1-10-19
The task of
killing of Jackal, the task of killing a Tiger are not of same skill
How many gynaecologist can assure a PCO woman
in 3rd decade of Life that her
future Quality of life( in PCO women) in 4th 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. Achieving preg is like killing a jackal but to keep her( your old
patient) healthy upto the decades of eighty with normolipidaemic normotensive, average wt , with no endometrial cancer free life
with no depression . God 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 A) CRP > 2.42
mg /1 .But luckily in those women with B) CRP
values < 1 mg / 1 are considered C) low risk
1-3 mg/ 1 are considered intermediate
risk and 3-10 mg / 1
are considered high risk for
cardiovascular disease .
PCO, insulin
resistance à 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 .
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
.
When administered to insulin resistant patients
these drugs act to increase target
tissue responsiveness in
order to reduce hyperinsulinemia .
In the
past limited studies
on the use of Diazoxide acarbose and somatostatin for PCOS women were conducted then thiazolidinediones aroused more interest while to
date metformin is the most
worldwide studied insulin
sensitizing agent . 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 in this chapter all the
beneficial effects of
metformin therapy in patients
with PCOS are highlighted.
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 .
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
Increased
peripheral insulin sensitivity
by activating glucose
transporters which allows
passage of glucose into hepatic
and muscle cells inhibition of
hepatic glucose production
Reduction of
circulating free fatty acid
concentration which helps
in reducing gluconeogenesis .
Metformin activates
the adenosine monophosphate
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.
Metformin affects ovarian function
in a dual mode.
Alleviation
of systemic insulin excess acting upon the ovary particularly on steroidogenesis and follicular growth
Direct ovarian
effect.
Furthermore metformin acts at the hypothalamic
levels on AMPK pathway the latter is essential in the modulation of LH secretion
During the last
two decades some studies demonstrated
that metformin inhibits androstenedione and testosterone production form theca cells through inhibition of the
steroidogenic acute regulatory protein
and 17 a hydroxylase expression.
At the
ovarian level hyperandrogenic intra follicular pattern is improved by a
decrease in IGF-1 availability
that has an important role in controlling
granulosa cell aromatase levels.
It has
been shown that granulosa cells from women with
PCOS have higher levels of
FSH receptor expression
compared with those from
normal ovaries .
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 .
Dosage and side
effects
Metformin is available as 500, 850 and 1,000 mg tablets with a target dose of
1,500-2,550 mg / day.
Metformin has a dose dependent absorption
in humans and its bioavailability is
limited to 50-60 % because the amount
available may result from pre
systemic clearance or binding to the intestinal wall.
Therapeutic
regimens of metformin administration are
not well standardized and its dose should probably be adjusted according
to the patient’s BMI and insulin
resistance .
For example
it was demonstrated that nonobese women with PCOS respond better than obese women to metformin treatment
at a dosage of 1,500 mg/ day
for 6 months Nonobese women in fact showed a statistically significant decrease
in serum androgen level and fasting insulin level and also an improvement
in menstrual cyclicity . Moreover it is
possible that women who did not respond to metformin 1.5 g dose
per day might show clinical
changes if the dose is increased to 2 g.
Common side effects are gastrointestinal such as diarrhea nausea vomiting bloating abdominal discomfort flatulence and unpleasant metallic taste in the mouth.
Lactic acidosis
and hypoglycemia are very rare.
To reduce
these side effects. It is recommended to
start metformin with a low dose
and then gradually increase
within a period of 4-6 weeks.
Why Creatinine
estimation on 6 monthly basis while on Met RY?: In cases of IGTT renal function
may be impaired. As such if a man or woman is on long term met therapy then before
initiation of metformin ,serum creatinine estimation seems prudent thereafter on 6 monthly basis .
.Metformin may cause vitamin B12
malabsorption and so every
patient should be monitored for signs and symptoms
of vitamin B 12 deficiency numbness paresthesia macroglossia
behavioral changes and pernicious anemia.
Metformin prescription
should be avoided in women with renal
insufficiency congestive heart failure
sepsis or hepatic dysfunction .Therefore testing
of hepatic and renal function is
necessary in advance of prescription and thereafter yearly testing
is indicated.
However it has been
demonstrated that metformin use
for up to 6 months dose not adversely
affect renal or liver function
in a large sample
of PCOS women even
those with mildly abnormal
baseline hepatic parameters .The length of metformin
treatment in PCOS patients
is not standardized but data present in literature showed that after a
long term metformin
treatment drug suspension is related
to a quick reversion of its beneficial effect
on peripheral insulin
sensitivity. The insulin resistance is associated
with
Abnormally
low levels of DCI in urine
plasma and insulin target tissues
Vote for MI :: NOTA to DCI::How many members believe that
“ PCO is often associated with excessive MI
urinary excretion : . Intracellular
MI deficiency in
insulin sensitive tissues In the contrary more recently Nestler
proposed that in a woman with
PCOS an initial genetic
or environmental insult causing
insulin resistance leads to
a compensatory hyperinsulinemia.
The latter induces a defect that increases renal
clearance of DCI and this
lead to a reduction in
circulating DCI and its availability to tissue. The consequence is an intracellular deficiency
of DCI and of DCI – IPG a mediator of insulin action .Diminished
release of DCI IPG in response
to stimulation by insulin results
in a further decrease in insulin
sensitivity . Moreover
defective DCI- IPG release
in response to insulin could be due to a qualitative
defect in the insulin signaling mechanism that
activates DCI IPG mediator
release from the membrane there may
be a primary defect in the union
of the insulin receptor B unit to the G protein or a defect
in G protein activation of phospholipase.
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