Metabolic syndrome, diet and exercise

Accepted Manuscript Chapter 11: Metabolic Syndrome, Diet and Exercise Sunita MC. De Sousa, MBBS(Hons), Dr., Robert J. Norman AO, BSc(Hons) MBChB(Hons) MD FRANZCOG FRCPA FRCPath FRCOG CREI FAHMS

PII:

S1521-6934(16)00007-9

DOI:

10.1016/j.bpobgyn.2016.01.006

Reference:

YBEOG 1591

To appear in:

Best Practice & Research Clinical Obstetrics & Gynaecology

Received Date: 14 January 2016 Accepted Date: 16 January 2016

Please cite this article as: De Sousa SM, Norman AO RJ, Chapter 11: Metabolic Syndrome, Diet and Exercise, Best Practice & Research Clinical Obstetrics & Gynaecology (2016), doi: 10.1016/ j.bpobgyn.2016.01.006. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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ACCEPTED MANUSCRIPT BEST PRACTICE & RESEARCH CLINICAL OBSTETRICS & GYNAECOLOGY Issue 30.8

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Chapter 11: Metabolic Syndrome, Diet and Exercise Sunita MC De Sousa MBBS(Hons),1,2 Robert J Norman AO BSc(Hons) MBChB(Hons) MD

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FRANZCOG FRCPA FRCPath FRCOG CREI FAHMS,3-6

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Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide, Australia

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Hormones and Cancer Group, Garvan Institute of Medical Research, Sydney, Australia Robinson Research Institute, University of Adelaide, Adelaide, Australia

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Fertility SA, Adelaide, Australia

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Reproductive Endocrinology and Fertility, Royal Adelaide Hospital, Adelaide, Australia

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Corresponding author:

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NHMRC Centre for Research Excellence in Polycystic Ovary Syndrome, Adelaide, Australia

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Dr Sunita MC De Sousa

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A: Endocrine and Metabolic Unit, Royal Adelaide Hospital, North Tce, Adelaide, Australia

Ph: +61 8 8222 2512 F: +61 8 8222 2888

E: [email protected]

Word count: 6961

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ACCEPTED MANUSCRIPT Abstract Polycystic ovary syndrome (PCOS) is associated with a range of metabolic complications including insulin resistance, obesity, dyslipidaemia, hypertension, obstructive sleep apnoea and non-alcoholic fatty liver disease. These compound risks result in a high prevalence of

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metabolic syndrome and possibly increased cardiovascular disease. As the cardiometabolic risk of PCOS is shared amongst the different diagnostic systems, all women with PCOS should undergo metabolic surveillance though the precise approach differs between

guidelines. Lifestyle interventions consisting of increased physical activity and caloric

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restriction have been shown to improve both metabolic and reproductive outcomes.

Pharmacotherapy and bariatric surgery may be considered in resistant metabolic disease.

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Issues requiring further research include the natural history of PCOS-associated metabolic disease, absolute cardiovascular risk, and comparative efficacy of lifestyle interventions.

Keywords: polycystic ovary syndrome; metabolic syndrome; insulin resistance;

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cardiometabolic risk; lifestyle intervention; diet; exercise.

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ACCEPTED MANUSCRIPT Introduction Polycystic ovary syndrome (PCOS) is one of the commonest endocrinopathies with prevalence rates of 6-18% depending on diagnostic criteria and ethnicity [1-5]. Timely diagnosis of PCOS and an understanding of the cardiometabolic ramifications of PCOS

potentially large benefits at a population level.

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provides the opportunity for cardiovascular (CV) and metabolic risk modification with

Though the aetiology of PCOS is yet to be fully elucidated, insulin resistance (IR) appears

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central to its pathogenesis, resulting in disordered folliculogenesis and increased

cardiometabolic risk most classically presenting as metabolic syndrome (MbS) [6]. IR is

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found in women with PCOS irrespective of their weight though it is more common with increasing weight and waist circumference (WC) [7], which is especially significant as PCOS women are more likely to be overweight and have central obesity compared to the general

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population [8].

The definition of MbS is a source of confusion, but generally rests upon the combination of multiple adverse CV risk factors [9]. The commonest definition used is the National

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Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) criteria whereby MbS is diagnosed in women if three of five criteria are present: WC ≥88cm in Caucasians or

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≥80cm in Asians, fasting triglycerides (TG) ≥1.7mmol/L, high-density lipoprotein cholesterol (HDL-C) <1.3mmol/L, blood pressure (BP) ≥130/85mmHg, and fasting glucose ≥5.5mmol/L [10].

Guidelines exist to support clinicians in the assessment and management of the metabolic aspects of PCOS and this review predominantly draws upon recommendations by the Androgen Excess and PCOS (AE-PCOS) Society [9], the US Endocrine Society [11], and the PCOS Australian Alliance [12]. Many recommendations are based on consensus opinion or suboptimal evidence due to deficits in the literature including reliance on referral centre

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patients, methodological discrepancies particularly regarding indices of IR, and inconsistency between lifestyle interventions.

Metabolic effects of PCOS

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The central role of IR in PCOS is supported by the high prevalence of IR even in lean PCOS women, the stimulatory role of insulin in ovarian androgenesis, the inhibitory role of insulin in hepatic synthesis of sex hormone binding globulin (SHBG), and exacerbation of the

reproductive and metabolic features of PCOS by concomitant IR [12, 13]. Importantly, IR

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appears to progress quickly in PCOS with a study of 67 women showing high rates of

conversion from normoglycaemia to impaired glucose tolerance (IGT) (9%), and IGT to

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T2DM (54%) over a mean follow-up of 6.2 years [14]. Obesity and hyperandrogenism may contribute to IR in PCOS, however a cross-sectional study of 178 overweight/obese PCOS women found that only SHBG which is a marker of IR, and not serum testosterone, was associated with PCOS diagnostic criteria, MbS and IR [15]. Nonetheless, IR is not universally

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present in PCOS with prevalence rates between 50-80% depending on weight and ethnicity suggesting that IR may be highly contributory but not necessary in PCOS [13].

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There is also an interplay between obesity and PCOS, but the exact causation remains to be determined. After adjustment for BMI, PCOS women still have increased rates of IR,

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dyslipidaemia, hypertension, obstructive sleep apnoea (OSA), MbS, pre-eclampsia, gestational diabetes, fetal macrosomia and adverse neonatal outcomes. Obesity increases these risks, and PCOS women have been consistently shown to have higher rates of obesity, although the degree of this risk varies between populations [16]. In a Chinese study, the strongest predictive factor for MbS amongst PCOS women was BMI (OR 1.420, 95% CI 1328-1.518) [17]. Variability in the role of obesity is partly due to ethnic differences in lifestyle and genetic factors with obesity present in 69% of US women with PCOS versus 38% of Italian women with PCOS despite similar caloric intake [18]. PCOS women also have higher

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ACCEPTED MANUSCRIPT rates of central adiposity and adipocyte dysfunction with reduced adiponectin even when adjusted for BMI [19, 20].

PCOS women are at increased risk for dyslipidaemia (OR 1.53, 95% CI 1.39-1.68) [21], with

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typical patterns including raised very-low-density lipoprotein, low-density lipoprotein cholesterol (LDL-C) and TG, and low HDL-C [22]. PCOS-associated dyslipidaemia is

primarily due to IR whereby the ability of insulin to suppress lipolysis is diminished, leading to increased breakdown of adipose tissue into free fatty acids. [9]. A retrospective study of 106

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US and 108 Italian women with PCOS found that US women had higher BMI and

commensurate increases in total cholesterol, LDL-C and TG, and lower HDL-C, however

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these differences persisted after controlling for weight indicating other genetic and environmental contributors [23]. PCOS women also have higher rates of hypertension (OR 1.41, 95% CI 1.31-1.51) independent of BMI [21].

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PCOS is an important risk factor for type 2 diabetes mellitus (T2DM). A meta-analysis of 30 studies found that PCOS women compared to the general population have odds ratios of 2.48 (95% CI 1.63-3.77) for IGT and 4.43 (95% CI 4.06-4.82) for T2DM [24]. Odds ratios

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remained elevated at 2.54 for IGT and 4.00 for T2DM when only BMI-matched studies were analysed. Even in the absence of overt T2DM or other evidence of IR, PCOS women

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demonstrate an excess of advanced glycosylation end-products (AGE) which are one of the principal mechanisms of hyperglycaemia-mediated tissue damage [25].

IR, obesity, dyslipidaemia, hypertension and hyperglycaemia are component features of MbS and all are more common in women with PCOS. Accordingly, a meta-analysis of 35 studies found increased rates of MbS in PCOS women in unmatched studies (OR 2.88, 95% CI 2.403.45) and in studies where PCOS women were compared against BMI-matched controls (OR 2.20, 95% CI 1.36-3.56) [24]. Again, whilst there is an independent relationship between PCOS and MbS, weight appears to have a modifying effect [26]. OSA is part of this cluster of

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ACCEPTED MANUSCRIPT PCOS-associated cardiometabolic complications, presenting with daytime somnolence, fatigue, and overnight snoring and apnoeic episodes [16]. In a case-control study, 53 PCOS women and 452 age-matched controls underwent polysomnography finding a 30-fold

increase in the prevalence of sleep-disordered breathing in PCOS women (OR 30.6, 95% CI

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7.2-139.4) [27]. IR, but not BMI or serum testosterone, was predictive of polysomnography abnormalities. Non-alcoholic fatty liver disease (NAFLD) is also associated with MbS and, as expected, NAFLD is more prevalent in women with PCOS [16], especially in the setting of low HDL, high TG and high fasting insulin which are predictive of raised aminotransferase

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levels [28].

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There has been much debate as to whether the adverse metabolic milieu of PCOS translates into increased CV disease or mortality. PCOS was originally assumed to increase CV disease due to clustering of traditional CV risk factors such as IR, dyslipidaemia and hypertension [16]. PCOS is also associated with non-traditional CV risk factors such as

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raised CRP, homocysteine, plasminogen activator inhibitor-1, lipoprotein A and AGE products [29], as well as endothelial dysfunction and reduced fibrinolysis [12]. Small studies demonstrate evidence of subclinical CV disease amongst PCOS women including increased

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carotid intima-media thickness [30], coronary artery calcification [31] and left ventricular mass [32]. Higher rates of angiographically diagnosed ischaemic heart disease, the combined

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endpoint of myocardial infarction and CV death, and stroke were revealed in a substudy of the Women’s Ischemia Evaluation Study, however these findings have since been withdrawn as the results could not be replicated [33]. Extrapolating from studies of risk factors and surrogate markers, it nonetheless appears that PCOS is associated with increased CV disease and that it is largely related to obesity and possibly also hyperandrogenism [9]. This is supported by a meta-analysis of five longitudinal studies which showed a BMI-adjusted relative risk of CV events of 1.55 (95%CI 1.27-1.89) for PCOS women compared to controls [34].

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The metabolic ramifications of PCOS extend into pregnancy with PCOS women experiencing higher rates of gestational diabetes, gestational hypertension, pre-eclampsia, and preterm birth compared to the general population [35, 36]. PCOS women are also at increased risk of obesity, multiple pregnancy and requiring assisted reproductive technology all of which may

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contribute to obstetric complications, however the risk of metabolic complications of pregnancy remains after correction for these factors [37]. The weight gain of pregnancy, which often persists beyond the postpartum period, may exacerbate the natural history of

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PCOS though this requires clarification by long-term prospective studies [38].

PCOS reproductive phenotypes and metabolic health

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The NIH, Rotterdam and AE-PCOS diagnostic systems may be viewed as different reproductive phenotypes of PCOS. The original National Institutes of Health (NIH) criteria require clinical or biochemical hyperandrogenism, and chronic oligo-ovulation or anovulation [39]. The non-NIH diagnostic criteria include the Rotterdam 2003 criteria and the AE-PCOS

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Society 2006 criteria, and are sometimes considered ‘milder’ forms of PCOS. The Rotterdam criteria require two of three criteria to be fulfilled: clinical or biochemical hyperandrogenism, chronic oligo-ovulation or anovulation, and polycystic ovaries [40]. The AE-PCOS criteria

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mandate either clinical or biochemical hyperandrogenism, in addition to either chronic oligo-

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ovulation or anovulation, or polycystic ovaries [41].

The diagnostic system employed influences the prevalence of PCOS as shown in a cohort study where PCOS was diagnosed in 8.7% of women by NIH criteria, 10.2% by AE-PCOS criteria and 11.9% by Rotterdam criteria [5]. Each phenotype appears to carry significant metabolic risk with some variation in the expression of this risk. Women with either PCO or PCOS together with irregular menstrual cycles have higher insulin and glucose concentrations than women with ovulatory PCOS [42]. Studies have also demonstrated higher rates of MbS [43] and IR [44] in NIH PCOS compared to non-NIH PCOS, however the women with PCOS by NIH criteria were also more likely to be obese in these studies [43,

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44]. When women of similar BMI and waist-to-hip ratio (WHR) are compared, NIH PCOS and non-NIH PCOS result in similar insulin sensitivity [45, 46], and rates of hypertension and dyslipidaemia [46]. Central adiposity is also contributory as PCOS women of comparable BMI experience increased IR proportional to increases in WC [47]. Overall, the risks of IR,

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T2DM and MbS appear similar amongst the PCOS phenotypes and generally dependent upon and proportionate to the severity of total and abdominal obesity [6, 17]. Lean PCOS women should also be monitored as weight, and thus cardiometabolic risk, may change with time [6, 46]. Given these findings demonstrating that cardiometabolic risk is shared amongst

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women with NIH PCOS and non-NIH PCOS, 1.5% or 3.2% of women at increased cardiometabolic risk may be missed if the NIH or AE-PCOS criteria are employed,

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respectively. The Rotterdam criteria are now universally supported by European Society for Human Reproduction and Embryology and the American Society of Reproductive Medicine who originally proposed the guidelines [48], as well as the NIH [49] and Australian PCOS Alliance [12]. In practice, women of all PCOS phenotypes should be assessed for metabolic

Interindividual variation

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complications.

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The metabolic effects of PCOS vary with other interindividual factors, especially ethnicity and age. Unlike other populations, Asian women with PCOS are no more likely to be obese

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compared to Asian women without PCOS, however obesity still has metabolic effects when present [46]. Indigenous women in Australia appear to be particularly at-risk for PCOS. An Australian study found that 15.3% of urban-dwelling Indigenous women had PCOS by NIH criteria [50], which was significantly higher than another Australian study which diagnosed PCOS in only 8.7% of the general population [5]. Interestingly, though central adiposity is proportionately greater amongst Indigenous Australians than non-Indigenous, only BMI and not WHR was predictive of PCOS in this study [50]. This is in contrast with other data, both in Caucasian and Asian women, showing that PCOS is closely linked with central obesity [8].

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Together, the evidence supports measurement of both BMI and WHR in cardiometabolic risk assessment.

Geographical location may exert a greater influence on the development of PCOS than

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ethnicity as American studies have failed to show statistically significant differences in PCOS prevalence in women of different races [1, 3]. The effect of ethnicity is also related to family history. An American study of 408 PCOS women found that family history of T2DM predicted WC, WHR, dehydroepiandrosterone sulphate, HbA1c and IR, whereas ethnicity after

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adjustment for family history only predicted HbA1c, fasting insulin levels and IR [51].

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PCOS is increasingly seen as a disease with variable expression over the lifespan. In adolescents, the presentation of PCOS is confounded by physiological menstrual irregularity and hirsutism associated with early puberty. Ultrasound is also plagued by methodological concerns and limited normative data in adolescents, however biochemical hyperandrogenism

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remains useful in the evaluation for PCOS in adolescents [52]. Securing the diagnosis is important despite these diagnostic difficulties as adolescents with PCOS have high rates of

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metabolic abnormalities, including IR in over 60% [53].

Metabolic surveillance

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Assessment of PCOS-associated cardiometabolic risk should begin with documentation of existing metabolic complications including obesity, dyslipidaemia, hypertension, IGT, T2DM, OSA and MbS, as well as family history of premature CV disease and adverse lifestyle factors such as smoking and sedentary lifestyle [11, 16]. The AE-PCOS guidelines [9], which also draw upon recommendations from the American Heart Association [54], indicate that PCOS women be classified at risk of CV disease if obesity, smoking history, hypertension, dyslipidaemia, subclinical vascular disease, IGT or family history of premature CV disease is present, whilst PCOS women with MbS, T2DM, clinically evident vascular disease or renal disease should be considered at high risk.

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PCOS women should be formally assessed for traditional CV risk factors [9, 11, 12], but exactly how this is undertaken differs between guidelines. Hypertension is a key priority in metabolic surveillance as reducing BP yields the greatest CV risk reduction [9]. The AE-

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PCOS and Endocrine Society guidelines recommend BP measurement at every visit [9, 11], and the AE-PCOS Society recommends a BP target of 120/80mmHg [9]. The PCOS

Australian Alliance guidelines state that BP measurement need only be performed yearly in lean women compared to every visit in overweight/obese PCOS women, and the only

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recommended BP target is ≤135/85mmHg in PCOS women who are at high risk of T2DM [12]. Factors which determine the risk of T2DM include age, ethnicity, parental history of

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T2DM, previous hyperglycaemia, antihypertensive requirement, smoking history, sedentary lifestyle and WC [12]. Hence, examination should include WC and BMI, and this should be re-assessed at every visit because of changes in the degree and distribution of obesity with time [9, 11, 12]. BMI classifies patients as underweight (BMI <18.5kg/m2), lean (18.5-

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24.9kg/m2), overweight (25-29.9kg/m2), obese (30.0-34.9kg/m2) or morbidly obese (≥35kg/m2) [55]. WC should be measured at the level of the anterior superior iliac spine for consistency [9]. WC of 80-87cm indicates increased metabolic risk and WC ≥88cm indicates

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a very high metabolic risk [55]. As women of some non-Caucasian ethnicities appear to have greater metabolic risks at a given adiposity, lower BMI and WC targets may be prudent in

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high-risk ethnic groups [9, 12]. The Endocrine Society guidelines additionally recommend inspection for cutaneous signs of IR, namely acanthosis nigricans and skin tags [11].

Investigations should include fasting lipid profiles at baseline [9, 11, 12], and then every two years if normal and weight is stable [9, 12]. The frequency of lipid studies should be increased to annually in women with dyslipidaemia and/or excess weight [12], and may be performed six weeks after initiating treatment to assess response [9]. The primary target from a cardiovascular perspective is LDL-C lowering to <1.8mmol/L if there is concomitant T2DM, clinical vascular disease or renal disease; <2.6mmol/L if concomitant MbS; and <3.4mmol/L

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in the absence of comorbidities [9, 12]. The primary metabolic goals are TG <1.7mmol/L [9, 12], and HDL-C >1.0mmol/L [12] or 0.7mmol/L above the LDL-C target [9]. Total cholesterol should be <4mmol/L [12]. The AE-PCOS guidelines specifically advise against measuring

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apolipoprotein B as testing is not currently standardised [9].

Consensus guidelines internationally recommend the 2-hour 75g oral glucose tolerance test (OGTT) to screen for IGT and T2DM in PCOS [9, 11, 12]. OGTT should be performed after an 8-hour fast with adequate carbohydrate intake (≥150g daily) for three preceding days as

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low carbohydrate intake may produce false-positive results [12]. Impaired fasting glucose (IFG) is defined as fasting plasma glucose 6.1-6.9mmol/L whilst IGT is defined as 2-hour

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plasma glucose 7.8-11.0mmol/L. T2DM is diagnosed when either fasting plasma glucose is ≥7.0mmol/L or 2-hour plasma glucose is ≥11.1mmol/L [12]. OGTT is favoured over fasting glucose measurement as this is frequently normal in PCOS women with IGT or T2DM [56]. Furthermore, IFG is a weaker prognostic marker than IGT [57]. The PCOS Australian

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Alliance recommends OGTT in all PCOS women at baseline and then either annually in women with T2DM risk factors or every second year in others [12]. In contrast, the AE-PCOS guidelines only recommend baseline OGTT in PCOS women with BMI >30kg/m2 or lean

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PCOS women older than 40 years, personal history of gestational diabetes or family history of T2DM [9]. Rescreening should be performed either every second year if the baseline

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OGTT results were normal, or annually if IGT is found or other risk factors emerge [9]. Citing the lack of evidence for rescreening, the Endocrine Society guidelines suggest baseline OGTT in all PCOS women followed by repeat OGTT every 3-5 years, or sooner if additional risk factors emerge [11]. HbA1c ≥6.5% is 99% specific for OGTT-defined T2DM in PCOS women, however sensitivity is poor at 35% [58] and hence this screening method should be employed only when OGTT is not possible [11]. There is no role for insulin measurement in clinical settings [12].

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ACCEPTED MANUSCRIPT Screening protocols for NAFLD and OSA are less clear and only the Endocrine Society

guidelines provide recommendations. For NAFLD, the guidelines recommend against routine biochemical screening and instead suggest targeted liver function tests in PCOS women with IR or other metabolic risk factors. Ultrasonography and liver biopsy should then be

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considered if biochemical dysfunction is present [11]. For OSA, symptomatic screening should be undertaken in overweight/obese PCOS women [11]. This involves asking for

classical symptoms including snoring, overnight apnoeas and daytime somnolence, or it may be more objectively assessed by the Epworth Sleepiness Score which assesses the degree

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of daytime somnolence in activities such as driving and reading [59]. If patients screen positive, the Endocrine Society recommends definitive testing using overnight

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polysomnography [11]. There may be clinical utility in diagnosing and treating OSA as a small study of 19 PCOS women found that even a short 8-week course of continuous positive airway pressure (CPAP) produced improved insulin sensitivity and benefits

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correlated with hours of CPAP usage and decreased BMI [60].

Lifestyle intervention in PCOS

Lifestyle intervention to achieve weight loss represents first-line management of PCOS-

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associated cardiometabolic risk [9, 12]. A systematic review of lifestyle intervention in PCOS identified six randomised controlled trials (RCT) comparing lifestyle treatment to minimal or

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no treatment. Lifestyle interventions consisted of exercise alone or a combination of dietary, exercise and behavioural intervention. Benefits in actively treated women included reduced total testosterone, hirsutism, weight, WC, central adiposity, and fasting and OGTT insulin levels; however there were no changes in BMI, bioavailable testosterone, SHBG, glucose or lipids. Patient satisfaction was not reported in the included studies, however the benefits observed may be useful in motivational counselling of PCOS women in clinical practice [61]. The benefits appear more pronounced in overweight/obese PCOS women as most studies have been conducted in women of higher BMI and it appears unlikely that weight loss in lean PCOS women will reverse established metabolic complications [11]. Lifestyle modifications

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should nonetheless be extended to lean women in order to prevent weight gain, particularly as PCOS women suffer an increased propensity for weight gain [12].

There is other data demonstrating improved mental health and reproductive outcomes with

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lifestyle intervention in PCOS women [9, 12]. Most recently, an RCT comparing the oral contraceptive pill (OCP), lifestyle modification with weight loss agents (sibutramine or

orlistat), and combined lifestyle modification and the OCP found that the interventions which included lifestyle modification yielded significant weight loss and higher ovulation rates.

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arm, was mitigated by lifestyle intervention [62].

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Additionally, the risk of MbS with later ovulation induction, which was observed in the OCP

As there is good evidence of general health benefits from dietary and exercise interventions, a combined approach is recommended [12]. Effective strategies for instigating lifestyle intervention include self-monitoring techniques such as food diaries and pedometers, time

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management advice, relapse prevention techniques, engagement of social support, and goal setting [9, 12]. Women should be advised that the benefits of lifestyle intervention may be observed with as little as 5% weight loss [12]. One of the earliest studies supporting this

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demonstrated that exercise and dietary intervention with 6.3kg weight loss in PCOS women resulted in resumption of ovulation in most women as well as improved fertility, decreased

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serum testosterone, decreased fasting insulin, increased SHBG and improved psychological scores [63]. Whether this relatively small weight difference continues to achieve such benefits with increasing BMI in contemporary clinical practice remains to be elucidated. For now, the AE-PCOS guidelines suggest a target of 5-10% weight loss in overweight/obese PCOS women with long-term goals of 10-20% weight loss and WC <80-88cm tailored to ethnicity [9]. The PCOS Australian Alliance recommends lifestyle management in all PCOS women [12].

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ACCEPTED MANUSCRIPT Of relevance to the PCOS population desiring fertility, intensive weight loss should be embarked upon prior to attempts to conceive as marked weight loss prior to IVF has been associated with adverse outcomes including increased cycle cancellation and decreased rates of fertilisation, implantation, ongoing pregnancy and live births [64]. The long-term

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effects of periconceptional weight loss on offspring through epigenetic changes are the focus of ongoing study [38].

Anxiety and depression frequently coexist with PCOS, though it is unclear if this is a direct

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consequence of PCOS or due to associated psychological stressors such as obesity,

hirsutism and infertility [16]. It is nonetheless reasonable for primary clinicians of PCOS

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women to screen for mental health illness and offer counselling and/or psychiatric referrals as required [9, 12]. Maintenance of long-term weight loss is particularly challenging and requires attention to other lifestyle factors including alcohol intake and smoking cessation

The role of diet

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which may also benefit from formal psychology input [65].

There has been significant interest in macronutrient variation to achieve weight loss. A study

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of 811 overweight adults randomised to one of four diets with different fat, protein and carbohydrate composition found that all patients achieved reductions in weight, lipids, BP

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and IR with similar degrees of weight loss, long-term weight maintenance, satiety, hunger, patient satisfaction and adherence between the groups [66]. In PCOS women, a study comparing high protein versus high carbohydrate diets found that both resulted in significant weight loss (-3.7 +/- 1.9 kg vs. -4.4 +/- 1.5kg, respectively) with no differences in degree of weight loss, androgen studies or IR [67].

It is currently recommended that PCOS women with BMI ≥25kg/m2 aim for weight loss via caloric restriction through balanced dietary approaches irrespective of diet composition [9, 11, 12]. In the general adult population, a target energy deficit of 2500kJ daily is

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ACCEPTED MANUSCRIPT recommended for weight loss [55]. The AE-PCOS guidelines provide further guidance as listed in Table 1 [9].

As for the general population, discussions regarding dietary intervention in PCOS women

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should take into account the degree of obesity, dietary preferences, and food availability. An alcohol history should also be taken given its high but frequently underestimated caloric

content [55]. It is important to be aware of the possibility of an eating disorder, especially in PCOS women who are 6.4-times more likely to have an eating disorder than women without

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PCOS [68]. If an eating disorder is suspected, referral to a dietitian should be considered. Other than similarly complex situations, dietary advice can and should be given by any health

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professional caring for PCOS women [12]. Helpful behavioural strategies in instigating lifestyle modifications include face-to-face advice and education, and advice on practical approaches to healthy eating tailored to the patient [12].

The role of exercise

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[INSERT TABLE 1]

Exercise-based studies are hampered by a lack of randomisation and counselling-based

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intervention rather than supervised exercise [38], however there is evidence of beneficial effects from exercise in PCOS women even in the absence of significant weight loss [9, 12].

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Thrice weekly exercise for 30 minutes has been demonstrated to reduce BMI, WC, WHR and IR, and improve maximal oxygen consumption during exercise in young PCOS women [69]. Another study employing a 12-week regimen of aerobic exercise for three hours weekly in overweight PCOS women resulted in reduced IR, serum TG, and total and abdominal fat mass despite no weight changes [70]. Overweight women without PCOS were also studied, however they did not achieve reductions in IR or serum TG suggesting that PCOS women may preferentially benefit from exercise which may be used as a motivational factor when counselling PCOS women.

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ACCEPTED MANUSCRIPT Most studies assess exercise or dietary intervention either separately or in combination, however one non-randomised study directly compared these strategies in 40 obese PCOS women with exercise producing greater menstrual cyclicity and ovulation compared to diet. On comparison of women who achieved ovulation via either approach, exercise yielded

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greater reductions in IR whilst dietary intervention resulted in greater reductions in body weight, BMI and WC [71].

Endocrine Society are provided in Table 2 [9, 11, 12].

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[INSERT TABLE 2]

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Exercise recommendations by the PCOS Australian Alliance, AE-PCOS Society and

Other management strategies for the metabolic effects of PCOS Metformin is the main pharmacological option for the metabolic effects of PCOS. A recent meta-analysis consisting of 608 PCOS women found that combined lifestyle intervention and

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metformin were associated with reduced BMI and adipose tissue as well as increased menstrual cycles compared to lifestyle intervention alone [72]. However, there were no differences in other parameters such as IR, lipids and BP, and weight and BMI were similar

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on comparison of metformin monotherapy and lifestyle intervention. The PCOS Australian Alliance guidelines recommend metformin as second-line pharmacotherapy after clomiphene

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in PCOS women who wish to conceive [12]. The AE-PCOS guidelines suggest metformin in PCOS women with IGT refractory to lifestyle intervention or if already lean [9]. The Endocrine Society guidelines suggest metformin as second-line therapy after lifestyle and hormonal therapies in all metabolic and reproductive settings apart from IVF where metformin is suggested periconceptionally to reduce the risk of ovarian hyperstimulation syndrome [11]. Thiazolidinediones also increase insulin sensitivity, however they currently have no role in PCOS due to an unfavourable risk-benefit profile [9, 11, 12].

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ACCEPTED MANUSCRIPT With regards to other medications, the AE-PCOS and Endocrine Society guidelines advise that statins and antihypertensives are additive if lipid and BP targets are exceeded despite

lifestyle intervention, however the teratogenicity of these medications must be considered [9, 11]. Though sibutramine and later orlistat were employed in the aforementioned RCT

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comparing metformin and lifestyle interventions [62], the AE-PCOS guidelines currently recommend against the use of weight-loss agents [9].

The most effective and durable treatment for obesity in the general population is bariatric

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surgery. In a prospective single-arm study of 36 PCOS women, bariatric surgery led to resolution of PCOS in all women present at long-term follow-up with decreases in

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hyperandrogenism, IR, menstrual irregularity and anovulation [73]. A systematic review found that maternal and neonatal complications amongst women following bariatric surgery were fewer compared to obese women who did not undergo surgery and/or similar to non-obese controls [74]. The AE-PCOS guidelines suggest consideration of bariatric surgery in PCOS

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women with BMI >40kg/m2, or BMI >35kg/m2 in the presence of severe obesity-related comorbidities, and refractoriness to lifestyle intervention [9]. The PCOS Australian Alliance guidelines state that bariatric surgery should be considered second-line therapy to improve

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fertility outcomes in PCOS women with anovulation and obesity (BMI ≥35kg/m2) refractory to intensive lifestyle modification and/or pharmacotherapy [12]. If pursued, pregnancy should

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probably be avoided for >12-18 months postoperatively, though the optimal timing of pregnancy after bariatric surgery remains to be elucidated [38].

Summary

The metabolic manifestations of PCOS include IR, obesity, dyslipidaemia, T2DM, MbS, OSA and NAFLD. Management of PCOS-associated cardiometabolic risk involves metabolic surveillance through serial history-taking, examination and selected investigations. Even with uncertainty surrounding the association of PCOS and CV disease, it remains prudent to optimise cardiometabolic risk using dietary and exercise interventions to induce weight loss

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and/or prevent weight gain. Pharmacotherapy and bariatric surgery are second-line options if lifestyle modifications fail, particularly in the presence of IGT or T2DM. A multidisciplinary, holistic approach including gynaecologists, endocrinologists, exercise physiologists, dietitians and psychologists is useful in women with PCOS who have established metabolic

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complications. Addressing the cardiometabolic risk of PCOS women with may have significant public health benefits given the high prevalence of PCOS which is expected to increase commensurate with the obesity epidemic, the predominance of CV disease in allcause mortality amongst females, and the relatively early presentation of PCOS providing the

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opportunity for primary prevention of CV disease [11, 12, 16].

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ACCEPTED MANUSCRIPT Table 1. Dietary recommendations for PCOS women by the AE-PCOS Society [9].

Caloric restriction (reduce current diet by 500-1000 kcal/day) Decreased intake of total fat (<30% total caloric intake) and saturated fat (<10% total

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caloric intake) Increased intake of fibre, wholegrain breads and cereals, vegetables, fruit, and monounsaturated and polyunsaturated fat

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Additional strategies in PCOS women with dyslipidaemia (and expected reductions in

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LDL-C):

Reduce saturated fat to 7% total energy (8-10%)

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Add 2g of plant stanols daily (6-10%)

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Add 5-10g viscous fibre daily (3-5%)

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Reduce dietary cholesterol to <200mg daily (3-5%)

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Reduce trans fat to 1% total energy (2%)

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Weight loss by 7-10% (5-8%)

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ACCEPTED MANUSCRIPT Table 2. Exercise recommendations for PCOS women derived from major international guidelines [9, 11, 12]. PCOS Australian Alliance:

≥150 minutes of exercise weekly, including 90 minutes of moderate-to-high intensity

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aerobic activity at 60-90% of maximal heart rate Exercise recommended for all women, especially if overweight/obese AE-PCOS Society:

≥30 minutes of moderate-intensity physical activity daily with gradual increase according

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to exercise tolerance

Personal goals to target weight loss e.g. if walking, daily aim should be 15,000 steps or

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45 minutes duration

Exercise recommended for all women, especially if dyslipidaemic Endocrine Society:

Exercise recommended together with dietary modification for overweight/obese PCOS

Referrals to consider:

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Exercise physiology if comorbidities that may worsen with exercise e.g. osteoarthritis

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Cardiology, including consideration of cardiac stress testing, if established cardiovascular

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symptoms e.g. exertional dyspnoea

Conflict of interest statement: Nothing to declare

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ACCEPTED MANUSCRIPT Practice points •

Women with PCOS are at risk of metabolic complications regardless of BMI, PCOS phenotype, ethnicity or age

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Metabolic surveillance protocols differ between guidelines, however consistent

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components include: Documentation of existing metabolic disease, smoking history, dietary and

Assessment of BP, WC and BMI

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Periodic fasting lipid profile and OGTT

Combined lifestyle intervention, aiming for 5-10% weight loss in overweight/obese

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exercise habits, and family history of premature CV disease

women and prevention of weight gain in lean women, is first-line therapy for PCOSassociated metabolic complications •

Dietary intervention should focus on caloric restriction and exercise should consist of regular aerobic activity after screening for CV symptoms

Behavioural strategies including face-to-face advice and screening for mental health

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disorders are integral to the success of lifestyle intervention •

Metformin, statins, antihypertensives and bariatric surgery are second-line therapies for

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PCOS-associated metabolic complications

Research agenda •

Lifecourse progress of metabolic problems and absolute risk of CV disease in PCOS

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Accuracy and cost-effectiveness of screening for IFG, IGT, T2DM, OSA and NAFLD

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Extent of benefits, durability and comparative advantages of different lifestyle and psychological interventions

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Methods to enhance patient engagement in lifestyle intervention

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Role of bariatric surgery in PCOS women, especially regarding reproductive outcomes

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BEST PRACTICE & RESEARCH CLINICAL OBSTETRICS & GYNAECOLOGY Issue 30.8 Chapter 11: Metabolic Syndrome, Diet and Exercise Highlights •

PCOS is associated with a range of complications necessitating metabolic

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surveillance Weight loss of 5-10% body weight has metabolic and reproductive benefits

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Lifestyle intervention consisting of dietary modifications and exercise is effective

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Uptake of lifestyle recommendations may be enhanced by behavioural strategies

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Pharmacotherapy and bariatric surgery are second-line therapies in PCOS

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