Today’s CPE - Polycystic Ovary Syndrome
Today’s Dietitian
By Carol Brannon, MS, RD, LD
Vol. 6, No. 10, p. 14

The emotional stress of infertility was taking its toll—at 33, my client and her husband had been trying to get pregnant for two years. She was losing hope while gaining weight. Like many women, she was infertile, secondary to polycystic ovary syndrome (PCOS). She needed assistance in losing weight, but in researching her case, I found intriguing aspects of this common condition that present challenges and opportunities for dietitians.

The problem goes beyond failure to conceive. PCOS may be a precursor to the metabolic or insulin resistance syndrome (IRS) and type 2 diabetes. Retrospective studies indicate that PCOS may increase a woman’s risk of cardiovascular disease (CVD), hyperlipidemia, hypertension, and possibly hyperestrogen-related cancers later in life.2,4

PCOS is the most common female endocrine disorder. Approximately 5% to 10% of U.S. women—10 million females—have PCOS.1,2 Identified first in 1935 as the Stein-Leventhal syndrome (named after the researchers who reported on it), PCOS was considered an obscure reproductive disorder. Today it is recognized as a common cause of infertility.3

The clinical definition of PCOS is oligomenorrhea (irregular menstrual cycles and menstrual flow) associated with ovarian hyperandrogenism (high levels of circulating androgens). Although this definition may sound simple and straightforward, in reality PCOS is a complex metabolic disorder. Other characteristics of PCOS include amenorrhoea (absence of or abnormal menstrual flow), anovulation (absence of ovulation), reproductive problems, insulin resistance (IR), and hyperinsulinemia.2,4 A woman with PCOS will exhibit at least two of the features described in Chart 1.2

PCOS has been described as “the thief of womanhood” because it steals a woman’s fertility while promoting masculine traits such as facial hair,4,5 which are attributed to high androgen levels. Androgens are a class of sex hormones, of which testosterone is the most important, responsible for secondary male characteristics.3,6

PCOS usually, but not always, includes the presence of numerous bilateral ovarian cysts—70% to 80% of women with PCOS have polycystic ovaries, which are generally enlarged and have at least 10 small peripheral cysts, the result of incomplete ovarian follicle development. (In normal ovulation, ovarian follicles mature and release a secondary oocyte that divides into a mature egg or ovum. In PCOS, follicles do not mature, so ovulation cannot occur.2,6)

The presence of polycystic ovaries, in the absence of oligomenorrhea or hyperandrogenism, does not constitute a diagnosis of PCOS and is not considered a defining feature. In fact, the incidence of polycystic ovaries may be more common than PCOS. A survey in the United Kingdom and New Zealand found that an estimated 20% to 25% of women had polycystic ovaries alone.7,8 Polycystic ovaries commonly develop during the early stages of puberty.9 These small cysts may also be found in women with bulimia or recovering from anorexia nervosa and in the presence of disorders or tumors of the adrenal, thyroid, or pituitary glands that cause hyperandrogenism.2

Etiology and Pathogenesis
The etiology of PCOS is unknown. Genetics appear to be involved (family history is a strong predictor6) and there is a possible link with obesity and inactivity, as risk factors for IR. The majority of women with PCOS, whether thin, overweight, or obese, exhibit some degree of IR. It is believed that abnormal insulin receptors, further down-regulated by obesity and inactivity, become less sensitive to insulin.10 Additional factors are aging, sedentary lifestyle, smoking, upper body or abdominal obesity, pregnancy, and drugs (eg, corticosteroids and thiazide diuretics).10

The primary role of insulin is glucose regulation. The pancreas secretes insulin in response to blood glucose levels. Insulin must bind to receptors located on cells before glucose can enter those cells. When insulin receptors, particularly on muscle cells, become insulin-resistant, the pancreas produces more insulin to maintain normoglycemia. Hyperinsulinemia results and sets up a type of metabolic “domino effect,” which includes increased abdominal fat, menstrual irregularities, anovulation, increased androgen production accompanied by undesirable skin and hair changes, and dyslipidemia.2,6,10 A discussion of these effects of hyperinsulinemia and their relation to PCOS follows.

• Adiposity: Increased body fat, especially in the upper body and abdomen, occurs with IR. Often called central obesity, upper body or abdominal body fat is a defining feature of PCOS. Even women with PCOS who have a healthy body mass index (BMI < 27) have a tendency toward central adiposity and have been found to have a higher waist-to-hip ratio (ratio > 0.8) compared with weight-matched women without PCOS.11 According to studies using ultrasound measurements, lean women with PCOS have a higher proportion of visceral adiposity compared with weight-matched control subjects.12 As body fat increases, so does the severity of IR, making weight loss extremely difficult.2

It is estimated that at least 50% of women with PCOS are overweight (BMI >27) or obese (BMI > 30). Studies indicate obese women with PCOS have more severe IR, higher levels of testosterone, and lower levels of luteinizing hormone (LH) than weight-matched controls.13 PCOS and obesity appear to have a separate but synergistic impact on IR. 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 type 2 diabetes more rapidly than weight-matched controls without PCOS.14

• Menstrual cycle irregularities: Hyperinsulinemia stimulates the theca cells in the ovaries to increase androgen production, particularly testosterone. Paradoxically, in PCOS, theca cells are hypersensitive to insulin, while muscle and liver cells are insulin-resistant. It may be that a gene or multiple genes are responsible for the insulin hypersensitivity of ovarian cells.15,16 There is some debate about whether hyperinsulinemia precedes hyperandrogenism or vice versa. More research is needed to provide a conclusive answer.16

Excessive production of ovarian testosterone results in increased conversion of testosterone to estrone, a potent form of estrogen associated with disease development. Estrone levels are high in women with PCOS, while estradiol levels are within the normal range. Estradiol is considered the “good” form of estrogen because it appears to protect against cancer development.16,17,18,19 High estrogen levels prevent regular endometrial shedding, which in turn increases the risk for endometrial overgrowth and possibly cancer.20

Hyperandrogenemia prevents ovulation by blocking follicle development and causes oligomenorrhea.2 Menstrual cycles are generally shorter than 21 days or longer than 35 days. PCOS is also associated with abnormal uterine bleeding, miscarriage, and other complications of pregnancy.16

• Skin and hair changes: Acanthosis nigricans, which are dark, velvety patches on skin, particularly on the back of the neck and underarms, are physical signs of hyperinsulinemia.2,6 High levels of testosterone cause skin to become oily, triggering acne. PCOS is the major cause of hirsutism, the excessive growth of thick, pigmented facial and body hair. Androgenic alopecia (hair loss similar to male pattern baldness) is common. However, it should be noted that hirstuism and androgenic alopecia might occur in the absence of PCOS.6

• Dyslipidemia: Blood lipid changes occur with IR. Approximately 70% of women with PCOS have at least one abnormal lipid level.13,21 Obese women with PCOS are likely to have dyslipidemia— specifically, elevated triglycerides and decreased high-density lipoprotein (HDL) cholesterol. Studies that controlled for IR showed elevated triglycerides and decreased HDL cholesterol linked to IR and not PCOS.2 High triglycerides and low HDL levels are strongly linked with CVD. High levels of low-density lipoprotein (LDL) cholesterol in association with PCOS have not been found consistently.2

PCOS affects women at all stages of their lives. Clinical onset usually occurs at puberty, which often occurs prematurely and is characterized by IR. Precocious puberty, menarche before the age of 8, is linked to PCOS. Teenagers experience hirsutism, acne, oligomenorrhea, and IR. Young women with PCOS risk developing an eating disorder in an effort to lose weight.16,22 Women in their reproductive years may experience infertility, miscarriages, and have a higher prevalence of gestational diabetes or impaired glucose tolerance during pregnancy.10 Later in life, women are predisposed to type 2 diabetes, heart disease, and possibly cancer. Women with PCOS may experience depression, which can complicate efforts of dieting and nutrition counseling.23

PCOS and Metabolic Syndrome
PCOS, with its links to IR, strongly resembles and may precede metabolic syndrome. Also called IRS or Syndrome X, metabolic syndrome is a clustering of abnormalities that has varying definitions. The World Health Organization proposes that diabetes, impaired glucose tolerance, or IR must be present, as well as two or more of the following: hypertension, microalbuminuria, central obesity, elevated triglycerides, and decreased levels of HDL cholesterol. The National Cholesterol Education Program Adult Treatment Panel III definition does not require the presence of IR but the presence of three or more of the following: elevated triglycerides and/or decreased HDL, central obesity, hypertension, and/or impaired glucose tolerance.24

PCOS closely resembles both definitions, except for hypertension, which is uncommon in PCOS.13 However, PCOS may predispose a woman to hypertension. A retrospective study of women treated 20 to 30 years ago for PCOS found increased incidence of hypertension and diabetes over weight-matched control subjects.25,26

Diagnosis
PCOS is often undiagnosed because its manifestations differ; there is no single, definitive diagnostic test. Diagnosis is based on physical examination, ultrasound, and laboratory tests.18

• Physical signs: Acanthosis nigricans, hirsutism, and acne are easily observed. Polycystic ovaries are diagnosed by ultrasound. A woman’s BMI and waist-to-hip ratio should also be evaluated.6,18

• Laboratory tests: Diagnosis includes a variety of blood tests to measure hormone, glucose, and insulin levels. Laboratory measurements that indicate PCOS include elevated levels of total and free testosterone and LH and normal levels of thyroid-stimulating hormone (TSH) and prolactin. It is necessary to rule out other causes of hyperandrogenism. TSH and prolactin levels are drawn to rule out adrenal tumors or pituitary or thyroid conditions.16

The glucose tolerance test is widely used to screen for glucose intolerance and measure IR. Measurements for both glucose and insulin should be obtained to screen for any abnormal levels.16 One clinical study found a fasting glucose-to-insulin ratio useful in the measurement of IR in obese non-Hispanic women.27

Managing PCOS
All aspects of PCOS can be managed with a combination of diet, exercise, and medication. The primary treatment goal is weight reduction.

• Diet therapy: The typical western diet (high in fat and refined carbohydrates and low in fiber) contributes to IR and chronic disease development. Weight loss of just 5% and diet modification lowers insulin levels, reduces hyperlipidaemia, reduces androgen and LH levels, and restores regular menstruation and ovulation.10,16

There is strong agreement that a hypocaloric diet is beneficial for overweight and obese women with PCOS. However, there is debate about the optimal balance of macronutrients in a weight-reduction diet. Proponents of low-carbohydrate (LC) diets advocate that high-carbohydrate, low-fat diets increase insulin levels, raise triglycerides, and lower HDL cholesterol. Opponents of LC diets argue that these diets are high in fat, leading to IR, weight gain, and heart disease.16

What then is the optimal diet for PCOS? Is the glycemic index relevant? We know diets rich in fruits, vegetables, complex carbohydrates, and fiber lower chronic disease risk.28,29,30 It appears that the type of dietary carbohydrates may be more critical than the percentage. High-fiber diets, particularly diets high in soluble fiber, prevent dyslipidemia and lower blood pressure.30 Studies indicate that high-fiber diets improve insulin sensitivity and facilitate weight loss.16

Many advocate a low glycemic index diet to improve insulin sensitivity. Low glycemic index foods are generally higher in fiber and less processed.31 Currently there is no conclusive evidence supporting the therapeutic benefit of the glycemic index diet.32

A diet rich in omega-3 fatty acids and monounsaturated fats can improve insulin sensitivity and promote heart health. In contrast, saturated fats increase IR and promote hyperlipidemia. Evidence supports consumption of a low-fat diet comprised mostly of unsaturated fats.19,21

Overall, findings are ambiguous regarding the supplemental use of flaxseed, glucomannan, guar gum, vitamin E, chromium, magnesium, and the botanical saw palmetto for PCOS.16 Fish oil supplements, which contain the omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid, have been found effective in improving glucose clearance, insulin sensitivity, decreasing fat deposition, and protecting against heart disease.33 Fish oil supplements may have a therapeutic role in PCOS treatment; however, currently there are no clinical studies to support a specific dietary recommendation.

Dietary Guidelines
It is easier to get women to focus on what to eat (whole grains, fruits, vegetables, foods rich in omega-3 fatty acids) than what not to eat. Positive habits will replace negative habits over time. Dietary guidelines for women with PCOS include the following35,36:

• Focus on whole and fiber-rich foods: whole grains, vegetables, and fruits.

• Balance intake of carbohydrates throughout the day.

• Consume carbohydrate foods with protein and/or low-fat foods.

• Consume at least 40 grams of carbohydrates daily to prevent ketosis.

• Choose foods containing omega-3 fatty acids (fish, flaxseed, nuts, and seeds) and monounsaturated fats (olive oil, canola oil, and nuts).

• Avoid refined carbohydrates, saturated fats, and processed foods.

• Eat smaller portions to reduce weight.

Exercise is proven to reduce IR and facilitate weight loss. It is highly recommended that women participate in regular aerobic exercise and strength training.10

Medications
Medications should be prescribed only as an adjunct to diet and exercise. Oral contraceptive pills (OCPs), androgen-blocking drugs, and insulin-sensitizing drugs are the three groups of medications used to treat PCOS. Fertility drugs are prescribed for women desiring pregnancy.10

• OCPs: Low-dose OCPs are prescribed for birth control because spontaneous ovulation can occasionally occur. Depending on the estrogen dose, OCPs can inhibit androgen, LH, and follicle stimulating hormone production, regulate menstrual periods, correct heavy bleeding, and treat hirsutism. However, it may take one year for improvement to be realized.20 Of concern is the effect of OCPs on glucose tolerance in women with PCOS. One study of 16 nondiabetic hyperandrogenic women found a decline in glucose tolerance over a six-month period, with two women developing diabetes. More research is needed to determine safety of OCPs in women with PCOS.10

• Androgen-blocking drugs: Spironolactone (Aldactazide) is an androgen-blocking, antihypertensive diuretic agent prescribed for the treatment of hirsutism, alopecia, and acne. It is contraindicated for women desiring pregnancy because it causes birth defects and is often prescribed along with an OCP. Abnormal uterine bleeding is a possible side effect, which could be problematic for women already experiencing abnormal bleeding.10,18,20

• Insulin-sensitizing drugs: Metaformin is commonly used in the treatment of type 2 diabetes. In comparison with other insulin-sensitizing drug, metaformin shows the most promise in treating PCOS. It acts by increasing glucose uptake by fat and muscle cells and improving insulin sensitivity. Metaformin decreases androgen levels and treats the symptoms of hyperandrogenism.16,34 There are no reported effects on weight, waist-to-hip ratio, or LDL levels. Side effects include gastrointestinal distress and discomfort. Pregnant women should not take metaformin. More studies are needed regarding metaformin and PCOS.34

• Fertility drugs: Clomiphene citrate (Clomid) is generally the first fertility medication prescribed. Approximately 70% of women with PCOS who take Clomid become pregnant. There is a risk of multiple births. Women who do not become pregnant on Clomid are prescribed human menstrual gonadotropin (Pergonal) or human chorionic gonadotropin. These drugs have a higher risk of multiple births and medical complications.20 Leuprolide (Lupron), a gonadotropin-releasing hormone agonist, is prescribed to reduce miscarriage risk in women with a history of miscarriage.20

While these medications are effective, the first line of treatment is diet and weight loss. Dietitians have the opportunity to help women make positive lifestyle changes that can alleviate the symptoms and prevent the long-term consequences of PCOS.

— Carol Brannon, MS, RD, LD, is a consulting dietitian at Fowler YMCA and in private practice in Georgia.

References
1. Knochenhauer ES, Key TJ, Kahsar-Miller M, et al. Prevalence of the polycystic ovary syndrome in unselected black and white women of the southeastern United States: A prospective study. J Clin Endocrinol Metab. 1998;83:3078-3082.

2. Norman RJ, Wu R, Stankiewicz MT. Polycystic ovary syndrome. MJA. 2004;180(3):132-137.

3. Boschert S. Insulin resistance in PCOS may be more common in Mexican Americans than whites - separate screening values needed? OB/GYN News. July 1, 2002.

4. Sharpless JL. Polycystic ovary syndrome and the metabolic syndrome. Clin Diabetes. Fall 2003.

5. Kitzinger C, Willmott J. The thief of womanhood: Women’s experience of polycystic ovarian syndrome. Soc Sci Med. 2002;54:349-361.

6. Barnes RB, Neithardt AB, Kalra SK. Hyperandrogenism, hirsutism and polycystic ovary syndrome. Chapter 6. Endotext.org, November 19, 2003. Available at: http://www.endotext.org

7. Farquhar CM, Birdsall M, Manning P, et al. The prevalence of polycystic ovaries on ultrasound scanning in a population of randomly selected women. Aust N Z J Obstet Gynaecol. 1994;34(1):67-72.

8. Polson DW, Adams J, Wadsworth J, et al. Polycystic ovaries — a common finding in normal women. Lancet. 1998;1: 870-872.

9. Nobels F, Dewailley D. Puberty and polycystic ovary syndrome: The insulin/insulin-like growth factor hypothesis. Fertil Steril. 1992;58:655-663.

10. Kidson W. Polycystic ovary syndrome: A new direction in treatment. MJA. 1998;169:537-540.

11. 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.

12. 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.

13. Sharpless JL. Polycystic ovary syndrome and the metabolic syndrome. Clin Diabetes. Fall 2003.

14. Norman RJ, Masters L, Milner CR, et al. Relative risk of conversion from normoglycaemia to impaired glucose tolerance or non-insulin dependent diabetes mellitus in polycystic ovarian syndrome. Hum Reprod. 2001;16(9):1995-1998.

15. Carey AH, Chan Kl, Short F, et al. Evidence for a single gene effect causing polycystic ovaries and male pattern baldness. Clin Endocrinol. 1993;38(6):653-658.

16. Marshall K. Polycystic ovary syndrome: Clinical considerations. Alt Med Rev. 2001;6(3):272-292.

17. Schneider J, Bradlow HL, Strain G, et al. Effect of obesity on estradiol metabolism: Decreased formation of nonuterotropic metabolites. J Clin Endocrinol Metab. 1983;56(5):973-978.

18. Clemons M, Goss P. Estrogen and the risk of breast cancer. N Engl J Med. 2001;344(4):276-285.

19. Hopkinson AEC, Sattar N, Fleming R, et al. Polycystic ovarian syndrome: The metabolic syndrome comes to gynaecology (Fortnightly review). Br Med J. l998;317:329-333.

20. Polycystic ovary syndrome. Women’s Health. Mylifepath Blue Shield of California; 2001. Available at: http://www.mylifepath.com. Accessed April 24, 2001.

21. Legro RS, Kunselman AR, Dunaif A. Prevalence and predictors of dyslipidemia in women with polycystic ovary syndrome. Am J Med. 2001;111(8):607-613.

22. McCluskey S, Evans C, Lacey JH, et al. Polycystic ovary syndrome and bulimia. Fertil Steril. 1991;55:287-291.

23. Redmond G. Polycystic ovary syndrome. The Hormone Help Center — A Service of the Hormone Center of New York. Center for Health Research, Inc. Available at: http://www.hormonehelpny.com. Accessed January 7, 2004.

24. Hoefner DM. The ruthless malady; metabolic syndrome. Medical Laboratory Observer. October 2003.

25. Dahlgren E, Johansson S, Lindstedt G, et al. Women with polycystic ovary syndrome wedge resected in 1956 to 1965: A long-term follow-up focusing on natural history and circulating hormones. Fertil Steril. 1992;57(3):505-513.

26. Wild S, Pierpoint T, Jacobs H, McKeigue P. Long-term consequences of polycystic ovary syndrome: Results of a 31 year follow-up study. Hum Fertil. 2000;3(2):101-105.

27. Legro RS, Finegood D, Dunaif A. A fasting glucose to insulin ratio is a useful measure of insulin sensitivity in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 1998;83(8):2694-2698.

28. Joshipura KJ, Ascherio A, Manson JE, et al. Fruit and vegetable intake in relation to risk of ischemic stroke. JAMA. 1999;282(13):1233-1239.

29. Ludwig DS, Pereira MA, Kroenke CH, et al. Dietary fiber, weight gain, and cardiovascular disease risk factors in young adults. JAMA. 1999;282(16):1539-1546.

30. Davy BM, Melby CL. The effect of fiber-rich carbohydrates on features of syndrome X. (Review) J Am Diet Assoc. 2003;103(1):86-96.

31. Jenkins DJA, Kendall CWC, Augustin LSA, et al. Glycemic index: Overview of implication in health and disease. Am J Clin Nutr. 2002;76(suppl): 266S-273S.

32. Franz MJ, Bantle JP, Beebe CA, et al. Evidence-based nutrition principles and recommendations for treatment and prevention of diabetes and related complications. Diabetes Care. 2002;25(1):202-212.

33. Brannon C. Essential fatty acids in prevention and treatment of disease. In Functional Foods Part 2. Ashland, Ore.: Nutrition Dimension Inc.; 2002.

34. Nothnagle M, Tylor JS. Does metformin improve clinical features of polycystic ovary syndrome? – Cochrane for clinicians: Putting evidence into practice. Am Fam Phys. December 1, 2003.

35. McKittrick M. PCOS and diet. OBGYN.net Publications. Available at: http://www.obgyn.net. Accessed April 25, 2001.

36. Hart CR, Grossman M. The Insulin-Resistant Diet. Lincolnwood, Ill.: Contemporary Books; 2001.

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