Heart rate recovery improves after weight loss in overweight and obese women with polycystic ovary syndrome

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1 POLYCYSTIC OVARY SYNDROME Heart rate recovery improves after weight loss in overweight and obese women with polycystic ovary syndrome Rebecca L. Thomson, B.Sc., a,b Jonathan D. Buckley, Ph.D., a Manny Noakes, Ph.D., b Peter M. Clifton, Ph.D., b Robert J. Norman, Ph.D., c and Grant D. Brinkworth, Ph.D. b a Australian Technology Network Centre for Metabolic Fitness & Nutritional Physiology Research Centre, Sansom Institute for Health Research, University of South Australia; b Preventative Health Flagship, Commonwealth Scientific and Industrial Research Organisation, Human Nutrition; and c Research Centre for Reproductive Health, Robinson Institute, University of Adelaide, Adelaide, Australia Objective: To determine the effects of weight loss on heart rate recovery (HRR) in overweight women with polycystic ovary syndrome (PCOS). Design: A 10-week prospective clinical intervention. Setting: Clinical research unit. Patient(s): Fifty-seven overweight and obese women with PCOS (age: years; body mass index [BMI] kg/m 2 ). Intervention(s): A dietary plan of 5 6 MJ/day (30% energy restricted). Main Outcome Measure(s): Heart rate recovery (defined as the reduction in heart rate after 1 minute from peak heart rate after a graded treadmill test to exhaustion), weight, waist circumference, blood pressure, glucose, insulin, homeostasis model assessment of insulin resistance, and sex steroids before and after the intervention. Result(s): The mean percentage of weight loss was ( %). There were significant reductions in waist circumference ( cm), blood pressure (-4.9/ /1.2 mm Hg), fasting insulin ( mu/l), fasting glucose ( mmol/l), homeostasis model assessment of insulin resistance ( ), T ( nmol/l), free androgen index ( ), and an increase in sex hormone-binding globulin [SHBG] ( nmol/l). The HRR improved from to beats/min and that was related to the reduction in body weight (r ¼ -0.34) and waist circumference (r ¼ -0.27). Conclusion(s): Weight loss in overweight and obese women with PCOS is associated with improvements in HRR, which suggests improved autonomic function. This highlights the importance of weight loss to reduce the cardiovascular disease risk in these women. (Fertil Steril Ò 2010;93: Ó2010 by American Society for Reproductive Medicine.) Key Words: Cardiovascular risk, autonomic function, obesity, diet, exercise Heart rate recovery (HRR), which is defined as the rate of decrease in heart rate (HR) 1 minute after a maximal graded exercise test, has been identified as a powerful independent predictor of cardiovascular disease (CVD) and all-cause mortality in healthy adults (1 5), and in patients with CVD (6, 7) and diabetes (8). HRR is a marker of autonomic function, Received August 12, 2008; revised November 10, 2008; accepted December 2, 2008; published online January 14, R.L.T. has nothing to disclose. J.D.B. has nothing to disclose. M.N. has nothing to disclose. P.M.C. has nothing to disclose. R.J.N. has nothing to disclose. G.D.B. has nothing to disclose. Supported by the National Health and Medical Research Council of Australia, grant number , Canberra, Australia Capital Territory, Australia. Rebecca Thomson was funded by a postgraduate scholarship from the South Australia Department of Health. Reprint requests: Grant Brinkworth, Ph.D., Commonwealth Scientific and Industrial Research Organisation Human Nutrition, P.O. Box 10041, Adelaide BC, South Australia, Australia 5000 (FAX: ; grant.brinkworth@csiro.au). with low HRR reflecting impaired parasympathetic activity (9) and vagal tone (10). In healthy adults, HRR has shown to be inversely related to insulin resistance and other risk factors, such as body mass index (BMI), abdominal obesity, and low high-density lipoprotein (HDL) cholesterol, and elevated fasting glucose and triglycerides that cluster with the insulin resistance syndrome (11 14). Previous studies have also suggested that hyperinsulinemia or insulin resistance is associated with sympathetic overactivity and may contribute to low cardiac vagal activity (15 17). Consequently, therapeutic interventions that improve insulin sensitivity and reduce hyperinsulinemia, such as weight loss, could improve cardiac parasympathetic tone. Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age, affecting 7% of this population (18). Polycystic ovary syndrome is characterized by the presence of polycystic ovaries, /10/$36.00 Fertility and Sterility â Vol. 93, No. 4, March 1, doi: /j.fertnstert Copyright ª2010 American Society for Reproductive Medicine, Published by Elsevier Inc.

2 menstrual dysfunction, infertility or reduced fertility, and biochemical or clinical hyperandrogenism (19). Many studies have also demonstrated that women with PCOS have an increased prevalence of obesity and abdominal obesity (20, 21), an adverse metabolic profile, including insulin resistance and compensatory hyperinsulinemia, impaired glucose tolerance, dyslipidemia, diabetes, and an impaired inflammatory pattern (22 25), which may elevate CVD risk (23, 26, 27). In addition, women with PCOS have been shown to have unfavorable cardiac autonomic profiles associated with increased sympathetic activity, which has been suggested to be related to lower E 2 and higher T levels (28). It has been suggested that hyperandrogenism combined with insulin resistance leads to autonomic dysfunction observed in women with PCOS (28). More recently it has been shown that HRR is impaired in young overweight women with PCOS (29, 30), and that this was inversely related to BMI and insulin resistance (29). This provides further evidence of potential imbalances in autonomic cardiovascular regulation in women with PCOS, which may represent a therapeutic target. Several studies have demonstrated that weight loss through energy restriction improves a number of CVD risk factors in overweight and obese women with PCOS including reductions in waist circumference, fasting blood glucose, lipids, and insulin resistance (31 35). However, there are currently no data available evaluating the effects of weight loss on HRR in overweight and obese women with PCOS. Therefore, this study aimed to determine whether weight loss after a hypocaloric diet can improve HRR in overweight and obese women with PCOS. MATERIALS AND METHODS Participants Fifty-seven sedentary overweight and obese women with PCOS (age: years; BMI: kg/m 2 ) were recruited by public advertisement and from general practitioner and specialist clinics (Table 1). Polycystic ovary syndrome was diagnosed according to the Rotterdam Consensus Workshop Group criteria (36), by the presence of two of the following three criteria: biochemical (elevated T[>2.0 nmol/l] and free androgen index [FAI; >5.4]) or clinical (hirsutism assessed by Ferriman-Gallwey score >8) hyperandrogenism; menstrual irregularity (cycle length <21 days or >35 days or variation between consecutive cycles of >3 days); presence of polycystic ovaries by transvaginal or transabdominal ultrasound examination. Potential participants were excluded if they were using fertility treatments or oral contraceptives, were smokers, pregnant, breastfeeding, or had a history of cardiovascular, liver, kidney, or respiratory disease, diabetes, uncontrolled hypertension, or a malignancy. Subjects were also excluded if they had any reproductive disorders unrelated to PCOS, thyroid abnormalities, or nonclassic adrenal hyperplasia. The protocol and potential risks and benefits of the study were explained to participants before they provided written TABLE 1 Physical characteristics, cardiovascular disease risk factors, and exercise test parameters before and after 10 weeks of a weight loss program. Variable Wk 0 Wk 10 Weight (kg) a Waist circumference (cm) a Systolic blood a pressure (mm Hg) Diastolic blood b pressure (mm Hg) Insulin (mu/l) a Glucose (mmol/l) a HOMA a T (nmol/l) a Sex hormone-binding globulin (nmol/l) a Free androgen index a Heart rate recovery (beats/min) a Peak heart a rate (beats/min) Peak V O 2 (L/min) Note: Values are mean SEM. a P%.001 significantly different from baseline. b P<.05 significantly different from baseline. Thomson. HRR and weight loss in PCOS. Fertil Steril informed consent. All experimental procedures were approved by the Human Ethics Committees of the Commonwealth Scientific and Industrial Research Organisation and the University of South Australia. Study Design The data analyzed for this study were obtained from a subset of women who completed exercise testing at Week 0 and 10 from a previous study evaluating the effects of a hypocaloric diet with and without exercise training on metabolic and reproductive outcomes (37). In this previous study subjects were randomized to undertake one of three weight loss interventions: diet only, diet and aerobic exercise (consisting of 5 walking/jogging sessions per week), or diet and combined aerobic resistance exercise (consisting of 3 walking/jogging session and 2 strength training sessions per week). Because no differences were observed between treatment groups for weight loss or the autonomic and metabolic measures, the data were pooled to evaluate the effects of weight loss on HRR in the present study. Before (baseline) and after the 10-week weight loss intervention, subjects attended the clinic after an overnight fast during which height (baseline only), 1174 Thomson et al. HRR and weight loss in PCOS Vol. 93, No. 4, March 1, 2010

3 body weight, waist circumference, and blood pressure were measured before the collection of a venous blood sample for the measurement of glucose, insulin, T, and sex hormone-binding globulin (SHBG). An incremental treadmill test to volitional exhaustion was then performed. Subjects were advised not to consume any alcohol or participate in vigorous physical activity during the 24 hours before these visits. All participants were prescribed the same weight loss program consisting of an energy-restricted, high protein diet (5 6 MJ/d, 30% energy restriction; 30% protein, 40% carbohydrate, 30% fat) based on a prescriptive fixed menu plan for a planned weight loss of 8 12 kg. At baseline and fortnightly throughout the intervention, participants attended the clinic for a weight check and met with a qualified dietitian who provided detailed dietary advice. Clinical and Biochemical Measurements Height and body weight were measured using a stadiometer (SECA, Hamburg, Germany) and electronic digital scales (Mercury, AMZ 14, Tokyo, Japan), respectively. The BMI was calculated as weight (in kilograms)/height(in meters) 2. Waist circumference was measured 2 cm above the uppermost lateral border of the iliac crest using an anthropometric tape (model W606PM; Lufkin, Houston, TX). Seated blood pressure was measured by automated oscillometry (model T8; Omron Corporation, Tokyo, Japan). Three readings were taken, with the average score recorded as the measured value. Fasting plasma and serum samples were collected and stored at -80 C for analysis after study completion. Plasma glucose was measured on a Hitachi 902 autoanalyzer (Roche Diagnostics, Indianapolis, IN) using a commercial enzymatic kit (Roche Diagnostics, Basel, Switzerland). Plasma insulin concentrations were determined using a commercial ELISA kit (Mercodia ELISA; ALPCO Diagnostics, Uppsala, Sweden). Insulin resistance was estimated using the homeostasis model assessment online calculator (HOMA2) (38). Serum SHBG was measured by coated-tube immunoradiometric assay using commercial kits (Diagnostic System Laboratories, Webster, TX). Testosterone was measured by RIA using commercial enzymatic kits (Diagnostic System Laboratories). The FAI was calculated as T/SHBG 100. Incremental Treadmill Test Subjects underwent a graded exercise test on a motorized treadmill (Trackmaster TMX425CP; Full Vision Inc., Newton, KS) to symptom-limited exhaustion. The treadmill speed was maintained constant at 4.8 km/h and the grade commenced at 0% and increased by 1% at the end of each 1-minute stage until exhaustion was reached. The cardiorespiratory response to exercise was assessed by indirect calorimetry (TrueOne 2400; Parvomedics, Sandy, UT). Peak oxygen uptake (peak) was taken to be the highest achieved during a 30-second measurement period. At the cessation of exercise, subjects were immediately placed in a seated position during which recovery assessments were performed. The HR data were recorded constantly during exercise and the immediate recovery period as 5-second averages using an HR monitor and chest transmitter (S610i Polar Heart Rate Monitor; Polar Electro Oy, Kempele, Finland). The HRR was defined as the difference between HR at the termination of exercise and HR after 1 minute of passive recovery (39). Data Analysis Statistical analysis was performed using SPSS for Windows 14.0 (SPSS, Chicago, IL). Normality of data were checked before analysis and non-normally distributed data was logarithmically transformed. The significance of the change in variables before and after weight loss was determined by paired Student s t tests, with subjects serving as their own controls. Correlational analysis was used to assess relationships between variables. Stepwise multiple regression analysis was used to determine independent predictors of change in HRR. An a level of significance was set at P<.05. Values are reported as mean SEM. RESULTS Overall the mean weight loss was kg (P<.001), which was accompanied by reductions in waist circumference ( cm, P<.001), systolic blood pressure ( mm Hg, P<.001), diastolic blood pressure ( mm Hg, P¼.03), fasting insulin ( mu/l, P<.001), fasting glucose ( mmol/l, P¼.001), HOMA2 ( , P<.001), T ( nmol/l, P<.001), and FAI ( , P<.001), and an increase in SHBG ( nmol/l, P<.001). The magnitude of the reduction in fasting insulin was inversely related to the baseline fasting insulin concentration (r ¼ -0.32, P¼.02). By Week 10, HRR improved by beats/min (P<.001). Peak HR decreased by beats/min by Week 10 (P<.001) and peak was unchanged (P¼.51). The improvement in HRR remained significant after controlling for the reduction in peak HR. The improvement in HRR correlated with weight loss (r ¼ -0.34, P¼.01; Fig. 1) and the reduction in waist circumference (r ¼ -0.27, P¼.04), but not with any other variable. Stepwise multiple regression, which included weight loss and changes in waist circumference, systolic and diastolic blood pressures, HOMA2, T, FAI, SHBG, and exercise treatment status as parameters, revealed that weight loss was the only significant independent predictor of the change in HRR (b ¼ -0.34, P¼.01). DISCUSSION This study showed that HRR was improved after weight loss in overweight and obese women with PCOS. This is consistent with previous studies that have shown improvements in HRR after weight loss with a moderate hypocaloric diet in overweight and obese men with components of the metabolic Fertility and Sterility â 1175

4 FIGURE 1 Correlation between change in heart rate recovery and body weight after a 10-week weight loss program. Thomson. HRR and weight loss in PCOS. Fertil Steril syndrome (40) and other obese subjects after surgical gastric restriction (41). Recovery of HR after exercise is mediated by vagal tone (42), and consequently impaired HRR is associated with reduced cardiovagal tone (10). We observed a positive association between the improvements in HRR and weight loss, suggesting that weight loss altered autonomic balance by modulating parasympathetic activity. In support of this, other studies have demonstrated that weight loss improves vagal tone in overweight populations (15, 43). Laaksonen et al. (43) showed that weight loss through dietary restriction in obese patients with the metabolic syndrome reduced HR and cardiac spectral indices of HR variability, indicating enhanced parasympathetic tone. Similarly, after a 6-month weight reduction program in healthy obese women, cardiac parasympathetic tone was increased after a 9.5% reduction in body weight (15). Collectively, this evidence suggests that weight loss improves HRR by mediating cardiac vagal tone, whereas data from the current study indicates that response also occurs in obese women with PCOS. The mechanism(s) responsible for the improvement in HRR with weight loss are not immediately clear from the present data. We observed a significant correlation between the decrease in waist circumference and the improvement in HRR. Waist circumference has shown to be an independent predictor of insulin resistance (44) and Giallauria et al. (29) reported impaired HRR in overweight PCOS women that correlated with BMI and insulin resistance. Accordingly, Lind and Andren (11) showed that HRR was inversely associated with insulin resistance and other risk factors tending to cluster with insulin resistance including BMI and abdominal obesity in healthy subjects. In addition, other studies have shown that cardiac vagal tone is reduced by insulin resistance and hyperinsulinemia (15 17) and that cardiac parasympathetic tone could be improved by the reduction of hyperinsulinemia with weight loss (15), with insulin resistance and sympathetic activity being linked through a positive feedback mechanism that leads to their reciprocal reinforcement (45). Thus, it is possible that the improvements in HRR after weight loss, as we observed, may reflect changes in autonomic function in response to improvements in insulin sensitivity. However, we found that after weight loss was controlled, the relationship between the improvement in HRR and the reduction in waist circumference was no longer significant. We also found no association between the changes in HRR and other surrogate measures of insulin resistance (fasting insulin and HOMA2). This is consistent with the findings of Ugur-Altun et al. (17), who also used HOMA as a surrogate marker of insulin resistance and found no relationship with HRR. Although some previous studies in women with PCOS have shown that surrogate markers are sensitive methods for detecting insulin resistance (46, 47), other studies have suggested that they are poor indicators of insulin resistance in PCOS (48), raising the possibility that these indices may lack sensitivity to detect any relationship with HRR in this population. This could possibly explain the discrepant findings of Giallauria et al. (29), who reported a significant correlation between abnormal HRR and insulin resistance that was determined by the insulin area under the curve in response to an oral glucose tolerance test in young overweight women with PCOS. Alternatively, compared with women in the study by Giallauria et al. (29), women in the present study had lower mean fasting insulin levels (15.6 vs mu/l). Given that the magnitude of the reduction in insulin was found to be inversely related to the baseline insulin concentration in the present study, and in previous studies that have examined the effects of lifestyle interventions (49 51), the relatively low baseline level of hyperinsulinemia may have tempered the potential reduction in insulin in response to weight loss, which could in turn reduce the likelihood of identifying an association between weight loss and HOMA2. Hyperandrogenism associated with PCOS has also been linked to an unfavorable cardiac autonomic profile with increased sympathetic activity (28). However, in the present study, no association between hormonal profile and HRR was observed. This could possibly be attributed to the lower degree of hyperandrogenism in our subjects compared with those women in the previous study (28), who reported higher levels of T (3.3 nmol/l). In addition to the growing body of evidence that impaired HRR is a strong independent predictor of cardiovascular and all-cause mortality (1 5), the presence of impaired HRR in women with PCOS (29, 30), combined with the derangement in other CVD risk factors (22, 23) and increased prevalence of metabolic disease (24, 25), has potential negative implications for long-term health. It has been previously established that weight loss improves an array of CVD risk factors in 1176 Thomson et al. HRR and weight loss in PCOS Vol. 93, No. 4, March 1, 2010

5 overweight and obese women with PCOS (31 33) and our results demonstrate that HRR is also a modifiable CVD risk factor, providing further evidence to support the clinical importance of weight loss for improving health outcomes in this patient group. Furthermore, the relationship between weight loss and improvements in HRR suggests the likelihood that improvements in HRR will occur after weight loss in other overweight and obese women without PCOS. However, further research is required to confirm this. This study has some limitations. Due to the absence of a control group it is not possible to determine whether factors other than weight loss were responsible for the improvement in HRR. Nevertheless, the improvement in HRR in response to following a weight loss program is consistent with other previous studies (40, 41) and we believe that these data are still of much interest and importance considering the elevated CVD risk profile in women with PCOS and their potential clinical application. The study had a relatively small sample size. Nevertheless, it was sufficiently powered to detect statistically significant differences in the primary outcome of HRR (a >99%, P<.05) and for secondary outcomes (weight, waist circumference, insulin, HOMA2, T, SHBG, and FAI; a >98%, P<.05). Compared with other women with PCOS studied, our study sample also had relatively low levels of insulin resistance (29) and hyperandrogenism (28), limiting the generalizability of the findings to the overall spectrum of women with PCOS. The subjects studied also did not have markedly abnormal HRR rates based on previously established criteria (1, 39), which also limits the generalizability of the results. Hence, further studies are needed to confirm the effects of weight loss on HRR in women with PCOS with varying degrees of hyperinsulinemia and hyperandrogenism, which may assist in determining any underlying factors of autonomic dysfunction associated with this condition. In conclusion, weight loss resulted in improvements in HRR in overweight and obese women with PCOS. Given that impaired HRR is an independent predictor of CVD and all-cause mortality, it is important to recognize that HRR can be modified through weight loss in overweight and obese women with PCOS. This provides further support that weight loss by dietary modification should formulate a cornerstone in the management of this syndrome. 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