J. Endocrinol. Invest. 14: 569-575, 1991

The role of hyperinsulinemia in the development of lipid disturbances in nonobese and obese women with the polycystic ovary syndrome J. Siowinska-Srzednicka*, s. Zgliczynski*, M. Wierzbicki*, M. Srzednicki**, U. Stopinska-Gluszak*, w. Zgliczynski*, P. Soszynski*, E. Chotkowska**, M. Bednarska**, and Z. Sadowski** *Department of Endocrinology, Medical Center for Postgraduate Education, and **Institute of Cardiology, Warsaw, Poland ABSTRACT. In order to establish the role of insulin in the pathogenesis of lipid abnormalities in hyperandrogenic women with the polycystic ovary syndrome (PCO) 49 women aged 18 to 35 yr with a normal glucose tolerance test were studied. They were divided into two groups: 27 women with PCO (9 obese and 18 nonobese), and 22 healthy women (12 with simple obesity and 10 with normal body weight). In the PCO group, the fasting insulin levels and the insulin response to oral glucose load were higher than in the matched controls. Significantly lower levels of HDL2cholesterol and higher levels of apolipoprotein B were observed in obese and non nonobese PCO patients.

In obese women with PCO this was associated with lower levels of HDL-cholesterol and apolipoprotein A-I (Apo A-I), whereas the levels of total triglycerides and VLDL-triglycerides (VLDL-TG) were increased. Multiple regression analysis in PCO women, after adjustment for age, body mass index and the levels of insulin and sex hormones, showed a strong positive correlation between the fasting insulin levels and total triglycerides and VLDL-TG, while a negative correlation was found between fasting insulin levels and apo A-I. These results indicate that hyperinsulinemia may playa role in the development of lipid disturbances in women with the PCO.

INTRODUCTION

amenorrhea, anovulation, hirsutism and bilateral cystic ovaries (4). The main feature of this syndrome is excessive production of androgens (4-6). It has been shown that in PCO women the plasma levels of TG and VLDL are higher (7-10), but the HDL-C levels are lower than in healthy women (7, 8). It is supposed that a male pattern of lipoprotein profile in PCO women is probably caused by hyperandrogen ism (7, 8). A very common finding in PCO women is insulin resistance and hyperinsulinemia (6, 9, 11, 12). Prospective epidemiological studies suggest that hyperinsulinemia may be a risk factor for CAD (1315). Abnormalities of lipoprotein metabolism, hypertriglyceridemia, increased VLDL secretion rate may be secondary to insulin resistance and hyperinsulinemia (16, 17). The aim of this study was to determine the role of hyperinsulinemia in the pathogenesis of lipoprotein disturbances in hyperandrogenic women with PCO.

In women, as well as in men, smoking, hypertension, high levels of cholesterol (c) and triglycerides, (TG) and low levels of high density lipoprotein (HDL) cholesterol have been associated with a high risk for acute myocardial infarction (1, 2). The higher incidence of coronary artery disease (CAD) in men than in women is due to differences in plasma lipoprotein risk factors (3). Women aged 20 to 50 years have lower plasma levels of low density lipoprotein (LDL) and very low density lipoprotein (VLDL), and higher HDL levels than men of similar age. The sex-related difference in HDL and LDL concentrations is probably due to differences in gonadal steroids (3). The polycystic ovary syndrome (PCO) is characterized by oligomenorrhea or

Key-words: Polycystic Ovary Syndrome, insulin, lipoproteins, sex hormones.

MATERIAL AND METHODS Subjects Twenty-seven women aged 18 to 38 yr (mean age

Correspondence: Dr. J. Siowiriska-Srzednicka, Department of Endocrinology, Bielanski Hospital, Ceglowska 80, 01-809 Warsaw, Poland.

Received September 3, 1990; accepted April 11, 1991.

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27.2 ± 6.1) with clinical and biochemical features of PCO were studied. All patients had oligomenorrhea, hirsutism, elevated plasma testosterone levels, LH: FSH ratio of 2 or more, and enlarged polycystic ovaries on ultrasonography. The body mass index (BMI) in 18 patients was below 25 (mean value 21.6 ± 2.2 kg/m 2), and these patients were classified as nonobese. In the remaining 9 subjects the BMI was over 25 (mean 33.8 ± 4.9 kg/m 2), and they were considered to be obese. Patients with Cushing's syndrome, androgen-secreting tumor, prolactinoma and with late-onset 21-hydroxylase deficiency were excluded from the study. The control group comprised 22 normally ovulating women aged 18 - 38 yr (mean 27.3 ± 6.3) - 10 with normal BMI (23.2 ± 2.4 kg/m2), and 12 obese ones (BMI 36.8 ± 3.8 kg/m2). The patients and controls drank alcohol only sporadically; six out of 27 PCO patients and 8 out of 22 controls smoked more than 10 cigarettes daily for over two years. In none of the studied women virilization, acanthosis nigricans, heart diseases or hypertension were found. In all subjects the glucose tolerance test was normal, according to the criteria of the National Diabetes Data Group.

concentrations were measured by RIA using Wien Laboratories Inc kits (New Jersey, USA), DHEA-S levels, with RSL kits (California, USA). Plasma concentrations of SHBG were determined by the immunoradiometric method (IRMA) using FarmosDiagnostics kits (Finland). Plasma prolactin, LH, FSH and insulin levels were measured by RIA. The within-assay and the between-assay coefficients of variation were 4-6% and 7-19% respectively, for all the methods used. The methods of the determination of plasma sex hormones were described previously (21). Statistical Analysis The results of hormonal and lipid determinations in the PCO group and in controls were compared by means of a one-way analysis of variance, followed by Fischer's least significant difference test. The integrated 3-hour glucose and insulin response after glucose load was calculated as the area under the curve by the trapezoid rule. The results of glucose and insulin levels and the integrated responses were subjected to statistical evaluation using oneway analysis of variance. The correlation analysis included univariate (simple) and multivariate regression methods. The univariate linear regression analysis was made using the least squares method. The multivariate regression analysis with stepwise variable selection was used. Both, the univariate and multivariate analyses, were made in all the cases of PCO. All biochemical data are presented as means ± SE, unless stated otherwise.

Assays Blood samples for determination of lipids, lipoproteins and hormones were obtained from all women after a 14-hour fast. In all subjects the levels of glucose and insulin were measured before and after 60, 120, 150 and 180 minutes after the standard glucose load (75 g). The plasma VLDL were isolated by ultracentrifugation using a Beckaman L8-55 ultracentrifuge at a density of 1.006 g/ml for 18 h, 40,000 x g, at 10 C. The piasma HDL-C was measured after precipitating VLDL and LDL with heparin and manganese chloride, followed by further fractionation of the supernatant into HDL2, and HDL3 by precipitation with 0.11 % dextran sulfate (18). The difference between total cholesterol and that of VLDL and HDL was accepted as the value of LDL-C. Total cholesterol was measured by a direct colorimetric method based on the Liebermann-Burchard reaction modified by Grafnetter et al. (19). Triglycerides were determined by the enzymatic method (20) using Boehringer-Mannheim kits. The plasma apolipoprotein A-I (apo A-I) and apolipoprotein B (apo B) were measured by radial immunodiffusion with Lipo-Partigen for apo A-I and MPartigen for apo B (Hoechst-Behring). Plasma testosterone and estradiol were determined by radioimmunoassay (RIA) after previous extraction with diethyl ether. Plasma androstenedione

RESULTS Hormonal and lipid results

In the PCO group, the plasma concentrations of testosterone, androstenedione and LH:FSH ratio were higher, and the levels of SHBC were lower than in controls. These changes were associated with lower levels of HDLTC and higher levels of apo B. In obese PCO patients, the concentrations of TG, VLDL-C, VLDL-TG were higher, and those of HDLC and apo A-I were lower than in controls (Table 1). The fasting insulin levels and insulin secretion after oral glucose load, expressed as integrated insulin area, in nonobese and obese PCO patients were higher than in controls with normal body weight. Similarly, the fasting insulin levels and the integrated insulin area were higher in obese patients with PCO than in obese controls. The insulin levels, both fasting and after glucose load, were found to be higher in obese patients with PCO than in non obese patients. No statistically significant dif-

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Table 1 - Plasma concentrations of sex hormones, prolactin, gonadotropins, lipids and lipoproteins in women with PCO and in healthy women!. Nonobese PCO women [n=18] 0.275

Estradiol (nmol/l)

±

Obese PCO women [n=9]

0.03

0.264

±

Nonobese healthy women [n=10]

0.04

0.345

±

0.03

Testosterone (nmol/l)

4.51 ± 0.34 2

5.90 ± 1.042

Androstenedione (nmol/I)

7.79 ± 0.87 2

9.16 ± 1.012

4.16 ± 0.66

Dehydroepiandosterone sulfate (flmol/l)

5.79 ± 0.60

5.86 ± 0.85

5.80 ± 0.67

SHBG (nmol/I)

36.7 ± 4.8 2

16.9 ± 2.6 2

64.4 ± 6.5

Prolactin (flg/l)

13.5 ± 1.3

15.5 ± 2.6

10.1 ± 1.6

LH (U/I)

14.0 ± 1.42

19.2 ± 4.22

6.5 ± 2.0

3.9 ± 0.5

4.1 ± 0.6

3.5 ± 0.3

Total Cholesterol (mmol/l)

5.31 ± 0.12

4.77 ± 0.27

4.48 ± 0.26

Total Triglycerides (mmol/l)

1.36 ± 0.11

1.65 ± 0.24 3

1.06 ± 0.08

VLDL-C (mmol/I)

0.41 ± 0.05

0.69 ± 0.20 3

0.33 ± 0.04

VLDL-TG (mmol/l)

0.58 ± 0.09

0.93 ± 0.15 2

0.50 ± 0.06

LDL-C (mmol/I)

3.58 ± 0.09

3.43 ± 0.26

3.25 ± 0.14

HDL-C (mmol/l)

1.32 ± 0.07

1.02 ± 0.06 2

1.42 ± 0.06

HDL 2-C (mmol/I)

0.36 ± 0.04 2

0.21 ± 0.04 2

0.57 ± 0.05

HDL3-C (mmol/I)

0.89 ± 0.06

0.76 ± 0.05

0.86 ± 0.05

Apo B (gil)

1.18 ± 0.05 2

1.26 ± 0.08 2

0.94 ± 0.06

Apo A-I (gil)

1.50 ± 0.09

1.07 ± 0.08 2

1.55 ± 0.08

FSH (U/I)

2.15 ± 0.34

'Conversion factors: Estradiol pg/ml = 272 x nmolA; Testosterone ng/ml = 0.288 x nmol/I; Androstenedione ng/dl = 28.6 x nmolA; DHEA-S ng/ml = 368 x Ilmol/I; Cholesterol mg/dl = 38.7 x nmol/I, TG mg/dl = 87.7 x mmol/I. 2PCO women vs healthy women, p < 0.01 3PCO women vs healthy women p < 0.05

Results of univariate analysis In women with PCO, the simple regression model revealed a positive correlation between the fasting

ferences were noted between the groups studied as regards the fasting glucose levels and integrated glucose after oral glucose load (Table 2).

Table 2 - The fasting glucose and insulin concentrations, the integrated glucose and insulin areas after glucose load in women with pca and in healthy women.

A

0

Nonobese PCO women [n=18]

B Obese PCO women [n=9]

C Obese healthy [n=12]

Nonobese healthy [n=10]

Fasting glucose (mmol/I)

3.70 ± 0.14

4.20 ± 0.18

3.70 ± 0.27

3.56 ± 0.25

Integrated glucose area (mmol/I 'min)

230.6 ± 44.4

307.3 ± 77.1

178.2 ± 25.8

234.7 ± 29.2

Fasting insulin (mUll)

18.1'

± 1.3

30.3 2 ± 4.0

21.43 ±1.4

12.0 ± 1.3

7694 ' ± 1044

150342 ± 2174

7893 ' ± 683

3926 ± 410

Group

Integrated insulin area (mU/I*min)

'p < 0.05 vs group D and p < 0.D1 vs group B; 2p < 0.01 vs group A, C and D. 3p

< 0.D1 vs group Band D.

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insulin response after glucose was positively correlated with BMI and negatively with SHBG (Table 3). The correlation coefficients and the statistical significance of the relationship between BMI, lipids and gonadal hormones are presented in Table 3. A positive correlation was disclosed between testosterone and VLDL-C (r== 0.56, p < 0.001) and VLDL-TG (r== 0.41, P < 0.05), with a negative correlation between DHEA-S and TG (r== -0.48, p < 0.01), and between androstenedione and TG (r== -0.475, p < 0.05). Moreover, a positive correlation between SHBG and HDLTC (r==0.47, p < 0.01) and apo A-I (r== 0.42, p < 0.05) was found.

Table 3 - Coefficients of simple linear correlation between the fasting insulin concentrations, the integrated insulin areas after glucose load, body mass index (BMI) and lipids, lipoproteins and sex hormones in PCO women [n=27].

BMI Total cholesterol

Fasting insulin

Integrated insulin area

0.735 2

0.428 1

- 0.302

BMI

0.328

- 0.564 2

TG

0.479 1

0.195

0.566 2

VLDL-C

0.495 1

0.196

0.457 1

VLDL-TG

0.507 1

0.262

0.450 1

LDL-C

0.360

0.257

0.460 1

HDL-C

- 0.420 1

- 0.287

- 0.551 2

HDL2-C

- 0.364

- 0.287

- 0.556 2

HDL3-C

- 0.100

- 0.013

- 0.193

Apo A-I

- 0.5822

- 0.243

- 0.558 2

Apo B

0.098

0.111

0.263

Testosterone

0.6622

0.164

0.465 1

0.033

0.107

Androstenedione

- 0.175

DHEA-S

-0.131

0.040

- 0.125

Estradiol

0.125

0.080

0.014

- 0.589 2

- 0.451 1

- 0.476 1

SHBG

Results of multivariate analysis To obtain an insight into the relationships between lipoproteins, sex hormones and insulin in PCO women a number of stepwise multiple regression analyses were carried out, which made it possible to evaluate jointly the effects of age, BMI, fasting insulin levels, integrated insulin area after glucose load, and the levels of estradiol, testosterone, androstenedione and DHEA-S. This was performed in order to find out which of the above variables affect lipoproteins independently. The stepwise multiple regression analysis showed a persistent, strong positive correlation between TG and fasting insulin levels and a negative correlation between TG and DHEA-S (Table 4). The positive correlation between VLDL-TG and fasting insulin, and the negative correlation between fasting insulin and apo A-I persisted further, and the negative correlation between HDL-C and HDL2-C, on the one hand, and the BMI, on the other, as well as the positive correlation between VLDL-C and testosterone were confirmed (Table 4). In addition, the positive correlation between fasting insulin and

1p< 0.01 2p < 0.001

insulin levels and the BMI, TG, VLDL-C, VLDL-TG and testosterone concentrations, and a negative correlation between the fasting insulin levels and HDL-C, apo A-I and SHBG. The integrated 3-hour

Table 4 - Stepwise multiple regression analysis: role of age, body mass index (8MI), fasting insulin levels, integrated insulin area after glucose load and the levels of estradiol, testosterone, androstenedione, OHEA-S and SHBG in predicting lipoprotein levels in women with PCO [n=27j1. Dependent variable Total TG

Predictor variable

Regression coefficients

F statistics

Insulin

1.816

8.494

- 0018

6.690

DHEA-S

r2

Significance level

0.462

0.002

1.725

7.926

0.277

0 .01

VLDL-C

Testosterone

12.287

8.228

0.286

001

HDL-C

BMI

- 0.809

4.773

0.170

0.05

HDLrC

BMI

- 0.562

6.320

0.228

0.02

Apo A-I

Insulin

- 0.204

8.562

0.320

0.01

VLDL-TG

Insulin

10nly those variables which were selected as significant are shown (F to enter = 4.0).

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Lipid disturbances in

BMI (r 2= 0.583, p < 0.001) and testosterone (r 2= 0.376, p < 0.001), and the negative correlation between fasting insulin and SHBG (r2= 0.278, p < 0.001) were found to persist.

peo

insulin and apo A-I. The HDL-C and HDL2-C fractions correlated negatively with BMI. Hyperinsulinism, associated with obesity development observed in 50% of PCO women (25), intensifies lipid disturbances. We have shown that in nonobese women with PCO only the HDL2-C subfraction levels were decreased, and the apo B levels were increased, which was associated with higher than normal fasting insulin concentrations and excessive insulin secretion after oral glucose load. Following obesity development, hyperinsulinism increases and TG metabolism is further disturbed, which leads to a rise in the concentrations of total TG and VLDL-TG, and a fall of HDL-C. The PCO syndrome should be regarded as a disease particularly predisposing to atherosclerosis development. The syndrome occurs in 87% of women with anovulation and/or with hirsutism (4). Ultrasonography enabled the diagnosis of polycystic ovaries to be made in 22% of women in the general population (26). It is possible that patients with PCO constitute a part of the group of women who are at increased risk for CAD, in whom raised triglyceride and/or VLDL levels and decreased HDL levels are found, with normal total cholesterol and LDL-C levels (27). In our group of patients, as in the reports of other authors (5, 6, 11, 28), the multivariate analysis of regression revealed a positive correlation between fasting insulin and testosterone levels, and a negative one between insulin and SHBG. Initially, it was considered that insulin resistance in PCO is a consequence of hyperandrogenism (6, 11). Now it is generally assumed that hyperandrogenism is a consequence of hyperinsulinism (29, 25). Insulin, or the insulin like growth factors, can affect directly the synthesis of steroids in the ovaries, and inhibit SHBG generation in the liver. The reduction of androgen concentration, obtained by subtotal resection of ovaries or pharmacological treatment, is ineffective in diminishing insulin resistance, but the reduction of insulin secretion with diazoxide in women with PCO decreses testosterone levels (29). In summary, in women with the PCO syndrome raised levels of plasma fasting insulin and increased insulin secretion after oral glucose load were found, together with elevated levels of TG, VLDL-TG and apo B, and with lower levels of HDLC, HDL2 C and apo A-I. The demonstration by multivariate regression analysis of a strong positive correlation between fasting insulin and TG and VLDLTG, as well as a negative one between fasting insulin and apo A-I points to an important contribution of hyperinsulinism in the development of lipid disturbances in PCO syndrome.

DISCUSSION In non obese women with PCO syndrome, the levels of the HDL2-C were decreased, and the apolipoprotein B levels were increased. In obese women with PCO, these changes were associated with increased concentration of total TG, VLDL-TG and VLDL-C, decreased concentration of HDL-C and apo A-I. No significant differences were noted in the concentrations of total cholesterol and LDL-C between PCO women and controls. In PCO the fasting insulin levels and insulin secretion after the oral glucose load were significantly higher than in the matched controls. The blood concentrations of HDL-C and HDLrC subfraction are closely connected with the catabolism of VLDL, and depend on the activity of hepatic lipase and lipoprotein lipase. In women with PCO, normal (9) as well as decreased (7) lipoprotein lipase activity was demonstrated in adipose tissue. A negative correlation was found between the activity of lipoprotein lipase and the concentrations of total testosterone (7) and free testosterone (9). Moreover, a negative correlation between testosterone and HDL-C or apo A-I was noted in the same patients (7). These facts support the view that lipid profile changes in women with PCO are a consequence of excessive androgen secretion (7, 8). Rebuffe-Scrive et al. (9) showed that the treatment of women with PCO with ethinyl estradiol and desogestrol led to normalization of free testosterone and SHBG levels, but did not improve the lipid profile and did not change the insulin secretion. This result may suggest that in the PCO syndrome the metabolic abnormalities are not caused solely by excessive androgen secretion. Probably, the key disorder in the PCO syndrome causing lipid disturbances is insulin resistance and hyperinsulinism, predisposing to the development of cardiovascular disease and hypertension (13-16, 22-24). In the PCO women studied a negative correlation was found between fasting insulin and HDL-C, apo A-I and SHBG, as well as a positive one between fasting insulin and TG, VLDL-C and VLDL-TG. The total insulin response after glucose load was negatively correlated with SHBG and positively with BMI. The multivariate regression analysis revealed a strong positive correlation between fasting insulin and TG or VLDL -TG, and a negative one between

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ACKNOWLEDGMENT This work was supported by the Research Grant CPBR 11.6.35 from UNPTiW, Warsaw, Poland

13.

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The role of hyperinsulinemia in the development of lipid disturbances in nonobese and obese women with the polycystic ovary syndrome.

In order to establish the role of insulin in the pathogenesis of lipid abnormalities in hyperandrogenic women with the polycystic ovary syndrome (PCO)...
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