A Review on Inocytol and Lipoic Acid Reinforcement from Current Therapeutic Agents in Polycistic Over Syndrome

Year 2021, , 184 - 196, 12.07.2021

Selma Fırat , Mehmet Fisunoğlu

https://doi.org/10.53394/akd.958775

Abstract

Polycystic ovary syndrome (PCOS) is an endocrine disorder seen in women of reproductive age and
causes reproductive, hormonal and metabolic anomalies. Different therapeutic agents with insulin
sensitizing properties are also used for the treatment of PCOS due to the accompany of insulin
resistance (IR). Inositol with insulin sensitizing properties and alpha lipoic acid with antioxidant
properties are among these therapeutic agents. Inositol (myo-inositol and di-chiroinositol) is a dietary
supplement that plays a role in insulin signal transduction as a secondary messenger and has been
shown to be effective in the treatment of PCOS. Studies have reported that ovulation rate, menstrual
cycles and metabolic profiles in women with PCOS have improved with inositol supplementation. The
use of α-lipoic acid (ALA) for the treatment of PCOS and IR is also considered a possible therapeutic
approach. In addition to being a potent antioxidant, ALA can increase insulin sensitivity through
activation of the 5'-adenosine monophosphate-activated protein kinase (AMPK), which is a cellular
energy sensor that induces the translocation of glucose carrier 4 (GLUT4) into the plasma membrane
through an insulin-independent mechanism. For this reason, it is stated that ALA can increase insulin
sensitivity and reproductive functions and correct metabolic abnormalities in women with PCOS
by reducing oxidative stress. In recent studies, it was found that better results were obtained with
combined therapy compared to the individual supplementation of inositol and lipoic acid. In this
review, the effects of inositol and ALA separately and the combined treatment of both in PCOS were
investigated.

Keywords

Polycystic ovary syndrome, Inositol, Lipoic acid, Therapeutic agent

Polikistik Over Sendromunda Güncel Terapötik Ajanlardan İnositol ve Alfa Lipoik Asit Takviyesi Üzerine Bir Derleme

Abstract

Polikistik over sendromu (PKOS) üreme çağındaki kadınlarda görülen bir endokrin bozukluk olup,
üreme, hormonal ve metabolik anomalilere neden olur. İnsülin direncinin (İD) eşlik etmesi nedeniyle
PKOS tedavisi için insülin duyarlaştırıcı özelliği bulunan farklı terapötik ajanlar da kullanılmaktadır.
İnsülin duyarlaştırıcı özelliği bulunan inositol ve antioksidan özelliği olan alfa lipoik asit de bu
terapötik ajanlar arasında yer almaktadır. İnositol (myo-inositol ve di-chiroinositol), ikincil bir haberci
olarak insülin sinyal iletimi transdüksiyonunda rol alan ve PKOS tedavisinde etkili olduğu gösterilen
bir besin takviyesidir. Yapılan çalışmalar, inositol takviyesi ile PKOS'lu kadınlarda yumurtlama hızı,
adet döngüleri ve metabolik profillerinde düzelmeler olduğunu bildirmektedir. PKOS ve İD tedavisi
için α-lipoik asit (ALA) kullanımı da olası bir terapötik yaklaşım olarak kabul edilmektedir. ALA güçlü
bir antioksidan olmanın yanı sıra insülinden bağımsız bir mekanizma ile glikoz taşıyıcı 4'ün (GLUT4)
plazma zarına translokasyonunu indükleyen bir hücresel enerji sensörü olan 5’-adenosin monofosfatla
aktive edilen protein kinazın (AMPK) aktivasyonu yoluyla insülin duyarlılığını artırabilir. Bu nedenle
PKOS'lu kadınlarda ALA'nın oksidatif stresi azaltarak insülin duyarlılığını ve üreme fonksiyonlarını
artırabileceği ve metabolik anormallikleri düzeltebileceği belirtilmektedir. Son zamanlarda yapılan
çalışmalarda ise inositol ve lipoik asidin ayrı ayrı takviyesine oranla kombine tedavi ile daha iyi sonuçlar
alındığı bulunmuştur. Bu derlemede inositol ve ALA’nın ayrı ayrı ve ikisinin kombine tedavisinin
PKOS’taki etkisi incelenmiştir.

Keywords

Polikistik over sendromu, İnositol, Lipoik asit, Terapötik ajan

References

• 1. Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril 2004;81(1):19-25.
• 2. Dumesic DA, Oberfield SE, Stener-Victorin E, Marshall JC, Laven JS, Legro RS. Scientific statement on the diagnostic criteria, epidemiology, pathophysiology, and molecular genetics of polycystic ovary syndrome. Endocr Rev 2015;36(5):487-525.
• 3. Escobar-Morreale HF. Polycystic ovary syndrome: definition, aetiology, diagnosis and treatment. Nat Rev Endocrinol 2018;14(5):270.
• 4. March WA, Moore VM, Willson KJ, Phillips DI, Norman RJ, Davies MJ. The prevalence of polycystic ovary syndrome in a community sample assessed under contrasting diagnostic criteria. Hum Reprod 2010;25(2):544-51.
• 5. Dewailly D. Diagnostic criteria for PCOS: is there a need for a rethink? Best Pract Res Clin Obstet Gynaecol 2016;37:5-11.
• 6. Nardo L, Patchava S, Laing I. Polycystic ovary syndrome: pathophysiology, molecular aspects and clinical implications. Panminerva Med 2008;50(4):267-78.
• 7. Xita N, Tsatsoulis A. Fetal programming of polycystic ovary syndrome by androgen excess: evidence from experimental, clinical, and genetic association studies. J Clin Endocrinol Metab 2006;91(5):1660-6.
• 8. Teede H, Misso M, Costello M, Dokras A, Laven J, Moran L, Piltonen T, Norman RJ. Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Fertil Steril 2018;110(3):364-79.
• 9. Pundir J, Psaroudakis D, Savnur P, Bhide P, Sabatini L, Teede H, Coomarasamy A, Thangaratinam S. Inositol treatment of anovulation in women with polycystic ovary syndrome: a meta‐analysis of randomised trials. BJOG 2018;125(3):299-308.
• 10. Unfer V, Carlomagno G, Dante G, Facchinetti F. Effects of myo-inositol in women with PCOS: a systematic review of randomized controlled trials. Gynecol Endocrinol 2012;28(7):509-15.
• 11. Croze ML, Soulage CO. Potential role and therapeutic interests of myo-inositol in metabolic diseases. Biochimie 2013;95(10):1811-27.
• 12. Fruzzetti F, Benelli E, Fidecicchi T, Tonacchera M. Clinical and metabolic effects of alpha-lipoic acid associated with two different doses of myo-inositol in women with polycystic ovary syndrome. Int J Endocrinol 2020:2901393.
• 13. 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.
• 14. Heimark D, McAllister J, Larner J. Decreased myoinositol 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.
• 15. Sun T-h, Heimark DB, Nguygen T, Nadler JL, 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(3):1092-8.
• 16. Baillargeon J-P, Diamanti-Kandarakis E, Ostlund RE, Apridonidze T, Iuorno MJ, Nestler JE. Altered D-chiroinositol urinary clearance in women with polycystic ovary syndrome. Diabetes care 2006;29(2):300-5.
• 17. Carlomagno G, Unfer V, Roseff S. The D-chiro-inositol paradox in the ovary. Fertil Steril 2011;95(8):2515-6.
• 18. Unfer V, Nestler JE, Kamenov ZA, Prapas N, Facchinetti F. Effects of inositol (s) in women with PCOS: a systematic review of randomized controlled trials. Int J Endocrinol 2016:1849162.
• 19. Crawford TJ, Crowther CA, Alsweiler J, Brown J. Antenatal dietary supplementation with myo-inositol in women during pregnancy for preventing gestational diabetes. Cochrane Database Syst Rev 2015:Cd011507.
• 20. Shay KP, Moreau RF, Smith EJ, Smith AR, Hagen TM. Alpha-lipoic acid as a dietary supplement: molecular mechanisms and therapeutic potential. Biochim Biophys Acta 2009;1790(10):1149-60.
• 21. Golbidi S, Badran M, Laher I. Diabetes and alpha lipoic acid. Front Pharmacol 2011;2:69.
• 22. Ma X, He P, Sun P, Han P. Lipoic acid: an immunomodulator that attenuates glycinin-induced anaphylactic reactions in a rat model. J Agric Food Chem 2010;58(8):5086-92.
• 23. Lee WJ, Song K-H, Koh EH, Won JC, Kim HS, Park H-S, Kim MS, Kim SW, Lee KU, Park JY. α-Lipoic acid increases insulin sensitivity by activating AMPK in skeletal muscle. Biochem Biophys Res Commun 2005;332(3):885-91.
• 24. Shen QW, Zhu MJ, Tong J, Ren J, Du M. Ca2+/calmodulin-dependent protein kinase kinase is involved in AMP-activated protein kinase activation by α-lipoic acid in C2C12 myotubes. Am J Physiol Cell Physiol 2007;293(4):1395-403.
• 25. Steinberg GR, Kemp BE. AMPK in health and disease. Physiol Rev 2009;89(3):1025-78.
• 26. Di Tucci C, Di Feliciantonio M, Vena F, Capone C, Schiavi MC, Pietrangeli D, Muzii L, Benedetti Panici P. Alpha lipoic acid in obstetrics and gynecology. Gynecol Endocrinol 2018;34(9):729-33.
• 27. Goodarzi MO, Dumesic DA, Chazenbalk G, Azziz R. Polycystic ovary syndrome: etiology, pathogenesis and diagnosis. Nat Rev Endocrinol 2011;7(4):219-31.
• 28. Rondanelli M, Perna S, Faliva M, Monteferrario F, Repaci E, Allieri F. Focus on metabolic and nutritional correlates of polycystic ovary syndrome and update on nutritional management of these critical phenomena. Arch Gynecol Obstet 2014;290(6):1079-92.
• 29. Galazis N, Docheva N, Nicolaides KH, Atiomo W. Proteomic biomarkers of preterm birth risk in women with polycystic ovary syndrome (PCOS): a systematic review and biomarker database integration. PloS One 2013;8(1):e53801.
• 30. Kriedt KJ, Alchami A, Davies MC. PCOS: diagnosis and management of related infertility. Obstetrics, Gynaecology & Reproductive Medicine 2018;29:1
• 31. Yıldızhan B, Anık İlhan G. Polikistik Over Sendromunda Uzun Dönem Sağlık Sorunları. Van Tıp Derg 2016;23(3):301-6.
• 32. Balen AH. Polycystic ovary syndrome (PCOS). The Obstetrician & Gynaecologist 2017;19:119-29.
• 33. Anagnostis P, Tarlatzis BC, Kauffman RP. Polycystic ovarian syndrome (PCOS): Long-term metabolic consequences. Metabolism 2018;86:33-43.
• 34. Hoeger K. Obesity and weight loss in polycystic ovary syndrome. Obstetrics and gynecology clinics of North America 2001;28(1):85-97.
• 35. Martinez-Bermejo E, Luque-Ramirez M, EscobarMorreale HF. Obesity and the polycystic ovary syndrome. Minerva Endocrinol 2007;32(3):129-40.
• 36. Panidis D, Farmakiotis D, Rousso D, Kourtis A, Katsikis I, Krassas G. Obesity, weight loss, and the polycystic ovary syndrome: effect of treatment with diet and orlistat for 24 weeks on insulin resistance and androgen levels. Fertil Steril 2008;89(4):899-906.
• 37. Moran LJ, Brinkworth GD, Norman RJ. Dietary therapy in polycystic ovary syndrome. Semin Reprod Med 2008;26(1):85-92.
• 38. Dessi A, Fanos V. Myoinositol: a new marker of intrauterine growth restriction? J Obstet Gynaecol 2013;33(8):776-80.
• 39. Malvasi A, Casciaro F, Minervini M, Kosmas I, Mynbaev O, Pacella E, Monti Condesnitt V, Creanza A, Di Renzo GC, Tinelli A. Myo-inositol, D-chiro-inositol, folic acid and manganese in second trimester of pregnancy: a preliminary investigation. Eur Rev Med Pharmacol Sci 2014;18(2):270-4.
• 40. Stracquadanio M, Ciotta L, Palumbo MA. Effects of myo-inositol, gymnemic acid, and L-methylfolate in polycystic ovary syndrome patients. Gynecol Endocrinol 2018;34(6):495-501.
• 41. Celentano C, Matarrelli B, Mattei PA, Pavone G, Vitacolonna E, Liberati M. Myo-Inositol Supplementation to Prevent Gestational Diabetes Mellitus. Curr Diab Rep 2016;16(3):30.
• 42. Schlemmer U, Frølich W, Prieto RM, Grases F. Phytate in foods and significance for humans: food sources, intake, processing, bioavailability, protective role and analysis. Mol Nutr Food Res 2009;53(2):330-75.
• 43. Condorelli R, La Vignera S, Mongioì L, Vitale S, Laganà A, Cimino L, Calogero AE. Myo-inositol as a male fertility molecule: speed them up. Eur Rev Med Pharmacol Sci 2017;21(2):30-5.
• 44. Monastra G, Unfer V, Harrath AH, Bizzarri M. Combining treatment with myo-inositol and D-chiroinositol (40: 1) is effective in restoring ovary function and metabolic balance in PCOS patients. Gynecol Endocrinol 2017;33(1):1-9.
• 45. Facchinetti F, Bizzarri M, Benvenga S, D’Anna R, Lanzone A, Soulage C, Di Renzo GC, Hod M, Cavalli P, Chiu TT, Kamenov ZA, Bevilacqua A, Carlomagno G, Gerli S, Oliva MM, Devroey P. 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.
• 46. 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 2009;13(2):105-10.
• 47. Genazzani AD, Lanzoni C, Ricchieri F, Jasonni VM. Myoinositol administration positively affects hyperinsulinemia and hormonal parameters in overweight patients with polycystic ovary syndrome. Gynecol Endocrinol 2008;24(3):139-44.
• 48. Minozzi M, Nordio M, Pajalich R. The combined therapy myo-inositol plus D-chiro-inositol, in a physiological ratio, reduces the cardiovascular risk by improving the lipid profile in PCOS patients. Eur Rev Med Pharmacol Sci 2013;26:5-1.
• 49. Nordio M, Proietti E. The combined therapy with myoinositol and D-chiro-inositol reduces the risk of metabolic disease in PCOS overweight patients compared to myoinositol supplementation alone. Eur Rev Med Pharmacol Sci 2012;16(5):575-81.
• 50. Gerli S, Papaleo E, Ferrari A, Di Renzo G. Randomized, double blind placebo-controlled trial: effects of myoinositol on ovarian function and metabolic factors in women with PCOS. Eur Rev Med Pharmacol Sci 2007;11(5):347-54.
• 51. Croze ML, Vella RE, Pillon NJ, Soula HA, Hadji L, Guichardant M, Soulage CO. Chronic treatment with myo-inositol reduces white adipose tissue accretion and improves insulin sensitivity in female mice. J Nutr Biochem 2013;24(2):457-66.
• 52. Unfer V, Carlomagno G, Papaleo E, Vailati S, Candiani M, Baillargeon JP. Hyperinsulinemia alters myoinositol to d-chiroinositol ratio in the follicular fluid of patients with PCOS. Reprod Sci 2014;21(7):854-8.
• 53. 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.
• 54. Minozzi M, D’Andrea G, Unfer V. Treatment of hirsutism with myo-inositol: a prospective clinical study. Reprod Biomed Online 2008;17(4):579-82.
• 55. Papaleo E, Unfer V, Baillargeon JP, De Santis L, Fusi F, Brigante C, Marelli G, Cino I, Redaelli A, Ferrari A. Myoinositol in patients with polycystic ovary syndrome: a novel method for ovulation induction. Gynecol Endocrinol 2007;23(12):700-3.
• 56. 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 2010;26(4):275-80.
• 57. Lowther KM, Weitzman VN, Maier D, Mehlmann LM. Maturation, fertilization, and the structure and function of the endoplasmic reticulum in cryopreserved mouse oocytes. Biol Reprod 2009;81(1):147-54.
• 58. Chiu TTY, Rogers MS, Briton‐Jones C, Haines C. Effects of myo‐inositol on the in‐vitro maturation and subsequent development of mouse oocytes. Hum Reprod 2003;18(2):408-16.
• 59. Colazingari S, Fiorenza MT, Carlomagno G, Najjar R, Bevilacqua A. Improvement of mouse embryo quality by myo-inositol supplementation of IVF media. J Assist Reprod Genet 2014;31(4):463-9.
• 60. Ciotta L, Stracquadanio M, Pagano I, Carbonaro A, Palumbo M, Gulino F. Effects of myo-inositol supplementation on oocyte’s quality in PCOS patients: a double blind trial. Eur Rev Med Pharmacol Sci 2011;15(5):509-14.
• 61. 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 2013;288(6):1405-11.
• 62. Mendoza N, Diaz-Ropero MP, Aragon M, Maldonado V, Llaneza P, Lorente J, Mendoza-Tesarik R, MaldonadoLobon J, Olivares M. Fonolla J. Comparison of the effect of two combinations of myo-inositol and D-chiro-inositol in women with polycystic ovary syndrome undergoing ICSI: a randomized controlled trial. Gynecol Endocrinol 2019;35(8):695-700.
• 63. Isabella R, Raffone E. CONCERN: Does ovary need D-chiro-inositol? Journal of Ovarian Research. J Ovarian Res 2012;5(1):14.
• 64. Artini PG, Di Berardino O, Papini F, Genazzani A, Simi G, Ruggiero M, Cela V. Endocrine and clinical effects of myo-inositol administration in polycystic ovary syndrome. A randomized study. Gynecol Endocrinol 2013;29(4):375-9.
• 65. Sene AA, Tabatabaie A, Nikniaz H, Alizadeh A, Sheibani K, Alisaraie MM, Tabatabaie M, Ashrafi M, Amjadi F. The myo-inositol effect on the oocyte quality and fertilization rate among women with polycystic ovary syndrome undergoing assisted reproductive technology cycles: a randomized clinical trial. Arch Gynecol Obstet 2019;299(6):1701-7.
• 66. Elibol E, Akdevelioğlu Y. İnositol ve Kadın Üreme Sağlığı. Turkiye Klinikleri J Health Sci 2017;2(3):201-6.
• 67. Mayr JA, Feichtinger RG, Tort F, Ribes A, Sperl W. Lipoic acid biosynthesis defects. J Inherit Metab Dis 2014;37(4):553-63.
• 68. Solmonson A, De Berardinis RJ. Lipoic acid metabolism and mitochondrial redox regulation. J Biol Chem 2018;293(20):7522-30.
• 69. Tibullo D, Volti GL, Giallongo C, Grasso S, Tomassoni D, Anfuso CD, Lupo G, Amenta F, Avola R, Bramanti V. Biochemical and clinical relevance of alpha lipoic acid: antioxidant and anti-inflammatory activity, molecular pathways and therapeutic potential. Inflamm Res 2017;66(11):947-59.
• 70. Gorąca A, Huk-Kolega H, Piechota A, Kleniewska P, Ciejka E, Skibska B. Lipoic acid–biological activity and therapeutic potential. Pharmacol Rep 2011;63(4):849-58.
• 71. Mohammadi V, Khalili M, Eghtesadi S, "Dehghani S, Jazayeri S, Aghababaee S, Sabour H, Saberi H, Eghtesadi M, Gohari MR. The effect of alpha-lipoic acid (ALA) supplementation on cardiovascular risk factors in men with chronic spinal cord injury: a clinical trial. Spinal Cord 2015;53(8):621-4.
• 72. Namazi N, Larijani B, Azadbakht L. Alpha-lipoic acid supplement in obesity treatment: A systematic review and meta-analysis of clinical trials. Clin Nutr 2018;37(2):419-28.
• 73. Bilska A, Wlodek L. Lipoic acid-the drug of the future. Pharmacol Rep 2005;57(5):570-7.
• 74. Kim W-J, Kang J-Y, Kwon D-K, Song Y-J, Lee K-H. Effects of α-lipoic acid supplementation on malondialdehyde contents and superoxide dismutase in rat skeletal muscles. Food Sci. Biotechnol 2011;20(4):1133-6.
• 75. Genazzani AD, Shefer K, Della Casa D, Prati A, Napolitano A, Manzo A, Despini G, Simoncini T. Modulatory effects of alpha-lipoic acid (ALA) administration on insulin sensitivity in obese PCOS patients. J Endocrinol Invest 2018:41(5):583-590.
• 76. Beckman JA, Creager MA, Libby P. Diabetes and atherosclerosis: epidemiology, pathophysiology, and management. JAMA 2002;287(19):2570-81.
• 77. Clavreul N, Bachschmid MM, Hou X, Shi C, Idrizovic A, Ido Y, Pimentel D, Cohen RA. S-glutathiolation of p21ras by peroxynitrite mediates endothelial insulin resistance caused by oxidized low-density lipoprotein. Arterioscler Thromb Vasc Biol 2006;26(11):2454-61.
• 78. Eason R, Archer H, Akhtar S, Bailey CJ. Obesity, Metabolism. Lipoic acid increases glucose uptake by skeletal muscles of obese‐diabetic ob/ob mice. Diabetes Obes Metab 2002;4(1):29-35.
• 79. Ghibu S, Richard C, Vergely C, Zeller M, Cottin Y, Rochette L. Antioxidant properties of an endogenous thiol: alpha-lipoic acid, useful in the prevention of cardiovascular diseases. J Cardiovasc Pharmacol 2009;54(5):391-8.
• 80. Gomes MB, Negrato CA. Alpha-lipoic acid as a pleiotropic compound with potential therapeutic use in diabetes and other chronic diseases. Diabetol Metab Syndr 2014;6(1):80.
• 81. Scaramuzza A, Giani E, Redaelli F, Ungheri S, Macedoni M, Giudici V, Bosetti A, Ferrari M, Zuccotti GV. Alphalipoic acid and antioxidant diet help to improve endothelial dysfunction in adolescents with type 1 diabetes: a pilot trial. J Diabetes Res 2015;474561.
• 82. Konrad D, Somwar R, Sweeney G, Yaworsky K, Hayashi M, Ramlal T, Klip A. The antihyperglycemic drug α-lipoic acid stimulates glucose uptake via both GLUT4 translocation and GLUT4 activation: potential role of p38 mitogen-activated protein kinase in GLUT4 activation. Diabetes 2001;50(6):1464-71.
• 83. Masharani U, Gjerde C, Evans JL, Youngren JF, Goldfine ID. Effects of controlled-release alpha lipoic acid in lean, nondiabetic patients with polycystic ovary syndrome. J Diabetes Sci Technol 2010;4(2):359-64.
• 84. Fruzzetti F, Fidecicchi T, Palla G, Gambacciani M. Long-term treatment with alpha-lipoic acid and myoinositol positively affects clinical and metabolic features of polycystic ovary syndrome. Gynecol Endocrinol 2020;36(2):152-155.
• 85. Genazzani AD, 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 overweight/obese patients with PCOS. Endocrinol Metab Synd 2014;3(3):1000140.
• 86. Cappelli V, Di AS, Musacchio M, De VL. Evaluation of a new association between insulin-sensitizers and α-lipoic acid in obese women affected by PCOS. Minerva Ginecol 2013;65(4):425-33.
• 87. Rago R, Marcucci I, Leto G, Caponecchia L, Salacone P, Bonanni P, Fiori C, Sorrenti G, Sebastianelli A. Effect of myo-inositol and alpha-lipoic acid on oocyte quality in polycystic ovary syndrome non-obese women undergoing in vitro fertilization: a pilot study. J Biol Regul Homeost Agents 2015;29(4):913-23.
• 88. Artini PG, Obino MER, Micelli E, Malacarne E, Vacca C, Papini F, Cela V. Effect of d-chiro-inositol and alpha-lipoic acid combination on COH outcomes in overweight/obese PCOS women. Gynecol Endocrinol 2020;36(9):755-9.
• 89. Morgante G, Cappelli V, Di AS, Massaro M, De VL. Polycystic ovary syndrome (PCOS) and hyperandrogenism: the role of a new natural association. Minerva Ginecol 2015;67(5):457-63.
• 90. 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.
• 91. Cirillo F, Catellani C, Lazzeroni P, Sartori C, Tridenti G, Vezzani C, Fulghesu AM, Madeddu E, Amarri S, Street ME. HMGB1 is increased in adolescents with polycystic ovary syndrome (PCOS) and decreases after treatment with myo-inositol (MYO) in combination with alphalipoic acid (ALA). Gynecol Endocrinol 2020;36(7):588-93.
• 92. Genazzani AD, Prati A, Santagni S, Ricchieri F, Chierchia E, Rattighieri E, Campedelli A, Simoncini T, Artini PG. Differential insulin response to myo-inositol administration in obese polycystic ovary syndrome patients. Gynecol Endocrinol 2012;28(12):969-73.
• 93. Genazzani AD, Santagni S, Rattighieri E, Chierchia E, Despini G, Marini G, Prati A, Simoncini T. Modulatory role of D-chiro-inositol (DCI) on LH and insulin secretion in obese PCOS patients. Gynecol Endocrinol 2014;30(6):438-43.
• 94. La Marca A, Grisendi V, Dondi G, Sighinolfi G, Cianci A. The menstrual cycle regularization following D-chiroinositol treatment in PCOS women: a retrospective study. Gynecol Endocrinol 2015;31(1):52-6.
• 95. De Cicco S, Immediata V, Romualdi D, Policola C, Tropea A, Di Florio C, Tagliaferri V, Scarinci E, Della Casa S, Lanzone A, Apa R. Myoinositol combined with alpha-lipoic acid may improve the clinical and endocrine features of polycystic ovary syndrome through an insulinindependent action. Gynecol Endocrinol 2017;33(9):698-701.
• 96. Genazzani AD, 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 myoinositol (MYO), alpha lipoic acid (ALA), or combination of both. Gynecol Endocrinol 2019:35(12):1088-93.