Metformin in PCO -How useful??

 How many gynaecologist can assure a PCO woman in 3^rd decade of her life that  her  future  Quality of life( in PCO women)  in 4^th to  6 th decade of life  will be normal. Let me tell you my dear members that the duty & responsibility of gynaecologits do not end with after achieving one or 2 live births in the florid PCO cases.  Our as gynaecologits aim should be to keep her healthy upto the decades of eighty as  normolipidaemic normotensive,  average wt , with no endometrial cancer, a life  with no depression . Good QOL(quality of life)  in PCO women as like a challenge with a tiger .

By this time we have to come know that PCO is correlated with raised CRP –->metabolic aberrations often seen in PCO women: Why & how? Ans: Vascular inflammatory   process is reflected by the CRP is the most    reliable    circulating marker of chronic low grade   inflammation in PCOS  . -PCOS is a pro inflammatory state    and emerging   data suggest that chronic low grade   inflammation   supports the development of metabolic aberration and ovarian dysfunction. CRP is the most    reliable    circulating marker of chronic low grade   inflammation in PCOS  . Recently    CRP   was found to be a direct promoter of the   atherosclerotic   processes and endothelial cell inflammation   leading to athero thrombosis . CRP has a  direct   role in the vascular  inflammatory   process  stimulating  the release   of inflammatory   cytokines  and increasing   endothelial  expression of cellular  adhesion   molecule  which mediate    leukocyte  migration .

Correlation with level of CRP with probality of heart attack??  Ans;-Findings of a study suggest that increased cardiovascular   risk may be seen in 83.3 % of the PCO women with CRP > 2.42  mg /L .  But luckily in those women with   CRP  values < 1  mg / L are  considered  low  risk  and finally  1-3   mg/ L are considered  intermediate  risk and  3-10   mg / L    are considered high   risk for cardiovascular   disease . 

PCO, insulin resistance à PCO: Should we perform GCT (Glucose  Challenge test  every 2 yrs for eavery PCO women asa sthy are prone to develop DM??

Hyperinsulinaemia, abnormal OGTT:--Till date the most accurate    method to diagnose insulin   resistance is the OGTT after 75 g glucose challenge even   in adolescent women. What is the normal value?? Normal values are the ( following ) euglycemia:

1)                 Fasting 70-100  mg/ dL 2) 60 min after   glucose  administration < 180  mg / dL 3)  120 min after glucose administration < 140 mg/ dL

II. But in case of IGTT :--Impaired  glucose   tolerance is defined  when glucose level is > 140  mg/ dL 2 h after glucose load   but < 200 mg /dL 

III. Diabetes   is defined   when glycemia is > 200 mg/ dL   2 h after   glucose load

What is the insulin level?? A) Normoinsulinemia: Fasting < 10 mUI /mL B) 60 min after glucose administration < 60 mUI/mL c) 120 min after  glucose   administration , =  10 mUI/mL .

Of course   the majority  of PCOS   patients   are not diabetic yet but only insulin resistant .

Insulin resistance is defined  when insulin value   1 h after OGTT  is  > 60 mUI/ mL  and / or   its level   is not very   close   to the fasting   insulin  value   after 2 h   post glucose administration.

It has been suggested that an OGTT    be performed   every   2 years   for those with normal   glucose tolerance and annually if IFG  or IGT    is present . Glucose screening recommendation for PCOS women are  summarized  .

HOMA index : OGTT is not a very comfortable  method  and it is  also expensive  and time consuming for this   reason the need for a simple way of measuring   insulin resistance   has led to the creation  of a large  number   of insulin sensitivity  indices.  The most    used model  is the HOMA     index.

The homeostatic  model for assessment   of insulin resistance    is a simple and noninvasive   method of estimating    insulin   sensitivity  from the steady  glucose   and insulin  concentrations  measured under  fasting  conditions  . it was calculated   using   the following formula .

  To prescribe nor not to prescribe Metformin in pco cases??  Ans:-Examining scientific literature studies are very conflicting  to each other   and a  unanimous opinion  on the effectiveness of insulin   sensitizing  drugs  has not yet been  reached. According  to the ASRM committee  of 2008   insulin   sensitizing  agents   should  be considered in patients    with impaired   glucose  tolerance   and PCOS.

In 2010  AE- PCOS  Society   consensus  treatment   emphasized that   metformin  should be  used in women with PCOS   who have  already   started  lifestyle    treatment      and do not   have improvement in IGT   or in those  who have normal   weight  but still having menst disorders  .

When   administered to insulin resistant patients metformin or allied druhs(Myo inositol, DCI, Vit D)  group of  drugs    act to increase glucose entry in  target  tissue  and  thereby decrese hyperinsulinemia .

. Moreover   statins  have also been used to improve   lipid profile  in PCOS women .

Metformin :-Despite  there is no   universal  consensus  on metformin benefits in PCOS  .The positive    effects of  metformin have been   demonstrated in nondiabetic women   with PCOS   and they are   associated   with increased   menstrual cyclicity improved   ovulation     and reduction in circulating   androgen levels. To date   neither   in Europe  nor in the  United  States   metformin   has been   approved for  the treatment   of insulin   resistance  associated  with PCOS  its use should be restricted to those   patients   with IGT   however it is largely  prescribed as an off label drug .

What is meant by Off level use of drugs??  Ans:-For   off label use of any medication it is extremely  important   to fulfill several criteria   for safe  use :

The condition  should  have health  consequences   significant   enough to   warrant     treatment

The   treatment    should have   demonstrated safety and efficacy

The proposed  treatment   should be  superior   to the presently available   alternatives 

 Mechanism   of Action of metformin:-

Metformin   is a second   generation  biguanide  used  as an  oral antihyperglycemic  agent   and it is  approved  by the US  Food   and Drug   Administration   as treatment   for type ll diabetes  mellitus . It is   considered an insulin   sensitizing  agent because   it lowers   glucose   levels  without   increasing    insulin secretion but   improving   insulin sensitivity 

Metformin causes a)  Increased   peripheral  insulin sensitivity by   activating  glucose   transporters   which  allows      passage of glucose into hepatic  and muscle cells  b) inhibition of hepatic   glucose production (helps    in reducing    gluconeogenesis ).

c) reduction of circulating free fatty    acid concentration  .In short : Metformin  activates  the adenosine

onophosphate  activated protein kinase pathway    phosphorylaction of threonine in AMPK   is necessary   for  metformin  action resulting   in decreased  glucose   production  and increased  fatty  acid oxidation in hepatocytes  skeletal muscle   cells   and mouse   ovarian tissue.

Furthermore metformin  inhibits  hepatic   gluconeogenesis  through  an AMP   activated protein    kinase   dependent regulation  of the orphan  nuclear    receptor   small heterodimer partner.

Importantly    the actions of metformin are nor  associated with an increase  in insulin secretion and consequently   with hypoglycemia.

Why Metformin in PCO?? How does an antidiabetic agent is in deep love with ovaries and comes as rescue ??  Metformin  affects ovarian   function    in a dual  mode.

1)     Counterattacks the   adverse effects of systemic  insulin   excess in PCO  acting  upon the ovary   particularly   on steroidogenesis  and follicular    growth  2) Metformin also has direct  ovarian   effect. 3) Modulates LH action acting at hypothalamus.

Metformin acts at the hypothalamic levels  on AMPK   pathway the latter  is essential in the modulation of LH  secretion 4) Does metformin redices

During    the last  two decades   some studies   demonstrated  that metformin  inhibits  Mechanism   of Action of metformin:-

Metformin   is a second   generation  biguanide  used  as an  oral antihyperglycemic  agent   and it is  approved  by the US  Food   and Drug   Administration   as treatment   for type ll diabetes  mellitus . It is   considered an insulin   sensitizing  agent because   it lowers   glucose   levels  without   increasing    insulin secretion but   improving   insulin sensitivity 

Metformin causes a)  Increased   peripheral  insulin sensitivity by   activating  glucose   transporters   which  allows      passage of glucose into hepatic  and muscle cells  b) inhibition of hepatic   glucose production (helps    in reducing    gluconeogenesis ).

c) reduction of circulating free fatty    acid concentration  .In short : Metformin  activates  the adenosine

onophosphate  activated protein kinase pathway    phosphorylaction of threonine in AMPK   is necessary   for  metformin  action resulting   in decreased  glucose   production  and increased  fatty  acid oxidation in hepatocytes  skeletal muscle   cells   and mouse   ovarian tissue.

Furthermore metformin  inhibits  hepatic   gluconeogenesis  through  an AMP   activated protein    kinase   dependent regulation  of the orphan  nuclear    receptor   small heterodimer partner.

Importantly    the actions of metformin are nor  associated with an increase  in insulin secretion and consequently   with hypoglycemia Mechanism   of Action of metformin:-

Metformin   is a second   generation  biguanide  used  as an  oral antihyperglycemic  agent   and it is  approved  by the US  Food   and Drug   Administration   as treatment   for type ll diabetes  mellitus . It is   considered an insulin   sensitizing  agent because   it lowers   glucose   levels  without   increasing    insulin secretion but   improving   insulin sensitivity 

Metformin causes a)  Increased   peripheral  insulin sensitivity by   activating  glucose   transporters   which  allows      passage of glucose into hepatic  and muscle cells  b) inhibition of hepatic   glucose production (helps    in reducing    gluconeogenesis ).

c) reduction of circulating free fatty    acid concentration  .In short : Metformin  activates  the adenosine

onophosphate  activated protein kinase pathway    phosphorylaction of threonine in AMPK   is necessary   for  metformin  action resulting   in decreased  glucose   production  and increased  fatty  acid oxidation in hepatocytes  skeletal muscle   cells   and mouse   ovarian tissue.

Furthermore metformin  inhibits  hepatic   gluconeogenesis  through  an AMP   activated protein    kinase   dependent regulation  of the orphan  nuclear    receptor   small heterodimer partner.

Importantly    the actions of metformin are nor associated with an increase in insulin secretion and consequently   with hypoglycemia

form theca  cells through inhibition  of  the steroidogenic    acute regulatory    protein   and 17 a hydroxylase  expression.

 How Meformin does helps PCO women??  1) It decreases the total load of insulin in women  2)  Metformin decreases  IGF 1 At the ovarian   level  . AS such  hyperandrogenic intra follicular    pattern is improved  by a   decrease   in IGF-1   availability  that has an important  role in  controlling  granulosa   cell aromatase   levels. 3) It reduces FSH receptors at Ovaries:-It has been  shown that  granulosa cells from  women with  PCOS have higher   levels of FSH  receptor    expression  compared with those   from normal   ovaries . AS such metformin reduces  FSH      without     altering   cAMP  levels.  This involves  blocking  activation    of CRE  on promoter  ii of CYP19   via inhibition of pCREB   and possible    disruption  of the formation of the CREB – CRTC  2  co activator complex.  This is   via an  AMPK  independent    mechanism .