|
Middle East Fertility Society Journal
Middle East Fertility Society
ISSN: 1110-5690
Vol. 12, Num. 3, 2007, pp. 174-178
|
Middle
East
Fertility
Society
Journal,
Vol.
12,
No.
3,
2007,
pp.
174-178
The
effect
of
administration
of
metformin
on
lipid
profile
changes
and
insulin
resistance
in
patients
with
polycystic
ovary
syndrome
Mohamad
Ali
Karimzadeh,
M.D. *,Maryam
Eftekhar,
M.D. *,Robabeh
Taheripanah,
M.D. ,Naeimeh
Tayebi,
M.D. *,Leili
Sakhavat,
M.D. *,Fatemeh
Zare,
M.D. *
Clinical
and
Research
Center
for
Infertility,
Shahid
Sadoughi
University.
Yazd,
Iran
* Research
and
Clinical
Center
for
Infertility,
Shahid
Sadoughi
University
of
Medical
Science,
Yazd,
Iran.
†Department
of
Ob & Gyn,
Shaheed
Beheshti
University
of
Medical
sciences,
Tehran,
Iran.
Correspondence:
M.
Karimzadeh:
makarimzadeh@yahoo.com
Received
on
January
27,
2007;
revised
and
accepted
on
May
30,
2007
Code
Number:
mf07033
ABSTRACT
Objective: Polycystic
ovary
syndrome
(PCOS)
is
one
of
the
most
common
metabolism
and
endocrine
disorders
among
women.
The
aim
of
the
present
study
was
to
evaluate
the
effects
of
metformin
on
lipid
profile
changes,
insulin
resistance,
body
mass
index
(BMI),
Ovulation
and
pregnancy
rates
in
patients
affected
by
PCO
syndrome.
Materials
and
Methods: In
this
randomized
controlled
study,
200
women
aged
20-35
years
with
PCOS
were
selected.
Diagnostic
criteria
were
based
on
the
diagnostic
criteria
of
PCO
syndrome
in
Noterdam
meeting
in
2003.
Samples
of
fasting
peripheral
blood
were
taken
from
all
patients
to
test
cholesterol,
LDL,
HDL,
TG,
FBS
and
Insulin
before
treatment.
Patients
were
then
divided
randomly
into
two
groups.
In
case
group
(n=100),
metformin
was
prescribed
three
times
a
day
(1500
mg
daily)
and
in
control
group
(n=100),
placebo
was
administered
in
the
same
way.
After
three
months,
sample
of
blood
was
taken
again
in
order
to
test
the
variance
of
the
above
mentioned
parameters
to
compare
with
these
amounts
before
test.
Also,
BMI
was
compared
before
and
after
treatment
in
both
groups.
Results: BMI
was
28.81±3.18
and
29.49 ± 4.7
Kg/m2
before
treatment
in
case
and
control
groups
respectively.
This
ratio
changed
after
treatment
to
28.45 ± 2.8
and
29.29 ± 4.8
Kg/m2
in
case
and
control
groups
respectively
(P-value>0.05).
FSH/insulin
ratio
was
4.67±0.9
and
5.03±1.3
in
case
and
control
group
respectively,
while
it
changed
after
treatment
to
6.07 ± 1.4
and
5.05 ±1.3
and
this
difference
was
significant
in
case
group
(P-value=0.0001),but
it
was
no
difference
in
control
group.
In
case
group,
HDL
level
increased
after
treatment
from
26.65±9.9
to
33.19± 9.9
MMoL/L
(P-value=0.0001),
and
Triglyceride
level
decreased
after
treatment
from
208.96±58.9
to
191.54±55.4
MMoL/L
(P-value=0.004);
whereas
there
was
no
change
in
control
group. LDL
and
cholesterol
levels
did
not
change
in
both
groups.
Ovulation
rate
and
pregnancy
rate
were
significantly
higher
in
case
group
than
in
control
group
(86%
vs.
20%)
(P-value=0.003)
and
(40%
vs.
11%)
(P=0.021)
respectively.
In
addition,
Metformin
had
no
significant
effect
on
BMI
in
case
group.
Conclusion: Treatment
with
metformin
during
3
months
causes
not
only
the
increase
in
ovulation
and
pregnancy
rates
but
also
the
decrease
in
insulin
resistance
and
lipid
profile
changes.
Key
words: metformin,
PCO
syndrome,
lipid
profile,
hyperinsulinemia
Polycystic
ovary
syndrome
is
one
of
the
most
common
metabolism
and
endocrine
disorders
among
women
with
the
prevalence
of
about
%5-
%10
worldwide
(1).One
study
investigated
its
prevalence
among
girl
students
in
Yazd,
Iran
and
reported
the
prevalence
of
%16
(2).
This
disorder
affects
women
in
reproductive
age.
The
signs
of
PCOS
include
hyperandrogenism
and
anovulation.
Since
the
cause
of
this
syndrome
has
not
been
diagnosed
yet,
therefore
its
treatment
will
be
depending
on
signs
and
patients
characteristics
such
as:
hirsutism,
obesity,
menstrual
disorder
and
infertility
(3).
The
long
term
damages
such
as
heart
complication,
diabetes
and
endometrial
cancer
should
be
considered
important
in
this
syndrome.
Therefore,
many
researches
lead
to
investigate
the
lipid
changes
and
metabolic
effects
in
PCO
patients
(3).
PCO
patients
are
resistance
to
insulin
and
it
is
not
related
to
obesity
(1),
while
different
studies
have
shown
that
insulin
has
a
main
role
in
pathogenesis
of
this
syndrome
and
has
direct
effect
on
ovarian
steroidogenesis
and
consequently,
it
stimulates
the
synthesis
of
androgens
in
theca
cells
and
reduces
steroid
hormone
binding
globulin
(SHGC)
in
liver
and
increases
the
level
of
androgen
(4).
Some
randomized
clinical
trials
indicated
that
treatment
with
metformin
in
PCOS
decreased
the
insulin
resistance
and
corrected
lipid
metabolism
(5,
6,
7).
The
other
studies
reported
that
using
this
drug
in
PCO
patients
reduced
serum
androgens
level
and
consequently
menstrual
periods
became
regular
(6,
8,9).
Banaszewska
et
al
(2006)
have
concluded
that
metformin
therapy
in
hyperinsulinemic
women
was
associated
with
a
significant
decrease
of
insulin
level,
total
cholesterol,
LDL
and
TG
that
this
drug
may
be
considered
as
a
prophylactic
therapy
lowering
cardiovascular
risk
factors
in
hyperinsulinemic
women
with
PCOS
(10)
Our
aim
is
to
investigate
the
effect
of
metformin
on
lipid
profile
changes,
insulin
resistance
and
BMI,
ovulation
and
pregnancy
rates
in
PCO
patients.
Materials
and
Methods
A
randomized
controlled
trial
was
conducted
to
compare
the
effect
of
metformin
on
lipid
profile
changes,
insulin
resistance,
BMI,
ovulation
and
pregnancy
rates
in
PCO
patients
before
and
after
treatment
between
August
2005
and
September
2006.
Ethical
committee
of
Yazd
Shahid
Sadughi
University
of
Medical
Science
approved
this
study.
In
total,
200
women
(The
range
of
age
was
20-35
years)
who
have
referred
to
our
clinic
because
of
menstrual
disorder,
hirsutism
and
infertility
were
diagnosed
with
PCOS. PCOS
was
diagnosed
according
to
its
definition
in
2003
Noterdam
meeting
namely
by
the
existence
of
at
least
two
of
the
following
criteria:
oligomenorrhea
(the
length
of
period
days
is
more
than
35
days)
or
hypo
menorrhea,
Clinical
signs
of
hirsutism,
hyperandrogenism,
and
sonographic
evidence
of
PCO
(such
as
ovarian
volume>10cm3
and
small
(6-8mm)
follicles
more
than
12
arranged
in
the
periphery
of
the
ovary).
The
exclusion
criteria
were
included
other
endocrinological
abnormalities
such
as
hyperprolactinaemia,
and
thyroid
dysfunction,
Cushing
syndrome,
congenital
adrenal
hyperplasia.
BMI
was
measured
and
recorded
in
all
patients
before
and
after
treatment.
The
sample
of
fasting
peripheral
blood
was
taken
in
order
to
measure
cholesterol,
HDL,
LDL,
triglyceride,
FBS
and
fasting
insulin.
Then
patients
were
randomly
(Randomization
was
performed
using
computer-generated
sequences
that
were
sealed
in
number
opaque
envelopes)
divided
into
two
groups.
Metformin
was
prescribed
for
case
group
(n=100)
and
placebo
for
control
group
(n=100).
Both
women
and
the
doctor
were
blinded
to
the
content
of
tablet
which
had
identical
appearance
and
were
packaged
by
the
clinic
pharmacist.
The
dose
of
metformin
was
started
from
one
tablet
500
mg
/day
and
increased
to
three
tablets
daily
during
a
week
with
respect
to
the
patients
tolerance.
Placebo
was
prescribed
for
control
group
in
the
same
method.
After
three
months,
the
sample
of
blood
peripheral
was
taken
again
in
order
to
check
the
mentioned
parameters.
Then
the
data
was
compared
with
these
amounts
before
treatment.
All
patients
were
asked
to
report
all
the
side
effects
such
as
nausea,
vomiting
and
diarrhea
during
the
treatment.
Ovulation
rates
were
determined
by
progesterone
levels
of
more
than
10ng/ml
in
the
luteal
phase
(timed
21
days
after
the
first
spontaneous
menstruation)
for
both
groups.
Pregnancy
outcomes
included
serum
B-HCG
of
more
than
50IU/L,
and
fetal
heart
activity
on
abdominal
ultrasound
scan,
after
8
weeks
of
gestation.
SSPS
version
13
was
used
to
do
the
appropriate
statistical
tests
including
Student's
T
Test
(two-tailed),
Fisher
exact
test.
The
results
are
expressed
as
means
and
standard
deviation.
Differences
were
considered
to
be
statistically
significant
if
p-value
was <0.05.
RESULTS
In
this
study,
200
PCO
patients
were
recruited
during
1
year.
100patients
were
in
the
metformin
group
and
100
in
the
placebo
group.
The
mean
age
of
patients
was
27.2±6.8
and
28.6±7.4
years
in case
Table
1. The
mean
level
of
Serum
FBS,
Cholesterol,
LDL,
HDL
and
Triglyceride
in
both
groups.
Variable
|
Case
|
Control
|
|
Pre-treatment
|
Post-treatment
|
P-value
|
Pre-treatment
|
Post-treatment
|
P-value*
|
|
|
|
|
|
|
|
FBS/Insulin
|
4.67±0.9
|
6.07±1.4
|
0.0001
|
5.03±1.3
|
5.05±1.3
|
0.77
|
Cholesterol
(mmol/L)
|
203.04±47.2
|
188.04±58.5
|
0.069
|
199.4±42.5
|
199.8±42.5
|
0.12
|
Cholesterol
HDL(mmol/L)
|
26.65±9.9
|
33.19±9.9
|
0.0001
|
26.28±9.5
|
26.34±9.5
|
0.16
|
Cholesterol
LDL(mmol/L)
|
142.32±34.5
|
141.86±35.1
|
0.22
|
144.7±33.9
|
145.7±33.1
|
0.28
|
Triglyceride
(mmol/L)
|
208.96±58.4
|
191.54±55.9
|
0.004
|
196.56±54.3
|
205.26±53.4
|
0.063
|
*Data
were
analyzed
by
paired
T
Test
The
results
are
expressed
as
means
and
standard
deviation.
Differences
were
considered
to
be
statistically
significant
if
p-value
was <0.05.
and
control
group
respectively
(P-value=
0.42).Duration
of
infertility
was
5.6±1.9
and
6,2±1.8years
in
case
and
control
groups
respectively(
P-value=
0.28).
Before
treatment,
the
patients
with
oligomenorrhea
were
82%
and
75%
in
case
and
control
groups
respectively
(P-value=0.31),
While
it
was
23%
and
70
%
in
case
and
control
groups
after
treatment
(P-value=0.003).
Hirsutism
was
86%
and
82%
in
case
and
control
groups
(P-value=0.51),
while
it
was
50%
and
70
%
in
case
and
control
groups
after
treatment
(P-value=0.07).
Before
the
treatment,
the
BMI
was
28.8±3.18
and
29.49±4.75Kg/m2
in
case
and
control
groups
respectively
(P-value=0.15).After
treatment;
it
was
28.45±2.8
and
29.29±4.8
in
case
and
control
groups
(P-value=0.18).
The
degree
of
the
sensitivity
to
insulin
was
4.67±0.9
in
case
group
and
5.03±1.3
in
control
group.
After
treatment,
the
sensitivity
to
insulin
increased
significantly
to
6.07±1.4
in
case
and
5.05±1.3
in
control
group
(P-value
=0.0001);
while
it
was
not
significant
in
control
group
(P
value
=0.77)
(Table1).
As
it
is
shown
in
table
1,
although
the
amount
of
cholesterol
reduced
from
203.04±47.2
to
188.04 ±58.5
in
case
group,
this
reduction
was
not
significant
statistically
(p=0.069);
while
no
change
was
seen
in
control
group
(199.4±42.5
vs.
199.8±42.5).
In
addition,
triglyceride
level
reduced
from
208.96±58.4
to
191.54±55.9
in
case
group
(p=0.004),
while
it
did
not
reduce
in
control
group
(196.56±54.3
vs.
205.26±53.4)
(p
=0.063).
Similarly,
HDL
level
increased
from
26.65±9.9
to
33.19±9.9
after
metformin
treatment
(P-value=0.0001),
while
this
change
was
not
seen
in
control
group.
Finally,
LDL
level
was
not
changed
in
both
groups.
Ovulation
rate
was
significantly
higher
in
case
group
than
in
control
group
(86%
vs.
20%)
(P-value=0.003).
Also,
clinical
pregnancy
rate
was
significantly
more
in
case
group
than
in
control
group
(40%
vs.
11%)
(P=0.021).
Four
pregnancies
in
case
group
and
three
in
group
B
ended
with
miscarriage
at
8
weeks
of
gestational
age
(P-value=0.092)
In
addition,
Metformin
had
no
significant
effect
on
BMI
in
case
group.
Side
effects
in
metformin
treatment
were
30%
nausea,
10%
diarrhea
and
15%
vomiting.
These
side
effects
were
not
severe
and
they
were
disappeared
with
continuing
treatment.
DISCUSSION
Hyperinsulinemia
and
hyperandrogenism
increase
the
risk
of
diabetes
in
PCO
patients
(1).
In
addition,
hyperinsulinemia
causes
hypertension
and
increases
the
risk
of
ischemic
heart
disease
(IHD)
in
these
patients
(11).
The
other
risk
factor
of
IHD
is
insulin
resistance
which
is
accompanied
with
increasing
of
triglyceride
and
reduction
of
HDL
level
(11).
Women
with
anovulation,
hyperandrogenism
and
hyperinsulinemia
are
more
exposed
to
the
risk
of
diabetes
mellitus
independent
from
insulin
(1).
Different
studies
have
shown
that
continuous
anovulation
made
the
patients
three
times
more
susceptible
to
endometrial
cancer
(12).
On
the
other
hand,
the
risk
of
breast
cancer
increases
in
patients
with
chronic
anovulation
three
or
four
times
(1).
Metformin
increases
the
sensitivity
to
insulin
that
decreases
the
chance
of
diabetes
(13-15).
This
drug
is
available
in
the
market
for
treatment
of
diabetes
more
than
10
years.
In
fact,
it
is
the
most
prescribed
medicine
for
the
treatment
of
hyperglycemia.
The
primary
effect
of
metformin
is
a
significant
reduction
in
gluconeogenesis.
Not
only
decreases
glucose
production
but
also
increases
target
tissue
sensitivity
to
insulin.
Metformin
has
useful
effects
in
reduction
of
the
cardiovascular
risk
factors
and
it
is
the
early
available
medication
against
hyperglycemia
which
decreases
macrovascular
complications
in
diabetic
patients
(16).
It
was
shown
that
treatment
with
1500
mg
of
metformin
for
8
weeks
decreases
the
level
of
serum
insulin
(8,
17).
Our
results
showed
that
sensitivity
to
insulin
(FBS/insulin
ratio)
has
increased
in
the
case
group
compared
to
the
control
group.
Although,
the
rise
of
androgen
and
consequently
the
lipid
changes
in
PCO
patients
cause
to
protect
against
osteoporosis
but
its
bad
effect
on
heart
disease
is
very
important
(16).
Atherosclerosis
is
more
common
among
women
who
have
anovulation
and
PCOD.
Cheang
and
et
al
(2004)
showed
that
metformin
not
only
recommended
for
PCO
patients
because
of
its
effect
on
induction
ovulation,
but
also
for
its
useful
influence
on
lipid
metabolism
(18).
Our
results
showed
that
treatment
with
metformin
caused
a
significant
increase
in
HDL
and
a
decrease
in
triglyceride
level.
However,
although
cholesterol
and
LDL
serum
levels
decreased
after
treatment
with
metformin,
it
was
no
significant
difference
between
before
and
after
treatment
in
case
group.
Therefore,
treatment
with
metformin
may
cause
the
prevention
of
long
term
risk
of
cardiovascular
and
diabetes
through
correcting
all
or
some
of
risk
factors
and
lipid
profile
changes
(19).
Tang
and
co-workers
(2006)
have
indicated
that
there
were
no
significant
changes
in
insulin
sensitivity
or
lipid
profiles
after
treatment
with
metformin.
Also,
in
this
study,
metformin
did
not
improve
weight
loss
or
menstrual
frequency
in
patients
with
PCOS
(20).
The
effect
of
metformin
has
been
controversial;
with
some
suggestion
that
the
ovulatory
response
is
the
result
of
the
weight
loss
that
often
accompanies
its
use.
In
a
study
designed
to
control
the
effect
of
body
weight,
the
administration
of
metformin
was
without
effect
on
insulin
resistance
in
extremely
overweight
women
with
polycystic
ovaries
(21).
In
another-well
designed
study,
metformin
again
had
no
effect
on
insulin
resistance
when
body
weights
remained
unchanged,
and
baseline
weights
and
hyperinsulinemia
were
only
modestly
increased
(22).
In
contrast
to
some
of
the
studies
that
metformin
has
a
good
effect
on
the
reduction
of
weight
and
BMI
(23,
24),
our
investigation
showed
that
there
was
no
significant
difference
in
weight
and
BMI
after
treatment
with
metformin.
Santana
et
al
(2004)
have
shown
that
treatment
with
metformin
increased
HDL
level
while
serum
total
cholesterol
and
LDL
levels
reduced.
Also,
there
were
no
changes
in
BMI
after
metformin
treatment
(25).
Arunas
study
(2004)
indicated
that
significant
improvement
menstrual
cyclicity,
ovulation
and
pregnancy
rates
were
noted
after
treatment
with
metformin
(26).Our
results
were
the
same
as
this
study.
However,
Treatment
with
metformin
will
decrease
insulin
resistance
and
lipid
profile
changes
and
increase
ovulation
and
pregnancy
rates.
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