Inositol(s) from Bench to Bedside in Endocrinology and GynecologyView this Special Issue
Clinical Study | Open Access
Elena Benelli, Scilla Del Ghianda, Caterina Di Cosmo, Massimo Tonacchera, "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, vol. 2016, Article ID 3204083, 5 pages, 2016. https://doi.org/10.1155/2016/3204083
A Combined Therapy with Myo-Inositol and D-Chiro-Inositol Improves Endocrine Parameters and Insulin Resistance in PCOS Young Overweight Women
Introduction. We evaluated the effects of a therapy that combines myo-inositol (MI) and D-chiro-inositol (DCI) in young overweight women affected by polycystic ovary syndrome (PCOS), characterized by oligo- or anovulation and hyperandrogenism, correlated to insulin resistance. Methods. We enrolled 46 patients affected by PCOS and, randomly, we assigned them to two groups, A and B, treated, respectively, with the association of MI plus DCI, in a 40 : 1 ratio, or with placebo (folic acid) for six months. Thus, we analyzed pretreatment and posttreatment FSH, LH, 17-beta-Estradiol, Sex Hormone Binding Globulin, androstenedione, free testosterone, dehydroepiandrosterone sulphate, HOMA index, and fasting glucose and insulin. Results. We recorded a statistically significant reduction of LH, free testosterone, fasting insulin, and HOMA index only in the group treated with the combined therapy of MI plus DCI; in the same patients, we observed a statistically significant increase of 17-beta-Estradiol levels. Conclusions. The combined therapy of MI plus DCI is effective in improving endocrine and metabolic parameters in young obese PCOS affected women.
Polycystic ovary syndrome (PCOS) is a heterogeneous syndrome, involving a growing number of women in reproductive age, diagnosed on the basis of three different factors: oligo- or anovulation, clinical/biochemical hyperandrogenism, and polycystic ovary, with the presence on ultrasound of ≥12 follicles in each ovary measuring mm in diameter and/or increased ovarian volume (>10 mL) [1, 2]. PCOS affected patients that had menstrual irregularity, followed in many cases by infertility [3, 4] and mood disorders, such as anxiety and depression . Though PCOS pathogenesis still remains unclear, insulin resistance (IR) and the consequential hyperinsulinemia are considered primary triggers, both in obese and in lean women with this syndrome [6–8]. Indeed, hyperinsulinemia induced by IR occurs in roughly 80% of PCOS obese women, as in 30–40% of PCOS lean women , suggesting that IR is independent but also exacerbated by obesity; this latter considered an enhancing factor that positively correlates with the multifactorial syndrome [10–12]. It was hypothesized that in patients with PCOS altered insulin signaling may generate the IR which in turn causes abnormal ovarian steroidogenesis [13, 14], so that several insulin-sensitizing compounds have been proposed as possibly safe and efficacious long-term treatment of PCOS . Among these drugs, metformin resulted to be the most used and studied drug, even if this molecule is predominantly associated with gastrointestinal discomforts consisting of bloating, nausea, and diarrhea [14, 16]. Interesting and promising results have been obtained focusing on two inositol stereoisomers, such as myo-inositol (MI) and D-chiro-inositol (DCI), acting like insulin mediators [17–19]. As insulin second messengers, both these molecules are involved in increasing insulin sensitivity of different tissues to improve metabolic and ovulatory functions . In particular, at low dosage, DCI restores normal insulin sensitivity in the typical insulin target tissues, reducing the circulating insulin and androgens and inducing an enhancement in ovulation frequency. On the contrary, MI exerts its beneficial effects mainly at the ovary level, where it is highly concentrated, both enhancing insulin pattern and also directly acting on a number of ovarian functions, including steroidogenesis . Some authors  postulated that PCOS affected women, with IR, presenting in the ovary a misbalance in MI/DCI ratio, resulting in DCI overproduction and in turn in a deficiency in MI, which would explain the excessive androgen biosynthesis. Other authors , instead, proposed that the increased androgen levels in PCOS patients might be linked to a decreased MI/DCI. In a recent study, Facchinetti et al.  discovered that the physiological MI/DCI ratio was 40 : 1 and, based on this finding, as well as on the specific behavior of both stereoisomers, we investigated the effects of a therapy that combines MI plus DCI in the ratio of 40 : 1, versus placebo, in order to improve some clinical outcomes in PCOS young overweight women.
2.1. Patients and Study Design
This randomized controlled trial enrolled 46 obese women with who were affected by PCOS according to Rotterdam criteria [1, 2]. All the women were enrolled at the Department of Clinical and Experimental Medicine, University of Pisa. Patients with diabetes, smokers, and alcohol users were ruled out from the study. After all patients subscribed their written informed consent to be involved into the study, they were randomly assigned to two groups, A and B. At baseline, patients in groups A and B did not differ significantly. In group A, 21 women received MI plus DCI combined treatment at the ratio of 40 : 1 (the physiologic ratio of the two isomers in the body) in soft gel capsule containing 550 mg of MI, 13.8 mg of DCI, and 200 μg of folic acid (INOFOLIC® COMBI, LO.LI.PHARMA) twice a day. Group B, with 25 women, received the same amount of folic acid (200 μg) as placebo twice a day. The treatments were performed for six months. At the beginning of the study, all the patients were in the follicular phase of the menstrual cycle.
2.2. Study Measurements
All patients were evaluated for FSH, LH, 17-beta-Estradiol (E), Sex Hormone Binding Globulin (SHBG), androstenedione, free testosterone, and dehydroepiandrosterone sulphate (DHEAS) levels at the baseline and after the six months of therapy with MI plus DCI association or with placebo. FSH and LH serum levels were detected by immune-enzymatic assay (Access Immunoassay System, hLH, hFSH, Beckman Coulter, Brea, CA, USA). Estradiol levels were measured by competitive immunoassay (Access Immunoassay System, Estradiol, Beckman Coulter, Brea, CA, USA). SHBG levels were detected by immunoassay (Access Immunoassay System, SHBG, Beckman Coulter, Brea, CA, USA). Serum levels of androstenedione were measured by conventional immune-enzymatic assay (Access Immunoassay System, androstenedione, Beckman Coulter, Brea, CA, USA). Free testosterone serum levels were measured by immune-enzymatic assay (Access Immunoassay System, free testosterone, Beckman Coulter, Brea, CA, USA). DHEAS was measured by conventional immunoassay (Access Immunoassay System, DHEAS, Beckman Coulter, Brea, CA, USA). Insulin resistance was measured by means of Homeostasis Model Assessment (HOMA) in addition to determining fasting glucose and insulin with the same timeline and modalities. Blood samples, taken at the baseline and after the six-month treatment period under similar conditions, were separated by centrifugation at 2000 ×g for 15 minutes at 4°C, and the serum obtained was stored at −20°C within one hour of collection. Before the analysis, all the serum samples were thawed and entirely mixed.
2.3. Statistical Analysis
Data reported indicate mean values ± standard deviation (SD). Paired -test was used to identify the differences between variables at baseline and after six months of treatment with MI plus DCI or with placebo, respectively. Differences were considered statistically significant at value <0.05.
3. Results and Discussion
The goal of this study was to investigate if the therapy combining MI and DCI in the ratio of 40 : 1 could improve the endocrine profile and the insulin resistance of obese women with a PCOS diagnosis. To address this issue, 46 young obese patients affected by this syndrome, whose characteristics are summarized in Table 1, were randomly included in two groups and then treated with MI plus DCI at the ratio of 40 : 1 with or placebo for six months. Insulin resistance, evaluated as HOMA index, fasting insulin, and fasting glucose, and also hormonal parameters were determined at the baseline and after the six-month therapy. As shown in Table 2, we observed that, with respect to the baseline values, only the combined therapy of MI plus DCI significantly rebalanced the endocrine and metabolic profiles of these patients, ameliorating their insulin resistance and the ovulatory function, as successfully recorded by ultrasound. As a matter of fact, LH and free testosterone levels decreased after the combined treatment, downregulating the hyperandrogenism, and even HOMA index and fasting insulin, markers of insulin resistance, resulted to be significantly reduced. On the other hand, E and SHBG significantly increased, showing restoring in ovulation capability. No relevant changes in these sex hormones were reported in group B, treated with placebo, and no significant modifications were observed after the treatment in both groups A and B for what concerns BMI, FSH, androstenedione, DHEAS, and fasting glucose. Importantly, no relevant side effect was recorded during the combined therapy with MI plus DCI. Overall, these results demonstrated the clinical importance of a combined therapy of MI plus DCI to correct the PCOS metabolic and reproductive aspects and they are largely in agreement with the issues discussed on the two international consensus conferences on MI, DCI, and their link with PCOS [25, 26]. PCOS is a syndrome whose pathogenesis remains still largely unclear, even though several etiological factors are demonstrated to be involved. Compelling evidences claimed the pivotal role of insulin resistance and/or compensatory hyperinsulinemia in this syndrome [9, 27–29]; indeed they tightly contribute both directly (increasing the ovarian production of androgens) and indirectly (modulating the hepatic SHBG synthesis) to hyperandrogenism development, one of the main features of those patients affected by PCOS [30, 31], especially in case of overweight women . Nevertheless, literature findings consistently demonstrated that a deficiency in the tissue availability and/or usage of MI and/or DCI in women diagnosed with PCOS could likely concur to the IR typical of this syndrome [22, 23]. The two inositol stereoisomers, MI and DCI, acting as insulin-sensitizers, have been demonstrated to positively influence the clinical history of PCOS patients, ameliorating their endocrine and metabolic profile both alone and in combination [19, 33–37]. DCI alone, at low dosage, may restore normal insulin sensitivity in the typical insulin target tissues, inducing an enhancement in ovulation frequency which could be ascribed to the general improved insulin sensitivity and to the reduced circulating insulin and androgens. On the contrary, MI exerts its beneficial effects mainly at the ovary level, both enhancing insulin pattern and also directly acting on a number of ovarian functions, including steroidogenesis . The ability of both inositol stereoisomers to regulate glucose metabolism in a different manner (DCI promotes glycogen synthesis, while MI may support glucose cell intake)  is mirrored by their different concentration in the tissues: while DCI is highly concentrated in glycogen storage tissues (liver, muscles, and fat), MI is more abundant in those tissues that need a large amount of glucose, such as brain, heart, or ovary . From this knowledge, a combined therapy with MI plus DCI in their physiological plasma ratio (MI/DCI 40 : 1) seems to be the most appropriated clinical approach to integrate the positive effects exerted by both inositol stereoisomers.
|BMI: body mass index.|
|E, 17-beta-Estradiol; P, progesterone; 17OHP, 17-OH-progesterone; SHBG, Sex Hormone Binding Globulin; DHEAS, dehydroepiandrosterone sulphate.|
The data reported are encouraging and they offer therapeutic options to the first-line treatments in PCOS women with moderate or severe hyperandrogenism and/or menstrual abnormalities, which are represented by metformin as well as by oral contraceptives. These compounds effectively suppress LH release and the consequent androgen production from the ovary; also they increase the sex hormone binding protein synthesis, lowering the levels of circulating free androgens . Unfortunately, if the patient aims to restore ovulation in order to conceive, contraceptives are not the clinical strategy to follow. Furthermore, prolonged use of contraceptives may increase homocysteine levels after six months of treatment , as well as the risk of venous thromboembolism . For what concerns metformin, several side gastrointestinal effects (diarrhoea, nausea, vomiting, and abdominal bloating) and metabolic complications have been evidenced after a long-term treatment . For all these reasons, even though more studies on a higher number of patients and with greater statistical significance are needed to confirm these striking posttreatment outcomes, safe combined use of inositol stereoisomers should be largely suitable and it might represent a valid clinical approach in PCOS management.
|HOMA:||Homeostasis Model Assessment|
|PCOS:||Polycystic ovary syndrome|
|SHBG:||Sex Hormone Binding Globulin.|
The authors declare that there are no competing interests regarding the publication of this paper.
- B. C. J. M. Fauser, “Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome,” Fertility and Sterility, vol. 81, no. 1, pp. 19–25, 2004.
- “Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS),” Human Reproduction, vol. 19, pp. 41–47, 2004.
- S. M. Sirmans and K. A. Pate, “Epidemiology, diagnosis, and management of polycystic ovary syndrome,” Clinical Epidemiology, vol. 6, no. 1, pp. 1–13, 2013.
- T. M. Barber, M. I. McCarthy, J. A. H. Wass, and S. Franks, “Obesity and polycystic ovary syndrome,” Clinical Endocrinology, vol. 65, no. 2, pp. 137–145, 2006.
- A. Podfigurna-Stopa, S. Luisi, C. Regini et al., “Mood disorders and quality of life in polycystic ovary syndrome,” Gynecological Endocrinology, vol. 31, no. 6, pp. 431–434, 2015.
- G. A. Burghen, J. R. Givens, and A. E. Kitabchi, “Correlation of hyperandrogenism with hyperinsulinism in polycystic ovarian disease,” Journal of Clinical Endocrinology & Metabolism, vol. 50, no. 1, pp. 113–116, 1980.
- A. Dunaif and A. R. Hoffman, “Insulin resistance and hyperandrogenism: clinical syndromes and possible mechanisms,” in Biorhythms and Stress in the Physiopathology of Reproduction, P. Pancheri and L. Zichella, Eds., pp. 293–317, Hemisphere, Washington, DC, USA, 1988.
- A. Dunaif, “Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis,” Endocrine Reviews, vol. 18, no. 6, pp. 774–800, 1997.
- M. Ciampelli, A. M. Fulghesu, F. Cucinelli et al., “Impact of insulin and body mass index on metabolic and endocrine variables in polycystic ovary syndrome,” Metabolism: Clinical and Experimental, vol. 48, no. 2, pp. 167–172, 1999.
- A. Gambineri and R. Pasquali, “Insulin resistance, obesity and metabolic syndrome in polycystic ovary syndrome,” Endocrinología y Nutricion, vol. 53, no. 1, pp. 41–55, 2006.
- F. Álvarez-Blasco, J. I. Botella-Carretero, J. L. San Millán, and H. F. Escobar-Morreale, “Prevalence and characteristics of the polycystic ovary syndrome in overweight and obese women,” Archives of Internal Medicine, vol. 166, no. 19, pp. 2081–2086, 2006.
- N. K. Stepto, S. Cassar, A. E. Joham et al., “Women with polycystic ovary syndrome have intrinsic insulin resistance on euglycaemic-hyperinsulaemic clamp,” Human Reproduction, vol. 28, no. 3, pp. 777–784, 2013.
- J. E. Nestler and J. F. Strauss III, “Insulin as an effector of human ovarian and adrenal steroid metabolism,” Endocrinology and Metabolism Clinics of North America, vol. 20, no. 4, pp. 807–823, 1991.
- J. C. Marshall and A. Dunaif, “Should all women with PCOS be treated for insulin resistance?” Fertility and Sterility, vol. 97, no. 1, pp. 18–22, 2012.
- J. E. Nestler, D. Stovall, N. Akhter, M. J. Iuorno, and D. J. Jakubowicz, “Strategies for the use of insulin-sensitizing drugs to treat infertility in women with polycystic ovary syndrome,” Fertility and Sterility, vol. 77, no. 2, pp. 209–215, 2002.
- V. De Leo, M. C. Musacchio, G. Morgante, P. Piomboni, and F. Petraglia, “Metformin treatment is effective in obese teenage girls with PCOS,” Human Reproduction, vol. 21, no. 9, pp. 2252–2256, 2006.
- J. Larner, “D-chiro-inositol—its functional role in insulin action and its deficit in insulin resistance,” International Journal of Experimental Diabetes Research, vol. 3, no. 1, pp. 47–60, 2002.
- A. D. Genazzani, C. Lanzoni, F. Ricchieri, and V. M. Jasonni, “Myo-inositol administration positively affects hyperinsulinemia and hormonal parameters in overweight patients with polycystic ovary syndrome,” Gynecological Endocrinology, vol. 24, no. 3, pp. 139–144, 2008.
- S. Gerli, M. Mignosa, and G. C. Di Renzo, “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, vol. 7, no. 6, pp. 151–159, 2003.
- M. Bizzarri and G. Carlomagno, “Inositol: history of an effective therapy for polycystic ovary syndrome,” European Review for Medical and Pharmacological Sciences, vol. 18, no. 13, pp. 1896–1903, 2014.
- M. Minozzi, D. Costantino, C. Guaraldi, and V. Unfer, “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,” Gynecological Endocrinology, vol. 27, no. 11, pp. 920–924, 2011.
- V. Unfer, G. Carlomagno, E. Papaleo, S. Vailati, M. Candiani, and J.-P. Baillargeon, “Hyperinsulinemia alters myoinositol to d-chiroinositol ratio in the follicular fluid of patients with PCOS,” Reproductive Sciences, vol. 21, no. 7, pp. 854–858, 2014.
- D. Heimark, J. McAllister, and J. Larner, “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, vol. 61, no. 2, pp. 111–117, 2014.
- F. Facchinetti, G. Dante, and I. Neri, “The ratio of MI to DCI and its impact in the treatment of polycystic ovary syndrome: experimental and literature evidences,” in Frontiers in Gynecological Endocrinology, Part of the series ISGE Series, pp. 103–109, Springer, Berlin, Germany, 2015.
- A. Bevilacqua, G. Carlomagno, S. Gerli et al., “Results from the international consensus conference on myo-inositol and D-chiro-inositol in obstetrics and gynecology—assisted reproduction technology,” Gynecological Endocrinology, vol. 31, no. 6, pp. 441–446, 2015.
- F. Facchinetti, M. Bizzarri, S. Benvenga 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,” European Journal of Obstetrics Gynecology and Reproductive Biology, vol. 195, pp. 72–76, 2015.
- J.-P. Baillargeon, M. J. Iuorno, and J. E. Nestler, “Insulin sensitizers for polycystic ovary syndrome,” Clinical Obstetrics and Gynecology, vol. 46, no. 2, pp. 325–340, 2003.
- J. E. Nestler, “Role of hyperinsulinemia in the pathogenesis of the polycystic ovary syndrome, and its clinical implications,” Seminars in Reproductive Endocrinology, vol. 15, no. 2, pp. 111–122, 1997.
- A. D. Genazzani, C. Battaglia, B. Malavasi, C. Strucchi, F. Tortolani, and O. Gamba, “Metformin administration modulates and restores luteinizing hormone spontaneous episodic secretion and ovarian function in nonobese patients with polycystic ovary syndrome,” Fertility and Sterility, vol. 81, no. 1, pp. 114–119, 2004.
- V. Unfer, G. Carlomagno, G. Dante, and F. Facchinetti, “Effects of myo-inositol in women with PCOS: a systematic review of randomized controlled trials,” Gynecological Endocrinology, vol. 28, no. 7, pp. 509–515, 2012.
- A. Dunaif, “Insulin resistance in women with polycystic ovary syndrome,” Fertility and Sterility, vol. 86, supplement 1, pp. S13–S14, 2006.
- R. Pasquali, C. Pelusi, C. Ragazzini, R. Hasanaj, and A. Gambineri, “Glucose tolerance, insulin secretion and insulin sensitivity in polycystic ovary syndrome,” Journal of the Pancreas, vol. 3, no. 1, pp. 1–7, 2002.
- D. Costantino, G. Minozzi, F. Minozzi, and C. Guaraldi, “Metabolic and hormonal effects of myo-inositol in women with polycystic ovary syndrome: a double-blind trial,” European Review for Medical and Pharmacological Sciences, vol. 13, no. 2, pp. 105–110, 2009.
- S. Gerli, E. Papaleo, A. Ferrari, and G. C. Di Renzo, “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, vol. 11, no. 5, pp. 347–354, 2007.
- A. S. Laganà, L. Barbaro, and A. Pizzo, “Evaluation of ovarian function and metabolic factors in women affected by polycystic ovary syndrome after treatment with D-Chiro-Inositol,” Archives of Gynecology and Obstetrics, vol. 291, no. 5, pp. 1181–1186, 2015.
- M. Nordio and E. Proietti, “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, vol. 16, no. 5, pp. 575–581, 2012.
- M. Minozzi, M. Nordio, and R. Pajalich, “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,” European Review for Medical and Pharmacological Sciences, vol. 17, no. 4, pp. 537–540, 2013.
- L. C. Huang, M. C. Fonteles, D. B. Houston, C. Zhang, and J. Larner, “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, vol. 132, no. 2, pp. 652–657, 1993.
- T.-H. Sun, D. B. Heimark, T. Nguygen, J. L. Nadler, and J. Larner, “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,” Biochemical and Biophysical Research Communications, vol. 293, no. 3, pp. 1092–1098, 2002.
- V. De Leo, G. Morgante, P. Piomboni, M. C. Musacchio, F. Petraglia, and A. Cianci, “Evaluation of effects of an oral contraceptive containing ethinylestradiol combined with drospirenone on adrenal steroidogenesis in hyperandrogenic women with polycystic ovary syndrome,” Fertility and Sterility, vol. 88, no. 1, pp. 113–117, 2007.
- N. Cinar, A. Harmanci, M. Bayraktar, and B. O. Yildiz, “Ethinyl estradiol-drospirenone vs ethinyl estradiol-drospirenone plus metformin in the treatment of lean women with polycystic ovary syndrome,” Clinical Endocrinology, vol. 78, no. 3, pp. 379–384, 2013.
- A. Van Hylckama Vlieg, F. M. Helmerhorst, J. P. Vandenbroucke, C. J. M. Doggen, and F. R. Rosendaal, “The venous thrombotic risk of oral contraceptives, effects of oestrogen dose and progestogen type: results of the MEGA case-control study,” The British Medical Journal, vol. 339, Article ID b2921, 2009.
- ACOG Committee on Practice Bulletins Gynecology, “ACOG Practice Bulletin No. 108: Polycystic ovary syndrome,” Obstetrics & Gynecology, vol. 114, no. 4, pp. 936–949, 2009.
Copyright © 2016 Elena Benelli et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.