Inositol and lipoic acid in the treatment of insulin resistance in women with polycystic ovary syndrome


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Abstract

Insulin resistance (IR) is a trigger for most pathogenetic changes in polycystic ovary syndrome (PCOS). The inositol stereoisomers myo-inositol (MI) and D-chiro-inositol (DCI) are actively involved in showing insulin effects. The MI/DCI ratio varies with tissue metabolic requirements and is under strict control with insulin. The MI/DCI ratio in plasma is 40:1, whereas that in follicular fluid is 100:1. In women with PCOS and IR, the concentration of DCI in insulin-sensitive tissues (muscles, brain, heart, adipose tissue) decreases drastically, which may be due to both a lack of total consumption of inositol and impaired expression/synthesis of epimerase that converts MI into DCI. The ovaries, on the other hand, respond to excess insulin by over-epimerization of MI in DCI and by a decrease in the MI/DCI ratio in follicular fluid to 0.2:1. Experimental and clinical studies have shown that MI in combination with DCI in the 40:1 ratio corresponding to the physiological content in blood plasma is the most optimal therapeutic regimen to reverse metabolic, hormonal, and reproductive disorders in women with PCOS. Regulation of glucose metabolism also occurs independently of inositol with endogenous alpha-lipoic acid (ALA) synthesized in the mitochondria. Conclusion. Supplementation of ALA with inositol improves insulin sensitivity and reproductive function in women with PC OS, especially in those with obesity and a genetic predisposition to diabetes mellitus. Thus, ALA in combination with MI and DCI creates a new comprehensive strategy for overcoming IR and its sequels in women with PCOS.

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About the authors

Olga A. Pustotina

F.I. Inozemtsev Academy of Medical Education

Email: pustotina@gmail.com
Dr. Med. Sci., Professor of the Department of obstetrics and gynecology with a course in reproductive medicine

References

  1. Teede H.J., Misso M.L., Costello M.F., Dokras A., Laven J., Moran L. et al. Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Hum. Reprod. 2018; 33(9): 1602-18. https://dx.doi.org/10.1093/humrep/dey256.
  2. Genazzani A.D., Ricchieri F., Lanzoni C. Use of metformin in the treatment of polycystic ovary syndrome. Womens Health. (Lond.). 2010; 6(4): 577-93. https://dx.doi.org/10.2217/whe.10.43.
  3. De Leo V., Musacchio M.C., Cappelli V., Massaro M.G., Morgante G., Petraglia F. Genetic, hormonal and metabolic aspects of PCOS: an update. Reprod. Biol. Endocrinol. 2016; 14(1): 38. https://dx.doi.ois/10.1186/s12958-016-0173-x.
  4. Behboudi-Gandevani S., Tehrani F.R., Dovom M.R., Farahmand M., Khomami M.B., Noroozzadeh M. et al. Insulin resistance in obesity and polycystic ovary syndrome: systematic review and meta-analysis of observational studies. Gynecol. Endocrinol. 2016; 32(5): 343-53. https://dx.doi.org/10.3109/09513 590.2015.1117069.
  5. Michell R.H. Do inositol supplements enhance phosphatidylinositol supply and thus support endoplasmic reticulum function? Br. J. Nutr. 2018 Jun 3; 1-16. https://dx.doi.org/10.1017/S0007114518000946.
  6. Bizzarri M, Fuso A., Dinicola S., Cucina A., Bevilacqua A. Pharmacodynamics and pharmacokinetics of inositol(s) in health and disease. Expert Opin. Drug Metab. Toxicol. 2016; 12(10): 1181-96. https://dx.doi.org/10.1080/17425255. 2016.1206887.
  7. Lagana A.S., Garzon S., Casarin J., Franchi M., Ghezzi F. Inositol in polycystic ovary syndrome: restoring fertility through a pathophysiology-based approach. Trends Endocrinol. Metab. 2018; 29(11): 768-80. https://dx.doi.org/10.1016/j. tem.2018.09.001.
  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/10.3109/0 9513590.2015.1054802.
  9. 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., Mikhailyukova A.S., Levin V.A., Petukhova N.L., Markin A.V., Steptsova E.M. Reserves for improving the quality of oocytes in polycystic ovary syndrome. Reproduction problems. 2017; 23(3): 50-4. (in Russian)].
  10. Parthasarathy R., Eisenberg F. Jr. The inositol phospholipids: a stereochemical view of biological activity. Biochem. J. 1986; 235(2): 313-22. https://dx.doi. org/10.1042/bj2350313.
  11. Bizzarri M., Carlomagno G. Inositol: history of an effective therapy for polycystic ovary syndrome. Eur. Rev. Med. Pharmacol. Sci. 2014; 18(13): 1896-903.
  12. 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.
  13. Lagana A.S., Vitale S.G., Nigro A., Sofo V., Salmeri F.M., Rossetti P. et al. Pleiotropic actions of peroxisome proliferator-activated receptors (PPARs) in dysregulated metabolic homeostasis, inflammation and cancer: current evidence and future perspectives. Int. J. Mol. Sci. 2016; 17(7): 999. https://dx.doi. org/10.3390/ijms17070999.
  14. Chukwuma C.I., Ibrahim M.A., Islam M.S. Myo-inositol inhibits intestinal glucose absorption and promotes muscle glucose uptake: a dual approach study. J. Physiol. Biochem. 2016; 7 (4): 791-801. https://dx.doi.org/10.1007/s13105-016-0517-1.
  15. 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): 111-7. https://dx.doi.org/10.1507/endocrj.ej13-0423.
  16. 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. https://dx.doi. org/10.1080/15604280212528.
  17. 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.
  18. 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. Front. Gynecol. Endocrinol. 2016; 3: 103-9.
  19. Unfer V., Carlomagno G., Papaleo E., Vailati S., Candiani M., Baillaargeon 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.
  20. Larner J., Brautigan D.L., Thorner M.O. D-chiro-inositol glycans in insulin signaling and insulin resistance. Mol. Med. 2010; 16(11-12): 543-52. https:// dx.doi.org/10.2119/molmed.2010.00107.
  21. Padmalayam I., Hasham S., Saxena U., Pillarisetti S. Lipoic acid synthase (LASY): a novel role in inflammation, mitochondrial function, and insulin resistance. Diabetes. 2009; 58(3): 600-8. https://dx.doi.org/10.2337/ db08-0473.
  22. Smith A.R., Shenvi S.V., Widlansky M., Suh J.H., Hagen T.M. Lipoic acid as a potential therapy for chronic diseases associated with oxidative stress. Curr. Med. Chem. 2004; 11(9): 1135-46. https://dx.doi.org/10.2174/0929867043365387.
  23. Masharani U., Gjerde C., Evans J.L., Youngren J.F., Goldfine I.D. Effects of controlled-release alpha lipoic acid in lean, nondiabetic patients with polycystic ovary syndrome. J. Diabetes Sci. Technol. 2010; 4(2): 359-64. https://dx.doi. org/10.1177/193229681000400218.
  24. Genazzani A.D. Expert’s opinion: integrative treatment with inositols and lipoic acid for insulin resistance of PCOS. GREM Gynecol. Reprod. Endocrinol. Metab. 2020; 1(3): 146-57.
  25. Unfer V., Orru B., Monastra G. Inositols: from physiology to rational therapy in gynecological clinical practice. Expert Opin. Drug Metab. Toxicol. 2016; 12(10): 1129-31. https://dx.doi.org/10.1080/17425255.2016.1225039.
  26. Facchinetti F., Bizzarri M., Benvenga S., DAnna 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. https://dx.doi.org/10.1016/j.ejogrb.2015.09.024.
  27. 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): 25574. https://dx.doi.org/10.1080/17425255.2020.1737675.
  28. Bevilacqua A., Carlomagno G., Gerli S., Oliva M.M., Devroey P., Lanzone A. et al. Results from the international consensus conference on myo-inositol and d-chiro-inositol in obstetrics and gynecology-assisted reproduction technology. Gynecol. Endocrinol. 2015; 31(6): 441-6. https://dx.doi.org/10.3109/0951359 0.2015.1006616.
  29. Vitagliano A., Sac cone G., Cosmi E., Visentin S., Dessole F., Ambrosini G., Berghella V. Inositol for the prevention of gestational diabetes: a systematic review and meta-analysis of randomized controlled trials. Arch. Gynecol. Obstet. 2019; 299(1): 55-68. https://dx.doi.org/10.1007/ s00404-018-5005-0.
  30. Nestler J.E., Jakubowicz D.J., de Vargas A.F., Brik C., Medina F. 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 5. https://dx.doi.org/10.1210/jcem.83.6.4886
  31. 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
  32. 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
  33. Zeng L., Yang K. Effectiveness of myoinositol for polycystic ovary syndrome: a systematic review and meta-analysis. Endocrine. 2018; 59(1): 30-8. https:// dx.doi.org/10.1007/s12020-017-1442-y.
  34. Pundir J., Psaroudakis D., Savnur P., Bhide P., Sabatini L., Teede H. et al. Inositol treatment of anovulation in women with polycystic ovary syndrome: a metaanalysis of randomised trials. BJOG. 2018; 125(3): 299-308. https://dx.doi. org/10.1111/1471-0528.14754.
  35. Unfer V., Facchinetti F, Orru 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.
  36. Воронцова А.В., Гаспарян С.А., Громова О.А., Джобава Э.М., Киселева Е.Ю., Коротких И.Н., Кулешов В.М., Обоскалова Т.А., Пустотина О.А., Сахаутдинова И.В., Спиридонова Н.В., Тапильская Н.И., Тхостова Е.Б. Заключение совещания экспертов «Обоснование применения средств на основе инозитола у пациенток с нарушениями менструального цикла». Проблемы репродукции. 2020; 26(1): 44-54. [Vorontsova A.V., Gasparyan S.A., Gromova O.A., Dzhobava E.M., Kiseleva E.Yu., Korotkikh I.N., Kuleshov V.M., Oboskalova T.A., Pustotina O.A., Sahautdinova I.V., Spiridonova N.V., Tapilskaya N.I., Tkhostova E.B. The Conclusion of the expert meeting "The rationale for the use of funds on the basis of inositol in patients with disorders of the menstrual cycle". Problems of Reproduction. 2020; 26(1): 44-54. (in Russian)].
  37. Jamilian H., Jamilian M., Foroozanfard F., Ebrahimi F.A., Bahmani F., Asemi Z. Comparison of myo-inositol and metformin on mental health parameters and biomarkers of oxidative stress in women with polycystic ovary syndrome: a randomized, double-blind, placebo-controlled trial. J. Psychosom. Obstet. Gynaecol. 2018; 39(4): 307-14. https://dx.doi.org/10.1080/016748 2X.2017.1383381.
  38. Shokrpour M., Foroozanfard F., Ebrahimi F.A., Vahedpoor Z., Aghadavod E., Ghaderi A., Asemi Z. Comparison of myo-inositol and metformin on glycemic control, lipid profiles, and gene expression related to insulin and lipid metabolism in women with polycystic ovary syndrome: a randomized controlled clinical trial. Gynecol. Endocrinol. 2019; 35(5): 406-11. https://dx.doi.org/10.1080/0951359 0.2018.1540570.
  39. Facchinetti F, Orru B., Grandi G., Unfer V. Short-term effects of metformin and myo-inositol in women with polycystic ovarian syndrome (PCOS): a metaanalysis of randomized clinical trials. Gynecol. Endocrinol. 2019; 35(3): 198206. https://dx.doi.org/10.1080/09513590.2018.1540578.
  40. Lagana A.S., Vitagliano A., Noventa M., Ambrosini G., D’Anna R. Myo-inositol supptementation 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.
  41. Gateva A., Unfer V., Kamenov Z. The use of inositol(s) isomers in the management of polycystic ovary syndrome: a comprehensive review. Gynecol. Endocrinol. 2018; 34(7): 545-50. https://dx.doi.org/10.1080/09513590.2017.1421632.
  42. Unfer V., Carlomagno G., Rizzo P., Raffone E., Roseff S. Myo-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. 2011; 15(4): 452-7.
  43. Isabella R., Raffone E. CONCERN: Does ovary need D-chiro-inositol? J. Ovarian Res. 2012; 5(1): 14. https://dx.doi.org/10.1186/1757-2215-5-14.
  44. Garzon S., Lagana A.S., Monastra G. Risk of reduced intestinal absorp- tion 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.
  45. 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. 2008; 24(3): 139-44. https://dx.doi.org/10.1080/09513590801893232.
  46. Cheang K.I., Baillargeon J.-P., Essah P.A., Ostlund Jr R.E., 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.
  47. Genazzani A.D., Santagni S., Rattighieri E., Chierchia E., Despini G., Marini G. et al. Modulatory role of D-chiro-inositol (DCI) on LH and insulin secretion in obese PCOS patients. Gynecol. Endocrinol. 2014; 30(6): 438-43. https://dx.doi. org/10.3109/09513590.2014.897321.
  48. La Marca A., Grisendi V., Dondi G., Sighinolfi G., Ciaci A. The menstrual cycle regularization following D-chiro-inositol treatment in PCOS women: a retrospective study. Gynecol. Endocrinol. 2015; 31(1): 52-6. https://dx.doi.org/ 10.3109/09513590.2014.964201.
  49. Lagana A.S., Unfer V. D-chiro-inositol’s action as aromatase inhibitor: rationale and potential clinical targets. Eur. Rev. Med. Pharmacol. Sci. 2019; 23(24): 10575-6.
  50. 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.
  51. 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.
  52. 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.
  53. Benelli E., Del Ghianda S., Di Cosmo C., Tonacchera M. A combined therapy with myo-inositol and D-chiro-inositol improves endocrine para- meters and insulin resistance in PCOS young overweight women. Int. J. Endocrinol. 2016; 2016: 3204083. https://dx.doi.org/10.1155/2016/3204083.
  54. Le Donne M., Metro D., Alibrandi A., Papa M., Benvenga S. Effects of three treatment modalities (diet, myoinositol or myoinositol associated with D-chiro-inositol) on clinical and body composition outcomes in women with polycystic ovary syndrome. Eur. Rev. Med. Pharmacol. Sci. 2019; 23(5): 2293-301. https:// dx.doi.org/10.26355/eurrev_201903_17278.
  55. Colazingari S.T.M., Najjar R., Bevilacqua A. Treatment of hyperandrogenism by Myo-inositol: results from a randomized controlled trial. Arch. Gynecol. Obstet. 2013; 11: 1405.
  56. Shen Q.W., Zhu M.J., Tong J., Ren J., Du M. Ca2+/calmodulin-dependent protein kinase kinase is involved in AMP-activated protein kinase activation by alpha-lipoic acid in C2C12 myotubes. Am. J. Physiol. Cell Physiol. 2007; 293(4): C1395-403. https://dx.doi.org/10.1152/ajpcell.00115.2007.
  57. Morikawa T., Yasuno R., Wada H. Do mammalian cells synthesize lipoic acid? Identification of a mouse cDNA encoding a lipoic acid synthase located in mitochondria. FEBS Lett. 2001; 498(1): 16-21. https://dx.doi.org/10.1016/ s0014-5793(01)02469-3.
  58. Gomes M.B., Negrato C.A. Alpha-lipoic acid as a pleiotropic com- pound with potential therapeutic use in diabetes and other chronic diseases. Diabetol. Metab. Syndr. 2014; 6(1): 80. https://dx.doi.org/10.1186/ 1758-5996-6-80.
  59. Scaramuzza A., Giani E., Radaelli F., Ungheri S., Macedoni M., Giudici V. et al. Alpha-lipoic acid and antioxidant diet help to improve endothelial dysfunction in adolescents with type 1 diabetes: a pilot trial. J. Diabetes Res. 2015; 2015: 474561. https://dx.doi.org/10.1155/2015/ 474561.
  60. Genazzani A.D., Shefer K., Della Casa D., Prati A., Napolitano A, Manzo A. et al. Modulatory effects of alpha-lipoic acid (ALA) administration on insulin sensitivity in obese PCOS patients. J. Endocrinol. Invest. 2018; 41(5): 583-90. https://dx.doi.org/10.1007/s40618-017-0782-z.
  61. Xie G.B., Xu P., Che Y.N., Xia Y.J., Cao Y.X., Wang W.J. et al. Microsatellite polymorphism in the fibrillin 3 gene and susceptibility to PCOS: a case-control study and meta-analysis. Reprod. Biomed. Online. 2013; 26(2): 168-74. https:// dx.doi.org/10.1016/j.rbmo.2012.10.014.
  62. Genazzani A.D., Prati A., Simoncini T., Napolitano A. Modulatory role of D-chiro-inositol and alpha lipoic acid combination on hormonal and metabolic parameters of overweight/obese PCOS patients. Eur. Gynecol. Obstet. 2019; 1(1): 29-33
  63. Cianci A., Panella M., Fichera M., Falduzzi C., Bartolo M., Caruso S. D-chiro-inositol and alpha lipoic acid treatment of metabolic and menses disorders in women with PCOS. Gynecol. Endocrinol. 2015; 31(6): 483-6. https://dx.doi. org/10.3109/09513590.2015.1014784
  64. De Cicco S., Immediata V., Romualdi D., Policola C., Tropea A., Di Florio C. et al. Myoinositol combined with alpha-lipoic acid may improve the clinical and endocrine features of polycystic ovary syndrome through an insulin-independent action. Gynecol. Endocrinol. 2017; 33(9): 698-701. https://dx.doi.org/10.1080/ 09513590.2017.1313972.
  65. Genazzani A.D., Despini G., Santagni S., Prati A., Rattighieri E., Chierchia E., Simoncini T. Effects of a combination of alpha lipoic acid and myo-inositol on insulin dynamics in over- weight/obese patients with PCOS. Endocrinol. Metab. Synd. 2014; 3: 3. https://dx.doi.org/10.4172/2161-1017.1000140

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