1 Department of Clinical Endocrinology, Institute of Endocrinology, Národní 8, 116 94 Prague 1, 2 Department of Preventive Cardiology, Institute for Clinical and Experimental Medicine, Vídenská 1958/9, 140 21 Prague 4, 3 Department of Diabetes, Institute for Clinical and Experimental Medicine, Vídenská 1958/9, 140 21 Prague 4 and 4 Statistics Unit, Institute for Clinical and Experimental Medicine, Vídenská 1958/9, 140 21 Prague 4, Czech Republic
5 To whom correspondence should be addressed at: Národní 8, 116 94 Prague 1, Czech Republic. e-mail: jvrbikova{at}endo.cz
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Abstract |
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Key words: dyslipidaemia/hypertension/impaired glucose tolerance/type-2 diabetes mellitus
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Introduction |
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Recently, two studies conducted in North American PCOS patients reported an increased frequency of impaired glucose tolerance (IGT) and Type-2 diabetes mellitus (DM 2) (Ehrmann et al., 1999; Legro et al., 1999b
). Similar results were obtained in South Asia (Weerakiet et al., 2001
). Although coronary risk factors in hyperandrogenic states have recently been given more attention (Wild et al., 1985
; Conway et al., 1992
; Dahlgren et al., 1992a
; Talbott et al., 1995
; 1998; Atiomo et al., 1998
; Wild et al., 2000
; Diamanti-Kandarakis et al., 2001
; Paradisi et al., 2001
; Yarali et al., 2001
), to the best of our knowledge, there has been only one paper addressing carbohydrate metabolism disorders and other risk factors for coronary heart disease in European women with PCOS compared with a healthy random population sample (Elting et al., 2001
). The incidence of IGT and DM 2 has been clearly shown to be race-related, being highest in Hispanic and Afro-American populations. Similarly, there have been only few papers focusing on the prevalence of arterial hypertension in PCOS women, with inconclusive results (Zimmermann et al., 1992
; Holte et al., 1996
; Sampson et al., 1996
).
The aim of our study was to compare the prevalence of cardiovascular risk factors in young Czech PCOS women and in a control group selected from a random population sample in the Czech Republic.
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Materials and methods |
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Biochemical assays
After a 1214 h fast, 34 PCOS patients had the oral glucose tolerance test (oGTT) using 75 g of glucose, with blood collections for glucose determination using the glucose oxidase method (Beckmann, Fullerton, USA) at 0, 60 and 120 min; the evaluation was made using the revised World Health Organization (WHO) criteria (Alberti and Zimmet, 1998). A baseline venous blood sample was used to determine total cholesterol, HDL-cholesterol and triglycerides, all of which were assessed by photometry (Ecoline 25; Merck Vitalab Eclipse, Darmstadt, Germany). Hormonal analysis was undertaken between days 15 of the spontaneous menstrual cycle, with testosterone, androstenedione, dehydroepiandrosterone-sulphate (DHEAS) and SHBG determined as stated previously (Vrbikova et al., 2001
). The mean (±SD) hormonal levels in our PCOS women were: testosterone 2.67 ± 1.12 nmol/l; androstenedione 7.1 ± 3.0 nmol/l; and SHBG 33.1 ± 14.4 nmol/l.
Controls
A control group of 335 women aged 2534 [mean (±SD) age 29.9 ± 3.1] years was made up from a randomly selected (1%) population sample of permanent residents of nine districts of the Czech Republic in the 199798 period as part of a cross-sectional survey of cardiovascular risk factors (Cifkova et al., 2000). As there are no data on IGT in the Czech general population, we used results of oGTTs obtained during a worksite screening project for thyroid dysfunction and carbohydrate metabolism disorders undertaken, in the late 1980s, among
koda car factory employees in Mladá Boleslav. The group of females examined comprised 54 individuals of similar age and body mass index (BMI) as the population random sample (age 34 ± 3 years; BMI 24.3 ± 3.8 kg/m2).
Biochemical assays
Blood glucose was determined by an enzymatic method (Lachema, Brno, Czech Republic). Total cholesterol and triglycerides were determined enzymatically (reagents from Boehringer Mannheim, Germany, using a Cobas Mira S autoanalyzer, Hoffman-La Roche, Basel, Switzerland); HDL-cholesterol was determined using the same method after precipitation.
Clinical investigations
All women were asked about the history of diabetes in their first- and second-degree relatives. BMI, as a measure of relative weight, was calculated as weight divided by height squared (kg/m2). Two blood pressure (BP) readings were obtained in sitting patients after a 10 min rest; the mean was determined from two values and was used for further analysis. BP values 140/90 mmHg or a history of antihypertensive use was defined as hypertension.
The study was approved by the Local Ethics Committees of both institutions.
Computations and statistical methods
LDL-cholesterol was calculated using Friedewalds formula (LDL-cholesterol = total cholesterol minus HDL-cholesterol minus triglycerides/2.19).
Statistical analysis of discrete variables was performed using the 2-test. Continuous variables were analysed using Students two-sample t-test. A highly skewed variable (triglycerides) was analysed after logarithmic transformation. A two-tailed P < 0.05 was considered statistically significant. As cases and controls differed significantly in BMI, we adjusted BP values, lipid parameters and fasting blood glucose values for BMI and analysed them using analysis of co-variance (ANCOVA).
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Results |
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Discussion |
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Coronary risk factors in hyperandrogenic states have been given more attention over the last decade (Wild et al., 1985; Conway et al., 1992
; Dahlgren et al., 1992b
; Talbott et al., 1995
; 1998; Atiomo et al., 1998
; Wild et al., 2000
; Diamanti-Kandarakis et al., 2001
; Paradisi et al., 2001
; Yarali et al., 2001
). A more adverse lipid profile (higher total and LDL-cholesterol) was found in young American PCOS women compared with the healthy population (Talbott et al., 1995
). Our search of the relevant literature did not produce a single report of a study directly examining coronary risk factors (including glucose tolerance) in Caucasian PCOS patients compared with apparently healthy individuals selected from a random population sample. We took advantage of our control group selected from a 1% random sample of permanent residents of nine districts of the Czech Republic in the 199798 period as part of a study designed to survey cardiovascular risk factors (Cifkova et al., 2000
). These nine districts cover 11.2% of the total area of the Czech Republic and are inhabited by 9.9% of the countrys population. As the respondent rate never fell below 60%, the sample is considered to be truly representative and the results allow generalization.
As there are no data on IGT in the Czech general population, we used data obtained during a worksite screening project for thyroid dysfunction and carbohydrate metabolism disorders undertaken, in the late 1980s, among employees in the koda car factory in Mladá Boleslav. IGT was not found in this particular group of female employees comprising 54 individuals (mean age 34 ± 3 years; mean BMI 24.3 ± 3.8 kg/m2). However, we cannot exclude the error of small numbers and, obviously, this was not a random population sample. In addition to that, the
koda car factory female workers were mostly from rural areas and smaller communities whereas the controls included almost equal proportions of individuals from small communities and larger towns/cities. One of the nine districts of the Czech Republic involved in the screening for cardiovascular risk factors was the city of Pilsen (currently with a population of 160 000).
Our PCOS patients have an IGT prevalence of 10%. This is rather low compared with USA or Asian PCOS patients with a prevalence of
35% (Ehrmann et al., 1999
; Legro et al., 1999b
; Weerakiet et al., 2001
). The higher prevalence of IGT in the USA and South Asia is probably the result of interaction of various ethnic backgrounds and environmental factors (especially obesity, as the average BMI was about 3036 kg/m2 in these studies compared with 29.2 kg/m2 in Czech PCOS subjects).
DM 2 may develop as a clinically silent condition. It is not unusual to meet patients at the time of diagnosis of DM with advanced micro- and macrovascular complications, which not only impair the quality of life but also have a negative predictive value in these patients. These complications may already be present at the stage of IGT. There seems to be no threshold level of blood glucose; the association between the risk for cardiovascular disease and blood glucose seems to be present even across blood glucose values regarded as the normal range (Coutinho et al., 1999). The increasing prevalence of DM 2 in the population has recently led to attention focusing on its early diagnosis. To simplify screening for impaired glucose metabolism, the American Diabetic Association (ADA) (The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus, 1997) proposed to determine fasting blood glucose instead of performing the oGTT. The ADA defined fasting blood glucose levels of 6.116.99 mmol/l as IFG. However, various authors have repeatedly criticized the introduction of the concept of IFG to replace performing the oGTT. Some reports pointed to the low concordance of these two diagnostic criteria (Burke et al., 1998
). This is presumably due to the fact that, as IGT/DM develop, post-prandial blood glucose levels tend to rise (apparently as a result of inadequate insulin secretion following stimulation) earlier than fasting blood glucose (Gerich, 1998
). In our series, no woman diagnosed as having IGT using the WHO criteria, was shown to have IFG according to the ADA classification. Fasting blood glucose within the IFG range was demonstrated in two patients (4%), but with normal results of their oGTTs.
In agreement with others (Wild et al., 1985; Conway et al., 1992
; Pirwany et al., 2001
) we found, in our PCOS patients, an adverse lipid profile characterized by low HDL-cholesterol, an increase in LDL-cholesterol and a decrease in the HDL/total cholesterol ratio. In some studies (Talbott et al., 1998
), increased total cholesterol and triglycerides are also seen in PCOS women. These discrepancies could probably be due to the differences in hormonal status and in sample definition. LDL-cholesterol sub-fractions were not determined in the present study. The atherogenic LDL-cholesterol sub-fraction is believed to be small, dense LDL particles (LDL III). It has been demonstrated (Pirwany et al., 2001
) that PCOS patients have higher levels of LDL III than healthy controls with comparable LDL-cholesterol levels; at the same time, the levels of plasma testosterone (unlike waist-to-hip ratio and insulinaemia) did not correlate with LDL III. This suggests a closer association of lipid metabolism disorders in PCOS patients with central obesity than with the levels of plasma androgens. Different results were reported by authors from the USA (Legro et al., 1999a
) based on a Hispanic population, not demonstrating differences in the proportion of small, dense LDL particles between cases (PCOS) and controls (both of Hispanic origin).
In our study, hypertension was found more frequently in PCOS patients than in the control population. Similarly, we observed higher systolic and diastolic BP values in PCOS patients compared with controls. A population-based study conducted in the Netherlands (Elting et al., 2001), but using a telephone questionnaire, demonstrated hypertension in 9.6% of 346 respondents aged 1756 years. Otherwise, data on the prevalence of hypertension in PCOS patients are inconsistent; 24 h BP monitoring showed both values comparable with those of the healthy population (Zimmermann et al., 1992
), and higher systolic and diastolic BP levels (Holte et al., 1996
).
PCOS women had a significantly higher BMI than the control group from the random population sample. Since blood pressure values, lipid levels and blood glucose are significantly associated with BMI, we reanalysed all our data after we had adjusted all these variables for BMI. Nevertheless, the results remained the same, suggesting that these abnormalities are closely related to PCOS status.
In conclusion, Czech PCOS patients present, already in their twenties to thirties, a cluster of atherosclerosis risk factors (obesity, adverse lipid profile, arterial hypertension and IGT). IGT/DM 2 seem to be less common than in other PCOS populations. The criteria developed by the ADA defining IFG are of little help in diagnosing carbohydrate metabolism disturbances in this patient population. Based on our results and literary data, we propose that all women, when diagnosed with PCOS, should have at least their total and HDL-cholesterol values determined; obese women should have the oGTT and, in addition, all these patients should have regular metabolic follow-up as a group at potential risk for early development of CHD.
Further investigations, preferably prospective studies, are needed to elucidate the exact effect of BMI and the incidence of cardiovascular events in PCOS in the next decades.
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Acknowledgments |
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References |
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Submitted on May 7, 2002; resubmitted on December 5, 2002; accepted on January 27, 2003.