Markers of Endothelial Function in Obese Women With PCOS
Markers of Endothelial Function in Obese Women With PCOS
This study demonstrated that there was no difference in changes in endothelial function following 20 weeks of lifestyle modification between the two exercising groups, DA and DC. There was also no additional effect of exercise training on the endothelial outcomes assessed in this study when comparing DO to DA and DC. It is possible that the overriding energy restriction/weight loss effect masked any additional exercise benefit. There were also no differential treatment effects seen in the insulin resistance and hormonal outcomes which may explain the absence of any additional effect on endothelial function markers. However, exercise training has been shown to induce direct benefits to the endothelium as a result of increases in NO bioavailability through repetitive increase of shear stress (Walther et al., 2004). Studies have previously shown that high-intensity aerobic interval training is better at improving endothelial function than either continuous moderate-intensity aerobic training or strength training, suggesting that it produces a greater shear stress which increases NO synthase (Wisløff et al., 2007; Schjerve et al., 2008). It is possible that the intensity of the exercise programme in the current study was not high enough to see an added benefit. There have been no studies that have examined the independent effect of exercise training alone without weight loss in PCOS on these outcomes and this is an area that requires further investigation.
An improvement in the markers of endothelial function was observed following the three lifestyle modification programmes, with no differences between treatments. There were reductions in sVCAM-1, sICAM-1 and PAI-1 observed at the end of the study. However, due to the lack of a non-dieting control group, it cannot be determined if these changes occurred due to the high-protein energy restricted diet and/or weight loss per se and it remains possible that improvements were due to factors unrelated to the diet. Nevertheless, the current data are comparable with previous studies conducted in other overweight and obese populations that have shown reductions in PAI-1 (Hamdy et al., 2003; Meckling et al., 2004; Murakami et al., 2007; Keogh et al., 2008), sVCAM-1 (Keogh et al., 2008) and sICAM-1 (Hamdy et al., 2003; Wegge et al., 2004; Rector et al., 2006; Keogh et al., 2008) following diet-induced weight loss with or without exercise. Several pharmacological studies in women with PCOS have also shown the beneficial effects of insulin sensitizers including metformin and rosiglitazone and oral contraceptive treatment on endothelial function (by reductions in PAI-1 and VCAM levels) after 3–12 months of treatment (Diamanti-Kandarakis et al., 2006a,b; Teede et al., 2010). Endothelial dysfunction is one of the first steps in atherogenesis and the reduction in these markers following weight loss has clinical relevance for this high CVD risk population as these markers have been shown to predict the development of CVD (Thögersen et al., 1998; Blankenberg et al., 2001; Valkonen et al., 2001). Further research is required to confirm the clinical impact of weight loss on markers of endothelial function and explore the mechanisms behind any improvements.
Previous studies have shown a relationship between vascular dysfunction and insulin resistance (Paradisi et al., 2001; Kravariti et al., 2005; Diamanti-Kandarakis et al., 2006a,b; Heutling et al., 2008; Moran et al., 2009a, 2011), 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) and chronic inflammation in women with PCOS (Diamanti-Kandarakis et al., 2006a,b; Moran et al., 2009a, 2011). In support, in the present study, sICAM-1 was associated with insulin resistance (fasting insulin and HOMA2) at baseline, and reductions in sICAM-1 during the intervention were associated with reductions in the weight, total body fat and abdominal fat mass. An association between the change in sVCAM-1 and testosterone and FAI was also observed. This is similar to other reports that have shown adverse effects of testosterone/FAI on measures of endothelial function (Paradisi et al., 2001; Orio et al., 2004; Diamanti-Kandarakis et al., 2006a,b). Testosterone has been found to promote VCAM-1 expression (McCrohon et al., 1999; Zhang et al., 2002). However, the contribution of hyperandrogenism to endothelial dysfunction remains controversial with reports that testosterone attenuates the expression of VCAM-1 in human umbilical vein endothelial cells, thus inhibiting the adhesion of monocytes to endothelial cells (Mukherjee et al., 2002), while other studies have shown no association between testosterone and endothelial function (Meyer et al., 2005). Furthermore, higher levels of ADMA were associated with lower levels of hyperandrogenism in the present study, which contrasts with previous reports (Heutling et al., 2008; Ozgurtas et al., 2008; Moran et al., 2009a). The specific reason for this discrepancy remains unclear. It has been previously demonstrated that increasing testosterone levels reduce ADMA levels; however, this occurred following testosterone administration in males in a hypogonadal state (Cakir et al., 2005; Leifke et al., 2008). Gender-related effects are thought to exist, suggesting that women with PCOS who have higher levels of testosterone may respond differently. Further research in women with PCOS is needed to understand this relationship. Irrespective of the precise mechanism, collectively the current and previous data suggest that metabolic and hormonal disturbances are associated with markers of vascular pathology in women with PCOS (Diamanti-Kandarakis et al., 2006a,b) and that weight loss induced by caloric restriction may attenuate this effect.
An important limitation of the current study is that because the original intervention (Thomson et al., 2008) was not designed to address endothelial function and the current data were obtained by analysis of stored blood samples, an a priori power analysis could not be performed. A post hoc power analysis suggests that, due to the relatively small sample size, the study may have been underpowered to detect differences between the treatment groups (power <45%, P < 0.05). It is possible that exercise may have an additional benefit; however, large studies are needed to determine this. While there were no significant differences between the three treatment groups, it does appear that those in the DO group were slightly heavier and had higher levels of hyperinsulineamia and hyperandrogenism at baseline compared with DA and DC. Thus, it is possible that this lack of difference is due to the small sample size and lack of power.
Discussion
This study demonstrated that there was no difference in changes in endothelial function following 20 weeks of lifestyle modification between the two exercising groups, DA and DC. There was also no additional effect of exercise training on the endothelial outcomes assessed in this study when comparing DO to DA and DC. It is possible that the overriding energy restriction/weight loss effect masked any additional exercise benefit. There were also no differential treatment effects seen in the insulin resistance and hormonal outcomes which may explain the absence of any additional effect on endothelial function markers. However, exercise training has been shown to induce direct benefits to the endothelium as a result of increases in NO bioavailability through repetitive increase of shear stress (Walther et al., 2004). Studies have previously shown that high-intensity aerobic interval training is better at improving endothelial function than either continuous moderate-intensity aerobic training or strength training, suggesting that it produces a greater shear stress which increases NO synthase (Wisløff et al., 2007; Schjerve et al., 2008). It is possible that the intensity of the exercise programme in the current study was not high enough to see an added benefit. There have been no studies that have examined the independent effect of exercise training alone without weight loss in PCOS on these outcomes and this is an area that requires further investigation.
An improvement in the markers of endothelial function was observed following the three lifestyle modification programmes, with no differences between treatments. There were reductions in sVCAM-1, sICAM-1 and PAI-1 observed at the end of the study. However, due to the lack of a non-dieting control group, it cannot be determined if these changes occurred due to the high-protein energy restricted diet and/or weight loss per se and it remains possible that improvements were due to factors unrelated to the diet. Nevertheless, the current data are comparable with previous studies conducted in other overweight and obese populations that have shown reductions in PAI-1 (Hamdy et al., 2003; Meckling et al., 2004; Murakami et al., 2007; Keogh et al., 2008), sVCAM-1 (Keogh et al., 2008) and sICAM-1 (Hamdy et al., 2003; Wegge et al., 2004; Rector et al., 2006; Keogh et al., 2008) following diet-induced weight loss with or without exercise. Several pharmacological studies in women with PCOS have also shown the beneficial effects of insulin sensitizers including metformin and rosiglitazone and oral contraceptive treatment on endothelial function (by reductions in PAI-1 and VCAM levels) after 3–12 months of treatment (Diamanti-Kandarakis et al., 2006a,b; Teede et al., 2010). Endothelial dysfunction is one of the first steps in atherogenesis and the reduction in these markers following weight loss has clinical relevance for this high CVD risk population as these markers have been shown to predict the development of CVD (Thögersen et al., 1998; Blankenberg et al., 2001; Valkonen et al., 2001). Further research is required to confirm the clinical impact of weight loss on markers of endothelial function and explore the mechanisms behind any improvements.
Previous studies have shown a relationship between vascular dysfunction and insulin resistance (Paradisi et al., 2001; Kravariti et al., 2005; Diamanti-Kandarakis et al., 2006a,b; Heutling et al., 2008; Moran et al., 2009a, 2011), 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) and chronic inflammation in women with PCOS (Diamanti-Kandarakis et al., 2006a,b; Moran et al., 2009a, 2011). In support, in the present study, sICAM-1 was associated with insulin resistance (fasting insulin and HOMA2) at baseline, and reductions in sICAM-1 during the intervention were associated with reductions in the weight, total body fat and abdominal fat mass. An association between the change in sVCAM-1 and testosterone and FAI was also observed. This is similar to other reports that have shown adverse effects of testosterone/FAI on measures of endothelial function (Paradisi et al., 2001; Orio et al., 2004; Diamanti-Kandarakis et al., 2006a,b). Testosterone has been found to promote VCAM-1 expression (McCrohon et al., 1999; Zhang et al., 2002). However, the contribution of hyperandrogenism to endothelial dysfunction remains controversial with reports that testosterone attenuates the expression of VCAM-1 in human umbilical vein endothelial cells, thus inhibiting the adhesion of monocytes to endothelial cells (Mukherjee et al., 2002), while other studies have shown no association between testosterone and endothelial function (Meyer et al., 2005). Furthermore, higher levels of ADMA were associated with lower levels of hyperandrogenism in the present study, which contrasts with previous reports (Heutling et al., 2008; Ozgurtas et al., 2008; Moran et al., 2009a). The specific reason for this discrepancy remains unclear. It has been previously demonstrated that increasing testosterone levels reduce ADMA levels; however, this occurred following testosterone administration in males in a hypogonadal state (Cakir et al., 2005; Leifke et al., 2008). Gender-related effects are thought to exist, suggesting that women with PCOS who have higher levels of testosterone may respond differently. Further research in women with PCOS is needed to understand this relationship. Irrespective of the precise mechanism, collectively the current and previous data suggest that metabolic and hormonal disturbances are associated with markers of vascular pathology in women with PCOS (Diamanti-Kandarakis et al., 2006a,b) and that weight loss induced by caloric restriction may attenuate this effect.
An important limitation of the current study is that because the original intervention (Thomson et al., 2008) was not designed to address endothelial function and the current data were obtained by analysis of stored blood samples, an a priori power analysis could not be performed. A post hoc power analysis suggests that, due to the relatively small sample size, the study may have been underpowered to detect differences between the treatment groups (power <45%, P < 0.05). It is possible that exercise may have an additional benefit; however, large studies are needed to determine this. While there were no significant differences between the three treatment groups, it does appear that those in the DO group were slightly heavier and had higher levels of hyperinsulineamia and hyperandrogenism at baseline compared with DA and DC. Thus, it is possible that this lack of difference is due to the small sample size and lack of power.
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