Metabolic dysfunction correction as a method of restoring the function of the reproductive system in women
https://doi.org/10.21518/ms2023-087
Abstract
Insulin resistance is the main pathogenetic component of many metabolic diseases, including obesity, type 2 diabetes mellitus, gestational diabetes mellitus, and polycystic ovary syndrome (PCOS). Despite the fact that to date the mechanisms of insulin resistance formation have not been established, one of the promising directions at present is the search for potential therapeutic strategies for its correction, due to the fact that this also improves the course of the concomitant underlying disease. Insulin sensitizers are a generally recognized method of PCOS therapy due to their safety and effectiveness in normalizing the metabolic and endocrine profile of patients with polycystic ovary syndrome. The leading position in this direction is occupied by the combination of myo-inositol (MI) with D-chiro-inositol (DHI) in a ratio of 40:1, which, according to the conducted studies, is comparable to the concentration of inositols in the blood plasma of healthy women. This ratio of MI/DHI is effective both for normalization of the metabolic profile, and for regulation of the menstrual cycle and overcoming anovulatory infertility. An analysis of the literature has shown that a number of biologically active substances, such as folic acid, vitamin D and alpha-lipoic acid, in combination with insulin sensitizers, have additional advantages, which gives grounds for continuing research on their significance as components of combined treatment, as well as in the search for the optimal dose and duration of such therapy.
About the Authors
G. E. Chernukha
Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology
Russian Federation
Russian Federation
Galina E. Chernukha, Dr. Sci. (Med.), Professor, Chief Researcher, Obstetrician-Gynecologist of the Department of Gynecological Endocrinology,
4, Academician Oparin St., Moscow, 117997
V. A. Pronina
Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology
Russian Federation
Russian Federation
Veronika A. Pronina, Obstetrician-Gynecologist, Postgraduate Student,
4, Academician Oparin St., Moscow, 117997
References
1. Puttabyatappa M., Sargis R.M., Padmanabhan V. Developmental programming of insulin resistance: are androgens the culprits? J Endocrinol. 2020;245(3):R23–R48. https://doi.org/10.1530/JOE-20-0044.
2. Lee S.H., Park S.Y., Choi C.S. Insulin Resistance: From Mechanisms to Therapeutic Strategies. Diabetes Metab J. 2022;46(1):15–37. https://doi.org/10.4093/dmj.2021.0280.
3. Olatunbosun S.T., Griffing G.T. Insulin Resistance. Medscape. 2017. Available at: https://emedicine.medscape.com/article/122501-overview.
4. Laganà A.S., Vitale S.G., Noventa M., Vitagliano A. Current management of polycystic ovary syndrome: from bench to bedside. Int J Endocrinol. 2018;2018:7234543. https://doi.org/10.1155/2018/7234543.
5. He F.F., Li Y.M. Role of gut microbiota in the development of insulin resistance and the mechanism underlying polycystic ovary syndrome: a review. J Ovarian Res. 2020;13:73. https://doi.org/10.1186/s13048-020-00670-3.
6. Xu Y., Qiao J. Association of Insulin Resistance and Elevated Androgen Levels with Polycystic Ovarian Syndrome (PCOS): A Review of Literature. J Healthc Eng. 2022;2022:9240569. https://doi.org/10.1155/2022/9240569.
7. Azziz R. Polycystic ovary syndrome, reproductive endocrinology and infertility. Obstet Gynecol. 2018;132(2):321–336. https://doi.org/10.1097/AOG.0000000000002698.
8. Azziz R., Carmina E., Chen Z., Dunaif A., Laven J.S., Legro R.S., Lizneva D. et al. Polycystic ovary syndrome. Nat Rev Dis Primers. 2016;2:16057. https://doi.org/10.1038/nrdp.2016.57.
9. Carmina E., Longo R.A., Rini G.B., Lobo R.A. Phenotypic variation in hyperandrogenic women influences the finding of abnormal metabolic and cardiovascular risk parameters. J Clin Endocrinol Metab. 2005;90:2545–2549. https://doi.org/10.1210/jc.2004-2279.
10. Carmina E., Nasrallah M.P., Guastella E., Lobo R.A. Characterization of metabolic changes in the phenotypes of women with polycystic ovary syndrome in a large Mediterranean population from Sicily. Clin Endocrinol. 2019;91:553–560. https://doi.org/10.1111/cen.14063.
11. Moghetti P., Tosi F., Bonin C., Di Sarra D., Fiers T., Kaufman J.M., Giagulli V.A. et al. Divergences in insulin resistance between the different phenotypes of the polycystic ovary syndrome. J Clin Endocrinol Metab. 2013;98(4):E628–E637. https://doi.org/10.1210/jc.2012-3908.
12. Dapas M., Lin F.T.J., Nadkarni G.N., Sisk R., Legro R.S., Urbanek M., Hayes M.G., Dunaif A. Distinct subtypes of polycystic ovary syndrome with novel genetic associations: An unsupervised, phenotypic clustering analysis. PLoS Med. 2020;17(6):e1003132. https://doi.org/10.1371/journal.pmed.1003132.
13. Vrbikova J., Hill M., Bendlova B., Grimmichova T., Dvorakova K., Vondra K. et al. Incretin levels in polycystic ovary syndrome. Eur J Endocrinol. 2008;159(2):121–127. https://doi.org/10.1530/EJE-08-0097.
14. Willis D.S., Watson H., Mason H.D., Galea R., Brincat M., Franks S. Premature response to luteinizing hormone of Granulosa cells from Anovulatory women with polycystic ovary syndrome: relevance to mechanism of Anovulation. J Clin Endocrinol Metab. 1998;83(11):3984–3991. https://doi.org/10.1210/jcem.83.11.5232.
15. Dumesic D.A., Oberfield S.E., Stener-Victorin E., Marshall J.C., Laven J.S., Legro R.S. Scientific Statement on the Diagnostic Criteria, Epidemiology, Pathophysiology, and Molecular Genetics of Polycystic Ovary Syndrome. Endocr Rev. 2015;36(5):487–525. https://doi.org/10.1210/er.2015-1018.
16. Chernukha G.E., Miroshina E.D., Kuznetsov S.Yu., Ivanov I.A. Body mass index, body composition and metabolic profile of patients with polycystic ovary syndrome. Akusherstvo i Ginekologiya (Russian Federation). 2021;(10):103– 111. (In Russ.) https://doi.org/10.18565/aig.2021.10.103-111.
17. Lee S.H., Park S.A., Ko S.H., Yim H.W., Ahn Y.B., Yoon K.H., Cha B.Y. Insulin resistance and inflammation may have an additional role in the link between cystatin C and cardiovascular disease in type 2 diabetes mellitus patients. Metabolism. 2010;59(2):241–246. https://doi.org/10.1016/j.metabol.2009.07.019.
18. Kelly C.C.J., Lyall H., Petrie J.R., Gould G.W., Connell J.M.C., Sattar N. Low grade chronic inflammation in women with polycystic ovarian syndrome. J Clin Endocrinol Metab. 2001;86:2453–2455. https://doi.org/10.1210/jcem.86.6.7580.
19. Aboeldalyl S., James C., Seyam E., Ibrahim E.M., Shawki H.E., Amer S. The Role of Chronic Inflammation in Polycystic Ovarian Syndrome-A Systematic Review and Meta-Analysis. Int J Mol Sci. 2021;22(5):2734. https://doi.org/10.3390/ijms22052734.
20. Teede H., Misso M., Costello M., Dokras A., Laven J., Moran L. et al. International evidence-¬based guideline for the assessment and management of polycystic ovary syndrome 2018. Melbourne, Australia: Monash University; 2018. 198 p. Available at: https://www.monash.edu/__data/assets/pdf_ file/0004/1412644/PCOS_Evidence-Based-Guidelines_20181009.pdf.
21. Dietz de Loos A., Jiskoot G., Beerthuizen A., Busschbach J., Laven J. Metabolic health during a randomized controlled lifestyle intervention in women with PCOS. Eur J Endocrinol. 2021;186(1):53–64. https://doi.org/10.1530/EJE-21-0669.
22. Wharton S., Lau D.C.W., Vallis M., Sharma A.M., Biertho L., CampbellScherer D., Adamo K. Obesity in adults: a clinical practice guideline. CMAJ. 2020;192(31):E875–E891. https://doi.org/10.1503/cmaj.191707.
23. Napolitano A., Miller S., Nicholls A.W., Baker D., Van Horn S., Thomas E., Rajpal D. et al. Novel gut-based pharmacology of metformin in patients with type 2 diabetes mellitus. PLoS ONE. 2014;9(7):e100778. https://doi.org/10.1371/journal.pone.0100778.
24. Zhao H., Xing C., Zhang J., He B. Comparative efficacy of oral insulin sensitizers metformin, thiazolidinediones, inositol, and berberine in improving endocrine and metabolic profiles in women with PCOS: a network meta-analysis. Reprod Health. 2021;18(1):171. https://doi.org/10.1186/s12978-021-01207-7.
25. Murthy P.P. Structure and nomenclature of inositol phosphates, phosphoinositides, and glycosylphosphatidylinositols. Subcell Biochem. 2006;39:1–19. https://doi.org/10.1007/0-387-27600-9_1.
26. 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):690–695. https://doi.org/10.1080/09513590.2016.1188282.
27. 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;287:6991–6999. https://doi.org/10.1074/jbc.M111.335539.
28. Nestler J.E., Unfer V. Reflections on inositol(s) for PCOS therapy: Steps toward success. Gynecol Endocrinol. 2015;31:501–505. https://doi.org/10.3 109/09513590.2015.1054802.
29. Sun T.H., Heimark D.B., Nguygen T., Nadler J.L., Larner J. 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;293:1092–1098. https://doi.org/10.1016/S0006-291X(02)00313-3.
30. Fan C., Liang W., Wei M., Gou X., Han S., Bai J. Effects of D-Chiro-Inositol on Glucose Metabolism in db/db Mice and the Associated Underlying Mechanisms. Front Pharmacol. 2020;11:354. https://doi.org/10.3389/fphar.2020.00354.
31. Yap A., Nishiumi S., Yoshida K., Ashida H. Rat L6 myotubes as an in vitro model system to study GLUT4-dependent glucose uptake stimulated by inositol derivatives. Cytotechnology. 2007;55:103–108. https://doi.org/10.1007/s10616-007-9107-y.
32. Heimark D., McAllister J., Larner J. Decreased myo-inositol to chiroinositol (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. https://doi.org/10.1507/endocrj.EJ13-0423
33. Larner J., Huang L.C., Tang G., Suzuki S., Schwartz C.F., Romero G. et al. Insulin mediators: structure and formation. Cold Spring Harb Symp Quant Biol. 1988;53(Pt. 2):965–971. https://doi.org/10.1101/SQB.1988.053.01.111.
34. 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:E237–E248. https://doi.org/10.1152/ajpendo.00162.2019.
35. Kennington A.S., Hill C.R., Craig J., Bogardus C., Raz I., Ortmeyer H.K., Hansen B.C., Romero G., Larner J. Low urinary chiro-inositol excretion in non-insulin-dependent diabetes mellitus. N Engl J Med. 1990;323:373–378. https://doi.org/10.1056/NEJM199008093230603.
36. Carlomagno G., Unfer V., Roseff S. The D-chiro-inositol paradox in the ovary. Fertil Steril. 2011;95:2515–2516. https://doi.org/10.1016/j.fertnstert.2011.05.027.
37. 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;21:854–858. https://doi.org/10.1177/1933719113518985.
38. 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-inositolcontaining inositolphosphoglycan mediator correlates with insulin sensitivity in women with polycystic ovary syndrome. Metabolism. 2008;57(10):1390–1397. https://doi.org/10.1016/j.metabol.2008.05.008.
39. Isabella R., Raffone E. CONCERN: Does ovary need D-chiro-inositol? J Ovarian Res. 2012;5(1):14. https://doi.org/10.1186/1757-2215-5-14.
40. 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):545–550. https://doi.org/10.1080/09513590.2017.1421632.
41. Facchinetti F., Dante G., Dante I. The ratio of MI to DCI and its impact in the treatment of polycystic ovary syndrome: experimental and literature evidences. ISGE Series. 2016;3:103–109. https://doi.org/10.1007/978-3-319-23865-4_13.
42. Bevilacqua A., Dragotto J., Giuliani A., Bizzarri M. Myo-inositol and D-chiroinositol (40:1) reverse histological and functional features of polycystic ovary syndrome in a mouse model. J Cell Physiol. 2019;234(6):9387–9398. https://doi.org/10.1002/jcp.27623.
43. Gilling-Smith C., Willis D.S., Beard R.W., Franks S. Hypersecretion of androstenedione by isolated thecal cells from polycystic ovaries. J Clin Endocrinol Metab. 1994;79(4):1158–1165. https://doi.org/10.1210/jcem.79.4.7962289.
44. 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):5512–5521. https://doi.org/10.26355/eurrev_201906_18223.
45. 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. https://doi.org/10.18203/2320-1770.ijrcog20190498.
46. 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):2293–2301. https://doi.org/10.26355/eurrev_201903_17278.
47. Tagliaferri V., Romualdi D., Immediata V., De Cicco S., Di Florio C., Lanzone A., Guido M. Metformin vs myoinositol: Which is better in obese polycystic ovary syndrome patients? A randomized controlled crossover study. Clin Endocrinol. 2017;86:725–730. https://doi.org/10.1111/cen.13304.
48. Greff D., Juhász A.E., Váncsa S., Váradi A., Sipos Z., Szinte J., Park S. Inositol is an effective and safe treatment in polycystic ovary syndrome: a systematic review and meta-analysis of randomized controlled trials. Reprod Biol Endocrinol. 2023;21(1):10. https://doi.org/10.1186/s12958-023-01055-z.
49. Fruzzetti F., Perini D., Russo M., Bucci F., Gadducci A. Comparison of two insulin sensitizers, metformin and myo-inositol, in women with polycystic ovary syndrome (PCOS). Gynecol Endocrinol. 2017;33(1):39–42. https://doi.org/10.1080/09513590.2016.1236078.
50. Facchinetti F., Orrù B., Grandi G., Unfer V. Short-term effects of metformin and myo-inositol in women with polycystic ovarian syndrome (PCOS): a meta-analysis of randomized clinical trials. Gynecol Endocrinol. 2019;35(3):198–206. https://doi.org/10.1080/09513590.2018.1540578.
51. Advani K., Batra M., Tajpuriya S., Gupta R., Saraswat A., Nagar H.D., Makwana L. et al. Efficacy of combination therapy of inositols, antioxidants and vitamins in obese and non-obese women with polycystic ovary syndrome: An observational study. J Obstet Gynaecol. 2020;40:96–101. https://doi.org/10.1080/01443615.2019.1604644.
52. Radzinskiy V.E. (ed.). Pregravid preparation: clinical protocol. Moscow: StatusPraesens; 2016. 80 p. (In Russ.) Available at: https://rpc03.ru/wp-content/uploads/2016/09/Pregravidarnaja-podgotovka.compressed.pdf.
53. Twigt J.M., Hammiche F., Sinclair K.D. Preconception folic acid use modulates estradiol and follicular responses to ovarian stimulation. J Clin Endocrinol Metab. 2011;96(2):E322-E329. https://doi.org/10.1210/jc.2010-1282.
54. Li D., Liu H.-X., Fang Y.-Y., Huo J.-N., Wu Q.-J., Wang T.-R., Ma X.-X. Hyperhomocysteinemia in polycystic ovary syndrome: decreased betainehomocysteine methyltransferase and cystathionine β-synthase-mediated homocysteine metabolism. Reproductive BioMedicine Online. 2018;37(2):234–241. https://doi.org/10.1016/j.rbmo.2018.05.008.
55. Kalyanaraman R., Pal L. A Narrative Review of Current Understanding of the Pathophysiology of Polycystic Ovary Syndrome: Focus on Plausible Relevance of Vitamin D. Int J Mol Sci. 2021;22(9):4905. https://doi.org/10.3390/ijms22094905.
56. Dravecká I., Figurová J., Javorský M., Petríková J., Vaľková M., Lazúrová I. The effect of alfacalcidiol and metformin on phenotype manifestations in women with polycystic ovary syndrome – a preliminary study. Physiol Res. 2016;65(5):815–822. https://doi.org/10.33549/physiolres.933266.
57. Tehrani H.G., Mostajeran F., Shahsavari S. The effect of calcium and vitamin D supplementation on menstrual cycle, body mass index and hyperandrogenism state of women with polycystic ovarian syndrome. J Res Med Sci. 2014;19:875–880. Available at: https://pubmed.ncbi.nlm.nih.gov/25535503.
58. Menichini D., Facchinetti F. Effects of vitamin D supplementation in women with polycystic ovary syndrome: A review. Gynecol Endocrinol. 2020;36:1–5. https://doi.org/10.1080/09513590.2019.1625881.
59. Guo S., Tal R., Jiang H., Yuan T., Liu Y. Vitamin D Supplementation Ameliorates Metabolic Dysfunction in Patients with PCOS: A Systematic Review of RCTs and Insight into the Underlying Mechanism. Int J Endocrinol. 2020;2020:7850816. https://doi.org/10.1155/2020/7850816.
60. Genazzani A.D., Prati A., Marchini F., Petrillo T., Napolitano A., Simoncini T. 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. Gynecological Endocrinology. 2019;1:6. https://doi.org/10.1080/09513590.2019.1640200.
61. Lee W.J., Song K.H., Koh E.H., Won J.C., Kim H.S., Park H.S. et al. Alpha-lipoic acid increases insulin sensitivity by activating AMPK in skeletal muscle. Biochem Biophys Res Commun. 2005;332:885–891. https://doi.org/10.1016/j.bbrc.2005.05.035.
62. 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):1395–1403. https://doi.org/10.1152/ajpcell.00115.2007.
Review
For citations:
Chernukha GE, Pronina VA. Metabolic dysfunction correction as a method of restoring the function of the reproductive system in women. Meditsinskiy sovet = Medical Council. 2023;(5):90-97. (In Russ.) https://doi.org/10.21518/ms2023-087
Views:
727
Email this article 