Nutrition Guide for Clinicians

In 1935, gynecologists Irving F. Stein and Michael L. Leventhal described a condition of ovarian cysts and ovulatory disturbances.[1] It soon became clear that these were symptoms of excessive androgen production.[2][3]

Polycystic ovary syndrome (PCOS) affects an estimated 6-8% of women in the United States.[4] Diagnosis can be difficult due to the variability of presentation, so actual prevalence may be considerably higher.
The etiology is complex, thought to arise from interactions between genes and the environment. While previously thought to be predominantly related to dysregulation of androgen production, it is now believed to be result of a “two-hit” scenario, the first “hit” being heritable factors and/or genetic variants related to insulin resistance, steroidogenesis, and ovarian function. The second consists of environmental or acquired factors such as obesity, hyperinsulinemia, or secondary androgen excess.[5]

The onset of PCOS is typically in peripubertal years, and clinical presentation is varied. The key features are androgen excess (hirsutism and acne) and ovulatory dysfunction; however, other features can include polycystic ovaries on ultrasound, obesity, insulin resistance, and infertility due to oligo-ovulation with accompanied menstrual irregularities. PCOS is also associated with dyslipidemia, type 2 diabetes, and obstructive sleep apnea.

The diagnosis of PCOS requires a history of biochemical and/or clinical evidence of hyperandrogenism and persistent oligomenorrhea with evaluation and exclusion of other causes of ovulatory dysfunction and hyperandrogenism.[6]

Patients with the diagnosis are at increased risk for depression and eating disorders and may have an impaired quality of life, compared with women with similar body mass indexes (BMI) who do not exhibit PCOS symptoms. Lifestyle changes, especially those that lead to weight loss, are the first line of therapy and can ameliorate multiple symptoms.

Risk Factors

Genetics. Twin studies suggest that more than 70% of cases can be attributed to polygenic heritable traits,[7] but it appears that other congenital or environmental factors must also be present for the condition to manifest.[8]

Obesity. Obesity, particularly abdominal obesity, increases risk of PCOS.

Chemical exposures. Some evidence exists for higher prevalence of PCOS in women using the prescription anti-seizure medication valproate. Additionally, high serum levels of environmental contaminents, including bisphenol A (BPA) and polychlorinated biphenyls (PCBs), have been correlated with increased prevalence of PCOS in some populations.[9][10]

Diagnosis

Diagnosis of PCOS can be difficult, as presentations can be atypical. Many patients are not hirsute or obese. A thorough history and physical examination are essential.

There are at least 3 different sets of diagnostic criteria for PCOS in adults, with the Rotterdam criteria being most used in the US. For diagnosis in adults, according to the Rotterdam Consensus Group criteria, 2 of the following 3 points should be met, and other diseases with similar clinical presentation should be ruled out:[6][11]

1. Menstrual irregularity. Anovulation, oligo-ovulation, amenorrhea, oligomenorrhea, or irregular bleeding.
2. Signs of hyperandrogenism. Hirsutism, acne, male-pattern baldness, or elevated serum total or free testosterone concentration. If serum testosterone is normal in the absence of drugs that cause or mask hyperandrogenism, PCOS is much less likely. Anabolic steroids and antiepileptic drugs cause symptoms similar to PCOS. Oral contraceptives and systemic acne medications may mask hyperandrogenism.
3. Polycystic ovaries, visible on transvaginal ultrasound. As an isolated finding, polycystic ovaries are not diagnostic of PCOS. Rotterdam criteria require 12 or more follicles of sufficient size and/or increased ovarian volume for this criterion to be fulfilled. Transvaginal ultrasound should be employed in atypical presentations to evaluate for ovarian or adrenal neoplasms.

In adolescents, PCOS can be diagnosed if clinical or biochemical evidence of hyperandrogenism is present along with a persistently abnormal menstrual pattern for age, present for > 1-2 years, after other pathologies have been excluded. Polycystic ovaries and anovulation may be present in normal stages of reproductive maturation, and are therefore not sufficient for diagnosis in this age group. As in older patients, ultrasound is recommended in atypical cases.

Postmenopausal women can be diagnosed with PCOS if they have a long-term history of oligomenorrhea and hyperandrogenism. Ultrasound abnormalities are less common in this population.

PCOS is a diagnosis of exclusion, as other possibly pathologies should always be considered. The laboratory studies that may be performed based on the individual’s history and physical exam include:

• DHEA-S (dehydroepiandrosterone sulfate) or 17-hydroxyprogesterone to screen for congenital adrenal hyperplasia or adrenal tumor.
• Prolactin to screen to screen for hyperprolactinemia.
• Cortisol to screen for Cushing’s syndrome.
• TSH to screen for thyroid dysfunction.
• IGF-1 to screen for acromegaly.
• FSH to rule out ovarian insufficiency.
• Urine human chorionic gonadotropin (hCG) to rule out pregnancy.
• A glucose tolerance test is indicated in most cases, especially if signs of insulin resistance are present, such as acanthosis nigricans and/or skin tags.

Patients with atypical features such as virilization, unexplained congenital hyperandrogenism, or unresponsiveness to standard PCOS treatment should be referred for specialized work-up.

Because PCOS confers increased cardiometabolic risk, cardiovascular risk factors, including BMI, blood pressure, blood sugar and lipids, should be evaluated. Smoking should be strongly discouraged, as in all patients.

PCOS is associated with nonalcoholic fatty liver disease and nonalcoholic steatohepatitis, although screening for these conditions is not recommended at this time.

Testing for sleep apnea (sleep questionnaire, overnight polysomnography) may be indicated, as women with PCOS are at increased risk.

If proper treatment options or referral sources are in place, patients with PCOS should be screened for depression and anxiety.[6]

Treatment

In both women and adolescents with obesity, weight loss strategies, particularly a low-fat, plant-based diet, should be considered first, as this improves many PCOS sequelae.

Apart from nutritional interventions, oral contraceptives are recommended as first-line pharmacologic therapy in adolescents and adults to manage menstrual irregularities, hirsutism, and acne. Combined estrogen-progestin oral contraceptives also protect against endometrial hyperplasia.

Weight loss, physical activity, and metformin are usually necessary to reduce insulin resistance. Metformin is not recommended as a first-line therapy for cutaneous symptoms, ovulation induction, prevention of pregnancy complications, or treatment of obesity. It can, however, be used to help with many PCOS symptoms in women who have an insufficient response to dietary interventions, or who have contraindications to oral contraceptives. The use of thiazolidinediones is not recommended in PCOS patients due to safety concerns.[6]

Physical means of hair removal (e.g., electrolysis, laser treatment) may be necessary to treat hirsutism. Acne is treated with topical or oral agents if oral contraceptives are contraindicated or do not improve symptoms.

Treatment of infertility is often necessary if the patient desires pregnancy.

• Weight loss, even small reductions, and exercise may be beneficial.
• Assisted reproductive technologies (e.g., in vitro fertilization) may be necessary.
• While not approved by the Food and Drug Administration for ovulation induction, letrazole is currently preferred given evidence of higher birth rates compared to clomiphene or metformin. Metformin is used as an adjuvant treatment in those undergoing in vitro fertilization in order to prevent ovarian hyperstimulation. While evidence suggests metformin can restore ovulation, and possibly promoting weight loss by improving insulin resistance, its role in treating infertility is limited.
• Gonadatropin therapy can induce ovulation, but treatment regimens are complex and carry risk of ovarian hyerstimulation syndrome.

Nutritional Considerations

PCOS appears to be related to diet and lifestyle factors, particularly as they influence body weight, insulin resistance, inflammation, oxidative stress, and, in turn, androgen activity. Between 30-75% of women with PCOS are obese, and women with PCOS often have excess body fat, particularly central adiposity, even in the absence of obesity.[12] A meta-analysis of diet studies found that weight loss improved PCOS symptoms in overweight women regardless of diet composition.[13] Other studies have shown that losing as little as 5-10% of weight results in resumption of menses and decrease in blood androgen levels.[14]

Dietary goals should target excess weight and insulin resistance. A low-fat, plant-based diet causes weight loss and reduces insulin resistance, which affects 50-70% of women with PCOS.[15] This is particularly important because of insulin’s tendency to reduce sex hormone-binding globulin (SHBG) and increase free testosterone concentrations.[16] Low-fat, high-fiber diets reduce circulating androgens, increase SHBG, and effectively address dyslipidemia (elevated triglycerides, low HDL) and elevations of C-reactive protein and homocysteine.[17]

Diets high in fruits, vegetables, whole grains, and legumes also reduce oxidative stress and inflammation.[18] These may be involved in PCOS for several reasons. First, a genetic basis exists for the inflammation found in PCOS, with polymorphisms for proinflammatory cytokines (e.g., tumor necrosis factor, interleukin-6) being found independent of obesity and in association with insulin resistance.[19] Second, a systematic review and meta-analysis found that several markers of oxidative stress were altered in women with PCOS, independent of obesity.[10] Oxidative stress impairs glucose uptake in muscle and adipose tissue in humans. In contrast, animal products and processed foods should be minimized or avoided. These foods contain cholesterol oxidation products and lipid peroxides that increase both oxidative stress and inflammation.[20]

One of the key nutrients in a diet that emphasizes whole grain intake, legumes, and nuts in place of refined carbohydrates is inositol hexaphosphate (Ip6, phytic acid). In clinical trials, inositol has been shown to improve insulin action, decrease androgen levels, and improve ovulatory function in both lean and obese women with PCOS.[21][22][23] The benefits of metformin in PCOS appear at least partly due to increasing inositol availability.[24]

A dietary supplement with at least the minimum intake of the trace mineral chromium (i.e., the Recommended Daily Allowance of 25 μg/day) may be helpful, for several reasons. Insulin-resistant women with PCOS were found to have significantly lower serum chromium levels compared with controls.[25] Double-blind, randomized controlled trials have shown that women with PCOS who were given supplemental chromium (between 200 and 1,000 μg/day) experienced significant improvements in insulin resistance.[26][27] In addition, a recent NHANES cohort study of more than 28,000 individuals found that individuals taking a dietary supplement containing chromium had a 27% lower risk for developing type 2 diabetes compared with those who took supplements without chromium.[28] Chromium supplementation has also been shown in women with PCOS to significantly improve the chances of ovulation and reduce hirsutism.[29]

Orders

See Basic Diet Orders chapter.

Exercise prescription.

Smoking cessation counseling, if appropriate.

Mood disorder screening, if appropriate.

What to Tell the Family

PCOS can often be effectively treated through dietary changes, weight loss, and medical therapies. Diets that are low in fat and high in fiber are likely to achieve the best results, particularly when coupled with exercise. Families of affected patients would do well to adopt a similar diet and increased exercise to facilitate the patient’s adherence, as well as for their own health benefits.

References

1. Stein IF, Leventhal ML. Amenorrhea associated with bilateral polycystic ovaries. Am J Obstet Gynecol. 1935;29:181-191.
2. Alpañés M, Fernández-Durán E, Escobar-Morreale HF. Androgens and polycystic ovary syndrome. Expert Rev Endocrinol Metab. 2012;7(1):91-102. [PMID:30736114]
3. American College of Obstetricians and Gynecologists' Committee on Practice Bulletins—Gynecology. ACOG Practice Bulletin No. 194: Polycystic Ovary Syndrome. Obstet Gynecol. 2018;131(6):e157-e171. [PMID:29794677]
4. Bozdag G, Mumusoglu S, Zengin D, et al. The prevalence and phenotypic features of polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod. 2016;31(12):2841-2855. [PMID:27664216]
5. Rosenfield RL, Ehrmann DA. The Pathogenesis of Polycystic Ovary Syndrome (PCOS): The Hypothesis of PCOS as Functional Ovarian Hyperandrogenism Revisited. Endocr Rev. 2016;37(5):467-520. [PMID:27459230]
6. Legro RS, Arslanian SA, Ehrmann DA, et al. Diagnosis and treatment of polycystic ovary syndrome: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2013;98(12):4565-92. [PMID:24151290]
7. Vink JM, Sadrzadeh S, Lambalk CB, et al. Heritability of polycystic ovary syndrome in a Dutch twin-family study. J Clin Endocrinol Metab. 2006;91(6):2100-4. [PMID:16219714]
8. Franks S, McCarthy MI, Hardy K. Development of polycystic ovary syndrome: involvement of genetic and environmental factors. Int J Androl. 2006;29(1):278-85; discussion 286-90. [PMID:16390494]
9. Joffe H, Taylor AE, Hall JE. Polycystic ovarian syndrome--relationship to epilepsy and antiepileptic drug therapy. J Clin Endocrinol Metab. 2001;86(7):2946-9. [PMID:11443148]
10. Kandaraki E, Chatzigeorgiou A, Livadas S, et al. Endocrine disruptors and polycystic ovary syndrome (PCOS): elevated serum levels of bisphenol A in women with PCOS. J Clin Endocrinol Metab. 2011;96(3):E480-4. [PMID:21193545]
11. Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod. 2004;19(1):41-7. [PMID:14688154]
12. Murri M, Luque-Ramírez M, Insenser M, et al. Circulating markers of oxidative stress and polycystic ovary syndrome (PCOS): a systematic review and meta-analysis. Hum Reprod Update. 2013;19(3):268-88. [PMID:23303572]
13. 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):520-45. [PMID:23420000]
14. Stamets K, Taylor DS, Kunselman A, et al. A randomized trial of the effects of two types of short-term hypocaloric diets on weight loss in women with polycystic ovary syndrome. Fertil Steril. 2004;81(3):630-7. [PMID:15037413]
15. Hahn S, Tan S, Elsenbruch S, et al. Clinical and biochemical characterization of women with polycystic ovary syndrome in North Rhine-Westphalia. Horm Metab Res. 2005;37(7):438-44. [PMID:16034717]
16. Holte J. Polycystic ovary syndrome and insulin resistance: thrifty genes struggling with over-feeding and sedentary life style? J Endocrinol Invest. 1998;21(9):589-601. [PMID:9856413]
17. Berrino F, Bellati C, Secreto G, et al. Reducing bioavailable sex hormones through a comprehensive change in diet: the diet and androgens (DIANA) randomized trial. Cancer Epidemiol Biomarkers Prev. 2001;10(1):25-33. [PMID:11205485]
18. Johnston C. Functional Foods as Modifiers of Cardiovascular Disease. Am J Lifestyle Med. 2009;3(1 Suppl):39S-43S. [PMID:20368755]
19. Escobar-Morreale HF, Luque-Ramírez M, González F. Circulating inflammatory markers in polycystic ovary syndrome: a systematic review and metaanalysis. Fertil Steril. 2011;95(3):1048-58.e1-2. [PMID:21168133]
20. Surai KP, Surai PF, Speake BK, Sparks NHC. Antioxidant-prooxidant balance in the intestine: food for thought. 1. Prooxidants. Nutr Genomics Functional Foods. 2003;1:51-70.
21. Nestler JE, Jakubowicz DJ, Reamer P, et al. Ovulatory and metabolic effects of D-chiro-inositol in the polycystic ovary syndrome. N Engl J Med. 1999;340(17):1314-20. [PMID:10219066]
22. Gerli S, Mignosa M, Di Renzo GC. Effects of inositol on ovarian function and metabolic factors in women with PCOS: a randomized double blind placebo-controlled trial. Eur Rev Med Pharmacol Sci. 2003;7(6):151-9. [PMID:15206484]
23. Bizzarri M, Carlomagno G. Inositol: history of an effective therapy for Polycystic Ovary Syndrome. Eur Rev Med Pharmacol Sci. 2014;18(13):1896-903. [PMID:25010620]
24. Baillargeon JP, Jakubowicz DJ, Iuorno MJ, et al. Effects of metformin and rosiglitazone, alone and in combination, in nonobese women with polycystic ovary syndrome and normal indices of insulin sensitivity. Fertil Steril. 2004;82(4):893-902. [PMID:15482765]
25. Chakraborty P, Ghosh S, Goswami SK, et al. Altered trace mineral milieu might play an aetiological role in the pathogenesis of polycystic ovary syndrome. Biol Trace Elem Res. 2013;152(1):9-15. [PMID:23322284]
26. Jamilian M, Asemi Z. Chromium Supplementation and the Effects on Metabolic Status in Women with Polycystic Ovary Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial. Ann Nutr Metab. 2015;67(1):42-8. [PMID:26279073]
27. Ashoush S, Abou-Gamrah A, Bayoumy H, et al. Chromium picolinate reduces insulin resistance in polycystic ovary syndrome: Randomized controlled trial. J Obstet Gynaecol Res. 2016;42(3):279-85. [PMID:26663540]
28. McIver DJ, Grizales AM, Brownstein JS, et al. Risk of Type 2 Diabetes Is Lower in US Adults Taking Chromium-Containing Supplements. J Nutr. 2015;145(12):2675-82. [PMID:26446484]
29. Jamilian M, Bahmani F, Siavashani MA, et al. The Effects of Chromium Supplementation on Endocrine Profiles, Biomarkers of Inflammation, and Oxidative Stress in Women with Polycystic Ovary Syndrome: a Randomized, Double-Blind, Placebo-Controlled Trial. Biol Trace Elem Res. 2016;172(1):72-78. [PMID:26613790]