PCOS or Polycystic ovary syndrome is a condition that is very close to my heart. There are many women who are afflicted by this condition, my own daughter included. Because PCOS is influenced by insulin receptors it is able to be influenced by nutrition. Insulin resistance has been demonstrated in the majority of patients who are obese who have PCOS and in nearly 45% of their lean counterparts who also have PCOS. There are many clients who suffer from PCOS who wish to manage their condition naturally and wish to avoid taking medication. This article provides insight into what supplements are helpful to PCOS and how changing their diet can affect their condition and subsequent symptoms.
The appearance of polycystic ovary syndrome is dependent on a combination of genetic and environmental factors. Environmental/nutritional factors may come into play even before birth, as birthweight depends both on genetic factors and maternal nutrition and uteroplacental function (Armitage et al. 2004). A positive correlation has been found between birthweight and subsequent presentation of polycystic ovaries. Conversely, large population-based studies in the United Kingdom clearly correlated low birth- weight to subsequent markers of metabolic syndrome. Rapid early postnatal weight gain strongly predicts later childhood obesity and insulin resistance. What we eat when we are pregnant has an immense impact on the health of the child in its adult years.
PCOS and insulin resistance
Insulin resistance is a major metabolic feature of PCOS and is probably central to many of its manifestations. In brief, insulin resistance occurs when a receptor has a diminished insulin response. As a result a higher insulin-glucose set-point occurs which leads to hyperinsulinemia. The high levels of insulin have secondary effects particularly on two crucial cell types: Vascular endothelia and ovarian theca cells.
There are a number of ways of modifying insulin resistance. Eating a diet that contains foods that low in glycaemic index. Eating whole foods and unprocessed foods. Ghrelin, a hormone implicated in appetite regulation, was found to be lower in PCOS women. Maintaining a healthy weight and having minimal visceral body fat improve insulin resisitance. Visceral fat is closely linked to insulin resistance and PCOS, even in lean PCOS women. PCOS sufferers also have defects in their ability to lipolyse visceral fat. Visceral fat cells also incorporate free fatty acids (FFA) less readily than peripheral fat, leading to high FFA levels after food consumption in insulin resistant women (Dunaif et al. 1992, Gennarelli et al. 2000).
Addition of fiber to the diet, especially guar gum and and separation of carbohydrate intake from protein intake also help to modulate insulin levels. This means not mixing carbs and protein in the one meal. The type of carbohydrate consumed is equally important as the amount consumed, and many studies have demonstrated the advantage of substituting simple carbohydrates with a high glycemic index with complex carbohydrates.
Fat intake also is of cardinal importance in insulin resistant states, including PCOS. High fat intake leads to high plasma levels of FFA, which compounds insulin resistance. Swapping saturated fat for polyunsaturated or monounsaturated fat improves insulin resistance. Walnuts are a particularly good source of PUFA and reduces the amount of FFA and oxidation. There have been multiple studies that show improvement of insulin resistance when a high monounsaturated fat diet replaced a high saturated fat diet. This benefit though was only applicable for total dietary fat levels being less than 38% of the caloric intake. Once the fat percentage increased the benefit disappeared. Examples of foods rich in monounsaturated or poly-unsaturated fat include liquid oils from olives, canola, soybeans, corn, flaxseed, sunflower, and peanuts. Also, fats derived from nuts, seeds, and deep-sea fish . The mediterranean diet has been shown to have positive effects for those with metabolic syndrome.
Vitamins and Supplements
Inositol
Dietary supplementation of inositol was evaluated in a double-blind, placebo controlled study in 281 women with PCOS. The treatment group lost weight and had more ovulations during the study period than control patients, although no significant differences in insulin parameters were found between the groups.
Folic Acid and B12 Supplementation
Homocysteine (Hcy) is an intermediate formed during the breakdown of the amino acid methionine, and may undergo remethylation to methionine, or trans-sulfuration to cystathione and cysteine. Folic acid and vitamin B12 are essential cofactors in the remethylation pathway. Classic homocysteinemia has been characterized as the accumulation of Hcy due to defects in enzymatic pathways, most commonly methyltetrahydrofolate reductase, or vitamin deficiencies, most commonly folic acid and vitamin B12 deficiency. Elevated levels of Hcy are associated with vascular inflammation, atherosclerosis, increased rates of miscarriage, and poor reproductive performance. Therefore reducing elevated Hcy could improve these parameters. Strategies for reducing Hcy may include folic acid and vitamin B12 supplementation, supplying additional sources of methyl donors to improve the conversion of Hcy to methionine, and reduction of insulin levels. Insulin levels have been implicated as a modulating factor of Hcy, in that insulin inhibits hepatic cystathione b synthase activity. Several studies demonstrated increased Hcy levels in PCOS patients.
Betaine (trimethylglycine)
Betaine (trimethylglycine) can be sourced from including spinach or beets. Several studies have shown that elevated Hcy levels in insulin resistant patients may be reduced by betaine supplementation. Folic acid (as folate), by itself, and in conjunction with vitamin B12, has consistently shown Hcy-lowering effects in many studies. Betaine acts via a different route in Hcy metabolism, and may enhance Hcy metabolism even when folic acid levels are insufficient. A reduction in Hcy improves endothelial function parameters, and lowers insulin levels, after 1 month of folic acid (5 mg/day) and vitamin B12 (0.5 mg/day). An example of a supplement that would positively benefit women with PCOS can be found here. This supplement will significantly reduce Hcy levels. The supplement had a better effect than metformin on the symptoms of PCOS. When the study population was divided into two major groups, those treated with homocysteine modulators and those not, irrespective of metformin treatment, the mean reduction in Hcy in the HM group was 33%, and mean reduction in the no-HM group was 18%.
Strategies for reducing Hcy may include folic acid and vitamin B12 supplementation, supplying additional sources of methyl donors to improve the conversion of Hcy to methionine, and reduction of insulin levels.
PPAR-gamma, retinoids, and post-insulin-receptor signalingRetinoids and thiazolidinediones (TZDs) are two classes of nuclear receptor ligands that induce insulin sensitization in mammalian cells. The TZDs are activators of peroxisome proliferator-activated receptor-gamma (PPAR-g), whereas retinoids and rexinoids are selective ligands for the retinoid X receptors (RXRs). Activated PPAR-g activates gene expression in adipose tissue, altering fatty acid metabolism and fatty acid blood levels and increasing skeletal muscle sensitivity. Activated PPAR-g also increases adiponectin and suppresses tumor necrosis factor-alpha (TNF-a) and resistin. Activation of RXRs by retinoids leads to improved insulin sensitivity. Most importantly, PPAR-g activation in ovarian theca cells decreased luteinizing hormone (LH) and/or insulin driven androgen production by impairing the ability of cytochrome CYP17 to synthesize androstenedione from available progestins. This pathway may prove to be the intracellular link between insulin resistance, hyperinsulinemia, and theca cell androgen overproduction.
Retinoic acid, the acid form of vitamin A, has been identified as a signal that inhibits the expression of resistin in adipocytes. Its effects were reproduced by selective agonists of retinoic acid receptors and retinoid receptors. Diets higher in vitamin A showed an inverse relationship with insulin resistance (Facchini et al. 1996), hence the importance of verifying normal vitamin A status in PCOS women.
Phytanic acid, a branched-chain fatty acid found in omnivore diets, can activate PPAR, and thus has a potential in respect to its impact on insulin sensitivity.
Green tea polyphenols, especially the catechin epigallocatechin gallate (EGCG) have been found to reduce food intake, body weight, testosterone, LH, and IGF-1. It was also found to suppress endothelial responsiveness to vascular endothelial growth factor (VEGF), thus reducing the risk for ovarian hyperstimulationsyndrome (OHSS) in PCOS patients. Insulin resistance may also be reversed by inhibition of the signalsome inhibitor of Kappa B kinase (IKK beta), which catalyzes nuclear factor-kappa B activation. This may be aided by polyphenols such as EGCG and milk-thistle extract silymarin. Three natural polyphenols – quercetin, myricetin, and catechingallate – were found to interact directly with the GLU4 glucose transporter in adipocytes and muscle cells; these may impact on insulin resistance through glucose uptake in cells. Natural sources of polyphenols include green tea, grape skin extracts (especially red grapes, and red wine), olive oil, flaxseed, apples, onions, garlic, and soybeans.
Cinnamon
Insulin resistance may also be reversed by inhibition of the signalsome inhibitor of Kappa B kinase (IKK beta), which catalyzes nuclear factor-kappa B activation. This may be aided by polyphenols such as EGCG and milk-thistle extract silymarin. Three natural polyphenols – quercetin, myricetin, and catechingallate – were found to interact directly with the GLU4 glucose transporter in adipocytes and muscle cells; these may impact on insulin resistance through glucose uptake in cells. Natural sources of polyphenols include green tea, grape skin extracts (especially red grapes, and red wine), olive oil, flaxseed, apples, onions, garlic, and soybeans.
Cinnamon contains a-phenyl cinnamic acid which was found to mimic the actions of PPAR-g. These compounds inhibit cytochrome P450c17 activated enzyme synthesis and improve insulin sensitivity, and may be of potential use in PCOS hypersecretion of androgens. Cinnamon also contains methylhydroxy- chalcone polymer. This compound has been examined in an animal fructose diet model, and was found to prevent insulin resistance. Cinnamon administration prevented the development of insulin resistance at least in part by enhancing insulin signaling and possibly via the NO pathway in skeletal muscle.
Magnesium
Available research suggests an association between magnesium deficiency and insulin resistance. Magnesium deficiency was a relatively common finding in both overweight adults and patients with Type 2 diabetes. Intracellular magnesium depletion was found to be a characteristic feature of insulin resistance in hypertensive patients; in fact experimentally increased insulin levels reduced cells’ ability to accumulate magnesium. A study conducted in PCOS women looked at the status of serum calcium and magnesium, and their ratio (Muneyyirci-Delale et al. 2001). Significantly lower serum magnesium ion and total body magnesium, and higher serum Ca2þ/Mg2þ ratios were found in PCOS women as compared to controls, irrespective of steroid hormone concentrations. Another aspect of mineral metabolism in women with PCOS was examined by Thys-Jacobs and colleagues (1999). They found relatively low levels of vitamin D and relatively high parathyroid hormone, with normocalcemia. Treatment with vitamin D and calcium normalized cycles in 7/13 women. Calcium supplementation (1500 mg/day for 6 weeks) improved insulin sensitivity in diabetic, insulin resistant patients (Sanchez et al. 1997); these patients did not have PCOS. Vitamin D may have an anti-inflammatory role, as its deficiency is associated with elevated C-reactive protein, and its supplementation has been shown to lower TNF- a, and have other anti-inflammatory effects (Bubanovic 2004). It appears that some patients with insulin resistance have non-optimal calcium and magnesium metabolism; thus efforts should be made to investigate divalent cation status and to correct deficiencies or imbalances, if found.
Evidence exists linking low levels of chromium and insulin resistance; this may be either primary, or secondary loss of chromium to the urine due to high insulin levels (Anderson et al. 1991, Morris et al. 1993). Nonetheless, chromium’s therapeutic role in insulin resistance remains equivocal. Studies that support the use of chromium–nicotinic acid complex, chromium-rich brewer’s yeast, Chelavite (chromium–niacin–amino-acid chelate form), or chromium picolinate have been published (Anderson et al. 1997, Kelly 2000, Rabinovitz et al. 2004) which among other effects, improved the lipid profile, and yet others have found no advantage to chromium (Joseph et al. 1999).
Evidence has been gathered which supports the concept that PCOS and insulin resistance are associated with a state of increased oxidative stress and endothelial inflammation. The pathophysiological focus of this association resides most likely within the vascular endothelial cell. Increased intracellular deposition of lipo-proteins leads to modifications in intracellular oxidation pathways, and the oxidation–reduction status is predisposed to an oxidative state; this is associated with increased lymphocyte and macrophage activation, thus perpetuating the inflammatory–oxidative stress situation. Increased oxidative stress and decreased antioxidant capacity in women with PCOS could be a contributing factor to the increased risk of cardiovascular disease in addition to classic risk factors as insulin resistance, hypertension, obesity, and dyslipidemia. These principles are well founded on clinical data as well as basic scientific findings.
Other studies demonstrate that women with PCOS, obese and non- obese, have elevated endothelin-1 levels (Diamanti-Kandarakis et al. 2001). A study using an in vitro ovarian theca–interstitial cell culture demonstrated a dose–response effect between oxidative stress (induced by hypoxanthine and xanthine oxidase) and theca cell proliferation (Duleba et al. 2004). These studies emphasize the importance of considering PCOS as a generalized systemic disease state, with insulin resistance and oxidative stress being central axes in the pathophysiology of both vascular endothelial and ovarian aspects of the syndrome. As such, nutritional balance in terms of oxidation–reduction is extremely important for both short-term results of infertility treatment and long-term health consequences.
Vitamin E
Vitamin E (a-tocopherol) and beta-carotene status was found to be inversely related with plasma insulin levels in children with multimetabolic syndrome (Molnar et al. 2004), and in adults with insulin resistance (Facchini et al. 2000). Animal models have also found a correlation between lipid peroxidation and other oxidative stress parameters and insulin resistance (Thirunavukkarasu et al. 2004). Elevated Hcy is also associated with oxidative stress, and, as previously mentioned, is correlated with insulin resistance in PCOS patients. These studies form a logical theoretical basis for the supplementation of antioxidants to the diet of patients with insulin resistant PCOS.
Fish oil is rich in omega-3 essential fatty acids; two active forms are eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Several studies have shown improved insulin sensitivity, decreased inflammatory markers, and improved blood lipids after EPA/DHA supplementation (Rivellese et al. 1996). Gamma linolenic acid (GLA), from borage oil or evening primrose oil, is an omega-6 fatty.
This fatty acid is more efficacious when administered with EPA/DHA than on its own. Gamma linolenic acid has been found to have anti-inflammatory effects, and, importantly for PCOS patients, can inhibit 5-alpha reductase, thus reducing skin dihydrotestosterone. Lopez-Garcia et al. (2004) examined the effect of n-3 fatty acid consumption on inflammation biomarkers in women from the Nurses Health Study. Intake of EPA/DHA was inversely associated with soluble intracellular adhesion molecule-1 (ICAM-1), soluble vascular cell adhesion molecule-1 (VCAM-1), C-reactive protein, interleukin-6, and E-selectin, which might explain in part the effect of these fatty acids in preventing cardiovascular disease.
Alpha-lipoic acid was examined in animal and clinical studies for its ability to improve insulin sensitivity. Using a high-fructose diet model in rats, a-lipoic acid improved both insulin sensitivity and decreased oxidation parameters such as lipid peroxidation and diene conjugate levels (Thirunavukkarasu et al. 2004). In clinical studies in humans, both intravenous and oral administration of a-lipoic acid increased insulin stimulated glucose disposal (mean improvement 27% in 74 patients treated with 600–1800 mg/day for 4 weeks) (Kelly 2000).
N-acetyl cysteine (NAC)
N-acetyl cysteine (NAC) is the acetylated form of the amino acid L-cysteine. Administration of this compound improves insulin sensitivity and inhibits VEGF, and can increase glutathione; thus it acts as an antioxidant, which also reduces plasma homocysteine. A prospective study investigating the eVect of NAC on hormone and lipid profile and Hcy levels in insulin resistant PCOS women showed that NAC may reduce Hcy levels and improve lipid profiles making it an alternative to other treatments (Kilic-Okman and Kucuk 2004). Another study with NAC in insulin resistant PCOS women demonstrated a significant reduction in insulin resistance, testosterone levels, and in free androgen index, when 37 PCOS patients were treated with 1800 mg/day of NAC (Fulghesu et al. 2002). Rizk et al. (2005) recently looked at the contribution of NAC to ovulation induction in clomiphene resistant PCOS patients. The clomiphene–NAC treated group had a significantly higher ovulation rate than the clomiphene–placebo group. These studies highlight the potential of NAC in treating PCOS; further studies are certainly forthcoming.
Polycystic ovary syndrome is a complicated endocrinological–metabolic syndrome which has insulin resistance as central to its multisystem manifestations. Nutrition/metabolic status has a critical effect on the appearance and probably the short- and long-term effects of the syndrome. Utilizing dietary recommendations and lifestyle modifications to optimize body weight and visceral fat status, both short-term fertility goals and long-term vascular health may be enhanced. Dietary recommendations should include consideration of the total caloric intake, distribution of carbohydrate/fat/protein intake, and type of fat consumed, especially unsaturated fats; those derived from nuts, seeds, olives, and fish are to be encouraged. Other dietary recommendations may include use of soybean products, fiber, and fresh leafy vegetables and whole grains as sources of folic acid, calcium, and B vitamins to reduce elevations of Hcy observed in insulin resistant PCOS. Foods rich in polyphenols, such as green tea, grape and soy products, milk thistle, and vitamin A, can be recommended as part of the strategy to improve nuclear receptor activation thus improving insulin sensitivity. Magnesium, calcium, and vitamin D status may also impact on insulin sensitivity. Finally, antioxidant status should be optimized, which may improve general vascular endothelial health in the long term. Vitamin E, N-acetyl-cysteine, and a-lipoic acid are supplements which seem to hold promise in this regard.
About the Author
Jacine Greenwood is an internationally recognised educator who is known within the industry for her up to date knowledge and her ability to deliver training in an easy to understand method.
Jacine holds 4 Diplomas and a Bachelor of Nursing and her knowledge is well respected by her peers. With over 19 years experience in the industry and a background of cosmetic formulation, Jacine has an immense knowledge of current trends in research and new developments in the industry.
Jacine has been continually educating herself in all aspects of skin function and cosmetic chemistry for the past 21 years. Jacine’s knowledge is current and has a vast knowledge of the active ingredients that are being released onto the market.
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