Polycystic Ovary Syndrome
PCOS Nutritional Protocol
“Inositol” is a term used to refer to a group of naturally occurring carbohydrate compounds that exist in nine possible chemical orientations called stereoisomers. The most common being myo-inositol, which is often sold as a dietary supplement labeled simply as inositol.
Inositol, particularly myo-inositol and another less common stereoisomer called D-chiro-inositol, plays a critical, but underappreciated, role in insulin signaling. Conditions such as hyperglycemia and diabetes are associated with disrupted inositol signaling, leading many researchers to suggest that this may be a key pathologic feature of insulin resistance (Manning 2010, Larner 2010).
Research has shown that the three inositol family members help to ameliorate conditions in which insulin resistance plays an important role, especially PCOS.
D-chiro inositol is perhaps the most promising inositol compound for PCOS. Our bodies produce D-chiro-inositol only after extensive inositol metabolism. DCI interacts with select sugars in the body to form conjugates known as inositiol phosphoglycans, which play a key role in mediating insulin actions. Low levels of DCI, and inositol phosphoglycans have been observed in individuals with impaired insulin sensitivity and PCOS (Susuki 1994, Jung 2005, Cheang 2008, Baillargeon 2010).
In one study, 44 overweight women with PCOS were given a daily 1,200 mg dose of D-chiro-inositol for six to eight weeks. During the course of the study, those who took DCI displayed significant improvements in insulin sensitivity, blood pressure, and triglyceride levels, as well as a marked decrease in serum testosterone levels. Moreover, 19 of 22 subjects receiving DCI ovulated during the study period, compared to only 6 of 22 in the placebo group. The investigators concluding statement highlights the efficacy of DCI in PCOS: “D-Chiro-inositol increases the action of insulin in patients with the polycystic ovary syndrome, thereby improving ovulatory function and decreasing serum androgen concentrations, blood pressure, and plasma triglyceride concentrations.” (Nestler 1999).
Similarly promising results were drawn from another study involving lean women with PCOS. Here, participants received 600 mg daily of DCI or a placebo for six to eight weeks. The DCI-treated participants improved significantly, displaying a large decrease of 73% in testosterone levels versus no change in the placebo group. Women taking DCI also experienced reductions in insulin and triglyceride levels and blood pressure, whereas none of these changes were evident in the placebo group (Luorno 2002).
Researchers looking at the effects of metformin in PCOS women concluded that the drug’s benefits could be related to its ability to improve the function of DCI phosphoglycans in the body. Thus, it appears that DCI may be highly effective when used in combination with metformin for PCOS (Baillargeon 2004).
Myo-inositol is a stereoisomer of DCI. Like DCI, it is a key factor in insulin signaling, and serves also as a precursor to DCI in endogenous inositol metabolism. It should then come as no surprise that studies using myo-inositol in women with PCOS produced results as promising as those obtained with DCI.
Double-blind, placebo-controlled investigations were carried out in 42 women with PCOS, subjects receiving myo-inositol fared much better when compared to the placebo group, displaying decreases in testosterone, triglycerides, and blood pressure; a significant improvement in insulin sensitivity; and a greatly increased frequency of ovulation (Costantino 2009).
In another study, 20 women with PCOS were given either 2 grams of myo-inositol plus 200 mcg folic acid, or a placebo of 200 mcg folic acid daily. After 12 weeks, the women taking myo-inositol showed improved insulin sensitivity and androgen levels. Strikingly, all the subjects receiving myo-inositol returned to normal menstrual cycles (Genazzani 2008).
In an Italian study of 92 PCOS patients, almost 50% showed significant weight loss and reduced leptin levels after receiving myo-inositol plus folic acid (4 g myo-inositol plus 400 mcg folic acid). After a 14-wk treatment, the myo-inositol plus folic acid group lost weight, whereas the placebo group gained weight (Gerli 2007).
A six-month study involving 50 PCOS women yielded similar results and gave researchers the time to evaluate the effects of myo-inositol on hirsutism. Along with decreases in testosterone and insulin levels, the participants who supplemented with myo-inositol experienced a reduction in hirsutism, and improvements in skin appearance, leading researches to conclude, “Myo-inositol administration is a simple and safe treatment that ameliorates the metabolic profile of patients with PCOS, reducing hirsutism and acne.” (Zacchè 2009).
In other well-designed clinical trials for follicular maturity and ovulation induction, myo-inositol has produced promising results, cementing its position as a novel therapy for PCOS management (Papaleo 2007, Papaleo 2009).
D-Pinitol is 3-O-methyl-D-chiro-inositol that occurs naturally in several different foods, including legumes and citrus fruits (Kang 2006). D-Pinitol is converted into d-chiro-inositol in the body. Like d-chiro-inositol, pinitol appears to favorably influence the action of insulin (Bates 2000). In a double-blind study of patients with type 2 diabetes, administration of 600 mg of pinitol twice a day for three months reduced blood glucose concentration by 19.3%, decreased hemoglobin A1c (HbA1c) concentration by 12.4% and significantly improved insulin resistance (Kim 2007). In a shorter-term double-blind study, administration of pinitol at a dose of 20 mg per kg of body weight per day for four weeks decreased mean fasting plasma glucose concentration by 5.3% (Kim 2005).
N-acetyl cysteine (NAC)
N-acetyl-cysteine (NAC) is a stable derivative of the sulfur-containing amino acid cysteine and an antioxidant that is needed for the production of glutathione, one of the body's most important natural antioxidants and detoxifiers. While cysteine is found in high protein foods, n-acetyl cysteine is not. A large body of evidence supports the use of NAC in women with PCOS.
- Improving Insulin Sensitivity
Women with PCOS frequently have an abnormally high insulin response to sugars and refined starches. A 2002 study evaluated the effect of NAC on insulin secretion and peripheral insulin resistance in women with PCOS (Fulghesu 2002). The study subjects who had an exaggerated insulin response to a glucose challenge and were treated with NAC showed an improvement in insulin function in their peripheral tissues. The NAC treatment also produced a significant decline in testosterone levels and in free androgen index values. The researchers concluded, "NAC may be a new treatment for the improvement of circulating insulin levels and insulin sensitivity in hyperinsulinemic patients with polycystic ovary syndrome." (Abu 2010)
- Restoring Fertility
NAC may also be useful for improving fertility in women with PCOS. In one study, NAC appeared to improve the effects of Clomid®, the widely used fertility drug. Clomid® plus NAC significantly improved ovulation rates in a study of 573 women with PCOS. According to the researchers, 52% of the study participants who took Clomid® plus NAC ovulated, whereas only 18% ovulated in the Clomid® alone group. The authors concluded: "N-Acetyl cysteine is proved effective in inducing or augmenting ovulation in polycystic ovary patients." (Badawy 2007).
Similarly, a study of Clomid®-resistant women has shown that NAC appears to make Clomid® more effective. In the study, 150 Clomid®-resistant women with PCOS were divided into two groups: one group took Clomid® and NAC. The other group took Clomid® and a placebo. In the NAC group, 49.3% ovulated and 1.3% became pregnant. In contrast, in the placebo group, only 21% ovulated and there were no pregnancies (Rizk 2005).
Worth noting, the same researchers compared the effects of a NAC- Clomid® combination with the metformin- Clomid® combination on ovulation induction in anovulatory Clomid®-resistant women with PCOS. The efficacy of the metformin- Clomid® combination therapy is significantly higher than that of NAC-Clomid® for inducing ovulation and achieving pregnancy among Clomid®-resistant PCOS patients (Abu 2010).
- Tackling Homocysteine
Women with PCOS are often given metformin to deal with their insulin problems. But metformin may increase homocysteine levels and many women with PCOS have high homocysteine levels to begin with (Badaway 2007). Elevated homocysteine is associated with coronary artery disease, heart attack, chronic fatigue, fibromyalgia, cognitive impairment, and cervical cancer. A 2009 study showed that people taking NAC for two months had a significant decrease in homocysteine levels (Rymarz 2009).
Many women with PCOS have significantly low serum and total magnesium, contributing to the progression of insulin resistance to type 2 diabetes and heart disease (Kauffman 2011).
Magnesium insufficiency is common in poorly controlled type 2 diabetes patients. In one study, 128 patients with poorly controlled type 2 diabetes received a placebo or a supplement with either 500 mg or 1000 mg of magnesium oxide (300 mg or 600mg element magnesium) for 30 days. All patients were treated also with diet or diet plus oral medication to control blood glucose levels. Magnesium levels increased in the group receiving 1,000 mg magnesium oxide daily but did not significantly change in the placebo group or the group receiving 500 mg of magnesium. The author suggested prolonged use of magnesium in doses that are higher than usual is needed in patients with type 2 diabetes to improve control or prevent chronic complications (De Lourdes Lima 1998).
In a related study, 63 diabetics with below normal serum magnesium levels received either 2.5 grams of oral magnesium chloride daily or a placebo. At the end of the 16-week study period, those who received the supplement had higher blood levels of magnesium and improved control of diabetes, as suggested by lower hemoglobin A1c (HbA1c) levels (Rodriguez-Moran 2003).
Another study found that oral magnesium supplements helped insulin resistant individuals avoid developing type 2 diabetes (Mooren 2011).
Since magnesium improves insulin-mediated glucose uptake and insulin secretion in type 2 diabetes patients, it is considered a critical mineral for women with PCOS.
Research shows a clear link between chromium and glucose metabolism. Indeed, chromium is one of the most widely studied nutritional interventions in the treatment of glucose and insulin-related irregularities. Chromium picolinate specifically is the form that has been used in a number of studies on insulin resistance. Researchers at the University of Texas Health Science Center at San Antonio found that chromium picolinate (200 mcg/day) improves glucose tolerance when compared with a placebo (Lucidi 2005) in women with PCOS.
Overwhelming evidence suggests that lipoic acid may be critical not only for maintaining optimal blood sugar levels (by helping the body use glucose), but also for supporting insulin sensitivity and key aspects of cardiovascular health, such as endothelial function. A review of experimental studies reveals that lipoic acid helps relieve several components of metabolic syndrome—a constellation of risk factors that often precedes full-blown type 2 diabetes. It appears that lipoic acid reduces blood pressure and insulin resistance, improves lipid profile, and reduces weight. Based on the results of key clinical studies, scientists are sanguine about lipoic acid’s potential as a therapeutic agent for individuals with metabolic syndrome (Pershadsingh 2007). Similarly positive effects have been observed in women with PCOS. In a 16-week study, women with PCOS were given 600 mg of lipoic acid twice daily, and, over the course of the study period, exhibited a sharp improvement in insulin sensitivity, and a reduction in triglycerides. Lipoic acid therapy also is associated with an improved LDL-particle pattern (or “bad” cholesterol particles), indicating a reduction in cardiovascular risk (Masharani 2010).
In an insightful associative study that highlighted the link between PCOS and vitamin D status, researchers found that women with higher blood levels of vitamin D were much less likely to be insulin resistant (Wehr 2011). A separate study found that vitamin D when administered with metformin was helpful for regulating the menstrual cycles in PCOS women (Rashidi 2009).
A study conducted by researchers at Columbia University found that Vitamin D combined with calcium supplementation helped normalize menstrual cycles for seven of 13 women with PCOS. Of the seven, two became pregnant and the others maintained normal menstrual cycles. These results suggest that abnormalities in calcium balance may be responsible, in part, for the arrested follicular development in women with PCOS and contribute to its pathogenesis (Thys-Jacobs 1999).
Omega-3 Fatty Acids
Evidence suggests that the anti-inflammatory activity of omega-3 fatty acids ameliorates non-alcoholic fatty liver disease, a common condition in women with PCOS. In an Australian study, omega-3 fatty acid supplementation reduced liver fat content and other cardiovascular risk factors in women with PCOS, including triglycerides, and systolic and diastolic blood pressure. In particular, said the researchers, omega-3 fatty acids were helpful in reducing hepatic fat in PCOS women with hepatic steatosis, which is defined as liver fat content greater than 5% (Cussons 2009).
The powerful lignans—plant compounds that have both estrogenic and antiestrogenic properties—in flaxseed may help reduce androgen levels in PCOS women. Flaxseed consumption have been shown to stimulate sex hormone-binding globulin (SHBG) synthesis (Shultz 1991). Changes in SHBG concentration result in relatively large changes in the amount of free and bound hormones.
In a 2007 study, daily flaxseed supplementation reduced androgen levels and hirsutism in PCOS patients, leading researchers to conclude, “The clinically-significant decrease in androgen levels with a concomitant reduction in hirsutism reported in this case study demonstrates a need for further research of flaxseed supplementation on hormonal levels and clinical symptoms of PCOS.” (Nowak 2007).
Scientists at the US Department of Agriculture (USDA) have been studying the effect of cinnamon on blood glucose for over a decade, leading to several interesting discoveries, including that of unique compounds in cinnamon bark that in laboratory studies produce a 20-fold increase sugar metabolism (Broadhurst 2000, Cao 2010). According to one government expert, “These polyphenolic polymers found in cinnamon may function as antioxidants, potentiate insulin action, and may be beneficial in the control of glucose intolerance and diabetes.” (Anderson 2004).
In a 2003 study, 60 diabetics taking 1, 3, or 6 grams/day of ground cinnamon for 40 days lowered their fasting serum glucose by 18% to 29%; triglycerides by 23% to 30%; LDL cholesterol by 7% to 27%; and total cholesterol by 12% to 26% (Khan 2003).
A 2007 study by researchers at Columbia University found that cinnamon reduced insulin resistance in fifteen women with PCOS. In the study, the women were divided into two groups: one group took cinnamon extract while the other group took a placebo. After 8 weeks, the cinnamon group showed significant reductions in insulin resistance while the placebo group did not. The authors did point out that, "A larger trial is needed to confirm the findings of this pilot study and to evaluate the effect of cinnamon extract on menstrual cyclicity."(Wang 2007).
A 2004 study by Italian researchers investigated the effect of licorice on androgen metabolism in nine healthy 22-26 year old women in the luteal phase of their menstrual cycle and found that licorice reduces serum testosterone. The authors suggested that licorice could be considered an “adjuvant therapy of hirsutism and polycystic ovary syndrome." This study was the first to follow up on earlier trials, which found that an herbal formula containing licorice reduced testosterone secretion in women with polycystic ovary syndrome (Armamani 2004, Takahashi 1988, Takeuchi 1991).
Spironolactone (Aldactone), an antagonist of mineralocorticoid and androgen receptors, is used as a primary medical treatment for hirsutism and female pattern hair loss. It is also associated with several side effects related to the diuretic activity of spironolactone. Interestingly, licorice was shown in a study of women with PCOS to counteract the side effects of spironolactone when the two were used in combination (Armanini 2007).
Green Tea: (epigallocatechin gallate, EGCG)
Green tea may be of benefit to women with PCOS. Green tea is known to have positive effects on glucose metabolism (Tsuneki 2004). In both human and animal studies, green tea has been shown to improve insulin sensitivity (Potenza 2007, Venables 2008). Animal research suggests that green tea epigallocatechin gallate (EGCG) may help prevent the onset of type 2 diabetes and slow its progression (Wolfram 2006). A clinical study from Japan found that daily supplementation of green tea extract lowered the hemoglobin A1c (HbA1c) level in individuals with borderline diabetes (Fukino 2008). Hemoglobin A1c is a form of hemoglobin that is used to help identify plasma glucose concentration over a period of time.
Green tea also is thought to lower TNF-alpha (Ivanov 2006). TNF-alpha or tumor necrosis factor is involved with systemic inflammation. Green tea is a potent antioxidant and, a study in the American Journal of Clinical Nutrition showed that just 90 mg of EGCG before each meal increased the body’s 24-hour metabolism rate by 4% and the metabolism of fat by an impressive 40% (Dulloo 1999).
A recent study by British researchers published in the journal Phytotherapy Research found a positive link between spearmint tea consumption and a reduction in hirsutism in PCOS women. In the study, 42 women were divided into two groups: one that took spearmint tea twice a day for a 1-month period and the other a placebo herbal tea. The spearmint tea group showed significant decreases in free and total testosterone levels and an increase in LH and FSH, leading the researchers to conclude that “spearmint (tea) has the potential for use as a helpful and natural treatment for hirsutism in PCOS.” (Grant 2010).
Saw palmetto inhibits the activity of an enzyme, 5-alpha reductase, thereby reducing the conversion of testosterone to dihydrotestosterone, the more androgenic form of male hormone. This may have implications for reducing acne, excess facial and body hair, as well as male pattern hair loss. Oral administered saw palmetto has been studied as part of a formula that slowed hair loss and improved hair density in patients with testosterone related hair loss (Prager, 2002).
Life Style and Diet Changes Recommendation
For women with polycystic ovary syndrome, daily physical activity and participation in a regular exercise regimen are essential for treating or preventing insulin resistance, lowering blood sugar levels and for helping weight-control efforts.
Since a majority of PCOS women are obese, and insulin resistance plays a critical role in the development of PCOS, a diet that is high in fiber, vitamins, minerals and disease-fighting phytonutrients, and low in saturated fatty acids may reduce certain risk factors and improve overall well-being.
Additional research may determine which specific dietary approach is best for PCOS, but it is clear that losing weight by reducing total caloric intake benefits the overall health of women with polycystic ovary syndrome.
A clinical study, short-term treatment of obese PCOS women on a ultra low calorie diet (350-450 kcal per day) decreased androgen signaling and reduced serum insulin (Kiddy 1992).
A study by Italian researchers concluded that comprehensive dietary change designed to lower insulin resulted in a significant decrease in testosterone, body weight, waist/hip ratio, total cholesterol, fasting blood glucose and insulin (Berrino 2001).
Diets high in monounsaturated fats have been shown to increase insulin sensitivity and lower the overall glycemic index. High fiber foods are slowly absorbed, causing less insulin to be released. High fiber diets increase SHBG, which binds to and lowers free testosterone. Fibers also can lower PAI-1 (plasminogen activator inhibitor, a glycosylated protein that plays a significant role in metabolic syndrome) as well as cholesterol and blood lipids (Kiddy 1992).
A study reported that just a moderate reduction in dietary carbohydrates reduced fasting and post-challenge insulin concentrations among women with PCOS, improving reproductive/endocrine outcomes (Douglas 2006). Echoed a 2005 report, "On the balance of evidence to date, a diet low in saturated fat and high in fiber from predominantly low-glycemic-index-carbohydrate foods is recommended [in the dietary management of PCOS]" (Marsh 2005).