http://informahealthcare.com/gye ISSN: 0951-3590 (print), 1473-0766 (electronic) Gynecol Endocrinol, 2014; 30(6): 397–402 ! 2014 Informa UK Ltd. DOI: 10.3109/09513590.2014.887673

PCO

Metabolic syndrome and polycystic ovary syndrome: an intriguing overlapping Donatella Caserta, Gloria Adducchio, Simona Picchia, Eleonora Ralli, Eleonora Matteucci, and Massimo Moscarini

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Department of Gynecological, Obstetrics and Urological Sciences, ‘‘Sapienza’’ University of Rome, Sant’Andrea Hospital, Rome, Italy

Abstract

Keywords

Metabolic syndrome is an increasing pathology in adults and in children, due to a parallel rise of obesity. Sedentary lifestyle, food habits, cultural influences and also a genetic predisposition can cause dyslipidemia, hypertension, abdominal obesity and insulin resistance which are the two main features of metabolic syndrome. Polycystic ovary syndrome (PCOS) is a condition directly associated with obesity, insulin resistance (HOMA index) and metabolic syndrome, and it is very interesting for its relationship and overlap with the metabolic syndrome. The relationship between the two syndromes is mutual: PCOS women have a higher prevalence of metabolic syndrome and also women with metabolic syndrome commonly present the reproductive/endocrine trait of PCOS. Prevention and treatment of metabolic syndrome and PCOS are similar for various aspects. It is necessary to treat excess adiposity and insulin resistance, with the overall goals of preventing cardiovascular disease and type 2 diabetes and improving reproductive failure in young women with PCOS. First of all, lifestyle changes, then pharmacological therapy, bariatric surgery and laparoscopic ovarian surgery represent the pillars for PCOS treatment.

BMI, HOMA, lifestyle, metabolic syndrome, PCOS, therapy

Review Over the years, metabolic syndrome has been defined in different ways, i.e. ‘‘Syndrome X’’, ‘‘Insulin resistance syndrome’’ or ‘‘the deadly quartet’’ [1]. Nowadays various diagnostic criteria have been proposed from WHO, EGIR, AACE and the most accredited are those of NCEP-ATP (National Cholesterol Education Program Adult Treatment Panel) III. Another definition of metabolic syndrome is the one proposed by IDF (International Diabetes Federation) which reproduces the NCEP-ATP III one but it also considers central obesity. The new criteria include central obesity (defined as waist circumference with ethnicity specific values) plus any 2 of the following: TG 150 mg/dl (or specific treatment), HDL 550 mg/dl for women and 440 mg/dl for men (or specific treatment), BP 130/85 mmHg (or use of hypertensive drugs), fasting plasma glucose 100 mg/dl (or previously diagnosed type 2 diabetes) [1]. The different definitions of metabolic syndrome can cause difficulties in comparing data; thus the prevalence is up to 34.5% and almost 40% when considering NCEPT-ATP III and IDF, respectively [2]. During the last decades, because of a parallel rise of obesity, the prevalence of metabolic syndrome has increased all over the world in the overall population and particularly in young women and now 4% of children and adolescents aged 2–19 years are obese [3].

Address for correspondence: Donatella Caserta, Department of Gynecological, Obstetrics and Urological Sciences, ‘‘Sapienza’’ University of Rome, Sant’ Andrea Hospital, Via di Grottarossa 10351039, 00189 Rome, Italy. Tel: +390633775696. Fax: +390633776660. E-mail: [email protected]

History Received 2 December 2013 Accepted 12 December 2013 Published online 19 February 2014

However, there are some important differences across ethnic groups in USA and also worldwide [4]. Society shows a deep contrast between women of African–American and Caucasian– American race [5]: it has been shown that non-Hispanic African– American women have the highest rate of obesity (39.2%) of any race, followed by non-Hispanic African–American men (31.6%), Hispanic women (29.4%), Hispanic men (27.8%), non-Hispanic Caucasian–American men (25.4%) and non-Hispanic Caucasian– American women (21.8%) [6]. Cultural influences affect the definitions of beauty and ideal body-shape for women and men. Caucasian–American women and men consider more beautiful and sexier a thin, toned and tall body, while African–American and Hispanic women and men prefer a curvier, voluptuous body-type [5] and are more satisfied with their body size [7]. A study demonstrated interactions between socioeconomic status (i.e. education, employment and income) and behaviors (i.e. smoking, alcohol intake and exercise), suggesting that their differential impact on metabolic syndrome’s incidence. Among African–American women and men, higher educational status was associated with reduced risk of metabolic syndrome, compared with lower educational one [4]. Diet is the most common factor involved in the metabolic syndrome: obesity is a typical well-being disease. In modern society, in the all too often frenetic pace of daily life, people spend less time cooking and prefer takeaway food because it is tastier, takes less time to be prepared and is often cheaper than fresh and healthful foods. Moreover, among African–Americans, food is the focus of many cultural and social events and is often seen as a comfort for the soul. Sedentary lifestyle is an increasing problem, due to the use of car or public transport. Also the wider use by both adult and

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children of entertainment media (i.e. TV, mobile phones, computers and video games) can contribute to obesity [8]. There is also supposed to be a common genetic predisposition for metabolic syndrome, central obesity or insulin resistance [4], even though no genes until now have been found as directly involved. Genes may be responsible for overeating (poor regulation of appetite and satiety), for being sedentary, for a reduced ability to use dietary fats as fuel and for a greater capacity to store body fat. That is why, not all people of industrialized countries with abundant food and reduced physical activity are or will become obese; nor will all obese people have the same body fat distribution or suffer the same health issues [9]. Insulin resistance is defined as the lack of insulin response on blood glucose control after meals or to a glucose stimulus (oral or iv) associated with an inadequate suppression of hepatic glucose production during overnight fasting. It is considered the main index of the metabolic syndrome and a common link between the coexisting abnormalities; it can be calculated by homeostasis model assessment of insulin resistance (HOMA-IR) as (fasting insulin mU/l)  (fasting glucose mmol/l)/22.5. The cutoff value of 2.71 for adult [10] and of 2.5 for children and adolescents [11]. Normally, insulin has effects on amino acid and protein metabolism, on adipose tissue triglyceride lipolysis, lipoprotein lipase activity, VLDL triglyceride secretion, on muscle and adipose tissue glucose uptake, and on muscle and liver glycogen synthesis [4]. So insulin resistance may have consequences on several tissues. In the liver, free fatty acids cause an increased gluconeogenesis and synthesis of proinflammatory cytokines; dyslipidemia with higher VLDL levels, lower HDL levels, increased density of LDL and alterations in lipoprotein lipase [4]. In muscle, increased plasma FFA reduces insulin sensitivity by inhibiting insulin-mediated glucose uptake thus reducing glycogen synthesis and increasing lipid storage [4]. In the adipose tissue, insulin resistance is important to the physiopathology of the metabolic syndrome. A larger visceral adipose tissue mass, metabolically more active than the subcutaneous one, results in an increased turnover of free fatty acids (FFA) and in an excessive release of proinflammatory cytokines (IL-6 and TNF-a) from adipocytes and monocyte-macrophages with an elevated inflammatory state [4,12,13]. Adipose tissue also produces angiotensinogen resulting in the activation of the RAA system; moreover non-esterified fatty acids might stimulate aldosterone production, independent of renin [14]; both pathways determine a state of sodium retention. Insulin resistance also determines a sympathetic tone overactivity [14] in addition to the endothelial dysfunction and decreased production of nitric oxide [15], all conditions that participate in the onset of hypertension. Another pathophysiologic feature of metabolic syndrome, in addition to insulin resistance, is the visceral adiposity. Obesity is a medical condition characterized by excess body fat: it can be measured with the body mass index (BMI) expressed as weight in kilograms divided by height in squared meters (kg/m2). BMI is commonly used to classify obesity among adults, defining overweight people (BMI 25–29.9 kg/m2) and obese (BMI 30 kg/m2) [16]. Other methods of estimating body fat and its distribution include measurements of skinfold thickness and waist circumference, calculation of waist-to-hip circumference ratios. Children’s weight status can be determined with an age- and sex-specific percentile for BMI [17], because children’s body composition varies with their age and between sex. So, people between 2 and 19 years of the same age and sex can be defined with specific BMI growth charts as overweight with a BMI 85th but 595th percentile and as obese with a BMI 95th percentile [18].

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Homeostasis model assessment of insulin resistance may be useful for early evaluating insulin resistance in children and could have a long-term benefit of preventive and diagnostic therapeutic intervention [11]. Obese individuals and those with preexisting diabetes also have a doubling of cardiovascular disease risk when the metabolic syndrome is present [19]. Obese children and young people (8–18 years) are more likely to become obese adults and to develop all metabolic syndrome’s features and thus cardiovascular disease, type 2 diabetes, polycystic ovary syndrome (PCOS), premature death and also several cancers [18]. There are also some pathological conditions directly associated with fat excess, insulin resistance and metabolic syndrome: for example non-alcoholic fatty liver disease, obstructive sleep apnea [4], cognitive decline, gallbladder and kidney disease, male hypogonadism, joint problems and musculoskeletal discomfort, endometrial, breast, prostate and colon cancers. Polycystic ovary syndrome, with a prevalence of 5–10% [20], deserves a separate mention for its relationship with the metabolic syndrome. The commonly used diagnostic criteria for PCOS are those proposed by the Rotterdam Consensus in 2003 [21]. According to them, at least 2 items are required: clinical (hirsutism and acne, detected during the physical examination) and/or biochemical hyperandrogenism; ovulatory dysfunction (reported in history); polycystic ovarian morphology. This last one can be studied with an accurate ultrasound evaluation (an operator-dependent technique) [22] with a transverse and longitudinal scansion to find out volume and the number of follicles present in ovaries. If 12 or more follicles of 2–9 mm in diameter are found per ovary and/or an ovarian size 10 ml, it can be referred to as polycystic [20]. It is enough if one ovary meets the criteria. Polycystic ovary syndrome and metabolic syndrome have several features in common: the relationship between the two syndromes is probably mutual; not only PCOS women have a higher (than general population) prevalence of metabolic syndrome, but also women with metabolic syndrome commonly present the reproductive/endocrine trait of PCOS. Both PCOS and metabolic syndrome have still not a universally accepted definition; however, they are the commonest endocrine disorders of reproductive aged women worldwide [23]. Even without an overt metabolic syndrome, obese and also thin women with PCOS, often present an atherogenic lipid profile, including increased total cholesterol and LDL-C levels, lower HDL-C levels and smaller size of HDL-particles [23,24]. Women with PCOS often show extra cardiovascular risk factors, not included in metabolic syndrome: higher plasminogen activator inhibitor-1 (PAI-1) levels [25], increased reactive oxygen species (ROS) generation from mononuclear cells [26], increased advanced glycation end products (AGEs) levels [27] and low-grade inflammation [28]. However, the association between the two syndromes is neither causative nor inseparable even if they often coexist. Obesity and insulin resistance/hyperinsulinemia, are neither necessary nor sufficient for the PCOS’ development; thus obese women can have regular menses and normal androgen levels [23,29]. This is due to intrinsic theca cell steroidogenesis defects (typical of PCOS women), which leads to increased ovarian androgen production, independently of other extraovarian factors. In the absence of these defects extraovarian factors cannot induce androgen overproduction by theca cells [23] (Figure 1). Visceral fat excess has been associated with an increased androgen production by the adipose tissue (due to the overactivation of 17b-hydroxysteroid dehydrogenase, which converts androstenedione to testosterone and of 5a-reductase, which converts testosterone to dihydrotestosterone) [23].

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Figure 1. Intrinsic theca cell defects in PCOS women and its consequences.

Hyperandrogenism aggravates the central adiposity and perpetuates insulin resistance [30,31] thus resulting as an endocrine modulator of metabolic syndrome. Also, prevention and treatment of metabolic syndrome and PCOS are similar: as a unifying pathophysiological mechanism resulting in the metabolic syndrome and in PCOS has not been found as yet, it seems to be necessary to treat each component (excess adiposity and insulin resistance) of the syndromes, with the overall goals of preventing cardiovascular disease, type 2 diabetes [4] and improving reproductive failure in young women with PCOS. Up to now, the first-level approach is based on non-pharmacological treatments (lifestyle changes). Weight loss is very important both in metabolic syndrome and PCOS: already a moderate weight loss of just 5% [32] of body weight decreases fasting blood glucose, serum insulin levels (basal and glucose-stimulated) and hemoglobin A1c with an improvement of the insulin resistance or diabetes [4,33]. Furthermore, weight loss can decrease abdominal fat, triglycerides and LDL-C and increase HDL-C [34]. In addition, sodium restriction is an important strategy in the prevention and treatment of hypertension: guidelines recommend to intake no more than 65–100 mmol daily [4]. A not too drastic magnitude of weight loss may be associated with better compliance and thus be more successful in long-term treatment of obesity. As acute weight loss can be obtained with severe caloric restriction, long-term weight maintenance is rare and acute weight loss potentially might have dangerous effects for reproduction [35]. Diet changes may affect physiological parameters and mood, even without weight loss or exercise. Hypoenergetic (i.e. highprotein and low-carbohydrate) diets seem to be able to improve depression and self-esteem, maybe because dietary protein rich in tryptophan might increase brain serotonin, thereby enhancing mood [36]. Specific for the PCOS treatment, as a result of weight loss, is the increase of SHBG concentration, thus reducing serum levels of androgen (i.e. testoterone, androstenedione and dehydroepiandrosterone-sulphate) and ameliorating of signs and symptoms of hyperandrogenism [32,36]. Moreover, weight loss may decrease luteinizing hormone pulse amplitude which, in turn, can be followed by reduced androgen production. In addition, lower levels of leptin associated with weight loss may lead to a deactivation of the neuroendocrine control of ovarian steroid

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secretion. Furthermore, weight loss improves menstrual cycle abnormalities regulating ovulation thus increasing the potential of pregnancy [32,37]. Cardiorespiratory fitness (i.e. aerobic capacity) appears to decrease cardiovascular disease risk, incidence of type 2 diabetes [38] and the development of metabolic syndrome and PCOS through their effects on each biological parameters involved. Regular exercise primarily improves glucose homeostasis: glucose uptake is improved through non-insulin-dependent work during muscle contraction and through an insulin-mediated mechanisms after the exercise [4,39,40]. Furthermore, physical activity has been shown to improve hypertension by reducing systolic and diastolic blood pressure and dyslipidemia by increasing HDL-C and decreasing triglycerides; mixed results on LDL-C [4,41,42]. Among women with PCOS, exercise also improves inflammatory profiles independently of improvements in obesity indices [36]. Lifestyle changes are often met with difficulties and frustration [4]. Thus, if they fail alone, pharmacological therapy is the second-line treatment. As stated earlier, a key role in the pathophysiology of both metabolic syndrome and PCOS is played by insulin resistance and central adiposity [4]. Insulin resistance must be treated with antidiabetic agents. More data are available for Metformin [32,37] (a biguanide) which primarily reduces hepatic glucose production and improves fasting glucose and waist circumference in adults [4,35]. These benefits have led to an increased use of Metformin (1.5 g/d for 6 months) also in obese children and young people (8–18 years) with hyperinsulinemia and/or impaired fasting glucose (IFG) or impaired glucose tolerance (IGT), as shown by the Metformin in Obese Children and Adolescents (MOCA) trial. The aim is to reduce BMI and waist to hip ratio, fasting and postprandial insulin and glucose levels, metabolic risk factors, and adipokines [43], to prevent the onset of metabolic syndrome, type 2 diabetes, cardiovascular disease and PCOS in the adulthood as shown by a systematic review [44]. Metformin is generally well tolerated, even if there may be gastrointestinal disorders, such as diarrhea and nausea. [37] Thiazolidinediones (selective ligands for the nuclear receptor PPAR-g] [32] can also be used; Rosiglitazone has been shown to slow the progression to type 2 diabetes in patients with impaired glucose tolerance by 60%. Although thiazolidinediones increase body weight, they are associated with a reduction in waist-to-hip ratio and improvements in blood pressure, triglycerides, HDL-C and liver-related transaminases [4,45,46]. Pharmacological therapy for obesity should be started, as suggested by the National Institutes of Health guidelines, in patients with a BMI 30 kg/m2 or with a BMI 27 kg/m2 and comorbidities associated; at present only Orlistat is FDA approved for long-term use [4]. Dyslipidemia, typical of metabolic syndrome and PCOS, is characterized by hypertriglyceridemia (triglycerides 150 mg/dl), low HDL-C levels, and elevated concentrations of small, dense LDL-C particles. Proper management is an important goal and has been shown to significantly reduce cardiovascular events and deaths [4,47]. The NCEP:ATPIII guidelines have identified high LDL-C as the major modifiable risk factor and thus the primary target of cholesterol lowering therapy. They recommend that LDL-C levels should be 5130 mg/dl or 5100 mg/dl in moderately high-risk patients and 570 mg/dl in the very high-risk patients [4,48]. The 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase inhibitors (also called statins) have become the most effective drugs for reducing LDL-C, total cholesterol and triglycerides levels [4,47]. They are also able to reduce

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testosterone levels [49]: that is why statins seem to be useful to treat women with PCOS. Simvastatin treatment seems to be superior to Metformin alone, whereas a combination of Simvastatin and Metformin seems to be not significantly superior to Simvastatin alone [50]. Bile acid sequestrants and cholesterol absorption inhibitors reduce LDL-C by decreasing absorption of intestinal bile acids and cholesterol, respectively [4]. Also, fibrates are effective for modifying atherogenic dyslipidemia and particularly for lowering serum triglycerides concentrations. They also produce moderate elevation of HDL-C and some lowering of LDL [47]. Niacin is most potent available drug to raise HDL-C, to reduce triglycerides, LDL-C, thus it is very useful to treat metabolic dyslipidemia. Niacin may also exert beneficial effects independent of changes in lipid levels, such as improving endothelial function and attenuating vascular inflammation [51]. Niacin and a statin together produce greater effects on lipid levels than both drugs alone [4]. About 2–4 g/day of omega-3 polyunsaturated fatty acids (PUFAs) may be indicated in metabolic syndrome patients to reduce fasting and post-prandial serum triglycerides. Additional benefits are improvements in inflammatory state, reduction in platelet aggregation, reductions in blood pressure, enhanced endothelial function and potential antiarrhythmic effects [4,52–55]. Management of high blood pressure is another key target in cardiovascular disease risk reduction in patients with metabolic syndrome. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC7) guidelines recommend the target blood pressure:5140/ 90 mmHg in patients without diabetes or chronic kidney disease

and 5130/80 mmHg for those with diabetes or chronic kidney disease [4,56]. To reach these goals, patients with metabolic syndrome will often require pharmacological therapy: Angiotensin converting enzyme (ACE) inhibitors or angiotensin II-receptor blockers should be the first-line drugs in patients with type 2 diabetes and early nephropathy as they reduce urinary albumin excretion preventing the progression of renal dysfunction and thus chronic kidney disease [57]. In obese people, a treatment of multiple risk factors of the metabolic syndrome lies in bariatric surgery. It has been associated with effective weight loss, with the improvement and/or resolution of hyperlipidemia, hypertension, obstructive sleep apnea, type 2 diabetes [58], non-alcoholic fatty liver disease [59], cardiopulmonary failure, cardiovascular disease, hyperuricemia [4] and PCOS [60]. In addition to the above, young women with PCOS require a specific therapy to treat reproductive failure and hyperandrogenism. Ovulation induction can be reached with Clomiphene citrate, with a starting dose of 50 mg/day for 5 days. If ovulation occurs but not a pregnancy, the therapy should be continued for the following cycles. Instead, if after the first cycle ovulation does not occur, the dose may be increased to 100 mg/day for 5 days at least 30 days after the previous course of therapy. After 3 courses of therapy, no more treatment is recommended. Clomiphene results in successful pregnancies in 30% of cases; however 20% results in miscarriages or stillbirths. Adverse effects include ovarian enlargement, ovarian hyperstimulation syndrome, multiple pregnancies and gastrointestinal distention [37,61]. To reduce hyperandrogenic manifestations such as hirsutism and acne, cosmetic treatments or laser and electrolysis are very useful even if they can be expensive and give adverse effects (i.e. skin redness and irritation) creating further problems.

Figure 2. Pathophysiology of PCOS/metabolic syndrome and therapeutic options.

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Regarding pharmacological therapy, it is based on antiandrogens which decrease androgen levels such as Spironolactone (25–100 mg 2/die), the most commonly used because of its safety, availability and low cost. At the same time, oral contraception with estro-progestinic is recommended for the increased teratogenic risk for male fetus. Newer oral contraceptives containing progestins (such as Drospirenone) seem to be more effective: approximately after 6–9 months of treatment women notice hirsutism reduction [37,62]. Alternatively, 5–10 mg/day for 10–14 days/month of Medroxyprogesterone acetate in women who are not wanting a pregnancy, can be used to treat amenorrhea, abnormal endometrial proliferation and dysfunctional uterine bleeding without suppressing ovarian androgen production [31,37]. When pharmacological therapy is not enough, laparoscopic ovarian surgery (also called ovarian drilling) can be very useful: it consists in an outpatient surgical treatment in which the ovarian surface and stroma is perforated several times. This technique destroys the androgen-producing tissue leading to decreased androgen levels [37], thus avoiding or reducing medical ovulation induction; nonetheless it can cause less trauma and fewer post-operative adhesions [63] (Figure 2).

Declaration of interest The authors report no declarations of interest.

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Metabolic syndrome and polycystic ovary syndrome: an intriguing overlapping.

Metabolic syndrome is an increasing pathology in adults and in children, due to a parallel rise of obesity. Sedentary lifestyle, food habits, cultural...
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