Polycystic Ovary Syndrome:
Clinical Considerations

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

Abstract

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.


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 disease⁸ and hyperestrogen-related cancers such as endometrial⁹ and breast¹⁰ 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.


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 disposal⁸⁹ 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.


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 increases⁹⁸ 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 growth¹⁰³ 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


Botanical Influences

Urtica Dioica

Urtica dioica, more commonly known as stinging nettle, has proven to have in vitro effects on SHBG. The roots of the stinging nettle contain a complex mixture of water and alcohol-soluble compounds including lectins, phenols, sterols, and lignans. The positive effects of the nettle extract are thought to be due to the lignans, which are predominantly in the glycoside form. The glycosides are cleaved in the digestive process with the intestinal microbial transformation products displaying a binding affinity to SHBG.¹¹⁴ Furthermore, lignans may influence the blood levels of free, active steroid hormones by displacing them from the SHBG binding site.¹¹⁵ Steroid hormones, as well as Urtica lignans, may inhibit the binding of SHBG to its receptor. This reaction would cause an increase in SHBG levels. SHBG is an allosteric protein in which the protein-receptor interaction depends on the occupancy of the steroid binding site. Bound to the receptor, SHBG is still able to bind to sex steroids, which results in the generation of the second messenger cAMP inside the cell.¹¹⁶ This reaction depends on the lignans of SHBG. An in vitro study by Hryb et al, examining the binding of SHBG to a soluble extract of human prostatic membranes, showed a dose-related inhibition of binding of SHBG to its receptor, thus increasing the levels of circulating SHBG.¹¹⁷ Although no human studies have been done, U. dioica root shows great promise in the treatment of PCOS by up-regulating circulating SHBG.

Serenoa Repens

Serenoa repens (saw palmetto) is one of the most widely used botanicals in the treatment of BPH. Once again, although studies have not been conducted on the use of Serenoa in the treatment of PCOS, this herb has been found to be comparable to the pharmaceutical agent finasteride for the treatment of BPH. The therapeutic extract is from the dried ripe fruit of the American dwarf saw palmetto plant. The Native Americans in Florida first used berries from the saw palmetto in the early 1700s to treat testicular atrophy, erectile dysfunction, and prostate gland swelling or inflammation.¹¹⁸ The mechanisms of action are not completely understood, but are believed to involve altered cholesterol metabolism,¹¹⁹ and antiestrogenic, antiandrogenic, and anti-inflammatory properties.¹²⁰ In an in vitro study by Bayne et al Serenoa exhibited marked inhibition of 5-alpha-reductase on epithelial and fibroblastic cells from samples of prostate tissue of men with BPH. Samples were obtained from the men following transurethral resection. The study also demonstrates that PSA levels did not rise with administration of Serenoa, suggesting this botanical does not interfere with other androgen-dependent processes, as do some pharmaceutical agents like the drug finasteride.¹²¹

A study in JAMA reviewed 18 randomized, controlled trials involving men with symptomatic BPH and treatment with a preparation of Serenoa alone or in combination with other phytotherapeutic agents. Sixteen of the studies were double-blinded. Treatment groups received either Serenoa, a placebo, or another pharmacological therapy for BPH. Overall, compared to men receiving placebo, men treated with Serenoa had notable improvement in self-rating of urinary tract symptoms, suggesting improvement in androgen regulation. A dosage of approximately 320 mg/day has been established as a safe and effective dose for the treatment of BPH and other androgen-related conditions.¹²² Studies on its use in PCOS are warranted.

Vitex agnus-castus

Vitex agnus-castus, commonly known as chastetree berry, has traditionally been used to treat menstrual irregularities, specifically to help establish a normal menstrual cycle and improve fertility. Vitex does not contain hormones but it is thought to exert hormonal activity by its action on the pituitary gland, specifically on the production of luteinizing hormone. It is thought Vitex has an adaptogenic effect on the anterior pituitary in the regulation of LH release. LH stimulates corpus luteal secretions after ovulation to produce progesterone, which ultimately regulates a woman's cycle. A double-blind study was conducted on 96 women with infertility, using 1.8 mL Vitex extract or placebo for three months. Results demonstrated that 56 percent of women using Vitex either became pregnant or resumed normal menstruation. The same group of women also had an increase in luteal hormone concentrations, compared to only 36 percent in the placebo group.¹²³ During the trial a total of 15 pregnancies occurred. The use of Vitex in the treatment of PCOS-related menstrual irregularities appears to show promise with regard to helping establish normal menstrual cycles and fertility.

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