All about Metformin prescription in
PCO cases: The question is should we prescribe to all PCO women or we should be
selective?? How long to prescribe?? Members
opinion please
Metformin
in PCO : When & how
Point 1:-Till
date there is no universal consensus
on metformin benefits in PCOS but
many researchers, and clinicians
too firmly believe that if used judiciously there are many beneficial
effects of metformin therapy in patients
with PCOS.
Point 2: Can we
prescribe metformin in nondiabetic PCO women? : Ans . Possibly yes. 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.
Point 3: Is it approved in US/UK for PCO women ?? Ans: No. 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
.
Point 5: What we the clinicians mean by the term as
“Off level “use of any drug?? 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
Point 6: How does Metformin
works in the system?? It is an antihyperglycemic agent Ans:- 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
Point 7:-What are the actions
of metformin at cellular level?? Metformin increases fatty
acid oxidation in hepatocytes & skeletal muscle cells
Ans:-Metformin
causes 1) increases peripheral insulin sensitivity by activating
glucose transporters which
allows passage of glucose
into hepatic and muscle cells 2) inhibition of hepatic glucose production 3)
reduction of
circulating free fatty acid
concentration which helps in reducing
gluconeogenesis .
Point
8: What else are the actions of metformin in cellular dynamics?? Ans :-
1) decreased glucose production at liver 2) inhibits hepatic
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.
Point 10: Lastly, to conclude, out of so many about 6 kinds of insulin sensitizers or
blood glucose lowering agents why metformin is considered as safest ,more so in
rural settings?? Ans:-
actions of metformin are nor associated
with an increase in insulin secretion
and consequently with hypoglycemia.
Q.
11: What is the beneficial effects on ovary ?? Ans:-Metformin affects ovarian function
in a dual way 1) alleviation of systemic
insulin excess acting upon the ovary particularly on steroidogenesis and follicular growth 2) direct ovarian
effect. 3) Modulates LHaction:-
metformin acts at the hypothalamic levels on AMPK
pathway the latter is essential
in the modulation of LH secretion 4)
Effects on androstenedione:-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.
5) Metformin reduces FSH without altering
cAMP levels
Point
12: What do a PCO woman is benefitted by decrease of serum FSH? How it helps at
granulosa cell level?? Ans: The indirect role of metformin on granulosa cells by
decreseing IGF-1 . This is very impotrtnat and most important opath, at least I
feel in that way that IGF-1 is notorious to cause & propagate PCO.
Metformin , at the ovarian level with
its hyperandrogenic intra
follicular pattern cause improved function by
a decrease in IGF-1
availability that has an
important role in controlling
granulosa cell aromatase levels.
Point 13: PCOS
have higher levels of FSH receptor
expression compared with those from normal
ovaries .Ans:-
It has been shown that
granulosa cells from women with 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 .
Metformin is
available as 500, 850 and 1,000 mg
tablets with a target dose
of 1,500-2,550 mg / day Dosage
and side effects
.
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.
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
Metformin –How long to
prescribe?? 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
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.
Metformin
in PCO : When & how
Point 1:-Till
date there is no universal consensus
on metformin benefits in PCOS but
many researchers, and clinicians
too firmly believe that if used judiciously there are many beneficial
effects of metformin therapy in patients
with PCOS.
Point 2: Can we
prescribe metformin in nondiabetic PCO women? : Ans . Possibly yes. 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.
Point 3: Is it approved in US/UK for PCO women ?? Ans: No. 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
.
Point 5: What we the clinicians mean by the term as
“Off level “use of any drug?? 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
Point 6: How does Metformin
works in the system?? It is an antihyperglycemic agent Ans:- 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
Point 7:-What are the actions
of metformin at cellular level?? Metformin increases fatty
acid oxidation in hepatocytes & skeletal muscle cells
Ans:-Metformin
causes 1) increases peripheral insulin sensitivity by activating
glucose transporters which
allows passage of glucose
into hepatic and muscle cells 2) inhibition of hepatic glucose production 3)
reduction of
circulating free fatty acid
concentration which helps in reducing
gluconeogenesis .
Point
8: What else are the actions of metformin in cellular dynamics?? Ans :-
1) decreased glucose production at liver 2) inhibits hepatic
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.
Point 10: Lastly, to conclude, out of so many about 6 kinds of insulin sensitizers or
blood glucose lowering agents why metformin is considered as safest ,more so in
rural settings?? Ans:-
actions of metformin are nor associated
with an increase in insulin secretion
and consequently with hypoglycemia.
Q.
11: What is the beneficial effects on ovary ?? Ans:-Metformin affects ovarian function
in a dual way 1) alleviation of systemic
insulin excess acting upon the ovary particularly on steroidogenesis and follicular growth 2) direct ovarian
effect. 3) Modulates LHaction:-
metformin acts at the hypothalamic levels on AMPK
pathway the latter is essential
in the modulation of LH secretion 4)
Effects on androstenedione:-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.
5) Metformin reduces FSH without altering
cAMP levels
Point
12: What do a PCO woman is benefitted by decrease of serum FSH? How it helps at
granulosa cell level?? Ans: The indirect role of metformin on granulosa cells by
decreseing IGF-1 . This is very impotrtnat and most important opath, at least I
feel in that way that IGF-1 is notorious to cause & propagate PCO.
Metformin , at the ovarian level with
its hyperandrogenic intra
follicular pattern cause improved function by
a decrease in IGF-1
availability that has an
important role in controlling
granulosa cell aromatase levels.
Point 13: PCOS
have higher levels of FSH receptor
expression compared with those from normal
ovaries .Ans:-
It has been shown that
granulosa cells from women with 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 .
Metformin is
available as 500, 850 and 1,000 mg
tablets with a target dose
of 1,500-2,550 mg / day Dosage
and side effects
.
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.
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
Metformin –How long to
prescribe?? 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
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.
PCO and ill effects on blood
vessels??
Nowadays
it is clear that 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 . Findings of a study
suggest that increased
cardiovascular risk may be seen
in 83.3 % of the PCO women with CRP >
2.42 mg /1 .CRP values < 1
mg / 1 are considered low risk
1-3 mg/ 1 are considered intermediate
risk and 3-10 mg / 1
are considered high risk for
cardiovascular disease . Why PCO is compared with Viper venom??
Nowadays it is clear that 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 . Findings of a study
suggest that increased
cardiovascular risk may be seen
in 83.3 % of the PCO women with CRP >
2.42 mg /1 .CRP values < 1
mg / 1 are considered low risk
1-3 mg/ 1 are considered intermediate
risk and 3-10 mg / 1
are considered high risk for
cardiovascular disease .
Lab diagnosis of insulin resistance?? How? By
what method??
There
have been debates about which method will be clinically superior to establish
the diagnosis of insulin resistance?? HOMA index though very accurate 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.
Q.1. Then ,
what is the best acceptable method of assessing
Insulin resistance in day to day clinical practice ?? Anms: A) OGTT
is most acceptable method till date which is useful in day to day practice.
Other available methods are cumbersome and not feasible for clinical use though
may be of help in research settings.
OGTT, is still the most accurate method to diagnose insulin resistance. One has to ingest 75 g
glucose challenge even in
adolescent women. Normal values are the
following a) Normoglycemia: fasting
70-100 mg/ dL
60 min after glucose administration < 180 mg / dL
120 min after glucose
administration < 140 mg/ dL
b)
Impaired glucose tolerance is defined
when glucose level is > 140
mg/ dL 2 hour after glucose
load but < 200 mg /dL .
c) Diabetes is defined
when glycemia is > 200 mg/
dL 2 h after glucose
load
Q. 2: What
is the normal insulin level in healthy women & men?? Ans:-What do we mean by normo
insulinaemiac?? Ans:- normoinsulinemia
: implies when a) Fasting
insulin is < 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 .
Q.3:-How to
define then insulin resitance based on serum insulin level?? Ans:-Insulin
resistance is defined when insulin value
one 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.
Q. 4: In a
diagnosed case of PCO how often one should perform PPBS then ?? 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 .
Q.5: What about HOMA index?? Ans- 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
.
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. .
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