Polycystic Ovarian Syndrome

Polycystic Ovarian Syndrome

CHAPTER 35 Polycystic Ovarian Syndrome Melinda Ring, MD Polycystic ovarian syndrome (PCOS) is the most common female endocrine disorder, affecting 1...

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CHAPTER 35

Polycystic Ovarian Syndrome Melinda Ring, MD

Polycystic ovarian syndrome (PCOS) is the most common female endocrine disorder, affecting 10% of women of reproductive age, yet it is frequently overlooked.1,2 PCOS affects young women and is associated with oligoovulation (which leads to oligomenorrhea in more than 75% of affected patients), infertility, acne, and hirsutism. It also has notable metabolic sequelae, including an elevated risk of diabetes and cardiovascular disease, and attention to these factors is important.3 The heterogeneous nature of PCOS and the diversity of presentations requires a symptom-based approach to treatment because PCOS manifests differently depending on many interacting factors, including environmental exposures, genetics, and lifestyle (Fig. 35.1). This chapter discusses the pathophysiology and integrative approaches to treatment of women with PCOS.

PATHOPHYSIOLOGY When PCOS was first described (as Stein-Leventhal syndrome) in the 1930s, the presence of cysts in the ovaries was believed to be a defining factor in the origin of the syndrome.4 Since then, research has shown that, in fact, cysts are only one potential expression of what begins as a disorder of the endocrine system. On pelvic ultrasound, 90% of women with biochemical features of PCOS will have characteristic changes; however, 20% to 30% of women without hormonal disturbance due to PCOS will have similar ultrasound features.5 Our current understanding, albeit incomplete, is the phenotypic expression of PCOS results from primary hormone imbalances. The three prevalent theories for the pathogenesis of PCOS are as follows: 1. Hypothalamic–pituitary dysfunction results in gonadotropin-releasing hormone and luteinizing hormone dysfunction, which then has downstream effects on ovarian hormone production. 2. A primary ovarian defect (with or without an adrenal defect) in steroidogenesis results in hyperandrogenism. 3. A metabolic disorder characterized by peripheral insulin resistance exerts adverse effects on the hypothalamus, pituitary, ovaries, and, possibly, the adrenal gland. A number of variables, including genetic factors and lifestyle choices, contribute to the wide range of manifested symptoms of PCOS and make the diagnosis challenging unless clinicians are aware of PCOS as a potential cause. A typically chronic time course assists in diagnosis, with symptoms often developing in adolescence and advancing over time. However, this pattern may

be disrupted by lifestyle factors, including weight loss impacting on frequency of ovulation, and contraceptive hormones masking symptoms, thereby complicating the diagnosis.6 Criteria for PCOS have been debated among leading organizations since 1990. The differences in criteria reflect the controversy over the origin of the syndrome, as well as its heterogeneous manifestations (Table 35.1).7,8,8a However, current diagnostic criteria have unifying trends. All require the presence of at least one of the stigmata of ovarian disease; a history of anovulation or the finding of classic polycystic ovaries on ultrasound. All three criteria are consistent in terms of the inclusion of hyperandrogenism, determined by either clinical (hirsutism or acne) or laboratory findings. Finally, all guidelines require exclusion of hormonal disorders that may mimic PCOS. Although insulin resistance has been noted consistently among women with PCOS, it is not included in any of the current diagnostic criteria. Based on current data, evaluation for PCOS should include a search for both primary markers and secondary dysfunction. History and physical examination should focus on symptoms and signs, such as oligomenorrhea, acne, hirsutism, and central obesity, as well as searching for manifestations of other confounding diseases. Laboratory tests should include androgen levels (dehydroepiandrosterone [DHEA] sulfate and total and free testosterone measured by equilibrium dialysis) and tests to rule out alternative diagnoses as warranted (e.g., congenital adrenal hyperplasia, androgen-secreting tumors, Cushing syndrome, 21-hydroxylase–deficient nonclassic adrenal hyperplasia, androgenic or anabolic drug use or abuse, syndromes of severe insulin resistance, thyroid dysfunction, or hyperprolactinemia). Laboratory testing for antimüllerian hormone is a newer diagnostic tool that, in combination with measurement of luteinizing hormone levels, has been shown to have high sensitivity and specificity for the diagnosis of PCOS. Polycystic ovaries contain an increased amount of antral follicles, which produce antimüllerian hormone.8b The ratio of total testosterone to dihydrotestosterone (TT/DHT) has demonstrated potential as a new biomarker for an adverse metabolic phenotype in PCOS patients. A study of 275 premenopausal PCOS patients and 35 BMI-matched, healthy controls found a correlation between a high TT/DHT ratio and various adverse hormonal, lipid, and glucose metabolism parameters in patients with PCOS.8c The presence of metabolic syndrome and cardiovascular risk should also be evaluated in patients suspected to have PCOS (e.g., insulin resistance measurement by oral glucose tolerance tests, including glucose and 361

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Androgen elevation

Genetic factors

Lifestyle choices

Obesity

Hormone changes

Hirsutism, acne

Anovulation

Irregular menses, infertility

Body image issues, mood disorders

Metabolic syndrome, inflammation

Insulin resistance

FIG. 35.1  □  Proposed relationships leading to phenotypic expression of polycystic ovarian syndrome.

TABLE 35.1 Differing Criteria for Polycystic Ovarian Syndrome Among Organizations Organization

Criteria

Ovarian Dysfunction

National Institutes of Health (1990)6

Both of the following and exclusion of related disorders

Oligo-ovulation (less than six menses per year)

Rotterdam Group (2003)7

Any two of three of the following and exclusion of related disorders

Oligo-anovulation (nonspecified)

Androgen Excess Society (2006)8

Hyperandrogenism as critical, with addition of at least one ovarian marker and exclusion of related disorders

Oligo-anovulation and/ or polycystic ovaries

insulin levels, and measurement of lipids and inflammatory markers such as C-reactive protein and fibrinogen). Pelvic ultrasound also has utility in supporting the diagnosis of PCOS.

A thorough clinical assessment is critical both to confirm the diagnosis and to identify risk factors for long-term health maintenance. This information helps clinicians prioritize integrative approaches when creating a management plan by elucidating the primary metabolic targets. Treatment plans should take into equal consideration each woman’s unique concerns, such as weight management, acne, hair loss, or infertility.

INTEGRATIVE THERAPY A holistic approach to PCOS addresses the impact of the syndrome on patient mental state and sense of self in addition to immediate symptoms and risk management.

Lifestyle Weight Management Weight management plays a central role in the expression of symptoms and long-term consequences of PCOS. A reported 50% to 70% of women with PCOS are obese and should be informed that even 5% to 10% loss of body mass is associated with significant improvements

Ovarian Morphology

Hyperandrogenism Clinical or biochemical (not specified)

Polycystic ovaries (>12 follicles 2 to 9 mm, or ovarian volume >10 mL) Oligo-anovulation and/ or polycystic ovaries

Clinical or biochemical (free testosterone or free testosterone index) Clinical or biochemical (free testosterone)

in clinical metabolic and hormonal markers.9-11 Guiding women in this arena can be challenging because insulin resistance may inherently make weight loss more difficult, and women are often frustrated by repeated failed attempts to lose weight. Current evidence suggests that the approaches described in the next sections may be most successful. Physical Activity Exercise is an important lifestyle approach in PCOS, with diverse benefits including improved insulin sensitivity and preservation of lean body mass. A significant relationship exists between PCOS and inappropriate diet and low physical activity.11 A 2010 systematic review of exercise therapy in PCOS identified eight studies (five randomized controlled and three cohort) involving moderate intensity physical activity (aerobic and/ or resistance) for 12 to 24 weeks.12 The most consistent reported improvements included improved ovulation, reduced insulin resistance (9% to 30%), and weight loss (4.5% to 10%). Because the optimal exercise regimen for PCOS has yet to be defined, current recommendations for interval training and full-body exercise should be used (see Chapter 91). A study published in Human Reproduction compared the effects of exercise versus a low-calorie diet in 40 women with PCOS.13 The exercise group had higher ovulation rates, better insulin sensitivity, and greater reduction in waist measurements despite less absolute weight loss.

35  Polycystic Ovarian Syndrome

Nutrition Macronutrients Although caloric restriction is clearly required for weight loss, to date only a few, small studies have examined the impact of macronutrient composition in PCOS. Several studies ranging from 1 to 6 months that compared a high-protein and low-carbohydrate diet with a highcarbohydrate and low-protein diet have reported no significant differences in weight loss, circulating androgens, glucose metabolism, or leptin levels.14,15 Conversely, two pilot studies reported that low-carbohydrate diets were associated with improved depression scores and selfesteem ratings, in addition to lower fasting insulin levels and lower rates of acute insulin response to glucose.16,17 None of these studies took into account the glycemic index of carbohydrates or the source of protein (animal versus plant based), which may be important factors in insulin resistance and hormone regulation. In 2010, the first study examining the impact of glycemic index in overweight and obese premenopausal women with PCOS (n = 96) randomized women to either an ad libitum low– glycemic index diet or a macronutrient-matched healthy diet and followed the women for 12 months or until they achieved a 7% weight loss. The attrition rate was high in both groups (49%). Of the women who completed the study, those on the low–glycemic index diet demonstrated greater improvements in insulin resistance (p = 0.03), menstrual cyclicity (95% compared with 63%; p = 0.03), and serum fibrinogen concentrations (p < 0.05). A randomized controlled clinical trial of 48 women diagnosed with PCOS found that following the DASH (Dietary Approaches to Stop Hypertension) diet for 8 weeks led to a significant reduction in serum insulin, triglycerides, and very-low-density lipoprotein cholesterol levels, and significant increases in plasma total antioxidant capacity (TAC) and total glutathione (GSH). The diet in this study consisted of 52% carbohydrates, 18% proteins, and 30% total fats.17a At this point, no firm recommendations can be given regarding macronutrient content, although trends indicate women may do best on a low-carbohydrate diet with inclusion of low–glycemic index, high-fiber carbohydrates (see Chapter 87). Soy Soy intake in PCOS is a controversial topic. Soy is a plant food and complete protein, meaning that it has all the required amino acids. Soy is also low in fat and contains essential fatty acids, numerous vitamins, minerals, and fiber. Foods containing soy include soy milk and cheese, tofu, tempeh, miso, soy sauce, and edamame. Soy contains phytoestrogens, which has led to debate regarding the benefits versus risks of soy consumption in PCOS. Currently, very few studies have evaluated soy intake in patients with PCOS. One study reported favorable results regarding the utility of soy in improving cholesterol among patients with PCOS.18 In this study, 12 obese women with PCOS and high insulin and high cholesterol levels consumed 36 g of soy each day for 6 months. The results demonstrated reduced low-density lipoprotein cholesterol levels following the consumption

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of soy. However, the investigators noted no effect on weight loss, hormones, or menstrual cycle. Conversely, many animal studies have demonstrated that soy intake can negatively affect fertility. A review of seven soy intervention studies performed in women using 32 to 200 mg/day of isoflavones demonstrated increased menstrual cycle length.19 Current evidence does not imply that soy prevents ovulation; however, soy may delay ovulation.

Further studies of soy consumption in polycystic ovarian syndrome (PCOS) are required. Women with PCOS who struggle with infertility, consume few calories, or eat a poor diet may wish to consider avoiding or limiting the consumption of soy products. Otherwise, moderate to low intake of soy (once a day or several times a week) can be part of a healthy diet for women with PCOS.

Omega-3 Fatty Acids Inflammation has been identified in patients with PCOS, whether as a consequence or a contributing factor remains unclear.20,21 In comparison with control subjects, patients with PCOS have decreased fibrinolytic activity, higher levels of plasminogen activator inhibitor-1, and increased C-reactive protein levels (in both obese and nonobese women), all of which are markers of inflammation.25,26 These findings indicate interventions to reduce cardiovascular risk should be more aggressive in women with PCOS who have increased C-reactive protein levels. Including omega-3 fatty acids may have utility in managing the inflammatory component of PCOS in addition to supporting cardiovascular health (see Chapter 88). The lignans in flaxseeds may provide additional benefit through promoting estrogen elimination.

Supplements Inositol Family Investigations into the cause of insulin resistance in PCOS led some researchers to investigate whether derangements in insulin signal transduction could be overcome by oral administration of d-chiro-inositol (DCI), a mediator of insulin action that is naturally formed in the human body from the metabolism of pinitol and myoinositol (commonly known as inositol) in the diet. In several early studies, evidence favored a benefit of DCI in improved insulin sensitivity, triglyceride, and testosterone levels, in addition to improving blood pressure, ovulation, and weight loss.22,23 In a separate study, 44 obese women with PCOS were randomly assigned to receive placebo or DCI (1200 mg once a day) for 8 weeks. Supplementation with DCI resulted in an improvement in insulin resistance (p = 0.07), a 55% reduction in the mean serum free testosterone concentration (p = 0.006), and an increase in ovulation from 27% to 86% compared with placebo (p < 0.001). The more readily commercially available d-pinitol (d-chiro (+)-O-methyl inositol) has been shown to raise DCI serum levels; however, results of clinical end points, such as impact on insulin sensitivity, have been mixed.24,25 In an important study of this

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nutrient in diabetic patients, 600 mg of pinitol twice per day for 3 months lowered blood glucose levels by 19.3%, lowered average glucose levels by 12.4%, and significantly improved insulin resistance.29 In another study, 25 women received inositol for 6 months. Twenty-two of the 25 (88%) had a single spontaneous menstrual cycle during treatment, of whom 18 (72%) maintained a normal ovulatory activity. Ten pregnancies (40% of patients) occurred during this study.

Dosage DCI: 600 mg daily in patients weighing less than 60 kg (130 lb) or 1200 mg daily in patients weighing more than 60 kg. Pinitol: 600 mg twice daily. Precautions No interactions with herbs and supplements are known. There is concern that high consumption of inositol may exacerbate bipolar disorder.

Chromium Chromium is an essential trace mineral that enhances the action of insulin. Although supplementation with chromium has been shown in studies to improve blood glucose control in type 2 diabetes mellitus, little research has focused specifically on patients with PCOS.26 A pilot study of six women with PCOS concluded that 1000 mcg per day of chromium for as little as 2 months improved insulin sensitivity by an average of 38% (statistically significant) and decreased baseline insulin by 22% (not statistically significant).27

Dosage Chromium picolinate: 600 to 1000 mcg in divided doses daily. Picolinate, a byproduct of the amino acid tryptophan, is combined to support absorption of chromium. Dietary sources include Brewer’s yeast, liver, mushrooms, wheat germ, oysters, and some fresh fruits. Precautions The adequate daily intake of chromium for women ranges from 20 to 45 mcg depending on age. Laboratory animals have tolerated 350 times this dose without adverse effects, although there is concern regarding mutagenicity with prolonged use. In humans, short-term use of chromium at 1000 mcg daily is safe; however, these doses are not recommended in pregnancy or renal insufficiency. Prolonged use should be avoided due to concerns regarding adverse effects.

Vitamin D Vitamin D plays a role in insulin resistance and egg follicle maturation and development. In a small trial of 13 women with PCOS and vitamin D deficiency, normal menstrual cycles resumed within 2 months of vitamin D repletion with calcium therapy in seven of the nine women who had irregular menstrual cycles.28 Two women subsequently had established pregnancies. The authors of the study posited that abnormalities in calcium balance may be responsible, in part, for arrested follicular development in

women with PCOS and may contribute to the pathogenesis of PCOS. Vitamin D also plays a key role in glucose regulation, notably in decreasing insulin resistance,29,30 and low levels of vitamin D have been negatively correlated with the incidence of type 1 and type 2 diabetes.

Dosage Vitamin D3: 2000 units daily. Higher doses may be prescribed based on serum 25-OH vitamin D levels. Overweight individuals have a greater risk of vitamin D deficiency because the bioavailability of vitamin D, a fat-soluble vitamin, may be reduced in fat tissue. Precautions Vitamin D is well tolerated. Gastrointestinal side effects are most commonly reported.

N-Acetylcysteine Many studies of N-acetylcysteine (NAC) have reported benefit in diabetes, with several demonstrating benefit in PCOS. NAC has multiple actions, including increasing levels of glutathione (an antioxidant), lowering inflammatory markers such as tumor necrosis factor-alpha, and improving insulin sensitivity.31,32 A study in clomiphene-resistant patients demonstrated improved ovulatory rates (49.3% vs. 1.3%) and pregnancy rates (21% vs. 0%).33 A prospective randomized placebo-controlled study of 60 women with PCOS aged 25–35 years undergoing intracytoplasmic sperm injection (ICSI) found that NAC improved oocyte and embryo quality. This study also compared the effects of NAC and metformin on oocyte quality, with the results indicating NAC represents an alternative to metformin for women with PCOS undergoing ICSI.33

Dosage Give 1200 to 1800 mg/day in divided doses. Precautions NAC is well tolerated, with occasional reports of nausea.

Selenium Selenium is an essential micronutrient involved in antioxidant reactions, such as catalyzed by glutathione peroxidase. Studies have suggested selenium also possesses insulin-like actions, and has a potential role in fat and carbohydrate metabolism. A recent randomized, doubleblind, placebo-controlled study of 70 women aged 18–40 years with PCOS found that selenium supplementation led to significantly decreased levels of serum insulin (−29 vs. 9 pmol/L), serum triglycerides (−0.14 vs. 0.11 mmol/L) and VLDL-C concentrations (−0.03 vs. 0.02 mmol/L) compared with placebo.33a Researchers from this study hypothesized these effects were attributable to inhibition of COX2 expression and inflammatory cytokines, including TNF-alpha and IL-1. Further studies are required to assess the potential benefits and toxicities associated with long-term selenium intake.

35  Polycystic Ovarian Syndrome Dosage Give 200 microgram per day for 8 weeks. Precautions No side effects were reported by any PCOS study participants who were taking selenium supplementation. While one study demonstrated selenium intake up to 200 mcg/d for up to 16 weeks is safe for patients over 18 years of age, other studies have reported adverse side effects of hair loss and dermatitis.

Botanicals Cinnamomum cassia Cinnamomum cassia (not Cinnamomum zeyanicum or Cinnamomum verum) has been studied in vitro and in humans for its effects in lowering glucose levels in patients with diabetes.34-36 A pilot study published in the July 2007 issue of Fertility and Sterility reported that 1/4 to 1/2 teaspoon of cinnamon powder reduced insulin resistance in 15 women with PCOS.

Dosage The dose is 1 to 6 g powdered cinnamon (1/4 to 1 teaspoon) or 200 to 300 mg cassia extract. Precautions Cinnamon is well tolerated. Gastrointestinal side effects are most common.

Licorice Licorice root and glycyrrhetinic acid have antiandrogen effects that may support treatment goals in PCOS. Licorice root as part of a traditional Chinese medicine formula has also been associated with reduced serum testosterone and ovulation induction in women with PCOS.37,38 Additionally, licorice is synergistic with spironolactone, with its effects on potassium loss, hypertension, and fluid retention counteracting the opposing actions of spironolactone. A study of 32 hirsute women with PCOS administered 100 mg of spironolactone per day, with half also receiving 3.5 g/day of a licorice root extract standardized to 7.6% glycyrrhetinic acid for 2 months.39 Licorice use was associated with amelioration of orthostatic symptoms, polyuria, and systolic blood pressure drops, particularly during the first 2 weeks of treatment.

Dosage Glycyrrhiza glabra: 500 mg standardized to 6% to 15% glycyrrhizin (approximately 3.0 to 8.0 g of crude plant material). Precautions Few adverse events have been reported at lower doses or normal consumption levels. A no-observed effects level has been proposed as purified glycyrrhizin, 2 mg/kg/day. The acceptable daily intake for glycyrrhizin is recommended as 0.2 mg/kg/day. Toxicity from excessive licorice ingestion is well established, including hypokalemia, hypertension, and fluid retention. Licorice is contraindicated in pregnancy.

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Chaste Tree Berry (Vitex Agnus-castus) Vitex is one of the most popular botanicals for PCOS, although data from well-conducted studies are not available. Vitex is believed to shift the estrogen–progesterone balance in favor of progesterone through increased luteinizing hormone levels and mild inhibition of follicle-stimulating hormone secretion. Vitex also reduces prolactin secretion, which may inhibit fertility when elevated. A small study involving women with fertility disorders examined pregnancy rates following the administration of a chaste berry–containing herbal blend versus placebo twice daily for 3 months.40 Women with secondary amenorrhea or luteal insufficiency in the active treatment group achieved pregnancy twice as often as in the group receiving placebo. However, the total number of patients conceiving was small (15 women). Two other publications explored the benefits of a Vitex-containing blend on progesterone levels, basal body temperature, menstrual cycle length, pregnancy rate, and side effect profile.41,42 Both were double-blind, placebocontrolled trials of a proprietary nutritional supplement containing chaste berry, green tea, l-arginine, and vitamins and minerals. The treatment group (n = 53) demonstrated increased mean midluteal progesterone levels, particularly among women with very low pretreatment levels. Cycle length and luteal basal body temperatures improved significantly. After 3 months, 14 women in the treatment group were pregnant (26%) compared with 4 of the 40 women in the placebo group (10%; p = 0.01). The results of these studies are difficult to extrapolate given the proprietary nature of the supplements, although the trends toward improvement with no side effects warrant further consideration. Several small studies in the German literature have also reported a benefit of Vitex for acne, with self-reports of improvements of up to 70%.43

Dosage Vitex products are available in many different forms, including fresh and dried berries, capsules containing powdered chaste berries, and liquid preparations, such as extracts and tinctures. The German Commission E recommends 30-40 mg of dried fruit extract daily, 2.6-4.2 mg of dry native extract (standardized to 0.6% casticin or agnuside), or 40 drops of tincture. Fluid extract ([1:1] g/mL) dosage ranges from 0.5-1.0 mL daily. Precautions Animal and human studies indicate Vitex may interfere with oral contraceptives and hormone therapy. Based on in vitro data, Vitex may also interact with dopamine agonists (e.g., bromocriptine, levodopa). Use during pregnancy is not recommended.

Complementary Healing Approaches Acupuncture Acupuncture has the potential to influence PCOS through its effects on the sympathetic nervous system, the endocrine system, and the neuroendocrine system.46,47 In a 2009 study, one group of women with PCOS was treated for 4 months with electroacupuncture, another group of women was given heart rate monitors and told

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to exercise three times a week, and a third control group was educated about the importance of exercise and a healthy diet but received no instructions. The investigators found that women who received acupuncture or who exercised had decreased sympathetic activity. The women who received electroacupuncture treatments also had more regular menstrual cycles, reduced testosterone levels, and reduced waist circumference. Experimental observations from animal and clinical studies indicate acupuncture exerts beneficial effects on insulin resistance and ovulation. Although research studies are limited, acupuncture may be considered as an adjunctive therapy in many women for its direct impacts on PCOS parameters in addition to associated mood disorders and stress.

Mind-Body Therapy Women with PCOS have a significantly increased prevalence of depression and anxiety.48-50 Mood disorders may be directly related to biochemical imbalances (altered androgen levels or insulin resistance), and may be exacerbated by stress related to body image issues and infertility. Addressing these concerns through mind-body approaches, self-care, and cognitive-behavioral therapy should be encouraged for all women. A randomized, controlled trial has shown that women with PCOS who participated in an 8-week mindfulness and stress management program experienced significant reductions in stress, depressive, and anxiety symptoms, along with an increase in life satisfaction and quality of life. The results of this study indicate mindfulness techniques can be used to supplement PCOS care to the benefit of patient mental health58 (see Chapter 100).

Pharmaceuticals Medication decisions should be based on the predominant symptoms and goals of individual patients. Major classes of pharmaceutical treatments for PCOS include insulin sensitizers, weight loss medications, and hormone modulators. Insulin Sensitizers Metformin improves insulin resistance and hyperandrogenism.51 Metformin is also associated with regulation of menstruation and ovulation, and may benefit up to 79% of women attempting to conceive. Metformin is considered weight neutral, as opposed to many other medications used for glucose regulation.

Dosage Start with 500 mg daily for 1 week, titrate to 500 mg twice daily in week 2, and as required thereafter. The maximum daily dose is 2.5 g in two or three divided doses. Precautions Side effects are predominantly gastrointestinal and include nausea and diarrhea. Metformin should be avoided if creatinine clearance is less than 30 mL/minute.

Thiazolidinediones are less thoroughly studied in PCOS compared with metformin. This class of medications is associated with weight gain, thus making it an unattractive choice for many women struggling with PCOS. Studies of troglitazone (now off the market due to hepatotoxicity), pioglitazone, and rosiglitazone have demonstrated improvements in insulin sensitivity, hyperandrogenemia, and ovulatory rates. Given the potential for adverse effects, this class of medications is best reserved for patients with established diabetes mellitus. Weight Loss Medications Orlistat, given with an energy-restricted diet, has been shown to improve insulin resistance in addition to lowering free testosterone in obese women in some, but not all, studies.52-54 As the trials were short term (3 to 6 months), further studies are required to determine the utility of orlistat for the treatment of patients with PCOS.

Dosage A dose of 120 mg three times daily containing fat (during or up to 1 hour after the meal) was used for 3-6 months in previous studies. Omit dose if meal is occasionally missed or contains no fat. Precautions Orlistat may cause fat-soluble vitamin deficiency and greasy stools.

Hormone Modulators Oral Contraceptives. Oral contraceptive pills (OCPs) are first-line options for symptoms of androgen excess, such as hirsutism and acne, in accord with the 2008 Endocrine Society Clinical Practice Guidelines. OCPs reduce luteinizing hormone secretion and thus ovarian androgen secretion; additional reductions in free androgen concentration occur through increased levels of sex hormone–binding globulin.55 OCPs provide additional benefit by protecting against endometrial hyperplasia in amenorrheic women with excess estrogen exposure.

Dosage Appropriate choices include OCP preparations containing 30 to 35 mcg of ethinyl estradiol combined with a progestin with minimal androgenicity, such as norethindrone, norgestimate, desogestrel, or drospirenone. Precautions Risks and side effects of OCPs are similar to those for women without PCOS. OCPs may increase cardiovascular risk factors, such as inflammatory markers and insulin resistance. Absence of pregnancy should be documented before OCPs are initiated. In patients with no menstrual period for 6 or more weeks, withdrawal bleeding should be induced by administration of 5 to 10 mg of medroxyprogesterone acetate daily for 10 days before initiation of OCP treatment (to minimize breakthrough bleeding when starting the pill).

35  Polycystic Ovarian Syndrome

Although the oral contraceptive pill (OCP) helps many women overcome the troublesome symptoms of polycystic ovarian syndrome (PCOS), these drugs have been associated with an increased risk of cardiovascular disease in the general population.56,57 The risk of cardiovascular disease is associated with increased age, smoking, and hypertension. Additional concerns include a negative impact on inflammatory markers and diabetes risk. Further studies are required in the PCOS population to assess the long-term benefit-to-risk ratio of using OCPs. For now, increased awareness and regular follow-up of metabolic and cardiovascular markers are critical for all patients taking the OCP. Progestins. Progestins are appropriate for women who require endometrial protection but are not interested in, or appropriate for, the OCP. Cyclic progestins promote withdrawal bleeding and prevent endometrial hyperplasia.

Dosage Synthetic progestin: medroxyprogesterone acetate 5–10 mg orally daily for 7 to 10 days every 1 to 2 months. Bio-identical progestin: micronized progesterone 200–400 mg orally daily for 10 days every 1 to 2 months. Bio-identical progesterone cream has not been evaluated in research studies, and whether such creams can provide consistent levels sufficient for uterine protection is unclear. Precautions Sedation or confusion may occur.

Antiandrogens. Antiandrogens, which block androgen binding to its receptor, are often used off label for hirsutism.58 The most commonly prescribed antiandrogen is spironolactone. Flutamide is another option despite an association with greater side effects.

Dosage Spironolactone, 50 to 200 mg/day; flutamide, 250 mg two to three times a day. Precautions Contraception is essential as an antiandrogens, such as spironolactone, may be teratogenic if pregnancy occurs. Discontinuation 3 months before conception is therefore recommended. If spironolactone is used alone, endometrial protection may be required.

Clomiphene Citrate. Clomiphene citrate is an antiestrogen and an effective option for ovulation induction for women with PCOS. Approximately 80% of women with PCOS ovulate in response to clomiphene citrate, and approximately 50% conceive.

Dosage The strategy is to use the lowest dose of clomiphene possible to initiate ovulation, starting with 50 mg/day for 5 days (usually days 5 to 9). If no follicle development occurs with this dose, the dose or duration of treatment can be increased.

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Statins. There is debate in the literature regarding the cardiovascular and endocrine benefit of statins in women with PCOS. The results of an initial study of 40 patients with PCOS randomly assigned to atorvastatin at 20 mg daily or placebo were promising.59 After 12 weeks, the researchers reported an absolute reduction in free androgen index (−32.7%) and total testosterone (−24.6%), and increased sex hormone–binding globulin (+13.7%) in the atorvastatin group compared to the placebo group. Patients in the atorvastatin group had lower serum insulin levels and homeostasis model of insulin resistance (HOMA-IR) values compared to the placebo group. Conversely, a study published in 2010, in which 20 patients with PCOS who had lowdensity lipoprotein levels higher than 100 mg/dL took atorvastatin at 40 mg/day or placebo for 6 weeks of treatment, reported reductions in androgen levels, biomarkers of inflammation, and blood pressure.60 However, atorvastatin worsened hyperinsulinemia and failed to improve endothelial function in women with PCOS. Until the potential benefit of statins in PCOS has been fully evaluated, reserving statin use for the treatment of hyperlipidemia rather than the treatment of hyperandrogenemia or insulin resistance seems prudent.

Dosage Doses are as per usual recommendations for hyperlipidemia. Precautions Statins are considered to have teratogenic potential in pregnancy. The usual concerns regarding liver and muscle issues apply.

Surgery When severe symptoms are not controlled with the therapies described above and a patient has morbid obesity, bariatric surgery may be considered. Results of two small studies on the effects of bariatric surgery have been published.61 A retrospective study evaluated 30 women with PCOS who underwent laparoscopic Roux-en-Y gastric bypass. Postoperative benefits included resolution of menstrual irregularity (100%), improvement in hirsutism (75%), resolution of type 2 diabetes, and ability to cease medications for hypertension (78%) and hyperlipidemia (92%). These results were confirmed in a prospective study evaluating 17 women with PCOS. Surgery may also be performed for ovulation induction in the management of clomiphene citrate–resistant anovulatory women with PCOS. Various types of ovarian surgery can be employed (e.g., wedge resection, electrocautery, laser vaporization, multiple ovarian biopsies), and all procedures result in an altered endocrine profile postoperatively. A plausible mechanism for the benefit of surgery for patients with PCOS is the restoration of appropriate gonadotrophin release due to rapid reductions in the secretion of all ovarian hormones restoring feedback to the hypothalamus and pituitary. These surgical procedures provide an option, albeit one used less often now, when natural and pharmaceutical approaches are unsuccessful in anovulatory patients with PCOS.

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PREVENTION PRESCRIPTION • M  aintain appropriate weight and a regular aerobic exercise routine. • Avoid excessive amounts of saturated fat such as those found in red meat, fried foods, and dairy. • Replace vegetable oils with olive or canola oil for cooking. • Consume omega-3–rich fats found in cold-water fish, nuts, greens, and ground flaxseed. • Encourage soy-based foods, such as soy milk, edamame, tempeh, miso, soy nuts, and nonge-

netically modified tofu. Try to eat 1 to 2 oz of soy-based foods per day. • Avoid dietary supplements or environmental exposures that may increase circulating hormone levels, such as pesticides, herbicides, and bovine growth hormone–rich dairy products. • Avoid supplements or drugs that include dehydroepiandrosterone, androstenedione, testosterone, or human growth hormone.

THERAPEUTIC REVIEW Lifestyle approaches are first-line recommendations for PCOS, both in conventional and integrative medicine approaches. Many women with PCOS do well with attention to diet, exercise, supplements, and acupuncture. A proportion of women require medications to achieve improvements when metabolic derangements are greater. LIFESTYLE • Remove exacerbating factors. Minimize exposure to hormone-disrupting chemicals. NUTRITION • Promote weight loss to achieve an ideal body weight. Start with achievable goals and provide adequate A support. • Eat 1 to 2 servings of soy-rich foods daily. Each 1 oz serving (approximately the size of the palm of the B hand) provides approximately 25 mg. • Encourage a low-carbohydrate diet that takes into B account the glycemic index of foods. • Encourage foods rich in omega-3 fatty acids (e.g., B salmon, nuts, or ground flaxseeds). PHYSICAL ACTIVITY • Recommend moderate exertion for 30 to 60 minutes daily. SUPPLEMENTS • Vitamin D3: 2000 units daily (dose based on serum 25-OH vitamin D level) • Chromium picolinate: 1000 mcg daily • d-chiro-inositol/pinitol: 600 mg once or twice per day • Selenium: 200 mcg per day for 8 weeks

A

1

1

1

1

1

B

1

B

2

B

2

B

2

BOTANICALS • Cinnamomum cassia: 1/4 to 1 teaspoon • Licorice root in conjunction with spironolactone for the amelioration of side effects and complementary action • Chaste tree berry (Vitex): 60 drops of tincture or 175 mg of extract, standardized to 0.6% agnusides

B

1

B

2

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COMPLEMENTARY THERAPIES • Acupuncture may reduce sympathetic nervous system tone and improve menstruation. It has additional A benefits for stress reduction and mood. • Mind-body therapies can help women cope with stress, depression, and anxiety related to PCOS. A PHARMACEUTICALS • Insulin sensitizers include metformin at 500 to 1000 mg twice daily. • If patients are unable to achieve satisfactory weight loss, consider support with orlistat. • Medications such as clomiphene may be prescribed in consultation with a reproductive endocrinologist for ovulation induction. • Antiestrogens for hirsutism include spironolactone at 50 to 200 mg/day, or flutamide, at 250 mg two to three times a day. • Oral contraceptive pills are prescribed for amenorrhea, hyperandrogenism, and uterine protection. SURGICAL THERAPY • Consider referral for bariatric surgery for patients with morbid obesity and significant comorbidities despite the measures listed above. • Ovarian surgery may be indicated for infertility.

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35  Polycystic Ovarian Syndrome

Key Web Resources American Association of Clinical Endocrinologists: This website contains a position statement on metabolic and cardiovascular consequences of PCOS, as well as practice management forms for new and follow-up visits for patients with PCOS. Womenshealth.gov: This website, from the U.S. Department of Health and Human Services Office on Women’s Health, provides patient education materials on PCOS. American Society for Reproductive Medicine: This website describes medical and surgical options for PCOS.

REFERENCES References are available online at ExpertConsult.com.

http://www.aace.com

https://www.womenshealth.gov/publications/our-publications/fact-sheet/polycystic-ovary-syndrome.html http://www.asrm.org

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