Comparison of clinical, metabolic and hormonal effects of metformin versus combined therapy with metformin and myoinositol and D- chiro-inositol in women with polycystic ovary

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

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

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

Research hasdocumented that insulin resistance in PCOS is due to defect in theinositolphosphoglycans (IPGs) second messenger in glucose metabolism.  A defect in tissue availability or alteredmetabolism of inositol and/or IPGs mediators may contribute to insulinresistance.

Recently, newinsulin sensitizers containing inositol have been proposed in the treatment ofPCOS patients. Inositol is a physiological compound belonging to the sugarfamily and nine stereoisomers are known, of which myo-inositol andD-chiro-inositol are the two main ones present in our body [17]. Myo-inositoladministration improves insulin sensitivity [18,19]. Moreover, it produces asecond messenger, the inositol triphosphate, that regulates several hormonessuch as FSH, TSH and Insulin [20,21]. In contrast to metformin, no side effectshave been reported during treatment with Myoinositol [22–24], while improvingreproductive and metabolic parameters in PCOS women [23,24].

Myoinositol

Inositols play an importantrole in generating calcium signals in mammalian oocytes. Calcium signalling inoocytes has been extensively studied as its putative role in oocyte maturationand the early stages of fertilization. Myoinositol (MI) is the most abundant formof inositol in humans and is a part of the B-complex family. It is a naturalinsulin 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 asinsulin sensitizers. MI in most of the tissues constitutes intracellular poolof inositol but in fat, muscle and liver, D-chiro-inositol (DCI) is the maininositol found and is responsible for glycogen synthesis. MI is converted toDCI according to specific tissue requirements. The role of these two inositolshas been clearly studied and documented in literature.

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

2.   Atovarian level, MI based second messenger is involved in both glucose uptake andFSH signaling whereas DCI-based second messenger is devoted to theinsulin-mediated androgen production.

3.   MIis essential in ensuring proper oocyte maturation.

 Specificrole of MI in PCOS

MI treatment has been shownto ameliorate the reproductive morbidities affecting PCOS women, i.e., hormonechanges, irregular menstrual cycle, anovulation and infertility. Specificfunctions, which have been proposed in different studies, include:

1. Endocrineeffects:

·        Reducesplasma LH, PRL

·        Reducesinsulin levels

·        Reductionin LH/FSH

·        Reductionin serum dehydroepiendrosterone sulphate

2. MetabolicBenefits:

·        Improvesinsulin sensitivity

·        Increasescirculating HDL

·        Reducesweight

·        Decreasesplasma triglycerides & total cholesterol

3. Clinical benefits:

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

 Combinedtherapy of MI & DCI is effective in PCOS women and its action is basedmainly on improving insulin sensitivity of target tissues, resulting in apositive effect on the reproductive axis (restores ovulation and improvesoocyte quality) and hormonal functions (reduces clinical and biochemicalhyperandrogenism and dyslipidemia) through the reduction of insulin plasmalevels.

The purpose ofthis study was to compare the metabolic and hormonal effects of metforminversus combined myo-inositol and D-chiro-inositol treatment in women withPolycystic Ovarian Syndrome (PCOS).