Effects of Inositol(s) in Women with PCOS: A Systematic Review of Randomized Controlled Trials

Vittorio Unfer, John E Nestler, Zdravko A Kamenov, Nikos Prapas, Fabio Facchinetti, Vittorio Unfer, John E Nestler, Zdravko A Kamenov, Nikos Prapas, Fabio Facchinetti

Abstract

Polycystic ovary syndrome (PCOS) is a common endocrine disorder, with complex etiology and pathophysiology, which remains poorly understood. It affects about 5-10% of women of reproductive age who typically suffer from obesity, hyperandrogenism, ovarian dysfunction, and menstrual irregularity. Indeed, PCOS is the most common cause of anovulatory infertility in industrialized nations, and it is associated with insulin resistance, type 2 diabetes mellitus, and increased cardiovascular risk. Although insulin resistance is not included as a criterion for diagnosis, it is a critical pathological condition of PCOS. The purpose of this systematic review is the analysis of recent randomized clinical trials of inositol(s) in PCOS, in particular myo- and D-chiro-inositol, in order to better elucidate their physiological involvement in PCOS and potential therapeutic use, alone and in conjunction with assisted reproductive technologies, in the clinical treatment of women with PCOS.

References

    1. The Rotterdam ESHRE/ASRM Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS) Human Reproduction. 2004;19(1):41–47.
    1. Ciampelli M., Fulghesu A. M., Cucinelli F., et al. Impact of insulin and body mass index on metabolic and endocrine variables in polycystic ovary syndrome. Metabolism: Clinical and Experimental. 1999;48(2):167–172. doi: 10.1016/S0026-0495(99)90028-8.
    1. Genazzani A. D., Battaglia C., Malavasi B., Strucchi C., Tortolani F., Gamba O. Metformin administration modulates and restores luteinizing hormone spontaneous episodic secretion and ovarian function in nonobese patients with polycystic ovary syndrome. Fertility and Sterility. 2004;81(1):114–119. doi: 10.1016/j.fertnstert.2003.05.020.
    1. Bigos A., Palkowska E., Rosolowska-Huszca D. Effect of artificial and natural sweeteners on glucose and insulin in plasma of rats. Journal of Pre-Clinical and Clinical Research. 2012;6(2):93–97.
    1. Dunaif A., Segal K. R., Futterweit W., Dobrjansky A. Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome. Diabetes. 1989;38(9):1165–1174. doi: 10.2337/diab.38.9.1165.
    1. Laven J. S. E., Mulders A. G. M. G. J., van Santbrink E. J. P., Eijkemans M. J. C., Fauser B. C. J. M. PCOS: backgrounds, evidence and problems in diagnosing the syndrome. International Congress Series. 2005;1279:10–15. doi: 10.1016/j.ics.2005.01.002.
    1. Nestler J. E. Role of hyperinsulinemia in the pathogenesis of the polycystic ovary syndrome, and its clinical implications. Seminars in Reproductive Endocrinology. 1997;15(2):111–122. doi: 10.1055/s-2007-1016294.
    1. Lord J. M., Flight I. H. K., Norman R. J. Metformin in polycystic ovary syndrome: systematic review and meta-analysis. British Medical Journal. 2003;327(7421):951–953.
    1. Pasquali R., Gambineri A. Insulin-sensitizing agents in polycystic ovary syndrome. European Journal of Endocrinology. 2006;154(6):763–775. doi: 10.1530/eje.1.02156.
    1. 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. European Review for Medical and Pharmacological Sciences. 2003;7(6):151–159.
    1. 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. European Review for Medical and Pharmacological Sciences. 2007;11(5):347–354.
    1. Iuorno M. J., Jakubowicz D. J., Baillargeon J.-P., et al. Effects of D-chiro-inositol in lean women with the polycystic ovary syndrome. Endocrine Practice. 2002;8(6):417–423. doi: 10.4158/EP.8.6.417.
    1. Nestler J. E., Jakubowicz D. J., Reamer P., Gunn R. D., Allan G. Ovulatory and metabolic effects of D-chiro-inositol in the polycystic ovary syndrome. The New England Journal of Medicine. 1999;340(17):1314–1320. doi: 10.1056/nejm199904293401703.
    1. Unfer V., Carlomagno G., Dante G., Facchinetti F. Effects of myo-inositol in women with PCOS: a systematic review of randomized controlled trials. Gynecological Endocrinology. 2012;28(7):509–515. doi: 10.3109/09513590.2011.650660.
    1. Nestler J. E., Unfer V. Reflections on inositol(s) for PCOS therapy: steps toward success. Gynecological Endocrinology. 2015;31(7):501–505. doi: 10.3109/09513590.2015.1054802.
    1. Nestler J. E., Jakubowicz D. J., de Vargas A. F., 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. The Journal of Clinical Endocrinology & Metabolism. 1998;83(6):2001–2005. doi: 10.1210/jc.83.6.2001.
    1. 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. Reproductive Sciences. 2014;21(7):854–858. doi: 10.1177/1933719113518985.
    1. Carlomagno G., Unfer V., Roseff S. The D-chiro-inositol paradox in the ovary. Fertility and Sterility. 2011;95(8):2515–2516. doi: 10.1016/j.fertnstert.2011.05.027.
    1. 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. Endocrine Journal. 2014;61(2):111–117. doi: 10.1507/endocrj.EJ13-0423.
    1. 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. Gynecological Endocrinology. 2008;24(3):139–144. doi: 10.1080/09513590801893232.
    1. Costantino D., Minozzi G., Minozzi F., Guaraldi C. Metabolic and hormonal effects of myo-inositol in women with polycystic ovary syndrome: a double-blind trial. European Review for Medical and Pharmacological Sciences. 2009;13(2):105–110.
    1. 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. European Review for Medical and Pharmacological Sciences. 2012;16(5):575–581.
    1. Benelli E., Del Ghianda S., Di Cosmo C., Tonacchera M. A combined therapy with myo-inositol and D-chiro-inositol improves endocrine parameters and insulin resistance in PCOS young overweight women. International Journal of Endocrinology. 2016;2016:5. doi: 10.1155/2016/3204083.3204083
    1. Adams J., Polson J. W., Franks S. Prevalence of polycystic ovaries in women with anovulation and idiopathic hirsutism. British Medical Journal. 1986;293:355–359.
    1. Papaleo E., Unfer V., Baillargeon J.-P., Fusi F., Occhi F., De Santis L. Myo-inositol may improve oocyte quality in intracytoplasmic sperm injection cycles. A prospective, controlled, randomized trial. Fertility and Sterility. 2009;91(5):1750–1754. doi: 10.1016/j.fertnstert.2008.01.088.
    1. 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. European Review for Medical and Pharmacological Sciences. 2011;15(5):509–514.
    1. Raffone E., Rizzo P., Benedetto V. Insulin sensitiser agents alone and in co-treatment with r-FSH for ovulation induction in PCOS women. Gynecological Endocrinology. 2010;26(4):275–280. doi: 10.3109/09513590903366996.
    1. Isabella R., Raffone E. Does ovary need D-chiro-inositol? Journal of Ovarian Research. 2012;5(1, article 14) doi: 10.1186/1757-2215-5-14.
    1. 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. European Review for Medical and Pharmacological Sciences. 2011;15(4):452–457.
    1. 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. Archives of Gynecology and Obstetrics. 2013;288(6):1405–1411. doi: 10.1007/s00404-013-2855-3.
    1. Chiu T. T. Y., Rogers M. S., Law E. L. K., Briton-Jones C. M., Cheung L. P., Haines C. J. Follicular fluid and serum concentrations of myo-inositol in patients undergoing IVF: relationship with oocyte quality. Human Reproduction. 2002;17(6):1591–1596. doi: 10.1093/humrep/17.6.1591.
    1. Papaleo E., Unfer V., Baillargeon J.-P., et al. Myo-inositol in patients with polycystic ovary syndrome: a novel method for ovulation induction. Gynecological Endocrinology. 2007;23(12):700–703. doi: 10.1080/09513590701672405.
    1. 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. Proceedings of the National Academy of Sciences of the United States of America. 1993;90(13):5924–5928. doi: 10.1073/pnas.90.13.5924.
    1. Kennington A. S., Hill C. R., Craig J., et al. Low urinary chiro-inositol excretion in non-insulin-dependent diabetes mellitus. The New England Journal of Medicine. 1990;323(6):373–378. doi: 10.1056/nejm199008093230603.
    1. Bevilacqua A., Carlomagno G., Gerli S., et al. Results from the International Consensus Conference on myo-inositol and D-chiro-inositol in Obstetrics and Gynecology-assisted reproduction technology. Gynecological Endocrinology. 2015;31(6):441–446. doi: 10.3109/09513590.2015.1006616.
    1. Larner J., Huang L. C., Schwartz C. F. W., et al. Rat liver insulin mediator which stimulates pyruvate dehydrogenase phosphatase contains galactosamine and D-chiroinositol. Biochemical and Biophysical Research Communications. 1988;151(3):1416–1426. doi: 10.1016/s0006-291x(88)80520-5.
    1. Huang L. C., Fonteles M. C., Houston D. B., 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.
    1. Chiu T. T. Y., Rogers M. S., Briton-Jones C., Haines C. Effects of myo-inositol on the in-vitro maturation and subsequent development of mouse oocytes. Human Reproduction. 2003;18(2):408–416. doi: 10.1093/humrep/deg113.
    1. 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. Biology of Reproduction. 2009;81(4):681–689. doi: 10.1095/biolreprod.109.076760.
    1. Baillargeon J.-P., Nestler J. E., Ostlund R. E., Apridonidze T., Diamanti-Kandarakis E. Greek hyperinsulinemic women, with or without polycystic ovary syndrome, display altered inositols metabolism. Human Reproduction. 2008;23(6):1439–1446. doi: 10.1093/humrep/den097.
    1. Baillargeon J.-P., Iuorno M. J., Apridonidze T., Nestler J. E. Uncoupling between insulin and release of a d-chiro-inositol-containing inositolphosphoglycan mediator of insulin action in obese women with polycystic ovary syndrome. Metabolic Syndrome and Related Disorders. 2010;8(2):127–135. doi: 10.1089/met.2009.0052.
    1. Baillargeon J.-P., Diamanti-Kandarakis E., Ostlund R. E., Jr., Apridonidze T., Iuorno M. J., Nestler J. E. Altered D-chiro-inositol urinary clearance in women with polycystic ovary syndrome. Diabetes Care. 2006;29(2):300–305. doi: 10.2337/diacare.29.02.06.dc05-1070.
    1. Goud P. T., Goud A. P., 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. Molecular Human Reproduction. 1999;5(5):441–451. doi: 10.1093/molehr/5.5.441.
    1. Ortmeyer H. K., Huang L. C., Zhang L., Hansen B. C., 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.
    1. Bizzarri M., Carlomagno G. Inositol: history of an effective therapy for polycystic ovary syndrome. European Review for Medical and Pharmacological Sciences. 2014;18(13):1896–1903.
    1. Carlomagno G., De Grazia S., Unfer V., Manna F. Myo-inositol in a new pharmaceutical form: a step forward to a broader clinical use. Expert Opinion on Drug Delivery. 2012;9(3):267–271. doi: 10.1517/17425247.2012.662953.
    1. Bevilacqua A., Bizzarri M. Physiological role and clinical utility of inositols in polycystic ovary syndrome. Best Practice & Research Clinical Obstetrics & Gynaecology. 2016 doi: 10.1016/j.bpobgyn.2016.03.007.

Source: PubMed

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