Hindawi Publishing Corporation

International Journal of Endocrinology

Volume 2016, Article ID 3204083, 5 pages
http://dx.doi.org/10.1155/2016/3204083

Clinical Study
A Combined Therapy with Myo-Inositol and D-Chiro-Inositol
Improves Endocrine Parameters and Insulin Resistance in PCOS
Young Overweight Women

Elena Benelli, Scilla Del Ghianda, Caterina Di Cosmo, and Massimo Tonacchera
Department of Clinical and Experimental Medicine, Section of Endocrinology, University Hospital of Pisa,
Via Paradisa 2, 56124 Pisa, Italy

Correspondence should be addressed to Massimo Tonacchera; mtonacchera@hotmail.com

Received 13 April 2016; Accepted 24 May 2016

Academic Editor: Vittorio Unfer

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.

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.

1. Introduction syndrome [10–12]. It was hypothesized that in patients with

PCOS altered insulin signaling may generate the IR which
Polycystic ovary syndrome (PCOS) is a heterogeneous syn- in turn causes abnormal ovarian steroidogenesis [13, 14],
drome, involving a growing number of women in repro- so that several insulin-sensitizing compounds have been
ductive age, diagnosed on the basis of three different fac- proposed as possibly safe and efficacious long-term treatment
tors: oligo- or anovulation, clinical/biochemical hyperandro- of PCOS [15]. Among these drugs, metformin resulted to
genism, and polycystic ovary, with the presence on ultra- be the most used and studied drug, even if this molecule is
sound of ≥12 follicles in each ovary measuring 2 ± 9 mm predominantly associated with gastrointestinal discomforts
in diameter and/or increased ovarian volume (>10 mL) [1, consisting of bloating, nausea, and diarrhea [14, 16]. Inter-
2]. PCOS affected patients that had menstrual irregularity, esting and promising results have been obtained focusing on
followed in many cases by infertility [3, 4] and mood two inositol stereoisomers, such as myo-inositol (MI) and D-
disorders, such as anxiety and depression [5]. Though PCOS chiro-inositol (DCI), acting like insulin mediators [17–19]. As
pathogenesis still remains unclear, insulin resistance (IR) and insulin second messengers, both these molecules are involved
the consequential hyperinsulinemia are considered primary in increasing insulin sensitivity of different tissues to improve
triggers, both in obese and in lean women with this syndrome metabolic and ovulatory functions [20]. In particular, at
[6–8]. Indeed, hyperinsulinemia induced by IR occurs in low dosage, DCI restores normal insulin sensitivity in the
roughly 80% of PCOS obese women, as in 30–40% of PCOS typical insulin target tissues, reducing the circulating insulin
lean women [9], suggesting that IR is independent but also and androgens and inducing an enhancement in ovulation
exacerbated by obesity; this latter considered an enhanc- frequency. On the contrary, MI exerts its beneficial effects
ing factor that positively correlates with the multifactorial mainly at the ovary level, where it is highly concentrated,
2 International Journal of Endocrinology

both enhancing insulin pattern and also directly acting on a Table 1: Characteristics of patients who received MI plus DCI
number of ovarian functions, including steroidogenesis [21]. (group A) or placebo treatment (group B).
Some authors [22] postulated that PCOS affected women,
Group A (𝑛 = 21) Group B (𝑛 = 25)
with IR, presenting in the ovary a misbalance in MI/DCI
ratio, resulting in DCI overproduction and in turn in a Age (years) 23 ± 6.8 25 ± 7.3
deficiency in MI, which would explain the excessive androgen Height (cm) 164 ± 6.7 168 ± 6.9
biosynthesis. Other authors [23], instead, proposed that the Weight (kg) 85 ± 13.5 88 ± 14
increased androgen levels in PCOS patients might be linked BMI 32 ± 4.8 31 ± 4.6
to a decreased MI/DCI. In a recent study, Facchinetti et BMI: body mass index.
al. [24] 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 Insulin resistance was measured by means of Homeostasis
a therapy that combines MI plus DCI in the ratio of 40 : 1, Model Assessment (HOMA) in addition to determining
versus placebo, in order to improve some clinical outcomes fasting glucose and insulin with the same timeline and
in PCOS young overweight women. 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,
2. Methods and the serum obtained was stored at −20∘ C within one hour
2.1. Patients and Study Design. This randomized controlled of collection. Before the analysis, all the serum samples were
trial enrolled 46 obese women with BMI > 30 who were thawed and entirely mixed.
affected by PCOS according to Rotterdam criteria [1, 2].
All the women were enrolled at the Department of Clinical 2.3. Statistical Analysis. Data reported indicate mean values ±
and Experimental Medicine, University of Pisa. Patients with standard deviation (SD). Paired 𝑡-test was used to identify the
diabetes, smokers, and alcohol users were ruled out from the differences between variables at baseline and after six months
study. After all patients subscribed their written informed of treatment with MI plus DCI or with placebo, respectively.
consent to be involved into the study, they were randomly Differences were considered statistically significant at 𝑝 value
assigned to two groups, A and B. At baseline, patients in <0.05.
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 3. Results and Discussion
body) in soft gel capsule containing 550 mg of MI, 13.8 mg
The goal of this study was to investigate if the therapy
of DCI, and 200 𝜇g of folic acid (INOFOLIC COMBI,
combining MI and DCI in the ratio of 40 : 1 could improve the
LO.LI.PHARMA) twice a day. Group B, with 25 women,
endocrine profile and the insulin resistance of obese women
received the same amount of folic acid (200 𝜇g) as placebo
with a PCOS diagnosis. To address this issue, 46 young obese
twice a day. The treatments were performed for six months.
patients affected by this syndrome, whose characteristics
At the beginning of the study, all the patients were in the
are summarized in Table 1, were randomly included in two
follicular phase of the menstrual cycle.
groups and then treated with MI plus DCI at the ratio of 40 : 1
with or placebo for six months. Insulin resistance, evaluated
2.2. Study Measurements. All patients were evaluated for as HOMA index, fasting insulin, and fasting glucose, and
FSH, LH, 17-beta-Estradiol (E), Sex Hormone Binding Glob- also hormonal parameters were determined at the baseline
ulin (SHBG), androstenedione, free testosterone, and dehy- and after the six-month therapy. As shown in Table 2, we
droepiandrosterone sulphate (DHEAS) levels at the baseline observed that, with respect to the baseline values, only the
and after the six months of therapy with MI plus DCI associa- combined therapy of MI plus DCI significantly rebalanced
tion or with placebo. FSH and LH serum levels were detected the endocrine and metabolic profiles of these patients, ame-
by immune-enzymatic assay (Access Immunoassay System, liorating their insulin resistance and the ovulatory func-
hLH, hFSH, Beckman Coulter, Brea, CA, USA). Estradiol tion, as successfully recorded by ultrasound. As a matter
levels were measured by competitive immunoassay (Access of fact, LH and free testosterone levels decreased after the
Immunoassay System, Estradiol, Beckman Coulter, Brea, CA, combined treatment, downregulating the hyperandrogenism,
USA). SHBG levels were detected by immunoassay (Access and even HOMA index and fasting insulin, markers of
Immunoassay System, SHBG, Beckman Coulter, Brea, CA, insulin resistance, resulted to be significantly reduced. On
USA). Serum levels of androstenedione were measured by the other hand, E and SHBG significantly increased, showing
conventional immune-enzymatic assay (Access Immunoas- restoring in ovulation capability. No relevant changes in
say System, androstenedione, Beckman Coulter, Brea, CA, these sex hormones were reported in group B, treated with
USA). Free testosterone serum levels were measured by placebo, and no significant modifications were observed after
immune-enzymatic assay (Access Immunoassay System, free the treatment in both groups A and B for what concerns
testosterone, Beckman Coulter, Brea, CA, USA). DHEAS was BMI, FSH, androstenedione, DHEAS, and fasting glucose.
measured by conventional immunoassay (Access Immunoas- Importantly, no relevant side effect was recorded during the
say System, DHEAS, Beckman Coulter, Brea, CA, USA). combined therapy with MI plus DCI. Overall, these results
International Journal of Endocrinology 3

Table 2: Baseline and posttreatment endocrine and metabolic parameters of groups A and B of PCOS patients.

Group A (𝑛 = 21) Group B (𝑛 = 25)

Baseline MI plus DCI p value Baseline placebo 𝑝 value
FSH (mIU/mL) 5.86 ± 1.75 4.96 ± 1.74 ns 5.67 ± 1.11 5.47 ± 0.63 ns
LH (mIU/mL) 12.5 ± 8 8.5 ± 4.04 𝑝 < 0.05 11.27 ± 7.2 11.25 ± 5.35 ns
E (pg/mL) 47.06 ± 18.20 107.42 ± 92.86 𝑝 < 0.01 50.37 ± 19.45 52 ± 20.2 ns
Fasting insulin (𝜇U/mL) 20.19 ± 8.14 10.74 ± 5.46 𝑝 < 0.001 18 ± 8 17.8 ± 8.2 ns
Fasting glucose (mg/dL) 85 ± 5.96 86 ± 7.12 ns 86.2 ± 9.1 84.73 ± 8.3 ns
Free testosterone (ng/dL) 0.76 ± 0.20 0.62 ± 0.15 𝑝 < 0.05 0.85 ± 0.22 0.83 ± 0.2 ns
SHBG (nmol/L) 24.11 ± 10.35 35.85 ± 24.3 𝑝 < 0.05 20.44 ± 8.77 21.36 ± 7.57 ns
Androstenedione (ng/mL) 4.25 ± 1.48 4.01 ± 1.70 ns 3.48 ± 1.21 3.12 ± 2.23 ns
DHEAS (𝜇g/dL) 327.32 ± 150.89 347.6 ± 170.98 ns 337.95 ± 155.79 315.83 ± 145.59 ns
HOMA 3.38 ± 1.97 1.97 ± 1.48 𝑝 < 0.05 3.48 ± 2.02 2.8 ± 1.4 ns
E, 17-beta-Estradiol; P, progesterone; 17OHP, 17-OH-progesterone; SHBG, Sex Hormone Binding Globulin; DHEAS, dehydroepiandrosterone sulphate.

demonstrated the clinical importance of a combined therapy most appropriated clinical approach to integrate the positive
of MI plus DCI to correct the PCOS metabolic and reproduc- effects exerted by both inositol stereoisomers.
tive 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 4. Conclusions
syndrome whose pathogenesis remains still largely unclear,
even though several etiological factors are demonstrated to The data reported are encouraging and they offer therapeutic
be involved. Compelling evidences claimed the pivotal role of options to the first-line treatments in PCOS women with
insulin resistance and/or compensatory hyperinsulinemia in moderate or severe hyperandrogenism and/or menstrual
this syndrome [9, 27–29]; indeed they tightly contribute both abnormalities, which are represented by metformin as well as
directly (increasing the ovarian production of androgens) by oral contraceptives. These compounds effectively suppress
and indirectly (modulating the hepatic SHBG synthesis) to LH release and the consequent androgen production from the
hyperandrogenism development, one of the main features of ovary; also they increase the sex hormone binding protein
those patients affected by PCOS [30, 31], especially in case synthesis, lowering the levels of circulating free androgens
of overweight women [32]. Nevertheless, literature findings [40]. Unfortunately, if the patient aims to restore ovulation in
consistently demonstrated that a deficiency in the tissue avail- order to conceive, contraceptives are not the clinical strategy
ability and/or usage of MI and/or DCI in women diagnosed to follow. Furthermore, prolonged use of contraceptives may
with PCOS could likely concur to the IR typical of this increase homocysteine levels after six months of treatment
syndrome [22, 23]. The two inositol stereoisomers, MI and [41], as well as the risk of venous thromboembolism [42].
DCI, acting as insulin-sensitizers, have been demonstrated For what concerns metformin, several side gastrointestinal
to positively influence the clinical history of PCOS patients, effects (diarrhoea, nausea, vomiting, and abdominal bloat-
ameliorating their endocrine and metabolic profile both ing) and metabolic complications have been evidenced after
alone and in combination [19, 33–37]. DCI alone, at low a long-term treatment [43]. For all these reasons, even
dosage, may restore normal insulin sensitivity in the typical though more studies on a higher number of patients and
insulin target tissues, inducing an enhancement in ovulation with greater statistical significance are needed to confirm
frequency which could be ascribed to the general improved these striking posttreatment outcomes, safe combined use of
insulin sensitivity and to the reduced circulating insulin and inositol stereoisomers should be largely suitable and it might
androgens. On the contrary, MI exerts its beneficial effects represent a valid clinical approach in PCOS management.
mainly at the ovary level, both enhancing insulin pattern
and also directly acting on a number of ovarian functions,
including steroidogenesis [22]. The ability of both inositol
stereoisomers to regulate glucose metabolism in a different
Abbreviations
manner (DCI promotes glycogen synthesis, while MI may DCI: D-Chiro-inositol
support glucose cell intake) [38] is mirrored by their different DHEAS: Dehydroepiandrosterone sulphate
concentration in the tissues: while DCI is highly concentrated E: 17-Beta-Estradiol
in glycogen storage tissues (liver, muscles, and fat), MI is HOMA: Homeostasis Model Assessment
more abundant in those tissues that need a large amount IR: Insulin resistance
of glucose, such as brain, heart, or ovary [39]. From this MI: Myo-inositol
knowledge, a combined therapy with MI plus DCI in their PCOS: Polycystic ovary syndrome
physiological plasma ratio (MI/DCI 40 : 1) seems to be the SHBG: Sex Hormone Binding Globulin.
4 International Journal of Endocrinology

Competing Interests [16] V. De Leo, M. C. Musacchio, G. Morgante, P. Piomboni, and

F. Petraglia, “Metformin treatment is effective in obese teenage
The authors declare that there are no competing interests girls with PCOS,” Human Reproduction, vol. 21, no. 9, pp. 2252–
regarding the publication of this paper. 2256, 2006.
[17] J. Larner, “D-chiro-inositol—its functional role in insulin action
and its deficit in insulin resistance,” International Journal of
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