Myoinositol as an alternative to metformin in PCO women where primary pathology is hyperinsulinaemia--?> Hyperandrgenism

 Pcod adjutants  are plenty. A proper RCT of metformin vs myo-chiro is the need of this hour..but who will do it
Metformin: Vs Myoinositol:-Many of us   use metformin in obese pcos n in pts with abnormal GTT only .In the rest of the pcod pts one has started prescribing  myoinositol some however received god results in few though can’t say that it was due to myoinositol only .  PCO being syndrome of varied etiology ...Multiple small studies, lot of promotion, so confusion whom to start...now combination are with metformin also...As indications of metformin use mentioned .some centers who can afford to prescribe at extra cost to patient should start replacing metformin with Myo / DCI & see results . It’s more like arginine for oligohydramnios / L-Arginine  , evidence doesn't support but still we keep on giving as empirical. Firstly, Firstly hyperinsulinemia with resultant hyperandrogenaemia is a major cause of PCOS. It is believed that persistent ovarian hyperandrogenaemia is the cause of follicular arrest in such women. But anovulation, Obesity, vascular changes and hepatic changes as observed in PCOS women though have a common etiology (insulin Resistance) –but the mechanism of damage of each type of organ is different. Different pathways are involved in causing ill effects on the cells. Secondly, if we can decrease the intensity of hyperinsulinaemia by some oral agents then hopeful the ovarian milieu will become favorable and will pave the way of proper follicular growth. Thirdly, not all IR are of same genetic origin. That is why Diabetologists goes on changing oral agents and to my knowledge there are about eight such oral agents used as oral anti diabetic drugs (OAD). Diabetologists, quite often go on changing such oral agents if desired results are not observed with primary drug.

 As a corollary, if we presume one particular PCOS woman is having ovarian hyperandrogenaemia induced by hyperinsulinaemia/ IR then what is te harm in trying another / alternative agent to reduce ovarian hyperandrogenemia if metformin/ wt reduction, exercise & CC/ Anastrazole do not work. ? Further, not all insulin sensitizer’s work in all organs of body identically, And Myo-inositol (one type of alcohol) preferentially acts on ovary.
Then question is:-To whom to prescribe MI? Who are the ideal candidates for MI? How do we identify such women? There is some urine test can pick up who are probably going to response with MI.

 A deficiency of the d-chiro-inositol phosphoglycan mediator of the action of insulin may result in resistance to insulin in a subset of PCOS women:-Some of the actions of insulin (not all men / women with insulin resistance) may involve low-molecular-weight inositol phosphoglycan mediators. When insulin binds to its receptor, mediators of this class are generated by hydrolysis of glycosylated-phosphatidyl-inositol lipids located at the outer leaflet of the cell membrane. Released mediators are then internalized and affect intracellular metabolic processes. Although different species (about seven types if I remember correctly) have been identified, an inositol phosphoglycan molecule containing d-chiro-inositol and galactosamine is known to have a role in activating key enzymes that control the oxidative and non-oxidative metabolism of glucose.
A deficiency of the d-chiro-inositol phosphoglycan mediator of the action of insulin may result in resistance to insulin. Insulin resistance has been linked to decreased urinary excretion of chiro-inositol (a component of the putative d-chiro-inositol phosphoglycan mediator) in humans with impaired glucose tolerance.

 In animal studies it has been shown that administration of d-chiro-inositol decreased hyperglycemia in rats with diabetes and improved glucose tolerance in normal rats, such was also the results monkeys with varying degrees of insulin resistance, d-chiro-inositol accelerated the disposal of glucose and decreased insulin secretion. Therefore it is logical to believe
That d-chiro-inositol, by virtue of its ability to increase sensitivity to insulin, would have beneficial effects on ovulation and ovarian production of androgens in women with the polycystic ovary syndrome.

 selective insulin resistance theory The central paradox in the pathophysiologic association between hyperinsulinemia and hyperandrogenemia in PCOS is that the ovary remains sensitive to insulin activity and consequent androgen production, despite a systemic insulin resistance: it is the so-called selective insulin resistance theory.

 There are several inositol isomers: Not all exert reduction of insulin load: :-Several inositol isomers, and in particular myoinositol (MI) and D-chiro-inositol (DCI), were shown to have insulin-mimetic properties and to be efficient in the treatment of PCOS.

 In fact, Inositol (cyclohexane-1, 2,3,4,5,6-hexol) is existing under nine stereo-isomeric forms depending on the spatial orientation of its six hydroxyl groups .

 Altered ratios of increased myoinositol to decreased D-chiro-inositol in urine have even been proposed as an index of insulin resistance in humans:

This may help us to pick up cases who will benefited for Ov induction as an adjunct.
Initially, MI was considered one of the B-complex vitamins, but now it is no more reputed an essential nutrient because it was shown that it is produced in sufficient amount in the human body from glucose. Altered ratios of increased myoinositol to decreased D-chiro-inositol in urine have even been proposed as an index of insulin resistance in humans:

 Different genes are involved in pathogenesis of ovarian hyperandrogenism: One group is abnormal epimerization:-A deficit in MI to DCI epimerization activity, due to an epimerase-type enzyme, was supposed. The insulin-sensitizing effect of a MI and DCI supplementation is probably due to their intracellular enhanced availability for the production of membrane IPG pre-cursors; numerous evidences support the hypothesis of a role of inositol gleeman insulin second messengers in insulin-mimetic properties of some inositol isomers

Thus, insulin resistance is associated with: A) Abnormally low levels of DCI in urine, plasma, and insulin target tissues (liver, muscle, fat)

 Excessive MI urinary excretion can predict which PCOS women will be benefited:-What we the clinicians can do cases of CC resistance/ Failure-we can examine Urine as suggested above before switching over to gonadotrophins : Intracellular MI deficiency in insulin-sensitive tissues. The decreased DCI content in insulin target tissues could reduce insulin signal transduction involving IPGs, in order to contribute to insulin resistance in those tissues.

Depleted plasma levels of DCI observed in PCOS patients underline the correlation between impaired plasma DCI and insulin resistance.

inositol phosphoglycan (IPG) second messenger :-A few studies hypothesized that insulin, other growth factors, and classical hormones stimulated the hydrolysis of glycosylated-phosphatidyl-inositol (GPI) generating water-soluble inositol phosphoglycan (IPG) second messenger- The origin of IPG-A is thought to be myoinositol-containing GPI

 :---But can we allow trial of Myoinositol for 6 months. Fortunately or unfortunately we the clinicians have not given trial of this important drug especially in young women before going to HMG/ LOD etc. Excessive MI urinary excretion can predict which PCOS women will be benefited:-

What we the clinicians can do cases of CC resistance/ Failure-we can examine Urine as suggested above before switching over to gonadotrophins:  Intracellular MI deficiency in insulin-sensitive tissues. The decreased DCI content in insulin target tissues could reduce insulin signal transduction involving IPGs, in order to contribute to insulin resistance in those tissues. Depleted plasma levels of DCI observed in PCOS patients underline the correlation between impaired plasma DCI and insulin resistance.

  Take home message:- If one is convinced that he/ she is dealing a case of PCOS which do not respond to CC/ Anastrazole in such a situation quite often many of us prescribe Metformin is co-administered. . I have a feeling in eastern part of the globe Met has a role in oi AS AN ADJUNCT therapy. But most of us use this (Metformin) prior to IVF to minimize OHSS. If Met too fails in OI and age of female partner is < 25 yrs then one can possibly consider Myo-inositol at the dose of 2Gm OD and allow planned relation. This may be allowed for say 6 months before proceeding to Gonadotrophins/ LOD. Therefore in CC resistant/ CC failure cases there are a role of Myoinositol –which is a natural product, synthesized in human gut. One therefore may not designate it as Pharmacological agent. I have used in a number cases in abovementioned settings (CC resistant/ CC failure/ Lean PCOS) and I am convinced that if age of female partner is< 25 yrs there is some rationality of trying this agent for 6-8 months. Further, it (Myo-inositol) does not require any monitoring, no side effects/Comp./OHSS/ Multiple Gestations etc. You may try in some cases as monotherapy if age is less and trying time is < 2 yrs..

Trade Preparations with Myoinositol only.

PCO Care:-   Akumentis: 1 Gm/ each Tab -- 12/- Tab : 1BD. For adolescent PCOS use PCO care 12/- 1  tab BD

Avocet:- Tablet each Tab is MI 1 Gm.

Ova grace: Mankind : Sachet form: 17 Sachet; 1 Sachet BD each contain  2 Gm.

My cyst Sachet: TTK: 2Gm: 22/-.