 (2003): 151–9.
Gerli, S., Papaleo, E., Ferrari, A., Di Renzo, G.C. “Randomized, double blind placebo-controlled trial: effects of myo-inositol on ovarian function and metabolic factors in women with PCOS.” Eur Rev Med Pharmacol Sci 11.5 (2007): 347–54.
Gunkov, S., Tatarchuk, T., Zhminko, P., Regeda, S. “Effect of manganese and nickel on prolactin levels in women with polycystic ovary syndrome.” Georgian Med News 289 (2019): 21–5.
Greene, N.D., Leung, K.Y., Copp, A.J. “Inositol, neural tube closure and the prevention of neural tube defects.” Birth Defects Res 109.2 (2017): 68–80. DOI: 10.1002/bdra.23533
Harwood, K., Vuguin, P., Di Martino-Nardi, J. “Current approaches to the diagnosis and treatment of polycystic ovarian syndrome in youth.” Horm Res 68.5 (2007): 209–17. DOI: 10.1159/000101538
Hinton, B.T., White, R.W., Setchell, B.P. “Concentrations of myo-inositol in the luminal fluid of the mammalian testis and epididymis.” J Reprod Fertil 58.2 (1980): 395–9. DOI: 10.1530/jrf.0.0580395
Isabella, R., Raffone, E. “Expression of Concern to: Does ovary need D-chiro-inositol?” J Ovarian Res 11.1 (2018): 98. DOI: 10.1186/s13048-018-0470-4
Islam, M.O., Selvam, P., Appukuttan Pillai, R., et al. “An enzymatic assay for quantification of inositol in human term placental tissue.” Anal Biochem 586 (2019): 113409. DOI: 10.1016/j.ab.2019.113409
Kim, H., McGrath, B.M., Silverstone, P.H. “A Review of the Possible Relevance of Inositol and the Phosphatidylinositol Second Messenger System (PI-Cycle) to Psychiatric Disorders – Focus on Magnetic Resonance Spectroscopy (MRS) Studies.” Hum Psychopharmacol 20 (2005): 309–26. DOI: 10.1002/hup.693
Korosi, T., Barta, C., Rokob, K., Torok, T. “Physiological Intra-Cytoplasmic Sperm Injection (PICSI) outcomes after oral pretreatment and semen incubation with myo-inositol in oligoasthenoteratozoospermic men: results from a prospective, randomized controlled trial.” Eur Rev Med Pharmacol Sci 21 Suppl 2 (2017): 66–72.
Laganà, A.S., Rossetti, P., Buscema, M., et al. “Metabolism and Ovarian Function in PCOS Women: A Therapeutic Approach with Inositols.” Int J Endocrinol 2016 (2016): 6306410. DOI: 10.1155/2016/6306410
Lisi, F., Carfagna, P., Oliva, M.M., et al. “Pretreatment with myo-inositol in non-polycystic ovary syndrome patients undergoing multiple follicular stimulation for IVF: a pilot study.” Reprod Biol Endocrinol 10 (2012): 52. DOI: 10.1186/1477-7827-10-52
Liu, D.Y., Clarke, G.N., Baker, H.W. “Hyper-osmotic condition enhances protein tyrosine phosphorylation and zona pellucida binding capacity of human sperm.” Hum Reprod 21.3 (2006): 745–52. DOI: 10.1093/humrep/dei364
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 11.1 (2018): 38. DOI: 10.1186/s13048-018-0411-2
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. DOI: 10.1155/2016/1674950
Mukai, T., Kishi, T., Matsuda, Y., Iwata, N. “A meta-analysis of inositol for depression and anxiety disorders.” Hum Psychopharmacol 29.1 (2014): 55–63. DOI: 10.1002/hup.2369
Pacchiarotti, A., Carlomagno, G., Antonini, G., Pacchiarotti, A. “Effect of myo-inositol and melatonin versus myo-inositol, in a randomized controlled trial, for improving in vitro fertilization of patients with polycystic ovarian syndrome.” Gynecol Endocrinol 32.1 (2016): 69–73. DOI: 10.3109/09513590.2015.1101444
Papaleo, E., Unfer, V., Baillargeon, J.P., et al. “Myo-inositol in patients with polycystic ovary syndrome: a novel method for ovulation induction.” Gynecol Endocrinol 23.12 (2007): 700–3. DOI: 10.1080/09513590701672405
Papaleo, E., Unfer, V., Baillargeon, J.P., et al. “Myo-inositol may improve oocyte quality in intracytoplasmic sperm injection cycles. A prospective, controlled, randomized trial.” Fertil Steril 91.5 (2009): 1750–4. DOI: 10.1016/j.fertnstert.2008.01.088
Parker, S.E., Yazdy, M.M., Tinker, S.C., et al. “The impact of folic acid intake on the association among diabetes mellitus, obesity, and spina bifida.” Am J Obstet Gynecol 209.3 (2013): 239.e1–8. DOI: 10.1016/j. ajog.2013.05.047
Pizzo, A., Laganà, A.S., Barbaro, L. “Comparison between effects of myo-inositol and D-chiro-inositol on ovarian function and metabolic factors in women with PCOS.” Gynecol Endocrinol 30.3 (2014): 205–8. DOI: 10.3109/09513590.2013.860120
Raffone, E., Rizzo, P., Benedetto, V. “Insulin sensitiser agents alone and in co-treatment with r-FSH for ovulation induction in PCOS women.” Gynecol Endocrinol 26.4 (2010): 275–80.
Regidor, P.A., Schindler, A.E. “Myoinositol as a Safe and Alternative Approach in the Treatment of Infertile PCOS Women: A German Observational Study.” Int J Endocrinol 2016 (2016): 9537632. DOI: 10.1155/2016/9537632
Rizzo, P., Raffone, E., Benedetto, V. “Effect of the treatment with МІ-inositol plus folic acid plus melatonin in comparison with a treatment with МІ-inositol plus folic acid on oocyte quality and pregnancy outcome in IVF cycles. A prospective, clinical trial.” Eur Rev Med Pharmacol Sci 14 (2010): 555–61.
Rosenquist, T.H., Ratashak, S.A., Selhub, J. “Homocysteine induces congenital defects of the heart and neural tube: effect of folic acid.” Proc Natl Acad Sci U S A 93.26 (1996): 15227–32. DOI: 10.1073/pnas.93.26.15227
Artini, P.G., 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 33.2 (2017): 109–12. DOI: 10.1080/09513590.2016.1254179
Sacchinelli, A., Venturella, R., Lico, D., et al. “Corrigendum to "The Efficacy of Inositol and N-Acetyl Cysteine Administration (Ovaric HP) in Improving the Ovarian Function in Infertile Women with PCOS with or without Insulin Resistance.” Obstet Gynecol Int 2016 (2016): 2026056. DOI: 10.1155/2016/2026056
Santamaria, A., Di Benedetto, A., Petrella, E., et al. “Myo-inositol may prevent gestational diabetes onset in overweight women: a randomized, controlled trial.” J Matern Fetal Neonatal Med 29.19 (2016): 3234–7. DOI: 10.3109/14767058.2015.1121478
Sasseville, L.J., Longpré, J.P., Wallendorff, B., Lapointe, J.Y. “The transport mechanism of the human sodium/myo-inositol transporter 2 (SMIT2/SGLT6), a member of the LeuT structural family.” Am J Physiol Cell Physiol 307.5 (2014): 431–41. DOI: 10.1152/ajpcell.00054.2014
Schmidt, R.J., Tancredi, D.J., Ozonoff, S., et al. “Maternal periconceptional folic acid intake and risk of autism spectrum disorders and developmental delay in the CHARGE (CHildhood Autism Risks from Genetics and Environment) case-control study.” Am J Clin Nutr 96.1 (2012): 80–9. DOI: 10.3945/ajcn.110.004416
Serrano, N.C., Quintero-Lesmes, D.C., Becerra-Bayona, S., et al. “Association of pre-eclampsia risk with maternal levels of folate, homocysteine and vitamin B12 in Colombia: A case-control study.” PLoS One 13.12 (2018): e0208137. DOI: 10.1371/journal.pone.0208137
Showell, M.G., Mackenzie-Proctor, R., Jordan, V., et al. “Inositol for subfertile women with polycystic ovary syndrome.” Cochrane Database Syst Rev 12.12 (2018): CD012378. DOI: 10.1002/14651858.CD012378.pub2
Simi, G., Genazzani, A.R., Obino, M.E., et al. “Inositol and In Vitro Fertilization with Embryo Transfer.” Int J Endocrinol 2017 (2017): 5469409. DOI: 10.1155/2017/5469409
Tahir, F., Majid, Z. “Inositol Supplementation in the Prevention of Gestational Diabetes Mellitus.” Cureus 11.9 (2019): e5671. DOI: 10.7759/cureus.5671
Teede, H.J., Misso, M.L., Costello, M.F., et al.; International PCOS Network. “Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome.” Hum Reprod 33.9 (2018): 1602–18. DOI: 10.1093/humrep/dey256
Turan, G.A., Eskicioglu, F., Sivrikoz, O.N., et al. “Myo-inositol is a promising treatment for the prevention of ovarian hyperstimulation syndrome (OHSS): an animal study.” Arch Gynecol Obstet 292.5 (2015): 1163–71. DOI: 10.1007/s00404-015-3747-5
Unfer, V., Carlomagno, G., Rizzo, P., et al. “Мyo-inositol rather than D-chiro-inositol is able to improve oocyte quality in intracytoplasmic sperm injection cycles. A prospective, controlled, randomized trial.” Eur Rev Med Pharmacol Sci 15 (2011): 452–7.
Unfer, V., Nestler, J.E., Kamenov, Z.A., et al. “Effects of Inositol(s) in Women with PCOS: A Systematic Review of Randomized Controlled Trials.” Int J Endocrinol 2016 (2016): 1849162. DOI: 10.1155/2016/1849162
Unfer, V., Porcaro, G. “Updates on the myo-inositol plus D-chiro-inositol combined therapy in polycystic ovary syndrome.” Expert Rev Clin Pharmacol 7.5 (2014): 623–31. DOI: 10.1586/17512433.2014.925795
Venturella, R., Mocciaro, R., De Trana, E., et al. “Assessment of the modification of the clinical, endocrinal and metabolical profile of patients with PCOS syndrome treated with myo-inositol.” Minerva Ginecol 64.3 (2012): 239–43.
Vitagliano, A., Saccone, G., Cosmi, E., et al. “Inositol for the prevention of gestational diabetes: a systematic review and meta- analysis of randomized controlled trials.” Arch Gynecol Obstet 299.1 (2019): 55–68. DOI: 10.1007/s00404-018-5005-0
Vucenik, I. “Anticancer Properties of Inositol Hexaphosphate and Inositol: An Overview.” J Nutr Sci Vitaminol (Tokyo) 65 (2019) (Supplement): S18–S22. DOI: 10.3177/jnsv.65.S18
Wang, Y., Zhao, N., Qiu, J., et al. “Folic acid supplementation and dietary folate intake, and risk of preeclampsia.” Eur J Clin Nutr 69.10 (2015): 1145–50. DOI: 10.1038/ejcn.2014.295
Wojciechowska, A., Osowski, A., Jóźwik, M., et al. “Inositols' Importance in the Improvement of the Endocrine-Metabolic Profile in PCOS.” Int J Mol Sci 20.22 (2019): 5787. DOI: 10.3390/ijms20225787
Zacchè, M.M., Caputo, L., Filippis, S., et al. “Efficacy of myo-inositol in the treatment of cutaneous disorders in young women with polycystic ovary syndrome.” Gynecol Endocrinol 25.8 (2009): 508–13. DOI: 10.1080/09513590903015544
Zulfarina, M.S., Syarifah-Noratiqah, S.B., Nazrun, S.A., et al. “Pharmacological Therapy in Panic Disorder: Current Guidelines and Novel Drugs Discovery for Treatment-resistant Patient.” Clin Psychopharmacol Neurosci 17.2 (2019): 145–54. DOI: 10.9758/cpn.2019.17.2.145
Hanson, M.A., Bardsley, A., De-Regil, L.M., et al. “The International Federation of Gynecology and Obstetrics (FIGO) recommendations on adolescent, preconception, and maternal nutrition: "Think Nutrition First"”. Int J Gynaecol Obstet 131 Suppl 4 (2015): S213–53. DOI: 10.1016/S0020-7292(15)30034-5
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