International Journal of Gynecology & Obstetrics 74 2001.

261267

Article

Polycystic ovarian syndrome PCOS/ and

insulin resistance
K.H. Park a , J.Y. Kima , C.W. Ahna,U , Y.D. Song b, S.K. Limb, H.C. Lee b
a

Department of Obstetrics and Gynecology, Yonsei Uni ersity College of Medicine, Seoul, South Korea
b
Department of Internal Medicine, Yonsei Uni ersity College of Medicine, Seoul, South Korea
Received 27 December 2000; received in revised form 18 May 2001; accepted 23 May 2001

Abstract
Objecti es: Polycystic ovary syndrome PCOS. presents a high risk of developing type 2 diabetes mellitus. We
studied a group of women with PCOS and evaluated this defect in insulin action. Methods: The study population
consisted of nine PCOS women, six obese type 2 diabetic patients, and five controls whose body mass index BMI.
was similar to that of the nine PCOS women. The 75-g oral glucose tolerance test OGTT. and the hyperinsulinemic
euglycemic glucose clamp test were performed. Clinical characteristics and the metabolic profiles, including the
insulin sensitivity index ISI., were compared. Results: PCOS women showed significantly elevated insulin responses
during OGTT, but their blood glucose levels were comparable with the controls. The subjects with PCOS had more
insulin resistance than the other groups. There was no difference among the groups in terms of clinical characteristics and metabolic profiles, except age, luteinzing hormone LH., testosterone, and sex hormone binding globulin
SHBG.. Conclusion: We conclude that PCOS women have significant insulin resistance which is independent of
adiposity. 2001 International Federation of Gynecology and Obstetrics. All rights reserved.
Keywords: Polycystic ovary syndrome; Pathogenesis; Insulin resistance

Corresponding author. Tel.: q822-361-5411; fax: q822-393-6884.

E-mail address: acw@yumc.yonsei.ac.kr C.W. Ahn..

0020-7292r01r$20.00 2001 International Federation of Gynecology and Obstetrics. All rights reserved.
PII: S 0 0 2 0 - 7 2 9 2 0 1 . 0 0 4 4 2 - 8

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K.H. Park et al. r International Journal of Gynecology & Obstetrics 74 (2001) 261267

1. Introduction
Polycystic ovarian syndrome PCOS. is one of
the most common endocrinologic disorders in
women of reproductive age, and according to a
recent study, 510% of pre-menopausal women
present with hyperandrogenemia, chronic anovulation, and polycystic ovarian syndrome w1x.
Dunaif et al. w2x have reported that PCOS
patients suffer from impaired insulin secretion,
which carries an associated risk of progression to
type 2 diabetes mellitus, and this has an earlier
onset than in the normal population. Insulin resistance is commonly found in various pathophysiological states, including type 2 diabetes mellitus
and obesity w3x. Lillioja et al. w4x have revealed a
characteristic progression of type 2 diabetes mellitus prior to the onset of diabetes mellitus.
Insulin resistance continues for a while, and then
with the impairment of insulin secretion, it develops into diabetes mellitus.
Therefore, we investigated the insulin resistance and its severity in PCOS by comparing type
2 diabetic patients and controls.

2. Materials and methods

2.1. Subjects
The study population consisted of nine PCOS
women, six obese type 2 DM patients, and five
controls whose body mass index BMI. was similar to that of the nine PCOS women.
The control group were non-diabetic, 31.0" 5.1
years of age mean " S.E.M.. with BMIs of 25.6
" 2.40 kgrm2 and 88.0" 4.0 mgrdl fasting blood
sugar, which was in the normal range. The diagnosis of PCOS group was based on clinical features of oligomenorrhea intermenstrual interval
of ) 35 days. andror hirsutism FerrimanGallwey score ) 7., together with a raised serum
testosterone or androstenedione, or both. The
presence of polycystic ovaries on transvaginal scan
of the pelvis on one or both sides was considered
confirmatory evidence of PCOS. The mean age
was 25.0" 4.1 years, BMI 26.0" 3.1 kgrm2 , fasting blood sugar 87 " 5.0 mgrdl, which was in the

normal range, and without glucose intolerance or

diabetes confirmed, as confirmed by the 75-g oral
glucose tolerance test OGTT.. The type 2 DM
group with normal ovary ultrasound had a mean
age of 37.0" 3.4 years, BMI of 27.0" 2.4 kgrm2 ,
and fasting blood sugar of 147.0" 14.0 mgrdl.
The sugar levels were controlled with medical
treatments such as oral biguanide or sulfonylureas. These patients were taken off medication 2
days prior to the study.
2.2. Methods
The study was performed at the clinic of the
Severance Hospital YUMC., and informed consent was obtained from each patient. The protocol adopted was approved by the ethics committee. Height, weight, waist and hips circumference
were measured following a standardized protocol.
BMI was used as an estimate of overall adiposity.
The waist hip ratio WHR. was used as an estimate of body fat distribution. Body composition
was determined using a bioelectric impedancemeter Bioimpedance method, Inbody 2.0, Biospace,
Korea., and the results were expressed as percent
fat mass. Plasma glucose was measured using the
glucose oxidase technique on an autoanalyzer
Beckman, Fullerton, CA, USA.. HbA 1C was analyzed by high performance liquid chromatography
HPLC. Variant II, Bio-Rad, Hercules, CA,
USA.. Insulin and C-peptide were measured by
radioimmunoassay Instar, Stillwater, MN, USA..
Plasma lipoprotein measurements were obtained
from fasting single fresh plasma samples using
microplate methods Behring ELISA processor II
plus, Marburg, Germany.. Total cholesterol and
triglyceride concentrations were measured in an
autochemical analyzer Hitachi 747, Nakashi,
Japan. using an enzymatic method Roche Diagnostics, Basel, Switzerland.. HDL cholesterol was
assayed using the selective inhibition test Daichii,
Tokyo, Japan.. LDL cholesterol was calculated
according to the Friedwald formula. The 75-g
OGTT was taken every 30 min to measure blood
glucose levels, the concentration of C-peptide,
and the insulin concentration. In this study, the
insulin sensitivity of the body fat matched controls, obese type 2 DM, and the PCOS group

K.H. Park et al. r International Journal of Gynecology & Obstetrics 74 (2001) 261267

were compared. The insulin sensitivity indices

ISI. of the three groups after 2 h of insulin
infusion, using the hyperinsulinemic euglycemic
clamp technique were also compared. Three days
prior to the study, the subjects were asked to
avoid alcoholic beverages, heavy meals, or stressful exercise not routinely undertaken. They were
all instructed to remain on their usual diet, containing at least 200 g of carbohydrate, for 3 days
and to fast for 1014 h before the study. On the
day of the study, the height, weight, blood pressure and body fat content were measured, and
blood sampling performed. The hyperinsulinemic
euglycemic clamp test was undertaken using a
computer program, which was developed on the
basis of the theories and formulas introduced by
DeFronzo et al. w5x. In order to obtain ISI, we
tried to keep blood glucose and insulin level in
the range free of involvement, maintaining them
at 90 mgrdl and 100 Urml, respectively w5,6x.
Before initiating the study, approximately 20 min
of rest was recommended to avoid excessive stress
hormone secretion.

263

2.3. Statistical analysis

The clinical characteristics and the metabolic
profiles including the ISI levels of the three groups
were compared using either the t-test or the 2
test SPSSr PC q 8.0., and P-value of less than
0.05 was considered to be statistically significant.
3. Results
3.1. Clinical and biochemical characteristics
No statistical differences were found in terms
of age, BMI, WHR, ideal body weight % IBWt.,
body fat, and lipid profile total cholesterol,
triglyceride, and HDL-cholesterol. between the
groups.
The basal serum insulin levels were 6.2" 0.9
Urml in the control group, 7.6" 1.2 Urml in the
obese type 2 diabetic group, and 17.6" 2 Urml
in the PCOS group; the basal serum insulin and
C-peptide level was higher in the PCOS group
P- 0.05..

Table 1
Clinical and biochemical characteristics of subjects

n
Age years.
BMI kgrm2 .
WHR
% IBWt
% Body fat
FBS mgrdl.
PP 2h mgrdl.
C-peptide ngrml.
Insulin Urml.
Total cholesterol mgrdl.
Triglyceride mgrdl.
HDL-cholesterol mgrdl.
LH mIUrml.
FSH mIUrml.
E2 pgrml.
T ngrml.
SHBG nmolrl.
ISI mgrkg per min.

PCOS

Type 2 DM

Controls

9
25.0" 4.1U
26.0" 3.1
0.98" 0.08
115.0" 12.0
25.2" 3.2
87.0" 5.0
137.0" 14.0
3.1" 1.2U
18.8" 9.0U
173.0" 34.0
160.0" 23.0
45.0" 7.0
22.3" 5.2U
10.2" 3.2
51.0" 14.0
0.99" 0.15U
20.1" 12.5U
2.3" 0.3U

6
37.0" 3.4
27.0" 2.4
1.01" 0.06
118.0" 9.0
27.2" 2.4
147.0" 14.0U
234.0" 18.0U
2.5" 1.1
12.1" 7.0U
223.0" 24.0
210.0" 34.0
36.0" 8.0
12.1" 3.4
9.2" 1.3
53.1" 14.5
0.32" 0.12
35.8" 12.3U
4.7" 1.2U

5
31.0" 5.1
25.6" 2.4
0.93" 0.07
113.0 " 13.0
25.4" 3.4
88.0" 4.0
123.0" 6.0
1.9" 0.8
4.5" 3.0
187.0" 23.0
173.0" 21.0
42.0" 9.0
12.0" 3.2
9.0" 2.4
54.0" 15.0
0.31" 0.13
89.1" 23.1
9.4" 2.3

Abbre iations: BMI, body mass index; WHR, waist hip ratio; IBWt, ideal body weight; FBS, fasting blood sugar; PP 2h,
postpradinal 2-h blood sugar; LH, luteinizing hormone; FSH, follicular stimulating hormone; E 2 , estradiol; T, testosterone; SHBG,
sex hormone binding globulin; ISI, insulin sensitivity index. U P - 0.05 compared with control, NIDDM, PCO. Values are
mean " S.E.M.

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K.H. Park et al. r International Journal of Gynecology & Obstetrics 74 (2001) 261267

Meanwhile, those with PCOS had higher levels

of luteinizing hormone LH., and testosterone
and lower levels of sex hormone binding globulin
SHBG. than the controls. However, there was no
significant difference in terms of follicle stimulating hormone FSH., and estradiol between the
groups Table 1..
3.2. The 75-g oral glucose tolerance test (OGTT)
In the 75-g OGGT test, blood glucose levels
proved to be higher in the type 2 diabetic patient
group than in either the control or PCOS groups
Fig. 1., while serum insulin level was highest in
the PCOS group. Moreover, in type 2 diabetic
patient group, the 90 and 120 min measurements
were significantly higher than the controls Fig.
2..

2 diabetic group, and 88.7" 1.4 mgrdl in the

PCOS group. The blood insulin level was 83.0"
4.0 Urml in the control group, 82.6" 3.6 Urml
in the obese type 2 DM group, and 96.6" 4.3
Urml in the PCOS group; these values were all
lower than the expected insulin level of 100 Urml
w5,6x. The insulin sensitivity index ISI., expressed
in terms of glucose infusion rate, was assessed
during the hyperinsulinemic euglycemic clamp test
for all the subjects. ISI was 9.4" 2.3 in the control, 4.7" 1.2 in the type 2 diabetic patient group,
and 2.3" 0.3 mlrkg per min per U per ml = 10 4 .
in the PCOS group, thus revealing significant
differences Table 1, Fig. 3.. However, the blood
glucose of the PCOS group was comparable with
the control Table 1..

4. Discussion
3.3. Hyperinsulinemic euglycemic clamp test
The 2-h-long euglycemic clamp test maintained
the blood sugar level to 90 mgrdl with adequate
consistency. The coefficient of variation CV. of
blood glucose during the last 60 min was less than
3% in all cases. During the last 20 min of the test,
the blood sugar level was 90.5" 1.9 mgrdl in the
control group, 89.5" 2.3 mgrdl in the obese type

PCOS is one of the most common causes of

ovarian dysfunction in women, and it is related to
infertility, masculinization, irregular menstruation
and endometrial neoplasm w1x. The currently recommended diagnostic criteria for PCOS are hyperandrogenism and ovulatory dysfunction, with
the exclusion of specific disorders, such as nonclassic adrenal 21-hydroxylase deficiency, hyper-

Fig. 1. Plasma glucose levels of the three groups during the 75-g OGTT. U P - 0.05 compared with the control group, NIDDM, and
PCO group.

K.H. Park et al. r International Journal of Gynecology & Obstetrics 74 (2001) 261267

Fig. 2. Plasma insulin levels of the three groups during the

75-g OGTT U P- 0.05 compared with the control group,
NIDDM, and PCO group.

prolactinemia, or androgen secreting neoplasm

w7x. The polycystic ovary morphology is consistent
with, but not essential for, the diagnosis of this
syndrome w8x.
PCOS is also related to hyperinsulinemia and
insulin resistance, and women with PCOS show

265

an abnormally high response to the OGTT w2x.

This is due to impaired insulin function and there
is a high risk of it developing into type 2 DM
w9,10x.
Felber et al. w11x have reported that insulin
resistance, which is one of the main components
of impaired glucose tolerance, is related to aging,
obesity, and type 2 DM. Both insulin resistance
and hyperinsulinemia are more frequently found
in obese people.
In general, obesity is defined as increase in %
body fat. Thus, the increasing body fat mass also
induces insulin resistance and hyperinsulinemia
w12x, which play a role in the pathogenesis of
diabetes and the derangement of -cell insulin
production. Yost et al. w13x proposed that weight
gain following sustained weight reduction can be
due to relatively increased insulin sensitivity accompanying the weight reduction. Therefore,
many studies have concentrated upon the elucidation of the role of insulin resistance in terms of
its relationship with obesity w14x. Insulin sensitiv-

Fig. 3. Glucose infusion rate insulin sensitivity index. of the three groups during the hyperinsulinemic euglycemic glucose clamp
test. U P- 0.05 compared with the control group, NIDDM, and PCO group.

266

K.H. Park et al. r International Journal of Gynecology & Obstetrics 74 (2001) 261267

ity is only partly related to differences in adverse

body fat distribution high waist circumference or
WHR. rather than in overall adiposity w12x. In
order to investigate insulin resistance in PCOS,
but excluding the impact of % body fat, we evaluated the body fat matched controls, type 2 DM,
and PCOS groups using the euglycemic clamp
test, and have shown that there is a difference in
the insulin resistance between the three groups;
the highest insulin resistance being found in
PCOS. Women with PCOS had a decreased insulin sensitivity, compared with type 2 diabetes as
well as controls. Therefore, insulin resistance,
which is independent of adiposity, can be said to
be associated with subjects with PCOS. Previous
studies have reported that insulin resistance is
associated blood pressure especially systolic pressure. w15x, elevated triglycerides and lower HDL
cholesterol levels w16,17x. Although the PCOS
group showed the most prominent decreased insulin sensitivity in this study, no difference in
BMI or lipid profile was found between the
groups. Therefore, the difference in the insulin
resistance might not be due to obesity or dyslipidemia. Insulin resistance and hyperinsulinemia
are well known characteristics of PCOS, and although much remains to be discovered, the relevant mechanism is proposed to be different from
that seen in type 2 diabetic patients w2,18,19x.
Other mechanisms of insulin resistance have been
suggested. The level of androgens is much higher
in PCOS women than normal women, which suggests that androgens decrease insulin sensitivity
w20x. The decrease of SHBG, which is an index of
insulin sensitivity, in PCOS group, might have
influenced the study result w2123x. However, their
-cells seemed to fully compensate for severe
insulin resistance, since the blood glucose levels
of the PCOS group were comparable with the
controls. These results suggested the importance
of insulin resistance in PCOS in terms of its
clinical manifestations as well as its pathogenesis.
One possible implication of this study is that fit
seems like that insulin resistant subjects with
PCOS may derived increased benefit from pharmacological agents that improve insulin sensitivity
w24,25x. In fact, subjects with PCOS are prone to
syndrome X, because of their insulin resistance.

Thus, a useful strategy could be to improve the

clinical course of PCOS and prevent syndrome X
by correcting those factors which are involved in
the mechanism of insulin resistance.
This study had some possible shortcomings in
terms of the evaluation of -cell function, which
is an important aspect of pathogenesis, which we
evaluated by fasting or postpradinal insulin and
C-peptide level during the 75-g OGTT. However,
insulin concentration, especially fasting insulin
concentrations a commonly used surrogate for
insulin resistance . may not be an optimal measurement in type 2 diabetic subjects, because diabetic subjects have increased levels of proinsulin,
which has considerable cross-reactivity with insulin. Moreover, advanced diabetic patients with
decompensated -cell function, could have lower
insulin or C-peptide levels with increased hyperglycemia glucotoxicity. w26x. Another potential
limitation of the current study is that the assessment of leptin w27x, and cellular or molecular
mechanisms w19x including postreceptor insulin
resistance was not performed. Apart from the
insulin secretory function, we conclude that PCOS
women as well as type 2 diabetic patients have
significant and profound insulin resistance. Further investigations on the cellular and molecular
mechanisms of insulin resistance in PCOS are
needed.
Acknowledgments
We are grateful to Professor J.M. Nam, Ph.D.
for statistical advise, and Dr John Roberts at
Yonsei Medical College for helpful discussion
and critical reading of the manuscript in this
study.
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