Obesity, insulin resistance and metabolic syndrome in PCOS
Overweight and obesity constitute a modern global pandemic, with rapidly growing rates both in developed and in developing areas of the world. Over the last half-century, the worldwide prevalence of obesity has nearly tripled; in 2016, 39% of the world’s adult population was overweight and 13% obese. Children and adolescents are equally affected, with over 340 million being overweight or obese as of 2016 . Obesity has a huge negative impact on health, as it is associated with the incidence of numerous comorbidities, including but not limited to type 2 diabetes mellitus, cardiovascular diseases, and various types of cancer . Consequently, this preventable disease not only has a negative impact on the patients’ quality of life but also creates a substantial economic burden.
Although obesity is not included in the diagnostic criteria of PCOS, it is a very common feature of the syndrome, as 38%–88% of the patients are overweight or obese . Notably, obesity is more prevalent in “classic” PCOS phenotypes, which are characterized by hyperandrogenemia and oligo-anovulation . Besides, there is a positive correlation between BMI and PCOS features, while even a moderate weight loss of 5% has been shown to result in significant attenuation of the endocrine and metabolic manifestations of the syndrome .
Despite the well-recognized link between obesity and PCOS, the complexity of the pathophysiologic mechanisms underpinning these conditions makes the establishment of causality extremely challenging. Obesity might contribute to PCOS development and, in turn, PCOS could be responsible for weight gain or prevent weight loss . Below, we will briefly explore the most important links between PCOS and obesity.
Insulin resistance
Insulin resistance (IR) and concomitant hyperinsulinemia represent an inherent attribute of PCOS: 60%–80% of the patients are insulin resistant and this is independent of obesity, although IR is more common in overweight/obese women with PCOS . In PCOS, apart from a defect in insulin action, there is also a defect in insulin production (beta-pancreatic cell dysfunction, leading to impaired first-phase insulin release) . Consequently, the prevalence of impaired glucose tolerance (IGT) and type 2 diabetes is markedly increased in PCOS, while the evolution from IGT to frank diabetes is 5–10 times faster than in controls .
The origins of IR in PCOS are not fully understood. It seems that there is a postreceptor defect in the intracellular signaling pathway of insulin involving phosphatidylinositol 3-kinase (PI3-kinase). The PI3-kinase pathway mediates metabolic actions of insulin, such as glucose transportation within target-tissues . The steroidogenic and cell growth effects of insulin are mediated through separate pathways, such as the Ras—Raf—MEK and the inositol glycan pathway, which are intact in PCOS . Hence, the presence of selective resistance to the metabolic actions of insulin leads to compensatory hyperinsulinemia, which induces hyperandrogenemia by acting on multiple levels. In the pituitary, it enhances LH production ; in the ovary, it promotes steroidogenesis via activation of CYP17 and IGF-1 mediated actions while it also promotes follicular cell dysfunction ; in the adrenals, it stimulates CYP17 leading to increased androgen production ; and in the liver, it suppresses sex hormone-binding globulin (SHBG) production, leading to increased levels of biologically active androgens .
The relationship between increased body weight and IR is well-defined. Undoubtedly, in predisposed individuals, weight gain and obesity aggravate IR . Similarly, in patients with PCOS, excess body weight worsens IR and hyperinsulinemia, as well as other metabolic and reproductive features of the syndrome . In contrast, weight loss is associated with significant improvement in insulin sensitivity, menstrual pattern, hirsutism and fertility . Besides, pharmacologic attenuation of IR (not involving weight loss) leads to reduced androgen levels, improved metabolic profile, menstrual cyclicity and fertility . These data prove the cardinal role of IR in the pathogenesis of PCOS and highlight the significant contribution of obesity in its pathogenesis.
However, IR in PCOS cannot be fully attributed to obesity. Indeed, there is a very high prevalence of IR in lean PCOS women, whereas weight loss improves but does not completely restore insulin sensitivity . Recent studies imply that obesity-related and PCOS-related IR might be explained by defects in different components of the intracellular insulin signaling pathways (more proximal to the insulin receptor in obesity and more distal in PCOS) . The co-existence of obesity with PCOS has an additive deleterious effect on the intrinsic IR characterizing the syndrome.
Central adiposity
The majority of women with PCOS (even lean individuals) have increased visceral fat deposition, which manifests clinically as increased waist circumference and increased waist-to-hip ratio . Visceral fat is less sensitive to insulin and more sensitive to catecholamines, while it also contributes to metabolic dysfunction and IR by altered secretion of adipokines and fatty acids . Androgens promote visceral fat deposition and hyperandrogenemia may therefore represent a link between PCOS status (cause) and central adiposity (effect). However, there are studies questioning the preponderance of visceral fat in women with PCOS .
Metabolic syndrome
MS is characterized by the clustering of several risk factors for cardiovascular disease (central adiposity, dyslipidaemia, hypertension, impaired glucose tolerance/diabetes). It is associated with long-term adverse outcomes such as cardiovascular disease (CVD), type 2 diabetes, obstructive sleep apnoea, certain cancers, etc. .
Given that IR has central role in the pathophysiology of both metabolic syndrome (MS) and PCOS, the common co-existence of these two syndromes is not surprising. In fact, MS affects about 1/3 of women with PCOS , with its prevalence in this population being 2–3 times that of healthy women of similar age and BMI . There are differences in MS frequency among PCOS populations from different geographic areas, possibly reflecting environmental and/or genetic effects . Furthermore, MS is more prevalent in women with “classic” PCOS phenotypes .
The frequent presence of one/more components of MS in PCOS patients classifies these women as high risk for future development of CVD and warrants the use of aggressive risk-reducing interventions. It has been shown that even young women with PCOS present chronic low-grade systemic inflammation , hyper-coagulable state , increased plasma viscosity and premature atherosclerosis ; hence, despite the fact that PCOS is usually diagnosed at a young age, the implementation of preventive measures should not delay.
Energy expenditure in PCOS
Basal metabolic rate and postprandial thermogenesis
Basal metabolic rate (BMR) is the energy expenditure of a healthy subject at rest and at least 12 h postprandial in a thermally neutral environment. It represents 50%–70% of total daily energy expenditure . Basic metabolic rate is associated with lean body mass, sex, age and climate.
As energy balance is depending upon both energy intake and energy expenditure, low BMR could contribute to the energy imbalance that characterizes obesity. Although most reported values of BMR in obesity, are usually within normal range , BMR has been linked to morbid rather than to moderate obesity .
There is a paucity of data in the literature regarding BMR in PCOS. The few existing studies have yielded conflicting results, with some showing decreased BMR in PCOS women versus controls and others finding no difference .
We have previously shown that adjusted BMR was significantly lower in 91 PCOS women compared to 41 normally menstruating women, matched for age and BMI ( p < 0.001). Adjusted BMR was calculated using the equation: adjusted BMR = (group mean BMR) + (measured BMR − predicted BMR). More precisely, in the control group ( n = 48), the adjusted BMR was 1841.05 ± 44 Kcal/day, while in PCOS women the adjusted BMR was 1445.57 ± 76 Kcal/day . The adjusted BMR was significantly lower in PCOS women both with and without IR compared to the control group ( p < 0.001). When adjusted BMR was adjusted for age and BMI, still the higher values were observed among normal women, and the lowest in the group of PCOS women with IR [ p = 0.007 between noninsulin resistant PCOS (PCOS-NIR), and PCOS-IR, p < 0.001 between PCOS-IR and controls, and p = 0.048 between PCOS-NIR and controls] ( Table 1 ) . It appears therefore that IR constitutes an independent aggravating parameter which contributes to the reduction of BMR in PCOS women.
| PCOS-IR vs PCOS-ΝIR n = 20, n = 40 | PCOS-IR vs Control n = 20, n = 35 | PCOS-NIR vs Control n = 40, n = 35 | |
|---|---|---|---|
| Age (years) | 23.27 ± 1.04 vs 24.13 ± 0.78 p = ns | 23.27 ± 1.04 vs 25.71 ± 0.82 p = ns | 24.13 ± 0.78 vs 25.71 ± 0.82 p = ns |
| ΒΜΙ (kg/m 2 ) | 27.89 ± 1.44 vs 25.04 ± 0.78 p = ns | 27.89 ± 1.44 vs 24.57 ± 1.04 p = ns | 25.04 ± 0.78 vs 24.57 ± 1.04 p = ns |
| BMR (Kcal/day) | 1116 ± 106 vs 1590 ± 130 p = 0.007 | 1116 ± 106 vs 1868 ± 41 p < 0.001 | 1590 ± 130 vs 1868 ± 41 p = 0.048 |
In another study, comparing 128 PCOS patients and 72 eumenorrheic, nonhirsute women, no significant difference in BMR between PCOS subjects (adjusted mean 5807 kJ/day, 95% CI 5715–5899) and controls (adjusted mean 5916 kJ/day, 95% CI 5786–6046) ( p = 0.193) was noted .
On the contrary, in a recent study concerning 36 women with PCOS compared to 37 healthy women, an increased estimated BMR was noted among PCOS women (1658.7 ± 201.1 kcal vs 1359.2 ± 103.7 kcal; P < 0.0001) .
Differences in methodology, in calculating adjusted BMR and energy intake, as well as different criteria in defining PCOS women included in each study are to be blamed for conflicting results. PCOS is a heterogeneous syndrome with clinical and/or biochemical hyperandrogenemia, chronic anovulation with or without PCOS like ovaries on ultrasound, also characterized by multiple metabolic issues, including obesity, diabetes, hypertension, dyslipidemia and fatty liver. Genetic heterogeneity might also play an additional role. A missense mutation at codon 12 in the PPAR gamma 2 (PPARG2) has been associated with increased BMI and attenuated IR in PCOS . In a case-control association study involving 156 PCOS women with biochemical hyperandrogenism, chronic anovulation and polycystic ovarian morphology in ultrasound and 56 unrelated healthy controls, we have shown that although genotype frequencies of the Pro12Ala polymorphism in PPARG2 did not differ among PCOS women and control subjects, the presence of Pro12Ala polymorphism of PPARG2 was associated with lower BMR (1475.7 ± 678.6 vs 893.2 ± 312.3 kcal/day, p = 0.04) particularly in lean PCOS (BMI < 25 kg/m 2 ) . Finally, another possible confounding factor in BMR and energy intake assessment could be IR, as women with PCOS and IR might represent a subgroup of PCOS women with significantly decreased BMR .
Based on these findings, insulin sensitizers can be a very helpful additional treatment, particularly in obese PCOS women with IR . Administration of insulin sensitizers should always be coupled with low-caloric diet and lifestyle change.
As BMR remains constant throughout the day, representing 60%–70% of the total energy consumption, women with PCOS should decrease their caloric energy intake in order to maintain their body weight within normal limits. The increase in body weight further augments IR creating a vicious circle. Therefore, in order to achieve energy balance, the decrease in energy intake should be coupled with a significant increase in energy expenditure by aerobic exercise. Besides, it has been shown that BMR in women with PCOS was increased after 12 weeks of endurance and resistance exercise .
Finally, there is also controversial data regarding the influence of PCOS status on postprandial thermogenesis or the rise in energy expenditure which normally follows a meal. Postprandial thermogenesis has been found to be markedly lower in patients with PCOS versus healthy women by some researchers , but not by others .
Gut-brain axis
Food intake is finely regulated by the central nervous system; hypothalamic circuits receive various inputs (optical stimuli; concentrations of glucose, amino acids and other nutrients in the bloodstream; levels of orexigenic and anorexigenic peptides secreted in the gut; levels of adipokines) and orchestrate an appropriate response .
The high prevalence of obesity among PCOS individuals has prompted the investigation of an underlying dysfunction in appetite circuits in women with PCOS, leading to impaired satiety and increased food intake. There might be a relation between hyperandrogenemia and increased appetite, as testosterone administration in rodents increases meal frequency , while treatment with antiandrogens decreases hunger in bulimic women, a population with some similarities to PCOS regarding eating behaviour .
Ghrelin is an orexigenic gut hormone which is normally increased in fasting and suppressed with food consumption. In women with PCOS smaller reduction in postprandial ghrelin has been shown compared with BMI-matched controls . Furthermore, ghrelin levels are inversely correlated with androgens and indices of IR . However, other studies did not find any correlation between ghrelin and PCOS status or androgen levels .
Similarly, there is conflicting data regarding cholecystokinin (an anorexigenic gut hormone) levels in PCOS; some researchers report lower postprandial levels in PCOS versus controls , while others found similar basal and meal-stimulated levels .
Glucagon-like peptide-1 (GLP-1) is an incretin peptide, which is secreted in the small intestine following food intake and has insulinotropic effects . GLP-1 has also anorexigenic actions, exerted either directly at the CNS or indirectly via stimulation of the vagus nerve . Regarding its possible role in PCOS, available evidence differ depending on patient BMI: in lean individuals, OGTT-stimulated GLP-1 levels were significantly lower in PCOS than in controls ; in contrast, no difference was shown in basal or stimulated GLP-1 levels between obese PCOS and obese controls .
Mental health and weight loss
PCOS patients are often obese and suffer to various extents from hirsutism, acne, irregular menses and subfertility. In this context, it is not unusual for women with PCOS to present with mental health issues, which affect all age groups. Numerous studies have demonstrated an increased prevalence of anxiety, depression and negative body image in PCOS . Diminished perceived self-control is another consistent finding in this population . All these mental problems can certainly have a negative impact on patients’ attempts to achieve and maintain weight loss, by hindering beneficial lifestyle modifications (healthy eating, engagement in physical activity, adequate sleeping, etc.) . In conclusion, although PCOS status does not seem to directly affect the physical ability of the patients to engage in physical activity, it certainly has an indirect negative effect mediated through emotional barriers .
Interventions aiming at weight loss in patients with PCOS
Pharmaceutical agents and weight in PCOS
Drugs traditionally used in PCOS—effect on weight
Combined oral contraceptive pills (COCPs)
COCPs have been for decades the first-line treatment for the menstrual irregularity and hyperandrogenic manifestations (acne, hirsutism) associated with PCOS. COCPs have been proven very effective in normalizing menses and reducing acne and hirsutism. Furthermore, they mitigate the risk for endometrial hyperplasia and carcinoma, which is increased in PCOS women with chronic oligo-anovulation .
However, COCPs have potentially untoward effects on carbohydrate and lipid metabolism , as well as on markers of subclinical cardiovascular disease , which may limit their use in PCOS patients with adverse metabolic profiles. As mentioned above, obesity is extremely common in PCOS and greatly contributes to the metabolic dysregulation of the syndrome. It is therefore interesting to explore whether there is an impact of COC use on body weight/body composition.
Weight gain is often considered a side effect of COCPs by both patients and clinicians, often leading to avoidance or discontinuation of use . There are some studies showing mild weight gain associated with the use of COCs, but data are very heterogeneous . In contrast, a substantial body of evidence suggests that COCP use leads to no significant alterations in BMI or fat deposition, both in lean and obese PCOS patients . Consequently, concerns over weight gain should not limit COCP use in patients with PCOS.
Antiandrogens
Antiandrogens are occasionally used in PCOS, in patients who have contra-indications or cannot tolerate COCPs, as well as in those where COCPs are not effective in controlling hyperandrogenic symptoms. Antiandrogens are used alone or in combination with COCPs . Commonly used medications of this category include the progestogen cyproterone acetate, the mineralocorticoid receptor antagonist spironolactone, the 5-a reductase inhibitors finasteride and dutasteride, and the androgen receptor inhibitor flutamide. Although data regarding the effect of these medications specifically in PCOS is scarce, none of them has been associated with weight gain, while flutamide use may rarely result in weight loss .
Insulin sensitizers
The understanding of the pivotal role of insulin resistance (IR) in the pathogenesis and clinical manifestations of PCOS has led to widespread use of insulin sensitizing agents in PCOS patients. These drugs have proven to be very effective in improving metabolic parameters (such as carbohydrate metabolism and dyslipidemia) and, to a lesser extent, menstrual irregularity and hyperandrogenic symptoms . Their impact on body weight is variable.
Metformin
Metformin is the most widely used medication of this category in PCOS. Case-control studies, randomized controlled trials and meta-analyses have assessed the effect of metformin on body weight in PCOS patients. Available evidence is conflicting; some studies show that metformin use (alone or as an add-on to COCP) results in significant weight loss , while others demonstrate a neutral effect on weight and no extra benefit when lifestyle measures are already in place . Considering the fact that the reported weight loss associated with metformin use is < 5%, the Endocrine Society Guidelines suggest that metformin should only be considered as a second-line treatment, reserved for obese PCOS patients who fail to lose weight with diet and exercise .
Thiazolidinediones
Thiazolidinediones (TZDs) are PPAR-gamma agonists which enhance insulin sensitivity in muscle, liver and adipose tissue but also exert an inhibitory effect on ovarian steroidogenesis . One of the main side effects of TZDs is water retention, which might lead to mild weight gain. Indeed, TZD use in PCOS has been shown to increase body weight , although this is not a consistent finding .
Inositols
Inositols are carbocyclic sugars which are abundant many tissues of the human body, participating in signal transduction of various hormones and neurotransmitters. Defects in tissue availability or altered metabolism of inositol have been shown in PCOS , while administration of the inositol isomers myo-inositol and D-chiro-inositol in PCOS subjects may improve both reproductive and metabolic abnormalities of the syndrome .
Regarding the impact of inositol on body composition and BMI results are controversial; there are studies where inositol treatment led to significantly decreased BMI , but other researchers have failed to reproduce this finding . Notably, an inverse relationship between BMI and inositol treatment efficacy was described by Gerli et al. and Kamenov et al. .
Drugs used to aid weight loss in PCOS
Orlistat
Orlistat is a potent inhibitor of gastric and pancreatic lipases which promotes weight loss by inhibiting intestinal fat absorption . It is one of the most widely used antiobesity medications, and it has also been studied in PCOS. Orlistat is clearly superior to placebo in achieving weight loss in women with PCOS . Regarding its comparison to metformin, data is conflicting; some studies demonstrated that orlistat is superior to metformin , while others (including two meta-analyses) suggest that their effect on weight reduction is similar . Notably, the magnitude of orlistat’s effect is modest, with a mean reported weight loss of 3.23 kg .
Bupropion/naltrexone
Bupropion/Naltrexone is a novel combination medication against obesity. Its components act synergistically to suppress appetite. Although bupropion/naltrexone is effective, leading to an average weight loss of 3.7%–5.7% in obese individuals, there is no evidence for its efficacy and safety in PCOS.
GLP-1 receptor agonists
Glucagon-like peptide-1 (GLP-1) receptor agonists are a new class of antidiabetic medications. They are injectable analogs of the gut hormone GLP-1, which act by activating the GLP-1 receptor. Apart from their insulinotropic effects, GLP-1 receptor agonists also promote weight loss via promoting satiety promotion, delaying gastric emptying and, possibly, modulating the gut microbial composition .
The significant impact of liraglutide (one of the GLP-1 receptor agonists) on weight loss, has prompted the development of an increased dose formulation (3.0 mg), indicated for use in obesity (regardless of diabetes co-existence). Its efficacy has been established in large randomized controlled trials .
There is considerable data in the literature demonstrating the efficacy of liraglutide in promoting weight loss in PCOS patients. Liraglutide has been shown to be superior to placebo, as well as to metformin and orlistat in head-to-head comparisons . Short-term administration of liraglutide (12–24 weeks) leads to a mean reported weight loss of 5–6 kg . Liraglutide can be combined with metformin, but it seems that the maximum liraglutide dose of 3.0 mg is more effective than the combination of 1.2 mg with metformin .
Bariatric surgery in PCOS
Bariatric surgery is the last resort for morbidly obese patients who fail to achieve/maintain adequate weight loss with lifestyle measures and medical treatments. In a vast majority of patients bariatric surgery leads to substantial weight loss (15 to 30% on average) and to significant improvement in metabolic abnormalities such as type 2 diabetes, dyslipidemia, etc. Unsurprisingly, in PCOS patients, besides improvements in metabolic parameters, bariatric surgery dramatically reduces menstrual irregularities, androgen levels and hyperandrogenic symptoms. Some patients even experience complete regression of the syndrome postsurgery . Therefore, bariatric surgery may be strongly considered as a treatment option for severely obese patients with PCOS, provided they fulfil the indications for such an intervention.
Diet
The patient profile in PCOS
The complex nature of PCOS and its close association with obesity has naturally instigated research on the effects of diet -alone or combined with exercise- in order to identify the most effective strategy in the management and treatment of the condition.
Women with PCOS have been described as having significantly poorer dietary habits characterized by a greater consumption of energy from high glycemic index foods, with excessive saturated fat and inadequate dietary fiber consumption . Moreover, a higher occurrence of under reporting and weight cycling has been identified in women with PCOS .
Patients with PCOS, especially those with IR, manifest a significantly lower basal metabolic rate , a corresponding higher respiratory exchange ratio and a considerably lower postprandial thermogenesis .
The prevalence of inactivity is higher in women with PCOS . However, physical inactivity has been positively correlated with emotional barriers that patients with PCOS experience and not to differences in muscle strength and levels of free-living physical activity . Indeed, obese women with PCOS are more susceptible to mental health problems, with body image and self-worth being positive predictors of anxiety and depression . Furthermore, depression and/or low self-esteem place women with PCOS at higher risk of emotional eating and decreased exercise, which contribute to a long-term positive energy balance and weight gain .
Data from the NFBC 1966 show association between early adiposity rebound during childhood and diagnosis of PCOS and obesity in adulthood .
In outlining the profile of the patient with PCOS, it becomes apparent that environmental influences, psychological status and biological variables play an intricate role in the management of the disease. Only when we manage to sufficiently address them all, we will be able to tackle effectively the complex nature of the disease.
Management strategies
Weight loss remains the most effective strategy for the management of PCOS. However, the high failure rates encountered in weight-loss maintenance augments the need for novel management strategies.
Development of such strategies (diet patterns, weight loss and maintenance, prescription exercise, psychological techniques, food products and/or supplements) for PCOS patients are a challenge faced by the scientific community.
Dietary interventions in PCOS
Dietary manipulations remain the mainstay of all obesity management programs. Dietary interventions that will lead to effective weight-loss remain the most effective and promising management strategy for women with PCOS . Current guidelines recommend a 5%–10% weight loss over 6 months in overweight women with PCOS as it is associated with beneficial effects on hormones, metabolism and clinical outcomes .
There is a scarcity of well-controlled studies on dietary impacts on PCOS. A recent systematic review assessing dietary effects on PCOS outcomes identified that the body of evidence was not sufficient to draw reliable conclusions about the optimal dietary composition for lifestyle management in PCOS .
Studies to date have looked into the effects that different dietary components and diet protocols may have on the manipulation and treatment of PCOS. Data exists for low and high protein , and low and high carbohydrate protocols .
Low carbohydrate diets (LCD)
Low carbohydrate diet refers to dietary protocols that limit the amount of carbohydrates to less than 45% of the total caloric intake and correspondingly increase the intake of protein and/or lipids in order to aid or prevent disease .
LCD is reported to control body weight, lower insulin levels, improve insulin resistance and total cholesterol more effectively than standard diets , with an additional 1%–5% significantly greater weight loss .
Moreover, the low fat/low carbohydrate diet (less than 35% fat, less than 45% carbohydrate), followed in the long term (more than four weeks), has demonstrated a significant increase in the levels of FSH and SHBG and a decrease in the level of testosterone, while it performs well in restoring the regularity of the menstrual cycle in patients with PCOS .
The beneficial actions of LCD protocols can be attributed to the LCD-induced decrease of circulating insulin and glucose , which in turn may be responsible for restoring the balance of inositol metabolism .
Available studies to date have demonstrated that changes in the circulating levels of IGF-1, insulin like growth factor binding protein 1 (IGFBP1), glucose and insulin are typical manifestations of diet control. Hence, such modifications may play a critical function in regulating aging and metabolic homeostasis and may have beneficial effects on ovarian function .
However, although LCD have been shown to be effective in improving selected clinical symptoms in patients with PCOS, there are limited well-controlled studies worldwide and, therefore, the full impact of LCD on the phenotypic and metabolic profile of PCOS women is not well-defined; hence, there is a need for more rigorous research .
High protein diets
The use of high protein diet protocols as a mean of reducing and maintaining weight in obesity has been exploited in recent years. High protein (HP) diets used in weight loss studies often include 30% of energy intake as protein. In general, protein as a percentage of energy is doubled from 15 to 30%. Notably, this does not mean that absolute protein intake (in grams per day) is doubled, as energy intake is reduced, with only a 20% increase in the actual amount (grams per day) of protein .
In general, it is accepted that a reduced carbohydrate, HP diet is associated with better fat loss and relatively less lean mass loss in obese individuals . There is convincing evidence that a higher protein intake increases thermogenesis and satiety compared to diets of lower protein content. The weight of evidence also suggests that high protein meals lead to a reduced subsequent energy intake .
Application of a modified hypocaloric-HP diet protocol in overweight and obese women with PCOS resulted in significantly increased insulin sensitivity . However, no changes in lipid profile were identified. Moreover, studies comparing high- with normal-protein diets in women with PCOS have demonstrated that weight loss has a beneficial effect on PCOS features, regardless of dietary composition .
In conclusion, calorie reduction, rather than protein content, seemed to affect body composition and hormonal profile in these studies .
The Mediterranean diet
The Mediterranean diet (MD) is a well-established health-promoting diet model. It is characterized by a regular consumption of unsaturated fatty acids, low glycemic index carbohydrates, fiber, vitamins and antioxidants, and moderate animal-derived proteins . Evidence support that adherence to MD is inversely associated with adiposity, IR, and risk of type 2 diabetes and cardiovascular disease .
On the basis that obesity and PCOS commonly co-exist and share similar metabolic characteristics, the MD protocol was adopted in a cross-sectional, observational study investigating the effects of MD on PCOS. In addition to weight loss, the study showed a direct association between adherence to MD and the clinical severity of PCOS. This finding remained significant when data were adjusted for BMI and total energy intake, suggesting an independent role of MD in ameliorating the PCOS phenotype . These results may be attributed to the antiinflammatory potential of MD.
The increased antiinflammatory activity of MD is mainly due to the microbiota-derived production of short chain fatty acids that is induced by dietary fiber, and the high intake of polyunsaturated fatty acids, omega-3 fatty acids and antioxidants found in fruits, vegetables, extra virgin olive oil and wine . Since chronic low-grade inflammation has been identified as a key contributor in the pathogenesis and development of PCOS, these data highlighted the nutraceutical potential and therapeutic role of single foods and nutrients of the MD in PCOS, achieved by contributing to a reduced inflammatory status . The findings of this study are aligned with research data that endorse the role of oxidative stress in the pathophysiology of PCOS , as well as with emerging evidence on the central role of microbiota in the progression of the PCOS-related metabolic dysfunction, and its prevention .
Emerging fields
A growing body of evidence highlights the importance of the biological clock—the so called “clock-genes”—as a modulator of energy balance and metabolism . It appears that when eating and sleeping habits are out of synchronization with the body’s circadian clock, metabolic disturbances ensue, which may predispose to cardio-metabolic diseases .
In humans, body functions follow an internal temporal order and synchronization occurs within an endogenous period of approximately 24 h. Biological rhythms can influence the activity of bioactive compounds, and at the same time, the intake of these compounds can modulate biological rhythms . Recent human studies suggest that earlier meal timing compared with late eating is associated with improved effectiveness of weight-loss therapy in overweight and obese patients .
Dietary interventions and long-term compliance
Energy-restricting dietary interventions have a well-documented low long-term compliance rate, while weight loss maintenance through lifestyle implementation is challenging and has a high failure rate . This phenomenon is even worse in patients with PCOS, with a Cochrane review reporting attrition rates in women with PCOS of up to 46% .
Moreover, weight management interventions seem to be less effective in women with, compared to women without PCOS, based on longitudinal evidence showing weight gain to be greater in PCOS patients .
Dietary prescription
A dietary intervention, in order to be effective, should be able to produce satisfactory results in weight loss, weight maintenance and to elicit significant improvements in the metabolic profile of the PCOS patient. Appetite control and satiety enhancement should be a concomitant feature in any dietary intervention in order to be effective. Moreover, dietary manipulations should target oxidative stress, inflammation status and the normalization of glucose metabolism.
The major nutrients themselves have an effect on both appetite and satiety, as does the rate and timing of food intake. Protein is the most satiating of the macronutrients, followed by carbohydrate, whereas fat in the diet has little effect on satiety or appetite. In addition, the nutraceutical potential of dietary fiber, polyunsaturated fatty acids and antioxidants on inflammation and oxidative stress have been clearly demonstrated.
Hence, the proposed dietary prescription is a modified Mediterranean Diet pattern (low fat – 30%, low carbohydrate – 40%, high protein – 30%), focusing on high-quality dietary carbohydrates and an increased intake of fiber and antioxidants. The energy intake should be “clocked-in” appropriately throughout the day, aiding the internal biological clock and thereby enhancing metabolism.
Physical activity
The benefits of physical activity (PA) include promotion of weight loss; improvement in fasting insulin levels, glucose levels, lipid profile, blood pressure, free androgen index; reduction in fat mass and waist circumference .
Furthermore, habitually active individuals have a more accurate appetite regulatory system than habitually inactive ones, suggesting that PA increases the sensitivity to satiety signals and that energy intake is more tightly regulated .
Therefore, PA and exercise constitute a key feature of lifestyle advice for the management of obesity and PCOS .
Exercise prescription
Despite the lack of well controlled studies in the area, available literature allows for meaningful comparison between studies on the effects of exercise on women with PCOS . Despite their limitations, data repeatedly highlight the beneficial role of moderate exercise to the overall improvement in metabolism (glucose disposal rate and cardiovascular fitness) in patients with PCOS (independent of weight loss).
In a systematic review of the literature, it was clearly demonstrated that exercise significantly influenced waist circumference; lipid profile; aerobic capacity and body fat mass, while it improved the physical functioning, general health, social functioning and mental health aspects of life of women with PCOS . Moreover, exercise appears to result in marked improvements in menstrual cyclicity and ovulation in almost 50% of women with PCOS .
Aerobic exercise has demonstrated more benefits in aerobic capacity, body composition, lipid profile and weight compared to resistance training. It was further noted that supervised and shorter duration moderate activity was better tolerated and shown improved change from baseline . Similar results have been elicited in a younger population. A study following a group of overweight girls at risk for PCOS attending a dance-based intervention over a period of 6 months, found the majority of individual girls to have a decreased waist circumference, triglycerides, and metabolic syndrome severity score, while 40% had decreased free testosterone levels .
It is worth highlighting the importance of promoting moderate exercise (30–60 min/day) and avoiding excessive exercise (> 60 min/day) as the latter can increase the risk of anovulation . Moreover, exercise activity should be matched to energy intake throughout 24 h in order to achieve permanent energy equilibrium of ± 300 calories . The key message elicited from available research to date on “exercise prescription” in women with PCOS is the promotion of moderate-intensity exercise.
In conclusion, a combination of aerobic and strength exercise seems to be the best approach. Exercise intensity is of pivotal importance in women with PCOS. Engagement in moderate-intensity exercise spread evenly throughout the week is encouraged (30–60 min/day), with moderate to vigorous intensity activities to be performed on 2 nonconsecutive days (75 min/week). Excessive exercise (> 60 min/day) should be avoided.
Key points
- •
PCOS is a reproductive disorder associated with metabolic dysfunction. The high prevalence of Insulin Resistance, obesity and elements of the metabolic syndrome increase the future risk of cardiovascular disease in PCOS patients. The beneficial effect of weight loss in ameliorating the metabolic profile of patients is well-established.
- •
Data on Basal Metabolic Rate (BMR) and postprandial thermogenesis in PCOS patients are controversial, due to differences in methodology, in calculating adjusted BMR and energy intake, as well as in defining PCOS (different criteria used).
- •
Concerns over weight gain should not preclude the use of combined oral contraceptives in PCOS.
- •
Metformin has a small (if any) effect on weight. Weight loss achieved with orlistat is modest. Liraglutide is so far the most effective medication for weight loss in PCOS.
- •
The beneficial effects of diet in managing PCOS rely on calorie reduction rather than macronutrient content.
- •
The Mediterranean diet, thanks to its antiinflammatory and antioxidative potential, is a well-established health promoting diet model.
- •
A combination of aerobic and strength exercise of moderate intensity, spread throughout the week (30–60 min/day) is the best approach to be promoted. Excessive exercise (> 60 min/day) should be avoided.
- •
Exercise activity should be matched to energy intake throughout 24 h in order to achieve permanent energy equilibrium of ± 300 calories.
References
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
