Exercise for the treatment and management of overweight women with polycystic ovary syndrome: a review of the literature

Transcription

1 Exercise for the treatment and management of overweight women with polycystic ovary syndrome: a review of the literature This is the peer reviewed author accepted manuscript (post print) version of a published work that appeared in final form in: Buckley, JD, Thomson, RL & Brinkworth, GD 2011 'Exercise for the treatment and management of overweight women with polycystic ovary syndrome: a review of the literature' Obesity reviews, vol. 12, no. 5, pp. e202-e210 This un-copyedited output may not exactly replicate the final published authoritative version for which the publisher owns copyright. It is not the copy of record. This output may be used for noncommercial purposes. The final definitive published version (version of record) is available at: Persistent link to the Research Outputs Repository record: General Rights: Copyright and moral rights for the publications made accessible in the Research Outputs Repository are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognize and abide by the legal requirements associated with these rights. Users may download and print one copy for the purpose of private study or research. You may not further distribute the material or use it for any profit-making activity or commercial gain You may freely distribute the persistent link identifying the publication in the Research Outputs Repository If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.

2 1 2 Exercise for the treatment and management of overweight women with polycystic ovary syndrome: a review of the literature 3 4 Rebecca L Thomson a,b, Jonathan D. Buckley a, Grant D. Brinkworth b a Australian Technology Network Centre for Metabolic Fitness & Nutritional Physiology Research Centre, Sansom Institute for Health Research, University of South Australia, Adelaide, Australia, 5001 b Preventative Health Flagship, Commonwealth Scientific and Industrial Research Organisation, Food and Nutritional Sciences, Adelaide, Australia, Keywords: exercise, lifestyle modification, weight loss, polycystic ovary syndrome Running title: Exercise in overweight women with PCOS Correspondence: Dr. Rebecca Thomson Nutritional Physiology Research Centre University of South Australia GPO Box 2471 Adelaide, South Australia 5001 Tel: Fax: rebecca.thomson@unisa.edu.au 24 Conflicts of interest: There are no potential conflicts of interest 1

3 Abstract Polycystic ovary syndrome (PCOS) is characterised by the presence of polycystic ovaries, menstrual dysfunction, infertility and biochemical and clinical hyperandrogenism and is associated with an increased prevalence of cardiometabolic risk factors and psychological problems. Despite the well-established benefits of exercise training and its recommendation as a cornerstone of PCOS management, few well-controlled randomised studies have been conducted evaluating the benefits of exercise training and specific exercise regimes in women with PCOS. From the limited studies there appears to be a beneficial effect of exercise either alone or in combination with energy restriction has shown to improve fitness, cardiovascular, hormonal, reproductive and psychological outcomes. While the addition of regular exercise to energy restriction appears to only have additional benefits for improving body composition, these greater improvements are likely to have long-term implications. While lifestyle modification including regular exercise appears to be an effective strategy for the management of overweight PCOS women, methodological limitations in the studies limits the generalisability of the findings. Future research with rigorous study designs is needed to determine specific exercise guidelines that will provide the greatest benefit for these women Abbreviations: PCOS, Polycystic ovary syndrome; IR, insulin resistance; CVD, cardiovascular disease; HRQOL, health-related quality of life; FAI, free androgen index; SHBG, sex-hormone binding globulin; BP, blood pressure; VO 2max, maximal aerobic capacity; BMI, body mass index; WHR, waist hip ratio; WC, waist circumference; HRR, heart rate recovery; HR, heart rate 47 2

4 Introduction Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age, presenting in ~7% of this population (1). PCOS is characterised by the presence of polycystic ovaries, menstrual dysfunction, infertility, and biochemical (elevated androgens) and clinical (hirsutism and/or acne) hyperandrogenism (2). PCOS increases the risk of fetal deformity, miscarriages and complications during pregnancy including a higher risk of premature deliveries and neonatal complications (3, 4). The pathogenesis of PCOS is complex and not entirely understood, but obesity and in particular abdominal obesity are common features that appear to play a central role in the syndrome s aetiology by contributing to the development of insulin resistance [IR] (5, 6). PCOS is also a major unrecognised cardiovascular disease (CVD) risk factor because of the increased prevalence of subclinical atherosclerosis, type 2 diabetes, dyslipidemia and impaired glucose tolerance (7-9); but whether PCOS women have an increased incidence of CVD requires confirmation (10). PCOS also promotes psychological morbidity including depression, poor body image and self-esteem, and reduced health-related quality of life (HRQOL) (11-13) While women with PCOS have an increased prevalence of obesity (14-16), a consensus on the proportion of overweight and obese women with PCOS is not clear, with estimates of between 40-60% (16, 17). The current obesity epidemic suggests the prevalence of PCOS may rise in the future (17), potentially impacting negatively on population growth and cardiovascular morbidity and mortality. Consequently, PCOS has become a major public health concern. The estimated economic burden of PCOS is $4 billion annually in 3

5 the United States alone (menstrual dysfunction 30% of total cost, infertility 12%, hirsutism 14%, and PCOS-associated diabetes 40%) (18) and does not include CVDrelated consequences which would potentially triple the costs (19). Given the multifaceted health implications of PCOS, it is important to identify effective therapies for the prevention and treatment of the syndrome to reduce its health and economic burdens Obesity and IR are closely linked to the development of PCOS and its clinical features, particularly menstrual irregularities and increased serum androgens (2, 20-22). IR and compensatory hyperinsulinemia act on ovarian tissue, disturbing ovarian hormone regulation and the menstrual cycle, resulting in infertility (5, 23, 24) and contribute directly to hyperandrogenemia by stimulating thecal cell androgen production (2, 25, 26). Due to the potential significance of IR in the manifestation of PCOS, and since obesity promotes IR (27), lifestyle modification focusing on dietary weight loss and increased physical activity is the preferred first-line treatment for PCOS (6) Lifestyle modification It is well documented that modest weight loss (5-14%) via energy restriction improves CVD risk factors, hormonal profile and reproductive function in overweight and obese women with PCOS. Improvements include reductions in abdominal fat, blood glucose, blood lipids and IR (21, 28-31), improvements in menstrual cyclicity, ovulation and fertility (20, 21, 28-33), reductions in testosterone levels and free androgen index (FAI) (21, 28, 30, 31) and increases in sex-hormone binding globulin (SHBG) (21, 33). Studies 4

6 have also shown improved self-esteem, depression, HRQOL and anxiety in obese infertile women including those with PCOS following lifestyle modification and/or energy restriction (20, 32, 34, 35) In women with PCOS reduction in insulin concentration is considered the primary determinant of most reproductive weight loss benefits (36), while metabolic improvements are primarily associated with reductions in abdominal fat (21). The mechanism responsible for modified ovarian morphology might involve improved insulin sensitivity and a more favourable endocrine environment following increases and decreases in SHBG and free androgens respectively, after weight loss (20, 32) Exercise training It is well known that exercise training improves an array of health-related outcomes, including protection against the development of CVD and diabetes, reduced morbidity and mortality (37-40), and psychological benefits including improvements in mood and psychological well-being (41-43). Participation in regular exercise is also a key predictor of long-term weight maintenance (44, 45). The combination of exercise and dieting has been extensively reported to substantially increase weight loss compared with dieting or exercise alone (46, 47), with the addition of exercise providing better longer term weight maintenance (48, 49) Aerobic exercise training improves body composition and a number of CVD risk markers independent of weight loss in overweight and obese individuals (46, 50). Resistance 5

7 training is also effective for improving insulin sensitivity and body composition and can preserve lean tissue during energy-restricted weight loss (51-53), which ameliorates weight loss induced reductions in resting metabolic rate (54). Combining aerobic and resistance exercise has been reported to be more efficacious for improving insulin sensitivity and glycemic control and reducing abdominal fat in various obese groups compared with either form of exercise alone (55-58) Exercise training in PCOS Exercise capacity Despite well-established benefits of exercise training and its recommendation as a cornerstone of PCOS management (36), few well-controlled studies have evaluated the benefits of exercise training in PCOS (Table 1). Prior to the prescription of an exercise regime, it is important to establish whether any functional limitations exist that may reduce an individual s ability to exercise. Three studies reported no difference in maximal aerobic capacity (VO 2max ), an indicator of functional capacity, between overweight women with PCOS and age- and body mass index (BMI)-matched controls (59-61). In contrast, Orio et al. (62) reported impaired maximal and submaximal cardiorespiratory responses in young overweight women with PCOS. The reason for discrepancy between these studies is not entirely clear, but may be related to varying degrees of IR. VO 2max is inversely related to markers of IR (59, 62), and in the study by Orio et al., fasting insulin concentrations were substantially higher than reported in other studies (20.2 vs ~15 IU/L). Although IR is common in PCOS it is not universally present (63) due to numerous PCOS phenotypes. It is possible that varying degrees of IR between 6

8 studies could explain discrepancies in the observed findings. Further studies are required that directly compare VO 2max in normoinsulinemic and hyperinsulinemic women with PCOS to better understand the interrelationships Muscle strength is a marker of exercise tolerance that predicts functional ability and participation in active living tasks (64, 65). Only one known study has examined the effects of PCOS on muscle strength (59) and found no differences in isometric or isokinetic knee extensor strength between women with PCOS and healthy controls. However, the study was limited by a small sample size and minimal differences in the degree of IR between the groups. Previous research has shown an inverse relationship between muscular strength and IR in a number of populations, including overweight and obese sedentary women (66) and reduced muscle strength in patients with metabolic disturbances, including type 2 diabetes (67). Hence, further research in PCOS with higher levels of IR is necessary to confirm these previous findings. Wright et al. (68) reported no difference in free-living physical activity levels between women with PCOS and controls suggesting that PCOS may not impact negatively on the ability to tolerate exercise or participate in daily living tasks and the inclusion of exercise programs in PCOS management should be as well tolerated as in other populations Effect of exercise on CVD risk factors In the first known study to investigate the effects of exercise in PCOS, Randeva et al. (69) showed that a 6-month walking program (n=12; minutes per fortnight) increased VO 2max and decreased waist-hip ratio (WHR), with no changes in BMI, fasting 7

9 insulin, lipids or FAI compared to women that did not adhere to the program (n=9). Participants in the exercising group completed 80% of the target exercise volume, indicating that walking was an achievable form of exercise; however nine failed to take up or complete the program. In a randomised controlled trial, Brown et al. (70) showed in 20 sedentary women with PCOS that a 5-month supervised aerobic exercise program (~228 minutes per week at 60% VO 2max ) had no effect on weight, waist circumference (WC) or fasting insulin; but a trend for improved area under the insulin curve (-26%). More recently, an uncontrolled study in 32 women with PCOS participating in supervised group exercise (goal of minutes per week) and nutrition classes showed that 66% of women lost more than 3% of body weight and those that exercised 2 or more times per week reduced their WC (71). However, on average participants completed only 8.8 weeks of out of the desired 14 weeks, with personal time commitments cited as the most common reason for discontinuing (71). This suggests that higher exercise levels may not be sustainable for these women over the long term. Young women have high perceived time pressure due to work and family commitments, which can be a barrier to healthy eating and physical activity participation (72). This may result in the development of a perception that recommended behavioural changes to achieve optimum lifestyle habits are not feasible (73). Promoting and encouraging activities that fit within the context of young women s daily routines may overcome this barrier, together with providing a supportive environment (74) More recently, larger studies have evaluated the effects of exercise in women with PCOS. In a randomised controlled study, Vigorito et al. (75) showed in 90 overweight women 8

10 with PCOS that a 3-month structured aerobic exercise program (40 minutes cycling at 60-70% VO 2max, 3 times per week) improved fasting insulin (9.0%), BMI (4.5%), and WC (2.9%) but not blood lipid levels compared with non-exercising controls. In an unrandomised, controlled study of 40 obese women with PCOS, Palomba et al. (76) compared 24-weeks of aerobic exercise (30 minutes cycling, 3 times per week) with a hypocaloric, high-protein diet. Although both interventions reduced body weight, WC, fasting insulin, IR and improved the reproductive hormone profile, greater improvements in WC, SHBG, FAI and insulin levels were reported with exercise, despite greater weight loss in the dieting subjects (76). This suggests that exercise training may offer greater benefits for improving IR and reproductive hormones compared with diet induced weight loss. However, treatments were self-selected in an unrandomised manner, which may have biased the results and limits inferences that can be drawn While the study by Palomba et al. (76) assessed the relative effects of diet and exercise, whether there was any additive exercise benefit when combined with energy restriction was not determined. A small, randomised study by Bruner et al. (77) showed that 12- weeks of nutritional counselling alone (n=5) or combined with aerobic-resistance exercise (n=7; 3 sessions per week of 30 minutes walking/cycling and 12 resistance exercises) both reduced fasting insulin levels, with the addition of exercise promoting greater reductions in body fat. More recently, we showed that three different 20-week lifestyle modification treatments, diet only (n=30; 5,000-6,000 kj/day), diet and aerobic exercise (n=31; minutes walking/jogging 5 times per week) and diet and combined aerobic-resistance exercise (n=33; minutes walking/jogging 3 times per week and 9

11 resistance training twice per week) reduced body weight, blood pressure (BP), triglycerides, cholesterol, glucose and insulin levels, with no differences between treatments (78). However, compared with diet alone, exercise provided more favourable effects on body composition with greater reductions in fat mass (~45%) and preservation of fat-free mass (~60%), with no difference between aerobic exercise and combined aerobic-resistance exercise (78). Other studies have demonstrated that preservation of fatfree mass assists in maintaining resting metabolic rate and long-term weight maintenance (44, 54, 79). Taken together, these data suggest that exercise training during energy restriction for weight loss may have important implications for long-term maintenance of weight loss in PCOS, however longer-term studies are required to confirm this Overall, considerable diversity in the degree of changes in IR in response to exercise treatments between studies was observed. While the heterogeneous nature of exercise interventions, including differences in exercise type, duration, frequency and intensity and intervention length could potentially explain these differences, varying degrees of hyperinsulinemia across study populations could be a contributing factor. Due to the heterogeneous diagnostic criteria of PCOS, numerous phenotypes have been identified and a minority of women (~16%) have normal insulin levels (1). It is therefore possible that whilst studies examining women with higher baseline values (~20 IU/L) showed greater improvements in fasting insulin compared to a non-exercising controls (122) or a diet group (123), in other studies the relatively low baseline insulin levels may have tempered the insulin response to exercise (124, 125). In the study by Bruner et al. (77), while both treatment groups experienced reductions in fasting insulin, initial levels varied 10

12 substantially between groups (33.6 v 16.8 IU/L). Consequently, it is possible that any additional effect of exercise was masked by the lower baseline insulin level in that group. Similarly, the somewhat lower baseline insulin levels (~16.1 IU/L) evident in women 235 examined by Thomson et al. (78) may explain the lack of any differences in improvements in insulin sensitivity between treatments; although the possibility that the potent effects of energy-restriction may have overridden and masked any additional effects of exercise cannot be dismissed. These data suggest the importance of specifically examining the effects of exercise in various PCOS phenotypes which may respond differently to interventions. It is also noteworthy that most studies to date have used indirect methods to assess IR (fasting insulin levels, HOMA) and visceral fat (WC, WHR) which may have influenced the results and the use of more sensitive methods (hyperinsulinemic-euglycemic clamp or CT) would be appropriate for future studies Heart rate recovery (HRR), defined as the reduction in heart rate (HR) 1 minute after a maximal exercise test, is an emerging powerful independent predictor of CVD and all cause mortality (80-82). HRR is inversely related to IR (83) and is impaired in young overweight women with PCOS (84-86). However, few studies have investigated the effect of lifestyle modification on HRR to determine whether it is a modifiable risk factor. We recently showed that HRR was improved in overweight and obese women with PCOS following a 10-week weight loss program incorporating diet with and without exercise (87). The improvement in HRR was related to weight loss and reductions in WC, with no independent effect of exercise (87). In a non-randomised controlled study, Giallauria et al. (88) reported significant improvements in HRR, BMI, WHR, fasting 11

13 insulin, IR and aerobic fitness following a 3-month exercise training program consisting of 30 minutes cycling at 60-70% VO 2max, 3 times per week compared to untrained controls (exercise=62; control=62). The researchers suggested that the exercise-induced improvement in HRR was mediated by reductions in BMI and improvements in insulin sensitivity, rather than increased fitness (88). From these studies it is evident that HRR is impaired in women with PCOS and lifestyle management can improve HRR in this population, which is likely mediated by reductions in body weight and IR Effect of exercise on reproductive function Several studies have examined the health effects of exercise as part of general lifestyle modification programs (20, 30, 32); however few studies have investigated specific effects of exercise training in PCOS on reproductive outcomes. A preliminary uncontrolled study by Aubuchon et al. (71) reported that 6 women became pregnant during the 14-week study or within 3 months of completion, which was 46% of women desiring pregnancy. There were no observed differences in body composition changes or eating behaviours between pregnancy occurrence, and no other measures were taken (71). Vigorito et al. (75) showed in previously anovulatory women with PCOS that a 3-month aerobic training program restored normal menstrual cyclicity in 60% (27/45) of women. Similarly, Palomba et al. (76) reported that 24 weeks of dieting or aerobic exercise improved menstrual cyclicity and ovulation in overweight women with PCOS, with no observed differences in quantity or cycle length between treatments. However, menses frequency and ovulation rates were higher in the exercising group with a trend for higher pregnancy rates and greater improvements in hormonal profile (76). Body weight, BMI, 12

14 WC, fasting insulin, IR, testosterone, SHBG and FAI improved in those that ovulated, while no changes were observed in any parameters in women who remained anovulatory (76). The investigators hypothesised that improved insulin sensitivity was the primary factor involved in ovarian function restoration given that the exercise group, which experienced greater improvements in insulin sensitivity, experienced the greatest ovulation improvements. More recently, we reported that 49% of women with PCOS improved ovulation and/or menstrual cyclicity following 20-weeks of an energyrestricted diet alone or combined with aerobic exercise or aerobic-resistance exercise, with no difference between treatments (78). Importantly, while there were no differences between treatments in the number of menstrual cycles during the 20 week intervention period, women in the combined diet and exercise groups experienced more ovulatory cycles than the diet only group. Overall, exercise studies have shown improvements in menstrual cyclicity and/or ovulation in ~50% of PCOS women; comparable to that observed with other weight loss interventions. Improvements in insulin and hormonal profile appear to play important mediating roles for improving reproductive function, although this is not exclusively the case. Further research is needed to explore the role of exercise and weight loss in improving reproductive function. Future research is also needed to investigate the effects of exercise during pregnancy as it may provide benefits such as limiting complications and preventing excess weight gain (128, 129) Exercise and psychological well-being in PCOS Currently, only two studies have investigated the effect of exercise on psychological outcomes in PCOS. A small, nonrandomised study in overweight and obese women with 13

15 PCOS reported that a 6-month self-directed brisk walking program improved body image distress scores (89). Recently, Thomson et al. (90) observed similar improvements in HRQOL and depression in overweight women with PCOS after 20-weeks following an energy-restricted diet with and without exercise (aerobic only or combined aerobicresistance exercise). Separate studies also show improvements in self-esteem, depression and anxiety following lifestyle modification programs aimed at improving fertility in obese infertile women that include information about increasing exercise (20, 32, 91). While these studies show promising results, further research is needed to evaluate the effects of exercise on numerous psychological outcomes in overweight women with PCOS Conclusion The multifaceted health implications of PCOS and its potential to increase in prevalence in the future have underscored the importance of identifying effective therapies for prevention and treatment of PCOS and its associated consequences. It is well documented that modest weight loss via energy restriction improves an array of deranged factors in PCOS women. However, despite the well-established benefits of exercise training for the general population, and its recommendation as a cornerstone of PCOS management, few well-controlled studies have evaluated the effect of exercise training in PCOS. Based on the limited data available, exercise appears to have beneficial effects, with reports of improvements in fitness, body composition, fasting insulin, IR, menstrual cyclicity, ovulation, self-esteem, quality of life scores and depression. However, the majority of studies are limited by small samples sizes, lack appropriate control groups and 14

16 assessments of habitual physical activity, non-randomisation to treatments and/or short study durations that limit the generalisability of the findings, making it difficult to draw definitive conclusions. Future research should endeavour to establish the necessary exercise dose, type, intensity and frequency required for treating and managing PCOS, with specific consideration of differing phenotypes. Additional research is also needed to further examine the health benefits of undertaking exercise in conjunction with energyrestricted weight loss for women with PCOS

17

18 334 References 1 Norman RJ, Dewailly D, Legro RS, Hickey TE. Polycystic ovary syndrome. Lancet. 2007; 370: Dunaif A. Insulin resistance and the polycystic ovary syndrome: Mechanism and implications for pathogenesis. Endocr Rev. 1997; 18: van der Spuy ZM, Dyer SJ. The pathogenesis of infertility and early pregnancy loss in polycystic ovary syndrome. Best Pract Res Clin Obstet Gynaecol. 2004; 18: Boomsma CM, Eijkemans MJ, Hughes EG, Visser GH, Fauser BC, Macklon NS. A meta-analysis of pregnancy outcomes in women with polycystic ovary syndrome. Hum Reprod Update. 2006; 12: Nestler JE, Clore JN, Blackard WG. The central role of obesity (hyperinsulinemia) in the pathogenesis of the polycystic ovary syndrome. Am J Obstet Gynecol. 1989; 161: Moran L, Norman RJ. Understanding and managing disturbances in insulin metabolism and body weight in women with polycystic ovary syndrome. Best Pract Res Clin Obstet Gynaecol. 2004; 18: Talbott EO, Zborowskii JV, Boudraux MY. Do women with polycystic ovary syndrome have an increased risk of cardiovascular disease? Review of the evidence. Minerva Ginecologica. 2004; 56: Shroff R, Kerchner A, Maifeld M, Van Beek EJR, Jagasia D, Dokras A. Young Obese Women with Polycystic Ovary Syndrome Have Evidence of Early Coronary Atherosclerosis. J Clin Endocrinol Metab. 2007; 92: Alexander CJ, Tangchitnob EP, Lepor NE. Polycystic ovary syndrome: a major unrecognized cardiovascular risk factor in women. Rev Obstet Gynecol. 2009; 2: Legro RS. Polycystic ovary syndrome and cardiovascular disease: A premature association? Endocr Rev. 2003; 24: Ching HL, Burke V, Stuckey BG. Quality of life and psychological morbidity in women with polycystic ovary syndrome: Body mass index, age and the provision of patient information are significant modifiers. Clinical Endocrinology. 2007; 66: Himelein MJ, Thatcher SS. Depression and body image among women with polycystic ovary syndrome. J Health Psychol. 2006; 11: Barnard L, Ferriday D, Guenther N, Strauss B, Balen AH, Dye L. Quality of life and psychological well being in polycystic ovary syndrome. Hum Repr. 2007; 22: Ehrmann DA. Polycystic ovary syndrome. N Engl J Med. 2005; 352: Azziz R, Woods KS, Reyna R, Key TJ, Knochenhauer ES, Yildiz BO. The prevalence and features of the polycystic ovary syndrome in an unselected population. J Clin Endocrinol Metab. 2004; 89: Lo JC, Feigenbaum SL, Yang J, Pressman AR, Selby JV, Go AS. Epidemiology and adverse cardiovascular risk profile of diagnosed polycystic ovary syndrome. J Clin Endocrinol Metab. 2006; 91: Pasquali R, Gambineri A, Pagotto U. The impact of obesity on reproduction in women with polycystic ovary syndrome. BJOG. 2006; 113:

19 18 Azziz R. Overview of long-term morbidity and economic cost of the polycystic ovary syndrome. In: Azziz R, Nestler JE, Dewailly D (eds.). Androgen excess disorders in women: Polycystic ovary syndrome and other disorders. Humana Press: Totowa, New Jersey 2006; Azziz R. Long-term morbidity of PCOS: Estimating the economic burden of PCOS. In: Azziz R (ed.). The polycystic ovary syndrome: Current concepts on pathogenesis and clinical care. Springer: New York, New York 2007; Clark AM, Ledger W, Galletly C, Tomlinson L, Blaney F, Wang X, Norman RJ. Weight loss results in significant improvement in pregnancy and ovulation rates in anovulatory obese women. Hum Repr. 1995; 10: Holte J, Bergh T, Berne C, Wide L, Lithell H. Restored insulin sensitivity but persistently increased early insulin secretion after weight loss in obese women with polycystic ovary syndrome. J Clin Endocrinol Metab. 1995; 80: Barber TM, McCarthy MI, Wass JAH, Franks S. Obesity and polycystic ovary syndrome. Clinical Endocrinology. 2006; 65: Barbieri RL, Smith S, Ryan KJ. The role of hyperinsulinemia in the pathogenesis of ovarian hyperandrogenism. Fertil Steril. 1988; 50: Insler V, Shoham Z, Barash A, Koistinen R, Seppala M, Hen M, Lunenfeld B, Zadik Z. Polycystic ovaries in non-obese and obese patients: Possible pathophysiological mechanism based on new interpretation of facts and findings. Hum Reprod. 1993; 8: Nelson VL, Qin K-n, Rosenfield RL, Wood JR, Penning TM, Legro RS, Strauss JF, III, McAllister JM. The biochemical basis for increased testosterone production in theca cells propagated from patients with polycystic ovary syndrome. J Clin Endocrinol Metab. 2001; 86: Nelson VL, Legro RS, Strauss JF, III, McAllister JM. Augmented androgen production is a stable steroidogenic phenotype of propagated theca cells from polycystic ovaries. Mol Endocrinol. 1999; 13: Westphal SA. Obesity, Abdominal Obesity, and Insulin Resistance. Clinical Cornerstone. 2008; 9: Moran LJ, Noakes M, Clifton PM, Tomlinson L, Norman RJ. Dietary composition in restoring reproductive and metabolic physiology in overweight women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2003; 88: Andersen P, Seljeflot I, Abdelnoor M, Arnesen H, Dale PO, Lovik A, Birkeland K. Increased insulin sensitivity and fibrinolytic capacity after dietary intervention in obese women with polycystic ovary syndrome. Metabolism. 1995; 44: Huber-Buchholz MM, Carey DG, Norman RJ. Restoration of reproductive potential by lifestyle modification in obese polycystic ovary syndrome: Role of insulin sensitivity and luteinizing hormone. J Clin Endocrinol Metab. 1999; 84: Moran LJ, Noakes M, Clifton PM, Wittert GA, Williams G, Norman RJ. Shortterm meal replacements followed by dietary macronutrient restriction enhance weight loss in polycystic ovary syndrome. Am J Clin Nutr. 2006; 84: Clark A, Thornley B, Tomlinson L, Galletley C, Norman R. Weight loss in obese infertile women results in improvement in reproductive outcome for all forms of fertility treatment. Hum Repr. 1998; 13:

20 33 Kiddy DS, Hamilton-Fairley D, Bush A, Short F, Anyaoku V, Reed MJ, Franks S. Improvement in endocrine and ovarian function during dietary treatment of obese women with polycystic ovary syndrome. Clinical Endocrinology. 1992; 36: Galletly C, Moran L, Noakes M, Clifton P, Tomlinson L, Norman R. Psychological benefits of a high-protein, low-carbohydrate diet in obese women with polycystic ovary syndrome--a pilot study. Appetite. 2007; 49: Mavropoulos JC, Yancy WS, Hepburn J, Westman EC. The effects of a lowcarbohydrate, ketogenic diet on the polycystic ovary syndrome: A pilot study. Nutrition and Metabolism. 2005; 2: Norman RJ, Davies MJ, Lord J, Moran LJ. The role of lifestyle modification in polycystic ovary syndrome. Trends Endocrinol Metab. 2002; 13: Jakicic JM, Otto AD. Treatment and prevention of obesity: What is the role of exercise? Nutrition Reviews. 2006; 64: S57-S Lynch J, Helmrich SP, Lakka TA, Kaplan GA, Cohen RD, Salonen R, Salonen JT. Moderately intense physical activities and high levels of cardiorespiratory fitness reduce the risk of non-insulin-dependent diabetes mellitus in middle-aged men. Arch Intern Med. 1996; 156: Manson JE, Greenland P, LaCroix AZ, Stefanick ML, Mouton CP, Oberman A, Perri MG, Sheps DS, Pettinger MB, Siscovick DS. Walking compared with vigorous exercise for the prevention of cardiovascular events in women. N Engl J Med. 2002; 347: Lee IM, Hsieh CC, Paffenbarger RS, Jr. Exercise intensity and longevity in men. The Harvard Alumni Health Study. JAMA: The Journal of the American Medical Association. 1995; 273: DiLorenzo TM, Bargman EP, Stucky-Ropp R, Brassington GS, Frensch PA, LaFontaine T. Long-term effects of aerobic exercise on psychological outcomes. Preventive Medicine. 1999; 28: Scully D, Kremer J, Meade MM, Graham R, Dudgeon K. Physical exercise and psychological well being: A critical review. British Journal of Sports Medicine. 1998; 32: Penedo FJ, Dahn JR. Exercise and well-being: A review of mental and physical health benefits associated with physical activity. Current Opinion in Psychiatry. 2005; 18: Tremblay A, Doucet E, Imbeault P. Physical activity and weight maintenance. Int J Obes. 1999; 23: S Anderson JW, Konz EC, Frederich RC, Wood CL. Long-term weight-loss maintenance: A meta-analysis of US studies. Am J Clin Nutr. 2001; 74: Shaw K, Gennat H, O'Rourke P, Del Mar C. Exercise for overweight or obesity. Cochrane Database of Systematic Reviews. 2006; 18: CD Wu T, Gao X, Chen M, van Dam RM. Long-term effectiveness of diet-plusexercise interventions vs. diet-only interventions for weight loss: A meta-analysis. Obesity Reviews Miller WC, Koceja DM, Hamilton EJ. A meta-analysis of the past 25 years of weight loss research using diet, exercise or diet plus exercise intervention. International Journal of Obesity and Related Metabolic Disorders. 1997; 21:

21 49 Klem M, Wing R, McGuire M, Seagle H, Hill J. A descriptive study of individuals successful at long-term maintenance of substantial weight loss. Am J Clin Nutr. 1997; 66: Carroll S, Dudfield M. What is the relationship between exercise and metabolic abnormalities? A review of the metabolic syndrome. Sports Med. 2004; 34: Cauza E, Hanusch-Enserer U, Strasser B, Ludvik B, Metz-Schimmerl S, Pacini G, Wagner O, Georg P, Prager R, Kostner K, Dunky A, Haber P. The relative benefits of endurance and strength training on the metabolic factors and muscle function of people with type 2 diabetes mellitus. Arch Phys Med Rehabil. 2005; 86: Ibanez J, Izquierdo M, Arguelles I, Forga L, Larrion JL, Garcia-Unciti M, Idoate F, Gorostiaga EM. Twice-weekly progressive resistance training decreases abdominal fat and improves insulin sensitivity in older men with type 2 diabetes. Diabetes Care. 2005; 28: Schmitz KH, Hannan PJ, Stovitz SD, Bryan CJ, Warren M, Jensen MD. Strength training and adiposity in premenopausal women: strong, healthy, and empowered study. Am J Clin Nutr. 2007; 86: Stiegler P, Cunliffe A. The role of diet and exercise for the maintenance of fatfree mass and resting metabolic rate during weight loss. Sports Med. 2006; 36: Cuff DJ, Meneilly GS, Martin A, Ignaszewski A, Tildesley HD, Frohlich JJ. Effective exercise modality to reduce insulin resistance in women with type 2 diabetes. Diabetes Care. 2003; 26: Sigal RJ, Kenny GP, Boule NG, Wells GA, Prud'homme D, Fortier M, Reid RD, Tulloch H, Coyle D, Phillips P, Jennings A, Jaffey J. Effects of aerobic training, resistance training, or both on glycemic control in type 2 diabetes: A randomized trial. Annals of Internal Medicine. 2007; 147: Park SK, Park JH, Kwon YC, Kim HS, Yoon MS, Park HT. The effect of combined aerobic and resistance exercise training on abdominal fat in obese middle-aged women. Journal of Physiological Anthropology & Applied Human Science. 2003; 22: Davidson LE, Hudson R, Kilpatrick K, Kuk JL, McMillan K, Janiszewski PM, Lee S, Lam M, Ross R. Effects of exercise modality on insulin resistance and functional limitation in older adults: A randomized controlled trial. Arch Intern Med. 2009; 169: Thomson R, Buckley J, Moran L, Noakes M, Clifton P, Norman R, Brinkworth G. Comparison of aerobic exercise capacity and muscle strength in overweight women with and without polycystic ovary syndrome. BJOG. In press. 60 Segal KR, Dunaif A. Resting metabolic rate and postprandial thermogenesis in polycystic ovarian syndrome. Int J Obes. 1990; 14: Cosar E, Köken G, Sahin FK, Akgün L, Üçok K, Genç A, Yilmazer M. Resting metabolic rate and exercise capacity in women with polycystic ovary syndrome. International Journal of Gynecology & Obstetrics. 2008; 101: Orio F, Jr., Giallauria F, Palomba S, Cascella T, Manguso F, Vuolo L, Russo T, Tolino A, Lombardi G, Colao A, Vigorito C. Cardiopulmonary impairment in young women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2006; 91: Carmina E, Napoli N, Longo RA, Rini GB, Lobo RA. Metabolic syndrome in polycystic ovary syndrome (PCOS): Lower prevalence in southern Italy than in the USA 20

22 and the influence of criteria for the diagnosis of PCOS. Eur J Endocrinol. 2006; 154: Wilson JR. Evaluation of skeletal muscle fatigue in patients with heart failure. J Mol Cell Cardiol. 1996; 28: Visser M, Newman AB, Nevitt MC, Kritchevsky SB, Stamm EB, Goodpaster BH, Harris TB. Reexamining the sarcopenia hypothesis. Muscle mass versus muscle strength. Health, Aging, and Body Composition Study Research Group. Ann N Y Acad Sci 2000; 904: Karelis AD, Tousignant B, Nantel J, Proteau-Labelle M, Malita FM, St-Pierre DH, Brochu M, Doucet E, Rabasa-Lhoret R. Association of insulin sensitivity and muscle strength in overweight and obese sedentary postmenopausal women. Appl Physiol Nutr Metab. 2007; 32: Jurca R, Lamonte MJ, Church TS, Earnest CP, Fitzgerald SJ, Barlow CE, Jordan AN, Kampert JB, Blair SN. Associations of muscle strength and fitness with metabolic syndrome in men. Med Sci Sports Exerc. 2004; 36: Wright CE, Zborowski JV, Talbott EO, McHugh-Pemu K, Youk A. Dietary intake, physical activity, and obesity in women with polycystic ovary syndrome. International Journal of Obesity and Related Metabolic Disorders. 2004; 28: Randeva HS, Lewandowski KC, Drzewoski J, Brooke-Wavell K, O'Callaghan C, Czupryniak L, Hillhouse EW, Prelevic GM. Exercise decreases plasma total homocysteine in overweight young women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2002; 87: Brown AJ, Setji TL, Sanders LL, Lowry KP, Otvos JD, Kraus WE, Svetkey PL. Effects of exercise on lipoprotein particles in women with polycystic ovary syndrome. Medicine & Science in Sports & Exercise. 2009; 41: Aubuchon M, Laughbaum N, Poetker A, Williams D, Thomas M. Supervised short-term nutrition and exercise promotes weight loss in overweight and obese patients with polycystic ovary syndrome. Fertil Steril. 2009; 91: Andajani-Sutjahjo S, Ball K, Warren N, Inglis V, Crawford D. Perceived personal, social and environmental barriers to weight maintenance among young women: A community survey. The International Journal of Behavioural Nutrition and Physical Activity. 2004; 1: Ball K, Crawford D, Warren N. How feasible are healthy eating and physical activity for young women? Public Health Nutrition. 2004; 7: Caperchoine C, Mummery WK, Joyner K. Addressing the challenges, barriers, and enablers to physical activity participation in priority women's groups. J Phys Act Health. 2009; 6: Vigorito C, Giallauria F, Palomba S, Cascella T, Manguso F, Lucci R, De Lorenzo A, Tafuri D, Lombardi G, Colao A, Orio F. Beneficial effects of a three-month structured exercise training program on cardiopulmonary functional capacity in young women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2007; 92: Palomba S, Giallauria F, Falbo A, Russo T, Oppedisano R, Tolino A, Colao A, Vigorito C, Zullo F, Orio F. Structured exercise training programme versus hypocaloric hyperproteic diet in obese polycystic ovary syndrome patients with anovulatory infertility: A 24-week pilot study. Hum Repr. 2007; 23:

23 77 Bruner B, Chad K, Chizen D. Effects of exercise and nutritional counseling in women with polycystic ovary syndrome. Appl Physiol Nutr Metab. 2006; 31: Thomson RL, Buckley JD, Noakes M, Clifton PM, Norman RJ, Brinkworth GD. The effect of a hypocaloric diet with and without exercise training on body composition, cardiometabolic risk profile, and reproductive function in overweight and obese women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2008; 93: Svendsen OL, Hassager C, Christiansen C. Effect of an energy-restrictive diet, with or without exercise, on lean tissue mass, resting metabolic rate, cardiovascular risk factors, and bone in overweight postmenopausal women. Am J Med. 1993; 95: Cole CR, Blackstone EH, Pashkow FJ, Snader CE, Lauer MS. Heart-rate recovery immediately after exercise as a predictor of mortality. New England Journal of Medicine. 1999; 341: Mora S, Redberg RF, Cui Y, Whiteman MK, Flaws JA, Sharrett AR, Blumenthal RS. Ability of exercise testing to predict cardiovascular and all-cause death in asymptomatic women: A 20-year follow-up of the Lipid Research Clinics Prevalence Study. JAMA. 2003; 290: Cole CR, Foody JM, Blackstone EH, Lauer MS. Heart rate recovery after submaximal exercise testing as a predictor of mortality in a cardiovascularly healthy cohort. Annals of Internal Medicine. 2000; 132: Lind L, Andren B. Heart rate recovery after exercise is related to the insulin resistance syndrome and heart rate variability in elderly men. American Heart Journal. 2002; 144: Giallauria F, Palomba S, Manguso F, Vitelli A, Maresca L, Tafuri D, Lombardi G, Colao A, Vigorito C, Orio F. Abnormal heart rate recovery after maximal cardiopulmonary exercise stress testing in young overweight women with polycystic ovary syndrome. Clinical Endocrinology. 2008; 68: Giallauria F, Orio F, Lombardi G, Colao A, Vigorito C, Tafuri MG, Palomba S. Relationship between heart rate recovery and inflammatory markers in patients with polycystic ovary syndrome: A cross-sectional study. Journal of Ovarian Research. 2009; 2: Tekin G, Tekin A, KIlIçarslan EB, Haydardedeoglu B, KatIrcIbasI T, Koçum T, Erol T, Çölkesen Y, Sezgin AT, Müderrisoglu H. Altered autonomic neural control of the cardiovascular system in patients with polycystic ovary syndrome. International Journal of Cardiology. 2008; 130: Thomson RL, Buckley JD, Noakes M, Clifton PM, Norman RJ, Brinkworth GD. Heart rate recovery improves after weight loss in overweight and obese women with polycystic ovary syndrome. Fertil Steril. 2010; 93: Giallauria F, Palomba S, Maresca L, Vuolo L, Tafuri D, Lombardi G, Colao A, Vigorito C, Orio F. Exercise training improves autonomic function and inflammatory pattern in women with polycystic ovary syndrome. Clinical Endocrinology. 2008; 69: Liao LM, Nesic J, Chadwick PM, Brooke-Wavell K, Prelevic GM. Exercise and body image distress in overweight and obese women with polycystic ovary syndrome: A pilot investigation. Gynecological Endocrinology. 2008; 24:

24 90 Thomson RL, Buckley JD, Lim SS, Noakes M, Clifton PM, Norman RJ, Brinkworth GD. Lifestyle management improves quality of life and depression in overweight and obese women with polycystic ovary syndrome. Fertil Steril. In press. 91 Galletly C, Clark A, Tomlinson L, Blaney F. A group program for obese, infertile women: weight loss and improved psychological health. Journal of Psychosomatic Obstetrics and Gynaecology. 1996; 17:

25 337 24

26 338 Table 1. Intervention trials investigating the effect of exercise in overweight women with polycystic ovary syndrome Study N=* Intervention Study Design Intervention Duration Randeva et al. (69) Aubuchon et al. (71) Brown et al. (70) Vigorito et al. (75) Palomba et al. (76) Bruner et al. (77) Thomson et al. (78) 21 progressive brisk walking program (12 completers vs 8 noncompleters) 32 supervised exercise sessions & nutrition classes 20 supervised aerobic exercise program (n = 8) vs control (n = 12) 90 structured aerobic exercise program (n = 45) vs untrained controls (n = 45) 40 aerobic exercise program (n = 20) vs hypocaloric high protein diet (n = 20) 12 nutritional counselling (n = 5) vs nutritional counselling and combined aerobic resistance exercise (n = 7) 94 diet (n = 30) vs diet and aerobic exercise (n = 31) vs diet and combined aerobic-resistance exercise (n=33) BMI (kg/m 2 )^ Cardiometabolic Outcomes Single arm 6 months 35.5 ± 7.6 aerobic fitness BMI, insulin, lipids WHR Reproductive Outcomes Single arm 14 weeks 36.4± 5.3 weight, BMI, WC, HC 6 pregnancies (46% who desired) Randomised controlled trial Randomised controlled trial Non randomised controlled trial (based on preference) Randomised controlled trial Randomised controlled trial 5 months Exercise: 37.9 (9.4) Control: 31.3 (14.9) 3 months Exercise: 29.3 ±2.9, Control: 29.4 ± weeks Exercise: 33.1 ±1.3 Diet: 33.2 ± weeks Nutrition: 37.1 ± 5.6 N+Exercise: 36.2 ± 4.6 insulin, glucose, insulin resistance weight, BMI, WC, HC, BP aerobic fitness insulin, insulin resistance BMI, WC, WHR, BP blood lipids, glucose aerobic fitness Weight (greater in diet group) WC, insulin (greater in exercise group) glucose fasting insulin WC body fat (exercise only) 20 weeks 36.1 ± 4.8 weight, WC BP, lipids, glucose insulin, HOMA body fat (greater in exercise groups) 60% restored normal menstrual cyclicity Improved menstrual cycles and fertility menses frequency, ovulation rate (higher in exercise) 49% improved menstrual cyclicity and ovulation Hormonal Outcomes FAI testosterone SHBG testosterone FAI testosterone SHBG (greater in exercise group) FAI (greater in exercise group) SHBG testosterone FAI testosterone SHBG FAI Psychological Outcomes 25

27 Thomson et al. (87) Giallauria et al. (88) Thomson et al. (90) 57 weight loss program (diet with and without exercise) 124 aerobic exercise program (n = 62) vs untrained controls (n = 62) 49 diet (n = 14) vs diet and aerobic exercise (n = 15) vs diet and combined aerobic-resistance exercise (n=20) Liao et al (89) 23 self directed walking program (12 completers vs 11 non-completers) Single arm study Non randomised controlled trial (based on preference) Randomised controlled trial 10 weeks 36.2 ±5.3 HRR weight, WC BP, glucose, insulin, HOMA 3 months Exercise: 29.2 ± 2.9 Control: 29.5 ± 3.5 BMI,WHR, insulin and insulin resistance HRR, aerobic fitness lipids, glucose, BP testosterone SHBG FAI 20 weeks 36.1 ± 4.8 weight depression scores HRQOL Single arm 6 months 36.9 ± 7.3 BMI body image distress Abbreviations: BMI, body mass index; BP, blood pressure; FAI, free androgen index; HOMA, homeostasis model assessment of insulin resistance; HRQOL, health-related quality of life; HRR, heart rate recovery; SHBG, sex-hormone binding globulin; WC, waist circumference; WHR, waist hip ratio;, unchanged;, decrease;, increase *participants that completed the intervention ^values are mean ± standard deviation values are mean (interquartile range)