ARTICLE
Auteur(s) : İlhan Tarkun1,
Emre Dikmen2, Berrin Çetinarslan1, Zeynep
Cantürk1
1Department of Endocrinology
and Metabolism
2Department of Internal Medicine, Faculty
of Medicine, Kocaeli University, Kocaeli, Turkey
accepté le 30 Juillet 2010
Polycystic ovary syndrome (PCOS) is the most common endocrine
disorder experienced by females of reproductive age. There are many
aspects to the pathophysiology of PCOS. Among them is insulin
resistance and its resultant hyperinsulinemia [1, 2].
Hyperinsulinemia has been shown to be one of the causes of the
excess hyperandrogenemia seen in this condition. For this reason,
insulin-sensitizing drugs have been used for many years in patients
with PCOS, and they have significantly improved the metabolic
state, ovulatory dysfunction and fertility rates in sufferers
[3].
Adipose tissue not only has the capacity to store large
quantities of fat as an energy source, it also synthesizes various
adipokines including leptin, resistin, adiponectin and visfatin,
which have effects on insulin resistance. In 2005, Fukaharo
et al. defined visfatin as a pre-B colony enhancing factor
(PBEF) [4]. Examination of visfatin's glucose-lowering effect was
undertaken. A significant decrease in plasma glucose levels
was observed when recombinant visfatin was administered to C57BL/6J
mice. This effect was dose-dependent, although no change occurred
in concurrent plasma insulin levels. In summary, a good deal of
evidence now exists to show that visfatin and insulin share common
in vivo and in vitro features.
Adiponectin is a protein hormone produced exclusively in adipose
tissue where circulating levels correlate positively with levels of
insulin sensitivity [5, 6]. Resistin is also a peptide secreted by
adipose tissue and is assumed to contribute to peripheral insulin
sensitivity [7].
The purpose of this study was to explore whether treatment of
patients with PCOS with metformin has an impact on adipokines such
as visfatin, adiponectin and resistin.
Donors and Methods
The study group consisted of 24 women with PCOS, and
25 healthy, age- and weight-matched, normally menstruating
women. The Local Research Ethics Committee approved the study, and
all patients involved gave their informed consent. Study groups
were composed of patients between 17-40 years old, who had been
admitted to endocrinology outpatient polyclinics with complaints of
irregular menstrual cycles and/or increased hair growth. The
diagnosis of PCOS was established according to the 2003 Rotterdam
ESHR/ASRM endocrine criteria (oligo-ovulation and/or anovulation,
clinical and/or biochemical hyperandrogenism and polycystic ovaries
as defined by ultrasonography). PCOS can be diagnosed after
the exclusion of other medical conditions and if two out of the
three criteria mentioned above are met. Patients with systemic
diseases (diabetes mellitus, thyroid disease, hypertension,
cardiovascular diseases, chronic renal failure, and malignancy)
were excluded from the study. Any patient with a history of taking
any other medication such as lipid lowering drugs, oral
contraceptive pills, ovulation induction products, anti-obesity
drugs, corticosteroids, anti-diabetic and anti-hypertensive drugs
within the previous six months were also excluded. Before entering
the study, a physical examination and appropriate laboratory tests
were performed. After overnight fasting, a 75 gram, oral
glucose tolerance test was performed for all patients, and
120 min values obtained. Any patients with diabetes (glucose
in 120 min of 75-gram OGTT ≥ 200 mg/dL) were excluded
from study. Diseases that mimic PCOS, such as late-onset,
congenital adrenal hyperplasia and Cushing's syndrome were ruled
out by testing for 17-hydroxyprogesterone, and the 1 mg
dexamethasone suppression screening test. All patients had normal
thyroid function tests and normal prolactin levels. Hirsutism was
graded using the Ferriman and Gallwey scoring system.
All of the women were treated with metformin, 850 mg twice
a day, for six months. Patients were seen every eight weeks for
verification of compliance, and assessment of side effects. After
six months of treatment, the women were admitted to the clinical
research center, where all clinical examination and laboratory
evaluations were repeated.
The control group was composed of healthy female volunteers who
had regular menstrual cycles and no signs of clinical or
biochemical hyperandrogenism. The PCOS and control groups were
matched for body mass index (BMI) and age. The BMI was calculated
as body weight in kilograms divided by height in meters squared
(kg/m2) at first admission. The waist circumference was
measured at the widest circumference. Most of the women in the PCOS
or control group were either obese or overweight, so both groups
were proposed similar diets and exercise programs.
Serum samples were obtained from all women during the interval
between the second to the fifth day of the early follicular phase
of the menstrual cycle. The plasma levels of glucose, insulin,
total cholesterol (TC), high-density lipoprotein cholesterol
(HDL-C), triglycerides (TG), low-density lipoprotein cholesterol
(LDL-C), free and total testosterone, LH, FSH, prolactin, free T4,
free T3, TSH, cortisol, dehydroepiandrosterone-sulfate (DHEA-SO4),
androstenedion, 17-OH progesterone, estradiol (E2), sex-hormone
binding globulin (SHBG), visfatin, adiponectin and resistin were
measured after 8-12 hours fasting. Blood samples were taken from an
antecubital vein. All parameters, apart from visfatin, adiponectin
and resistin, were measured immediately. The blood samples were
centrifuged at 4000 rpm for ten minutes, separated and stored at
- 80°C until analyzed for visfatin, adiponectin and
resistin.
Laboratory analyses
Visfatin-C concentration was measured using an enzyme-linked
immunosorbent assay (ELİSA); a Visfatin C terminal (Human) EIA
(Catalog No: EK-003-80 Phoenix Pharmaceuticals, Inc., California,
USA) kit. Adiponectin was measured using an enzyme-linked
immunosorbent assay (ELISA); an AssayMax Human Adiponectin (Acrp30)
ELISA (Catalog EA2500-1 Lot 0201815 AssayPro, USA) kit. Resistin
was measured using an AssayMax Human Resistin ELISA (Catalog ER
1001 Lot 0257822 AssayPro, USA) kit. Glucose, TC, HDL, TG, LDL were
analyzed with an Aeroset analyzer using an Abbott Diagnostics,
Wiesbaden, Germany kit. Insulin, free T4, free T3, TSH, cortisol,
prolactin, FSH, LH, DHEA-SO4, E2, total testosterone levels
measured using an electrochemiluminescent immunometric assay test
method with a Cobas analyzer (Roche Diagnostics, Mannheim,
Germany). SHBG levels were measured using a chemiluminescent
immunometric assay test method with an Immulite 2000 analyzer
(Siemens Medical Solutions Diagnostics, Los Angeles, USA). Free
testosterone, androstenedion levels were measured using an
enzyme-linked immunosorbent assay (ELISA). The 17-OH progesterone
level was measured using an enzyme-immune assay method with a
Dynex-Dsx analyzer.
Insulin resistance (IR) was determined using a number of
different methods including fasting insulin, the homeostasis model
assessment (HOMA), and the quantitative insulin sensitivity check
index (QUICKI). The estimate of insulin resistance, the HOMA-IR
score, was calculated using the formula: fasting serum insulin (μU)
x fasting plasma glucose (mg/dL/405. QUICKI was derived by
calculating the inverse sum of logarithmically expressed values of
fasting insulin and glucose.
Ultrasonography
Transvaginal and/or transabdominal ultrasonography was performed in
all patients. The morphology of the polycystic ovaries was
considered if there were 12 or more follicles of 2-9 mm
diameter in each ovary, and/or an enlarged ovary (>
10 cm3).
Statistical analysis
The Statistical Package for the Social Science (SPSS version 13.0
for Windows, SPSS Inc., Chicago, IL, USA) was used for the
statistical analysis. The person performing the data analysis was
blind to diagnosis. Results were expressed as mean ± SD. The
characteristics of distribution were tested using the
Kolmogorov-Smirnof test. Because of skewed distribution insulin,
testosterone and adiponectin levels, we used log-transformed values
in the subsequent statistical analysis. The clinical and laboratory
characteristics for the two groups were compared using Student's
t-test for unpaired data in a normally distributed group.
Undistributed groups were compared using the Mann-Whitney
U test. For all analyses, a p-value less than < 0.05 was
considered statistically significant. Bivariate correlation
analysis (calculation of the Pearson coefficient) was used to
assess the correlation of serum visfatin, adiponectin and resistin
levels with each parameter.
Results
Twenty-four female patients diagnosed with PCOS, and
25 healthy women of compatible age and BMI were included in
the study. Table 1 shows anthropometric,
biochemical and hormonal data for the women diagnosed with PCOS
before and after treatment, and for the healthy controls. As
expected, serum insulin, HOMA, total testosterone, free
testosterone and androstenedione levels in the PCOS group were
found to be significantly higher compared to the controls.
Following a six-month treatment with metformin in patients with
PCOS, the hirsutism score and the serum fasting insulin level
decreased significantly. Also, statistically significant decreases
were demonstrated in total testosterone and androstenedione levels.
Table 2 shows serum visfatin,
adiponectin and resistin levels in women diagnosed with PCOS before
and after treatment, and in healthy controls. Serum visfatin levels
were found to be significantly higher in patients with PCOS,
compared to controls (129.49 ± 152.97 ng/mL vs 25.70 ± 14.06
ng/mL). Following metformin treatment, a significant decrease was
observed in visfatin levels compared to the baseline (129.49 ±
152.97 ng/mL vs 48.22 ± 33.49). A positive correlation was
found between serum visfatin levels, BMI, waist circumference,
HOMA, insulin and triglyceride levels (table 3). There was a negative correlation
with QUICKI.
No statistically significant difference was observed in terms of
serum adiponectin levels in women with PCOS before and after
treatment, or in healthy controls (23.01 ± 13.78 ng/mL, 28.06 ±
11.43 ng/mL and 28.00 ± 14.25 ng/mL, respectively). Serum-resistin
levels were significantly reduced by metformin treatment.
A negative correlation was found between serum adiponectin
levels, fasting insulin, triglyceride levels and HOMA-IR.
A positive correlation was observed between resistin, BMI, and
waist circumference, and a negative correlation with
HDL-cholesterol levels.
Table 1 Anthropometric, biochemical and hormonal data
for women diagnosed with PCOS before and after treatment, and
in healthy controls
|
PCOS Before (n = 24)
|
PCOS After (n = 24)
|
Controls (n = 25)
|
P1
|
P2
|
|
Age
|
25.21 ± 5.99
|
25.21 ± 5.99
|
24.25 ± 3.76
|
NS
|
0.551
|
|
BMI (kg/m2)
|
31.69 ± 6.52
|
30.7 ± 6.65
|
31.35 ± 6.31
|
0.777
|
0.864
|
|
Waist (cm)
|
100.21 ± 14.74
|
98.44 ± 15.26
|
100.9 ± 17.38
|
0.129
|
0.937
|
|
WHR
|
0.9 ± 0.07
|
0.91 ± 0.06
|
0.89 ± 0.08
|
0.659
|
0.458
|
|
Ferriman-Gallwey score
|
10.7 ± 1.7
|
8.6 ± 1.72
|
-
|
0.03
|
-
|
|
f-glucose (mg/dL)
|
92 ± 9.50
|
88.94 ± 6.72
|
88.45 ± 6.10
|
0.493
|
0.810
|
|
f-insulin (μIU/mL)
|
10.99 ± 4.57
|
7.75 ± 4.03
|
6.09 ± 2.09
|
0.002
|
0.001
|
|
HOMA-IR
|
2.94±1.76
|
1.61 ± 1.12
|
1.24 ± 1.27
|
0.03
|
0.02
|
|
QUICKI
|
0.35 ± 0.02
|
0.37 ± 0.02
|
0.34 ± 0.02
|
0.05
|
0.09
|
|
Cholesterol (mg/dL)
|
177 ± 32.31
|
181.31 ± 24.33
|
159.40 ± 18.80
|
0.407
|
0.002
|
|
TG (mg/dL)
|
120.73 ± 68.80
|
118.42 ± 65.12
|
79.65 ± 39.75
|
0.760
|
0.007
|
|
HDL-C (mg/dL)
|
52.66 ±10.40
|
53.36 ± 12.97
|
50 ± 9.93
|
0.572
|
0.390
|
|
LDL-C (mg/dL)
|
100.08 ± 27.66
|
102.26 ± 18.08
|
93.47 ± 16.69
|
0.629
|
0.123
|
|
LH (mIU/mL)
|
13.51 ± 11.01
|
10.06 ± 6.01
|
5.34 ± 1.82
|
0.344
|
0.002
|
|
FSH (mIU/mL)
|
5.61 ± 1.66
|
5.67 ± 1.28
|
6.48 ± 1.65
|
0.481
|
0.098
|
|
LH/FSH
|
2.4 ± 1.74
|
1.91 ± 1.27
|
0.85 ± 0.32
|
0.305
|
0.001
|
|
DHEA-S (mcg/dL)
|
288.57 ± 110.05
|
270.72 ± 113.64
|
169.48 ± 69.38
|
0.387
|
0.002
|
|
Estradiol (pg/mL)
|
97.71 ± 105.86
|
72.15 ± 58.26
|
73.26 ± 70.13
|
0.314
|
0.808
|
|
SHBG (nmol/L)
|
23.71 ± 12.32
|
25.77 ± 14.29
|
40.91 ± 21.21
|
0.273
|
0.013
|
|
Testosterone (ng/dL)
|
76.44 ± 29.36
|
61.43 ± 31.03
|
33.08 ± 13.57
|
0.038
|
0.000
|
|
Free testosterone (pg/mL)
|
3.55 ± 1.53
|
2.89 ± 2.69
|
2.39 ± 1.61
|
0.059
|
0.08
|
|
Androstenedion (ng/mL)
|
7.27 ± 5.56
|
3.58 ± 2.89
|
2.36 ± 0.93
|
0.05
|
0.05
|
Table 2 Serum visfatin, adiponectin and resistin levels
in women diagnosed with PCOS before and after treatment, and
in healthy controls
|
PCOS Before (n = 24)
|
PCOS After (n = 24)
|
Controls (n = 25)
|
P1
|
P2
|
|
Visfatin (ng/mL)
|
129.49 ± 152.97
|
48.22 ± 33.49
|
25.70 ± 14.06
|
0.014
|
0.023
|
|
Adiponectin (ng/mL)
|
23.01 ± 13.78
|
28.06 ± 11.43
|
28.00 ± 14.25
|
0.057
|
0.087
|
|
Resistin (ng/mL)
|
1.479 ± 0.474
|
1.277 ± 0.32
|
1.61 ± 0.79
|
0.007
|
0.134
|
Table 3 Relationship between serum adiponectin,
resistin and visfatin and anthropometric biochemical and hormonal
parameters in patients with PCOS.
|
Adiponectin
|
Resistin
|
Visfatin
|
|
r
|
p
|
r
|
p
|
r
|
p
|
|
Age (years)
|
0.025
|
0.887
|
0.105
|
0.267
|
0.034
|
0.769
|
|
BMI (kg/m2)
|
- 0.217
|
0.098
|
0.288
|
0.034
|
0.499
|
0.001
|
|
Waist circumference
|
- 0.145
|
0.199
|
0.305
|
0.024
|
0.405
|
0.003
|
|
İnsulin (μU/mL)
|
- 0.345
|
0.008
|
0.185
|
0.177
|
0.264
|
0.039
|
|
HOMA-IR
|
- 0.338
|
0.012
|
0.218
|
0.110
|
0.289
|
0.034
|
|
QUICKI
|
0.317
|
0.015
|
- 0.297
|
0.106
|
- 0.290
|
0.032
|
|
Total cholesterol (mg/dL)
|
- 0.156
|
0.310
|
0.029
|
0.836
|
- 0.065
|
0.603
|
|
LDL-C (mg/dL)
|
- 0.167
|
0.098
|
0.185
|
0.177
|
- 0.139
|
0.312
|
|
HDL-C (mg/dL)
|
0.126
|
0.312
|
- 0.453
|
0.001
|
- 0.124
|
0.342
|
|
Triglyceride (mg/dL)
|
- 0.276
|
0.041
|
0.216
|
0.113
|
0.340
|
0.02
|
|
LH (mIU/mL)
|
0.015
|
0.887
|
- 0.020
|
0.885
|
- 0.140
|
0.298
|
|
FSH (mIU/mL)
|
- 0.066
|
0.603
|
- 0.104
|
0.449
|
0.189
|
0.254
|
|
Total testosterone(ng/dL)
|
- 0.163
|
0.256
|
- 0.133
|
0.333
|
0.043
|
0.765
|
|
SHBG (nmol/L)
|
0.308
|
0.022
|
- 0.234
|
0.086
|
- 0.139
|
0.287
|
Discussion
PCOS is a syndrome, the etiology of which remains controversial. It
is frequently observed in reproductive-age women, accompanied by
hyperandrogenism, insulin resistance and increased type 2 DM.
Following the discovery of the hormone leptin in 1994, it has been
confirmed that fatty tissue not only regulates energy metabolism in
our body, it also releases many biological molecules collectively
referred as adipo(cyto)kines, which contribute to peripheral
insulin sensitivity. The role of adipokines in the pathogenesis of
the important features of PCOS, such as insulin resistance and
central obesity, has attracted much attention. Studies are
proceeding currently on the effect and benefit of drugs used in the
treatment of this syndrome with regard to reducing insulin
resistance. This study was designed to show the effect of
metformin, one of the most important drugs used to reduce insulin
resistance in patients with PCOS, on these adipokines.
Recent studies have demonstrated that visfatin, an adipokine
secreted from visceral fatty tissue, could influence insulin
sensitivity. In fact in several studies, high visfatin levels were
found in patients with type 2 DM and gestational DM [8, 9]. The
effects of visfatin in PCOS have attracted attention as a result of
the identification of its insulin-like effects. In our study, serum
visfatin levels were found to be significantly higher in patients
with PCOS compared to controls. In addition, in six case-control
studies previously conducted in patients with PCOS, it was found
that plasma/serum visfatin levels were significantly higher than in
a BMI-matched, healthy control group [10-15].
The actual reason for the increased visfatin levels in patients
with PCOS has not been clearly established. In several previous
studies, plasma visfatin levels in patients with normal weight and
PCOS were found to be higher than those in the control group with
normal weight [11, 13, 14]. Tan et al. found results
similar to those of our study, that plasma visfatin levels in
overweight and obese patients with PCOS were higher than in the
control group [10]. In the same study, in parallel with plasma
visfatin levels, visfatin mRNA expression in subcutaneous and
omental fatty tissue was demonstrated to be significantly higher
than that found in the control group.
Controversial results have been obtained in studies
investigating the relationship between obesity and the plasma
visfatin level. Haider et al. found significantly higher
plasma visfatin levels in obese subjects relative to individuals of
normal weight, however, Pagano et al. demonstrated lower
levels [16, 17]. Similarly, the relationship between visfatin and
BMI, waist circumference and waist/hip ratio is also controversial
[11, 12, 14, 17, 18]. In our study, there was a positive
correlation between visfatin levels in patients with PCOS, and BMI,
waist circumference, insulin levels and the HOMA index. Similarly,
Chan et al. demonstrated a positive correlation between plasma
visfatin levels in PCOS patients and BMI [12].
Metformin has been used for more than 10 years in the
treatment of PCOS. Metformin regulates insulin resistance in
peripheral tissues and reduces insulin release. Özkaya et al.
conducted a study, investigating the relationship between metformin
treatment and serum visfatin levels in patients with PCOS [19]. In
this study, a significant decrease was observed in visfatin levels
following a three-month treatment of patients with PCOS, similar to
that observed in our study. Conversely, Steiner et al. showed
that serum visfatin levels in PCOS patients were increased after
metformin treatment [20]. However, there are several
inconsistencies in this study. For example, insulin resistance as
measured by HOMA-IR did not improve with metformin, in contrast to
a number of other studies, and interestingly, visfatin levels did
not change in the rosiglitazone treatment arm. Heider et al.
showed that insulin and glucose levels over phosphotidyl inositol
3 kinase and protein kinase B pathways directly affected
visfatin levels [21]. The decrease in visfatin observed in patients
with PCOS may be the result of a reduction in insulin resistance
and insulin levels. The effect of a reduction in body weight and
fatty tissue in these results cannot be overlooked.
Adiponectin is possibly the most important adipokine. The reason
for this is that it is the only cytokine synthesized in and
released from fatty tissue, and it has well established,
anti-atherogenic, anti-inflammatory and insulin-sensitizer
properties. It is known that adiponectin levels are decreased
significantly in obese subjects as compared to subjects of normal
weight [22]. Moreover, it has been found that serum adiponectin
concentrations are inversely related to the severity of insulin
resistance [23]. The relationship between PCOS, obesity and insulin
resistance, the role of adiponectin in the pathogenesis of PCOS,
and whether or not there is any relationship to the treatment of
insulin resistance in PCOS, have attracted our attention.
Studies on adiponectin levels in PCOS patients have produced
some controversial results. Women with PCOS generally show
hypoadiponectemia. Authors have suggested that obesity, insulin
resistance or hyperandrogenemia may be the cause of this
hypoadiponectemia in this patient group. In our study, adiponectin
levels were found to be lower in the PCOS group than in the control
group. However, this decrease did not reach the statistical
significance. In several previous studies, serum adiponectin levels
were found to be similar in patients with PCOS and a BMI-matched
control group, which further supported the results of our study
[24-28]. The lack of any significant difference in serum
adiponectin levels between PCOS patients and control groups with
similar BMI has led to the suggestion that adiponectin has no
direct role in the pathogenesis of PCOS [24-27]. Studies on
adiponectin levels in PCOS patients following metformin treatment
have also had controversial results. In some studies, serum
adiponectin levels increased significantly after metformin
treatment in PCOS patients [28, 29]. In other studies, an
increase in serum adiponectin was observed with metformin
treatment, but this increase was not statistically significant, as
in our study [30, 31]. In the present study, we found a negative
correlation between adiponectin levels and serum insulin and HOMA,
and a positive correlation with QUICKI.
Resistin is an adipokine thought to be released in large amounts
from macrophages, as well as from human fatty tissue: the
relationship between resistin and obesity and insulin resistance
has yet to be clarified. This molecule is regarded as a hormone
that facilitates insulin resistance as it has been demonstrated
that while serum resistin level increase in obese mice, the
anti-diabetic agent rosiglitasone decreased levels, and that
administration of recombinant resistin to mice caused impairment in
glucose tolerance and the insulin effect. Therefore, Steppan
et al. named this new hormone resist+in[sulin] [7]. Although
there are studies supporting the relationship between resistin,
obesity and insulin resistance, there are also studies reporting
contrary views [32-35].
As in many other studies, our study could not determine any
difference between BMI-matched PCOS patients and control groups in
terms of serum resistin levels. In our study, a linear relationship
was determined in the group of patients with PCOS between serum
resistin levels and BMI and waist circumference, and this finding
was compatible with those in the literature. Seow et al.,
found not only that serum resistin levels in patients with PCOS
were similar to that of a control group, they also determined that
resistin mRNA expression in adipocytes was two-fold higher in the
group of patients with PCOS than the control group. In the light of
this finding, they suggested that resistin might exert a local
paracrine effect in obesity and insulin resistance in PCOS
[36].
Steiner et al. investigated the effect of metformin and
rosiglitazone treatment on resistin levels in patients with PCOS
[20]. They showed no changes in resistin levels at the end point in
any of the treatment arms. However, in this study, resistin levels
were very low at baseline and insulin resistance did not improve
after treatment. This study is the first to show that treatment
with metformin significantly reduces resistin levels. This
reduction may be associated with a reduction in insulin resistance
or weight loss. However, this subject warrants further study.
Despite the limitation due to the number of subjects included,
our study evaluates the response of adipokines, such as serum
visfatin, adiponectin and resistin, which are directly associated
with insulin resistance, to treatment with metformin in patients
with PCOS. A reduction was shown in serum visfatin and
resistin levels with metformin treatment in patients with PCOS.
Detailed retrospective studies with long-term follow-up and larger
populations are required to confirm the clinical significance of
these findings.
Disclosure
None of the authors has any conflict of interest or financial
support to disclose.
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