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Metabolic consequences of obesity and insulin resistance in polycystic ovary syndrome: diagnostic and methodological challenges

Published online by Cambridge University Press:  22 February 2017

Yvonne M. Jeanes
Affiliation:
Health Science Research Centre, Department of Life Sciences, University of Roehampton, London SW15 4JD, UK
Sue Reeves*
Affiliation:
Health Science Research Centre, Department of Life Sciences, University of Roehampton, London SW15 4JD, UK
*
*Corresponding author: Dr Sue Reeves, email s.reeves@roehampton.ac.uk
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Abstract

Women with polycystic ovary syndrome (PCOS) have a considerable risk of metabolic dysfunction. This review aims to present contemporary knowledge on obesity, insulin resistance and PCOS with emphasis on the diagnostic and methodological challenges encountered in research and clinical practice. Variable diagnostic criteria for PCOS and associated phenotypes are frequently published. Targeted searches were conducted to identify all available data concerning the association of obesity and insulin resistance with PCOS up to September 2016. Articles were considered if they were peer reviewed, in English and included women with PCOS. Obesity is more prevalent in women with PCOS, but studies rarely reported accurate assessments of adiposity, nor split the study population by PCOS phenotypes. Many women with PCOS have insulin resistance, though there is considerable variation reported in part due to not distinguishing subgroups known to have an impact on insulin resistance as well as limited methodology to measure insulin resistance. Inflammatory markers are positively correlated with androgen levels, but detailed interactions need to be identified. Weight management is the primary therapy; specific advice to reduce the glycaemic load of the diet and reduce the intake of pro-inflammatory SFA and advanced glycation endproducts have provided promising results. It is important that women with PCOS are educated about their increased risk of metabolic complications in order to make timely and appropriate lifestyle modifications. Furthermore, well-designed robust studies are needed to evaluate the mechanisms behind the improvements observed with dietary interventions.

Type
Review Article
Copyright
Copyright © The Authors 2017 

Introduction

Polycystic ovary syndrome (PCOS) is a common endocrine–metabolic disorder affecting 12–18 % of women, depending on the diagnostic criteria used( Reference March, Moore and Willson 1 ). Women with PCOS are at lifelong risk of metabolic dysfunction and have increased risk of insulin resistance (IR), type 2 diabetes mellitus (T2DM), dyslipidaemia and atherosclerosis( Reference Wild 2 ). The pathophysiology of PCOS is complex and to some extent remains unclear; PCOS has a genetic heritability and several potential genes have been identified. However, research in this area is still in its infancy( Reference Kokosar, Benrick and Perfilyev 3 , Reference Obermayer-Pietsch, Trummer and Schwetz 4 ) and is influenced by environmental factors, most notably diet and increased body weight( Reference Pasquali, Stener-Victorin and Yildiz 5 ). The progression of research and translation into clinical practice are hindered by the variability of diagnostic and methodological issues endemic in studies of PCOS( Reference Moran, Norman and Teede 6 ).

Therefore the aim of this review is to present current knowledge on the association between obesity, IR and PCOS and in doing so highlight some of the diagnostic and methodological challenges encountered in research and clinical practice. Targeted searches were conducted to identify all available data concerning the association of obesity and IR with PCOS in order to summarise current knowledge on this topic up to September 2016. PubMed and Science Direct were utilised in order to locate relevant scientific reports and papers and ensure an extensive review of the literature. Articles were considered if they were peer reviewed, in English and included women with PCOS (all diagnostic methods).

PCOS is a heterogeneous condition, the symptoms of which often first present during the teenage years( Reference Hecht Baldauff and Arslanian 7 ), though the symptoms vary in their severity and can also change with age. The symptoms include: menstrual irregularity, acne, excess male pattern hair (hirsutism), male pattern alopecia, central adiposity and fertility issues. Many of the symptoms associated with PCOS have been shown to lead to a reduction in health-related quality of life( Reference Jones, Hall and Balen 8 ) and consequently depression and anxiety are commonly reported in women with PCOS, independent of body-weight status( Reference Dokras, Clifton and Futterweit 9 ). Although obesity is a common feature of PCOS, lean women with PCOS are also at increased disease risk when compared with matched controls and can also suffer debilitating symptoms( Reference Kokosar, Benrick and Perfilyev 3 ). IR is not within any of the diagnostic criteria; however, the majority of lean and overweight women with PCOS have a form of IR intrinsic to PCOS and the compensatory hyperinsulinaemia drives many of the phenotypic features of PCOS( Reference Stepto, Cassar and Joham 10 ). Hyperinsulinaemia promotes ovarian hyperandrogenism which is present in 60–80 % of women with PCOS; the androgen excess predominately results from increased synthesis and release of ovarian androgens( Reference Stepto, Cassar and Joham 10 ). In combination, hyperinsulinaemia and hyperandrogenaemia can disrupt follicle growth; this is accompanied by menstrual irregularity, anovulatory sub-fertility and accumulation of immature follicles( Reference Pasquali, Stener-Victorin and Yildiz 5 ).

The most widely used criteria for clinical diagnosis of PCOS involve the presence of two of the three features listed in Table 1, with the exclusion of other endocrine disorders as developed by the European Society of Human Reproduction and Embryology (ESHRE) and the American Society for Reproductive Medicine (ASRM)( 11 ), and are otherwise known as the Rotterdam criteria.

Table 1 Diagnostic criteria for polycystic ovary syndrome (PCOS)( Reference Azziz, Carmina and Dewailly 18 )

NIH, National Institutes of Health; AE, androgen excess.

* The presence of two of the following three features with the exclusion of other endocrine disorders.

There are distinct phenotypic presentations associated with PCOS, and over the years several sub-categories have been suggested. In 2012 at the National Institutes of Health workshop there was a general consensus( 12 ) and these categories are as follows:

Androgen excess + ovulatory dysfunction;

Androgen excess + polycystic ovarian morphology;

Ovulatory dysfunction + polycystic ovarian morphology;

Androgen excess + ovulatory dysfunction + polycystic ovarian morphology.

Several studies have highlighted that women with PCOS who have regular ovulatory cycles often have normal insulin sensitivity with milder metabolic abnormalities compared with women with PCOS with ovulatory dysfunction( Reference Carmina, Chu and Longo 13 , Reference Strowitzki, Capp and von Eye Corleta 14 ). Women who are anovulatory with hyperandrogenism are considered to be at the greatest metabolic risk( Reference Bil, Dilbaz and Cirik 15 ). Women with hyperandrogenic PCOS generally present with a worse cardiometabolic profile compared with women with non-hyperandrogenic PCOS( Reference Barber, Wass and McCarthy 16 Reference Azziz, Carmina and Dewailly 18 ). It is generally agreed that the heterogeneity in the PCOS population, studies not reporting specific PCOS phenotypes, and the different methodologies used to report IR and obesity/visceral fat have led to controversy in the relationship between obesity, IR and PCOS( Reference Moran, Norman and Teede 6 , Reference Teede, Deeks and Moran 19 ).

Obesity and polycystic ovary syndrome

Obesity is a common feature of PCOS. A meta-analysis of cross-sectional and retrospective studies illustrated there is a greater prevalence of obesity in PCOS; BMI >30 kg/m2 (relative risk 2·77; 95 % CI 1·88, 4·10; PCOS n 4165; controls n 4885) compared with healthy women( Reference Lim, Davies and Norman 20 ). The variability of data reporting the prevalence of obesity in women with PCOS is likely to reflect geographical, environmental and population variability between studies. There is also uncertainty as to whether PCOS causes weight gain and obesity or if obesity is linked to the development of PCOS( Reference Hoeger and Oberfield 21 , Reference Teede, Joham and Paul 22 ). Furthermore, clarification of the role of adiposity in PCOS entails measurements other than the measurement of BMI.

A meta-analysis clearly indicated that overweight or obese women with PCOS had significantly worse metabolic and reproductive outcomes when compared with healthy-weight women with PCOS( Reference Lim, Norman and Davies 23 ). Palomba et al.( Reference Palomba, de Wilde and Falbo 24 ) confirmed that obesity has a bidirectional relationship with PCOS and noted that excessive weight gain could unmask a latent PCOS condition. IR promotes the development of visceral adiposity in women with PCOS, whereas the role of androgens is less clear( Reference Spritzer, Lecke and Satler 25 ). Tosi et al. ( Reference Tosi, Di Sarra and Kaufman 26 ) have recently shown adiposity to be correlated with IR and free testosterone levels (fat mass determined by dual-energy X-ray absorptiometry (DXA), IR with euglycaemic clamp and serum free testosterone by liquid chromatography–MS; n 100 women with PCOS). However, insulin sensitivity, but not adiposity, was found to be an independent predictor of free testosterone concentrations. The central:peripheral fat ratio identified by DXA was shown to be related to androgen levels in twenty-four women with PCOS( Reference Godoy-Matos, Vaisman and Pedrosa 27 ). Details of the complex relationship between androgens and obesity are gradually unfolding( Reference Rojas, Chávez and Olivar 28 ); adipocytes seem to be prone to hypertrophy when exposed to androgen excess, and both adipose tissue hypertrophy and hyperandrogenism are related to IR( Reference Barber and Franks 29 ). What is known is that weight reduction, even as little as 5 %, improves PCOS symptoms in overweight or obese women with PCOS( Reference Moran, Pasquali and Teede 30 , Reference Haqq, McFarlane and Dieberg 31 ).

Whether women with PCOS present with increased abdominal adiposity compared with women in the general population continues to be debated. A diagnostic method of abdominal obesity has not yet been defined and thus a range of methods is used. Visceral adiposity index (VAI) is a simple surrogate marker of visceral adiposity which utilises BMI, waist circumference, TAG and HDL measurements and has been increasingly used since it was established in 2010( Reference Amato, Giordano and Galia 32 ). Anthropometric studies that include waist circumference measurements have shown that, regardless of BMI, women with PCOS typically have an increased abdominal fat distribution( Reference Yucel, Noyan and Sagsoz 33 Reference Herriot, Whitcroft and Jeanes 36 ). A meta-analysis by Lim et al. ( Reference Lim, Davies and Norman 20 ) also reported that women with PCOS had increased prevalence of central obesity (risk ratio 1·73; 95 % CI 1·31, 2·30; PCOS n 1191; controls n 2396) (Fig. 1).

Fig. 1 Meta-analysis( Reference Amato, Galluzzo and Finocchiaro 113 Reference Hahn, Tan and Sack 118 ) of the prevalence of central obesity in women with and without polycystic ovary syndrome (PCOS) (taken from Lim et al. ( Reference Lim, Davies and Norman 20 )). M-H, Mantel–Haenszel.

When body composition has been assessed by MRI, amounts of visceral adipose tissue have been found to be similar in women with PCOS and controls with comparable BMI (n 31), despite increased waist:hip ratios( Reference Manneras-Holm, Leonhardt and Kullberg 37 ) in the women with PCOS. However, it is worth noting that in this study a number of participants were only 1 week after ceasing the insulin-sensitising agent, metformin, which has been shown to reduce visceral adiposity in women with PCOS( Reference Velazquez, Mendoza and Hamer 38 , Reference Pasquali, Gambineri and Biscotti 39 ). Until relatively recently, studies infrequently reported PCOS phenotypes, which are known to have an impact on metabolic risk. Panidis et al.( Reference Panidis, Tziomalos and Misichronis 40 ), in a relatively small study (n 100 PCOS), reported significantly higher VAI in the hyperandrogenism and oligo/anovulation phenotype, when compared with other phenotypes. Additionally, Androulakis et al.( Reference Androulakis, Kandaraki and Christakou 41 ) reported that women with PCOS with menstrual disorders had significantly higher VAI when compared with PCOS without menstrual disorders. A more recent, albeit relatively small, study( Reference Bil, Dilbaz and Cirik 15 ) reported a higher VAI in PCOS women with hyperandrogenism and oligo/annovulation compared with other phenotypes. Further research is clearly warranted with more accurate assessments of adiposity for different PCOS phenotypes to help clarify the link between obesity and PCOS.

Visceral adipose tissue is an important endocrine organ, producing and releasing several adipokines; any specific differences in resistin, leptin and visfatin in PCOS women compared with controls remain uncertain; however, a clear role for adiponectin in PCOS has been reported. Adiponectin is down-regulated in obesity and is associated with IR; it also has strong insulin-sensitising, anti-inflammatory and anti-diabetic functions. Adiponectin circulates in different polymer complexes; it has been suggested that its actions are mediated primarily by the high-molecular-weight form of adiponectin( Reference Liu and Liu 42 ). In 2014( Reference Li, Huang and Zhong 43 ), a meta-analysis based on thirty-eight trials (n 1944 PCOS; n 1654 healthy controls) highlighted significantly lower total adiponectin levels in PCOS women compared with healthy controls, independent of BMI (weighted mean difference −2·67; 95 % CI −3·22, −2·13). Visceral fat secretes less adiponectin compared with subcutaneous fat( Reference Motoshima, Wu and Sinha 44 ), so the proposed increased visceral adiposity in women with PCOS could be a reason behind decreased high-molecular-weight adiponectin levels. Metformin, a common treatment option for PCOS, was associated with significantly elevated serum adiponectin concentrations in women with PCOS (standard mean differences −0·43, 95 % CI −0·75, −0·11)( Reference Kong, Niu and Zeng 45 ). In addition, it is likely that adiponectin levels are different in the PCOS phenotypes as suggested by Cankaya et al.( Reference Cankaya, Demir and Aksakal 46 ); in a small study (n 40), adolescents with androgen excess PCOS phenotype had significantly lower high-molecular-weight adiponectin levels compared with non-hyperandrogenic women. Testosterone has been found to contribute to high-molecular-weight adiponectin variance( Reference O’Connor, Phelan and Tun 47 ); however, in a 2009 meta-analysis testosterone levels were not associated with adiponectin levels( Reference Toulis, Goulis and Farmakiotis 48 ). Further high-quality studies are needed to help clarify the role of testosterone and adiponectin in PCOS.

Obesity is evidently complex and the location of excess adiposity is key and all too rarely measured in combination with presenting PCOS phenotypes. In particular, visceral fat plays a key role in generating the insulin-resistant state which leads to impaired glucose tolerance (IGT) and is a significant and independent risk factor for T2DM( Reference Barber, McCarthy and Wass 49 ).

Insulin resistance in polycystic ovary syndrome

A link between PCOS and IR was first highlighted in 1980, whereby obese women with PCOS were shown to have an increased insulin response to an oral glucose tolerance test compared with obese controls( Reference Burghen, Givens and Kitabchi 50 ). Prevalence rates of IR have been reported between 44 and 85 %( Reference Stepto, Cassar and Joham 10 , Reference Diamanti-Kandarakis and Dunaif 51 ). This variability is in part due to differences in PCOS phenotype and ethnicity( Reference Bil, Dilbaz and Cirik 15 , Reference Daan, Louwers and Koster 17 ). Reports of the prevalence of IR are limited by the methods used to determine insulin sensitivity; the euglycaemic insulin clamp technique is the most accurate method to diagnose IR, but its high cost limits use; thus the surrogate markers, fasting insulin and homeostasis model assessment of insulin resistance (HOMA-IR)( Reference Levy, Matthews and Hermans 52 ), are often reported.

IR and compensatory hyperinsulinaemia are fundamental to the exacerbation of PCOS symptoms and metabolic complications( Reference Moran and Norman 53 ). Several studies have shown that the majority of women with PCOS, both lean and overweight, have a form of IR that is intrinsic to the syndrome( Reference Stepto, Cassar and Joham 10 ). Researchers have shown that obesity and PCOS have a separate and synergistic relationship with IR( Reference Dunaif and Thomas 54 ). Defects in both insulin sensitivity and secretion are present in lean women with PCOS( Reference Dunaif, Segal and Futterweit 55 ). The pathogenesis of IR in PCOS is complex and incompletely understood, though it is agreed there is a post-binding defect in insulin receptor signalling( Reference Diamanti-Kandarakis and Dunaif 51 ). There is an increasing body of evidence to suggest a genetic susceptibility to PCOS and its associated IR as well as evidence to suggest tha PCOS may also have fetal origins due to androgen exposure at critical periods of growth or due to intra-uterine growth restrictions( Reference Obermayer-Pietsch, Trummer and Schwetz 4 ).

IR is a common feature in annovulatory women with PCOS; however, it is not as frequently observed in ovulatory women with PCOS, even when hyperandrogenism is present( Reference Baptiste, Battista and Trottier 56 ). Bil et al.( Reference Bil, Dilbaz and Cirik 15 ) reported significantly greater HOMA-IR in the androgen excess PCOS phenotype compared with non-hyperandrogenic women (n 100). Some older studies have failed to demonstrate IR in lean women with PCOS( Reference Nestler, Jakubowicz and de Vargas 57 , Reference Wijeyaratne, Balen and Barth 58 ), although this may be accounted for by the inability to distinguish between the different PCOS phenotypes which resulted in the inclusion of women who were ovulatory.

Chronic inflammation and its role in IR in PCOS continues to be investigated( Reference Victor, Rovira-Llopis and Bañuls 59 ). The increase in multiple markers of inflammation such as leucocyte count, C-reactive protein, IL-18, protein-1, and monocyte chemo-attractant in addition to increased oxidative stress and endothelial dysfunction are evidence that PCOS is commonly coupled with low-level systemic inflammation( Reference Escobar-Morreale, Luque-Ramírez and González 60 ). However, there are limited studies that assess the presence of chronic inflammation independent of adiposity in women with PCOS. Circulating markers of oxidative stress are abnormal in women with PCOS independent of weight excess and IR( Reference Murri, Luque-Ramírez and Insenser 61 ). The close association between oxidative stress and inflammation make it difficult to determine their individual contribution to PCOS and the mechanism of oxidative stress-induced IR remains unclear( Reference Zuo, Zhu and Xu 62 ). Oxidative stress and inflammation markers are positively correlated with androgen levels in PCOS patients( Reference González, Minium and Rote 63 ); thus they seem to contribute to hyperandrogenaemia, but detailed interactions still need to be identified, and as of yet few investigations have been done.

Insulin acts directly on the ovary by stimulating the thecal cells to increase androgen production and by activation of the cytochrome P450c17α( Reference Nestler, Jakubowicz and de Vargas 57 , Reference Conway, Avy and Rumsby 64 ). Hyperinsulinaemia further exacerbates the pathogenesis of PCOS by inhibiting the production of insulin-like growth factor-1 (IGF-1) binding protein in the liver, leading to elevated circulating levels of IGF-1, which in turn stimulates ovarian thecal cell androgen production( Reference Hopkinson, Sattar and Fleming 65 ). Hyperinsulinaemia reduces hepatic production of sex hormone-binding globulin, thus increasing free testosterone levels( Reference Cassar, Misso and Hopkins 66 ). In combination, hyperinsulinaemia and hyperandrogenaemia can disrupt follicle growth; this is accompanied by menstrual irregularity, anovulatory sub-fertility and accumulation of immature follicles( Reference Diamanti-Kandarakis and Dunaif 51 ). Diamanti-Kandarakis & Dunaif( Reference Diamanti-Kandarakis and Dunaif 51 ) in a review described the modulating action of insulin on ovarian steroidogenesis as well as the importance of the insulin signalling pathway in the control of ovulation.

Women with PCOS commonly have postprandial dysglycaemia( Reference Legro, Kunselman and Dodson 67 , Reference Ehrmann, Kasza and Azziz 68 ), which reflects peripheral, primarily skeletal muscle, IR. In lean women with PCOS hyperinsulinaemia is often evident postprandially but not in the fasted state( Reference Morales, Laughlin and Butzow 69 ). IR and compensatory hyperinsulinaemia have also been proposed as a cause of reactive hypoglycaemia in women with PCOS. A cross-sectional study of sixty-four lean young women with PCOS reported the rate of reactive hypoglycaema to be 50 %( Reference Altuntas, Bilir and Ucak 70 ). A survey of clinical practice (n 88) also indicated a high prevalence of hypoglycaemia; self-reported in 71 % of women with PCOS( Reference Herriot, Whitcroft and Jeanes 36 ). A recent study also indicated a higher prevalence of reactive hypoglycaemia in PCOS (n 88) compared with age- and BMI-matched controls (n 34), though a much lower prevalence of 17 %( Reference Mumm, Altinok and Henriksen 71 ). Robust studies investigating hypoglycaemia are sparse.

Impaired glucose tolerance and type 2 diabetes mellitus

The prevalence of IGT and T2DM in women with PCOS is substantially higher compared with age- and weight-matched healthy women; a meta-analysis of cross-sectional and cohort studies reported an OR of 2·54 (95 % CI 1·44, 4·47) for OGT and 4·00 (95 % CI 1·97, 8·10) for T2DM( Reference Moran, Misso and Wold 72 ). Differences in the diagnostic criteria for IGT and PCOS were evident, and there were inadequate data to allow for PCOS phenotype sub-analysis; additionally, differences in ethnicity and BMI have resulted in variable risk estimates between PCOS studies. Studies in the USA have indicated a prevalence of 23–35 % for IGT and 4–10 % for T2DM( Reference Legro, Kunselman and Dodson 67 , Reference Ehrmann, Kasza and Azziz 68 ), whereas in non-US studies prevalence rates in women with PCOS are elevated although not all to the same extent, with prevalence rates of 16 % for IGT and 2·5 % for T2DM described in an Italian cohort( Reference Gambineri, Pelus and Manicardi 73 ). In the US studies, even lean women with PCOS had increased rates of IGT and T2DM compared with healthy controls( Reference Legro, Kunselman and Dodson 67 ), the onset of IGT occurring in their thirties and forties which is earlier than the normal population( Reference Pelusi, Gambineri and Pasquali 74 ). A more recent longitudinal study following women for at least 10 years reported that the age-standardised prevalence of diabetes at the end of follow-up was 39·3 %, significantly higher than in healthy women (prevalence of 5·8 %)( Reference Gambineri, Patton and Altieri 75 ).

The Royal College of Obstetrics and Gynaecology 2014 guidelines( 76 ) state that women presenting with PCOS with a BMI ≥ 25 kg/m2 and lean women with PCOS, but who have additional risk factors such as advanced age (> 40 years), personal history of gestational diabetes or family history of T2DM, should have a 2-h post-75 g oral glucose tolerance test.

Metabolic syndrome and non-alcoholic liver disease in polycystic ovary syndrome

PCOS commonly includes many metabolic syndrome components, such as abdominal obesity, dyslipidaemia, hyperglycaemia and hypertension, which predispose women with PCOS to the development of T2DM and CVD. There is a higher prevalence of the metabolic syndrome in women with PCOS compared with women in the general population( Reference Moran, Misso and Wild 77 ), estimated to be between 34 and 46 %, based on studies of Caucasian women with PCOS from the USA using the National Cholesterol Education Program Adult Treatment Panel III criteria( Reference Ehrmann, Liljenquist and Kasza 78 Reference Apridonidze, Essah and Iuorno 80 ). Women diagnosed with PCOS using National Institutes of Health criteria are more likely to have a higher prevalence of the metabolic syndrome compared with controls, compared with women diagnosed with PCOS using the ESHRE/ASRM guidelines( Reference Moran, Misso and Wold 72 , Reference Panidis, Macut and Tziomalos 81 ). Studies that clearly indicate the prevalence of the metabolic syndrome in differing PCOS phenotypes are lacking.

IR and obesity are strong predictors of non-alcoholic fatty liver disease (NAFLD)( Reference Marchesini, Brizi and Morselli-Labate 82 , Reference Bugianesi, Gastaldelli and Vanni 83 ); thus it is not surprising that there is a higher prevalence of NAFLD in women with PCOS compared with age- and BMI-matched controls; prevalence rates ranging from 27 to 62 %( Reference Cerda, Perez-Ayuso and Riqelme 84 Reference Ramezani-Binabaj, Motalebi and Karimi-Sari 87 ). This variation can be attributed to differences in laboratory diagnostic criteria (for example, liver function tests, liver imaging studies, liver biopsy) and differences in study populations relating to ethnicity, age, BMI and PCOS diagnostic criteria( Reference Vassilatou 88 ). Vassilatou( Reference Vassilatou 88 ) has highlighted the increasing evidence that hyperandrogenism is related to NAFLD in PCOS and suggested that hyperandrogensim should be considered as an additional link in the synergy with obesity and IR for the development of NAFLD in PCOS. However, sub-analyses with the PCOS phenotypes were not reported and would seem prudent for further evaluation.

Of clinical importance, the prevalence of non-alcoholic steatohepatitis (NASH) in women with PCOS is particularly high( Reference Koroli, Fatima and Chandra 89 ). Bariatric surgery has shown beneficial outcomes on NASH( Reference Weiner 90 ). With the exception of weight loss through lifestyle modification and encouraging exercise in obese women, few evidence-based effective treatments specifically target NAFLD/NASH in women with PCOS( Reference Chen and Ho 91 ).

Dietary influences of the metabolic aspects of polycystic ovary syndrome

With no cure for PCOS, clinical management focuses on treating the presenting symptoms. Lifestyle management is advocated as the primary therapy in overweight and obese women with PCOS since even a modest weight loss of just 5–10 %, without medical intervention, improves many of the symptoms associated with PCOS( Reference Moran, Pasquali and Teede 30 , Reference Moran, Hutchison and Norman 92 , Reference Marzouk and Sayed Ahmed 93 ).

The optimal method of achieving sustainable weight loss is under constant debate; studies demonstrating the clinical benefits of weight loss in women with PCOS incorporate a variety of methods to reduce energy intake and achieve a negative energy balance( Reference Moran, Ko and Misso 94 ). Behaviour-change strategies have long been recognised as being instrumental in managing chronic conditions, particularly weight management. However, lifestyle modification programmes are often reported to have low compliance and high dropout rates( Reference Domecq, Prutsky and Mullan 95 ). Furthermore, many overweight or obese women with PCOS are not following a diet that would promote weight loss( Reference Jeanes, Reeves and Gibson 96 ). Bariatric surgery, on the other hand, in women with PCOS has resulted in substantial weight loss and marked improvement of multiple biochemical abnormalities( Reference Jamal, Gunay and Capper 97 , Reference Eid, Cottam and Velcu 98 ). A recent meta-analysis of thirteen studies (2130 women) reported a reduction in the incidence of PCOS preoperatively from 45·6 %, to 6·8 % at 12-month follow-up( Reference Skubleny, Switzer and Gill 99 ).

Dietary modification to improve IR may produce benefits greater than those achieved by modest weight loss and would also be suitable for lean IR women with PCOS. Modifying the carbohydrate content and fatty acid content of the diet have both been proposed as methods to improve insulin sensitivity. The concept of a low-glycaemic index (GI) diet aims to reduce the glycaemic load (GL) and hence insulin response to ingested foods and drinks. Greater improvement in insulin sensitivity and regular menses were reported after weight loss with a low dietary GI approach (n 29) compared with weight loss through conventional healthy eating (n 20)( Reference Marsh, Steinbeck and Atkinson 100 ). In this study, women were followed for 12 months or until they achieved 7 % weight loss. Barr et al. ( Reference Barr, Reeves and Sharp 101 ) also demonstrated an improvement in insulin sensitivity after following an isoenergetic diet with a reduction in dietary GI in twenty-one women with PCOS over a 12-week intervention period. Furthermore, one study( Reference Mehrabani, Salehpour and Amiri 102 ) reported a reduction in IR after a 12-week hypoenergetic diet, high in protein (30 % protein: n 23), with a low GL compared with a conventional hypoenergetic healthy eating intervention (15 % protein: n 26). A low-GL diet in lean women with PCOS (n 41) resulted in a reduction in waist circumference( Reference Herriot, Whitcroft and Jeanes 36 ). These small studies suggest a benefit for promoting lower GI dietary advice to lean women with PCOS, many of whom are also insulin resistant. However, exploring the mechanisms behind the intervention and assessing IR with the euglycaemic clamp technique and evaluating the effect of modifying dietary GI in a subgroup of IR women with PCOS is prudent to improving the evidence base for dietary recommendations.

Inflammation is implicated in the pathogenesis of PCOS; dietary constituents such as SFA can influence inflammatory mediators, such as TNF-α and IL-1β and disrupt insulin signalling( Reference Lyons, Kennedy and Roche 103 , Reference Gonzales 104 ). Conversely, MUFA and PUFA do not interrupt metabolism and inflammation to the same extent. SFA intake has been shown to influence glucose metabolism through the altering of insulin signalling and cell membrane function, with a diet high in SFA associated with a decrease in insulin sensitivity when compared with a high-MUFA diet( Reference Lyons, Kennedy and Roche 103 ). Of interest, it has been reported that 68 % of women with PCOS had a total fat intake greater than a 35 % contribution to total energy, with SFA intake accounting for 12 % of total energy, substantially exceeding the reference nutrient intake (<10 % energy)( Reference Barr, Hart and Reeves 105 , Reference Hart, Barr and Reeves 106 ). Thus, a reduction of total fat intake should focus on lowering SFA intake concurrently with the encouragement of the maintenance of MUFA and PUFA in women with PCOS. There is some evidence to show that by reducing the consumption of saturated fat( Reference Turner, Cooney and Kraegen 107 ) and reducing the GI and GL of the diet( Reference Turner, Cooney and Kraegen 107 ), insulin sensitivity can be improved in insulin-resistant populations; however, there remains a paucity of studies in women with PCOS( Reference Schwingshackl and Hoffmann 108 ).

Advanced glycation end products (AGEs) are elevated in PCOS( Reference Diamanti-Kandarakis, Piperi and Kalofoutis 109 ); these pro-inflammatory molecules trigger a state of intracellular oxidative stress and inflammation after binding to their cell membrane receptors (RAGE). They are highly reactive molecules formed by non-enzymic reactions of carbonyl group of carbohydrates with free amino groups of proteins, nucleic acids or lipids. AGEs within the body are from endogenous production or ingested in high amounts from cooked fast food( Reference Goldberg, Cai and Peppa 110 ). A small study( Reference Tantalaki, Piperi and Livadas 111 ) (twenty-three PCOS participants) has shown that a 2-month intervention of a low dietary intake of AGEs is associated with improved levels of serum testosterone, oxidative stress and HOMA-IR in PCOS. The role of dietary AGEs as mediators of metabolic and reproductive alterations in PCOS is an exciting and emerging area of dietary modification for PCOS.

An area yet to be explored in PCOS is the role of the gut microbiota( Reference Canfora, Jocken and Blaak 112 ), which could influence glucose homeostasis and insulin sensitivity by fermenting indigestible dietary components to produce SCFA. These SCFA have been shown to beneficially modulate adipose tissue, skeletal muscle and liver tissue function. Furthermore, research, including well-designed robust studies, is needed to evaluate the mechanisms behind the improvements observed with dietary modification and inherent with all weight-reduction interventions to improve adherence to interventions and weight maintenance.

Conclusion

PCOS is a diverse condition that manifests itself in a variety of symptoms linked to ovulatory dysfunction and the overproduction of androgens. Women with PCOS are at a greater risk of metabolic dysfunction and consequently need regular monitoring for risk of diabetes and CVD. Whilst treatment is mostly aimed at addressing the presenting symptoms, dietary adaptations to improve metabolic symptoms will be beneficial for long-term health. Young women with PCOS often present to healthcare professionals due to infrequent menses or infertility; it is at this stage that they can be educated about the increased long-term risk of metabolic complications of the syndrome in order to make timely and appropriate lifestyle modifications.

Acknowledgements

No funding was received for this review. Both authors were involved at all stages and contributed equally.

There are no conflicts of interest.

References

1. March, WA, Moore, VM, Willson, KJ, et al. (2010) The prevalence of polycystic ovary syndrome in a community sample assessed under contrasting diagnostic criteria. Hum Reprod 25, 544551.Google Scholar
2. Wild, RA (2012) Dyslipidemia in PCOS. Steroids 77, 295299.Google Scholar
3. Kokosar, M, Benrick, A, Perfilyev, A, et al. (2016) Epigenetic and transcriptional alterations in human adipose tissue of polycystic ovary syndrome. Add Sci Rep 15, 22883.CrossRefGoogle Scholar
4. Obermayer-Pietsch, B, Trummer, C, Schwetz, V, et al. (2015) Genetics of insulin resistance in polycystic ovary syndrome. Curr Opin Clin Nutr Metab Care 18, 401406.CrossRefGoogle ScholarPubMed
5. Pasquali, R, Stener-Victorin, E, Yildiz, BO, et al. (2011) PCOS Forum: research in polycystic ovary syndrome today and tomorrow. Clin Endocrin 74, 424433.Google Scholar
6. Moran, LJ, Norman, RJ & Teede, JH (2015) Metabolic risk in PCOS: phenotype and adiposity impact. Trends Endocrinol Metab 26, 136143.CrossRefGoogle Scholar
7. Hecht Baldauff, N & Arslanian, S (2014) Optimal management of polycystic ovary syndrome in adolescence. Arch Dis Child 100, 10761083.Google Scholar
8. Jones, GL, Hall, JM, Balen, AH, et al. (2008) Health-related quality of life measurement in women with polycystic ovary syndrome: a systematic review. Hum Reprod Update 14, 1525.Google Scholar
9. Dokras, A, Clifton, S, Futterweit, W, et al. (2011) Increased risk for abnormal depression scores in women with polycystic ovary syndrome: a systematic review and meta-analysis. Obstet Gynecol 117, 145152.CrossRefGoogle ScholarPubMed
10 Stepto, NK, Cassar, S, Joham, AE, et al. (2013) Women with polycystic ovary syndrome have intrinsic insulin resistance on euglycaemic–hyperinsulaemic clamp. Hum Reprod 28, 777784.Google Scholar
11. ESHRE and ASRM-Sponsored PCOS Consensus Workshop Group (2004) Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril 81, 1925.Google Scholar
12. National Institutes of Health (2012) Evidence-based Methodology Workshop on Polycystic Ovary Syndrome: Final Report. Bethesda, MD: National Institutes of Health.Google Scholar
13 Carmina, E, Chu, MC, Longo, RA, et al. (2005) Phenotypic variation in hyperandrogenic women influences the findings of abnormal metabolic and cardiovascular risk parameters. J Clin Endocrinol Metab 90, 25452549.CrossRefGoogle ScholarPubMed
14. Strowitzki, T, Capp, E & von Eye Corleta, H (2010) The degree of cycle irregularity correlates with the grade of endocrine and metabolic disorders in PCOS patients. Eur J Obstet Gynecol Reprod Biol 149, 178181.Google Scholar
15 Bil, E, Dilbaz, B, Cirik, DA, et al. (2016) Metabolic syndrome and metabolic risk profile according to polycystic ovary syndrome phenotype. J Obstet Gynaecol Res 42, 837843.Google Scholar
16 Barber, TM, Wass, JA, McCarthy, MI, et al. (2007) Metabolic characteristics of women with polycystic ovaries and oligo-amenorrhoea but normal androgen levels: implications for the management of polycystic ovary syndrome. Clin Endocrinol 66, 513517.Google Scholar
17 Daan, NM, Louwers, YV, Koster, MP, et al. (2014) Cardiovascular and metabolic profiles amongst different polycystic ovary syndrome phenotypes: who is really at risk? Fertil Steril 102, 14441451.CrossRefGoogle ScholarPubMed
18 Azziz, R, Carmina, E, Dewailly, D, et al. (2006) Position Statement: criteria for defining polycystic ovary syndrome as a predominantly hyperandogenic syndrome: an Androgen Excess Society Guideline. J Clin Endocrinol Metab 91, 42374245.CrossRefGoogle ScholarPubMed
19 Teede, H, Deeks, A & Moran, L (2010) Polycystic ovary syndrome: a complex condition with psychological, reproductive and metabolic manifestations that impacts on health across the lifespan. BMC Medicine 8, 41.Google Scholar
20. Lim, SS, Davies, MJ, Norman, RJ, et al. (2012) Overweight, obesity and central obesity in women with polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod Update 18, 618637.Google Scholar
21. Hoeger, KM & Oberfield, SW (2012) Do women with PCOS have a unique predisposition to obesity? Fertil Steril 97, 1317.Google Scholar
22. Teede, HJ, Joham, AE, Paul, E, et al. (2013) Longitudinal weight gain in women identified with polycystic ovary syndrome: results of an observational study in young women. Obesity 21, 15261532.Google Scholar
23. Lim, SS, Norman, RJ, Davies, MJ, et al. (2013) The effect of obesity on polycystic ovary syndrome: a systematic review and meta-analysis. Obes Rev 14, 95109.Google Scholar
24. Palomba, S, de Wilde, MA, Falbo, A, et al. (2015) Pregnancy complications in women with polycystic ovary syndrome Hum Reprod 21, 575592.Google Scholar
25. Spritzer, PM, Lecke, SB, Satler, F, et al. (2015) Adipose tissue dysfunction, adipokines, and low-grade chronic inflammation in polycystic ovary syndrome. Reproduction 149, R219R227.Google Scholar
26. Tosi, F, Di Sarra, D, Kaufman, JM, et al. (2015) Total body fat and central fat mass independently predict insulin resistance but not hyperandrogenemia in women with polycystic ovary syndrome. J Clin Endocrinol Metab 100, 661669.CrossRefGoogle Scholar
27. Godoy-Matos, AF, Vaisman, F, Pedrosa, AP, et al. (2009) Central-to-peripheral fat ratio, but not peripheral body fat, is related to insulin resistance and androgen markers in polycystic ovary syndrome. Gynaecol Endocrinol 25, 793798.CrossRefGoogle Scholar
28. Rojas, J, Chávez, M, Olivar, L, et al. (2014) Polycystic ovary syndrome, insulin resistance, and obesity: navigating the pathophysiologic labyrinth. Int J Reprod Med 2014, 719050.CrossRefGoogle ScholarPubMed
29. Barber, TM & Franks, S (2013) Adipocyte biology in polycystic ovary syndrome. Mol Cell Endocrinol 373, 6876.CrossRefGoogle ScholarPubMed
30. Moran, LJ, Pasquali, R, Teede, HJ, et al. (2009) Treatment of obesity in polycystic ovary syndrome: a position statement of the Androgen Excess and Polycystic Ovary Syndrome Society. Fertil Steril 92, 19661982.Google Scholar
31. Haqq, L, McFarlane, J, Dieberg, G, et al. (2014) Effect of lifestyle intervention on the reproductive endocrine profile in women with polycystic ovarian syndrome: a systematic review and meta-analysis. Endocr Connect 28, 3646.Google Scholar
32. Amato, MC, Giordano, C, Galia, M, et al. (2010) Visceral adiposity index: a reliable indicator of visceral fat function associated with cardiometabolic risk. Diabetes Care 33, 920922.Google Scholar
33. Yucel, A, Noyan, V & Sagsoz, N (2005) The association of serum androgens and insulin resistance with fat distribution in polycystic ovary syndrome. Eur J Obstet Gynaecol Reprod Biol 126, 8189.CrossRefGoogle ScholarPubMed
34. Cascella, T, Palomba, S, De Sio, I, et al. (2008) Visceral fat is associated with cardiovascular risk in women with polycystic ovary syndrome. Hum Reprod 23, 153159.Google Scholar
35. Amato, MC, Verghi, M, Galluzzo, A, et al. (2011) The oligomenorrhoic phenotypes of polycystic ovary syndrome are characterized by a high visceral adiposity index: a likely condition of cardiometabolic risk. Hum Reprod 26, 14861494.Google Scholar
36. Herriot, A, Whitcroft, S & Jeanes, Y (2008) A retrospective audit of patients with polycystic ovary syndrome: the effects of a reduced glycaemic load diet. J Hum Nutr Diet 21, 337345.CrossRefGoogle ScholarPubMed
37. Manneras-Holm, L, Leonhardt, H & Kullberg, J (2011) Adipose tissue has aberrant morphology and function in PCOS: enlarged adipocytes and low serum adiponectin, but not circulating sex steroids, are strongly associated with insulin resistance. J Clin Endocrinol Metab 96, E304E311.Google Scholar
38. Velazquez, E, Mendoza, S, Hamer, T, et al. (1994) Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia and systolic blood pressure, while facilitating normal menses and pregnancy. Metabolism 43, 647654.Google Scholar
39. Pasquali, R, Gambineri, A & Biscotti, D (2000) Effect of long term treatment with metformin added to hypocaloric diet on body composition, fat distribution and androgen and insulin levels in abdominally obese women with and without polycystic ovary syndrome. J Clin Endocrinol Metabol 85, 27672774.Google Scholar
40. Panidis, D, Tziomalos, K, Misichronis, G, et al. (2012) Insulin resistance and endocrine characteristics of the different phenotypes of polycystic ovary syndrome: a prospective study. Hum Reprod 27, 541549.Google Scholar
41. Androulakis, II, Kandaraki, E, Christakou, C, et al. (2014) Visceral adiposity index (VAI) is related to the severity of anovulation and other clinical features in women with polycystic ovary syndrome. Clin Endocrinol 81, 426431.Google Scholar
42. Liu, F & Liu, F (2014) Regulation of adiponectin multimerization, signalling and function. Best Prac Res Clin Endocrinol Metab 14, 2531.Google Scholar
43. Li, S, Huang, X, Zhong, H, et al. (2014) Low circulating adiponectin levels in women with polycystic ovary syndrome: an updated meta-analysis. Tumour Biol 35, 3961e73.Google ScholarPubMed
44. Motoshima, H, Wu, X, Sinha, MK, et al. (2002) Differential regulation of adiponectin secretion from cultured human omental and subcutaneous adipocytes: effects of insulin and rosiglitazone. J Clin Endocrinol Metab 87, 56625667.Google Scholar
45. Kong, W, Niu, X, Zeng, T, et al. (2015) Impact of treatment with metformin on adipocytokines in patients with polycystic ovary syndrome: a meta-analysis. PLOS ONE 10, e0140565.Google Scholar
46. Cankaya, S, Demir, B, Aksakal, SE, et al. (2014) 2014 Insulin resistance and its relationship with high molecular weight adiponectin in adolescents with polycystic ovary syndrome and a maternal history of polycystic ovary syndrome. Fertil Steril 102, 826830.Google Scholar
47. O’Connor, A, Phelan, N, Tun, TK, et al. (2010) High-molecular-weight adiponectin is selectively reduced in women with polycystic ovary syndrome independent of body mass index and severity of insulin resistance. J Clin Endocrinol Metab 95, 13781385.Google Scholar
48. Toulis, KA, Goulis, DG, Farmakiotis, D, et al. (2009) Adiponectin levels in women with polycystic ovary syndrome: a systematic review and a meta-analysis. Hum Reprod Update 15, 297307.Google Scholar
49. Barber, TM, McCarthy, MI, Wass, JAH, et al. (2006) Obesity and polycystic ovary syndrome. Clin Endocrinol 65, 137145.Google Scholar
50. Burghen, GA, Givens, JR & Kitabchi, AE (1980) Correlation of hyperandrogenism with hyperinsulinemia in polycystic ovarian disease. J Clin Endocrinol Metabol 50, 113116.Google Scholar
51. Diamanti-Kandarakis, E & Dunaif, A (2012) Insulin resistance and the polycystic syndrome revisited: an update on mechanisms and implications. Endocr Rev 33, 9811030.Google Scholar
52. Levy, JC, Matthews, DR & Hermans, MP (1998) Correct homeostasis model assessment (HOMA2) evaluation uses the computer program. Diabetes Care 21, 21912192.Google Scholar
53. Moran, L & Norman, RJ (2004) Understanding and managing disturbances in insulin metabolism and body weight in patients with polycystic ovary syndrome. Best Prac Res Clin Obstet 18, 719736.Google Scholar
54. Dunaif, A & Thomas, A (2001) Current concepts in the polycystic ovary syndrome. Ann Rev Med 52, 401419.Google Scholar
55. Dunaif, A, Segal, KR & Futterweit, W (1989) Profound insulin resistance, independent of obesity, in polycystic ovary syndrome. Diabetes 38, 11651174.Google Scholar
56. Baptiste, CG, Battista, MC, Trottier, A, et al. (2010) Insulin and hyperandrogenism in women with polycystic ovary syndrome. J Steroid Biochem Mol Biol 122, 4252.Google Scholar
57. Nestler, JE, Jakubowicz, DJ, de Vargas, AF, et al. (1998) Insulin stimulates testosterone biosynthesis by human thecal cells from women with polycystic ovary syndrome by activating its own receptor and using inositolglycan mediators as the signal transduction system. J Clin Endocrinol Metab 83, 20012005.Google Scholar
58. Wijeyaratne, C, Balen, AH, Barth, JH, et al. (2002) Clinical manifestations and insulin resistance (IR) in polycystic ovary syndrome (PCOS) among South Asians and Caucasians: is there a difference? Clin Endocrinol (Oxf) 57, 343350.Google Scholar
59. Victor, VM, Rovira-Llopis, S, Bañuls, C, et al. (2016) Insulin resistance in PCOS patients enhances oxidative stress and leukocyte adhesion: role of myeloperoxidase. PLOS ONE 11, e0151960.CrossRefGoogle ScholarPubMed
60. Escobar-Morreale, HF, Luque-Ramírez, M & González, F (2011) Circulating inflammatory markers in polycystic ovary syndrome: a systematic review and meta-analysis. Fertil Steril 95, 10481058.e1–2.Google Scholar
61. Murri, M, Luque-Ramírez, M, Insenser, M, et al. (2013) Circulating markers of oxidative stress and polycystic ovary syndrome (PCOS): a systematic review and meta-analysis. Hum Reprod Update 19, 268288.Google Scholar
62. Zuo, T, Zhu, M & Xu, W (2016) Roles of oxidative stress in polycystic ovary syndrome and cancers. Oxid Med Cell Longev 6, 8589318.Google Scholar
63. González, F, Minium, J, Rote, NS, et al. (2005) Hyperglycemia alters tumour necrosis factor-α release from mononuclear cells in women with polycystic ovary syndrome. J Clin Endocrinol Metab 90, 53365342.Google Scholar
64. Conway, GS, Avy, C & Rumsby, G (1994) The tyrosine kinase domain of the insulin receptor gene is normal in women with hyperinsulinaemia and polycystic ovary syndrome. Hum Reprod 9, 16811683.CrossRefGoogle ScholarPubMed
65. Hopkinson, ZEC, Sattar, N, Fleming, R, et al. (1998) Polycystic ovarian syndrome: metabolic syndrome comes to gynaecology. BMJ 317, 329332.Google Scholar
66. Cassar, S, Misso, ML, Hopkins, WG, et al. (2016) Insulin resistance in polycystic ovary syndrome: a systematic review and meta-analysis of euglycaemic–hyperinsulinaemic clamp studies. Hum Reprod 31, 26192631.Google Scholar
67. Legro, RS, Kunselman, AR & Dodson, WC (1999) Prevalence and predictors of risk for type 2 diabetes melitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women. J Clin Endocrinol Metab 84, 165169.Google Scholar
68. Ehrmann, DA, Kasza, K, Azziz, R, et al. (2005) Effects of race and family history of type 2 diabetes on metabolic status of women with polycystic ovary syndrome. J Clin Endocrinol Metab 90, 6671.CrossRefGoogle ScholarPubMed
69. Morales, AJ, Laughlin, GA, Butzow, T, et al. (1996) Insulin, somatotrophic, and luteinizing hormone axes in lean and obese women with polycystic ovary syndrome: common and distinct features. J Clin Endocrinol Metab 81, 28542864.Google Scholar
70. Altuntas, A, Bilir, M & Ucak, S (2005) Reactive hypoglycaemia in lean young patients with PCOS and correlations with insulin sensitivity and β cell function. Eur J Obstet Gynecol Reprod Biol 119, 198205.CrossRefGoogle ScholarPubMed
71. Mumm, H, Altinok, ML, Henriksen, JE, et al. (2016) Prevalence and possible mechanisms of reactive hypoglycemia in polycystic ovary syndrome. Hum Reprod 31, 11051112.Google Scholar
72. Moran, LJ, Misso, ML, Wold, RA, et al. (2010) Impaired glucose tolerance, type 2 diabetes and metabolic syndrome in polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod Update 16, 347363.CrossRefGoogle ScholarPubMed
73. Gambineri, A, Pelus, C, Manicardi, E, et al. (2004) Glucose intolerance in a large cohort of Mediterranean women with polycystic ovary syndrome: phenotype and associated factors. Diabetes 53, 23532358.Google Scholar
74. Pelusi, B, Gambineri, A & Pasquali, R (2004) Type 2 diabetes and the polycystic ovary syndrome. Minerva Ginecologica 56, 4151.Google Scholar
75. Gambineri, A, Patton, L, Altieri, P, et al. (2012) Polycystic ovary syndrome is a risk factor for type 2 diabetes: results from a long-term prospective study. Diabetes 61, 23692374.Google Scholar
76. Royal College of Obstetricians and Gynaecologists (RCOG) (2014) Long-term consequences of polycystic ovary syndrome (Green-top Guideline No. 33). https://www.rcog.org.uk/en/guidelines-research-services/guidelines/gtg33/ (accessed January 2017).Google Scholar
77. Moran, LJ, Misso, ML, Wild, RA, et al. (2010) Impaired glucose tolerance, type 2 diabetes and metabolic syndrome in polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod Update 16, 347363.Google Scholar
78. Ehrmann, D, Liljenquist, DR, Kasza, K, et al. (2006) Prevalence and predictors of the metabolic syndrome in women with PCOS. J Clin Endocrinol Metab 91, 4853.Google Scholar
79. Dokras, A, Bochner, M, Hollinrake, E, et al. (2005) Screening women with polycystic ovary syndrome for metabolic syndrome. Obstet Gynecol 106, 131137.Google Scholar
80. Apridonidze, T, Essah, PA, Iuorno, MJ, et al. (2005) Prevalence and characteristics of the metabolic syndrome in women with polycystic ovary syndrome. J Clin Endocrinol Metab 90, 19291935.Google Scholar
81. Panidis, D, Macut, D, Tziomalos, K, et al. (2013) Prevalence of metabolic syndrome in women with polycystic ovary syndrome. Clin Endocrinol 78, 586592.Google Scholar
82. Marchesini, G, Brizi, M, Morselli-Labate, AM, et al. (1999) Association of non-alcoholic fatty liver disease with insulin resistance. Am J Med 107, 450455.Google Scholar
83. Bugianesi, E, Gastaldelli, A, Vanni, E, et al. (2005) Insulin resistance in non-diabetic patients with non-alcoholic fatty liver disease: sites and mechanisms. Diabetologia 48, 634642.CrossRefGoogle ScholarPubMed
84. Cerda, C, Perez-Ayuso, RM, Riqelme, A, et al. (2007) Non-alcoholic fatty liver disease in women with polycystic ovary syndrome. J Hepatol 47, 412417.Google Scholar
85. Romanowski, MD, Parolin, MB, Freitas, AC, et al. (2015) Prevalence of non-alcoholic fatty liver disease in women with polycystic ovary syndrome and its correlation with metabolic syndrome. Arch Gastroenterol 52, 117123.Google Scholar
86. Macut, D, Tziomalos, K, Bozic-Antic, I, et al. (2016) Non-alcoholic fatty liver disease is associated with insulin resistance and lipid accumulation product in women with polycystic ovary syndrome. Hum Reprod 31, 13471353.Google Scholar
87. Ramezani-Binabaj, M, Motalebi, M, Karimi-Sari, H, et al. (2014) Are women with polycystic ovarian syndrome at a high risk of non-alcoholic fatty liver disease; a meta-analysis. Hepat Mon 14, e23235.Google Scholar
88. Vassilatou, E (2014) Non-alcoholic fatty liver disease and polycystic ovary syndrome. World J Gastroenterol 20, 83518363.Google Scholar
89. Koroli, R, Fatima, J, Chandra, A, et al. (2013) Prevalence of hepatic steatosis in women with polycystic ovary syndrome. J Hum Reprod Sci 6, 914.Google Scholar
90. Weiner, RA (2010) Surgical treatment of non-alcoholic steatohepatitis and non-alcoholic fatty liver disease. Dig Dis 28, 274279.Google Scholar
91. Chen, MJ & Ho, HN (2016) Hepatic manifestations of women with polycystic ovary syndrome. Best Pract Res Clin Obstet Gynaecol 37, 119128.Google Scholar
92. Moran, LJ, Hutchison, SK & Norman, RJ (2011) Lifestyle changes in women with polycystic ovary syndrome. Cochrane Database Syst Rev, issue 2, CD007506.Google Scholar
93. Marzouk, TM & Sayed Ahmed, WA (2015) Effect of dietary weight loss on menstrual regularity in obese young adult women with polycystic ovary syndrome. J Pediatr Adolesc Gynecol 28, 457461.Google Scholar
94. Moran, LJ, Ko, H, Misso, M, et al. (2013) Dietary composition in the treatment of polycystic ovary syndrome: a systematic review to inform evidence-based guidelines. J Acad Nutr Diet 113, 520545.Google Scholar
95. Domecq, JP, Prutsky, G, Mullan, RJ, et al. (2013) Lifestyle modification programs in polycystic ovary syndrome: systematic review and meta-analysis. J Clin Endocrinol Metab 98, 46554663.Google Scholar
96. Jeanes, Y, Reeves, S, Gibson, EL, et al. (2017) Binge eating behaviours and food cravings in women with PCOS. Appetite 109, 2432.Google Scholar
97. Jamal, M, Gunay, Y, Capper, A, et al. (2014) Roux-en-Y gastric bypass ameliorates polycystic ovary syndrome and dramatically improves conception rates: a 9-year analysis. Surg Obes Relat Dis 8, 440444.Google Scholar
98. Eid, GM, Cottam, DR, Velcu, LM, et al. (2005) Effective treatment of polycystic ovarian syndrome with Roux-en-Y gastric bypass. Surg Obes Relat Dis 1, 7780.Google Scholar
99. Skubleny, D, Switzer, NJ, Gill, RS, et al. (2016) The impact of bariatric surgery on polycystic ovary syndrome: a systematic review and meta-analysis. Obes Surg 26, 169176.Google Scholar
100. Marsh, K, Steinbeck, KS, Atkinson, FS, et al. (2010) Effect of a low glycaemic index compared with a conventional healthy diet on polycystic ovary syndrome. Am J Clin Nutr 92, 8392.Google Scholar
101. Barr, S, Reeves, S, Sharp, K, et al. (2013) An isocaloric low glycemic diet improves insulin sensitivity in women with polycystic ovary syndrome. J Acad Nutr Diet 113, 15231531.Google Scholar
102. Mehrabani, HH, Salehpour, S & Amiri, Z (2012) Beneficial effects of a high-protein, low-glycemic-load hypocaloric diet in overweight and obese women with polycystic ovary syndrome: a randomized controlled intervention study. J Am Coll Nutr 31, 117125.Google Scholar
103. Lyons, CL, Kennedy, EB & Roche, HM (2016) Metabolic inflammation-differential modulation by dietary constituents. Nutrients 8, E247.Google Scholar
104. Gonzales, F (2015) Nutrient-induced inflammation in polycystic ovary syndrome: role in the development of metabolic aberration and ovarian dysfunction. Semin Reprod Med 33, 276286.Google Scholar
105. Barr, S, Hart, K, Reeves, S, et al. (2011) Habitual dietary intake, eating pattern and physical activity of women with polycystic ovary syndrome. Eur J Clin Nutr 65, 11261132.Google Scholar
106. Hart, KH, Barr, S, Reeves, S, et al. (2015) Suboptimal dietary intake is associated with cardiometabolic risk factors in women with polycystic ovary syndrome. Nutr Diet 73, 177183.Google Scholar
107. Turner, N, Cooney, GJ, Kraegen, EW, et al. (2014) Fatty acid metabolism, energy expenditure and insulin resistance in muscle. J Endocrinol 15, T61T79.Google Scholar
108. Schwingshackl, L & Hoffmann, G (2013) Long-term effects of low glycemic index/load vs. high glycemic index/load diets on parameters of obesity and obesity-associated risks: a systematic review and meta-analysis. Nutr Metab Cardiovasc Dis 23, 699706.Google Scholar
109. Diamanti-Kandarakis, E, Piperi, C, Kalofoutis, A, et al. (2005) Increased levels of serum advanced glycation end-products in women with polycystic ovary syndrome. Clin Endocrinol 62, 3743.Google Scholar
110. Goldberg, T, Cai, W, Peppa, M, et al. (2004) Advanced glycoxidation end products in commonly consumed foods. J Am Diet Assoc 104, 12871291.Google Scholar
111. Tantalaki, E, Piperi, C, Livadas, S, et al. (2014) Impact of dietary modification of advanced glycation end products (AGEs) on the hormonal and metabolic profile of women with polycystic ovary syndrome (PCOS). Hormones 13, 6573.Google Scholar
112. Canfora, EE, Jocken, JW & Blaak, EE (2015) Short-chain fatty acids in control of body weight and insulin sensitivity. Nat Rev Endocrinol 11, 577591.Google Scholar
113. Amato, MC, Galluzzo, A, Finocchiaro, S, et al. (2008) The evaluation of metabolic parameters and insulin sensitivity for a more robust diagnosis of the polycystic ovary syndrome. Clin Endocrinol (Oxf) 69, 5260.Google Scholar
114. Bernasconi, D, Del Monte, P, Meozzi, M, et al. (1996) The impact of obesity on hormonal parameters in hirsute and nonhirsute women. Metabolism 45, 7275.Google Scholar
115. Chae, SJ, Kim, JJ, Choi, YM, et al. (2008) Clinical and biochemical characteristics of polycystic ovary syndrome in Korean women. Hum Reprod 23, 19241931.Google Scholar
116. Cheung, LP, Ma, RCW, Lam, PM, et al. (2008) Cardiovascular risks and metabolic syndrome in Hong Kong Chinese women with polycystic ovary syndrome. Hum Reprod 23, 14311438.Google Scholar
117. Glueck, CJ, Papanna, R, Wang, P, et al. (2003) Incidence and treatment of metabolic syndrome in newly referred women with confirmed polycystic ovarian syndrome. Metabolism 52, 908915.Google Scholar
118. Hahn, S, Tan, S, Sack, S, et al. (2007) Prevalence of the metabolic syndrome in German women with polycystic ovary syndrome. Exp Clin Endocrinol Diabetes 115, 130135.CrossRefGoogle ScholarPubMed
Figure 0

Table 1 Diagnostic criteria for polycystic ovary syndrome (PCOS)(18)

Figure 1

Fig. 1 Meta-analysis(113118) of the prevalence of central obesity in women with and without polycystic ovary syndrome (PCOS) (taken from Lim et al.(20)). M-H, Mantel–Haenszel.