Myo inositol in Hirsutism, Acanthois & Obesity

Excessive facial hair  is a racial trait for the Indian sub continent  running within families and especially    strong in certain  ethnic groups. This should be  kept in mind  while  evaluating   patients   complaining of excessive   facial / body  hair. Androgens  affect  various  aspects  of follicular   activity  Acting via androgen   receptors    and secretory factors   they increase the growth   rate diameter  and melanization  of hair  in androgen  - sensitive  areas. It is  these thick  coarse terminal hair in androgen dependent areas which  are unsightly  on a female  and point  to an underlying  hyper  androgenic  state. Evaluation   of the degree hirsutism is   done by adopting  a modified  ferriman Galway score   which evaluates   9 body   areas on a scale of 1 to 4  . the total  scores  are significant  if more than 6 to 8 . Overall 60-75% of patients  with  PCOS will have  hirsutism.

Acanthosis nigricans

Typically thick dark velvety skin  situated  on the nape of the neck  axillae groins  and other frictional  areas   may often  be the first clue  of insulin  resistance . The thickening occurs due to the stimulation  of tyrosine kinase  growth  factor – signaling   pathways in  the epidermis . Insulin   - kike  growth factor receptor 1   is present in many tissues including the epidermis and ovary High levels of insulin   directly or indirectly   stimulate  the IGF1R  resulting  in the skin  changes  . skin  tags  in the frictional areas like the neck    axillae groins infra mammary    or even under a pendulous abdominal   fold are common especially  in obese  individuals.

Obesity

Obesity is a  common  finding in PCOS   and aggravates many  of its   reproductive   and metabolic features. In fact  approximately  50% of PCOS   women are overweight   or obese and  the history of the  weight  gain frequently precedes the onset of  oligomenorrhea and hyperandrogenism    suggesting a pathogenetic   role of     obesity in the subsequent    development   of the syndrome PCOS   women are   characterized  by a high  prevalence of several metabolic abnormalities    which are  strongly  influenced by  the presence of obesity. Adequate  confirmation   on the genuine  role   of obesity     in determining  hyperinsulinemia    and insulin  resistance in women    with PCOS drives from studies  comparing  groups  of normal weight  and obese  PCOS women  . both  festingand  glucose  stimulated  insulin  concentrations  are in  fact significantly  higher  in obese  than  in non obese  PCOS  subgroups.

It is well documented  that women   with PCOS   have a high prevalence of abdominal body fat distribution even if they are normal   weight   . The impact of  abdominal  obesity on PCOS may be greater  than expected  since    this phenotype   is associated  with a more   pronounced hyperandrogenism and insulin resistance than  the peripheral one .

 Multiple therapies  may be needed to address the variety  of PCOS  symptoms  However  it is  important  to address the common cause  linked to these PCOS  symptoms .

PCO & Its Etio pathogensis: This is the arena of battlefield:-Insulin Resistance – A pathophysiological contributor in 50-80%  of the PCOS women

According  to Indian   journal of Endocrinology and  metabolism    , 2011   insulin resistance is   a pathophysiologicla  contributor   in around 50-80 % of  women with PCOS  especially in those with more sevdere  PCOS diagnosed on the basis of National institutes of health  criteria   and in women     who are overweight.

Insulin resistance  contributes   not only to metabolic  features  but also to reproductive features  through  augmenting androgen    production and increasing free  androgens  by reducing   sex hormone  binding globulin    . Obesity increases   hyperandrogenism hirsutism   infertility and pregnancy  complications both  independently  and by exacerbating   PCOS. Further more  women with PCOS  have increased risk factors for T2DM  cardiovascular disease   impaired glucose  tolerance.

Glucose metabolism in a normal  cell includes several  processes

·     Insulin first binds to its receptor   located on the cell  wall forming  a complex called insulin receptor  substrate.

·     This complex enters into the cell  for stimulating  the most  vital  messenger  called  phosphatidylinositol  3 kinase.

·     Once PI 3 kinase is activated  it causes  translocations of glucose  transport 4  to its cell membrane.

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

·     Once energy   is utilized through  glucose the IRS  complex   breaks  down releasing the receptor to relocate back to its original site.

·      This is how glucose utilization takes place in the presence of normal insulin sensitive condition.

Phosphatidylinositol 3- Kinase – A key messenger in Insulin sensitivity

Phosphatidylinositol 3 kinase is a key messenger / enzyme responsible for activation of glucose   transport so as to utilize glucose   and liberating energy. It plays   very important  role in preserving insulin actions and   thus improving  insulin sensitivity.  This enzyme  plays  a vital role in PCOS in which  the most prominent cause   is IR. Inositol   acts as  a precursor for the synthesis  of  phosphatidyl inositol . Inositol    acts as a precursor for the synthesis of phosphatidyl inositol. Inositol  plays   an important  role in the production of PI3   kinase. Hence  inositol is an integral  part  of PI3  kinase.

Therory 2:-Inositol & PCO:_PCOS…characterized by reduced levels  of inositol 

Evidences suggest that a deficiency of  inositol  contribute  to insulin  resistance   in PCOS individuals  . It was observed that  deficiency  of inositol   shows   defective  insulin  signaling  pathway  in patients with PCOS. The  women with PCOS   and normal    women were assessed for circulating   inositol  and 24 hr urinary clearance of inositol  and insulin sensitivity . The findings  indicated a marked   alteration in inositol  urinary  clearance    and deficient insulin stimulated PI 3 kinase release in PCOS   women.

Plasma   concentrations of inositol is  significantly lower in PCOS  women compared  with normal control   subjects   consequently  urinary  clearance of Inositol was  significantly  higher  in
CPOS women   compared with normal  control    subjects .

Increased urinary  clearance   of inositol is an independent predictor of insulin  resistance in PCOS patients

Consequently AUC inositol was significantly  lower in PCOS women compared with normal   control  subjects

These  findings strongly suggest a contribution of abnormal  metabolism of inositol to the insulin resistance in PCOS patient   which leads to a reduction in circulating   inositol and its availability  to the  tissues . Finally in conclusion  a defect in  tissue availability of inositol in PCOS contributes  to the  insulin resistance     leading to decreased  cellular  availability of the PI 3 kinase  mediated  insulin action.

Theroy 3: Altered   insulin signaling and its relationship with IR and PCOS. 

PI 3  kinase is a mediator for glucose metabolism and  its utilization by the cell.

Deficiency of inositol alters  activity of PI3  kinase.

Reduced activity of PI 3 kinase  reduces  translocation of GLUT 4 thereby causing  hyperglycemia 

This brings about  altered  insulin  signaling causing  hyperinsulinemia   and   thus IR . Insulin resistance   thus is  responsible for PCOS. 

Pathway of inositol  deficiency and PCOS 

Metformin fails to manage Insulin Resistance in PCOS women

Metformin  is the most  commonly prescribed insulin   senstising drug  in the treatment   of PCOS. It  enhances insulin sensitivity   by activating PI 3   kinase  but it has been postulated  that Metformin has  a very restrictive mechanism of action due to which  it is not  a right  treatment   option for PCOS.How useful is metformin??Authentic journal statements  on the use of  metformin in PCOS 

In the absence of large  adequately powered placebo controlled trials  it is   difficult   to provide useful answers   about the longer  term   benefits  of metformin in PCOS women. However   there are more   side effects  with metformin  like lactic acidosis and malabsorption  including  poor adsorption of vitamin B12

Thus there arises a therapy which  cares  for each and every symptom of PCOS along with documented  safety. 

Now coming back to efficacy of MI:-How important is MI??  Myo- inositol – The Ultimate  Insulin Sensitizer

Myo- inositol a six  carbon sugar alcohol present abundantly in the body. The chemical name of myo inositol is 1,2, 3,,5/4,6- Hexahydroxycyclohexane   . It is a precursor of various cell membrane phospholipids.

Generally myo inositol  is present  in the cells. Serum  concentrations are   high during fetal life and later on falls However  during certain conditions like  polycystic  ovary   syndrome  physiological requirements  of myo inositol increased.

Myo inositol is an insulin  sensitizing agent produced by the human body from glucose  and is one of 9 distinct   isomers of  the nutrient inositol naturally produced by the human   body. It is  a vitamin  B  complex derived product that has been evaluated  in a number of controlled  studies  looking at ovulation frequency , time   to ovulation   follicular maturation and the quality of  oocyte    production  cell morphogenesis  and   cytogenesis   lipid synthesis the structure of cell membranes  and cell  growth . Myo   inositol plays  an important  role as the structural basis for a  number of  secondary messengers  like to synthesise phosphatidylinositol 3 kinase   a key messenger   to improve  insulin sensitivity   and glucose  utilization along with reduction of insulin  resistance.