What is 40 : 1 In management of Dr. Jyoti Agarwal Dr. Sharda Jain Dr. Jyoti Bhaskar

What is

40 : 1 In management of

Dr. Jyoti Agarwal Dr. Sharda Jain Dr. Jyoti Bhaskar

Not end of the storyToday knowledge regarding PCOS

has revived and efforts have been undertaken to explore new options

created significant development in t/t of

PCOD

Insulin resistance is a primary

ROOT cause in PCOS

Indian Journal of Endocrinology and Metabolism, 2011

Central player : IR

Insulin Resistance

A pathophysiological contributor in

50 – 80 % of the PCOS women

Indian J Endocrinol Metab. 2011 Oct-Dec; 15(4): 239–241.

75% of PCOS patients are obese

• Relative risk of MI is 7.4 times higher wrt age matched controls.

• risk of diabetes associated death.

• PCO is present in 42 % of CVD patients.

J.Clin.Endocrinol.Metab., December 2013

PCOS and metabolic syndrome

The use of insulin lowering or insulin sensitizing therapy may help to improve ovarian function and menstrual cyclicity.

Word “M ”in the PCOS world

First being - Metformin

Miracle pill - Myoinositol

MYO-INOSITOL and METFORMIN

Myo-inositol

Improves insulin

sensitivity Decreases insulin

resistance levels

Improves glucose

utilization

Restores menstruation and normal ovulation

Reduces free testosterone

Improves pregnancy

rate

MYO-INOSITOL - takes TOTAL CARE OF SYMPTOMS

Insulin acts like a key which can open the

door on the cell surface

1 •Insulin binds to its receptor forms a complex called insulin receptor substrate (IRS).

2 •IRS stimulates messenger called PI 3 kinase

3 •Activated PI 3 kinase activates GLU T 4

4 •Glucose is then taken by GLUT 4 through glucose channel for utilizing energy.

5 •Then IRS complex breaks down releasing the receptor to go back to its original site.

Glucose metabolism in a normal cell

Phosphatidyl inositol 3-kinase is the key messenger

• We need production & activation of PI 3 kinase

for normal cell glucose metabolism.

• Inositol produces as well as activates PI3 kinase

Inositol acts as a precursor for PI 3 kinase

Fertility and Sterility Volume 86, Issue 3, Supplement 1, September 2006, S461 J Pediatr Endocrinol Metab 2000;13 Suppl 5:1295-8

What is the connection between PCOS and

inositols ???

In PCOS there is deficiency of

inositolDIABETES CARE 2006, 29, 300-305

Inositol levels in PCOS and Normal women

PCOS Subjects Normal Subjects 0

0.02

0.04

0.06

0.08

0.1

0.12

0.14

0.16

0.18

0.2

0.1

0.190000000000001

p=0.035

PCOS Subjects Normal Subjects 0

0.5

1

1.5

2

2.5 2.3

0.700000000000001

p= 0.043

Diabetes Care 2006;29:300–305

Plasma inositol (µmol/l) 24 h urinary inositol ((µmol/l/day)

Normal Plasma inositol (µmol/l) levels – 0.13-0.28

PCOS Subjects Normal Subjects 02468

10121416

15.3

2.7

p= 0.001

Inositol clearance levels in PCOS and Normal women

Diabetes Care 29:300–305, 2006

Urin

ary

clea

ranc

e of

Inos

itol

(ml/

min

)

5 -6 times more Urinary

clearance of Inositol in PCOS

Could inositols be considered

to treat PCOD ???

Myoinositol is not a drug• It is naturally occuring

one of the nine isomer of a C6 sugar alcohol that belongs to the vitamin B complex group (B 7 )

• Synthesised in the liver from glucose in our body

• Water soluble so each dose is well tolerated and is devoid of toxicity

It is commonly found in fruits (grapefruit being a rich source), vegetables (leafy vegetables the

lowest) and in all foods containing seeds (beans, almonds and walnuts the

highest).

Enzyme Epimerase converts Myo inositol to D chiro Inositol

Conversion is insulin dependent

When insulin resistance occurs, the conversion rate is affected

Excess insulin in the ovary triggers Epimerasation

In overweight PCOS BMI > 25 • The insulin resistance is

very high.• Epimerase activity is

triggered.• Disturbs the

physiological 40 : 1 plasma ratio of Myo-inositol : D Chiro Inositol.

Insulin regulates blood glucose by two ways

1) Promoting glucose cell

uptake

2) Glycogen synthesis

Eur.Rev.Med.Pharmacol.Sci., 2013

Insulin action needs “second messengers”

MYO promotes glucose cell intake

DCI stimulates glycogen

synthesis.

DCI is present in high concentrations in glycogen storage tissue (liver, muscles and fat)

low in tissue needing elevated energy levels (brain, ovary, heart).

Myo – inositol• Acts at ovary

• Increases glucose cell intake

• Normalises LH :FSH ratio

• Increases oocytes quality

• Reduces the amount of FSH used during IVF cycles

• Improves IVF results

DCI• Acts at peripheral tissues

• Stimulates glycogen synthesis

• Reduces IR• Increases insulin sensitivity• Reduces hyperinsulinemia

• No effect at ovarian level• No direct effect on fertility

• Reduces risk of metabolic syndrome

• 19 out of 22 obese pts ovulated (1.2 mgm/day)

• These results were not confirmed in second clinical trial when double dose of DCI was given.

• Negative effect of DCI at ovaryNestler et al 1999

The DCI “paradox” in the ovary

In overwt. PCOS

High Insulin levels increases conversion of MI to DCI in the ovary

Ovary unlike other tissues never shows insulin resistance

The DCI “paradox” in the ovary

• In the ovary, MYO is involved in FSH signalling, while

• DCI is responsible for insulin-mediated testosterone production.

Endocrine J., 2014

Net result is that in the ovary

• Increase DCI• Promotes androgen

synthesis

• MI depletion• Worsens the energy

state of the occyctes

These events together impair FSH signalling and oocyte

quality

Treat PCOS the right way !!

MI/DCI physiological plasma ratio

40:10

10

20

30

40

50

Study 1 Study 2 Study 1+2

Clinical Evidences forMYO-INOSITOL and D –

chiro inositol combination

50 overwt. PCOS

Treatment results seen at 3 & 6 mnths

Significant improvement in plasma glucose,insulin concentration at 3 months

Improvement in total testosterone and SHBG was seen at both 3 and 6 months

20 overwt. PCOS

With combination therapy a significant improvement was seen in

• Lipid profile• BMI• Waist : Hip ratio• Blood pressure• Homa index

Thus……

Combined treatment in physiological ratio of 40 : 1 is able to restore both hormonal and metabolic

parameters in overweight PCOS women earlier than with MI alone

And hence the Rationale of

40 : 1MI : DCI

Safety of inositol combination

Remarkably, in all the studies analyzed, no side effects have been reported.

No drug interactions documented yet

• Start the treatment as soon as the diagnosis of PCOD is made

• Dose is 2 grams of MYO and 50 mg of DCI twice a day (powder).

• If taken as powder , presence of caffiene decreases its absorption

Caffeine-induced MYO malabsorption

Carry Home Message PCOD treatment

is a challenge.

Treatment should address the root cause.

Best therapy should include a 360° approach to the problem, taking into consideration the complexity of the syndrome.

Combined therapy may be the first line approach in

overweight PCOS

European Review for Medical and Pharmacological Sciences

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