The rationale of the myo-inositol and D-chiro-inositol combined treatment for polycystic ovary syndrome

Journal of Clinical Pharmacology

Volumn 54, Issue 10, 2014, Pages 1079-1092

  Dinicola, Simona ^a   Chiu, Tony T Y ^b   Unfer, Vittorio ^c   Carlomagno, Gianfranco ^c   Bizzarri, Mariano ^a  

^a SAPIENZA UNIVERSITY OF ROME   (Italy)

^b and Hong Kong Branch of CAS Center for Excellence in Animal Evolution and Genetics   (Hong Kong)

^c LoLi Pharma Medical Department   (Italy)

Author keywords

embryo; infertility; inositol; oocyte; polycystic ovarian syndrome

Indexed keywords

ANDROGEN; D CHIRO INOSITOL; GLUCOSE; INOSITOL; INOSITOL DERIVATIVE; INSULIN; UNCLASSIFIED DRUG; VITAMIN B COMPLEX;

ANDROGEN BLOOD LEVEL; ARTICLE; CYTOLOGY; FEMALE; GLUCOSE METABOLISM; HUMAN; INSULIN RESISTANCE; METABOLIC SYNDROME X; OOCYTE; OVARY FUNCTION; OVARY POLYCYSTIC DISEASE; ANIMAL; BLOOD; CHEMISTRY; DRUG COMBINATION; METABOLISM; PATHOPHYSIOLOGY; POLYCYSTIC OVARY SYNDROME; STEREOISOMERISM;

ANDROGENS; ANIMALS; DRUG THERAPY, COMBINATION; FEMALE; HUMANS; INOSITOL; INSULIN RESISTANCE; OOCYTES; POLYCYSTIC OVARY SYNDROME; STEREOISOMERISM; VITAMIN B COMPLEX;

EID: 84922185299     PISSN: 00912700     EISSN: 15524604     Source Type: Journal    
DOI: 10.1002/jcph.362     Document Type: Article

References (105)

1. Clements RS, Jr, Darnell B,. Myo-inositol content of common foods: development of a high-myo-inositol diet. Am J Clin Nutr. 1980; 33 (9): 1954-1967.
2. Hooper NM,. Glycosyl-phosphatidylinositol anchored membrane enzymes. Clin Chim Acta. 1997; 266 (1): 3-12.
3. Di Paolo G, De Camilli P,. Phosphoinositides in cell regulation and membrane dynamics. Nature. 2006; 443 (7112): 651-657.
4. Chen IW, Charalampous CF,. Biochemical studies on inositol. IX. D-Inositol 1-phosphate as intermediate in the biosynthesis of inositol from glucose 6-phosphate, and characteristics of two reactions in this biosynthesis. J Biol Chem. 1966; 241 (10): 2194-2199.
5. Carman GM, Henry SA,. Phospholipid biosynthesis in yeast. Ann Rev Biochem. 1989; 58: 635-669.
6. Berridge MJ,. Inositol trisphosphate and calcium signalling. Nature. 1993; 361 (6410): 315-325.
7. Huang LC, Fonteles MC, Houston DB, Zhang C, Larner J,. Chiroinositol deficiency and insulin resistance. III. Acute glycogenic and hypoglycemic effects of two inositol phosphoglycan insulin mediators in normal and streptozotocin-diabetic rats in vivo. Endocrinology. 1993; 132 (2): 652-657.
8. 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.
9. Larner J, Huang LC, Schwartz CF, et al. Rat liver insulin mediator which stimulates pyruvate dehydrogenase phosphate contains galactosamine and D-chiroinositol. Biochem Biophys Res Commun. 1988; 151 (3): 1416-1426.
10. Romero G, Gamez G, Huang LC, Lilley K, Luttrell L,. Anti-inositolglycan antibodies selectively block some of the actions of insulin in intact BC3H1 cells. Proc Natl Acad Sci USA. 1990; 87 (4): 1476-1480.
11. Alvarez JF, Sanchez-Arias JA, Guadano A, et al. Transport in isolated rat hepatocytes of the phospho-oligosaccharide that mimics insulin action. Effects of adrenalectomy and glucocorticoid treatment. Biochem J. 1991; 274 (Pt 2): 369-374.
12. Sun TH, 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): 1092-1098.
13. Downes CP,. The cellular functions of myo-inositol. Biochem Soc Trans. 1989; 17 (2): 259-268.
14. Downes CP, Macphee CH,. Myo-inositol metabolites as cellular signals. Eur J Biochem. 1990; 193 (1): 1-18.
15. Diaz JR, de las Cagigas A, Rodriguez R,. Micronutrient deficiencies in developing and affluent countries. Eur J Clin Nutr. 2003; 57 (Suppl 1): S70-S72.
16. Eisenberg F, Jr., Bolden AH,. Reproductive tract as site of synthesis and secretion of inositol in the male rat. Nature. 1964; 202: 599-600.
17. Ghafoorunissa,. Effect of dietary protein on the biosynthesis of inositol in rat testes. J Reprod Fertil. 1975; 42 (2): 233-238.
18. Lewin LM, Beer R,. Prostatic secretion as the source of myo-inositol in human seminal fluid. Fertil Steril. 1973; 24 (9): 666-670.
19. Lewin LM, Yannai Y, Melmed S, Weiss M,. Myo-inositol in the reproductive tract of the female rat. Int J Biochem. 1982; 14 (2): 147-150.
20. Chiu TT, Tam PP,. A correlation of the outcome of clinical in vitro fertilization with the inositol content and embryotrophic properties of human serum. J Assist Reprod Genet. 1992; 9 (6): 524-530.
21. Zacche MM, Caputo L, Filippis S, Zacche G, Dindelli M, Ferrari A,. Efficacy of myo-inositol in the treatment of cutaneous disorders in young women with polycystic ovary syndrome. Gynecol Endocrinol. 2009; 25 (8): 508-513.
22. Matsuda M, Tsutsumi K, Kanematsu T, et al. Involvement of phospholipase C-related inactive protein in the mouse reproductive system through the regulation of gonadotropin levels. Biol Reprod. 2009; 81 (4): 681-689.
23. Goud PT, Goud AP, Van Oostveldt P, Dhont M,. Presence and dynamic redistribution of type I inositol 1,4,5-trisphosphate receptors in human oocytes and embryos during in-vitro maturation, fertilization and early cleavage divisions. Mol Hum Reprod. 1999; 5 (5): 441-451.
24. 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): 147-154.
25. Chiu TT, 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): 408-416.
26. Kane MT, Norris M, Harrison RA,. Uptake and incorporation of inositol by preimplantation mouse embryos. J Reprod Fertil. 1992; 96 (2): 617-625.
27. Fahy MM, Kane MT,. Incorporation of [3H]inositol into phosphoinositides and inositol phosphates by rabbit blastocysts. Mol Reprod Dev. 1993; 34 (4): 391-395.
28. Holm P, Booth PJ, Schmidt MH, Greve T, Callesen H,. High bovine blastocyst development in a static in vitro production system using SOFaa medium supplemented with sodium citrate and myo-inositol with or without serum-proteins. Theriogenology. 1999; 52 (4): 683-700.
29. Holub BJ,. Metabolism and function of myo-inositol and inositol phospholipids. Annu Rev Nutr. 1986; 6: 563-597.
30. 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): 463-469.
31. Stachecki JJ, Armant DR,. Transient release of calcium from inositol 1,4,5-trisphosphate-specific stores regulates mouse preimplantation development. Development. 1996; 122 (8): 2485-2496.
32. Huang C, Liang NC,. Increase in cytoskeletal actin induced by inositol 1,4-bisphosphate in saponin-permeated pig platelets. Cell Biol Int. 1994; 18 (8): 797-804.
33. Ducibella T, Kurasawa S, Duffy P, Kopf GS, Schultz RM,. Regulation of the polyspermy block in the mouse egg: maturation-dependent differences in cortical granule exocytosis and zona pellucida modifications induced by inositol 1,4,5-trisphosphate and an activator of protein kinase C. Biol Reprod. 1993; 48 (6): 1251-1257.
34. Orihuela PA, Parada-Bustamante A, Zuniga LM, Croxatto HB,. Inositol triphosphate participates in an oestradiol nongenomic signalling pathway involved in accelerated oviductal transport in cycling rats. J Endocrinol. 2006; 188 (3): 579-588.
35. Carlomagno G, Roseff S, Harter S, Murphy Cohen S, Unfer V,. A novel approach for treating infertile patients with diminished ovarian reserve (DOR). 14th World Congress on Controversies in Obstetrics, Gynecology & Infertility (COGI), Monduzzi Eds, 2011, Paris, France.
36. Visser JA, Themmen AP,. Anti-Mullerian hormone and folliculogenesis. Mol Cell Endocrinol. 2005; 234 (1-2): 81-86.
37. Visser JA, de Jong FH, Laven JS, Themmen AP,. Anti-Mullerian hormone: a new marker for ovarian function. Reproduction. 2006; 131 (1): 1-9.
38. Quirk JG, Jr., Bleasdale JE,. Myo-Inositol homeostasis in the human fetus. Obstet Gynecol. 1983; 62 (1): 41-44.
39. Hallman M, Arjomaa P, Hoppu K,. Inositol supplementation in respiratory distress syndrome: relationship between serum concentration, renal excretion, and lung effluent phospholipids. J Pediatr. 1987; 110 (4): 604-610.
40. Greene ND, Copp AJ,. Inositol prevents folate-resistant neural tube defects in the mouse. Nat Med. 1997; 3 (1): 60-66.
41. Hendricks KA, Nuno OM, Suarez L, Larsen R,. Effects of hyperinsulinemia and obesity on risk of neural tube defects among Mexican Americans. Epidemiology. 2001; 12 (6): 630-635.
42. Reece EA, Khandelwal M, Wu YK, Borenstein M,. Dietary intake of myo-inositol and neural tube defects in offspring of diabetic rats. Am J Obstet Gynecol. 1997; 176 (3): 536-539.
43. Goldman AS, Goto MP,. Biochemical basis of the diabetic embryopathy. Isr J Med Sci. 1991; 27 (8-9): 469-477.
44. Cavalli P, Copp AJ,. Inositol and folate resistant neural tube defects. J Med Genet. 2002; 39 (2): E5.
45. Beemster P, Groenen P, Steegers-Theunissen R,. Involvement of inositol in reproduction. Nutr Rev. 2002; 60 (3): 80-87.
46. Dunaif A, Segal KR, Futterweit W, Dobrjansky A,. Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome. Diabetes. 1989; 38 (9): 1165-1174.
47. Ehrmann DA, Barnes RB, Rosenfield RL, Cavaghan MK, Imperial J,. Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome. Diabetes Care. 1999; 22 (1): 141-146.
48. Legro RS, Finegood D, Dunaif A,. A fasting glucose to insulin ratio is a useful measure of insulin sensitivity in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 1998; 83 (8): 2694-2698.
49. Legro RS, Blanche P, Krauss RM, Lobo RA,. Alterations in low-density lipoprotein and high-density lipoprotein subclasses among Hispanic women with polycystic ovary syndrome: influence of insulin and genetic factors. Fertil Steril. 1999; 72 (6): 990-995.
50. Franks S,. Polycystic ovary syndrome. N Engl J Med. 1995; 333 (13): 853-861.
51. Giordano D, Corrado F, Santamaria A, et al. Effects of myo-inositol supplementation in postmenopausal women with metabolic syndrome: a perspective, randomized, placebo-controlled study. Menopause. 2011; 18 (1): 102-104.
52. Ortmeyer HK,. Dietary myoinositol results in lower urine glucose and in lower postprandial plasma glucose in obese insulin resistant rhesus monkeys. Obes Res. 1996; 4 (6): 569-575.
53. Schofield L, Hackett F,. Signal transduction in host cells by a glycosylphosphatidylinositol toxin of malaria parasites. J Exp Med. 1993; 177 (1): 145-153.
54. Ortmeyer HK, Bodkin NL, Lilley K, Larner J, Hansen BC,. Chiroinositol deficiency and insulin resistance. I. Urinary excretion rate of chiroinositol is directly associated with insulin resistance in spontaneously diabetic rhesus monkeys. Endocrinology. 1993; 132 (2): 640-645.
55. Asplin I, Galasko G, Larner J,. Chiro-inositol deficiency and insulin resistance: a comparison of the chiro-inositol- and the myo-inositol-containing insulin mediators isolated from urine, hemodialysate, and muscle of control and type II diabetic subjects. Proc Natl Acad Sci USA. 1993; 90 (13): 5924-5928.
56. Ortmeyer HK, Huang LC, Zhang L, Hansen BC, Larner J,. Chiroinositol deficiency and insulin resistance. II. Acute effects of D-chiroinositol administration in streptozotocin-diabetic rats, normal rats given a glucose load, and spontaneously insulin-resistant rhesus monkeys. Endocrinology. 1993; 132 (2): 646-651.
57. Ehrmann DA,. Insulin-lowering therapeutic modalities for polycystic ovary syndrome. Endocrinol Metab Clin North Am. 1999; 28 (2): 423-438.
58. Hasegawa I, Murakawa H, Suzuki M, Yamamoto Y, Kurabayashi T, Tanaka K,. Effect of troglitazone on endocrine and ovulatory performance in women with insulin resistance-related polycystic ovary syndrome. Fertil Steril. 1999; 71 (2): 323-327.
59. Nestler JE, Jakubowicz DJ, Evans WS, Pasquali R,. Effects of metformin on spontaneous and clomiphene-induced ovulation in the polycystic ovary syndrome. N Engl J Med. 1998; 338 (26): 1876-1880.
60. Baillargeon JP, Iuorno MJ, Jakubowicz DJ, Apridonidze T, He N, Nestler JE,. Metformin therapy increases insulin-stimulated release of D-chiro-inositol-containing inositolphosphoglycan mediator in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2004; 89 (1): 242-249.
61. Baillargeon JP, Diamanti-Kandarakis E, Ostlund RE, Jr, Apridonidze T, Iuorno MJ, Nestler JE,. Altered D-chiro-inositol urinary clearance in women with polycystic ovary syndrome. Diabetes Care. 2006; 29 (2): 300-305.
62. Nestler JE, Jakubowicz DJ, Reamer P, Gunn RD, Allan G,. Ovulatory and metabolic effects of D-chiro-inositol in the polycystic ovary syndrome. N Engl J Med. 1999; 340 (17): 1314-1320.
63. Iuorno MJ, Jakubowicz DJ, Baillargeon JP, et al. Effects of d-chiro-inositol in lean women with the polycystic ovary syndrome. Endocr Pract. 2002; 8 (6): 417-423.
64. Cheang KI, Baillargeon JP, Essah PA, et al. Insulin-stimulated release of D-chiro-inositol-containing inositolphosphoglycan mediator correlates with insulin sensitivity in women with polycystic ovary syndrome. Metabolism. 2008; 57 (10): 1390-1397.
65. Isabella R, Raffone E,. Does ovary need D-chiro-inositol. J Ovarian Res. 2012; 5 (1): 14.
66. Palomba S, Falbo A, Di Cello A, Cappiello F, Tolino A, Zullo F,. Does metformin affect the ovarian response to gonadotropins for in vitro fertilization treatment in patients with polycystic ovary syndrome and reduced ovarian reserve? A randomized controlled trial. Fertil Steril. 96 (5): 1128-1133.
67. Pak Y, Huang LC, Lilley KJ, Larner J,. In vivo conversion of [3H]myoinositol to [3H]chiroinositol in rat tissues. J Biol Chem. 1992; 267 (24): 16904-16910.
68. Chaudhary K, Babu KN, Joshi VN, Srivastava S, Chakravarty BN,. NMR-based metabolomics reveals differently expressed metabolites in follicular fluid of pcos women: potential biomarkers for good quality oocyte?. Hum Reprod. 2011; 26: i226-i246.
69. Pinero-Sagredo E, Nunes S, de Los Santos MJ, Celda B, Esteve V,. NMR metabolic profile of human follicular fluid. NMR Biomed. 2010; 23 (5): 485-495.
70. Arya BK, Haq AU, Chaudhury K,. Oocyte quality reflected by follicular fluid analysis in poly cystic ovary syndrome (PCOS): A hypothesis based on intermediates of energy metabolism. Med Hypotheses. 2012; 78 (4): 475-478.
71. Ma X, Fan L, Meng Y, et al. Proteomic analysis of human ovaries from normal and polycystic ovarian syndrome. Mol Hum Reprod. 2007; 13 (8): 527-535.
72. 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. Published on line 4 February. Reprod Sci. 2014:DOI: 10.1177/1933719113518985.
73. Matalliotakis I, Kourtis A, Koukoura O, Panidis D,. Polycystic ovary syndrome: etiology and pathogenesis. Arch Gynecol Obstet. 2006; 274 (4): 187-197.
74. Carlomagno G, Unfer V, Roseff S,. The D-chiro-inositol paradox in the ovary. Fertil Steril. 2011; 95 (8): 2515-2516.
75. 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. 2013; 61 (2): 111-117.
76. Nestler JE, Jakubowicz DJ, de Vargas AF, Brik C, Quintero N, 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): 2001-2005.
77. Papaleo E, Unfer V, Baillargeon JP, Fusi F, Occhi F, De Santis L,. Myo-inositol may improve oocyte quality in intracytoplasmic sperm injection cycles. A prospective, controlled, randomized trial. Fertil Steril. 2009; 91 (5): 1750-1754.
78. 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): 452-457.
79. Papaleo E, Unfer V, Baillargeon JP, et al. Myo-inositol in patients with polycystic ovary syndrome: a novel method for ovulation induction. Gynecol Endocrinol. 2007; 23 (12): 700-703.
80. Genazzani AD, Lanzoni C, Ricchieri F, Jasonni VM,. Myo-inositol administration positively affects hyperinsulinemia and hormonal parameters in overweight patients with polycystic ovary syndrome. Gynecol Endocrinol. 2008; 24 (3): 139-144.
81. Chiu TT, Rogers MS, Law EL, Briton-Jones CM, Cheung LP, Haines CJ,. Follicular fluid and serum concentrations of myo-inositol in patients undergoing IVF: relationship with oocyte quality. Hum Reprod. 2002; 17 (6): 1591-1596.
82. Morgante G, Orvieto R, Di Sabatino A, Musacchio MC, De Leo V,. The role of inositol supplementation in patients with polycystic ovary syndrome, with insulin resistance, undergoing the low-dose gonadotropin ovulation induction regimen. Fertil Steril. 2011; 95 (8): 2642-2644.
83. Gerli S, Mignosa M, Di Renzo GC,. 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. 2003; 7 (6): 151-159.
84. Minozzi M, Costantino D, Guaraldi C, Unfer V,. The effect of a combination therapy with myo-inositol and a combined oral contraceptive pill versus a combined oral contraceptive pill alone on metabolic, endocrine, and clinical parameters in polycystic ovary syndrome. Gynecol Endocrinol. 2011; 27 (11): 920-924. DOI: 10.3109/09513590.2011.564685.
85. Minozzi M, D'Andrea G, Unfer V,. Treatment of hirsutism with myo-inositol: a prospective clinical study. Reprod Biomed Online. 2008; 17 (4): 579-582.
86. 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): 275-280.
87. Nordio M, Proietti E,. The combined therapy with myo-inositol and D-chiro-inositol reduces the risk of metabolic disease in PCOS overweight patients compared to myo-inositol supplementation alone. Eur Rev Med Pharmacol Sci. 2012; 16 (5): 575-581.
88. Homburg R, Polycystic ovary, syndrome -, from gynaecological, curiosity to, multisystem endocrinopathy,. Hum Reprod. 1996; 11 (1): 29-39.
89. Dunaif A, Segal KR, Shelley DR, Green G, Dobrjansky A, Licholai T,. Evidence for distinctive and intrinsic defects in insulin action in polycystic ovary syndrome. Diabetes. 1992; 41 (10): 1257-1266.
90. Nestler JE,. Insulin resistance and the polycystic ovary syndrome: recent advances. Curr Opin Endocrinol. 2000; 7 (6): 345-349.
91. Lobo RA, Carmina E,. The importance of diagnosing the polycystic ovary syndrome. Ann Intern Med. 2000; 132 (12): 989-993.
92. Revised,. 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril. 2004; 81 (1): 19-25.
93. Revised,. 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod. 2004; 19 (1): 41-47.
94. Akpinar Z, Tokgoz S, Gokbel H, Okudan N, Uguz F, Yilmaz G,. The association of nocturnal serum melatonin levels with major depression in patients with acute multiple sclerosis. Psychiatry Res. 2008; 161 (2): 253-257.
95. Groenen PM, Merkus HM, Sweep FC, Wevers RA, Janssen FS, Steegers-Theunissen RP,. Kinetics of myo-inositol loading in women of reproductive age. Ann Clin Biochem. 2003; 40 (Pt 1): 79-85.
96. Carlomagno G, Unfer V,. Inositol safety: clinical evidences. Eur Rev Med Pharmacol Sci. 2011; 15: 931-936.
97. 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): 509-515.
98. Papaleo E, Unfer V, Baillargeon JP, Chiu TT,. Contribution of myo-inositol to reproduction. Eur J Obstet Gynecol Reprod Biol. 2009; 147 (2): 120-123.
99. Pal L, Jindal S, Witt BR, Santoro N,. Less is more: increased gonadotropin use for ovarian stimulation adversely influences clinical pregnancy and live birth after in vitro fertilization. Fertil Steril. 2008; 89 (6): 1694-1701.
100. Lisi F, Carfagna P, Oliva MM, Rago R, Lisi R, et al. Pretreatment with myo-inositol in non polycystic ovary syndrome patients undergoing multiple follicular stimulation for IVF: a pilot study. Reprod Biol Endocrinol. 2012; 10: 52.
101. 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): 1405-1411.
102. Personal communication at international Consensus Conference held in Florence December. 2013.
103. Costantino D, Minozzi G, Minozzi E, et al. Metabolic and hormonal effects of myo-inositol in women with polycystic ovary syndrome: a double-blind trial. Eur Rev Med Pharmacol Sci. 2009; 13: 105-110.
104. Papaleo E, Unfer V, Baillargeon JP, et al. Myo-inositol in patients with polycystic ovary syndrome: a novel method for ovulation induction. Gynecol Endocrinol. 2007; 23 (12): 700-703.
105. Gerli S, Papaleo E, Ferrari A, et al. 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. 2007; 11 (5): 347-354.