Markers of Endothelial Function in Obese Women With PCOS
Markers of Endothelial Function in Obese Women With PCOS
BACKGROUND Women with polycystic ovary syndrome (PCOS) present with vascular abnormalities, including elevated markers of endothelial dysfunction. There is limited evidence for the effect of lifestyle modification and weight loss on these markers. The aim of this study was to determine if 20 weeks of a high-protein energy-restricted diet with or without exercise in women with PCOS could improve endothelial function.
METHODS This is a secondary analysis of a subset of 50 overweight/obese women with PCOS (age: 30.3 ± 6.3 years; BMI: 36.5 ± 5.7 kg/m) from a previous study. Participants were randomly assigned by computer generation to one of three 20-week interventions: diet only (DO; n = 14, ~6000 kJ/day), diet and aerobic exercise (DA; n = 16, ~6000 kJ/day and five walking sessions/week) and diet and combined aerobic-resistance exercise (DC; n = 20, ~6000 kJ/day, three walking and two strength sessions/week). At Weeks 0 and 20, weight, markers of endothelial function [vascular cell adhesion molecule-1 (sVCAM-1), inter-cellular adhesion molecule-1 (sICAM-1), plasminogen activator inhibitor-1 (PAI-1) and asymmetric dimethylarginine (ADMA)], insulin resistance and hormonal profile were assessed.
RESULTS All three treatments resulted in significant weight loss (DO 7.9 ± 1.2%, DA 11.0 ± 1.6%, DC 8.8 ± 1.1; P < 0.001 for time; P = 0.6 time × treatment). sVCAM-1, sICAM-1 and PAI-1 levels decreased with weight loss (P≤ 0.01), with no differences between treatments (P≥ 0.4). ADMA levels did not change significantly (P = 0.06). Testosterone, sex hormone-binding globulin and the free androgen index (FAI) and insulin resistance also improved (P < 0.001) with no differences between treatments (P≥ 0.2). Reductions in sVCAM-1 were correlated to reductions in testosterone (r = 0.32, P = 0.03) and FAI (r = 0.33, P = 0.02) as well as weight loss (r= 0.44, P = 0.002). Weight loss was also associated with reductions in sICAM-1 (r= 0.37, P = 0.008).
CONCLUSIONS Exercise training provided no additional benefit to following a high-protein, hypocaloric diet on markers of endothelial function in overweight/obese women with PCOS.
Clinical Trials Registration Number: ACTRN12606000198527.
Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age, presenting in 8–18% of this population (Norman et al., 2007; March et al., 2010). PCOS is associated with a number of reproductive disorders and is characterized by the presence of polycystic ovaries, menstrual dysfunction, infertility and hyperandrogenism. PCOS also increases the prevalence and risk of cardiovascular disturbances including insulin resistance, hypertension and dyslipidaemia (Norman et al., 2007; Wild et al., 2010), which impact negatively on the long-term health and leads to the development of cardiovascular disease (CVD).
Women with PCOS present with vascular abnormalities including endothelial dysfunction (Paradisi et al., 2001; Diamanti-Kandarakis et al., 2005; Kravariti et al., 2005; Orio et al., 2005; Carmina et al., 2006; Diamanti-Kandarakis et al., 2006a,b; Ilie et al., 2008). This is not surprising since endothelial dysfunction has been linked to insulin resistance (Paradisi et al., 2001; Tarkun et al., 2004; Kravariti et al., 2005; Diamanti-Kandarakis et al., 2006a,b; Heutling et al., 2008; Moran et al., 2009a, 2011) and hyperandrogenism (Paradisi et al., 2001; Kravariti et al., 2005; Diamanti-Kandarakis et al., 2006a,b; Heutling et al., 2008; Ozgurtas et al., 2008; Moran et al., 2009a, 2011; Teede et al., 2010). A recent meta-analysis indicated that PCOS is not only related to low-grade chronic inflammation and more specifically endothelial inflammation but to disorders of coagulation and endothelial cell proliferation (Toulis et al., 2011). Endothelial dysfunction is an early feature of atherosclerosis and plays an important role in the development of atherosclerotic diseases. Endothelial function can be investigated by measuring circulating markers, produced by the endothelium, such as asymmetric dimethylarginine (ADMA), an endogenous competitive inhibitor of nitric oxide (NO) synthase; plasminogen activator inhibitor-1 (PAI-1), a prothrombotic factor that inhibits fibrinolysis; and intra-cellular adhesion molecule-1 (sICAM-1) and vascular cell adhesion molecule-1 (sVCAM-1), both of which reflect low-grade chronic inflammation of the endothelium (Ilie et al., 2008). ADMA, PAI-1, sVCAM-1 and sICAM-1 concentrations are elevated in women with PCOS compared with non-PCOS controls (Carmassi et al., 2005; Diamanti-Kandarakis et al., 2006a,b; Charitidou et al., 2008; Heutling et al., 2008; Ozgurtas et al., 2008; Moran et al., 2009a, 2011; Rajendran et al., 2009; Mohamadin et al., 2010) and have been shown to predict the development of CVD (Thögersen et al., 1998; Blankenberg et al., 2001; Valkonen et al., 2001).
Lifestyle modification incorporating diet and exercise is considered the first-line treatment for the management of PCOS and its associated complications (Moran et al., 2006, 2009b; Wild et al., 2010). However, despite the well-established benefits of weight loss via moderate energy restriction and exercise on insulin resistance, hyperandrogenism and CVD risk markers in overweight women with PCOS (Andersen et al., 1995; Holte et al., 1995; Moran et al., 2003; Palomba et al., 2007; Vigorito et al., 2007; Giallauria et al., 2008; Thomson et al., 2008), there are limited data available on the effect of diet and exercise on endothelial function in women with PCOS. To date only one small (n = 9) pilot study showed reductions in PAI-1 following 4 weeks of a very low-calorie diet or 20 weeks of a low-calorie diet (Andersen et al., 1995). Previous studies have also shown a favourable effect of exercise training on endothelial function in both healthy and diseased populations, some specifically with reductions in sICAM-1 (Adamopoulos et al., 2001; Zoppini et al., 2006; Saetre et al., 2011) and sVCAM-1 (Adamopoulos et al., 2001; Rankovic et al., 2009), ADMA (Richter et al., 2005; Schlager et al., 2011; Tsarouhas et al., 2011) and PAI-1 (Jahangard et al., 2009). However, this is not a consistent effect (Olson et al., 2007) and there is limited research comparing the effects of diet with and without exercise. Previous research has also shown that combined aerobic-resistance exercise is more efficacious than aerobic or resistance training alone for improving insulin sensitivity and reducing abdominal fat in a range of obese populations (Cuff et al., 2003; Park et al., 2003). It is believed that these improvements may also translate to improvements in endothelial function due to the relationship between endothelial dysfunction and insulin resistance (Paradisi et al., 2001; Tarkun et al., 2004; Kravariti et al., 2005; Diamanti-Kandarakis et al., 2006a,b; Heutling et al., 2008; Moran et al., 2009a, 2011).
Therefore, the aims of this study were: (i) determine the additive effect of aerobic or aerobic-resistance exercise training when combined with energy restriction, in overweight women with PCOS, for improving endothelial function assessed by the measurement of ADMA, PAI-1, sVCAM-1 and sICAM-1 and (ii) determine relationships between the markers of endothelial function, hormonal profile and insulin resistance.
Abstract and Introduction
Abstract
BACKGROUND Women with polycystic ovary syndrome (PCOS) present with vascular abnormalities, including elevated markers of endothelial dysfunction. There is limited evidence for the effect of lifestyle modification and weight loss on these markers. The aim of this study was to determine if 20 weeks of a high-protein energy-restricted diet with or without exercise in women with PCOS could improve endothelial function.
METHODS This is a secondary analysis of a subset of 50 overweight/obese women with PCOS (age: 30.3 ± 6.3 years; BMI: 36.5 ± 5.7 kg/m) from a previous study. Participants were randomly assigned by computer generation to one of three 20-week interventions: diet only (DO; n = 14, ~6000 kJ/day), diet and aerobic exercise (DA; n = 16, ~6000 kJ/day and five walking sessions/week) and diet and combined aerobic-resistance exercise (DC; n = 20, ~6000 kJ/day, three walking and two strength sessions/week). At Weeks 0 and 20, weight, markers of endothelial function [vascular cell adhesion molecule-1 (sVCAM-1), inter-cellular adhesion molecule-1 (sICAM-1), plasminogen activator inhibitor-1 (PAI-1) and asymmetric dimethylarginine (ADMA)], insulin resistance and hormonal profile were assessed.
RESULTS All three treatments resulted in significant weight loss (DO 7.9 ± 1.2%, DA 11.0 ± 1.6%, DC 8.8 ± 1.1; P < 0.001 for time; P = 0.6 time × treatment). sVCAM-1, sICAM-1 and PAI-1 levels decreased with weight loss (P≤ 0.01), with no differences between treatments (P≥ 0.4). ADMA levels did not change significantly (P = 0.06). Testosterone, sex hormone-binding globulin and the free androgen index (FAI) and insulin resistance also improved (P < 0.001) with no differences between treatments (P≥ 0.2). Reductions in sVCAM-1 were correlated to reductions in testosterone (r = 0.32, P = 0.03) and FAI (r = 0.33, P = 0.02) as well as weight loss (r= 0.44, P = 0.002). Weight loss was also associated with reductions in sICAM-1 (r= 0.37, P = 0.008).
CONCLUSIONS Exercise training provided no additional benefit to following a high-protein, hypocaloric diet on markers of endothelial function in overweight/obese women with PCOS.
Clinical Trials Registration Number: ACTRN12606000198527.
Introduction
Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age, presenting in 8–18% of this population (Norman et al., 2007; March et al., 2010). PCOS is associated with a number of reproductive disorders and is characterized by the presence of polycystic ovaries, menstrual dysfunction, infertility and hyperandrogenism. PCOS also increases the prevalence and risk of cardiovascular disturbances including insulin resistance, hypertension and dyslipidaemia (Norman et al., 2007; Wild et al., 2010), which impact negatively on the long-term health and leads to the development of cardiovascular disease (CVD).
Women with PCOS present with vascular abnormalities including endothelial dysfunction (Paradisi et al., 2001; Diamanti-Kandarakis et al., 2005; Kravariti et al., 2005; Orio et al., 2005; Carmina et al., 2006; Diamanti-Kandarakis et al., 2006a,b; Ilie et al., 2008). This is not surprising since endothelial dysfunction has been linked to insulin resistance (Paradisi et al., 2001; Tarkun et al., 2004; Kravariti et al., 2005; Diamanti-Kandarakis et al., 2006a,b; Heutling et al., 2008; Moran et al., 2009a, 2011) and hyperandrogenism (Paradisi et al., 2001; Kravariti et al., 2005; Diamanti-Kandarakis et al., 2006a,b; Heutling et al., 2008; Ozgurtas et al., 2008; Moran et al., 2009a, 2011; Teede et al., 2010). A recent meta-analysis indicated that PCOS is not only related to low-grade chronic inflammation and more specifically endothelial inflammation but to disorders of coagulation and endothelial cell proliferation (Toulis et al., 2011). Endothelial dysfunction is an early feature of atherosclerosis and plays an important role in the development of atherosclerotic diseases. Endothelial function can be investigated by measuring circulating markers, produced by the endothelium, such as asymmetric dimethylarginine (ADMA), an endogenous competitive inhibitor of nitric oxide (NO) synthase; plasminogen activator inhibitor-1 (PAI-1), a prothrombotic factor that inhibits fibrinolysis; and intra-cellular adhesion molecule-1 (sICAM-1) and vascular cell adhesion molecule-1 (sVCAM-1), both of which reflect low-grade chronic inflammation of the endothelium (Ilie et al., 2008). ADMA, PAI-1, sVCAM-1 and sICAM-1 concentrations are elevated in women with PCOS compared with non-PCOS controls (Carmassi et al., 2005; Diamanti-Kandarakis et al., 2006a,b; Charitidou et al., 2008; Heutling et al., 2008; Ozgurtas et al., 2008; Moran et al., 2009a, 2011; Rajendran et al., 2009; Mohamadin et al., 2010) and have been shown to predict the development of CVD (Thögersen et al., 1998; Blankenberg et al., 2001; Valkonen et al., 2001).
Lifestyle modification incorporating diet and exercise is considered the first-line treatment for the management of PCOS and its associated complications (Moran et al., 2006, 2009b; Wild et al., 2010). However, despite the well-established benefits of weight loss via moderate energy restriction and exercise on insulin resistance, hyperandrogenism and CVD risk markers in overweight women with PCOS (Andersen et al., 1995; Holte et al., 1995; Moran et al., 2003; Palomba et al., 2007; Vigorito et al., 2007; Giallauria et al., 2008; Thomson et al., 2008), there are limited data available on the effect of diet and exercise on endothelial function in women with PCOS. To date only one small (n = 9) pilot study showed reductions in PAI-1 following 4 weeks of a very low-calorie diet or 20 weeks of a low-calorie diet (Andersen et al., 1995). Previous studies have also shown a favourable effect of exercise training on endothelial function in both healthy and diseased populations, some specifically with reductions in sICAM-1 (Adamopoulos et al., 2001; Zoppini et al., 2006; Saetre et al., 2011) and sVCAM-1 (Adamopoulos et al., 2001; Rankovic et al., 2009), ADMA (Richter et al., 2005; Schlager et al., 2011; Tsarouhas et al., 2011) and PAI-1 (Jahangard et al., 2009). However, this is not a consistent effect (Olson et al., 2007) and there is limited research comparing the effects of diet with and without exercise. Previous research has also shown that combined aerobic-resistance exercise is more efficacious than aerobic or resistance training alone for improving insulin sensitivity and reducing abdominal fat in a range of obese populations (Cuff et al., 2003; Park et al., 2003). It is believed that these improvements may also translate to improvements in endothelial function due to the relationship between endothelial dysfunction and insulin resistance (Paradisi et al., 2001; Tarkun et al., 2004; Kravariti et al., 2005; Diamanti-Kandarakis et al., 2006a,b; Heutling et al., 2008; Moran et al., 2009a, 2011).
Therefore, the aims of this study were: (i) determine the additive effect of aerobic or aerobic-resistance exercise training when combined with energy restriction, in overweight women with PCOS, for improving endothelial function assessed by the measurement of ADMA, PAI-1, sVCAM-1 and sICAM-1 and (ii) determine relationships between the markers of endothelial function, hormonal profile and insulin resistance.