Understanding Polycystic Ovary Syndrome – PCOS

compiled by John G. Connor, M.Ac., L.Ac., edited by Barbara Connor, M.Ac., L.Ac.

Table of Contents

• Introduction
• Mechanism behind PCOS
• Western Medical Treatments in PCOS
• Integrative Medical Treatments in PCOS
• Anti-Inflammatory Herbs and Nutrients
• Anti-Inflammatory Foods
• Foods High in Antioxidants
• Natural Compounds that Improve Insulin Sensitivity
• Advanced Glycation End Products (AGEs) and PCOS
• Natural Compounds that Prevent the Accumulation of AGEs
• Foods to Avoid
• Exercise

Introduction

Polycystic ovary syndrome (PCOS) is a common endocrine disorder that is characterized by chronic hyperandrogenic anovulation leading to symptoms of hirsutism, acne, irregular menses, and infertility. Multiple metabolic and cardiovascular risk factors are associated with PCOS, including insulin resistance, obesity, type 2 diabetes, hypertension, inflammation, and subclinical atherosclerosis. However, current treatments for PCOS are only moderately effective at controlling symptoms and preventing complications. (Raja-Khan et al 2011)

Currently, there is no cure for PCOS. Despite the growing incidence of this syndrome, limited research has been done that encompasses the entirety of PCOS spectrum. (Barthelmess & Naz 2014)

Polycystic ovary syndrome is a common condition in women at reproductive age associated with reproductive and metabolic dysfunction. Proposed diagnosed criteria for PCOS include two out of three features: androgen excess, menstrual irregularity, and polycystic ovary appearance on ultrasound (PCO), after other causes of hyperandrogenism and dysovulation are excluded. (Spritzer PM 2014)

Approximately 15%–30% of adult women with PCOS present with acne. Although the demonstration of insulin resistance is not required to make the diagnosis of PCOS, it is clear that hyperinsulinemic insulin resistance plays a prominent role in PCOS. The prevalence of insulin resistance in PCOS ranges from 50%–70% and occurs independently of obesity. The effect of obesity on insulin resistance is additive to that of PCOS. An increased risk of dyslipidemia has been demonstrated in PCOS. Lipid abnormalities include reduced high density lipoprotein-cholesterol (HDL-C), increased triglycerides, and increased low density lipoprotein-cholesterol (LDL-C). Women with PCOS are also at increased risk of a number of mental health disorders including depression, bipolar disorder, anxiety, and eating disorders. During systematic screening, Hollinrake et al demonstrated that 35% of women with PCOS suffered from depression compared to 10.7% in controls. (Simrans & Pate 2014)

More than half of women with PCOS have insulin resistance and hyperinsulinemia. These insulin abnormalities might play a significant role in the pathogenesis of PCOS, not only by influencing the reproductive abnormalities of PCOS, but also by amplifying metabolic defects. Hyperinsulinemia may contribute to a hyperandrogenic state by increasing androgen production of theca cells and influencing hepatic production of sex hormone binding globulin, resulting in higher concentrations of free androgens. (Xu et al 2014)

There are a number of markers of the inflammation process. They are also observed in PCOS and may indicate an increased risk of cardiovascular disease in women. More than 46% of women with PCOS can be diagnosed with metabolic syndrome. Because of the fact that patients with PCOS are at higher risk group of the earlier development of complications such as diabetes t 2, atherosclerosis, hypertension and cardiovascular system diseases, it is important to carry out metabolic disorders diagnosis in every patient with PCOS. (Marciniak et al 2013)

Acne is the most common skin disorder, affecting approximately 40-50 million people in the United States. This condition results from the formation of comedones, due to sebum accumulation, along with desquamated follicular epithelial cells, which allows colonization by the bacterium, Propionibacterium acnes (P. acnes). Androgens may worsen acne formation by increasing sebum production within the pilosebaceous unit. Many PCOS women with acne exhibit facial lesions and up to 50% of individuals demonstrate lesions on the neck, chest, and upper back. (Chuan & Chang 2010)

Past studies have shown that androgen levels are elevated in women with acne, although the severity of acne has not been positively correlated with any particular hormone, with the exception of the adrenal androgen, dehydroepiandrosterone sulfate (DHEA-S). Notably, several studies have demonstrated an inverse relationship with sex-hormone binding globulin (SHBG). (Chuan & Chang 2010)

A large body of clinical studies has implicated the important role of sex hormones in the development of type 2 diabetes. Researchers at UCLA have discovered a possible molecular mechanism behind coffee’s protective effect. A protein called sex hormone-binding globulin (SHBG) regulates the biological activity of the body’s sex hormones, testosterone and estrogen, which have long been thought to play a role in the development of type 2 diabetes. And coffee consumption, it turns out, increases plasma levels of SHBG. (Goto et al 2011)

Mechanism behind PCOS

Genetically-determined hypersecretion of the androgens from the ovary is proposed to be the primary event that leads to the development of PCOS by favouring excess luteinising hormone (LH) secretion and insulin resistance. However, insulin resistance with or without a genetic mutation may be the initiator, followed by hyperandrogenism, as is seen in hyper-androgenism-insulin resistance-acanthosis nigricans (HAIR-AN) syndrome. (Cirik & Dilbaz 2014)

Most women with PCOS, both obese and lean, have a degree of insulin resistance. (Jakubowski L 2005)

Insulin resistance is an important contributing factor to abnormal steroidogenesis in PCOS. Insulin acts with LH to increase androgen production and promotes LH binding to the receptors. Hyperinsulinaemia stimulates insulin like growth factor-I (IGF-I) pathway in theca cells of the ovary by cross-reacting with the receptors for IGF. This state blocks the down-regulation of androgens by LH surge and leads to the hyperandrogenic environment in the ovary. Treatments include weight loss, which lowers insulin levels, restores ovulation and lowers the ovarian androgen levels. (Cirik & Dilbaz 2014)

The total 5alpha-reductase activity was approximately 4-fold higher in PCOS follicles than in control follicles. These data demonstrate elevated 5alpha-reductase activity in polycystic ovaries and support the hypothesis that 5alpha-reduced androgens may play a role in the pathogenesis of PCOS. (Jakimiuk et al 1999)

A proposed mechanism for anovulation and elevated androgen levels suggests that under the increased stimulatory effect of luteinizing hormone (LH) secreted by the anterior pituitary, stimulation of the ovarian theca cells is increased. In turn, these cells increase the production of androgens (eg, testosterone, androstenedione). Because of a decreased level of follicle-stimulating hormone (FSH) relative to LH, the ovarian granulosa cells cannot aromatize the androgens to estrogens, which leads to decreased estrogen levels and consequent anovulation. Growth hormone and insulin-like growth factor 1 may also augment the effect on ovarian function. (Badawy & Elnashar 2011)

Markers of chronic subclinical inflammation, such as IL-6, have been shown to be independent risk predictors for the development of type 2 diabetes. Several studies have now documented an increase in IL-6 levels in PCOS patients. Both Mohlig et al. and Gonzalez et al. have pointed out that elevated IL-6 levels may have links with insulin resistance and hyperandrogenism in PCOS. Taken together, these studies support the hypothesis that PCOS increases the risk of diabetes by activating chronic inflammation. (Xu et al 2014)

In the present study, we have provided evidence for a direct involvement of inflammation in the maintenance and progression of PCOS. Clinical observations also suggest that PCOS is associated with inflammation and proliferation of circulating inflammatory molecules such as IL-6, COX-2 and VEGF. (Karimzadeh et al 2013)

Thirty-one patients with hyperinsulinemic (no.=13) and normoinsulinemic (no.=18) PCOS and 29 healthy controls were included in this study. Serum glucose, insulin, total testosterone, DHEAS, HOMA-IR levels, and LH/FSH ratios were higher in young non-obese women with PCOS. Serum MDA and PC levels were also higher but GSH, vitamin C and E levels, and GST enzyme activity were lower in these women than in healthy controls, independently of the status of IR. Oxidative stress characterized by increased oxidants and decreased antioxidant levels which are independent of insulin resistance (IR) may be involved in the pathogenesis of PCOS in young non-obese women. (Kurdoglu et al 2012)

Modifications of dietary Advanced Glycation End products (AGEs) intake are associated with parallel changes in serum AGEs, metabolic, hormonal and oxidative stress biomarkers in women with PCOS. These novel findings support recommendations for a low AGEs dietary content along with lifestyle changes in women with PCOS. (Tantalaki et al 2014) Reduction in dietary AGEs might be of benefit in women with PCOS. (Bargiota & Diamanti-Kandarakis 2012)

PCOS was associated with elevated serum IL-6 and MCP-1 but lower TNF-α concentration. (Younis et al 2014)

Indices of insulin resistance (insulin and HOMAIR) were significantly higher in PCOS group and positively correlated with level of malondialdehyde (MDA) as well as glutathione peroxidase (GPX) activity. Our results indicate that insulin resistance could be responsible for the existence of subtle form of oxidative stress in young, nonobese PCOS women. Hence, presence of insulin resistance, hyperinsulinemia and oxidative damage are likely to accelerate slow development of cardiovascular disease in PCOS. (Macut et al 2011)

Nine protein biomarkers were similarly either under or over expressed in women with EC (endometrial cancer) and PCOS (polycystic ovary syndrome) in various tissues. These include transgelin, pyruvate kinase M1/M2, gelsolin-like capping protein (macrophage capping protein), glutathione S-transferase P, leucine aminopeptidase (cytosol aminopeptidase), peptidyl-prolyl cis-transisomerase, cyclophilin A, complement component C4A and manganese-superoxide dismutase. (Galazis et al 2013)

A panel of six biomarkers was overexpressed both in women with OC (ovarian cancer) and in women with PCOS. These biomarkers include calreticulin, fibrinogen-γ, superoxide dismutase, vimentin, malate dehydrogenase, and lamin B2. (Galazis et al 2012)

Elevated serum IL-18 levels were associated with cardiovascular risk factors and carotid intima-media wall thickness (IMT) in patients with PCOS. (Kaya et al 2010)

Our aim was to study the protein expression profiles of omental adipose tissue biopsies obtained from morbidly obese women with or without polycystic ovary syndrome (PCOS) at the time of bariatric surgery to evaluate the possible involvement of visceral adiposity in the development of PCOS. The most relevant finding was an increase of glutathione S-transferase M3 (GSTM3) in the omental fat of PCOS patients confirming previous studies conducted by our group. (Corton et al 2008)

The present study has demonstrated increase in mean serum homocysteine concentrations in women with PCOS. (Maleedhu et al 2014)

In PCOS women, plasma levels of homocysteine (Hcy) and C-reactive protein (CRP) were significantly elevated compared with age- and BMI-matched controls. Although most of the PCOS-related endocrine and metabolic changes are related to elevated plasma Hcy and CRP levels in PCOS women, BMI seems to be the major factor determining type 2 diabetes mellitus and coronary heart disease in women with PCOS. (Guzelmeric et al 2007)

The increased TGF-β1 bioavailability in PCOS is not only due to increased TGF-β1 levels but also to decreased levels of its receptor, sENG. These data suggest that increased TGF-β1 bioavailability may contribute to the pathogenesis of PCOS and its increased risk for ovarian hyperstimulation. (Tal et al 2013)

Western Medical Treatments in PCOS

The main interventions to minimize cardiovascular and metabolic risks in PCOS are lifestyle changes, pharmacological therapy, and bariatric surgery. Treatment with metformin has been shown to improve insulin sensitivity, lowering blood glucose and androgen levels. These effects are more potent when combined with lifestyle interventions. (Spritzer PM 2014)

A key perturbation in women with PCOS is excessive ovarian androgen production and consequently, excessive estrogen production by GCs (granulosa cells). Although the improvement in androgen concentrations in the circulating and follicular environment of women with PCOS treated with metformin may bring indirect beneficial effects to the developing oocytes, any direct effects of metformin on GC glucose metabolism have yet to be identified. (Maruthini et al 2014)

Metformin has insulin-lowering effects by improving insulin sensitivity and, in turn, can decrease circulating androgen levels. In addition, it also plays a critical role in the treatment of PCOS because women with PCOS are at an increased risk of insulin resistance. Indeed, metformin improves insulin-mediated glucose disposal in women with PCOS. Thus, metformin has become one of the key drugs in the treatment of PCOS. (Xu et al 2014)

Metformin likely plays its role in improving ovulation induction in women with PCOS through a variety of actions, including reducing insulin levels and altering the effect of insulin on ovarian androgen biosynthesis, theca cell proliferation, and endometrial growth. In addition, potentially through a direct effect, it inhibits ovarian gluconeogenesis and thus reduces ovarian androgen production.

Several dose regimens have been proposed. In order to increase patient tolerance, metformin is started at 500 mg daily with food. After 1 week, the dose is increased to 1000 mg for another week and then to 1500 mg daily. The target dose is 1500–2550 mg/day (500 or 850 mg three times daily). Clinical response is usually seen at the dose of 1000 mg daily. It appears that some PCOS patients who do not respond to metformin at a dose of 1500 mg daily will respond favorably to 2000 mg daily. The most common side effects of metformin are nausea and diarrhea. Lactic acidosis has been described mainly in patients with renal impairment, congestive heart failure, and sepsis. (Badawy & Elnashar 2011)

Spironolactone, an aldosterone antagonist, is an anti-androgen that primarily acts by binding to the androgen receptor as an antagonist. It also inhibits ovarian and adrenal steroidogenesis, directly inhibits 5-α-reductase activity, and competes for androgen receptors in hair follicles. (Sirmans & Pate 2014)

Finasteride is an antiandrogen that competitively inhibits tissue and hepatic 5-α-reductase resulting in inhibition of the conversion of testosterone to dihydrotestosterone and suppression of serum dihydrotestosterone levels. (Sirmans & Pate 2014)

Integrative Medical Treatments in PCOS

Acupuncture and Chinese herbal medicines – A total of 31 articles (28 in Chinese, 3 in English) containing 2,321 cases of PCOS patients met the included criteria. Meta-analysis showed that the clinical efficacy of simple acupuncture was the same as that of western medicine, and the efficacy of acupuncture combined with Chinese herbal medicine interventions was obviously higher than that of western medicine (P < 0.05). In addition, simple acupuncture intervention and acupuncture combined with Chinese herbal medicines or with moxibustion treatment have advantages in reducing serum luteinizing hormone/follicle-stimulating hormone (LH/FSH), insulin resistance (IR), testosterone (T), and body mass index (BMI). However, the quality of the collected articles is generally lower due to unclear bias, no sample quantity estimation, incorrect randomization methods, no follow-up survey, etc. Acupuncture therapy may be effective for PCOS, but needs to be confirmed further by larger sample randomized controlled trials. (Ren et al 2014)

Alpha lipoic acid – We administered controlled-release alpha lipoic acid (CRLA) 600 mg twice daily for 16 weeks to six lean, nondiabetic patients with PCOS. At the end of 16 weeks of CRLA treatment, there was a 13.5% improvement in insulin sensitivity as determined by the euglycemic, hyperinsulinemic clamp (p < .03). There was also a lowering of triglyceride levels (p < .04) and a shift in the distribution of low-density lipoprotein (LDL) particles toward the larger, more buoyant LDL subclass fraction. (Masharani et al 2010)

Androgen antagonists – can broadly be defined as any compound that has the biological effect of blocking or suppressing the action of male sex hormones such as testosterone within the human body. This may occur at any point in the hypothalamic-pituitary-gonadal-end-organ axis and could be through a direct effect on gonadotropin production at the level of the pituitary or by competing for binding sites at the receptor level on the normally androgen sensitive tissues in the body. Androgens themselves have a diverse range of effects in both males and females and their dysregulation can give rise to a variety of clinical disorders, including polycystic ovarian syndrome, the most common endocrine disorder in females, which affects up to 7% of the population; hirsutism; acne vulgaris; prostatic hyperplasia; and male pattern baldness. (Grant & Ramasamy 2012)

Cinnamon extract – has been shown to potentiate the insulin effect through upregulation of glucose uptake in cultured adipocytes . Cinnamon extract also improves insulin action via increasing glucose uptake in vivo, as it has been shown to enhance the insulin-signaling pathway in skeletal muscle in rats. An RCT of 15 women with PCOS showed significant reductions in IR in the cinnamon group (333 mg of cinnamon extract, 3 times a day) but not in the placebo group. (Raja-Khan et al 2011) 

Diet and exercise – This review article also focuses on the beneficial effects of exercise training and diet on glucose metabolism and hyperandrogenism in PCOS women, pointing out that whether in conjunction with pharmacotherapy or as a stand-alone treatment, diet and exercise training represent a fundamental strategy in the treatment of PCOS women. (Giallauria et al 2009)

Fenugreek seeds – Adjuvant therapy to the fenugreek seeds extract (with metformin) in PCOS women improved the sonographic results and menstrual cyclicity. (Hassanzadeh Bashtian et al 2013) 

Ganoderma lucidum (Reishi, Ling Zhi) – In a research study exploring the anti-androgenic effects of 20 species of mushrooms, reishi mushrooms had the strongest action in inhibiting testosterone. That study found that reishi mushrooms significantly reduced levels of 5-alpha reductase, preventing conversion of testosterone into the more potent DHT. High levels of DHT are a risk factor for conditions such as benign prostatatic hypertrophy (BPH), acne, and baldness. (Grant & Ramasamy 2012)

Green tea – In addition to supporting the cardiovascular system and somewhat reducing the risk of cancer and type 2 diabetes (8), green tea may also have an important anti-androgen effect because it contains epigallocatechins, which inhibit the 5-alpha-reductase conversion of normal testosterone into DHT. (Grant & Ramasamy 2012)

Green tea –  The principal component of green tea, (−)-epigallocatechin-3-gallate (EGCG), significantly reduced body weight and circulating testosterone, estradiol, leptin, insulin, IGF-I, LH, glucose, cholesterol, and triglyceride in Sprague-Dawley rats and lean and obese Zucker rats. In vitro studies demonstrate that green tea extract and EGCG inhibit basal and stimulated testosterone production in rat Leydig cells. The mechanisms underlying the effects of EGCG involve the in vitro inhibition of the PKA/PKC signaling pathways as well as the inhibition of P-450 side-chain cleavage enzyme and 17β-hydroxysteroid dehydrogenase function during testicular steroidogenesis. (Raja-Khan et al 2011) 

Licorice – A small clinical trial published in 2004 by Armanini and colleagues found that licorice root significantly decreases testosterone levels in healthy female volunteers. Women taking daily licorice root experienced a drop in total testosterone levels after 1 month and testosterone levels returned to normal after discontinuation. It is unclear as to whether licorice root affects free testosterone levels. The endocrine effect is thought to be due to phytoestrogens and other chemicals found in licorice root, including the steroid glycyrrhizin and glycyrrhetic acid, which also have a weak anti-androgen effect. (Grant & Ramasamy 2012)

N-acetylcysteine (NAC) plus inositol plus folic – The association NAC + Inositol + folic, regardless of insulin-resistance state, seems to improve ovarian function in PCOS patients. (Sacchinelli et al 2014) 

Omega-3 – supplementation could reduce serum concentrations of testosterone and regulate menstrual cycle without significant effect on sex hormone-binding protein (SHBG), testosterone, free androgen index (FAI). (Nadjarzadeh et al 2013)

Omega-3 fatty acids – The purpose of this study was to evaluate the efficacy and safety of omega-3 in the treatment of polycystic ovary syndrome and to compare the clinical, hormonal, TNF-α and resistin levels in the patients treated with omega-3. A total of 45 non-obese PCOS women were studied. Women were treated with daily oral 1,500 mg of omega-3 for 6 months. BMI, F-G scoring, insulin and HOMA levels decreased significantly during treatment, but glucose levels did not change. In the hormonal profile, serum LH and testosterone levels decreased and sex hormone-binding globulin levels increased significantly after the 6 months of therapy. On the other hand, TNF-α levels showed a significant increase, whereas resistin levels showed no change. Omega-3 may be also effective in improving hirsutism and insulin resistance in patients with PCOS. (Oner & Muderris 2013)

Omega-3 fatty acids, α-lipoic acid and N-acetylcysteine – Supplementation with omega-3 fatty acids, α-lipoic acid and N-acetylcysteine is considered to have an anti-inflammatory and antioxidant effect and to improve dyslipidemia and insulin sensitivity in PCOS women. (Macut et al 2013)

Omega-3 fatty acid supplementation has a beneficial effect on liver fat content and other cardiovascular risk factors in women with PCOS, including those with hepatic steatosis. (Cussons et al 2009) 

Selenium – Polycystic ovary syndrome (PCOS) is a common inflammatory disease with an uncertain pathogenesis, although one consistent finding is increased neutrophil activity. It has been recently reported that the essential antioxidant element selenium has protective effects on oxidative stress and cytosolic Ca(2+) concentrations in human neutrophil. In conclusion, we observed the importance of Ca(2+) influx into the neutrophils through TRPV1 channels in the pathogenesis of the patients with PCOS. The selenium appeared to provide a protective effect against oxidative stress and Ca(2+) entry through modulation of neutrophil TRPV1 calcium channels. (Kose & Naziroglu 2014)

Selenium – The plasma Se level was significantly lower in PCOS women compared to the control group. When we combined the all women in two groups, regarding them as one group (combined group, n=69), a negative correlation between Se and LH and tT was present. Our results show decreased plasma concentrations of Se and a negative correlation between Se and LH, serum total testosterone (tT) in women with PCOS. These results indicate that Se may play a role in the pathogenesis of PCOS related with hyperandrogenism. (Coskun et al 2013)

Spearmint tea – In regard to spearmint tea, an RCT of 41 PCOS women showed that spearmint tea twice a day for 1 mo significantly decreased free and total testosterone levels, improved patients’ subjective assessments of their hirsutism, and increased LH and FSH compared with a placebo herbal tea. Further studies are needed to confirm these findings and further elucidate the mechanisms underlying the antiandrogenic effects of spearmint tea. (Raja-Khan et al 2011)

Spearmint tea – Recent research in Turkey has shown that spearmint tea has antiandrogenic properties in females with hirsutism. There was a clear and significant alteration in the relevant hormone levels. This is associated clinically with a reduction in the self-reported degree of hirsutism but unfortunately not with the objectively rated score. It was demonstrated and confirmed that spearmint has antiandrogen properties, the simple fact that this does not clearly translate into clinical practice is due to the relationship between androgen hormones and follicular hair growth and cell turnover time. Simply put, the study duration was not long enough. (Grant P 2010)

Type 2 diabetes diet – Women with PCOS should also consider maintaining a diet that is patterned after the type 2 diabetes diet. This diet includes an increase in fiber and a decrease in refined carbohydrates, as well as a decrease in trans and saturated fats and an increase in omega-3 and omega-9 fatty acids. Foods that contain anti-inflammatory compounds (fiber, omega-3 fatty acids, vitamin E, and red wine) should also be emphasized. (Liepa et al 2008)

Vitamin B12 and folate – Two recent studies suggest that B vitamins may be important in PCOS. In the first study, IR, obesity, and elevated homocysteine were associated with lower serum vitamin B12 concentrations in PCOS patients. The second study was a nonrandomized, placebo-controlled, double-blind trial that demonstrated that supplementation with folate (400 μg daily) for 6 mo increases the beneficial effect of metformin on the vascular endothelium in women with PCOS. However, the mechanisms are still unclear. (Raja-Khan et al 2011)

Vitamin B12 – Serum vitamin B(12) concentrations were significantly lower in obese PCOS women in comparison with obese control women. Fasting insulin, insulin resistance and homocysteine are independent determinants of serum vitamin B(12) concentrations in PCOS patients. Insulin resistance, obesity, and elevated homocysteine were associated with lower serum vitamin B(12) concentrations in PCOS patients. (Kaya et al 2009)

Vitamin D – The beneficial effects of vitamin D supplementation on insulin resistance, ovarian follicles maturation, ovulation and menstrual regularity were confirmed. Due to limited evidence, the additional randomized trials are required to establish the correct dose of vitamin D and confirm the effectiveness of vitamin D treatment in PCOS disorders. However; it seems evident that correct supplementation of vitamin D is beneficial in the management of women with PCOS and low 25(OH)D serum levels, and that it could be helpful in improving the effects of PCOS treatment. (Brzozowska & Karowicz-Billinska 2013)

Vitamin D –  Current evidence suggests an inverse association between vitamin D status and metabolic disturbances in PCOS. Owing to the heterogeneity of the studies, it is hard to draw a definite conclusion. (Kurl-Poel et al 2013)

Vitamin D –  Accumulating evidence suggests that vitamin D deficiency may be a causal factor in the pathogenesis of insulin resistance (IR) and the metabolic syndrome in PCOS. Furthermore, 25-hydroxyvitamin D levels are closely associated with impaired β-cell function, IGT, and the metabolic syndrome in PCOS women. Two small, uncontrolled studies demonstrate that vitamin D may improve insulin resistance (IR) and lipid profiles in PCOS patients. One of these studies demonstrated a significant reduction in homeostatic model assessment of insulin resistance (HOMA-IR) 3 wk after a single oral vitamin D3 dose of 300,000 IU in 11 obese, insulin-resistant women with PCOS. Moreover, vitamin D supplementation may also improve anovulation in PCOS. A pilot RCT of 60 infertile PCOS patients showed that the number of dominant follicles (≥14 mm) during 2–3 mo of follow-up was higher in the calcium (1,000 mg/day) plus vitamin D (400/day) plus metformin (1,500 mg/day) group than in the calcium + vitamin D-only group or the metformin-only group. (Raja-Khan et al 2011)

Vitamin D and calcium – This study showed the positive effects of calcium & vitamin D supplementation on weight loss, follicle maturation, menstrual regularity, and improvement of hyperandrogenism, in infertile women with PCOS. (Firouzabadi et al 2012)

Walnuts and Almonds – Walnuts increased insulin response during OGTT by 26% (P < 0.02). Both walnuts and almonds increased adiponectin (walnuts from 9.5 ± 1.6 to 11.3 ± 1.8 μg per 100 ml, P = 0.0241; almonds from 10.1 ± 1.5 to 12.2 ± 1.4 μg/dl, P = 0.0262). Walnuts decreased HgBA1 from 5.7 ± 0.1 to 5.5 ± 0.1% (P = 0.0006) with significant intergroup difference from almonds (P=0.0470). Walnuts increased sex hormone-binding globulin from 38.3 ± 4.1 to 43.1 ± 4.3 nmol/l (P=0.0038) and almonds reduced free androgen index from 2.6 ± 0.4 to 1.8 ± 0.3 (P = 0.0470). Nut intake exerted beneficial effects on plasma lipids and androgens in PCOS. (Kalgaonkar et al 2011)

Anti-Inflammatory Herbs and Nutrients

Anti-Inflammatory Foods

Foods High in Antioxidants

1. Artichoke is a vegetable rich in antioxidants. (Carlsen et al 2010)
2. Beverages high in antioxidants include espresso, coffee and pomegranate juice. (Carlsen et al 2010)
3. Broccoli and spinach – Lutein is known to be a nonprovitamin A carotenoid found in broccoli and spinach. Our results demonstrate that administration of lutein affords strong neuroprotective effect against transient cerebral ischemic injury and that the effect might be associated with its antioxidant property. (Sun et al 2014)
4. Buckwheat, millet and barley – Grains highest in antioxidants are buckwheat, millet and barley. (Carlsen et al 2010) 
5. Carrots – Daily intake of fresh carrot juice is a simple and effective approach to increasing plasma total carotenoids and in turn reducing oxidative stress, but not inflammatory markers, in women previously treated for breast cancer. (Butalla et al 2012)
6. Fruits highest in antioxidants include amla, bilberries (dried), black currants, wild strawberries, cranberries, dried apples, dried plums, dried apricots and prunes. (Carlsen et al 2010) 
7. Fruits and vegetables in the medium antioxidant range are dried dates, dried mango, black and green olives, red cabbage, red beets, paprika, guava and plums. (Carlsen et al 2010) 
8. Nuts high in antioxidants include walnuts, pecans and sunflower seeds. (Carlsen et al 2010) 
9. Spices highest in antioxidants include clove, peppermint, allspice, cinnamon, oregano, and thyme.  (Carlsen et al 2010) 

Other powerful antioxidants include the supplements: alpha-lipoic acid, N-acetylcysteine, coenzyme Q10, vitamin C & vitamin E.

Natural Compounds that Improve Insulin Sensitivity

Alpha Lipoic Acid – has several beneficial effects on the whole body including the liver, eyes, brain, pancreas, kidneys and skin.  Alpha lipoic acid helps break down sugars so that energy can be produced through cellular respiration.  It is an extraordinarily broad-spectrum antioxidant able to quench a wide range of free radicals.  Lipoic acid protects against and reduces glycation. In one study the contents of glucose, glycated protein, glycated haemoglobin and fructosamine were significantly lowered on alpha-lipoic acid administration to high fructose-fed rats. Alpha-lipoic acid prevented in vitro glycation and the accumulation of advanced glycation end products. Further alpha-lipoic acid enhanced glucose utilization in the rat diaphragm. This effect was additive to that of insulin and did not interfere with the action of insulin. The findings provide evidence for the therapeutic utility of lipoic acid in diabetes and its complications. (Thirunavukkarasu et al 2005)

Bitter Melon – Studies have shown that bitter melon repairs damaged beta-cells, increases insulin levels, and enhances the sensitivity of insulin. (Chaturvedi P 2012)

Chromium – supplementation may improve insulin sensitivity at a dose of 200-1000 mcg/day.  Chromium promotes better insulin utilization, which leads to an overall decrease in serum triglycerides and total cholesterol, while increasing “good” HDL levels and improving glucose tolerance. Chromium functions as a cofactor in all insulin-related activities. A systematic review of the effect of chromium supplementation on glucose metabolism and lipid levels found that chromium supplementation significantly improved glycemia among patients with diabetes. (Balk et al 2007)

Cinnamon Bark – In this randomized, placebo-controlled, double-blind clinical trial intake of 2g of cinnamon for 12 weeks significantly reduced the HbA1c, as well as mean systolic and diastolic blood pressures among poorly controlled type 2 diabetes patients. The  authors concluded that cinnamon supplementation could be considered as an additional dietary supplement option to regulate blood glucose and blood pressure levels along with conventional medications to treat type 2 diabetes mellitus. (Akilen et al 2010) 

Cinnamon Bark – This meta-analysis found that cinnamon intake, either as whole cinnamon or as cinnamon extract, results in a statistically significant lowering in fasting blood glucose (FBG). Thus, the authors conclude, cinnamon extract and/or cinnamon improves FBG in people with type 2 diabetes or prediabetes. (Davis & Yokoyama 2011)

Fenugreek seeds – improve glycemic control and decreases insulin resistance in mild type II diabetic patients.  There are also favorable effects on hypertriglyceridemia (high triglycerides).  Fenugreek possesses insulintrophic and anti-diabetic properties and is anti-inflammatory, anti-ulcer and lipid-lowering.  It can be used to assist people who have insulin resistance and elevated lipids. A double blind placebo controlled study concluded that adjunct use of fenugreek seeds improves glycemic control and decreases insulin resistance in mild type-2 diabetic patients. It also found that serum triglycerides decreased and HDL cholesterol increased significantly in the group receiving the fenugreek seed extract. (Gupta et al 2001)

Goat’s rue – is one of the most effective natural agents to stabilize blood sugar and it can complement the actions of adaptogens like Devil’s Club. The identification of guanidine and related compounds in Goat’s Rue led to the development of biguanides eg., Metformin. (Perla & Jayanti 2013)

Panax Notoginseng – Panax Notoginseng saponins possess anti-hyperglycemic and anti-obese activities by improving insulin- and leptin sensitivity, and Rb1 is responsible for the anti-hyperglycemic effect among the five saponins in KK-Ay mice. (Yang et al 2010)

Panax Notoginseng – Panax Notoginseng saponins (SPN), a naturally occurring agent used to treat ischemic cardio-cerebral vascular disease in China, enhanced insulin-stimulated glucose uptake and glycogen synthesis in adipocytes. The results of this study indicate that SPN may have a therapeutic potential for hyperglycaemia in type 2 diabetes. (Kim et al 2009)

Salacia reticulata — A randomized, double-blind, placebo-controlled study revealed that treatment with Salacia reticulata was safe and well-tolerated and may be beneficial in the management of prediabetes and mild to moderate hyperlipidemia. (Shivprasad et al 2013)

Vanadium – has the ability to beneficially effect insulin activity in diabetics.  Vanadium supplementation has shown in several studies to produce positive changes in glucose metabolism.  Food sources for vanadium include shellfish, mushrooms, parsley, dill seed and black pepper. In this study fourteen type 1 diabetic patients received oral vanadyl sulfate (50 – 100 mg TID) for a period of 30 months. The daily doses of insulin decreased from 37.2 ± 5.5 to 25.8 ± 17.3 units/day and at the same time the mean fasting blood sugar decreased from 238 ± 71 to 152 ± 42 mg/dL. (Soveid et al 2013)

Advanced Glycation End Products (AGEs) and PCOS

Reduction in dietary advanced glycation end products (AGEs) might be of benefit in women with PCOS. (Bargiota & Diamanti-Kandarakis 2012) 

The Western diet is rich in AGEs. AGEs are formed when food is processed at elevated temperatures, such as during deep-frying, broiling, roasting, grilling; high-temperature processing for certain processed foods such as pasteurized dairy products, cheeses, sausages, and processed meats; and commercial breakfast cereals. Endogenous AGEs are generated at higher rates in diabetics due to altered glucose metabolism. (Semba et al 2010)

Examples of food with high exogenous AGEs include roasted duckskin, cake, donuts, soy sauce, Classic coke and Diet coke. (Koschinsky et al 1997)

Natural Compounds that Prevent the Accumulation of AGEs

Aged garlic and S-allyl cysteine – Both aged garlic extract and S-allyl cysteine inhibited formation of glucose and methylglyoxal derived advanced glycation endproducts and showed potent Amadorin activity when compared to pyridoxamine. S-allyl cysteine inhibited formation of carboxymethyllysine (CML), a non-crosslinked advanced glycation endproduct derived from oxidative processes. Further studies are required to assess whether aged garlic extract and S-allyl cysteine can protect against the harmful effects of glycation and free radicals in diabetes and ageing. (Ahmad et al 2007)

Alpha-lipoic acid – The contents of glucose, glycated protein, glycated haemoglobin and fructosamine were significantly lowered on alpha-lipoic acid (LA) administration to high fructose-fed rats. LA prevented in vitro glycation and the accumulation of advanced glycation end products. Further LA enhanced glucose utilization in the rat diaphragm. This effect was additive to that of insulin and did not interfere with the action of insulin. The findings provide evidence for the therapeutic utility of lipoic acid in diabetes and its complications. (Thirunavukkarasu et al 2005)

Carbohydrate-rich foods such as vegetables, fruits, whole grains, and milk – Dry heat promotes new dietary advanced glycation end products (dAGE) formation by >10- to 100-fold above the uncooked state across food categories. Animal-derived foods that are high in fat and protein are generally AGE-rich and prone to new AGE formation during cooking. In contrast, carbohydrate-rich foods such as vegetables, fruits, whole grains, and milk contain relatively few AGEs, even after cooking. The formation of new dAGEs during cooking was significantly reduced by cooking with moist heat, using shorter cooking times, cooking at lower temperatures, and by use of acidic ingredients such as lemon juice or vinegar. (Uribarri et al 2010)

Cinnamon bark – In this study, the inhibitory effect of cinnamon bark on the formation of advanced glycation endproducts (AGEs) was investigated in a bovine serum albumin (BSA)-glucose model. This is the first report that proanthocyanidins can effectively scavenge reactive carbonyl species and thus inhibit the formation of AGEs. (Peng et al 2008)

Cranberry phytochemical powder and its fractions significantly inhibited the formation of glycated hemoglobin. (Liu et al 2011)

EGCG – The results demonstrated that EGCG may exhibit protective effects against AGEs-induced injury in neuronal cells through its antioxidative properties, as well as by interfering with AGEs-RAGE interaction mediated pathways, suggesting a beneficial role for this tea catechin against neurodegenerative diseases. (Lee et al 2007)

Genistein & EGCG – Results from this study, as well as our previous findings on (-)-epigallocatechin 3-gallate (EGCG), phloridzin and phloretin, indicate that dietary flavonoids that have the same A ring structure as genistein, EGCG, phloridzin, and phloretin may have the potential to inhibit the formation of AGEs by trapping reactive dicarbonyl species. (Lv et al 2011)

Ginkgo biloba and alpha-lipoic acid – AGEs contents increased and RAGE expression was up-regulated in the circulation and local renal tissues in diabetic neuropathy (DN) rats. Ginkgo biloba and alpha-lipoic acid could inhibit AGEs production and down-regulate RAGE expressions by reducing oxidative stress, thus further improving the renal tissue structure and renal functions of DN rats. They had better application prospects in the treatment and prevention of DN. (Li et al 2011)

Guava (aqueous extract) – Psidium guajava at 0.01 mg/mL effectively inhibited with 63.45% efficiency on AGEs induced by glucose. We conclude that Psidium guajava virtually is a potent antiglycative agent, which can be of great value in the preventive glycation-associated cardiovascular and neurodegenerative diseases. (Hseih et al 2005)

Resveratrol – Collectively, our results indicate that resveratrol prevents the impairment of AGE on macrophage lipid homeostasis partially by suppressing RAGE via PPARgamma activation, which might provide new insight into the protective role of resveratrol against diabetic atherosclerosis. (Zhang et al 2010)

Foods to Avoid

White sugar, white flour, white rice, white pasta, sugary pastries and cakes, ice cream and sodas – 

Oxidative stress in the presence of intracellular hyperglycemia results in the production of reactive intracellular dicarbonyls which react with amino acids to form advanced glycation end (AGE) products that go on to bind AGE receptors and induce expression of inflammatory cytokines in macrophages and procoagulatory and proinflammatory molecules in endothelial cells. Acute hyperglycemia results in elevated levels of circulating inflammatory cytokines including TNFα, IL-6, and IL-18 and more extreme responses in these parameters are observed when glucose spikes; this response is attenuated by administration of glutathione confirming the presence of an oxidative stress-related mechanism. (Munoz & Costa 2013)

We have previously shown that 300 kcal from glucose intake induces a significant increase in reactive oxygen species (ROS) generation and nuclear factor-κB (NF-κB) binding in the circulating mononuclear cells in healthy normal subjects. (Ghanim et al 2007)

Soft drinks – 

During regular soft drinks consumption, fat accumulates in the liver by the primary effect of fructose which increases lipogenesis, and in the case of diet soft drinks, by the additional contribution of aspartame sweetener and caramel colorant which are rich in advanced glycation end products that potentially increase insulin resistance and inflammation. (Nseir et al 2010)

Exercise

Current evidence supports that exercise training, such as aerobic and resistance exercise, reduces chronic inflammation, especially in obese individuals with high levels of inflammatory biomarkers undergoing a longer-term intervention. Several studies have reported that this effect is independent of the exercise-induced weight loss. (You et al 2013)

Chronic inflammation is involved in the pathogenesis of insulin resistance, atherosclerosis, neurodegeneration, and tumour growth. Evidence suggests that the prophylactic effect of exercise may, to some extent, be ascribed to the anti-inflammatory effect of regular exercise mediated via a reduction in visceral fat mass and/or by induction of an anti-inflammatory environment with each bout of exercise (e.g. via increases in circulating anti-inflammatory cytokines including interleukin (IL)-1 receptor antagonist and IL-10). (Walsh et al 2011)

Exercise is associated with improvements in ovarian hormones in women with abnormal ovarian function. This suggests that mechanisms associated with ovarian dysfunction can be improved by exercise in PCOS. (Moran et al 2011)

Regular exercise reduces CRP, IL-6, and TNF-αlevels and also increases anti-inflammatory substances such as IL-4 and IL-10. In healthy young adults, a 12-week high-intensity aerobic training program down regulates cytokine release from monocytes. In fact, even leisure time physical activity (e.g., walking, jogging, or running, etc.) reduces hs-CRP concentration in a graded manner. Subjects with higher baseline CRP levels (>3.0mg/L) will benefit more. (Golbidi & Laher 2012)

Exercise also resulted in an increase in mitochondrial antioxidant enzymes (copper-zinc superoxide dismutase, manganese superoxide dismutase, and glutathione peroxidase) and prevented the ischemia-reperfusion (IR)-induced release of proapoptotic proteins from the mitochondria. Collectively, these novel findings reveal that exercise-induced cardioprotection is mediated, at least in part, through mitochondrial adaptations resulting in a mitochondrial phenotype that resists IR-induced damage. (Lee et al 2012)

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Compassionate Acupuncture and Healing Arts, providing craniosacral acupuncture, herbal and nutritional medicine in Durham, North Carolina. Phone number 919-475-1005.