RD20 Understanding PCOS

RD20 Understanding PCOS By Sarah Coffin, MS, RD Carol Brannon, RD, MS, LD Revised 2013 Approved for: 2 CPEU Summary Polycystic ovarian syndrome (PCOS) is a complex hormonal disorder and the most common of all female endocrine disorders. PCOS is multifaceted and involves multiple organ systems within the body, and is strongly correlated with insulin resistance. PCOS is one of the leading causes of infertility, and can be diagnosed at any age. There is a wide variation in the etiology, signs and symptoms of PCOS, which makes diagnosing difficult. Individualized treatment plans for PCOS include diet, lifestyle changes, weight reduction, exercise and medication. Optimal dietary composition is unclear, but weight loss should be targeted in all overweight women with PCOS by counseling and coaching on reduced calories, adequate nutritional intake, healthy food choices and exercise. Goal and Objectives The goal of this polycystic ovarian syndrome continuing education program is to help the dietitian, dietary manager, fitness professional and health educator understand the etiology and diagnosis of PCOS, and how individualized treatment with diet, exercise, medication, and lifestyle changes alleviate symptoms, discomfort, and infertility. Upon completion of this module, the learner will be able to: Describe the physical and clinical signs of PCOS Describe the role of insulin, androgens, dyslipidemia and environmental factors in PCOS Explain how lifestyle changes, including diet, medications, exercise, weight reduction, and behavioral changes may play a role in the therapy and treatment of PCOS

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Once thought to be extremely rare, polycystic ovarian syndrome affects an estimated 10 million U.S. women (6% to 21% of the adult female population), depending on diagnostic criteria applied. 1 Originally named Stein-Leventhal syndrome after the researchers who first reported it in l935, PCOS is a leading cause of infertility in women. 2-4 It is critical for healthcare professionals of various disciplines to understand the complexities of PCOS, including the link between infertility and insulin resistance, and the key role that nutrition therapy plays in the management of PCOS. The mission of practitioners should be to educate, encourage, and empower women living with PCOS to make the necessary dietary and lifestyle changes for successful weight loss, improvement in insulin resistance, and improved chances of conception. What Is PCOS? PCOS is the most common female endocrine disorder that could be described as the perfect endocrine storm. It has a complex presentation, affecting a woman s reproductive, metabolic and physiological features. PCOS is often a precursor to metabolic syndrome or insulinresistance syndrome. It is a risk factor for type 2 diabetes, contributes to hyperlipidemia and hypertension, and increases a woman s risk of cardiovascular disease (CVD). It may also increase the risk of estrogen-related cancers later in life. 2 Obesity and abdominal obesity are prevalent, and intensify the reproductive, metabolic, and psychological effects, all mediated though insulin resistance. Infertility is worsened by insulin resistance through augmentation of ovarian androgen production and reduced ovulation. 1,5,6 In 1990, the initial clinical definition of PCOS was proposed by the National Institute of Health as oligomenorrhea (irregular menstrual flow and cycles), associated with clinical and biochemical signs of ovarian hyperandrogenism (high levels of circulating androgens), as well as an increase in nitrogen and water retention. Androgen hormones are a class of sex hormones that include testosterone, which are responsible for the development and maintenance of secondary male sexual characteristics. 7,8 In 2003, researchers and physicians at the Rotterdam workshop agreed that the PCOS diagnosis criteria needed expanding, as findings showed the existence of different phenotypes. For example, studies that involved families demonstrated that one sister could have regular menses while another has amenorrhea or oligomenorrhea, even though both presented with androgen excess and polycystic ovaries. 8 The outcome of a consensus workshop was the Rotterdam criteria for PCOS, where a patient must have at least two of the following: 8 Chronic oligoovulation or anovulation

Androgen excess Polycystic ovaries on ultrasound Diagnostic criteria and definition of PCOS is still debated. 1,7 Most internists feel the NIH criteria is sufficient, but endocrinologists, dermatologists and gynecologists often recognize that the characteristics of PCOS are broad, can manifest differently in each woman, and that polycystic ovaries are not always present in some who experience PCOS. 4,8

Signs and Symptoms of PCOS 1,3,7,9 Oligomenorrhea (irregular or infrequent periods of intervals greater than 35 days) Hyperandrogenism (excess androgen production) Amenorrhea (absence or abnormal menstrual flow, infrequent or prolonged periods) Anovulation (absence of ovulation; in adolescence, absent or infrequent menstruation may be a sign) Oligoovulation (infrequent ovulation, fewer than eight cycles/year) Polycystic ovaries (proven via ultrasound) Infertility Unexplained weight gain and difficulty losing weight Acanthosis nigricans (dark velvety patches on skin) Hirsutism (excessive facial and bodily hair growth) Androgenic alopecia (male-patterned baldness, thinning hair on scalp) Pelvic pain Acne Central obesity Dyslipidemia Hyperinsulinemia (elevated levels of insulin) Obstructive sleep apnea Depression Despite the debate about the diagnostic criteria for PCOS, it generally includes at least two PCOS signs and symptoms; diagnosis is determined by physical examination, blood tests and ultrasound. Polycystic ovaries usually develop during the early stages of puberty. One theory is that the onset and symptoms of PCOS (hirsutism and central adiposity) negatively affect the body image and self-esteem of young girls, which results in the development of distorted eating habits and eating disorders in an effort to control weight. It is also believed that some women recovering from anorexia nervosa or bulimia may develop PCOS. 10 Another finding revealed that simply gaining or losing weight could move a woman up or down the spectrum of the disorder. For example, irregular cycles may become regular as a woman loses weight. 1 Women with PCOS may exhibit masculine traits of excessive facial and body hair (hirsutism) and female scalp hair loss similar to androgenic alopecia secondary to elevated androgen levels. 11 Many women with PCOS have obstructive sleep apnea syndrome (OSAS), which is an independent risk factor for cardiovascular disease. These patients may have excessive daytime somnolence and may experience apnea/hypopnea episodes during sleep. 12 Despite the condition s name, polycystic ovaries alone do not confirm the diagnosis. It is estimated that 70% to 80% of women with PCOS have polycystic ovaries. Some with polycystic ovaries may not have PCOS, while some with PCOS have ovaries that appear normal. PCOS is usually, but not always, associated with enlarged ovaries that have numerous small ovarian cysts (fluid-filled sacs) along the outer edge of the ovary. In normal

ovulation, ovarian follicles mature and release a secondary oocyte that divides into a mature egg or ovum. In many women with PCOS, ovarian follicles do not mature, thus preventing ovulation. 9 Feature Polycystic ovaries (PCO) Hyperandrogenism Anovulation Hyperinsulinemia/ Insulin Resistance Defining Features of PCOS Description/Manifestations Enlarged ovaries with 10 small, peripheral cysts Amenorrhea, oligomenorrhea Pelvic pain Increased ovarian androgen production Hirsutism Androgenic alopecia Acne Acanthosis nigricans Absence of ovulation Infertility Increased circulating insulin levels (due to insulin resistance) Acanthosis nigricans Central obesity Unexplained weight gain or difficulty losing weight Anovulation Dyslipidemia Depression Etiology and Pathogenesis Early diagnosis and treatment may reduce long-term complications such as type 2 diabetes and heart disease. 9 The precise etiology of PCOS is unknown, but many factors, such as insulin resistance, hyperinsulinemia, acanthosis nigricans, dyslipidemia, anovulation and elevated androgen levels, adiposity, inflammation, heredity and the environment may play a role. Insulin resistance appears to be at the center of the multifaceted hormonal and metabolic abnormalities seen in PCOS. The exact etiology of insulin resistance is unknown, although obesity, genetics, lifestyle and environmental factors are known contributors. The majority of women with PCOS, regardless of body weight or BMI, exhibit insulin resistance, although it is less likely in women who are lean. 8 The primary role of insulin is glucose regulation. The pancreas secretes insulin in response to a rise in blood glucose levels. Insulin binds to insulin receptors on the cells, allowing glucose

to enter the cell. When insulin receptors become insulin resistant, the pancreas compensates by producing more insulin to reduce blood sugar levels, resulting in very high levels of insulin. Hyperinsulinemia is amplified by obesity that may cause an increase in the production of androgens, resulting in an increase in abdominal fat, menstrual irregularities, anovulation, acne, hirsutism and dyslipidemia. Hyperinsulinemia may also result in suppression of hepatic generation of sex hormone-binding globulin (SHBG), which may increase androgenicity. 4,9,13 In addition, insulin resistance in PCOS is associated with adiponectin, a hormone secreted by adipocytes that regulates lipid metabolism and glucose levels. Lean and obese women with PCOS have lower adiponectin levels than those without PCOS. 12 Insulin resistance may be caused by a genetic trait that produces abnormal insulin receptors. Obesity and inactivity are lifestyle factors that cause a down-regulation of insulin receptors, making them less sensitive to insulin. 13 As fat cells become larger, it takes more insulin to have the same metabolic effect. Factors contributing to insulin resistance include: 13,14 Genetic predisposition Aging Sedentary lifestyle Smoking Centralized obesity Pregnancy Medications (corticosteroids, thiazide diuretics) Ethnicity Acanthosis nigricans is a diffuse, dark, velvety thickening and hyperpigmentation on the skin, particularly on the back of the neck and underarms, beneath the breasts, and on exposed areas (knuckles and elbows). In patients with PCOS, acanthosis nigricans is thought to be the result of insulin resistance. Acanthosis nigricans can also be a cutaneous marker of malignancy. Pruritus may be present. Lesions begin as hyperpigmented macules and patches, and progress to palpable plaques. 12

Figure 1. Acanthosis nigricans located under the arm. (http://en.wikipedia.org/wiki/file:acanthosis-nigricans4.jpg ) Dyslipidemia is also associated with insulin resistance. Blood lipids change and levels of plasminogen activator inhibitor-1 (PAI-1) are elevated in patients with PCOS. Elevated PAI- 1 levels are a risk factor for intravascular thrombosis. 12 About 70% of women with PCOS have at least one abnormal lipid level. 12 Obese women with PCOS are likely to have dyslipidemia, specifically elevated triglycerides and decreased HDL cholesterol. Some studies (controlled for insulin resistance), found that elevated triglyceride levels and decreased HDL cholesterol levels are linked to insulin resistance, not PCOS. High triglycerides and low HDL levels are linked strongly to CVD. 12 Ethnic differences in the prevalence and severity of insulin resistance as a component of PCOS, although being studied, have yet to be proved conclusively. One retrospective study of 102 women with PCOS found that insulin resistance is more prevalent and more severe in Mexican-American women compared with non-hispanic white American women. 15 In fact, in a review of the relationship of ethnicity to PCOS, one study found that ethnic differences are closely linked to the pathophysiology of PCOS and due to environmental and genetic traits specific to ethnic groups. 16 Hyperinsulinemia can be connected with increased production of androgens (male hormones). It is unclear whether hyperinsulinemia precedes hyperandrogenism or vice versa.

High serum concentrations of androgenic hormones, such as testosterone, androstenedione, and dehydroepiandrosterone sulfate (DHEA-S) may be seen in patients with PCOS. Individual variation is considerable, and it is possible for some PCOS patients to have normal androgen levels. Hyperandrogenemia prevents ovulation by blocking follicle development and causes oligomenorrhea. Menstrual cycles are generally shorter than 21 days or longer than 35 days. The menstrual irregularities in PCOS often present around the time of menarche. 12 PCOS is also associated with abnormal uterine bleeding, miscarriage, and other complications of pregnancy, such as gestational diabetes and pregnancy-induced hypertension (previously called preeclampsia). Anovulation and elevated androgen levels may be the result of luteinizing hormone (LH) secreted by the anterior pituitary, and stimulation of the ovarian theca cells. These cells produce androgens (testosterone, androstenedione). Because of a decreased level of folliclestimulating hormone (FSH) relative to LH, this leads to decreased estrogen levels and consequent anovulation. Growth hormone (GH) and insulin-like growth factor-1 (IGF-1) may also augment the effect on ovarian function. 17 Some evidence suggests that patients have a functional abnormality of cytochrome P450c17, the 17-hydroxylase, which is the rate-limiting enzyme in androgen biosynthesis. 12 Excessive exposure to androgens in fetal life may prevent normal gene expression (gene function). This may promote a male pattern of abdominal fat distribution, which increases the risk of insulin resistance and low-grade inflammation. This is an area of current research with PCOS. 9 Excessive production of ovarian testosterone results in increased conversion of testosterone to estrone, a potent, disease-promoting form of estrogen. Estrone levels are high in women with PCOS, while estradiol levels are within the normal range. High estrogen levels prevent regular endometrial shedding, which increases the risk for endometrial overgrowth and cancer. Women with PCOS are about three times more likely to develop endometrial cancer than those without it. 18 Elevated testosterone levels may result in the physical signs of PCOS, including acne, hirsutism, increased muscle mass, voice deepening, clitoromegaly and androgenic alopecia. 19 Ethnic variability in hirsutism is observed; for example, there are fewer incidences of hirsutism in East and Southeast Asian women than white women given the same serum androgen values. In a study that assessed hirsutism in southern Chinese women, investigators found a prevalence of 10.5%. In women with hirsutism, there was a significant increase in the incidence of acne, menstrual irregularities, polycystic ovaries and acanthosis nigricans. 9,12 Central obesity, which is upper body or abdominal body fat, is a defining feature of PCOS and occurs secondary to insulin resistance. Even women with PCOS who have a BMI of less than 27 have a tendency toward central adiposity and have a higher waist-to-hip ratio (ratio greater than 0.8) compared with weight-matched women without PCOS. 20 Studies using U.S.

measurements found that lean women with PCOS have a higher proportion of visceral adiposity compared with weight-matched control subjects. 21 As body fat increases so does the severity of insulin resistance, making weight loss extremely difficult. 1,3 It is estimated that 50% of women with PCOS are overweight (with a BMI greater than 27), or obese (with a BMI greater than 30). Studies indicate obese women with PCOS have more severe insulin resistance, higher levels of testosterone, and lower levels of LH than weightmatched controls. 14 PCOS and obesity each have a separate and synergistic impact on insulin resistance. The long-term health consequences are more serious in obese females with PCOS. Many U.S. and European studies indicate that obese women with PCOS progress from normal glucose tolerance to impaired glucose intolerance, or to type 2 diabetes, more rapidly than weight-matched controls without PCOS. 22 The evidence is overwhelming that obesity is involved in the development and maintenance of PCOS pathology. Even modest reductions in weight generally translate into significant improvements in menstrual regularity, fertility and hyperandrogenic features. 13,23 Obesity further worsens insulin resistance and the reproductive presentation of PCOS. 1 Women with PCOS often have low-grade inflammation, which occurs under normal circumstances when the body's white blood cells produce substances to fight an infection or fight any pathogen/antigen that gets into the body. A chronically low level of inflammation exacerbates the risk of atherosclerosis, especially in those who are obese and have elevated androgen levels. 9,24 Inflammation is also caused by obesity. As a person gains weight, adipocytes get bigger, and there are more macrophages in the cells. The types and amounts of adipocytokines released from adipocytes change when weight changes and fat cells get bigger. As weight increases, there is a decrease in the amount of adiponectin, an anti-inflammatory substance, and an increase in leptin and resistin, which are pro-inflammatory. The alteration in the types and amounts of adipocytokines causes an increase in the pro-inflammatory cytokines and in acute phase proteins, such as C-reactive protein (CRP). 25,26 Some of the chronic inflammation seen in obesity may, in part, be due to an increase in leptin and a decrease in adiponectin. CRP is a marker of inflammation. Several research studies have found that women with PCOS are more likely to have elevated levels of CRP, as well as elevated levels of other inflammation markers, including inflammatory cytokines. Elevated levels of CRP are also associated with diabetes, insulin resistance and heart disease. Obesity is linked strongly to inflammation, and this explains why inflammation is seen often with PCOS. 27 An important link between PCOS and obesity was corroborated genetically by data from a case-control study in the U.K. that involved 463 patients with PCOS and more than 1,300 female controls. The investigators demonstrated that a variant within the fat mass and obesity-associated (FTO) gene rs9939609 was significantly associated with susceptibility to the development of PCOS. 28,29

PCOS may be hereditary. Researchers are examining the possibility that mutated genes are linked to the disorder, and have long suspected a genetic link among hyperinsulinemia, obesity and PCOS. 9,30 A 2009 British study involving 463 women with PCOS and 1,336 women without found that women who were carriers of the FTO gene (a common gene variant that predisposes carriers to obesity) were not only predisposed to obesity, but also at higher risk for PCOS. 28 A 2012 meta-analysis of 2,548 women in smaller studies also showed an association between FTO and PCOS. The effect of FTO on obesity-related traits in PCOS seems to be more than two times greater than the effect found in large population-based studies. This suggests an interaction between FTO and the metabolic context or polygenic background of PCOS. 30 Studies of family members with PCOS indicate that an autosomal dominant mode of inheritance occurs for many families. Fathers of women with PCOS can be abnormally hairy; female siblings may have hirsutism and oligomenorrhea; and mothers may have oligomenorrhea. 29 Research has suggested that in a large cohort of women with PCOS, a family history of type 2 diabetes in a first-degree family member is associated with an increased risk of metabolic abnormality, impaired glucose tolerance, and type 2 diabetes. In addition, a Dutch twin-family study showed a PCOS heritability of 0.71 in monozygotic twin sisters, versus 0.38 in dizygotic twins and other sisters. 12 A recent study found that 71 women with PCOS had higher blood levels of the neurotoxic chemical bisphenol A (BPA) compared with 100 healthy women without PCOS. BPA is found in many plastic household items made of polycarbonate hard plastic or lined with epoxy resins, and is in some dental sealants and composites. BPA can leach into the bloodstream from these sources. A known hormone disrupter, BPA is associated with higher blood levels of androgens in women with PCOS compared with healthy women (both lean and obese). Blood levels of BPA, compared with controls, were nearly 60% higher in lean women with PCOS, and more than 30% higher in obese women with PCOS. 31 Past studies demonstrate that BPA levels are elevated in women who have had recurrent miscarriages. More research is needed, and it has not been proved that reducing BPA levels will benefit women with PCOS. However, women with PCOS may want to limit exposure to BPA, although there is no proof that reducing BPA levels in patients with PCOS will have beneficial effects. 31 The presence of PCOS makes the following conditions more likely (especially when obesity is a cofactor): 9 Type 2 diabetes High blood pressure Cholesterol and lipid abnormalities (elevated triglycerides or low HDL) Elevated levels of CRP

Metabolic syndrome (cluster of signs and symptoms that indicate a significantly increased risk of CVD) Nonalcoholic steatohepatitis (severe liver inflammation caused by fat accumulation in the liver) Sleep apnea Abnormal uterine bleeding Cancer of the uterine lining (endometrial cancer, caused by exposure to continuous high levels of estrogen) Gestational diabetes or pregnancy-induced high blood pressure PCOS and Metabolic Syndrome Metabolic syndrome is a complex disorder defined by a cluster of interconnected factors that increase the risk of cardiovascular atherosclerotic diseases and type 2 diabetes. PCOS strongly resembles and often precedes metabolic syndrome. Currently, several different definitions of metabolic syndrome exist, causing substantial confusion as to whether they identify the same individuals or represent a surrogate of risk factors. Many organizations have defined metabolic syndrome, including the WHO, European Group for the Study of Insulin Resistance, National Cholesterol Education Program (NCEP), American Association of Clinical Endocrinology, International Diabetes Federation (IDF), and American Heart Association/National Heart, Lung and Blood Institute (AHA/NHLBI). 32 The consensus definition incorporating IDF and AHA/NHLBI is the most suitable for practical use in clinical medicine, as it resembles what is characteristically seen in PCOS. 12 Adoption of this consensus criteria incorporates the most important aspects of the syndrome. Metabolic Syndrome Diagnostic Criteria 32 Metabolic syndrome must contain any three of the following: Elevated WC According to population/country-specific definitions Triglycerides 150 mg/dl HDL < 40 mg/dl BP 130/85 mmhg Fasting glucose 100 mg/dl Accumulating evidence suggests an association of vitamin D deficiency with metabolic syndrome. One study found insufficient levels of 25-hydroxyvitamin D (< 30 ng/ml) in almost 75% of patients with PCOS, with lower levels in those with metabolic syndrome (17.3 ng/ml) than in those without metabolic syndrome (25.8 ng/ml). 12

PCOS and the Stages of a Woman s Life PCOS affects premenopausal women, but the clinical onset most often occurs perimenarchal, or before age 16. Puberty often occurs prematurely and is characterized by insulin resistance. Precocious puberty, onset of menstruation before age 8, is linked to PCOS. Teenagers experience hirsutism, acne, oligomenorrhea, and insulin resistance. Young women with PCOS may be recovering from, or may be at an increased risk of developing an eating disorder. 10,33 Lean women who are genetically predisposed to PCOS may not show signs of PCOS until they subsequently gain weight. 23 Women may experience infertility, a high rate of miscarriages, gestational diabetes or impaired glucose tolerance during pregnancy. Many women are not diagnosed with PCOS until they try to get pregnant and fail, although they may have had the disease for many years. Later in life, women are likely to develop type 2 diabetes, heart disease and possibly cancer. In addition, females with PCOS are at higher risk for developing clinical depression, which should not be overlooked by healthcare practitioners. 33 Diagnosis PCOS is often underdiagnosed because it manifests differently in each woman. There is no single, definitive diagnostic test to confirm PCOS, so a diagnosis is made based on physical examination, ultrasound, and laboratory tests, and by ruling out other disorders. 11 The physical signs, including acanthosis nigricans, hirsutism, androgenic alopecia, amenorrhea, masculinization and acne are detected easily. Polycystic ovaries are diagnosed by ultrasound. A woman s BMI and waist-to-hip ratio should also be assessed. 3,9 Laboratory and imaging measurements indicative of PCOS include: 12 Elevated total testosterone to assess androgen excess Elevated free testosterone to asses androgen excess Normal LH levels Normal thyroid-stimulating hormone (TSH) and prolactin levels (rule out adrenal tumors and pituitary or thyroid conditions) Normal or elevated DHEA-S Low DHEA-S Elevated androstenedione levels Normal to low FSH Normal TSH and free thyroxine levels (abnormalities may be the source of amenorrhea and hirsutism) Abnormal glucose tolerance test Elevated cholesterol >200 mg/dl and LDL >160 mg/dl Transvaginal ovarian ultrasonography

Impaired glucose tolerance and type 2 diabetes is prevalent in women with PCOS, especially with a BMI > 30, family history of type 2 diabetes, and those older than 40. Women diagnosed with prepregnancy PCOS have a greater risk of gestational diabetes and should be screened for gestational diabetes before 20 weeks gestation. 12 Lifestyle Modifications Lifestyle management for weight loss and weight gain prevention, which includes any combination of diet, exercise and behavioral interventions, is recommended for women with PCOS. The majority of women (80%) with PCOS are obese. The primary treatment goal is weight reduction. 1,34 A recent review compared the dietary composition of 137 women with PCOS who were not taking anti-obesity medications, and followed all prescribed weight loss or maintenance regimens. This study reviewed 4,154 PCOS articles; only six articles from five studies met the selection criteria. Analysis showed subtle differences between diets (Evidence-based Guideline for the Assessment and Management of Polycystic Ovary Syndrome is available from this review, see www.managingpcos.org.au/pcos-evidence-based-guidelines). 1,34,35 Meta-Analysis of Diet Results 1 Type of Diet Result High monounsaturated fat diet Greater weight loss Low-glycemic index diet Improved menstrual regularity Greater reductions in insulin resistance, fibrinogen, total cholesterol and HDL Improved quality of life High-carbohydrate diet Increased free androgen index Low-carbohydrate diet Greater reductions in insulin resistance, fibrinogen, total cholesterol and HDL High-protein diet Improved depression and self-esteem Weight loss improves the symptoms of PCOS regardless of the diet and should be targeted in all overweight women with PCOS by reducing caloric intake, irrespective of diet composition. 1,12 Unfortunately, many have a difficult time losing weight. There may be a connection between high male hormone levels, increased appetite, and glucose intolerance with difficulty losing weight. 3 Successful weight loss involves meeting all dietary nutrient requirements, restructuring eating habits, starting an exercise regimen, managing depression and anxiety, and incorporating stress reduction techniques into daily life. 1,9 With no conclusive guidelines established for diet composition, reduced calorie healthy food choices are a starting point, and should include lean proteins, healthy fats and moderate amounts of carbohydrates with a low glycemic index. 3,36

Diet Interventions The evidence is overwhelming that diets rich in whole fruits, vegetables, complex carbohydrates and fiber lower chronic disease risk. High-fiber diets, particularly diets high in soluble fiber, help dyslipidemia and lower blood pressure. Studies indicate high-fiber diets improve insulin sensitivity and facilitate weight loss. 36,37 A low glycemic index diet has been shown to improve insulin sensitivity and possibly improve the androgen profile of women with PCOS. 3 The glycemic index is a measure of how quickly and how strongly a food increases blood sugar and insulin levels. Choosing foods with a lower glycemic index, especially whole, intact grains that are high in fiber, may help to reduce carbohydrate cravings. 3 Low-GI diets elicit lower postprandial insulin levels, which are thought to increase fat oxidation for several hours after a meal, thereby reducing hunger, overeating and weight gain. A diet that contains low GI foods can also improve insulin sensitivity. Low-GI foods are generally higher in fiber and less processed and contain products with whole grains such as whole grain breads, brown rice, steel-cut oats, barley, couscous, and quinoa. Dried beans, fruits (such as berries), nuts and lean proteins are also low-gi foods. 9 A 12-month study of 96 women with PCOS compared the effect of an ad libitum low-gi diet with a conventional low-fat healthy diet on weight loss, whole body insulin sensitivity, glucose tolerance, plasma lipids and menstrual regularity. 38 The attrition rate was 49%; and only 47 women completed the study (21 in the low-gi group and 26 in the conventional diet group). Of those who completed this study, insulin sensitivity was improved significantly in the low-gi diet group even after adjustment for metformin (Glucophage) use and weight loss. The low-gi diet group also exhibited an increase in menstrual regularity. Both groups were below target for dietary fiber intake and had no significant difference in dietary fat intake or in physical activity as measured by daily pedometer readings. Although this may be the first study to support the use of a low-gi diet, there are not enough scientific studies yielding 1, 35-37 evidence to support the therapeutic use of the glycemic index diet. Women with an abnormal lipid profile should be counseled on ways to manage dyslipidemia. 12 A diet rich in omega-3 fatty acids and monounsaturated fats can improve insulin sensitivity and promote heart health in healthy people and those with diabetes. In contrast, dietary saturated fats increase insulin resistance and promote hyperlipidemia. Evidence supports consumption of a low-fat diet for women with PCOS, composed mostly of unsaturated fats. 3 Overall, decreases in lipids occur with weight loss independent of diet composition. 1 The Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III, or ATP III) (2001), serves as a guide for the treatment of women with PCOS and

dyslipidemia. (The NCEP is updating the ATP III guidelines; see the NHLBI website for the most recent guidelines at http://www.nhlbi.nih.gov/guidelines/cholesterol/atp4/index.htm. 12 ) Elevated levels of omega-3 fatty acids (alpha-linolenic acid [ALA], eicosapentaenoic acid [EPA], and docosahexaenoic acid [DHA]) appear to enhance ovulation. Foods high in omega-3 and omega-9 fatty acids, and fish oil supplements may have a therapeutic role in PCOS treatment, especially for women with coronary heart disease (CHD), hypertriglyceridemia, and/or depression; however, there is a lack of scientific evidence to support a specific recommendation. 38 Foods rich in omega-3 fatty acids include fatty fish, flaxseed, flaxseed oil, walnuts, chia seeds and eggs, while olive oil is rich in omega-9 fatty acids. Fish oil supplements, which contain the omega-3 fatty acids EPA and DHA, have been found effective in improving glucose clearance, insulin sensitivity, decreasing fat deposition, reducing liver fat, protecting against heart disease, promoting ovulation and treating depression. 38 The AHA recommends consuming fish at least twice weekly, and people with CHD should take 1 g of EPA/DHA daily. AHA suggests that a supplement of 2 g to 4 g may be helpful for those with elevated triglyceride levels. Those taking more than 3 g/day should be monitored by a physician, as omega-3 fatty acids will thin the blood and increase the risk of bleeding. 37,38 Healthy Diet and Lifestyle Guidelines for PCOS 37,38 Focus on whole foods (avoid processed and refined foods) Focus on fiber-rich foods: whole grains, vegetables, legumes, fruits Balance carbohydrate intake throughout the day Avoid high glycemic index food choices At meals and snacks always combine carbohydrate foods with protein and/or low-fat foods Consume at least 40 g of carbohydrates daily to prevent ketosis Choose several servings of foods rich in omega-3 fatty acids at least twice weekly (salmon and tuna, flaxseed, nuts, seeds) Include monounsaturated fats (olive oil, canola oil, nuts) Pay attention to portion sizes and avoid overeating Practice mindful or intuitive eating principles Exercise regularly, including aerobic exercise and strength training Behavioral change techniques including motivational interviewing Stress reduction

Medications Medications are used to treat metabolic derangements, anovulation, hirsutism and menstrual irregularity. There are three groups of medications used for PCOS treatment: Oral contraceptive agents (OCA) Androgen-blocking drugs Insulin-sensitizing drugs Fertility drugs are prescribed for women trying to get pregnant. 3,12 The Endocrine Society has published a clinical practice guideline on hirsutism evaluation and treatment in premenopausal women. This guideline suggests testing for elevated androgen levels in women with hirsutism and treating with either pharmacological therapy or direct hair removal methods. For pharmacological therapy, OCAs are recommended for the majority of women; then after six months if the response is suboptimal and the patient cannot or chooses not to conceive, an antiandrogen should be added. Insulin-lowering drugs are not recommended for hirsutism. For women who choose hair removal therapy, laser hair removal or photoepilation is suggested. 39 Low-dose combination OCAs are prescribed for birth control because spontaneous ovulation can occur occasionally. OCAs, depending on the estrogen dose, can inhibit androgen, LH, and FSH production; increase SHGB production; stimulate regular menstrual periods; correct heavy uterine bleeding; and treat hirsutism and acne. 3,12 Antiandrogen drugs reduce the effects of androgens. They are used to treat hirsutism, alopecia, and acne, and are often prescribed along with an OCA. Examples include spironolactone (Aldactone), finasteride (Proscar), and flutamide (Eulexin), which are all contraindicated for women desiring pregnancy. If the patient has concomitant adrenal hyperandrogenism, treatment with low-dose prednisone or dexamethasone may be considered. 12,40 Metformin is a popular insulin-sensitizing medication prescribed for the management of type 2 diabetes. Although metformin is not an FDA-approved treatment of PCOS, it has been shown to decrease androgen levels and facilitate weight loss as early as adolescence, and reduce gestational diabetes and pregnancy-induced hypertension in pregnant women with PCOS. 12 Metformin acts by improving insulin sensitivity and increasing glucose uptake in fat and muscle cells. Adverse effects may include gastrointestinal distress and discomfort. While the use of metformin during pregnancy has not been recommended, new research is showing that there seem to be benefits during pregnancy, without adverse outcomes. 42 A long-term study suggested that metformin continued to improve the metabolic profile of women with PCOS over a 36-month treatment course, particularly improving circulating HDL, diastolic blood pressure and BMI. 41 However, data are insufficient as yet to

recommend metformin to all women with PCOS. Some physicians have advised trying other insulin-resistance drugs, including glitazones (pioglitazone [Actos] or rosiglitazone [Avandia]). 3,12 Clomiphene citrate (Clomid) is usually the first fertility medication prescribed to women with PCOS. About 70% of women with PCOS who take clomiphene citrate become pregnant; however, there is a risk of multiple births. For those women who do not become pregnant on clomiphene citrate, human menstrual gonadotropin (Pergonal) or human chorionic gonadotropin (HCG) are the next drugs of choice, but these have a higher risk of multiple births and medical complications. 12 Leuprolide acetate (Lupron Depot) is effective in suppressing ovarian hormone production, which induces menopause; therefore, hormone replacement is needed with this treatment, although it is not commonly used. Several medications, including benzoyl peroxide, topical retinoids (Retin-A), and topical and oral antibiotics are effective for acne treatment. Systemic isotretinoin (Soriatane) is used for severe acne. 12 Exercise Exercise reduces insulin resistance and improves other markers of health, including decreases in systolic and diastolic blood pressure, waist circumference, resting heart rate, and improved mood. 12 Women with PCOS are advised to exercise at least 150 minutes/week, especially those with a BMI 25, given the metabolic risks of PCOS and long-term benefits of exercise. Of this 150 minutes, 90 minutes is recommended to be aerobic of moderate-to-high intensity. Encouraging patients with PCOS to exercise is the responsibility of the entire healthcare team, and exercise therapists are important members of the team. Appropriate assessment should be undertaken by relevant healthcare professionals where there are significant comorbid risk factors. 12 Conclusion All aspects of PCOS can be managed with a combination of diet, exercise, medication and behavioral change techniques. Although an exact diet composition has not proved to be necessary for PCOS, a healthy diet is strongly encouraged for overall health. Women with PCOS are encouraged follow a balanced diet similar to what is recommended for type 2 diabetes: calorie-controlled, high in fiber, low in refined carbohydrates, with emphasis on low-gi index foods, low in saturated and trans fats, and high in omega-3 and omega-9 fatty acids. 38,39 Weight loss has improved menstrual regularity in some PCOS patients. 37 PCOS patients with complex dietary issues and obesity should be referred to a registered dietitian for an individualized diet treatment plan. Healthcare professional team members treating PCOS patients should include behavioral change techniques, including motivational interviewing. The healthcare provider and the client must agree on achievable goals (losing

5% to 10% total body weight in overweight women; a BMI between 18.5 and 24.9). 12 Physicians, dietitians, nurses, exercise therapists, social workers and other allied health providers have a unique opportunity to empower women to alleviate the symptoms and prevent the long-term consequences of PCOS. The disorder can have reproductive, metabolic and psychological challenges, and symptomatic women should seek medical attention for evaluation and treatment. While the first line of treatment is diet and weight loss, it is important to also recognize that PCOS is complex and multifactorial with overlapping symptoms. Women with PCOS have very different experiences with the disease, and treatment should always be individualized. All healthcare professionals can play an important role by coaching and empowering women with PCOS. References 1. Moran LJ, Ko H, Misso M, et al. Dietary composition in the treatment of polycystic ovary syndrome: a systematic review to inform evidence-based guidelines. J Acad Nutr Diet. 2013;113(4):520-545. 2. Kitzinger C, Willmott J. The thief of womanhood : women s experience of polycystic ovarian syndrome. Soc Sci Med. 2002;54(3):349-361. 3. Redfern J. Combating polycystic ovary disease through diet. Brigham and Women's Hospital Web site. http://www.brighamandwomens.org/patients_visitors/pcs/nutrition/services/healtheweightforwome n/special_topics/intelihealth0703.aspx. Updated March 23, 2012. Accessed September 18, 2013. 4. Welcome to PCOSupport. Polycystic Ovarian Syndrome Association Web site. http://www.pcosupport.org. Accessed September 18, 2013 5. Moran LJ, Misso ML, Wild RA, Norman RJ. Impaired glucose tolerance, type 2 diabetes and metabolic syndrome in polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod Update. 2010;16(4):347-363. 6. Barry JA, Kuczmierczyk AR, Hardiman PJ. Anxiety and depression in polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod. 2011;26(9):2442 2451. 7. DiMarcantonio T. Controversy around the definition of PCOS continues. Healio Endocrinology Web site. www.endocrinetoday.com/view.aspx?rid=27868. Updated April 25, 2008. Accessed September 18, 2013. 8. Berthold J. A silent syndrome with serious side effects. ACP Internist Web site. http://www.acpinternist.org/archives/2009/02/pcos.htm. Published 2009. Accessed September 18, 2013. 9. Polycystic ovary syndrome. Mayo Clinic Web site. http://www.mayoclinic.com/health/polycysticovary-syndrome/ds00423. Updated August 4, 2011. Accessed September 18, 2013. 10. Grassi A. Are polycystic ovary syndrome and eating disorders related? PCOS Network Web site. http://www.pcosnetwork.com/articles/dieting-weightloss/pcos-and-eating-disorders. Accessed September 18, 2013. 11. Polycystic ovary syndrome (PCOS) - topic overview. Web MD Web site.

http://women.webmd.com/tc/polycystic-ovary-syndrome-pcos-topic-overview. Updated May 11, 2010. Accessed September 18, 2013. 12. Lucidi RS. Polycystic ovarian syndrome. Medscape Reference Web site. http://emedicine.medscape.com/article/256806-overview. Updated March 4, 2013. Accessed September 18, 2013. 13. Barber TM, McCarthy MI, Wass JA, Franks S. Obesity and polycystic ovary syndrome. Clin Endocrinol (Oxf). 2006;65(2):137-145. 14. Kidson W. Polycystic ovary syndrome: a new direction in treatment. Med J Aust. 1998;169(10):537-540. 15. Nur MM, Newman IM, Siqueira LM. Glucose metabolism in overweight Hispanic adolescents with and without polycystic ovary syndrome. Pediatrics. 2009;124(3):e496-e502. 16. Wijeyaratne CH, Udayangani SA, Balen AH. Ethnic-specific polycystic ovary syndrome: epidemiology, significance and implications. Expert Rev Endocrinol Metab. 2013;8(1):71-79. 17. Dunaif A, Wu X, Lee A, Diamanti-Kandarakis E. Defects in insulin receptor signaling in vivo in the polycystic ovary syndrome (PCOS). Am J Physiol Endocrinol Metab. 2001;281(2):E392-399. 18. Haoula Z, Salman M, Atiomo W. Evaluating the association between endometrial cancer and polycystic ovary syndrome. Hum Reprod. 2012;27(5):1327-1331. 19. Barber TM, Wass JA, McCarthy MI, Franks S. Metabolic characteristics of women with polycystic ovaries and oligo-amenorrhea but normal androgen levels: implications for the management of polycystic ovary syndrome. Clin Endocrinol (Oxf). 2007;66(4): 513-517. 20. Pasquali R, Antenucci D, Casimirri F, et al. Clinical and hormonal characteristics of obese amenorrheic hyperandrogenic women before and after weight loss. J Clin Endocrinol Metab. 1989;68(1):173-179. 21. Clark AM, Ledger W, Galletly C, et al. Weight loss results in significant improvement in pregnancy and ovulation rates in anovulatory obese women. Hum Reprod. 1995;10(10): 2705-2712. 22. Norman RJ, Wu R, Stankiewicz MT. 4: Polycystic ovary syndrome. Med J Aust. 2004;180(3):132-137. 23. Moran LJ, Pasquali R, Teede HJ, Hoeger KM, Norman RJ. Treatment of obesity in polycystic ovary syndrome: a position statement of the Androgen Excess and Polycystic Ovary Syndrome Society. Fertil Steril. 2009;92(6):1966-1982. 24. González F, Rote NS, Minium J, Kirwan JP. Evidence of proatherogenic inflammation in polycystic ovary syndrome. Metabolism. 2009;58(7):954-962. 25. Tilg H, Moschen AR. Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nat Rev Immunol. 2006;6(10):772-783. 26. Fernández-Riejos P, Najib S, Santos-Alvarez, et al. Role of leptin in the activation of immune cells. Mediators Inflamm. 2010:2010:568343. 27. Galan N. The relationship between PCOS and inflammation. About.com PCOS Web site. http://pcos.about.com/od/relatedconditions/f/the-relationship-between-pcos-and- Inflammation.htm. Updated October 31, 2011. Accessed September 18, 2013. 28. Wojciechowski P, Lipowska A, Rys P, et al. Impact of FTO genotypes on BMI and weight in polycystic ovary syndrome: a systematic review and meta-analysis. Diabetologia. 2012;55(10):2636-

2645. 29. Barber TM, Bennett AJ, Groves CJ, et al. Association of variants in the fat mass and obesity associated (FTO) gene and polycystic ovary syndrome. Diabetologia. 2008;51(7):1153-1158. 30. Ehrmann DA, Kasza K, Azziz R, et al. Effects of race and family history of type 2 diabetes on metabolic status of women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2005;90(1):66-71. 31. Riskind AG, Lohr A. Women with polycystic ovary syndrome have higher BPA blood levels. Endocrine Society Web site. http://www.endo-society.org/media/press/2010/women-with- Polycystic-Ovary-Syndrome-Have-Higher-BPA-Blood-Levels.cfm. Published June 22, 2010. Accessed September 18, 2013. 32. Kassi E, Pervanidou P, Kaltsas G, Chrousos G. Metabolic syndrome: definitions and controversies. BMC Med. 2011;9:48. 33. Himelein MJ, Thatcher SS. Polycystic ovary syndrome and mental health: a review. Obstet Gynecol Surv. 2006;61(11):723-732. 34. Teede HJ, Misso ML, Deeks AA, et al. Assessment and management of polycystic ovary syndrome: summary of an evidence-based guideline. Med J Aust. 2011;195(6):S65 S112. 35. PCOS Australian Alliance. Evidence-based Guidelines for Assessment and Management of Polycystic Ovary Syndrome. Melbourne, Australia: Polycystic Ovary Syndrome Alliance; 2011. 36. Jenkins DJ, Kendall CW, Augustin LS, et al. Glycemic index: overview of implication in health and disease. Am J Clin Nutr. 2002;76(1):266S-273S. 37. Liepa GU, Sengupta A, Karsies D. Polycystic ovary syndrome (PCOS) and other androgen excess-related conditions: can changes in dietary intake make a difference? Nutr Clin Pract. 2008;23(1):63-71. 38. Liperoti R, Landi F, Fusco O, Bernabei R, Onder G. Omega-3 polyunsaturated fatty acids and depression: a review of the evidence. Curr Pharm Des. 2009;15(36):4165-4172. 39. Martin KA, Chang RJ, Ehrmann DA, et al. Evaluation and treatment of hirsutism in premenopausal women: an Endocrine Society clinical practice guideline. Health and Human Service Web site. J Clin Endocrinol Metab. 2008;93(4):1105-1120. 40. BMG Group/ Anti-androgen drugs. Web MD Web site. http://www.webmd.boots.com/a-to-zguides/polycystic-ovary-syndrome-anti-androgen-drugs. Accessed September 18, 2013. 41. Cheang KI, Huszar JM, Best AM, et al. Long-term effect of metformin on metabolic parameters in the polycystic ovary syndrome. Diab Vasc Dis Res. 2009;6(2):110-119. 42. Feig DS, Moses RD. Metformin therapy during pregnancy good for the goose and good for the gosling too? Diabetes Care. 2011;34(10):2329-2330.

Test 1. Which statement BEST describes polycystic ovarian syndrome (PCOS)? a. It affects about 25% of women in the U.S. b. It is a hormone imbalance resulting in low levels of testosterone. c. It is characterized by low levels of circulating insulin and insulin resistance. d. It is characterized by insulin resistance and elevated androgen levels. e. It is an uncommon syndrome, hard to diagnose. 2. Which of the following is NOT a possible sign or symptom of PCOS? a. Androgenic alopecia b. Oligomenorrhea c. Amenorrhea d. Hirsutism e. Hypoandrogenism 3. Hirsutism is: a. Excessive facial and bodily hair growth b. The loss of female scalp hair c. Elevated levels of estrogen d. Caused by low levels of testosterone e. Excessive loss of body fat 4. Based on the consensus workshop in Rotterdam, which must be present in women with PCOS? a. Polycystic ovaries, anorexia and acanthosis nigricans b. Chronic oligoovulation/anovulation, androgen excess and polycystic ovaries c. Unexplained weight loss, androgen excess and polycystic ovaries d. Androgen excess, depression and polycystic ovaries e. Androgen deficiency, chronic anovulation and amenorrhea f. 5. Which BEST describes how to diagnose PCOS? a. The oral glucose tolerance test (GTT) is the primary diagnostic tool. b. It is usually made during menopause. c. It is determined solely by the presence of polycystic ovaries. d. It is determined by a physical examination, blood tests and ultrasound. e. It is determined by blood work and hormone levels. 6. Which plays a significant role in the pathology and symptoms of PCOS? a. Decreased androgen production secondary to hyperinsulinemia b. Hyperlipidemia and hypertension c. Obesity secondary to elevated serum glucose levels d. Increased insulin production secondary to insulin resistance e. Hypertension secondary to altered hormones 7. What percent of women with PCOS have at least one abnormal lipid level? a. 50% b. 60% c. 70% d. 80% e. 90%

8. Insulin resistance is most likely associated with all of the following EXCEPT: a. Genetic predisposition and ethnicity b. Central obesity and inactivity c. Dyslipidemia d. Corticosteroids and thiazide diuretics e. BMI < 20 9. Which is elevated during low-grade inflammation? a. Total cholesterol b. A-reactive protein c. Hemoglobin d. Blood pressure e. C-reactive protein 10. Having PCOS and also being obese makes which condition more likely? a. Multiple sclerosis b. Breast cancer c. High blood pressure d. Infections e. Endometrial cancer 11. Why is metformin used in women with PCOS? a. It improves insulin sensitivity. b. It is an antihypertensive agent. c. It is proven safe for pregnant women. d. It helps decrease menstrual bleeding. e. It decreases problems with hirsutism. 12. Which foods are important to include in the diet of a woman with PCOS? a. Beef, corn tortillas and oranges b. Chicken, white potatoes and juice c. Fish, black beans and sweet potatoes d. Pork, vegetables and pasta e. Eggs, citrus fruits and juices and rice