Polycystic Ovary Syndrome:
Clinical Considerations

This section is compiled by Frank M. Painter, D.C.
Send all comments or additions to:    Frankp@chiro.org

FROM:   Alternative Medicine Review 2001 (Jun); 6 (3): 272-292 ~ FULL TEXT

Keri Marshall, ND Candidate 2001

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Polycystic ovary syndrome (PCOS) is one of the most frequently encountered endocrine disorders occurring in women of reproductive age. Clinically, a patient usually presents with menstrual irregularities, infertility, and hirsutism. If not treated properly, a patient is at risk for type 2 diabetes, cardiovascular disease, and hyperestrogen-related cancers. The hallmark endocrine disorders of this syndrome are hyperandrogenism and hyperinsulinemia. Great controversy exists as to which state precedes the other. There also appears to be a defect in the hypothalamic-pituitary-adrenal (HPA) axis in patients presenting with polycystic ovary syndrome. Research consistently demonstrates that the first line of treatment for this condition is weight loss. Weight loss and dietary changes appear to affect all parameters of hormonal fluctuation. Due to the vast array of side effects associated with many pharmaceutical agents typically prescribed to treat PCOS, natural therapeutics including nutrient supplementation and botanicals may be a less invasive and equally effective approach. Due to the seriousness of this syndrome when left untreated, prompt evaluation and treatment is essential.

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Introduction

Polycystic ovary syndrome (PCOS) is a prevalent and frequently encountered endocrine disorder. [1] It has been suggested that this condition occurs in as many as 4-10 percent of women of reproductive age, [2] with onset manifesting as early as puberty. [3] Because of the diversity of clinical and metabolic findings in PCOS, there has been great debate as to whether it represents a single disorder or multiple associated pathologic conditions. PCOS is primarily characterized by hyperandrogenism, insulin resistance, and chronic anovulation. [4] Hyperandrogenism and insulin were linked as early as 1921, when Achard and Thiers published a classic description of bearded women with diabetes. [5] However, polycystic ovary syndrome was not described until 1935, when Stein and Leventhal described the syndrome as having pathognomonic ovarian findings and the clinical triad of hirsutism, amenorrhea, and obesity. [6] Today, a patient usually presents clinically with concerns regarding menstrual irregularities, infertility, and hirsutism. The syndrome is also associated with dyslipidemia and acanthosis nigricans, [7] and may increase the risk for cardiovascular disease [8] and hyperestrogen-related cancers such as endometrial [9] and breast [10] cancers. During the reproductive years, PCOS is associated with significant reproductive morbidity, including infertility, abnormal uterine bleeding, miscarriage, and other complications of pregnancy. [11]

PCOS usually begins in adolescence, and it is difficult to predict whether the symptoms of the syndrome will self correct or persist into adulthood. Up to 50 percent of women affected with PCOS are obese, a condition that has been found to increase the magnitude of underlying insulin resistance. [12] Obesity tends to be less of a problem in women with PCOS in the adolescent population. [13] However, both the adolescent and middle age groups tend to have android body types, with waist-to-hip ratios greater than 0.8, even in the presence of normal body mass index. [12] Obesity has also been linked to increased androgen production and hirsutism. [14] Because of the wide range of symptoms and maladies associated with PCOS, thorough evaluation and diagnosis is essential to prevent further pathology.

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Lifestyle Interventions

Because of potential side effects of many medications, weight reduction of obese patients should be the primary goal of treatment. The addition of antiandrogenic and insulin regulating agents should be added only to enhance the effects of weight loss. Experimental evidence has indicated that the typical western diet, which is high in fat and refined carbohydrate and low in fiber, induces insulin resistance and precedes obesity. [76] Epidemiological evidence indicates that a diet rich in fruits, vegetables, and high fiber complex carbohydrates is associated with a lower risk of chronic disease. [77,78] Studies of obese women with menstrual abnormalities have demonstrated that cycles can potentially normalize and fertility be re-established following weight loss. [79,80] Traditionally, sex steroids and thyroid hormones have been considered to be the major regulators of SHBG concentration, but dietary factors may be a more important consideration.

It has been shown that short-term treatment of obese PCOS women on a very low calorie diet (350-450 kcal per day) leads to a two-fold increase in serum SHBG levels and an accompanying fall in serum insulin. [81] This prompted a second study by the same group to question whether long-term calorie restriction and weight reduction could not only improve hormone levels, but also restore regular ovulatory menstrual cycles and fertility. Results showed that with weight loss of less than five percent there was not only significant biochemical improvement but clinical as well. Reversal of ovarian dysfunction was striking, with 82 percent of women in the group showing marked improvement in fertility, including five pregnancies in women who had long standing infertility. [82]

Insulin sensitivity has also proven to be influenced by dietary modifications, especially a low glycemic diet. Because circulating FFAs have an influence on insulin sensitivity in muscle and adipose tissue, the sensitivity of adipose tissue to insulin is thought to be a determinant of general insulin sensitivity. [83] Metabolic changes occur with increasing visceral obesity, including fasting hyperinsulinemia and decreased plasma HDL cholesterol. These metabolic atherogenic changes associated with abdominal obesity are thought to result from increased FFAs reaching the liver as a consequence of reduced visceral adipocyte insulin sensitivity. [84] This net effect suggests the body needs to decrease glucose oxidation and hepatic insulin clearance while increasing hepatic glucose production. This can be achieved by eating a low glycemic diet. The glycemic index of a carbohydrate is a measure of its postprandial effect on blood glucose. [85] The lower the glycemic index, the smaller the effect of the carbohydrate on postprandial glucose and insulin values. Because of the correlation between PCOS and hyperinsulinemia, a low glycemic diet could potentially decrease hyperinsulinemia with greater regulation of FFAs postprandially.

Recently Longcope et al analyzed data from a large cross-sectional sample from the Massachusetts Male Aging Study. After controlling for a number of confounding variables, the authors concluded that fiber intake was found to be significantly positively correlated to serum SHBG concentrations, whereas protein intake showed a clear negative association with SHBG. [86] The authors propose that as protein ingestion is known to inhibit insulin secretion, insulin has in turn been shown to inhibit hepatic SHBG production. However, dietary carbohydrate intake, a stimulus for insulin release, did not show significant association with SHBG. It is further thought that the relationship of protein to SHBG levels involves more than only an effect on insulin. Further studies need to be performed to evaluate this role.

Studies have been designed to explore caloric content and the role of dietary fat in the regulation of energy intake and weight loss. A study was performed to evaluate caloric consumption in women who each consumed a sequence of three two-week diets of low, medium, and high fat content. Results showed that by altering the type of food consumed, specifically fat, even without restrictions on amounts, spontaneous weight loss could be achieved in both obese and non-obese individuals on a low fat diet. [87]

Eating disorders and body image problems often begin in adolescence and are carried into adulthood. Because women with PCOS are often instructed by their physician to lose weight, it is important to encourage safe dietary practices. PCOS has been associated with a high incidence of eating disorders, including binge eating and fasting. [88] The extreme variations in energy intake of these behaviors may contribute to or exacerbate insulin resistance as well as be associated with thyroid conditions, particularly hypothyroidism. All women with PCOS should be evaluated for eating disorders, especially in the adolescent population.

Physical exercise can be an important adjunct in the prevention and treatment of insulin resistance. In the context of overall glucose homeostasis, a single instance of exercise can markedly increase rates of whole body glucose disposal [89] and increase the sensitivity of skeletal muscle glucose uptake to insulin. [90] These effects can last for several hours after completion of exercise. During insulin-stimulated conditions, fatty acid oxidation in skeletal muscles is normally suppressed, yet incomplete suppression of fatty acid oxidation occurs in obesity-related insulin resistance. [91] A prospective clinical study revealed that reduced fatty acid oxidation is a metabolic risk factor for weight gain and that enzyme activities within skeletal muscle pertaining to lipid metabolism might contribute to lower fatty acid concentrations. [92,93] Moreover, after weight loss, skeletal muscle in post-obese individuals may continue to be inefficient in the oxidation of fat. Reduced activity of oxidative enzymes in skeletal muscle has been found in obesity and insulin resistance. [94] Improvements in insulin responsiveness can last up to two weeks in trained individuals, but can begin to decline within one week in untrained or obese individuals. This clearly indicates that regular physical activity is required to have a lasting effect on insulin responsiveness.

In an observational study of adolescent women with PCOS, van Hooff et al found a significant decrease in the frequency of self-reported acne, dysmenorrhea, and menstrual irregularities in those engaging in more than eight hours of sporting activity per week. [47] Although few studies have reported on the link between exercise and PCOS, clear associations have been made with regard to exercise and its effects on obesity and insulin resistance.

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Nutritional Supplementation

Many of the conventional treatments being utilized are not specific for PCOS but have been used because the mechanisms of action indicate a potential benefit. There are a number of natural products which may have potential benefit without the possible side effects of abnormal uterine bleeding, weight gain, and liver failure seen with some of the conventional approaches.

Dietary Fiber   The health benefits of dietary fiber in reducing the risk of chronic disease have been well-established. [95] Several characteristics of dietary fiber have been established, including the bulking effect that increases fecal volume, limits caloric intake, slows stomach emptying, and dilutes the content of urine. [96] Dietary fiber also has the capacity to bind and eliminate organic compounds, which could reduce the interaction of potentially carcinogenic compounds within the intestinal mucosa. Several lines of evidence also suggest that dietary fiber may play a key role in the regulation of circulating insulin levels. Fiber reduces insulin secretion by slowing the rate of nutrient absorption following a meal. [97] Studies show that insulin sensitivity increases [98] and body weight decreases in people on high fiber diets. [99] A recent study in The Journal of the American Medical Association (JAMA) confirmed that fiber consumption could predict insulin levels, weight gain, and other cardiovascular risk factors more strongly than saturated fat consumption. [100]

Flaxseed   Flaxseed is one of the most significant sources of plant lignans, one of the main classes of estrogenic compounds called phytoestrogens. [101] Phytoestrogens represent a family of plant compounds that have been shown to have both estrogenic and antiestrogenic properties. Flaxseed and its isolated lignans have been shown to have numerous chemoprotective effects both in vitro and in vivo. Many of the chemoprotective effects may be mediated through their influence on endogenous sex hormone production, metabolism, and biological activity. Consumption of flaxseed and its isolated lignans have been shown to stimulate SHBG synthesis, [102] as well as reduce mammary tumor growth [103] and formation. [104] Changes in total hormone concentration result in relatively small changes in the size of free hormone fraction, whereas changes in SHBG concentration result in relatively large changes in the amount of free and bound hormones. Both lignans and isoflavones have been reported to stimulate the synthesis of SHBG by Hep G2 liver cancer cells in culture. [105] This is consistent with an observational study of 34 women in whom urinary lignan concentrations significantly and directly correlated with SHBG concentrations and inversely correlated with the proportion and concentration of free estradiol. [106] Although the association between the intake of phytoestrogens, specifically flaxseed, and increases in SHBG concentration is still quite weak, it shows great potential for phytoestrogens as a means of reducing free estrogen concentrations. [105]

Fish Oil   Adjusting the quality of food eaten ­ specifically fats ­ appears to be an important component of treatment of PCOS. The fatty acid components of dietary lipids not only influence hormonal signaling events by modifying membrane lipid composition, but fatty acids may directly influence molecular events that govern gene expression. It is thought that this regulation of gene expression by dietary fats has the greatest impact on the development of obesity and insulin resistance.107 Fish oils, which are comprised of the essential fatty acids eicosapentaenoic acid (EPA, C20:5n-3) and docosahexaenoic acid (DHA, C22:6n-3), fall into a larger category of fats called polyunsaturated fatty acids (PUFAs). Compared to other types of fats, PUFAs are more readily used for energy and enhance the rate of glycogen storage, which allows the skeletal muscle to increase its uptake of glucose, even under conditions where fatty acid oxidation is accelerated. The same studies have also found that ingestion of fish oils decreases lipid droplet size and number, which has been found to improve insulin sensitivity. [108] More specifically, fish oils have been shown to increase thermogenesis, decrease body fat deposition, and improve glucose clearance. [107] Clinical trials have shown that a dose of 4 g/day is effective at regulating postprandial lipemia. [109]

D-chiro-inositol   Recent studies have suggested that women with PCOS may have insulin resistance and hyperinsulinemia due to a D-chiro-inositol deficiency. D-chiro-inositol is a component of a phosphoglycan that has been shown to mediate the action of insulin. The amount of chiro-inositol in muscle has been shown to be lower in subjects with type 2 diabetes than in normal subjects. [110] A study in The New England Journal of Medicine by Nestler et al found that 1200 mg D-chiro-inositol daily had multiple beneficial effects in the treatment of PCOS. [111] Not only did inositol increase the action of insulin, but 86 percent of the women ovulated during treatment with D-chiro-inositol compared to only 27 percent in the placebo group. Serum androgen levels also decreased in the treatment group, as did ovarian androgen production as reflected by a decreased 17a-hydroxyprogesterone response to leuprolide. Additionally, the women in the treatment group had decreases in both systolic and diastolic blood pressures and plasma triglyceride concentrations.

Chromium   Chromium is one of the most widely studied nutritional interventions in the treatment of glucose- and insulin-related irregularities. While research shows a clear link between chromium and glucose metabolism, evidence for its interaction in insulin resistant states is a bit more ambiguous. Chromium picolinate is the form of chromium which has been used in a number of studies on insulin resistance. In a study by Anderson et al on non-diabetic individuals with moderate post-glucose challenge hyperglycemia, a dose of 200 mcg chromium picolinate resulted in improvements in both glucose tolerance and circulating insulin levels. These changes were assumed to be due in part to increased tissue sensitivity to insulin. [112] Further studies by Anderson et al investigated the use of chromium picolinate as the sole treatment for type 2 diabetic patients. Patients were instructed to resume normal dietary and lifestyle habits during the treatment period. Subjects were assigned to one of three treatment groups: placebo, 100 mcg chromium picolinate twice daily, or 500 mcg chromium picolinate twice daily. Both fasting and two-hour postprandial glucose levels significantly decreased for both chromium treatment groups, suggesting an improvement in insulin resistance with chromium supplementation. [113]

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