Middle East Fertility Society Journal Vol. 12, No.

3, 2007
Copyright Middle East Fertility Society

The effect of administration of metformin on lipid

profile changes and insulin resistance in patients
with polycystic ovary syndrome
Mohamad Ali Karimzadeh, M.D. * Naeimeh Tayebi, M.D. *
Maryam Eftekhar, M.D. * Leili Sakhavat, M.D. *
Robabeh Taheripanah, M.D. Fatemeh Zare, M.D. *

Clinical and Research Center for Infertility, Shahid Sadoughi University. Yazd, Iran

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 28.813.18 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 4.670.9 and 5.031.3 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 26.659.9 to 33.19 9.9
MMoL/L (P-value=0.0001), and Triglyceride level decreased after treatment from 208.9658.9 to 191.5455.4
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).
*
Research and Clinical Center for Infertility, Shahid Sadoughi
University of Medical Science, Yazd, Iran.
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

Department of Ob & Gyn, Shaheed Beheshti University of complication, diabetes and endometrial cancer
Medical sciences, Tehran, Iran. should be considered important in this syndrome.
Correspondence: M. Karimzadeh: makarimzadeh@yahoo.com Therefore, many researches lead to investigate the lipid

174 Karimzadeh et al. Metformin and polycystic ovary syndrome MEFSJ

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
Vol. 12, No. 3, 2007 Karimzadeh et al.
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 27.26.8 and 28.67.4 years in case
Metformin and polycystic ovary syndrome 175
Table 1. The mean level of Serum FBS, Cholesterol, LDL, HDL and Triglyceride in both groups.
Variable Case
Pre-treatment Post-treatment
FBS/Insulin 4.670.9 6.071.4 0.0001
Cholesterol 203.0447.2 188.0458.5
(mmol/L)
Cholesterol 26.659.9 33.199.9 0.0001
HDL(mmol/L)
Cholesterol 142.3234.5 141.8635.1
LDL(mmol/L)
Triglyceride 208.9658.4 191.5455.9
(mmol/L)
*
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 5.61.9 and
6,21.8years 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 28.83.18
and 29.494.75Kg/m2 in case and control groups
respectively (P-value=0.15).After treatment; it was
28.452.8 and 29.294.8 in case and control
groups (P-value=0.18).
The degree of the sensitivity to insulin was
4.670.9 in case group and 5.031.3 in control
group. After treatment, the sensitivity to insulin
increased significantly to 6.071.4 in case and
5.051.3 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 203.0447.2 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 (199.442.5 vs.
199.842.5).
In addition, triglyceride level reduced from
208.9658.4 to 191.5455.9 in case group
(p=0.004), while it did not reduce in control group
176 Karimzadeh et al. Metformin and polycystic ovary syndrome
Control
P-value Pre-treatment Post-treatment P-value*
5.031.3 5.051.3 0.77
0.069 199.442.5 199.842.5 0.12
26.289.5 26.349.5 0.16
0.22 144.733.9 145.733.1 0.28
0.004 196.5654.3 205.2653.4 0.063
(196.5654.3 vs. 205.2653.4) (p =0.063).
Similarly, HDL level increased from 26.659.9 to
33.199.9 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).
MEFSJ
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).
Vol. 12, No. 3, 2007 Karimzadeh et al.
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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Received on January 27, 2007; revised and accepted on May 30, 2007
MEFSJ