Polycystic Ovary Syndrome (PCOS)
Inositol is a sugar alcohol that has many possible forms, or isomers. Myo-inositol (MI) is the most common of these isomers, while D-chiro-inositol (DCI) makes up a small percentage. Some MI is converted to DCI in the body.63,64
Inositol is a crucial structural component of cell membrane lipids and is active in cell-to-cell signaling.63 In addition, by transmitting external signals from insulin to the working interior of cells, inositol compounds called inositol phosphoglycans act as second messengers of insulin. Dysregulation of the inositol phosphoglycan second messenger system is associated with insulin resistance and related disorders, including PCOS.65,66 MI and DCI supplements have been shown to positively impact the hormonal and reproductive disturbances associated with PCOS.66
Myo-inositol. A number of controlled trials have demonstrated that MI can improve insulin sensitivity and metabolic markers, normalize reproductive hormone levels, and restore menstrual cycles in women with PCOS.67-70 MI supplementation has been shown to increase quality and maturity of oocytes (ie, cells that may go on to become eggs) retrieved from ovaries of PCOS patients71-73 and may enhance fertility in women affected by this condition.74 In a comparison study, 4 grams of MI plus 400 mcg of folic acid per day was more effective than 1,500 mg per day of metformin (Glucophage) in restoring ovulation in infertile women with PCOS. In addition, the total pregnancy rate was higher in women treated with MI (48.4%) than metformin (36.6%).75
In a randomized controlled trial, 50 overweight PCOS patients were given either 2 grams of MI plus 200 mcg of folic acid or 200 mcg of folic acid daily. After 12 weeks, the women taking MI had decreased insulin, testosterone, and prolactin levels, and increased markers of insulin sensitivity. In addition, menstrual cycles were restored in all of the subjects receiving MI who reported few or no menstrual cycles at the beginning of the trial. No changes occurred in the control group.76 Another controlled clinical trial included 92 participants with PCOS treated with either 4 grams of MI plus 400 mcg of folic acid per day or 400 mcg of folic acid daily. After 14 weeks, the MI-treated women had improvements in ovulation, reduced leptin levels, and significant weight loss versus the control group whose body weight increased.77 A six-month study involving 50 women with PCOS also reported benefits on hormonal parameters and found that MI supplementation reduced hirsutism and acne.78
D-chiro-inositol. Clinical evidence suggests DCI is important for mediating the insulin response and may play a role in the therapeutic effect of blood glucose-lowering drugs such as metformin and pioglitazone (Actos) in women with PCOS.79-81 Insulin resistance is associated with low serum levels and increased urinary loss of DCI, and a high ratio of MI to DCI is considered a marker of insulin resistance.63,64 In women with PCOS, deficiency of DCI has been noted despite normal MI availability.65,82,83 Although DCI does not act directly on the ovaries, its systemic insulin-sensitizing effect appears to benefit women with PCOS.63,84
In a controlled trial, 44 obese women with PCOS were given 1,200 mg of DCI or placebo daily for six to eight weeks. The DCI group had significant reductions in glucose-induced insulin release, blood pressure, and triglyceride and testosterone levels, while none of these parameters changed significantly in the placebo group. Moreover, 86% of subjects receiving DCI ovulated during the study period compared with 27% in the placebo group.85 Similar results were seen in normal weight PCOS patients treated with 600 mg of DCI daily for six to eight weeks.86 DCI supplementation has resulted not only in improvements in metabolic and hormonal parameters, but also resumption of menstrual cycles87,88 and reduced body mass index (BMI) in overweight or obese PCOS patients.89
It is important to note that some evidence suggests high-dose DCI supplementation may have a negative impact on oocyte maturation: one study found oocyte maturity diminished with DCI supplementation of 600 mg per day and higher, but not at 300 mg per day,90 and another found DCI-treated women had more immature oocytes than MI-treated women with PCOS.73
Myo-inositol plus d-chiro-inositol. Because of differences in their effects, it is possible that MI and DCI may have complementary actions.91,92 A randomized controlled trial compared the effects of six months combined treatment with 1,100 mg of MI plus 27.6 mg of DCI plus 400 mcg of folic acid to 400 mcg of folic acid per day in 46 women with PCOS. The 40:1 ratio of MI to DCI used in the treatment protocol was chosen to reflect normal conditions in the blood. MI plus DCI was more effective than folic acid alone in correcting hormonal disturbances and improving insulin sensitivity.93 Treatment with the same ratio of MI to DCI led to improved metabolic profiles and reduced cardiovascular risk in obese subjects with PCOS after six months.94 In another six-month trial, PCOS-affected women were treated with either MI plus DCI or MI alone. Markers of metabolic health improved in both groups, but those who received DCI plus MI had more improvement after three months of treatment.95 In PCOS patients undergoing in vitro fertilization, combination therapy with 1,100 mg MI plus 27.6 mg DCI daily resulted in improved oocyte and embryo quality, higher pregnancy rates, and was superior to 500 mg DCI per day alone.96
D-pinitol. D-Pinitol is 3-O-methyl-D-chiro-inositol that occurs naturally in several different foods, including legumes and citrus fruits.97 D-Pinitol is converted into d-chiro-inositol in the body. Like d-chiro-inositol, pinitol appears to favorably influence the action of insulin.98 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.99 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%.100
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.101 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."102
- 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."103
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.104
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.45
- 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.105 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.106
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.107
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 1,000 mg of magnesium oxide (300 mg or 600 mg elemental 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.108
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.109
Another study found that oral magnesium supplements helped insulin resistant individuals avoid developing type 2 diabetes.110
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 placebo111 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.112 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.113
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.114 A separate study found that vitamin D when administered with metformin was helpful for regulating the menstrual cycles in PCOS women.115
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.116
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%.117
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.118 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.”119
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 in sugar metabolism.120,121 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.”122
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%.123
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 eight 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."124
A 2004 study by Italian researchers investigated the effect of licorice on androgen metabolism in nine healthy 22- to 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.125-127
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.128
Green Tea (Epigallocatechin Gallate)
Green tea may be of benefit to women with PCOS. Green tea is known to have positive effects on glucose metabolism.129 In both human and animal studies, green tea has been shown to improve insulin sensitivity.130,131 Animal research suggests that green tea epigallocatechin gallate (EGCG) may help prevent the onset of type 2 diabetes and slow its progression.132 A clinical study from Japan found that daily supplementation of green tea extract lowered the hemoglobin A1c (HbA1c) level in individuals with borderline diabetes.133 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 tumor necrosis factor (TNF)-alpha.134 TNF-alpha 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%.135
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 one-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.”136
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.137
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