Obesity and PCOS prevalence

The relationship between obesity and PCOS is intricate, undeniable, but not straightforward. As obesity levels escalate at an alarming rate, 56% of women in England are classified as overweight or obese [7], and with an apparent increase in the prevalence of PCOS, it could be extrapolated that the two are rising in parallel and a potential causative relationship inferred. Cause and effect is yet to be fully deduced and although pubertal obesity is known to be associated with hyperandrogenism [8], it is not yet clear whether this serves as a precursor to the development of PCOS. Some studies have concurred that the prevalence of PCOS is increased in obese populations [9], whereas others have merely demonstrated a modest incidental increase in risk [10]. This translates into a multifactorial etiology implicating both intrinsic and extrinsic factors, with possibly a genetically susceptible population being influenced by environmental components.

Early intrauterine life

Conception and gestation are vulnerable periods and embryonic cells have a complex system to integrate signals emanating from their environment and can adapt their development accordingly [11]. Certainly, an abnormal metabolic environment may contribute to programming alterations during a crucial window for developmental plasticity and beyond. Ultimately, as these changes in physiology, metabolism, and development are metabolically imprinted they may manifest postnatally and later in adult life. Certainly, it has been appreciated that the presence of maternal obesity in pregnancy renders the female offspring more susceptible to the development of PCOS [12] and likewise, female offspring born to mothers with PCOS have insulin defects [13].

Developmental origins and fetal programming theory of PCOS has been increasingly substantiated from primate and sheep studies demonstrating that, in utero, excess androgen exposure may affect fetal programming leading to the development of PCOS later in life. It has been demonstrated that testosterone-exposed offspring have higher birth weights with associated hyperglycemia and hyperinsulinemia [14– 16]. Similar findings are yet to be reproduced in humans but much work is underway [17].

These are important data to consider when counselling women with PCOS of the therapeutic strategies that can be employed, as there is responsibility not only for the women’s health but for also the perceivable health of their future generation.

Obesity and the pathophysiology of PCOS

The endocrine and metabolic milieu work in elaborate symbiosis to ensure successful ovulation and reproduction. This balance can be disturbed by many factors and obesity is a dominant perpetrator, as witnessed by the presence of obesity in 35–60% of women with PCOS [18]. Even in the absence of PCOS, obesity upsets the hormonal balance.

Interestingly, more specifically than BMI per se, it appears that the pattern of fat distribution may mediate the clinical consequences to varying extents, with accumulation of fat in the abdomen, indicated by a waist:hip ratio >0.8 or a waist circumference of over 80 cm [19], being associated with worsening reproductive and metabolic sequelae [20]. This has been coined the “abdominal phenotype.” Even in the absence of the BMI criteria fulfillment for obesity, women with PCOS will often have an abdominal “roundness” and this pattern of adiposity is associated with more pronounced states of hyperandrogenemia and hyperinsulinemia [21,22].

A postulated mechanism for the development of abdominal obesity in PCOS proposes that with high calorific intake, fat is initially preferentially laid down in the intra-abdominal compartment and with saturation of this area, it is subsequently shunted to the subcutaneous abdominal area. Due to the metabolic activity of the visceral adipocytes there is enlargement of this fat depot, exacerbated by androgen excess and an associated flux of free fatty acids to the liver and muscles. Increasing liver and muscle fat deposition is thought to be responsible for the associated rise in insulin resistance and compensatory insulin release [23,24,]. Testosterone’s role and function in the development of insulin resistance is still being fully investigated.

It would appear that insulin is the dominant instigator orchestrating and perpetuating the changes in biochemical parameters, with subsequent rise and fall in testosterone and sex hormone-binding globulin (SHBG) respectively. Hyperinsulinemia impedes the liver’s synthesis of SHBG and the negative correlation between abdominal adiposity and SHBG, as a result, leads to elevated levels of free testosterone being presented to the target tissues and higher clearance rates. Women with central, visceral obesity tend to have lower SHBG levels even when compared to their peripherally obese counterparts of the same weight [20] and have a positive net balance of androgens, as production exceeds clearance, leading to a state of relative functional hyperandrogenemia [25].

It should not be overlooked that adipose tissue also has a fundamental storage role affecting steroid hormone bioavailability and is also an extraglandular source of steroidogenesis. Indeed alterations in enzyme systems including 11β-hydroxysteroid dehydrogenase, 5α-reductase, and 5β-reductase have all been investigated [26–28]. Therefore not only is the “reserved” pool of steroid hormones greater in obese women, but also more “machinery is available” with steroidogenetic enzymes present for conversion and metabolism.

It has been speculated that the link between obesity and PCOS may lie in the metabolic role of adipocytes and their role in metabolic regulatory pathways. Adipocytes produce over 50 adipocytokines and many of these have been investigated and are thought to mediate obesity-associated insulin resistance via regulation of lipid and glucose metabolism [29,30].

Leptin, an adipocytokine that plays a fundamental signaling role in metabolism and reproduction, has generated much research attention. At the level of the hypothalamus leptin serves to decrease food intake and in the periphery is antagonistic of insulin in fat and glucose metabolism [30]. Therefore, it appears contradictory that high leptin levels are observed in women with obesity and PCOS. There is, however, a degree of leptin resistance and high circulating leptin levels can modulate the insulin resistance and ovulatory dysfunction shared in obesity and PCOS. In common with insulin, the resistance to leptin does not extend to the ovaries and in the ovary leptin has an inhibitory effect and reduces steroidogenesis, follicular development, and ovulation [19,31,) Furthermore, in the hypothalamus and pituitary, leptin levels can disturb gonadotropin-releasing hormone and gonadotropin secretion [32]. At present, leptin is one of the many adipocytokines incriminated and being explored in the pathogenesis of PCOS and obesity.

Obesity and disease presentation

PCOS is both heterogeneous and unpredictable in its presentation. There is remarkable individual variation and a spectrum of severity. With concurrent obesity there is a detrimental effect on the phenotypic hallmarks of PCOS, as witnessed by the exponential relationship between rising BMI and worsening features of anovulation [33,34]

Women with PCOS and obesity are more prone to menstrual irregularity compared with their low-weight peers and hyperinsulinemia, secondary to a state of insulin resistance, is thought to contribute to this ovulatory dysfunction [35,36]. The reduction in insulin sensitivity is not uniform or applicable to all tissues, and on the contrary, a synergetic action of insulin can be seen with luteinizing hormone acting on thecal cells to augment ovarian androgen production, ultimately culminating with follicular growth arrest, atresia, and anovulation [37]. Furthermore, insulin resistance and obesity have also been associated with detrimental oocyte development [38] and in combination, a degree of endometrial insulin resistance and high circulating insulin levels has been speculated to affect endometrial development and receptivity, with conceivable risks for implantation and fertility[39].

Certainly, for a substantial proportion of women, a PCOS diagnosis will come to fruition in the reproductive years with the inability to conceive naturally, as PCOS is the most common cause of anovulatory infertility. With the UK National Institute for Health and Care Excellence (NICE) guidelines representing evidence-based medicine, it is with reason that they have set their recommendation for women to have BMI of less than 30 kg/m² before assisted conception and eligibility for NHS-funded fertility treatment, as the literature delivers a wealth of evidence demonstrating the adverse effects of obesity on reproduction and pregnancy outcome. Independent of any other coexisting pathology, the probability of infertility increases threefold with obesity alone [33]. Certainly, in PCOS with superimposed obesity, there are unfavorable effects on conception rates both spontaneous and after treatment, efficacy of pharmacological agents, and pregnancy outcomes. When undergoing assisted reproduction, obese women have lower pregnancy rates and a greater threat of miscarriage compared with women with a BMI <25 kg/m² [38,40]. In addition, other deleterious effects include a relative resistance to ovarian-stimulating medications, fewer oocytes collected, poorer quality and maturation of the oocyte, and ultimately fewer live births. [2,7,41].

Women with PCOS commonly cite hirsutism as being one of the most distressing aspects with both aesthetic and psychological repercussions [42]. In conjunction, obesity and PCOS lend themselves to worsening symptoms associated with androgen excess including hirsutism, alopecia, and acne [43].

A relatively high proportion of women with PCOS (20–49%) will present with glucose intolerance, reiterating the importance of glucose tolerance tests in clinical practice for the workup of PCOS. Obese women with PCOS tend to have a more severe insulin-resistant state. In comparison with normal weight women with PCOS, obese PCOS women have higher concentrations of both fasting and glucose-stimulated insulin[43]. The stigma of insulin resistance acanthosis nigricans is more clinically apparent when obesity accompanies PCOS [32].

PCOS represents a chronic disease in its own right but, importantly, it is also interrelated to other diseases, affecting both the morbidity and mortality of this cohort of women in the long term. PCOS, secondary to its metabolic disturbances, is associated with the metabolic syndrome with a predisposition to cardiovascular disease and diabetes risk [44]. Obesity is also a well-recognized independent risk factor for these comorbidities and therefore, if occurring in combination, the risk is summative with a cluster of risk factors including dyslipidemia, altered blood vessel function, hypertension, and glucose intolerance. In the absence of obesity, PCOS rarely heralds glucose intolerance and likewise the lipogenic effects in PCOS are exaggerated with obesity, with a pattern vulnerable to atherosclerosis of high total cholesterol levels and triglycerides and lower levels of high-density lipoproteins [43].

PCOS and psychological stress

Common to PCOS, obesity and other chronic illness, quality of life can be severely compromised and be affected by depression, anxiety, and other psychiatric ailments [45,46]. Stress has an important role in PCOS, both as cause and consequence, and can often fuel a vicious cycle.

Many mechanisms have been proposed associating stress with the pathophysiology of PCOS. Stress is associated with food cravings and “stress eating,” often with poor nutritional choice and high-calorific foods [47], can compound obesity and this, in addition to psychological stress itself, can aggravate the endocrine disequilibrium of PCOS to a greater extent. Obesity alone is linked with a reduction in the frequency of sexual activity but, in the presence of overeating which is itself associated with a decreased sexual drive, can contribute to reduced fecundity with psychosocial and relationship struggles.

Both acute and chronic stress can provoke and alter aspects of the hypothalamic–pituitary–adrenal axis and this seems to be heightened in PCOS. In response to stress there appears to be excessive and prolonged cortisol release, which in turn propagates worsening obesity and enhances insulin resistance [48].

Conversely, although stress can heighten PCOS, the emotional distress that can ensue from the inability to conceive with an infertility diagnosis secondary to PCOS can be vast [49]. Moreover, the cosmetic and body image consequences of obesity, hyperandrogenemia with hirsutism, alopecia, and acne can be the overriding complaint especially in younger females, which may precipitate social, psychological, and sexual impairment [42].

Despite optimism being given in the form of medical intervention, the pressures and expectations associated with treatment and required lifestyle changes can lead to immense strain, relationship breakdown, and treatment dropout. Indeed 15–20% of couples undertaking reproductive treatment require counseling, with psychological interventions demonstrating successful outcomes in pregnancy rates [50].

Not to be overlooked, stress constitutes a risk factor for cardiovascular disease and diabetes independent of PCOS and obesity and therefore recognition and alleviation of stress prior to, during treatment, and long term is paramount and should be strongly advocated.

Lifestyle interventions

With concomitant obesity having such profound effects on all aspects of PCOS it is with justification that lifestyle interventions comprise the recommended first line of its treatment [51]. Indeed modest amounts of weight loss (>5% of body weight) have been shown to have significant beneficial effects clinically, and in terms of cost effectiveness [24,51,52]. For women with PCOS, weight loss can be even more difficult to achieve, the effects of hyperinsulinemia and psychological barriers being to blame, and therefore specialized help must be at hand.

Obesity is a challenge as its pathophysiology is complex, involving both physical and psychological dimensions. Interventions, therefore, require a multidisciplinary approach utilizing the expertise of psychologists, dieticians, and exercise specialists, providing competent support in all aspects of the complex issues that constitute weight management. The objectives should include the avoidance of further weight gain and the attainment of a degree of weight loss, all whilst endorsing habitual alterations in nutrition and physical activity. This should be in concordance with the approach advocated by NICE who, in their guidance on tackling obesity, emphasize the need for weight management programs.

Emphasis needs be placed on a comprehensive, systematic approach to weight control and symptom modification. To aid compliance and motivation, it should be reiterated that small adaptations can be enough to lead to beneficial effects with restoration of ovulation and increased pregnancy rates [53] A complete upheaval of lifestyle may seem daunting to both patient and physician but, by adopting a holistic multifaceted approach, potentially through group or supervised programs, benefits have been observed with dietary modification and this, in combination with exercise, can lead to cumulative improvement and long-term weight maintenance [54]. Behavior modification interventions, in addition to addressing and alleviating psychological problems, have proven beneficial in complementing dietary and exercise advice to help achieve sustained weight loss and enduring change [55].

Dietary advice: With regard to specific dietetic advice and particular eating patterns, there is a paucity of data and although many diets have been tested, superiority of a specific diet plan has not been fully determined. With no official guidelines for dietary advice in PCOS, dietician referral should be considered and initial counseling should encourage a high glycemic index diet and reduced calorie intake incorporating a healthy balanced diet [56]. Equally, rapid weight loss and extreme dieting should not be promoted as this too can be related to poor reproductive outcome.

The intake of fats, especially saturated fats, is of particular concern in PCOS as they can further upset insulin signaling causing worsening of insulin resistance. It therefore seems prudent that low-saturated fat diets should be encouraged in PCOS given their more explicit effect on hyperinsulinemia [57]. Focus on the role of particular nutrients in the pathogenesis of PCOS has led to the analysis of advanced glycosylated end products (AGEs). The higher levels of AGEs found in PCOS stimulated interest in this subject. AGEs, which are found exogenously from cooking at high temperatures, can promote insulin resistance and are positively related to androgen levels [58]. Reducing AGEs by dietary modification may serve as an adjunct in lifestyle interventions for the control of PCOS.

Exercise: The metabolic cascade, implicated in the pathogenesis of PCOS, is amplified and exacerbated by increased adiposity. It therefore would seem intuitive that by engaging in lifestyle modification with the aim of weight loss and avoidance of weight gain, a degree of reversal can be achieved, with alleviation in insulin resistance, reduced androgen levels, and resumption in ovulation. With calorific restriction and exercise it has been theorized, but not concluded, that there is initial loss of intra-abdominal visceral fat due to its increased metabolic composition and this, in contrast to its superficial counterpart, contributes most to symptom improvement due to its modulation in insulin resistance [23,24]. A 5–10% reduction in weight is associated with both lower fasting and glucose-induced insulin levels, and notably, the effects of weight loss appear to be superior to those of insulin-sensitizing medications [59]. The beneficial effect is perhaps derived from altered secretion in adipocytokines corroborated by the positive effects of weight loss on leptin levels [29,31].

It could be logical to assume that the beneficial effects of lifestyle changes are secondary to weight reduction induced by dietary control with or without exercise, but interestingly evidence also suggests that exercise can improve some aspects of PCOS independent of weight loss. Improvements in insulin sensitivity and body glucose control can be demonstrated after exercise alone [22]. In addition, exercise can modulate sympathetic nerve activity and reduce androgen production. This demonstrates that the scope of lifestyle intervention goes beyond that of only weight loss, which is of clinical relevance as, although not all women with PCOS are overweight and some may find it difficult to lose weight, they may still benefit from lifestyle modification with introduction of exercise.

Lifestyle interventions can impact positively on many components that make up PCOS and overall can lead to improvement in psychological wellbeing and quality of life [60]. Many studies have demonstrated a normalization of menstrual irregularity and improvement of hyperandrogenemia symptoms, with decreased testosterone levels and higher SHBG levels secondary to lifestyle interventions in both the adolescent and adult populations [4,61]. However, the favorable effects demonstrated on features of the metabolic syndrome, with associated projected long-term health benefits, seen secondary to interventions in obese adolescents are not consistently replicated in the comparable adult population [4,61]. This stresses the importance of intervention early in life.

Delineating the precise mechanisms and causal relationships between obesity and PCOS may be arduous, but clinically is of major importance considering the alarming increase in both adult and childhood obesity over the past three decades [55]. PCOS typically presents during the early adolescence period, and importantly early atherosclerosis harboring dangerous repercussions for later life can be seen even at this seemingly early age. Beneficial effects on testosterone levels are also seen with peripubertal weight loss [61]. Therefore efforts need to be targeted towards this vulnerable population and maybe even earlier for preventative and therapeutic lifestyle interventions. It has been reported that 70% of children who are obese during adolescence become obese adults [62] and therefore we need to preempt and impede this transition to adult obesity to prevent the considerable ramifications that this may have on PCOS presentation, infertility prevalence, and long-term health comorbidities in the future.