1 Department of Endocrinology and Metabolism, Kr
kkale University Faculty of Medicine, K
r
kkale, 2 Department of Biochemistry and 3 Department of Endocrinology and Metabolism, Gazi University Faculty of Medicine, Ankara, Turkey
4 To whom correspondence should be addressed at: Murat Ylmaz MD Ç
nar Sokak 77/4, Yenimahalle-Ankara-Turkey. Email: murartt{at}hotmail.com
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Abstract |
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Key words: adiponectin/family/homocysteine/insulin resistance/PCOS
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Introduction |
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Familial aggregation of PCOS consistent with a genetic aetiology has been well documented in the literature (Hague et al., 1988; Lunde et al., 1989
; Legro et al., 1998
; Govind et al., 1999
). Family studies of PCOS have focused mainly on ovarian morphology, menstrual disturbances, symptoms of hyperandrogenism, hyperandrogenaemia, glucose intolerance disorders and insulin resistance (IR) (Ferriman and Purdie, 1979
; Carey et al., 1993
; Norman et al., 1996
; Colilla et al., 2001
; Kahsar-Miller et al., 2001
; Sir-Petermann et al., 2002
; Legro et al., 2002
; Y
ld
z et al., 2003
; Ehrman et al., 2005
). These studies have found higher insulin resistance, serum androgen levels, and Type II DM as well as glucose tolerance disorder in the first degree relatives of PCOS patients compared to the control groups.
Relatively few studies have investigated cardiovascular risk in the first degree relatives of PCOS patients. It was shown in one of these studies (Kaushal et al., 2004) that brothers of PCOS patients had insulin resistance and endothelial dysfunction in the early stages of their life. Similarly, another study found a positive relationship between PCOS and CVD cases in the family (Atiomo et al., 2003
). Elevated plasma Hcy levels are also considered to be an independent risk factor for CVD (Clarke et al., 1991
). Adiponectin has been postulated to play an important role in the modulation of glucose and lipid metabolism in insulin-sensitive tissues. Levels of adiponectin are also lower in patients with essential hypertension, DM, obesity and CVD (Ouchi et al., 2003
; Hotta et al., 2000
; Matsuzawa et al., 2004
).
The aim of the present study was to evaluate insulin resistance, glucose tolerance status and cardiovascular risk factors in first degree relatives of PCOS patients.
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Material and methods |
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The body mass index (BMI) and waist:hip (W:H) ratio were calculated. Weight and height of the subject were measured wearing light clothing and no shoes. BMI was calculated as weight divided by height squared (kg/m2). Waist circumference was measured at the narrowest level between the costal margin and the iliac crest, and the hip circumference was measured at the widest level over the buttocks with the subject standing and breathing normally.
A standard 75 g oral glucose tolerance test (OGTT) and insulin response to oral glucose loading were performed between 08:3010:30, following a fasting period of 1012 h. Glucose tolerance state was then evaluated using the criteria of the American Diabetes Association (2003). Those patients with glucose tolerance disorder were not included in the measurements of insulin resistance. The response of glucose and insulin to the OGTT was analysed by calculating the (AUCI and AUCG) using the trapezoidal method. Insulin sensivity index (ISI) was calculated the by the method of Matsuda and De Fronzo (1999)
. The homeostasis model (HOMA) insulin resistance index (HOMA-IR) was calculated according to the following formula: fasting glucose (mmol/l)xfasting insulin (QU/ml)/22.5 (Matthews et al., 1985
). Log versions of HOMA were calculated. The quantitative insulin sensitivity check index (QUICKI) was calculated according to the following formula: 1/[log fasting serum insulin (QU/ml)+log fasting plasma glucose (mg/dl)] (Katz et al., 2000
).
Serum levels of total cholesterol (Total-C), high density lipoprotein (HDL)-C, low density lipoprotein (LDL)-C and triglyceride (Tg) were measured using Abbott-Aeroset (Chicago, IL, USA) autoanalyser with original kits. Lipoprotein (a) [Lp (a)], Apoprotein A (Apo A) and Apoprotein B (Apo B) levels were determined by nephelometric assay using Beckman 360 protein array system. Serum levels of FSH, LH, prolactin, dehydroepiandrosterone sulphate (DHEA-S), insulin, cortisol and thyroid-stimulating hormone (TSH) were measured with specific chemiluminescence assays using the Abbott Architect system. Serum levels of 17-OH-progesterone, free testosterone, androstenedione were measured by radioimmunoassay analyser (Tosoh Bioscience, Tokyo, Japan). Serum vitamin B12 level was measured using Immulyte 2000 (BioDPC, CA, USA) analyser with chemiluminescence method. Folate level was determined by Tosoh analyser (Tokyo, Japan). Serum adiponectin levels were determined by enzyme-linked immunosorbent assay (Kit: B-Bridge International, Inc., CA, USA). Resistin levels were determined using human Resistin assay kit (ImmunoDiagnostik, BenSheim, Germany) which was based on a competitive enzyme immunoassay. Plasma Hcy levels were measured with high performance liquid chromatography using Chromsystems kits with fluorescence detector.
Statistical analysis
Data analysis was performed using the 10.0 PC package (SPSS, Inc., Chicago, IL, USA). All parameters are shown as the mean±SD. The unpaired t-test and MannWhitney U-test were used when appropriate. Bivariate correlation analysis was performed. P<0.05 was considered statistically significant.
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Results |
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The first degree relatives of PCOS patients had significantly higher serum fasting insulin (P<0.001), HOMA-IR (P<0.001), log HOMA (P<0.001) and AUCI (P<0.001) levels in all subgroups than the control subjects. The control group subjects had significantly elevated ISI (P<0.001) and QUCKI (P<0.001) levels compared to the first degree relatives of PCOS patients in all subgroups.
Adiponectinresistin
While the serum resistin levels increased significantly in both FathersPCOS (P<0.05) and MothersPCOS (P<0.05), the resistin levels were similar in BrothersPCOS and SistersPCOS (P>0.05) when compared to their control subjects. When subjects with GI were excluded, serum resistin levels were similar in both FathersPCOS and MothersPCOS compared to their control groups (P>0.05). However, the control group subjects had significantly elevated adiponectin levels compared to the first degree relatives of PCOS patients in all subgroups (P<0.001). Serum adiponectin levels showed a significantly negative correlation with BMI, W:H ratio, HOMA-IR, log HOMA, serum insulin and AUCI levels, and a positive correlation with ISI and QUCKI levels (P<0.005). However, no correlation between resistin and BMI, W:H ratio HOMA-R, AUCI, ISI, QUCKI, log HOMA and serum insulin measurements was found (P>0.05).
Homocysteine (Hcy), lipids and blood pressure
While the plasma Hcy levels increased significantly in both FathersPCOS (P<0.001) and MothersPCOS (P<0.001), the Hcy values in BrothersPCOS and SistersPCOS (P>0.05) non-significantly increased when compared to their control subjects. No correlation was found between plasma Hcy and BMI, W:H ratio HOMA-R, AUCI, ISI, QUCKI, log HOMA and serum insulin measurements (P>0.05). Serum vitamin B12 and folic acid levels were similar in all groups (P>0.05).
Serum Total-C, LDL-C, Tg, Apo B and Lp (a) levels were significantly increased in FathersPCOS subjects compared to the control group (P<0.005). However, their HDL-C and Apo A levels were lower than the control group (P<0.05). In MothersPCOS, Total-C, LDL-C, Tg, Apo B and Lp (a) (P<0.005) levels were higher when compared to the control group. However, their HDL-C and Apo A levels were similar when compared the control subjects. (P>0.05). In SistersPCOS Total-C, Tg, LDL-C, HDL-C, Apo A and Apo B were similar when compared to control subjects (P>0.05). However, Lp (a) level was higher than control subjects (P<0.005). In BrothersPCOS Total-C, Tg, LDL-C, Apo B and Lp (a) levels were higher than the control subjects (P<0.005). However, their HDL-C and Apo A levels were similar when compared to the control subjects (P>0.05).
Compared to the control groups, the systolic and diastolic blood pressure measurements were higher in PCOSFathers and PCOSMothers groups (P<0.05); however, in BrothersPCOS and SistersPCOS groups this measurements were similar in their control groups (P>0.05).
Ten patients (26.3%) with hyperlipidaemia and eight patients (20%) with hypertension were present in PCOSFathers group. Nine (22.5%) patients with hyperlipidaemia and nine (22.5%) patients with hypertension were present in the PCOSMothers group. Two (10%) patients with hyperlipidaemia and two (10%) patients with hypertension were present in both ControlMothers and ControlFathers subgroups. These differences were statistically significant (P<0.05).
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Discussion |
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Similarly, the family history of heart disease is consistent with those studies which demonstrated several risk factors for heart disease in PCOS women, such as obesity, insulin resistance, hyperlipidaemia, and raised plasminogen activator inhibitor-1 (Legro et al., 2003). Whether these risk factors are genetic, programmed in utero or environmental is unclear. Few studies have investigated the risk of CVD in the first degree relatives of PCOS patients. One of these studies (Atiomo et al., 2003
) investigated CVD retrospectively and a high frequency was found. Another study (Kaushal et al., 2004
) focused on brothers only and suggested that endothelial dysfunction, elevated IR and dyslipidaemia pose a risk of CVD in the early stages. Adiponectin is highly and specifically expressed in differentiated adipocytes and circulates at high levels in the bloodstream. Adiponectin has been postulated to play an important role in the modulation of glucose and lipid metabolism in insulin-sensitive tissues.
Levels of adiponectin are also lower in patients with essential hypertension, DM, obesity and CVD (Ouchi et al., 2003; Hotta et al., 2000
; Matsuzawa et al., 2004
). Some studies have found low levels of serum adiponectin in PCOS patients (Ducluzeau et al., 2003
; Panidis et al., 2003
; Spranger et al., 2004
) whereas the other studies did not support this finding (Orio et al., 2003
b
, Orio et al., 2004
). The present study has found low adiponectin levels in the first degree relatives of PCOS patients when compared to the age-, sex- and BMI-matched control groups. As low adiponectin levels constitute a risk factor for (CVD), these subjects are at high risk.
Homocysteine is an intermediate formed during the breakdown of the amino acid methionine; it may undergo remethylation to methionine, or trans-sulphuration to cystathione and cysteine. Previous studies suggest that Hcy as an independent risk factor for CVD (Clarke et al., 1991). Additionally, treatment to decrease the Hcy level was also found to reduce the risk for CVD. In PCOS patients, increased Hcy levels may partly explain recent findings of early atherosclerosis and an increased risk of CVD as compared with healthy control subjects (Loverro et al., 2002
; Schachter et al., 2003
; Wijeyaratne et al., 2004
). However, Orio et al. (2003a
) and Boulman et al. (2004)
found no significant difference of Hey levels between the PCOS and control groups. While the present study found high levels of Hcy in the mother and father groups, no difference was detected in the sister and brother groups. Increased serum Hcy level is an independent risk factor for CVD, which may put these subjects at a higher risk of developing CVD.
Resistin is a novel protein, discovered in pre-adipocytes that undergo differentiation into mature adipocytes. Resistin has been reported to induce insulin resistance and IGT (Kim et al., 2001; Kershaw and Flier, 2004
). Resistin levels were found to be significantly elevated in FathersPCOS and MothersPCOS groups compared with their control groups. Resistin has been shown to promote endothelial cell activation, with increased expression of the adhesion molecule VCAM-1 and the chemotactic protein VCAM-1 (Verma et al., 2003
). Therefore, resistin can play a role in pathogenesis of cardiovascular diseases which develop in first degree relatives of PCOS. Dyslipidaemia may be the most common metabolic abnormality in PCOS, although the type and extent of the findings have been variable (Wild et al., 2000
; Legro, 2003
). Although various lipid parameters were high, dyslipidaemia was seen in all groups. Dyslipidaemia is an accepted risk factor for CVD. Therefore, the first degree relatives of PCOS subjects should be examined for dyslipidaemia and treated with antilipidaemic treatment. The prevalences of hypertension and hyperlipidaemia were found to be significantly increased in first degree relatives of patients with PCOS. Along with low serum adiponectin levels and high homocystein and resistin levels, the findings may imply that first degree relatives of patients with PCOS are more prone to develop DM and have higher risk of CVD.
In the present study, control groups were selected from family members without history of DM or CVD. As is well known, Type II DM is hereditary. First degree relatives of patients with Type II DM have an increased prevalance of insulin resistance and related parameters. Furthermore, insulin resistance and hyperinsulinaemia are main constituents of metabolic syndrome, which in turn leads to increased CVD (Ezenwaka et al., 2004; Nyholm et al., 2004
; Pankow et al., 2004
). It was for this reason that we selected such a control group, which may not represent the general population. This may be a limiting factor for the present study since CVD risk for relatives of patients with PCOS may be found relatively elevated.
As is known, PCOS patients have increased risk of developing DM and CVD. The present study found a high frequency of glucose intolerance disorders and CVD risk in the first degree relatives of PCOS patients when compared to the control group. This finding shows that the first degree relatives of PCOS patients need also to be closely examined for DM and CVD. We could thus take preventive measures against the development of disease in these subjects.
In conclusion, the results of the present study support the finding that, similar to PCOS patients, their first degree relatives also carry an increased risk of CVD. This points to a need for the first degree relatives of PCOS patients to be monitored for DM and CVD development, and suggests that preventive measures be taken. Further, larger-scale and longitudinal studies are needed in this field.
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Yld
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Submitted on February 7, 2005; resubmitted on March 29, 2005; accepted on April 12, 2005.
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