Arch Gynecol Obstet (2014) 290:1079–1092 DOI 10.1007/s00404-014-3433-z

REVIEW

Focus on metabolic and nutritional correlates of polycystic ovary syndrome and update on nutritional management of these critical phenomena Mariangela Rondanelli • Simone Perna • Milena Faliva • Francesca Monteferrario Erica Repaci • Francesca Allieri

•

Received: 14 February 2014 / Accepted: 22 August 2014 / Published online: 9 September 2014  Springer-Verlag Berlin Heidelberg 2014

Abstract Introduction Polycystic ovary syndrome (PCOS) is associated with numerous metabolic morbidities (insulin resistance (IR), central obesity) and various nutritional abnormalities (vitamin D deficit, mineral milieu alterations, omega6/omega3 PUFA ratio unbalance). Methods We performed a systematic literature review to evaluate the till-now evidence regarding: (1) the metabolic and nutritional correlates of PCOS; (2) the optimum diet therapy for the treatment of these abnormalities. This review included 127 eligible studies. Results In addition to the well-recognized link between PCOS and IR, the recent literature underlines that in PCOS there is an unbalance in adipokines (adiponectin, leptin, visfatin) production and in omega6/omega3 PUFA ratio. Given the detrimental effect of overweight on these metabolic abnormalities, a change in the lifestyle must be the

M. Rondanelli (&)
S. Perna
M. Faliva
F. Monteferrario
E. Repaci
F. Allieri Department of Public Health, Experimental and Forensic Medicine, Section of Human Nutrition, Endocrinology and Nutrition Unit, University of Pavia, Azienda di Servizi alla Persona, Pavia, Italy e-mail: [email protected] S. Perna e-mail: [email protected] M. Faliva e-mail: [email protected] F. Monteferrario e-mail: [email protected] E. Repaci e-mail: [email protected] F. Allieri e-mail: [email protected]

cornerstone in the treatment of PCOS patients. The optimum diet therapy for the PCOS treatment must aim at achieving specific metabolic goals, such as IR improvement, adipokines secretion and reproductive function. These goals must be reached through: accession of the patient to hypocaloric dietary program aimed at achieving and/or maintaining body weight; limiting the consumption of sugar and refined carbohydrates, preferring those with lower glycemic index; dividing the food intake in small and frequent meals, with high caloric intake at breakfast; increasing their intake of fish (4 times/week) or taking omega3 PUFA supplements; taking Vitamin D and chromium supplementation, if there are low serum levels. Conclusion Lifestyle intervention remains the optimal treatment strategy for PCOS women. A relatively small weight loss (5 %) can improve IR, hyperandrogenism, menstrual function, fertility. Keywords Polycystic ovary syndrome
Dietary management
Dietary supplement
Overweight
Adipokines
Insulin resistance

Introduction Polycystic ovary syndrome (PCOS) is one of the most common female endocrine disorders with a prevalence of approximately 5–10 % in women of reproductive age [1, 2], and women with PCOS are at increased risk of reproductive abnormalities [3]. PCOS is a heterogeneous syndrome characterized by increased ovarian and adrenal androgen secretion with hyperandrogenic symptoms, such as hirsutism, acne and/or alopecia, menstrual irregularity, anovulation and infertility [3]. A positive diagnosis is made when the patient has any two of the three features: oligo-

123

1080

ovulation/anovulation, clinical and/or biochemical signs of hyperandrogenism, and polycystic ovaries on ultrasound examination, according to Rotterdam ESHRE/ASRMsponsored PCOS consensus workshop [4]. Besides the endocrinological abnormalities observed in this syndrome, profound metabolic alterations have also been documented: insulin resistance (IR), hyperinsulinemia, central obesity and metabolic syndrome (MeTS) [5], which increase risks for developing type 2 diabetes (T2DM), cardiovascular disorders, hypertension, atherosclerosis and dyslipidemia [6]. Hyperinsulinemia and IR stimulate ovarian androgen production [7, 8] and decrease serum sex hormone-binding globulin (SHBG) concentrations [9, 10], leading to increased levels of circulating free testosterone. This association between IR and ovarian hyperandrogenism suggests that insulin directly influences ovarian function [11]. Women with PCOS have increased ovarian cytochrome P450c17a activity, as evidenced by an elevated serum 17OHP (17a-hydroxyprogesterone) in response to stimulation by GnRH (gonadotropin-releasing hormone) agonists [12]; ovarian cytochrome P450c17a appears to be stimulated by insulin in PCOS. Given this background, the aim of the present systematic review is to summarize the state of the art according to the extant literature about two topics: (1) the metabolic and nutritional correlates of PCOS and (2) the optimum diet therapy for the treatment of these abnormalities.

Methods The present systematic review was performed following the steps by Egger et al. [13] as follows: (1) configuration of a working group: three operators skilled in endocrinology and clinical nutrition, of whom one acting as a methodological operator and two participating as clinical operators. (2) Formulation of the revision question on the basis of considerations made in the abstract: ‘‘the state of the art on metabolic and nutritional correlates of PCOS and their nutritional treatment’’. (3) Identification of relevant studies: a research strategy was planned, on PubMed [Public Medline run by the National Center of Biotechnology Information (NCBI) of the National Library of Medicine of Bathesda (USA)], as follows: (a) definition of the key words (Polycystic Ovary Syndrome, dietary management, dietary supplement, overweight, adipokines, insulin resistance), allowing the definition of the interest field of the documents to be searched, grouped in inverted commas (‘‘…’’) and used separately or in combination; (b) use of: the Boolean (a data type with only two possible values: true or false) AND operator that allows the establishments of logical relations among concepts; (c) research modalities: advanced search; (d) limits: time limits: papers

123

Arch Gynecol Obstet (2014) 290:1079–1092

published in the last 20 years; humans; languages: English; (e) manual search performed by the senior researchers experienced in clinical nutrition through the revision of reviews and individual articles on microbiota in elderly published in journals qualified in the Index Medicus. (4) Analysis and presentation of the outcomes: the data extrapolated from the revised studies were collocated in tables; in particular, for each study we specified: the author, the name of the journal where the study was published and year of publication, study characteristics. (5) The analysis was carried out in the form of a narrative review of the reports. At the beginning of each section, the keywords considered and the kind of studies chosen have been reported. Suitable for the systematic review were studies of any design, which considered women with PCOS diagnosed consistently to The Rotterdam ESHRE/ASRMSponsored PCOS Consensus Workshop Group, 2004 [4].

Results Metabolic correlates in PCOS Obesity and insulin resistance This research has been carried out based on the keywords: ‘‘Polycystic Ovary Syndrome’’ AND ‘‘obesity’’ AND ‘‘insulin resistance’’; 1,248 articles were sourced. Among them, 22 retrospective studies, 12 reviews, 7 cross-over studies, 3 double-blind studies, 2 retrospective studies and 1 cohort study have been selected and discussed. Obesity is not necessarily a defect intrinsic to PCOS [14], but is a significant characteristic of this syndrome [4, 15, 16], with a pooled estimated prevalence of 49 %, as shown in a recent meta-analysis [17] and, specifically central obesity, worsens the phenotype [18]. Adiposity-dependent IR is linked with PCOS, given that the prevalence of obesity among women with PCOS is higher than that of age-matched healthy women without this syndrome, as determined at referral centers [13]. IR occurs in approximately 50–70 % of women with PCOS and in 95 % of obese women with PCOS [19, 20]. The degree of IR in PCOS is greater than that predicted by the Body Mass Index (BMI-ratio between weight and the square of the height), although 40–50 % of women with PCOS are not obese [21–23]. The prevalence of MetS and IR varies between the different female hyperandrogenic phenotypes [24]. In another study [25], non-hyperandrogenic anovulatory cases of PCOS were found to show only marginal risk. Given this well-documented association between PCOS and IR, insulin-sensitizing agents have been used in the therapy of PCOS. As shown in a 2003 Cochrane, over 50 intervention studies have demonstrated a positive effect of metformin on both reproductive and metabolic

Arch Gynecol Obstet (2014) 290:1079–1092

aspects of PCOS [26]. It is peculiar that numerous randomized controlled trials (RCT) showed this positive effect of metformin therapy on endocrine and metabolic variables, not only in obese or insulin-resistant PCOS patients, but even in lean and insulin-sensitive women [27–31]. A recent consensus on women’s health aspects of PCOS [32] has defined that metformin treatment is indicated in those with impaired glucose tolerance (IGT) who do not respond adequately to calorie restriction and lifestyle changes. As regards the relationship between IR and menstrual disturbance, PCOS patients with isolated primary or secondary amenorrhea or oligomenorrhea and patients with secondary amenorrhea alternating with regular menstrual cycles had more pronounced IR than women with regular menstrual cycles [33]. In contrast, patients with oligomenorrhea alternating with secondary amenorrhea or with regular menstrual cycles did not differ in markers of IR from women with regular menstrual cycles. Two previous studies reported that patients with PCOS and oligomenorrhea or amenorrhea had more severe IR than patients with PCOS and regular cycles [34, 35]. In contrast, in two other more recent studies that analyzed patients with amenorrhea separately from patients with oligomenorrhea, only the former had more pronounced IR than patients with regular menses [36, 37]. As regards intraovarian hyperinsulinemic pathways, hyperinsulinemia may have preferentially impaired oocyte developmental competence, resulting in reduced rates of fertilization, embryonic development and implantation in PCOS patients with obesity [38, 39]. Data from in vitro cell culture models suggest that co-incubation of insulin and follicle-stimulating hormone (FSH) with mouse [40] and bovine [41] oocytes promotes FSH-induced up-regulation of GC (granulose cells) LH (luteinizing hormone) receptor mRNA expression [42–44], inhibiting FSH stimulation of aromatase activity [41], thus reducing the percentage of fertilized oocytes that develop into blastocysts [45, 40]. Insulin may induce local androgen production, which results in oocytes of lower quality, post-maturity [46]. At the molecular level, insulin binds to its receptor, localized on GC and theca cells, and oocytes, to stimulate follicle recruitment [45, 47], consequently altering expression of multiple genes involved in meiotic/mitotic spindle dynamics and centrosome function in PCOS oocytes [48]. This indicates that insulin may be an important mediator of oocyte developmental competence via a ligand-receptor regulating system [45]. Chronic low-grade inflammation has emerged as a key contributor to the pathogenesis of PCOS and emerging data suggest that this chronic low-grade inflammation underpins the development of metabolic aberration, such as IR, and ovarian dysfunction in PCOS [49, 50]. Most importantly, there is a strong association between hyperandrogenism and inflammation in PCOS [51–54].

1081

In summary, IR is a relative common finding in PCOS women, independent of obesity. Assessment of insulin sensitivity may allow identification of patients at higher risk for metabolic sequelae and allow the selection of patients most likely to respond to treatment with insulinsensitizing drugs. Adipokines unbalance in PCOS This research has been carried out based on the keywords: ‘‘Polycystic Ovary Syndrome’’ AND ‘‘adipokines’’ AND ‘‘insulin resistance’’ 220 articles were sourced. Among these, 9 reviews, 29 prospective studies, 17 cross-over studies and 3 single-blinded studies have been selected and discussed. Paracrine dysregulation of adipokine production by macrophage-secreted cytokines in PCOS favors development of IR [55]. Considering the frequent clustering of obesity and IR-associated disorders in PCOS patients, adipokines have been proposed to play a role in the pathogenesis of PCOS [56]. Adipokines may thus serve as an endocrine link between obesity and PCOS [57]. Moreover, a possible role for cytokine products of fat (adipokines) as a link between reproductive and metabolic abnormalities has been mooted [58, 59]. Abnormal serum levels of various adipokines in PCOS have been reported in the literature [60]. Adiponectin Adiponectin is considered to be one of the most important adipokines in human physiology and differs from most other adipokines by having a protective effect on development of obesity. The disruption of adiponectin and its receptors is a major mechanism that links metabolic and reproductive dysfunction in women with polycystic ovary syndrome [61]. Serum adiponectin levels are decreased in PCOS patients [56, 62–67], yet this result may be explained by the concurrence of obesity [64], IR [65, 66] and/or IGT [67] in these women, whereas other researches reported that serum adiponectin concentrations did not seem to differ between PCOS and controls [68]. A meta-analysis [69] revealed that serum adiponectin levels are lower in women with PCOS compared with BMImatched healthy controls and that the more insulin-resistant women with PCOS recruited, the lower serum adiponectin levels were found. The effects of adiponectin are mediated by at least two main receptors that have been identified recently [70]: adiponectin receptor-1 (AdipoR1) that is abundantly expressed in skeletal muscle, and adiponectin receptor-2 (AdipoR2) that is predominantly expressed in the liver. PCOS patients had lower baseline serum adiponectin and AdipoR1 compared to healthy women after controlling for BMI [71].

123

1082

Leptin In humans, leptin acts as an afferent satiety signal, regulating appetite and weight and is mainly produced in the adipocyte of white adipose tissue [72]. However, recent studies have confirmed that other tissues also express leptin, including placenta, ovaries, skeletal muscle, stomach, pituitary, and liver [73]. Leptin appears to act as an endocrine and paracrine factor for the regulation of puberty and reproduction; it affects maternal, placental and fetal function, modifies insulin sensitivity in the muscle or liver, prevents ectopic lipid deposition, and links the endocrine and immune systems [74, 75]. Leptin levels have been reported to be increased in women with PCOS in comparison to weight-matched controls [76–79] although this was not supported by many other studies [80–83]. Wang also reported significantly higher mRNA expression of leptin in subcutaneous adipose tissue of PCOS patients compared with controls [81–84]. No significant difference was found in circulating leptin levels between the ovulatory and anovulatory PCOS patients either [83]. Furthermore, a recent study showed that there was no effect of PCOS on either adipose leptin expression or plasma leptin levels [85]. As regards relationship with IR, no significant differences were observed in serum leptin or leptin receptor (LEPR) levels between PCOS IR and PCOS non-IR women [84]. However, Yildizhan [79] observed an association between serum leptin levels with IR in young women with PCOS. Visfatin Visfatin is a more recently described adipokine that also appears to have insulin-like effects [86]. It has previously been reported that the gene expression and circulating levels of visfatin were increased in women with PCOS compared with age- and BMI-matched controls [87– 94]. However, several recently published studies did not find a difference in plasma or serum visfatin levels between patients with PCOS and control groups [95–97] Moreover, Chan [88] did not observe any correlation between visfatin concentrations and testosterone, insulin, and LH levels in either PCOS or control groups. A positive correlation, however, was found between plasma visfatin concentration, fasting insulin, and homeostasis model assessment (HOMA)-IR, as reported by Tan [87]. In summary, at present, any indication to measure routinely circulating levels of such adipokines is present in the literature, but this topic represents an intriguing topic of research in PCOS women. Weight loss and adipokines There is a paucity of data on the effects of weight loss on serum adipokine levels in overweight/obese patients with PCOS [98, 99]. A recent prospective study by Spanos [94] demonstrated that weight loss (about 12 %) by diet and

123

Arch Gynecol Obstet (2014) 290:1079–1092

orlistat results in a significant reduction in serum leptin levels in both patients with PCOS and controls, and this decrease is comparable in the two groups. On the other hand, serum adiponectin, resistin, and visfatin levels are not affected by weight loss. Previous short-term (1–8 weeks) studies on the effects of hypocaloric diet in PCOS patients showed that serum leptin levels decline in parallel with weight loss [98, 100, 101]. This finding is somewhat expected because the degree of obesity is the major determinant of serum leptin levels in patients with PCOS [81, 102, 103]. In summary, our current understanding of the role for adipokines in PCOS is far from complete. Moreover, there is a paucity of data on the effects of weight loss on serum adipokine levels in overweight/obese patients with PCOS. Nutritional correlates in PCOS Mineral deficiency and its treatment This research has been carried out based on the keywords: ‘‘Polycystic Ovary Syndrome’’ AND ‘‘mineral’’; 59 articles were sourced. Among them, 2 reviews, 11 prospective studies and 5 cross-over studies have been selected and discussed. Magnesium Decreased magnesium level was reported in women with increased testosterone levels [104] and/or IR [105]. A prospective study demonstrated that the PCOS women with IR exhibited significantly lower serum levels of magnesium than controls and PCOS women without IR and that circulating serum magnesium significantly correlated with fasting insulin levels [106]. Hypomagnesemia is associated with T2DM and MetS [107]. Copper Two recent prospective studies showed that higher serum copper level is observed in PCOS patients than in the controls [106, 108], which significantly increases with the association of insulin resistance [106]. Moreover, copper, in addition to its enzymatic roles, similarly can induce oxidative stress by catalyzing the formation of reactive oxygen species and decreasing glutathione levels [77]. Many studies conferred the role of increased oxidative stress resulting from high generation of reactive oxygen species (ROS) in the pathogenesis of PCOS [53, 109]. Chrome Chrome picolinate consists of trivalent chromium (Cr3?), an extremely safe [110] and highly tolerable trace mineral that is present in the normal diet [111], complexed to picolinic acid to enhance gut absorption. After cleavage of picolinic acid, Cr3? is transported by transferrin and later, by chromodulin, its binding protein.

Arch Gynecol Obstet (2014) 290:1079–1092

1083

Table 1 Metabolic or nutritional correlates in PCOS and recommended treatment Metabolic or nutritional correlates

Recommended treatment

References

Type of study

Results after recommended treatment

Insulin resistance

Intake of foods with low glycemic index

Graff [151]

Cross-sectional study

Dietary GI is increased in the classic PCOS phenotype and associated with a less favorable anthropometric and metabolic profile

Mehrabani [150]

Single blind clinical trials: hypocaloric diet (CHCD) (15 % of daily energy from protein) and a modified hypocaloric diet (MHCD) with a high-protein, low-glycemic load (30 % of daily energy from protein plus low-glycemic-load foods)

Both hypocaloric diets significantly led to reduced body weight and androgen levels in these two groups of women with PCOS. The combination of high-protein and low-glycemic-load foods in a modified diet caused a significant increase in insulin sensitivity and a decrease in hsCRP level when compared with a conventional diet

Overweight or obesity

Low caloric diet with high protein and low glycemic load

Moran [148]

Systematic review

Greater weight loss for a monounsaturated fat-enriched diet; improved menstrual regularity for a low-glycemic index diet; increased free androgen index for a highcarbohydrate diet; greater reductions in insulin resistance, fibrinogen, total, and high-density lipoprotein cholesterol for a lowcarbohydrate or low-glycemic index diet; improved quality of life for a low-glycemic index diet; and improved depression and selfesteem for a high-protein diet. Weight loss improved the presentation of PCOS regardless of dietary composition in the majority of studies. Weight loss should be targeted in all overweight women with PCOS through reducing caloric intake in the setting of adequate nutritional intake and healthy food choices irrespective of diet composition

Alterations in the secretion of adipokines and cytokines

Balanced low-calorie diet with adequate timing of intake of meals and supplements with omega3 fatty acids

Rafraf [135]

Intervention study: 720 mg/day eicosapentaenoic acid and 480 mg/ day docosahexaenoic acid

Increased serum adiponectin levels, insulin resistance and lipid profile

Leidy [152]

Intervention study: two isocaloric (*1,800 kcal) maintenance diets with different meal timing distribution: a BF (breakfast diet) (980 kcal breakfast, 640 kcal lunch and 190 kcal dinner) or a D (dinner diet) group (190 kcal breakfast, 640 kcal lunch and 980 kcal dinner)

high caloric intake at breakfast with reduced intake at dinner results in improved insulin sensitivity indices and reduced cytochrome P450c17a activity, which ameliorates hyperandrogenism and improves ovulation rate

Low blood levels of 25 hydroxy vitamin D

Intake of vitamin D supplement

Pal [129]

Intervention study: 8,533 UI/day of vitamin D

Androgen and Blood Pressure profiles improved

Wehr [130]

Intervention study: 20,000 IU cholecalciferol weekly

Vitamin D treatment might improve glucose metabolism and menstrual frequency

123

1084

Arch Gynecol Obstet (2014) 290:1079–1092

Table 1 continued Metabolic or nutritional correlates

Recommended treatment

References

Type of study

Results after recommended treatment

Alteration of the milieu of trace minerals

Intake of chromium picolinate supplement

Lydic [117]

Intervention study: dietary supplement with 1,000 lg as CrP/day

Improved glucose disposal

GI glycemic index, hsCRP high-sensitivity C-reactive protein

This complex binds the insulin receptor [111]. Active glucose transport is enhanced through tyrosine kinase phosphorylation, without inhibition of phosphotyrosine phosphatase [84]. Chrome deficiency as a cause of glucose intolerance was recognized first in 1977 [112]. Chromium appeared to improve the effects of insulin and worked at the level of the cell membrane [113]. The interaction between chromium and insulin has been elucidated by the discovery of low-molecular weight chromium-binding substance, which binds chromium and the insulin receptor, activating the insulin receptor’s kinase activity [114, 115]. Morris and colleagues [116] showed diminished plasma Cr3? levels in T2DM subjects, suggesting that Cr3? losses diminish insulin sensitivity and worsen T2DM. As demonstrated, Cr3? (1,000 lg as chrome picolinate) improved glucose disposal in five obese PCOS subjects after 2 months [117]. In summary, some studies suggest that PCOS women have mostly insufficient magnesium levels, so magnesium replacement therapy may have a beneficial effect on ameliorating the IR. Also, CrP supplementation may improve IR in PCOS, as shown in the literature (Table 1). Higher serum copper level is observed in PCOS patients than the controls, so RCT must be performed to evaluate if therapy with copper chelators may be useful in PCOS women with elevated blood levels of copper. Nutritional correlates in PCOS: vitamin D deficiency and its treatment This research has been carried out based on the keywords: ‘‘Polycystic Ovary Syndrome’’ AND ‘‘vitamin D’’; 59 articles were sourced. Among them, 6 reviews, 7 prospective studies and 1 cross-over study have been selected and discussed. Vitamin D is rapidly emerging as an important biomolecule with effects beyond the already established role in calcium and phosphorus metabolism. The various pathways include apoptotic pathway, insulin metabolism, growth and differentiation [118]. There is some evidence suggesting that vitamin D deficiency might be involved in

123

the pathogenesis of insulin resistance and the metabolic syndrome in PCOS [119, 120]. Vitamin D deficiency has been shown to be associated with impaired glucose clearance and insulin secretion in both human [121] and animal models [122]. 25-Hydroxyvitamin D (25-OH-VD) is positively correlated with the insulin sensitivity and negatively with beta-cell function [123]. A recent review by Thomson et al. [124] suggests that there is an association between vitamin D status and hormonal and metabolic dysfunctions in PCOS. The underlying mechanism is, however, yet to be elucidated. One of the plausible mechanisms may be the dysregulation of the complex mechanism that regulated ovarian apoptosis [125]. Due to its immunomodulatory functions, hypovitaminosis D might induce a higher inflammatory response, which is again associated with IR [126, 127]. An interesting study on obese and non-obese PCOS patients [128] demonstrated that low serum concentrations of 25-OH-VD have been associated with higher BMI and total cholesterol values. This study also confirmed the association between abdominal obesity, hyperandrogenism, and IR. A recent single-arm, open-label trial performed for 3 months in 23 PCOS women supplemented with Vitamin D and calcium suggests potential therapeutic benefits of these nutrients supplementation in ameliorating the hormonal milieu (significant reduction in total testosterone) and PCOS-related sequelae in women deficient in vitamin D [129]. Another intervention study by Wehr [130] conducted in fifty-seven PCOS women, which received 20,000 IU cholecalciferol weekly for 24 weeks, suggested that vitamin D treatment might improve glucose metabolism and menstrual frequency in PCOS women. The positive effect on glucose metabolism is in according to the study by Selimoglu [131] that showed improvement in HOMA indices within 3 weeks of a single oral mega dose of 300,000 IU D3 in a pilot study on 11 PCOS women. In summary, there are data that suggest pathophysiological relevance of vitamin D deficiency for PCOS. Some studies demonstrated that women with PCOS have mostly insufficient vitamin D levels, and vitamin D replacement therapy may have a beneficial effect on ameliorating the hormonal status (significant reduction in total testosterone

Arch Gynecol Obstet (2014) 290:1079–1092

and menstrual disturbances) and PCOS-related sequelae (improvement in IR) in women deficient in vitamin D (Table 1). Nutritional correlates in PCOS: imbalance in the n-6/n-3 PUFA ratio and its treatment This research has been carried out based on the keywords: ‘‘Polycystic Ovary Syndrome’’ AND ‘‘plasma fatty acids’’; 12 articles were sourced. Among them, 1 review, 2 prospective studies, 2 cross-over studies and 2 double-blind studies have been selected and discussed. An interesting study reported that increased dietary polyunsaturated fatty acids (PUFA) intake could be associated with improved endocrine and metabolic characteristics in women with PCOS [132]. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are n-3 long-chain polyunsaturated fatty acids (n-3 LC PUFA) found primarily in fatty fish. In current diets, n-6 fatty acids are predominant PUFA and imbalance in the n-6/n-3 PUFA ratio may be related to chronic disease [133]. Many studies, as well documented in the literature, have shown increasing evidence for antiatherogenic and anti-inflammatory effects of fish oil supplementation and it is conceivable that dietary PUFA might also have benefit effects on glycemic control and lipid profile [133–135]. Moreover, it seems that the positive effect of EPA and DHA on metabolic parameters could be partially due to enhancement of adiponectin production [114, 136]. A recent RCT has demonstrated that a supplementation for 8 weeks with 720 mg/day eicosapentaenoic acid and 480 mg/day docosahexaenoic acid increases serum adiponectin levels, insulin resistance and lipid profile in a group of overweight or obese PCOS patients [135, 137]. In conclusion, the data currently available, although the research carried out are few, are very promising and show that an adequate intake of omega3 fatty acids may be useful in the control and prevention of metabolic complications of PCOS patient, as shown in Table 1.

1085

may benefit from LSM through adiposity reduction [140], improved ovulatory function [141] and reduction in overall cardiovascular risk [142]. Previous observational studies demonstrated that LSM can be associated with clinical improvement in PCOS, as shown in Table 2 Kiddy and colleagues [143] demonstrated that moderate weight loss (equal to 5 %) during long-term calorie restriction (6 months) is associated with a marked clinical improvement in menstrual function and fertility. Clark et al. [144] demonstrated in a retrospective study that weight loss (the average weight loss in the PCOS group was 6.3 kg, during 6 months of LSM program) is associated with improvement in ovulation, pregnancy outcome, self-esteem and endocrine parameters in women who are infertile and overweight. Thomson demonstrated that in overweight and obese women with PCOS and reproductive dysfunction, a 20-week weight loss intervention (with weight loss equal to 9 kg) resulted in significant reduction in fasting insulin, homeostasis model assessment, testosterone and Free Androgen Index (FAI), an increase in sex hormone-binding globulin (SHBG) and in improvements in reproductive function, but no change in anti-Mullerian hormone levels [145]. A significant correlation between the weight reduction (5–6 kg lost or lost 5–10 % of starting body weight is highly recommended) and the improvement in metabolic parameters could be attributed to decreased insulin resistance or to other related factors. Clinicians prescribing LSM interventions must consider the patient’s capacity to sustain diet and exercise adherence and weight maintenance over time in order for the clinical benefits on PCOS to continue [146]. In summary, lifestyle modification (dietary intervention and increased physical activity) remains the optimal treatment strategy for overweight/obese women with PCOS. The studies currently available showed that a relatively small weight loss (equal to 5–10 %), achieved with long-term caloric restrictions (5–6 months), can improve IR and hyperandrogenism, menstrual function and fertility, as reported in 2011 Cochrane by Moran [147]. Weight loss can also improve long-term metabolic health.

Management of metabolic and nutritional correlates of PCOS: lifestyle modification

Dietary composition and meal timing

This research has been carried out based on the keywords: ‘‘Polycystic Ovary Syndrome’’ AND ‘‘lifestyle’’ AND ‘‘diet’’; 101 articles were sourced. Among them, 7 reviews, 4 prospective studies, 6 cross-over studies 2 single-blinded studies have been selected and discussed. Lifestyle modification programs (LSM), comprised of diet and physical activity, are recommended for in high risk patients (prediabetic) to delay the onset of T2DM [138, 139], one of the most serious complications of PCOS. Additionally, overweight and obese women with PCOS

The most important determinant of dietary intervention for weight loss in PCOS women is energy balance, though for many other reasons various types of diet have been proposed and tested, as shown in a recent review by Moran [148]. This review and meta-analysis reported that weight loss should be targeted in all overweight women with PCOS through reducing caloric intake in the setting of adequate nutritional intake and healthy food choices, irrespective of diet composition. Table 1 summarizes the studies investigating the optimum diet therapy and the

123

1086

optimum dietary supplementation for the treatment of PCOS. A crossover study conducted by Douglas demonstrated that a moderate low-carbohydrate diet (43 %), conducted for 16 days, reduced the fasting and postchallenge insulin concentrations among PCOS women, which, over time, may improve reproductive/endocrine outcomes [149]. A following study conducted by Marsh in 96 PCOS women confirmed this result: with only modest weight loss (4–5 % of body weight), the low-carbohydrate diet provided a threefold greater improvement in whole-body insulin sensitivity, improved menstrual regularity and better emotion scores, compared to conventional hypocaloric diet. By contrast, both the low-carbohydrate and the conventional diets led to similar improvements or changes in blood lipid and androgenic hormones concentrations, markers of inflammation, and other measures of quality of life. A further recent 12-week single-blind clinical trial, in which a total of 60 PCOS overweight and obese women were recruited and randomly assigned to (1) a conventional hypocaloric diet (CHCD) (15 % of daily energy from protein) and (2) a modified hypocaloric diet (MHCD) with a high-protein, low-glycemic load (30 % of daily energy from protein plus low-glycemic-load foods), demonstrated that both hypocaloric diets significantly led to reduced body weight and androgen levels, but the combination of high-protein and low-glycemic-load foods in a modified diet caused a significant increase in insulin sensitivity and a decrease in high-sensitivity C-reactive protein level, when compared with a conventional diet [150]. However, in a recent cross-sectional study, Graff [151] demonstrated that the intake of food with high glycemic index is increased in the classic PCOS phenotype than in control women and is associated with a less favorable anthropometric and metabolic profile. Concerning protein supplementation, in PCOS patients a 2-month hypocaloric diet, associated with a 240-kcal supplement containing whey protein, reduced body weight, fat mass, serum cholesterol, and apoprotein B more than the same hypocaloric diet associated with a 240-kcal supplement containing simple sugars instead of whey protein [98]. As regards the meal timing, recently, Jakubowicz and colleagues found in 60 lean PCOS women that high caloric intake at breakfast than high caloric intake at dinner led to greater weight loss, improved glucose metabolism and insulin sensitivity indices, which lead to the reduction of ovarian P450c17a activity and, as a result, to decreased ovarian testosterone synthesis [152]. Thus, the improvement of insulin resistance indices found after high caloric intake at breakfast suggests that the high caloric intake in the morning might represent a schedule more synchronized with the circadian pacemaker. This clock resetting could be protective also against the disruption in hormone secretion reported in PCOS patients [153, 154].

123

Arch Gynecol Obstet (2014) 290:1079–1092

In summary, a weight loss of 5–10 % of original body weight improves insulin sensitivity and short-term reproductive fitness in PCOS overweight women and is additionally crucial for improving short- and long-term metabolic health.

Discussion and conclusion The adipose tissue of women with PCOS is characterized by hypertrophic adipocytes and impairments in insulin action. Amenorrhea is associated with more pronounced IR and hyperandrogenemia in patients with PCOS. Therefore, the type of menstrual cycle abnormality might represent a useful tool for identifying a more severe metabolic profile in PCOS. The expression and secretion of a wide variety of adipokines implicated in IR are also altered in PCOS. Collectively, the available data indicate that adipose tissue dysfunction plays a pivotal role in the metabolic abnormalities observed in PCOS. Whether these abnormalities are primary or secondary to hyperandrogenism or other abnormalities in PCOS is not yet known. However, a comprehensive evaluation of the circulating levels of several adipokines in patients with PCOS has not been performed to date and the results of the studies that have evaluated how the weight loss has resulted in a change of the levels of adipokines, are very few, conducted for short periods and difficult to interpret. So, new studies in this interesting topic must be conducted. There is well-established evidence for the detrimental effect of overweight and obesity in PCOS women. A weight loss of 5–10 % of original body weight improves insulin sensitivity and shortterm reproductive activities in PCOS overweight women and is additionally crucial for improving short- and longterm metabolic health. This can be accomplished through lifestyle intervention, with the overall aim of energy expenditure exceeding energy intake over a short or medium period. Following weight loss, metabolic and endocrine variables were improved to a level similar to that of BMI-matched non-PCOS controls. However, even if the studies performed on specific diets are heterogeneous and final conclusions can not be drown, it appears useful to limit the consumption of sugar and refined carbohydrates, with preference of products with low glycemic index in order to favor metabolic improvements. In addition, it can be suggested to divide the food intake in small and frequent meals, with high caloric intake at breakfast. Moreover, the majority of studies were also of short- to medium-term duration, with only one 12-month study. Because the longterm sustainability of anthropometric and metabolic improvements is more important than acute changes, there is a significant gap in the literature. Additional research is warranted that assesses the effect of dietary composition on

Arch Gynecol Obstet (2014) 290:1079–1092

1087

Table 2 Effects of LMS program on metabolic correlates of PCOS (modified from Domecq et al. [155]) Author and year

Age

Followup (months)

n

Groups

BMI

Characteristics

Main conclusions

Brown, 2009 [156]

18–50 years

6

11

LMS

38 (median)

Ex Prog: moderate to intensive, 228 min/week for 5–6 m

Improved lipoprotein profiles in PCOS women

31

C

31 (median)

No intervention

Guzik, 1994 [157]

32 mean age

5

12

LMS

38 (mean)

Diet (1,200–1,000 kcal/day ? Ex Prog. (walking 2 miles/day, 5 days/week) for 3 m

Hoeger, 2004 [158]

28 mean age

12

27

LMS

39 (mean)

Diet (500–1,000 kcal/day) ? Ex Prog. (150 min/week for) 12 m

C

No intervention

Met 12–18 years

6 months

32

LMS

No intervention [25 (above the 95th percentile)

Met Control Karimzadeh, 2010 [160]

27 mean age

6

25

LMS

Met LMS

Palomba, 2010 [161]

18–35 years

1.5

5 64

Qublan, 2007 [162]

31 mean age

3

46

32 (mean)

30 mean age

4

84

Vigorito, 2007 [164]

2 mean age

3 months

90

LMS

1,700 mg/day ? LSM ? oral contraceptives for 6 m

Reduction of CA, total T and increased HDL, no WL

Diet (delta 500 kcal/day) ? Ex Prog (120 min/day from 3 to 5 times/week) for 6 m 1,500 mg/dia Diet ? Ex Prog (3 times/week) for 1.5 m

LMS improved LP in PCOS women

Increased ovulation in ob. PCOS women resistant to clomiphene

Diet (120–1,400 kcal/day) for 3 m

Ameliorated hyperinsulinemia and hyperandrogenemia

1,700 mg/day for 3 m

Improved clinical parameters and ameliorated reproductive function in PCOS ob. women

27 (mean)

Ex Prog. (30–45 min. 3 day/ week ? 1 day of reinforcement) for 4 m No intervention

Improved reproductive function in PCOS women

29 (mean)

Ex. Prog. (30 min/day 3 times/ week) for 3 m

Improved oxygen peak consumption, reduced BMI, C-reactive protein and ISI

Control LMS

Enhancement of androgen and reduction of SHBGT in ob. adolescents PCOS women

No intervention 32 (mean)

Met

StenerVictorin, 2009 [163]

Diet ? Ex Prog. ? Behav. Int. ? oral contraceptives for 6m

Placebo for 6 m 27 (mean)

Control LMS

WL may restore ovulation in PCOS ob. women

1,700 mg/dia for 12 m

C Hoeger, 2008 [159]

WL in ob PCOS women reduces I and n-SHBGT conc., may restore ovulation

Control

No intervention

When not specifically indicated, the value of the age means the mean age; follow-up period is expressed in months after the end of the study; when not specifically indicated, the value of the BMI means the mean of BMI values BMI Body Max Index (ratio between weight and the square of the height), C control group, CA central adiposity, Ex Prog exercise program, I insulin, Diet hypocaloric diet, ISI insulin sensitivity index, LMS life modification program, LP lipid profile, PCOS polycystic ovary syndrome, T testosterone, m months, Met metformin, ob. obese, SHGT conc. SHGT concentrations, WL weight loss, Y years

weight maintenance or prevention of weight gain in both lean and overweight women with PCOS, and the effect of dietary composition on reproductive, metabolic, and psychological parameters independent of changes in weight in PCOS lean women. Finally, a supplementation of vitamin D and chrome improve glycemic control and IR in PCOS woman, but at the present the specific dose for supplementation of these nutrients is not yet well established.

Finally, as regards minerals, magnesium supplementation and use of copper chelators may be promising topics. Moreover, also a supplementation of omega3 PUFA (DHA and EPA) improves IR and counteracts the damage derived from oxidative stress. Further research is needed, including high-quality, longterm RCTs that assess a range of diet compositions, including low GI, and use of dietary supplement, in PCOS

123

1088

Arch Gynecol Obstet (2014) 290:1079–1092

for both weight management and optimizing reproductive, metabolic, and psychological outcomes. Conflict of interest

There are no conflicts of interest.

References 1. Calvo AM, San Millan RM, Sancho JL, Avila SJ, EscobarMorreale HF (2000) A prospective study of the prevalence of the polycystic ovary syndrome in unselected Caucasian women from Spain. J Clin Endocrinol Metab 85:2434–2438 2. Dunaif A (1997) Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis. Endocr Rev 18:774–800 3. Goodarzi MO, Dumesic DA, Chazenbalk G, Azziz R (2011) Polycystic ovary syndrome: etiology, pathogenesis and diagnosis. Nat Rev Endocrinol 7:219–231 4. Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group (2003) Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod 19:41–47 5. Ehrmann DA (2005) Polycystic ovary syndrome. N Engl J Med 352:1223–1236 6. Solomon CG (1999) The epidemiology of polycystic ovary syndrome. Prevalence and associated disease risks. Endocrinol Metab Clin North Am 28:247–263 7. Dunaif A, Graf M, Mandeli J, Laumas V, Dobrjansky A (1987) Characterization of groups of hyperandrogenic women with acanthosis nigricans, impaired glucose tolerance, and/or hyperinsulinemia. J Clin Endocrinol Metab 65:499–507 8. Jakubowicz DJ, Nestler JE (1997) 17 alpha-hydroxyprogesterone responses to leuprolide and serum androgens in obese women with and without polycystic ovary syndrome offer dietary weight loss. J Clin Endocrinol Metab 82:556–560 9. Plymate SR, Matej LA, Jones RE, Friedl KE (1998) Inhibition of sex hormone-binding globulin production in the human hepatoma (Hep G2) cell line by insulin and prolactin. J Clin Endocrinol Metab 67:460–464 10. Nestler JE, Powers LP, Matt DW et al (1991) A direct effect of hyperinsulinemia on serum sex hormone-binding globulin levels in obese women with the polycystic ovary syndrome. J Clin Endocrinol Metab 72:83–89 11. Utsunomiya T, Taniguchi I, Sadanaga A, Iwasato K, Mizoguchi Y, Terawaki S (1993) Insulin resistance in non-obese patients with polycystic ovary syndrome. Jpn J Fertil Steril 38:77–81 12. Rosenfield RL, Barnes RB, Ehrmann DA (1994) Studies of the nature of 17-hydroxyprogesterone hyperresponsiveness to gonadotropin-releasing hormone agonist challenge in functional ovarian hyperandrogenism. J Clin Endocrinol Metab 79:1686–1692 13. Egger M, Smith GD, Altman DG (2001) Systematic reviews in health care: meta-analysis in context. BMJ 2001:3–68 14. Yildiz BO, Knochenhauer ES, Azziz R (2008) Impact of obesity on the risk for polycystic ovary syndrome. J Clin Endocrinol Metab 93:162–168 15. Apridonidze T, Essah PA, Iuorno MJ, Nestler JE (2005) Prevalence and characteristics of the metabolic syndrome in women with polycystic ovary syndrome. J Clin Endocrinol Metab 90:1929–1935 16. Peppard HR, Marfori J, Iuorno MJ, Nestler JE (2001) Prevalence of polycystic ovary syndrome among premenopausal women with type 2 diabetes. Diabetes Care 24:1050–1052 17. Lim SS, Norman RJ, Davies MJ, Moran LJ (2013) The effect of obesity on polycystic ovary syndrome: a systematic review and meta-analysis. Obes Rev 14:25–109

123

18. Gambineri A, Pelusi C, Vicennati V, Pagotto U, Pasquali R (2002) Obesity and the polycystic ovary syndrome. Int J Obes Metab Disord 26:883–896 19. DeUgarte CM, Bartolucci AA, Azziz R (2005) Prevalence of insulin resistance in the polycystic ovary syndrome using the homeostasis model assessment. Fertil Steril 83:1454–1460 20. Carmina E, Lobo RA (2004) Use of fasting blood to assess the prevalence of insulin resistance in women with polycystic ovary syndrome. Fertil Steril 82:661–665 21. Azziz R, Carmina E, Dewailly D et al (2009) The Androgen Excess and PCOS Society criteria for the polycystic ovary syndrome: the complete task force report. Fertil Steril 91:456–488 22. Carmina E, Bucchieri S, Esposito A (2007) Abdominal fat quantity and distribution in women with polycystic ovary syndrome and extent of its relation to insulin resistance. J Clin Endocrinol Metab 92:2500–2505 23. Diamanti-Kandarakis E (2006) Insulin resistance in PCOS. Endocrine 30:13–17 24. Geistho¨vel F (2010) Novel systematics of nomenclature and classification of female functional androgenization (including polycystic ovary syndrome and non-classic congenital adrenal hyperplasia). J Reprod Med Endokrinol 7:6–26 25. Goverde AJ, van Koert AJ, Eijkemans MJ, Knauff EA, Westerveld HE, Fauser BC, Broekmans FJ (2009) Indicators for metabolic disturbances in anovulatory women with polycystic ovary syndrome diagnosed according to the Rotterdam consensus criteria. Hum Reprod 24:710 26. Lord JM, Flight IH, Norman RJ (2003) Insulin sensitising drugs (metformin, troglitazone, rosiglitazone, pioglitazone, D-chiroinositol) for polycystic ovary syndrome. Cochrane Database Syst Rev 3:CD003053 27. Palomba S, Orio F Jr, Falbo A, Manguso F, Russo T, Cascella T, Tolino A, Carmina E, Colao A, Zullo F (2005) Prospective parallel randomized, double-blind, double-dummy controlled clinical trial comparing clomiphene citrate and metformin as the first-line treatment for ovulation induction in nonobese anovulatory women with polycystic ovary syndrome. J Clin Endocrinol Metab 90(7):4068–4074 28. Palomba S, Orio F Jr, Nardo LG, Falbo A, Russo T, Corea D, Doldo P, Lombardi G, Tolino A, Colao A, Zullo F (2004) Metformin administration versus laparoscopic ovarian diathermy in clomiphene citrate-resistant women with polycystic ovary syndrome: a prospective parallel randomized double-blind placebo-controlled trial. J Clin Endocrinol Metab 89(10): 4801–4809 29. Maciel GA, Soares Ju´nior JM, Alves da Motta EL, Abi Haidar M, de Lima GR, Baracat EC (2004) Nonobese women with polycystic ovary syndrome respond better than obese women to treatment with metformin. Fertil Steril 81(2):355–360 30. Kumari AS, Haq A, Jayasundaram R, Abdel-Wareth LO, Al Haija SA, Alvares M (2005) Metformin monotherapy in lean women with polycystic ovary syndrome. Reprod Biomed Online 10(1):100–104 31. Tan S, Hahn S, Benson S, Dietz T, Lahner H, Moeller LC, Schmidt M, Elsenbruch S, Kimmig R, Mann K, Janssen OE (2007) Metformin improves polycystic ovary syndrome symptoms irrespective of pre-treatment insulin resistance. Eur J Endocrinol 157(5):669–676 32. Fauser BC, Tarlatzis BC, Rebar RW, Legro RS, Balen AH, Lobo R, Carmina E, Chang J, Yildiz BO, Laven JS, Boivin J, Petraglia F, Wijeyeratne CN, Norman RJ, Dunaif A, Franks S, Wild RA, Dumesic D, Barnhart K (2012) Consensus on women’s health aspects of polycystic ovary syndrome (PCOS): the Amsterdam ESHRE/ASRM-Sponsored 3rd PCOS Consensus Workshop Group. Fertil Steril 97:28–38

Arch Gynecol Obstet (2014) 290:1079–1092 33. Panidis D, Tziomalos K, Chatzis P, Papadakis E, Delkos D, Tsourdi EA, Kandaraki EA, Katsikis I (2013) Association between menstrual cycle irregularities and endocrine and metabolic characteristics of the polycystic ovary syndrome. Eur J Endocrinol 168(2):145–152 34. Robinson S, Kiddy D, Gelding SV, Willis D, Niththyananthan R, Bush A, Johnston DG, Franks S (1993) The relationship of insulin insensitivity to menstrual pattern in women with hyperandrogenism and polycystic ovaries. Clin Endocrinol (Oxf) 39(3):351–355 35. Gill S, Taylor AE, Martin KA, Welt CK, Adams JM, Hall JE (2001) Specific factors predict the response to pulsatile gonadotropin-releasing hormone therapy in polycystic ovarian syndrome. J Clin Endocrinol Metab 86(6):2428–2436 36. Cupisti S, Kajaia N, Dittrich R, Duezenli H, Beckmann M W, Mueller A (2008) Body mass index and ovarian function are associated with endocrine and metabolic abnormalities in women with hyperandrogenic syndrome. Eur J Endocrinol 158(5):711–719. doi:10.1530/EJE-07-0515 37. 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(2):178–181. doi:10.1016/j.ejogrb.2009.12.024 38. Wang JX, Davies MJ, Norman RJ (2001) Polycystic ovarian syndrome and the risk of spontaneous abortion following assisted reproductive technology treatment. Hum Reprod 16(12):2606–2609 39. Boomsma CM, Fauser BC, Macklon NS (2008) Pregnancy complications in women with polycystic ovary syndrome. Semin Reprod Med 26(1):72–84. doi:10.1055/s-2007-992927 40. Eppig JJ, O’Brien MJ, Pendola FL, Watanabe S (1998) Factors affecting the developmental competence of mouse oocytes grown in vitro: follicle-stimulating hormone and insulin. Biol Reprod 59(6):1445–1453 41. Galal A, Mitwally MF (2009) Insulin sensitizers for women with polycystic ovarian syndrome. Expert Rev Endocrinol Metab 4:183–192 42. Dumesic DA, Schramm RD, Peterson E, Paprocki AM, Zhou R, Abbott DH (2002) Impaired developmental competence of oocytes in adult prenatally androgenized female rhesus monkeys undergoing gonadotropin stimulation for in vitro fertilization. J Clin Endocrinol Metab 87(3):1111–1119 43. Tao Z, Yan L (2005) Luteinizing hormone and insulin inducing earlier and excess expression of luteinizing hormone receptor messenger ribonucleic acids in granulosa cells of polycystic ovary syndrome. Fertil Steril 84(Suppl):S426–S427 44. Diamanti-Kandarakis E (2008) Polycystic ovarian syndrome: pathophysiology, molecular aspects and clinical implications. Expert Rev Mol Med 10:e3 45. Jabara S, Coutifaris C (2003) In vitro fertilization in the PCOS patient: clinical considerations. Semin Reprod Med 21(3): 317–324 46. Cano F, Garcı´a-Velasco JA, Millet A, Remohı´ J, Simo´n C, Pellicer A (1997) Oocyte quality in polycystic ovaries revisited: identification of a particular subgroup of women. J Assist Reprod Genet 14(5):254–261 47. Kezele PR, Nilsson EE, Skinner MK (2002) Insulin but not insulin-like growth factor-1 promotes the primordial to primary follicle transition. Mol Cell Endocrinol 192(1–2):37–43 48. Wood JR, Dumesic DA, Abbott DH, Strauss JF (2007) Molecular abnormalities in oocytes from women with polycystic ovary syndrome revealed by microarray analysis. J Clin Endocrinol Metab 92:705–713. doi:10.1210/jc.2006-2123 49. Gonza´lez F, Rote NS, Minium J, Kirwan JP (2006) Increased activation of nuclear factor kB triggers inflammation and insulin

1089

50.

51.

52.

53.

54.

55.

56.

57.

58. 59.

60.

61.

62.

63.

64.

65.

66.

resistance in polycystic ovary syndrome. J Clin Endocrinol Metab 91:1508–1512 Piotrowski PC, Rzepczynska IJ, Kwintkiewicz J, Duleba AJ (2005) Oxidative stress induces expression of CYP11A, CYP17, STAR and 3bHSD in rat theca-interstitial cells. J Soc Gynecol Invest 12(2 Suppl):319A Gonza´lez F, Minium J, Rote NS, Kirwan JP (2005) Hyperglycemia alters tumor necrosis factor-a release from mononuclear cells in women with polycystic ovary syndrome. J Clin Endocrinol Metab 90:5336–5342 Gonza´lez F, Rote NS, Minium J, Kirwan JP (2006) In vitro evidence that hyperglycemia stimulates tumor necrosis factor-a release in obese women with polycystic ovary syndrome. J Endocrinol 188:521–529 Gonza´lez F, Rote NS, Minium J, Kirwan JP (2006) Reactive oxygen species-induced oxidative stress in the development of insulin resistance and hyperandrogenism in polycystic ovary syndrome. J Clin Endocrinol Metab 91:336–340 Gonza´lez F, Rote NS, Minium J, Kirwan JP (2009) Evidence of proatherogenic inflammation in polycystic ovary syndrome. Metabolism 58:954–962 Chazenbalk G, Trivax BS, Yildiz BO (2010) Regulation of adiponectin secretion by adipocytes in the polycystic ovary syndrome: role of tumor necrosis factor-{alpha}. J Clin Endocrinol Metab 95:935–942 Carmina E, Orio F, Palomba S (2005) Evidence for altered adipocyte function in polycystic ovary syndrome. Eur J Endocrinol 152:389–394 Chen X, Jia X, Qiao J, Guan Y, Kang J (2013) Adipokines in reproductive function: a link between obesity and polycystic ovary syndrome. J Mol Endocrinol 50:21–37 Carmina E (2013) Obesity, adipokines and metabolic syndrome in polycystic ovary syndrome. Front Horm Res 40:40–50 Chabrolle C, Tosca L, Rame´ C, Lecomte P, Roye`re D, Dupont J (2009) Adiponectin increases insulin-like growth factor l-induced progesterone and estradiol secretion in human granulosa cells. Fertil Steril 92:1988–1996 Pusalkar M, Meherji P, Gokral J, Savardekar L, Chinnaraj S, Maitra A (2010) Obesity and polycystic ovary syndrome: association with androgens, leptin and its genotypes. Gynecol Endocrinol 26:874–882 Comim FV, Hardy K, Franks S (2013) Adiponectin and its receptors in the ovary: further evidence for a link between obesity and hyperandrogenism in polycystic ovary syndrome. PLoS ONE 18(8):e80416 Panidis D, Kourtis A, Farmakiotis D, Mouslech T, Rousso D, Koliakos G (2003) Serum adiponectin levels in women with polycystic ovary syndrome. Hum Reprod 18:1790–1796 Ardawi MS, Rouzi AA (2005) Plasma adiponectin and insulin resistance in women with polycystic ovary syndrome. Fertil Steril 83:1708–1716 Escobar-Morreale HF, Villuendas G, Botella-Carretero JI, Alvarez-Blasco F, Sancho´n R, Luque-Ramı´rez M, San Milla´n JL (2006) Adiponectin and resistin in PCOS: a clinical, biochemical and molecular genetic study. Hum Reprod 21(9):2257–2265 Pinhas-Hamiel O, Singer S, Pilpel N, Koren I, Boyko V, Hemi R, Pariente C, Kanety H (2009) Adiponectin levels in adolescent girls with polycystic ovary syndrome (PCOS). Clin Endocrinol (Oxf) 71(6):823–827. doi:10.1111/j.1365-2265.2009.03604.x Mannera˚s-Holm L, Leonhardt H, Kullberg J, Jennische E, Ode´n A, Holm G et al (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(2):E304–E311. doi:10.1210/jc.2010-1290

123

1090 67. Shin HY, Lee DC, Lee JW (2011) Adiponectin in women with polycystic ovary syndrome. Korean J Fam Med 32(4):243–248. doi:10.4082/kjfm.2011.32.4.243 68. Lecke SB, Mattei F, Morsch DM, Spritzer PM (2011) Abdominal subcutaneous fat gene expression and circulating levels of leptin and adiponectin in polycystic ovary syndrome. Fertil Steril 95(6):2044–2049. doi:10.1016/j.fertnstert.2011.02.041 69. Toulis KA, Gouli DG, Farmakiotis D, Georgopoulos NA, Katsikis I, Tarlatzis BC, Papadima I, Panidis D (2009) Adiponectin levels in women with polycystic ovary syndrome: a systematic review and a meta-analysis. Hum Reprod Update 15:297–307. doi:10.1093/humupd/dmp006 70. Yamauchi T, Kamon J, Ito Y et al (2003) Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature 423:762–769 71. Hossam OH (2013) Role of adiponectin and its receptor in prediction of reproductive outcome of metformin treatment in patients with polycystic ovarian syndrome. J Obstet Gynaecol Res 39:1596–1603 72. Considine RV, Caro JF (1997) Leptin and the regulation of body weight. Int J Biochem Cell Biol 29:1255–1272 73. Muoio DM, Lynis DG (2002) Peripheral metabolic actions of leptin. Best Pract Res Clin Endocrinol Metab 16:653–666 74. Bjorbaek C, Kahn BB (2004) Leptin signaling in the central nervous system and the periphery. Recent Prog Horm Res 59:305–331 75. Margetic S, Gazzola C, Pegg GG, Hill RA (2002) Leptin: a review of its peripheral actions and interactions. Int J Obes Relat Metab Disord 26:1407–1433 76. Brzechffa PR, Jakimiuk AJ, Agarwal SK, Weitsman SR, Buyalos RP, Magoffin DA (1996) Serum immunoreactive leptin concentrations in women with polycystic ovary syndrome. J Clin Endocrinol Metab 81(11):4166–4169 77. Vicennati V, Gambineri A, Calzoni F, Casimirri F, Macor C, Vettor R, Pasquali R (1998) Serum leptin in obese women with polycystic ovary syndrome is correlated with body weight and fat distribution but not with androgen and insulin levels. Metabolism 47(8):988–992 78. Pehlivanov B, Mitkov M (2009) Serum leptin levels correlate with clinical and biochemical indices of insulin resistance in women with polycystic ovary syndrome. Eur J Contracept Reprod Health Care 14(2):153–159. doi:10.1080/1362518080 2549962 79. Yildizhan R, Ilhan GA, Yildizhan B, Kolusari A, Adali E, Bugdayci G (2011) Serum retinol binding protein 4, leptin, and plasma asymmetric dimethylarginine levels in obese and nonobese young women with polycystic ovary syndrome. Fertil Steril 96:246–250 80. Chapman IM, Wittert GA, Norman RJ (1997) Circulating leptin concentrations in polycystic ovary syndrome: relation to anthropometric and metabolic parameters. Clin Endocrinol (Oxf) 46(2):175–181 81. Rouru J, Anttila L, Koskinen P, Penttila¨ TA, Irjala K, Huupponen R, Koulu M (1997) Serum leptin concentrations in women with polycystic ovary syndrome. J Clin Endocrinol Metab 82(6):1697–1700 82. Gennarelli G, Holte J, Wide L, Berne C, Lithell H (1998) Is there a role for leptin in the endocrine and metabolic aberrations of polycystic ovary syndrome? Hum Reprod 13(3):535–541 83. Carmina E, Bucchieri S, Mansueto P, Rini G, Ferin M, Lobo RA (2009) Circulating levels of adipose products and differences in fat distribution in the ovulatory and anovulatory phenotypes of polycystic ovary syndrome. Fertil Steril 1(4 Suppl):1332–1335. doi:10.1016/j.fertnstert.2008.03.007 84. Wang P, Holst C, Astrup A et al (2012) Blood profiling of proteins and steroids during weight maintenance with

123

Arch Gynecol Obstet (2014) 290:1079–1092

85.

86. 87.

88.

89.

90.

91.

92.

93.

94.

95.

96.

97.

98.

99.

manipulation of dietary protein level and glycaemic index. Br J Nutr 107:106–119 Svendsen PF, Christiansen M, Hedley PL, Nilas L, Pedersen SB, Madsbad S (2012) Adipose expression of adipocytokines in women with polycystic ovary syndrome. Fertil Steril 98(1):235–241. doi:10.1016/j.fertnstert.2012.03.056 Stofkova A (2010) Resistin and visfatin: regulators of insulin sensitivity, inflammation and immunity. Endocr Regul 44:25–36 Tan BK, Chen J, Digby JE, Keay SD, Kennedy CR, Randeva HS (2006) Increased visfatin messenger ribonucleic acid and protein levels in adipose tissue and adipocytes in women with polycystic ovary syndrome: parallel increase in plasma visfatin. J Clin Endocrinol Metab 91(12):5022–5028 Chan TF, Chen YL, Chen HH, Lee CH, Jong SB, Tsai EM (2007) Increased plasma visfatin concentrations in women with polycystic ovary syndrome. Fertil Steril 88(2):401–405 Kowalska I, Straczkowski M, Nikolajuk A, Adamska A, Karczewska-Kupczewska M, Otziomek E, Wolczynski S, Gorska M (2007) Serum visfatin in relation to insulin resistance and markers of hyperandrogenism in lean and obese women with polycystic ovary syndrome. Hum Reprod 22(7):1824–1829 Panidis D, Farmakiotis D, Rousso D, Katsikis I, Delkos D, Piouka A, Gerou S, Diamanti-Kandarakis E (2008) Plasma visfatin levels in normal weight women with polycystic ovary syndrome. Eur J Intern Med 19(6):406–412. doi:10.1016/j.ejim. 2007.05.014 Ozkaya M, Cakal E, Ustun Y, Engin-Ustun Y (2010) Effect of metformin on serum visfatin levels in patients with polycystic ovary syndrome. Fertil Steril 93(3):880–884. doi:10.1016/j. fertnstert.2008.10.058 Plati E, Kouskouni E, Malamitsi-Puchner A, Boutsikou M, Kaparos G, Baka S (2010) Visfatin and leptin levels in women with polycystic ovaries undergoing ovarian stimulation. Fertil Steril 94(4):1451–1456. doi:10.1016/j.fertnstert.2009.04.055 Seow KM, Hwang JL, Wang PH, Ho LT, Juan CC (2011) Expression of visfatin mRNA in peripheral blood mononuclear cells is not correlated with visfatin mRNA in omental adipose tissue in women with polycystic ovary syndrome. Hum Reprod 26(10):2869–2873. doi:10.1093/humrep/der267 Spanos N, Tziomalos K, Macut D, Koiou E, Kandaraki EA, Delkos D, Tsourdi E, Panidis D (2012) Adipokines, insulin resistance and hyperandrogenemia in obese patients with polycystic ovary syndrome: cross-sectional correlations and the effects of weight loss. Obes Facts 5(4):495–504. doi:10.1159/ 000341579 Gu¨du¨cu¨ N, ˙Is¸ c¸i H, Go¨rmu¨s¸ U, Yig˘iter AB, Du¨nder I (2012) Serum visfatin levels in women with polycystic ovary syndrome. Gynecol Endocrinol 28(8):619–623. doi:10.3109/ 09513590.2011.650749 Lajunen TK, Purhonen AK, Haapea M, Ruokonen A, Puukka K, Hartikainen AL et al (2012) Full-length visfatin levels are associated with inflammation in women with polycystic ovary syndrome. Eur J Clin Invest 42(3):321–328. doi:10.1111/j.13652362.2011.02586.x Olszanecka-Glinianowicz M, Madej P, Zdun D, Bo_zentowiczWikarek M, Sikora J, Chudek J, Skałba P (2012) Are plasma levels of visfatin and retinol-binding protein 4 (RBP4) associated with body mass, metabolic and hormonal disturbances in women with polycystic ovary syndrome? Eur J Obstet Gynecol Reprod Biol 162(1):55–61. doi:10.1016/j.ejogrb.2012.01.026 Kasim-Karakas SE, Almario RU, Cunningham W (2009) Effects of protein versus simple sugar intake on weight loss in polycystic ovary syndrome (according to the National Institutes of Health criteria). Fertil Steril 92:262–270 Moran LJ, Noakes M, Clifton PM, Wittert GA, Belobrajdic DP, Norman RJ (2007) C-reactive protein before and after weight

Arch Gynecol Obstet (2014) 290:1079–1092

100.

101.

102.

103.

104.

105.

106.

107.

108.

109.

110.

111. 112.

113. 114.

115.

116.

117.

loss in overweight women with and without polycystic ovary syndrome. J Clin Endocrinol Metab 92:2944–2951 Stamets K, Taylor DS, Kunselman A, Demers LM, Pelkman CL, Legro RS (2004) A randomized trial of the effects of two types of short-term hypocaloric diets on weight loss in women with polycystic ovary syndrome. Fertil Steril 81:630–637 Van Dam EW, Roelfsema F, Veldhuis JD, Helmerhorst FM, Frolich M, Meinders AE, Krans HM, Pijl H (2002) Increase in daily LH secretion in response to short-term calorie restriction in obese women with PCOS. Am J Physiol Endocrinol Metab 282:E865–E872 Laughlin GA, Morales AJ, Yen SS (1997) Serum leptin levels in women with polycystic ovary syndrome: the role of insulin resistance/hyperinsulinemia. J Clin Endocrinol Metab 82:1692–1696 Mantzoros CS, Dunaif A, Flier JS (1997) Leptin concentrations in the polycystic ovary syndrome. J Clin Endocrinol Metab 82:1687–1691 Muneyvirci-Delale O, Nacharaju VL, Altura BM, Altura BT (1998) Sex steroid hormones modulate serum ionized magnesium and Ca levels throughout the menstrual cycle in women. Fertil Steril 69:958–962 Rumawas ME, McKeown NM, Rogers G, Meigs JB, Wilson PWF, Jacques PF (2006) Magnesium intake is related to improved insulin homeostasis in the Framingham offspring cohort. J Am Coll Nutr 25:486–492 Chakraborty P, Ghosh S, Goswami SK, Syed NK, Baidyanath C, Kuladip J (2013) Altered trace mineral milieu might play an aetiological role in the pathogenesis of polycystic ovary syndrome. Biol Trace Elem Res 152:9–15 Kauffman RP, Tullar PE, Nipp RD, Castracane VD (2011) Serum magnesium concentrations and metabolic variables in polycystic ovary syndrome. Acta Obstet Gynecol Scand 90:452–458 Kurdoglu Z, Kurdoglu M, Demir H, Sahin HG (2012) Serum trace elements and heavy metals in polycystic ovary syndrome. Hum Exp Toxicol 31(5):452–456. doi:10.1177/096032711 1424299 Kelly CC, Lyall H, Petrie JR, Gould GW, Connell JMC, Sattar N (2001) Low grade chronic inflammation in women with polycystic ovary syndrome. J Clin Endocrinol Metab 86:2453–2455 Slesinski RS, Clarke JJ, San RH, Gudi R (2005) Lack of mutagenicity of chromium picolinate in the hypoxanthine phosphoribosyltransferase gene mutation assay in Chinese hamster ovary cells. Mutat Res 585:86–95 Cefalu WT, Hu FB (2004) Role of chromium in human health and in diabetes. Diabetes Care 11:2741–2751 Jeejeebhoy KN, Chu RC, Marliss EB, Greenberg GR, BruceRobertson A (1977) Chromium deficiency, glucose intolerance, and neuropathy reversed by chromium supplementation, in a patient receiving long-term total parenteral nutrition. Am J Clin Nutr 30:531–538 Mertz W (1998) Chromium research from a distance: from 1959 to 1980. J Am Coll Nutr 17:544–547 Davis CM, Vincent JB (1997) Chromium oligopeptide activates insulin receptor tyrosine kinase activity. Biochemistry 36:4382–4385 Vincent JB (1999) Mechanisms of chromium action: lowmolecular-weight chromium-binding substance. J Am Coll Nutr 18:6–12 Morris BW, MacNeil S, Hardisty CA, Heller S, Burgin C, Gray TA (1999) Chromium homeostasis in patients with type II (NIDDM) diabetes. J Trace Elem Med Biol 13:57–61 Lydic ML, McNurlan M, Bembo S, Mitchell L, Komaroff E, Gelato M (2006) Chromium picolinate improves insulin

1091

118. 119.

120.

121.

122.

123.

124.

125.

126. 127. 128.

129.

130.

131.

132.

133. 134.

135.

136.

sensitivity in obese subjects with polycystic ovary syndrome. Fertil Steril 86:243–246 Verstuyf A, Carmeliet G, Bouillon R, Mathieu C (2010) Vitamin D: a pleiotropic hormone. Kidney Int 78:140–145 Alvarez JA, Ashraf A (2010) Role of vitamin D in insulin secretion and insulin sensitivity for glucose homeostasis. Int J Endocrinol 2010:351–385 Ngo DT, Chan WP, Rajendran S et al (2011) Determinants of insulin responsiveness in young women: impact of polycystic ovarian syndrome, nitric oxide, and vitamin D. Nitric Oxide 25:326–330 Ortlepp JR, Metrikat J, Albrecht M, von Korff A, Hanrath P, Hoffmann R (2003) The vitamin D receptor gene variant and physical activity predicts fasting glucose levels in healthy young men. Diabet Med 20:451–454 Bourlon PM, Billaudel B, Faure-Dussert A (1999) Influence of vitamin D3 deficiency and 1, 25 dihydroxyvitamin D3 on de novo insulin biosynthesis in the islets of the rat endocrine pancreas. J Endocrinol 160:87–95 Chiu KC, Chu A, Go VL, Saad MF (2004) Hypovitaminosis D is associated with insulin resistance and beta cell dysfunction. Am J Clin Nutr 79:820–825 Thomson RL, Spedding S, Buckley JD (2012) Vitamin D in the aetiology and management of polycystic ovary syndrome. Clin Endocrinol 7:343–350 Homburg R, Amsterdam A (1998) Polycystic ovary syndrome— loss of the apoptotic mechanism in the ovarian follicles? J Endocrinol Invest 21:552–557 Bikle D (2009) Nonclassic actions of vitamin D. J Clin Endocrinol Metab 94:26–34 Shoelson SE, Herrero L, Naaz A (2007) Obesity, inflammation, and insulin resistance. Gastroenterology 132:2169–2180 Yildizhan R, Kurdoglu M, Adali E et al (2009) Serum 25-hydroxyvitamin D concentrations in obese and non-obese women with polycystic ovary syndrome. Arch Gynecol Obstet 280:559–563 Pal L, Berry A, Coraluzzi L (2012) Therapeutic implications of vitamin D and calcium in overweight women with polycystic ovary syndrome. Gynecol Endocrinol 28:965–968 Wehr E, Pieber TR, Obermayer-Pietsch B (2011) Effect of vitamin D3 treatment on glucose metabolism and menstrual frequency in polycystic ovary syndrome women: a pilot study. J Endocrinol Invest 34:757–763 Selimoglu H, Duran C, Kiyici S, Ersoy C, Guclu M, Ozkaya G, Tuncel E, Erturk E, Imamoglu S (2010) The effect of vitamin D replacement therapy on insulin resistance and androgen levels in women with polycystic ovary syndrome. J Endocrinol Invest 33:234–238 Kasim-Karakas SE, Almario RU, Gregory L, Wong R, Todd H, Lasley BL (2004) Metabolic and endocrine effects of a polyunsaturated fatty acid-rich diet in polycystic ovary syndrome. J Clin Endocrinol Metab 89:615–620 Oh R (2005) Practical applications of fish oil (Omega-3 fatty acids) in primary care. J Am Board Fam Pract 18:28–36 Ebbesson SO, Risica PM, Ebbesson LO, Kennish JM, Tejero ME (2005) Omega-3 fatty acids improve glucose tolerance and components of the metabolic syndrome in Alaskan Eskimos: the Alaska Siberia project. Int J Circumpolar Health 64:396–408 Rafraf M, Mohammadi E, Asghari-Jafarabadi M, Farzadi L (2012) Omega-3 fatty acids improve glucose metabolism without effects on obesity values and serum visfatin levels in women with polycystic ovary syndrome. J Am Coll Nutr 31:361–368 Kratz M, Swarbrick MM, Callahan HS, Matthys CC, Havel PJ, Weigle DS (2008) Effect of dietary n-3 polyunsaturated fatty acids on plasma total and high-molecular-weight adiponectin concentrations in overweight to moderately obese men and women. Am J Clin Nutr 87:347–353

123

1092 137. Mohammadi E, Rafraf M, Farzadi L, Asghari-Jafarabadi M, Sabour S (2012) Effects of omega-3 fatty acids supplementation on serum adiponectin levels and some metabolic risk factors in women with polycystic ovary syndrome. Asia Pac J Clin Nutr 21(4):511–518 138. Gillies CL, Abrams KR, Lambert PC et al (2007) Pharmacological and lifestyle interventions to prevent or delay type 2 diabetes in people with impaired glucose tolerance: systematic review and meta-analysis. BMJ 334:299 139. Colberg SR, Albright AL, Blissmer BJ et al (2010) Exercise and type 2 diabetes: American College of Sports Medicine and the American Diabetes Association: joint position statement. Exercise and type 2 diabetes. Med Sci Sports Exerc 42:2282–2303 140. Lee S, Kuk JL, Davidson LE et al (2005) Exercise without weight loss is an effective strategy for obesity reduction in obese individuals with and without Type 2 diabetes. J Appl Physiol 99:1220–1225 141. Moran LJ, Pasquali R, Teede HJ, Hoeger KM, Norman RJ (2009) Treatment of obesity in polycystic ovary syndrome: a position statement of the Androgen Excess and Polycystic Ovary Syndrome Society. Fertil Steril 92:1966–1982 142. Bianchi C, Miccoli R, Penno G, Del Prato S (2008) Primary prevention of cardiovascular disease in people with dysglycemia. Diabetes Care 31:208–214 143. Kiddy DS, Hamilton-Fairley D, Bush A et al (1992) Improvement in endocrine and ovarian function during dietary treatment of obese women with polycystic ovary syndrome. Clin Endocrinol (Oxf) 36:105–111 144. Clark AM, Ledger W, Galletly C et al (1995) Weight loss results in significant improvement in pregnancy and ovulation rates in anovulatory obese women. Hum Reprod 10:2705–2712 145. Thomson RL, Buckley JD, Moran LJ, Noakes M, Clifton PM, Norman RJ, Brinkworth GD (2009) The effect of weight loss on anti-Mu¨llerian hormone levels in overweight and obese women with polycystic ovary syndrome and reproductive impairment. Hum Reprod 24:1976–1981 146. Holte J, Bergh T, Berne C, Wide L, Lithell H (1995) Restored insulin sensitivity but persistently increased early insulin secretion after weight loss in obese women with polycystic ovary syndrome. J Clin Endocrinol Metab 80:2586–2593 147. Moran LJ, Hutchison SK, Norman RJ, Teede HJ (2011) Lifestyle changes in women with polycystic ovary syndrome. Cochrane Database Syst Rev 7:CD007506. doi:10.1002/ 14651858.CD007506 148. Moran LJ, Ko H, Misso M, Marsh K, Noakes M, Talbot 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(4):520–545. doi:10.1016/j. jand.2012.11.018 149. Douglas CC, Gower BA, Darnell BE, Ovalle F, Oster RA, Azziz R (2006) Role of diet in the treatment of polycystic ovary syndrome. Fertil Steril 85:679–688 150. Mehrabani HH, Salehpour S, Amiri Z, Farahani SJ, Meyer BJ, Tahbaz F (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 31:117–125 151. Graff SK, Ma´rio FM, Alves BC, Spritzer PM (2013) Dietary glycemic index is associated with less favorable anthropometric and metabolic profiles in polycystic ovary syndrome women with different phenotypes. Fertil Steril 100:1081–1088

123

Arch Gynecol Obstet (2014) 290:1079–1092 152. Leidy HJ, Racki EM (2010) The addition of a protein-rich breakfast and its effects on acute appetite control and food intake in ‘breakfast-skipping’ adolescents. Int J Obes 34:1125–1133 153. Zumoff B, Freeman R, Coupey S, Saenger P, Markowitz M, Kream J (1983) A chronobiologic abnormality in luteinizing hormone secretion in teenage girls with the polycystic-ovary syndrome. N Engl J Med 309:1206–1209 154. Prelevic GM, Wurzburger MI, Balint-Peric L (1993) 24-hour serum cortisol profiles in women with polycystic ovary syndrome. Gynecol Endocrinol 7:179–184 155. Domecq JP, Prutsky G, Mullan RJ, Hazem A, Sundaresh V, Elamin MB, Phung OJ, Wang A, Hoeger K, Pasquali R, Erwin P, Bodde A, Montori VM, Murad MH (2013) Lifestyle modification programs in polycystic ovary syndrome: Systematic review and meta-analysis. J Clin Endocrinol Metab 98(12):4655–4663. doi:10.1210/jc.2013-2385 156. Brown AJ, Setji TL, Sanders LL, Lowry KP, Otvos JD, Kraus WE, Svetkey PL (2009) Effects of exercise on lipoprotein particles in women with polycystic ovary syndrome. Med Sci Sports Exerc 41:497–504 157. Guzick DS, Wing R, Smith D, Berga SL, Winters SJ (1994) Endocrine consequences of weight loss in obese, hyperandrogenic, anovulatory women. Fertility, Sterility 61:598–604 158. Hoeger KM, Kochman L, Wixom N, Craig K, Miller RK, Guzick DS (2004) A randomized, 48-week, placebo-controlled trial of intensive lifestyle modification and/or metformin therapy in overweight women with polycystic ovary syndrome: a pilot study. Fertil Steril 82:421–429 159. Hoeger K, Davidson K, Kochman L, Cherry T, Kopin L, Guzick DS (2008) The impact of metformin, oral contraceptives, and lifestyle modification on polycystic ovary syndrome in obese adolescent women in two randomized, placebo-controlled clinical trials. J Clin Endocrinol Metab 93:4299–4306 160. Karimzadeh MA, Javedani M (2010) An assessment of lifestyle modification versus medical treatment with clomiphene citrate, metformin, and clomiphene citrate-metformin in patients with polycystic ovary syndrome. Fertil Steril 94:216–220 161. Palomba S, Falbo A, Giallauria F, Russo T, Rocca M, Tolino A, Zullo F, Orio F (2010) Six weeks of structured exercise training and hypocaloric diet increases the probability of ovulation after clomiphene citrate in overweight and obese patients with polycystic ovary syndrome: a randomized controlled trial. Hum Reprod 25:2783–2791 162. Qublan HS, Yannakoula EK, Al-Qudah MA, El-Uri FI (2007) Dietary intervention versus metformin to improve the reproductive outcome in women with polycystic ovary syndrome. A prospective comparative study. Saudi Med J 28:1694–1699 163. Stener-Victorin E, Jedel E, Janson PO, Sverrisdottir YB (2009) Low-frequency electroacupuncture and physical exercise decrease high muscle sympathetic nerve activity in polycystic ovary syndrome. Am J Physiol Regul Integr Comp Physiol 297:R387–R395 164. Vigorito C, Giallauria F, Palomba S, Cascella T, Manguso F, Lucci R, De Lorenzo A, Tafuri D, Lombardi G, Colao A, Orio F (2007) Beneficial effects of a three-month structured exercise training program on cardiopulmonary functional capacity in young women with polycystic ovary syndrome. J Clin Endocrinol Metab 92:1379–1384