The polycystic ovary syndrome (PCOS) affects about 6–10% of women in the reproductive age, characterized by chronic anovulation, hirsutism and acne, sterility and polycystic ovarian ultrasound morphology (PCOM) [1,2]. More than 50% may be obese [3]. Most of the patients with PCOS are affected by insulin resistance [2,4], dyslipidemia [5], a low grade of chronic inflammation, vascular and endothelial dysfunctions [6,7]. These metabolic features are worsened by obesity and can increase the risk of glucose intolerance, type 2 diabetes mellitus, hypertension, and cardiovascular diseases [8,9].

Insulin resistance plays a pivotal role in the development of the clinical and metabolic abnormalities of PCOS. Consequently, PCOS patients have a higher insulin production that in turn stimulates ovarian androgen secretion, as well as the release of other factors from different tissues that are involved in the metabolic damage [10].

To prevent the long-term health consequences of PCOS, besides lifestyle modifications [11,12], the use of insulin-sensitizers has been proposed, and metformin has been commonly used [13,14]. A large body of evidence shows that metformin may have metabolic and reproductive benefits, including weight reduction, decrease in plasma insulin and lipid levels, decrease in blood pressure, decrease in androgen plasma levels, restoration of a normal menstrual cyclicity and ovulation [14–16]. However, the use of metformin may be limited by gastrointestinal side effects [15,16].

Research has documented that insulin resistance in PCOS is due to defect in the inositolphosphoglycans (IPGs) second messenger in glucose metabolism.  A defect in tissue availability or altered metabolism of inositol and/or IPGs mediators may contribute to insulin resistance.

Recently, new insulin sensitizers containing inositol have been proposed in the treatment of PCOS patients. Inositol is a physiological compound belonging to the sugar family and nine stereoisomers are known, of which myo-inositol and D-chiro-inositol are the two main ones present in our body [17]. Myo-inositol administration improves insulin sensitivity [18,19]. Moreover, it produces a second messenger, the inositol triphosphate, that regulates several hormones such as FSH, TSH and Insulin [20,21]. In contrast to metformin, no side effects have been reported during treatment with Myoinositol [22–24], while improving reproductive and metabolic parameters in PCOS women [23,24].

Myoinositol

Inositols play an important role in generating calcium signals in mammalian oocytes. Calcium signalling in oocytes has been extensively studied as its putative role in oocyte maturation and the early stages of fertilization. Myoinositol (MI) is the most abundant form of inositol in humans and is a part of the B-complex family. It is a natural insulin sensitizer and is a component of membrane phospholipids, glycosylphophatidylinositol anchors that bind glycoproteins to cell membranes, and inositol phosphate second messengers (8-9). Thus these INS function as insulin sensitizers. MI in most of the tissues constitutes intracellular pool of inositol but in fat, muscle and liver, D-chiro-inositol (DCI) is the main inositol found and is responsible for glycogen synthesis. MI is converted to DCI according to specific tissue requirements. The role of these two inositols has been clearly studied and documented in literature.

1.    MI is converted to an inositolphosphoglycan (IPG) insulin second messenger (MI-IPG) involved in cellular glucose uptake, whereas DCI is converted to an IPG insulin second messenger (DCI-IPG) involved in glycogen synthesis.

2.    At ovarian level, MI based second messenger is involved in both glucose uptake and FSH signaling whereas DCI-based second messenger is devoted to the insulin-mediated androgen production.

3.    MI is essential in ensuring proper oocyte maturation.

Specific role of MI in PCOS

MI treatment has been shown to ameliorate the reproductive morbidities affecting PCOS women, i.e., hormone changes, irregular menstrual cycle, anovulation and infertility. Specific functions, which have been proposed in different studies, include:

1.    Endocrine effects:

·         Reduces plasma LH, PRL

·         Reduces insulin levels

·         Reduction in LH/FSH

·         Reduction in serum dehydroepiendrosterone sulphate

2.    Metabolic Benefits:

·         Improves insulin sensitivity

·         Increases circulating HDL

·         Reduces weight

·         Decreases plasma triglycerides & total cholesterol

       3. Clinical benefits:

• Restores menstrual cyclicity
• Reduces ovarian volumes and rapid follicular maturation
• Conception without ovulation induction

Combined therapy of MI & DCI is effective in PCOS women and its action is based mainly on improving insulin sensitivity of target tissues, resulting in a positive effect on the reproductive axis (restores ovulation and improves oocyte quality) and hormonal functions (reduces clinical and biochemical hyperandrogenism and dyslipidemia) through the reduction of insulin plasma levels.

The purpose of this study was to compare the metabolic and hormonal effects of metformin versus combined myo-inositol and D-chiro-inositol treatment in women with Polycystic Ovarian Syndrome (PCOS).