Nutritional strategies to help manage PCOS

Dr Nina BaileyBSc Hons, MSc, PhD, RNutr

1

Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting women in their reproductive years and affecting ~5%-10% of women worldwide

The syndrome is characterised by the presence of at least two of the three classical features: Hyperandrogenism (androgen excess) Ovulation issues of either:

Anovulation (the ovaries do not release an oocyte during a menstrual cycle Oligoovulation (infrequent or irregular ovulation)

Polycystic ovaries containing a large number of harmless follicles that are up to 8mm (approximately 0.3in) in size.

Women with PCOS, particularly those with menstrual irregularities, may have difficulties conceiving because of anovulation

Besides that, PCOS patients frequently have metabolic disturbances with cardiovascular, type II diabetes, dyslipidaemia, visceral obesity, endothelial dysfunction and cancer risk factors

Therefore, PCOS is not just a cosmetic and fertility problem but potentially also a major health problem that could shorten women’s life expectancy

Gonadotropin-releasing hormone (GnRH)

• Increased frequency of hypothalamic GnRH pulses leads to an increase in LH secretion

Luteinizing hormone (LH) and follicle stimulating hormone (FSH)

• At the beginning of the cycle, LH and FSH levels usually occur at a ratio of 1:1

• An LH surge occurs 24 hours before ovulation (LH then returns to normal)

• Women with PCOS still have LH and FSH within the normal range but the LH to FSH ratio is often as high as 3:1

• LH pulse frequency is persistently rapid at approximately one LH pulse per hour (no LH surge = no ovulation)

Testosterone

• Women with PCOS often have an increased level of both total testosterone and free testosterone (due to low SHBG) - even a slight increase can suppress normal menstruation and ovulation

Oestrogen

• Thecal cells produce androgens in response to LH, which are then converted into estrogen by FSH-induced aromatase in the neighbouring granulosa cells

• Low FSH results in high levels of androgens secreted from the ovary (hyperandrogenism), and a failure of follicle development to progress

https://courses.washington.edu/conj/bess/reproductive/pcos.htm; http://youngwomenshealth.org/2014/02/25/polycystic-ovary-syndrome/

PCOS associated health issues

Infertility

Weight gain/obesity

Metabolic syndrome & type II diabetes

Cardiovascular disease & stroke

Dementia [especially vascular dementia]

Hormone driven cancers including endometrial, ovarian and breast cancer

Non-alcoholic fatty liver disease

Additional obesity-linked health issues [joint and bone]

Potential pregnancy complications Miscarriage Gestational diabetes Low weight/early birth

Weight gain that is difficult to manage

Fatigue, low energy & poor sleep [including sleep apnoea]

Hirsutism (unwanted hair growth) on the face, arms, back, chest, thumbs, toes & abdomen

Thinning hair on the head which appears to increase in middle age

Infertility - PCOS is a leading cause of female infertility

Acne, skin tags [proliferation marker] and darkened patches of skin [acanthosis nigricans, increased epidermal hyperkeratosis and dermal fibroblast proliferation]

Mood swings, depression & anxiety

Pelvic pain and heavy bleeding

Headaches

Many women do not receive a formal diagnosis until they experience issues conceiving!

Signs and symptoms of PCOS

Genetics:PCOS is believed to be a complex disorder, with genetic as well as environmental factors contributing to development of the disease

20-40% of female first-degree relatives of women with PCOS also have the syndrome, suggesting that the disease is partially heritable and clusters in families. Prevalence and severity of presentation vary with ethnicity, with South Asians at a higher risk of disease.

Intrauterine exposures:exposures to testosterone in utero may predispose to the later development of PCOS

Animal studies have demonstrated that in utero exposure is correlated with development of a PCOS-like syndrome including hyperinsulinemia, hyperandrogenism, oligoanovulation, and polycystic ovaries. Exposure to androgens may impair estrogen and progesterone inhibition of gonadotrophin-releasing hormone (GnRH), contributing to increased pulse frequency.

Environment/lifestyle:several lifestyle factors and environmental exposures have been associated with a more severe PCOS phenotype

Sedentary lifestyle is associated with increased metabolic dysfunction, and weight gain is associated with oligoanovulation and hyperandrogenism. Environmental androgen-disrupting chemicals may accumulate to a greater extent in individuals with PCOS because of decreased hepatic clearance; these also induce androgen production and insulin resistance.

Obesity:although obesity is not believed to cause PCOS, it is known to exacerbate the symptoms of the disease

Obesity is present in 30-75% of women with PCOS. Adipose dysfunction contributes to the development of glucose intolerance and hyperinsulinemia, which in turn can exaggerate the manifestations of hyperandrogenism. Obese women with PCOS are at increased risk of anovulation and consequent sub-fertility.

Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilisation

Spironolactone. finasteride and flutamide act to reduce androgen excess - a-5 reductase inhibitors

OCPs: oral contraceptive pill

Clomiphene is a non-steroidal fertility medicine. It causes the pituitary gland to release hormones needed to stimulate ovulation (the release of an egg from the ovary)

Metabolic syndrome is a combination of a number of significant risk factors:

There is a close connection between PCOS and obesity - approximately 30-75% of PCOS cases are overweight or obese

• Abdominal obesity• BMI >30 kg/m2 and/or waist:hip ratio >0.9 in men, >0.85 in women

• Dyslipidemia (high cholesterol/high triglycerides)• Plasma triglycerides ≥150 mg/dL (≥1.7 mmol/L)• HDL cholesterol <35 mg/dL (<0.9 mmol/L) in men or <39 mg/dL (1.0 mmol/L) in

women• Raised blood pressure

• ≥140 mm Hg systolic or ≥90 mm Hg diastolic

• Insulin resistance / glucose intolerance• Pro-inflammatory state• Pro-thrombotic state

The more symptoms present, the higher the chance of having significant health issues, including type II diabetes, heart disease and dementia

Adipose tissue produces the enzymes aromatase and hydroxysteroid dehydrogenase (17ß-HSD)

So in obese individuals, there is typically an increased conversion of the androgens androstenedione (∆4A) and testosterone (T) into the oestrogens oestrone (E1) and oestradiol (E2), respectively, by aromatase

17ß-HSD converts the less biologically active hormones ∆ 4A and E1 into the more active hormones T and E2, respectively

Obesity also leads to hyperinsulinaemia, which in turn causes a reduction in the hepatic synthesis and circulating levels of sex-hormone-binding globulin (SHBG)

Effects of obesity on hormone production

The combined effect of increased formation of oestrone and testosterone, along with reduced levels of SHBG, leads to an increase in the bioavailable fractions of E2 and T that can diffuse to target cells, where they bind to oestrogen and androgen receptors

The effects of sex steroids binding their receptors can vary, depending on the tissue types, but in some tissues (for example, breast epithelium and endometrium) they promote cellular proliferation and inhibit apoptosis

Calle EE, Kaaks R. Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nat Rev Cancer. 2004 Aug;4(8):579-91

In obesity, increased release from adipose tissue of free fatty acids (FFA), tumour-necrosis factor-α (TNFα) and resistin (pro-inflammatory cytokine), and reduced release of adiponectin (modulates glucose regulation and fatty acid oxidation) lead to the development of insulin resistance and compensatory, chronic hyperinsulinaemia

Increased insulin levels, in turn, lead to reduced liver synthesis and blood levels of insulin-like growth factor binding protein 1 (IGFBP1), and probably also reduce IGFBP1 synthesis locally in other tissues

Effects of obesity on growth-factor production

Increased fasting levels of insulin in the plasma are generally also associated with reduced levels of IGFBP2 in the blood

This results in increased levels of bioavailable IGF1

Insulin and IGF1 signal through the insulin receptors (IRs) and IGF1 receptor (IGF1R), respectively, to promote cellular proliferation and inhibit apoptosis in many tissue types. These effects might contribute to tumorigenesis

Calle EE, Kaaks R. Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nat Rev Cancer. 2004 Aug;4(8):579-91

Obesity, hormones and endometrial cancer

Obesity leads to increased insulin levels and increased IGF1 activity which may lead to an increase in androgen production by the ovaries leading to chronic anovulation which leads to progesterone deficiency

Increased adiposity also increases aromatase activity, leading to increased levels of bioavailable oestrogen which increases endometrial cell proliferation and inhibits apoptosis via increased IGF1 activity in endometrial tissue

Progesterone normally counteracts these effects through various mechanisms, in part by promoting synthesis of IGFBP1 -- the most abundant IGFBP in endometrial tissue

The lack of progesterone (because of ovarian androgen production and continuous anovulation) reduces the production of IGFBP1

High insulin reduces concentrations of SHBG which then increases the levels of bioavailable oestrogens that can diffuse into endometrial tissue

IGF1: insulin-like growth factor 1; IGFBP1 IGF-binding protein 1; SHBG: sex-hormone-binding globulinCalle EE, Kaaks R. Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nat Rev Cancer. 2004 Aug;4(8):579-91

Sex Hormone Binding Globulin SHBG concentrations are negatively correlated with body mass index (BMI) and, more particularly, to

indices of central adiposity

A standard western-style diet [higher intakes of red and processed meats, refined grains, sweets and desserts] is associated with a higher level of estradiol and lower concentrations of SHBG

High carbohydrate diets and/or diets high in refined grains and simple carbohydrate (sugar = glucose) that elicit a high insulin response will also lower SHBG, by increasing fat synthesis in the liver, which in turn shuts off the gene involved in SHBG production

Glucose, and particularly fructose, stimulate hepatic lipogenesis and subsequently reduce SHBG production via down-regulation of hepatocyte nuclear factor-4α (HNF-4α), a transcription factor that plays a pivotal role in the expression and synthesis of SHBG

Fructose also increases fat content of the liver, which increases inflammation and the production of cytokines such as tumour necrosis factor alpha (TNFα), interleukin 1 beta (IL1β) - cytokines that induce a down-regulation of hepatic SHBG production

Addressing the type and amount of carbohydrate in the diet is therefore a key target for nutritional intervention and regulating SHBG and hormones

Low adiponectin is also associated with low SHBG production

Fung TT, Hu FB, Barbieri RL, Willett WC, Hankinson SE. Dietary patterns, the Alternate Healthy Eating Index and plasma sex hormone concentrations in postmenopausal women. Int J Cancer. 2007 Aug 15;121(4):803-9.

Selva DM, Hogeveen KN, Innis SM, Hammond GL. Monosaccharide-induced lipogenesis regulates the human hepatic sex hormone-binding globulin gene. J Clin Invest. 2007 Dec;117(12):3979-87.

Over the past decade, the visceral adipocyte itself has emerged as a key contributor rather than passive bystander in the genesis of metabolic syndrome

Rather than being a simple storage bin for excess triglyceride, the visceral adipocyte is an active endocrine cell secreting a variety of signal hormones known collectively as adipokines

In optimal health, the predominant recognised adipokine is adiponectin, linked to insulin-sensitising, anti-inflammatory, anti-thrombotic & pro-vasodilatory effects

By contrast, metabolic syndrome is characterised by reduced adiponectin and increased inflammatory adipokine secretion, [and low SHBG] with downstream effects of insulin resistance, heightened inflammation, pro-thrombosis, and vasoconstriction

Adiponectin and metabolic syndrome

Freitas Lima LC, Braga VA, do Socorro de França Silva M, Cruz JC, Sousa Santos SH, de Oliveira Monteiro MM, Balarini CM. Adipokines, diabetes and atherosclerosis: an inflammatory association. Front Physiol. 2015 Nov 3;6:304

Adiponectin and PCOS

Adiponectin circulating levels correlate negatively with the body mass index (BMI) and with abdominal fat accretion = low adiponectin in PCOS

Freitas Lima LC, Braga VA, do Socorro de França Silva M, Cruz JC, Sousa Santos SH, de Oliveira Monteiro MM, Balarini CM. Adipokines, diabetes and atherosclerosis: an inflammatory association. Front Physiol. 2015 Nov 3;6:304

Adiponectin influences the HPG-axis by regulating pituitary gonadotropic function

In normal situations, adiponectin acts to regulate LH release and GnRH-stimulated LH secretion

When adiponectin is low this is associated with a persistently rapid LH pulse frequency, impaired FSH production, and inadequate follicular development

In PCOS, plasma LH is commonly increased, thus low adiponectin levels will exacerbate the ovulatory issues observed in PCOS

Dietary approaches to increasing adiponectin may lead to improved fertility in PCOS?

Adiponectin up-regulates SHBG!

Adiponectin decreased the mRNA and protein levels of enzymes related to hepatic lipogenesis (ACC) and increases those related to fatty acid oxidation (ACOX and CPTI)

Higher levels of adiponectin therefore reduces lipogenesis and increases fatty acid oxidation [and vice versa!]

This causes a reduction in the hepatic fatty acid pool thereby increasing (HNF-4) levels that in turn increase SHBG production [and vice versa!]

These adiponectin-induced changes in hepatic enzymes resulted in a reduction of total triglyceride and free fatty acids and an increase of HNF-4

Adiponectin regulates hepatic SHBG production

HNF-4:hepatocyte nuclear factor-4α; SHBG: sex hormone binding globulin

Simó R, Saez-Lopez C, Lecube A, Hernandez C, Fort JM, Selva DM.Adiponectin upregulates SHBG production: molecular mechanisms and potential implications. Endocrinology. 2014 Aug;155(8):2820-30.

Adiponectin offers insulin-sensitising, anti-inflammatory and endothelial protective effects

Decreased circulating adiponectin levels (especially in combination with increased oxidative stress - ROS further suppress adiponectin production in adipocytes) increases the risk of obesity-associated metabolic, cardiovascular and cancer disease

Lower adiponectin levels are associated with a higher risk of both breast cancer and endometrial cancer

Low adiponectin reduces SHBG

Ye J, Jia J, Dong S, Zhang C, Yu S, Li L, Mao C, Wang D, Chen J, Yuan G. Circulating adiponectin levels and the risk of breast cancer: a meta-analysis. Eur J Cancer Prev. 2014 May;23(3):158-65.

Zheng Q, Wu H, Cao J. Circulating adiponectin and risk of endometrial cancer. PLoS One. 2015 Jun 1;10(6):e0129824.

• CRP is an inflammatory cytokine product and elevated CRP is a useful biomarker of chronic obesity-related inflammation

• Both TNF-α and NF-κB are induced by the direct pro-inflammatory action of CRP

• Adiponectin decreases the production of CRP and inhibits the stimulation of NF-κB signalling and TNF-α secretion from macrophages

• Adiponectin enhances AMPK, inhibits NF-κB activation and suppresses inflammation through its ability to promote the removal of early apoptotic cells by macrophages

AMPK: 5' adenosine monophosphate-activated protein kinase; CRP: C-reactive protein; TNF-a: tumour necrosis factor-alpha; nuclear factor kappa beta

Because low adiponectin impairs the clearance of early apoptotic cells, this can increase systemic inflammation (apoptotic cells release noxious substances, triggering an inflammatory response)

Adiponectin – the anti-inflammatory

Disturbed homocysteine metabolism in PCOS women

Homocysteine is a natural by-product of the methylation cycle and can be remethylated to methionine or directed to the transsulfuration pathway. During times of methionine adequacy (via dietary protein), excess methionine is shunted towards cysteine synthesis because increased SAM functions to activate cystathionine β-synthetase (transsulfuration) and inhibit methylenetetrahydrofolate reductase (MTHFR) thereby limiting homocysteine re-methylation

SAH is also an activator of cystathionine β-synthetase thereby working synergistically with SAM to ensure the flux of homocysteine through the transsulfuration pathway

Insulin resistance is associated with increased plasma homocysteine

Insulin inhibits the hepatic cystathionineβ-synthetase activity, which increases serum homocysteine and reduces glutathione

Eskandari Z, Sadrkhanlou RA, Nejati V, Tizro G. PCOS women show significantly higher homocysteine level, independent to glucose and E2 level. Int J Reprod Biomed (Yazd). 2016 Aug;14(8):495-500.

PCOS and methylene tetrahydrofolate reductase (MTHFR)

Common cause of mildly to moderately elevated plasma homocysteine levels (normal blood

levels of homocysteine should fall between 4 and 15 µmol/L)

The MTHFR deficiency involves a variation at position 677 in the MTHFR gene in which cytosine

is replaced by thymidine (thus called C677T or 677C>T)

~10% of the population are homozygous for the TT variant

~43% are heterozygous (CT)

~47% are unaffected (CC)

677 C>T substitution in the 5, 10-methylene tetrahydrofolate reductase (MTHFR) gene

compromises activity of the MTHFR enzyme by about 50%

Heterozygotes have slightly higher homocysteine levels than unaffected people, while people

with the TT genotype have approximately 20% higher homocysteine levels

Women with PCOS may have predispositions for higher homocysteine levels than

other healthier women

Jain M, Pandey P, Tiwary NK, Jain SMTHFR C677T polymorphism is associated with hyperlipidemia in women with polycysticovary syndrome. J Hum Reprod Sci. 2012 Jan;5(1):52-6.Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ. 2002 Nov 23;325(7374):1202.

Methionine recycling

Methionine

SAM: universal methyl donorMethylates:

neurotransmitters, proteins, RNA, DHA, catecholamines, phosphatidylcholine, melatonin, myelin, creatine

Homocysteine

SAM

SAH

Methionine synthase

5-methyl THF

THF

FOLIC ACID

CYCLE

Processes affectedNeurotransmitter function Fatty acid metabolismAllergic responsesMyelinationCellular energyCell membrane and proteinstructure and function

Cystathionine

Virus fightingInflammation regulationAntioxidant production

DetoxificationIntestinal integrity

Cysteine

Glutathione

MetallathioninesAffects potent metal-

binding and redoxcapabilities

Cysteinesulflinic acid

Phenol sulfur-transferase

Phenol processing

DigestionDetoxification

Gut barrier

Sulfate

Sulphite

Taurine

Production of bile salts

SULPHATION

TRANSSULFURATION

METHYLATION

Magnesium

Magnesium, vitamin B6, zinc

Vitamin B6

S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH ); tetrahydrofolate (THF)

Folate, VitaminsB6 & B12

Vitamin B6

Methionine is required for protein synthesis and provides a methyl group for >50 critical transmethylation reactions

Methionine recycling

Methionine

Homocysteine

SAM

SAH

Methionine synthase

5-methyl THF

THF

FOLIC ACID CYCLE

Disrupts gene expressionDecreased neurotransmitter functionDecreased myelinationDisrupted cellular energy transferDisrupted fatty acid metabolismIncreased allergic reactions

Cystathionine

Reduced detoxification of toxins and heavy metals

Cysteine

Glutathione

MetallathioninesAffects potent metal-

binding and redoxcapabilities

Cysteinesulflinic acid

Phenol sulfur-transferase

Poor phenol processing

Poor digestion

Sulphate

Sulphite

Taurine

Production of bile salts

SULPHATION

TRANSSULFURATION

METHYLATION

Gut and blood brain barrier integrity compromised

Poor detoxification

Inactivates MAT and decreases

SAM synthesis

Villi flatten and lose function

Reduced antioxidant

function

Th1 decreasesTh2 increases

S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH); methionine adenosyltransferase (MAT; tetrahydrofolate (THF)

SAM/SAH ratio can be used as an index of the methylation potential in a cell

Homocysteine and cardiovascular health

• The link between homocysteine and cardiovascular disease is well established, and decreasing plasma total homocysteine by providing nutritional cofactors for its metabolism has been shown to reduce the risk of cardiovascular events

• Elevated homocysteine is linked to:

– Aggregation of cholesterol and low density lipoprotein (LDL) leading to the formation of plaques which are the major risk factor for atherosclerosis

– Increased oxidative stress, inflammation, higher CRP & pro-inflammatory cytokines

– Reduced nitric oxide, resulting in impaired vasodilation

– Increased blood clotting

– Endothelial dysfunction

The increased risk of atherosclerosis and stroke associated with elevated homocysteine increases the risk for vascular dementia

Ganguly P, Alam SF. Role of homocysteine in the development of cardiovascular disease. Nutr J. 2015 Jan 10;14:6.

Homocysteine neurotoxicity - the neurological pathologies associated with hyperhomocysteinaemia are hypothesised to be caused by oxidative stress, excitotoxicity via glutamate receptors, and via DNA hypomethylation

Homocystic acid is an oxidative product of homocysteine that functions as an excitatory neurotransmitter activating NMDA receptors and enhancing calcium influx which damages neurones, leading to cell death

Other known NMDA agonists:

• Quinolinic acid

• Kainic acid

Obeid R, Herrmann W. Mechanisms of homocysteine neurotoxicity in neurodegenerative diseases with special reference to dementia. FEBS Lett. 2006 May 29;580(13):2994-3005.

Murri M, Luque-Ramírez M, Insenser M, Ojeda-Ojeda M, Escobar-Morreale HF. Circulating markers of oxidative stress and polycystic ovary syndrome (PCOS): a systematic review and meta-analysis. Hum Reprod Update. 2013 May-Jun;19(3):268-88

Kim JW, Han JE, Kim YS, Won HJ, Yoon TK, Lee WS. High sensitivity C-reactive protein and its relationship with impaired glucose regulation in lean patients with polycystic ovary syndrome. Gynecol Endocrinol. 2012 Apr;28(4):259-63.

Low-grade chronic inflammation & oxidative stress are common to PCOS and may contribute to both PCOS and its metabolic associations

C-reactive protein (CRP) is a strong independent predictor of future CVD and/or stroke

High CRP levels observed in PCOS [regardless of BMI] may explain why some PCOS women are at an increased risk for the development of early-onset CVD

When oxidative stress appears as a primary disorder, inflammation develops as a secondary disorder and further enhances oxidative stress. On the other hand,

inflammation as a primary disorder can induce oxidative stress as a secondary disorder which can further enhance inflammation!

Biswas SK. Does the Interdependence between Oxidative Stress and Inflammation Explain the Antioxidant Paradox? Oxid Med Cell Longev. 2016;2016:5698931.

ROS production and antioxidant depletion

Primary disorder Inflammation

Inflammation secondary disorder

Cytokine &chemokine

NF-kb activation

Oxidative stress secondary disorder

NF-kb activation

Cytokine &chemokine

Primary disorder oxidative stress

Activation of tryptophan 2,3-dioxygenase (TDO), present in liver and brain, is up-regulated by cortisol whilst cytokines (such as IL-1. IL-6 and TNF-a) activate IDO and kynurenine monooxygenase (KMO)

Not only are serotonin levels reduced as a result of the diversion of tryptophan but elevated quinolinic acid production has neurotoxic effects via agonist actions on N-methyl-D-aspartate receptors (NMDA), triggering neuronal apoptosis

Elevated quinolinic acid accumulation in certain areas of the brain tissue is linked to cognitive issues

Oxenkrug, G. F. (2010). "Tryptophan kynurenine metabolism as a common mediator of genetic and environmental impacts in major depressive disorder: the serotonin hypothesis revisited 40 years later." Isr J Psychiatry Relat Sci 47(1): 56-63.

PCOS – the link to mood and memory

The kynurenine (KYN) pathway, which is initiated by indoleamine 2,3-dioxygenase (IDO), is a main tryptophan metabolic pathway and shares tryptophan with the serotonin (5-HT) pathway

Cooney LG, Lee I, Sammel MD, Dokras A.High prevalence of moderate and severe depressive and anxiety symptoms in polycystic ovary syndrome: a systematic review and meta-analysis.Hum Reprod. 2017 May 1;32(5):1075-1091.

Meusel et al., J Curr Clin Care 2012; 2(1):6-16.

Deficient Insufficient Optimal

< 30 nmol/l 30 - 50 nmol/l >50 nmol/l

Vitamin D deficiency

Vitamin D deficiency is very common in the UK; according to the latest National Diet and Nutrition survey results, around a fifth of adults aged 19 to 64 years and a sixth of children aged 11 to 18 years and adults aged 65 years and over had levels below 25nmol/L Vitamin D deficiency is common in women with PCOS

~67-85% of women with PCOS have serum concentrations of 25-hydroxy vitamin D (25OHD) <50 nmol/ml

Observational studies show low 25OHD levels are associated with insulin resistance, ovulatory and menstrual irregularities, lower pregnancy success, hirsutism, hyper-androgenism, obesity and elevated cardiovascular disease risk factors

Lin MW, Wu MH. The role of vitamin D in polycystic ovary syndrome. Indian J Med Res. 2015 Sep;142(3):238-40

Strategies for the management of PCOS and associated conditions

Ameliorating inflammation and ROS Up-regulates SHBG

Insulin resistanceImproved glycaemic control increases adiponectin & SHBG

SHBGIncreased SHBG improves hormone regulation

AdiponectinIncreasing adiponectin will increase SHBG and lower total triglyceride and free fatty acids Increasing adiponectin decreases ROS and inflammation

Homocysteine Regulating homocysteine supports methylation, transsulfuration & sulfation pathways

Weight lossImproves glycaemic control/insulin signalling, lowers IGF-1, improves hormone regulation - as little as 5% of initial weight has resulted in lower circulating androgen levels, and decreased levels of circulating insulin

PCOS and diet: focus on weight loss and improved insulin signalling

PCOS coupled with weight gain drives insulin resistance

Dietary intervention in PCOS should aim to promote weight loss and reduce insulin

By improving insulin signalling, we reduce the health burden associated with insulin resistance, primarily metabolic syndrome and type II diabetes

By regulating insulin, we improve hormone status ‘blunting’ the insulin/PCOS cycle

Low-carbohydrate, Ketogenic diets have been shown to lead to greater improvement in glycaemic control over a 24-week period in patients with obesity and type II diabetes

Low-carbohydrate ,Ketogenic diet led to significant improvement in weight, percent free testosterone, LH/FSH ratio, and fasting insulin in women with obesity and PCOS over a 24 week period

Six months of a low-carbohydrate, Ketogenic diet led to significant weight loss and histological improvement of fatty liver disease [steatosis, fibrosis & inflammatory grade]

Tendler D, Lin S, Yancy WS Jr, Mavropoulos J, Sylvestre P, Rockey DC, Westman EC. The effect of a low-carbohydrate, ketogenic diet on nonalcoholic

fatty liver disease: a pilot study. Dig Dis Sci. 2007 Feb;52(2):589-93. Epub 2007 Jan 12.

Mavropoulos JC, Yancy WS, Hepburn J, Westman EC. The effects of a low-carbohydrate, ketogenic diet on the polycystic ovary syndrome: a pilot study.

Nutr Metab (Lond). 2005 Dec 16;2:35.

Westman EC, Yancy WS Jr, Mavropoulos JC, Marquart M, McDuffie JR. The effect of a low-carbohydrate, ketogenic diet versus a low-glycemic index diet

on glycemic control in type 2 diabetes mellitus. Nutr Metab (Lond). 2008 Dec 19;5:36.

Salas-Salvadó J, Guasch-Ferré M, Lee CH, Estruch R, Clish CB, Ros E. Protective Effects of the Mediterranean Diet on Type 2 Diabetes and Metabolic Syndrome.J Nutr. 2016 Mar 9. pii: jn218487

Protective Effects of the Mediterranean Diet on Type 2 Diabetes and Metabolic Syndrome

Olive oil

Fruit

Vegetables

Oily fish

Nuts & seeds

Legumes & cereals

Monounsaturated fat (oleic acid)

Antioxidants(i.e. polyphenols)

Vitamin A,B,C & E

Vitamin D

Omega-3 fatty acids(ALA, EPA & DHA)

Minerals(i.e. selenium, iron &

iodine)

Amino acids(i.e. taurine, tyrosine &

tryptophan)

Moderate red wine

Lean meat

Moderate dairy

Neuronal survivalEnergy metabolismNeurotrophinsNeurotransmissionMembrane fluidityCell membrane integrity Glucose transportNutrient synthesisNutrient metabolismGene expressionMethylationCerebral blood flow

Blood pressureOxidative damageNeuronal cell deathNeuroinflammationFree radicals

Parletta N, Milte CM, Meyer BJ. Nutritional modulation of cognitive function and mental health. J Nutr Biochem. 2013 May;24(5):725-43.

Dietary management can be an effective therapeutic means of increasing adiponectin levels

Daily intake of fish or omega-3 supplementation increased adiponectin levels by amounts ranging from 14 to 60%

Daily intake of fish or omega-3 supplementation can increase adiponectin levels by 14-60%

Weight loss achieved with a low-calorie diet plus exercise has been shown to increase adiponectin levels in the range of 18-48%

Diets high in polyphenols [i.e. resveratrol, EGCG, curcumin]

A 60-115% increase in adiponectin levels has been obtained with fibre supplementation

Close adherence to a Mediterranean-type diet is associated with higher adiponectin concentrations

Silva FM, De Almeida JC, Feoli AM. Effect of diet on adiponectin levels in blood. Nutr Rev. 2011;69:599–612.

Mantzoros CS, Williams CJ, Manson JE, Meigs JB, Hu FB. Adherence to the Mediterranean dietary pattern is positively associated with plasma adiponectin concentrations in diabetic women. Am J Clin Nutr. 2006;84:328–335.

AnthocyanidinsIsoflavonesFlavanolsFlavonols

Polyphenols

Flavonoids Stilbenes Phenolic acids

FlavonesFlavonones

Catechin

Epicatechin

Epigalloatechin

Epigallocatechin

gallate (EGCG)

Rutin

Quercetin

Kaempherol

Myricetin

Genistein

Daidsein

Glycetin

Formanantine

Cyanidin

Malvidin

Pelargonidin

Delphinidin

Hesperetin

Naringenin

Isoxanthohumol

Taxifolin

Apigenin

Luteolin

Resveratrol Benzoic & Cinnamic acids

Salicylic acidCaffeic acidGallic acid

Ferulic acid

Curcuminoids

CurcuminDesmethoxycurcumin

Bisdemethoxycurcumins

Polyphenols: benefits for glucose control and insulin sensitivity

The effects of green tea and green tea extract on glucose control and insulin sensitivity

Seventeen RCTs comprising a total of 1133 subjects

Consumption of green tea/EGCG supplements have favourable effects, i.e. decreasing fasting glucose and Hb A1c concentrations

Eleven studies comprising a total of 388 subjects

Resveratrol consumption significantly reduced fasting glucose, insulin, Hb A1c, and insulin resistance (measured by using the homeostatic model assessment) levels in participants with diabetes but not in non-diabetes

‘Optimal’ doses??

Liu K, Zhou R, Wang B, Chen K, Shi LY, Zhu JD, Mi MT. Effect of green tea on glucose control and insulin sensitivity: a meta-analysis of 17 randomized controlled trials. Am J Clin Nutr. 2013 Aug;98(2):340-8

Liu K, Zhou R, Wang B, Mi MT. Effect of resveratrol on glucose control and insulin sensitivity: a meta-analysis of 11 randomized controlled trials.Am J Clin Nutr. 2014 Jun;99(6):1510-9.

EGCG and caffeine levels in tea

Fermenting the leaves results in less EGCG

Green tea leaves are not fermented and therefore have the highest amount of EGCG(oolong tea is partially fermented and black tea is fully fermented)

NOTE: green tea catechins may have an affinity for iron; green tea infusions may therefore cause a significant decrease of the iron bioavailability from the diet

Cabrera C, Giménez R, López MC. Determination of tea components with antioxidant activity. J Agric Food Chem. 2003;51(15):4427-35.

Turmeric contains an average of 5-10% curcuminoids Curcumin (75%) Demethoxycurcumin (DMC -15%) Bis-demethoxycurcumin (BDMC – 10%)

Other components include: Volatile (essential) oils 3-7%; fibre 2-7%; mineral matter 3-7%; protein 6-8% fat

5-10%; moisture 6-13% & carbohydrates 60-70%

Average intake (India) is as much as 2-3g daily

Pulido-Moran M, Moreno-Fernandez J, Ramirez-Tortosa C, Ramirez-Tortosa M Curcumin and Health. Molecules. 2016 Feb 25;21(3):264.

Antioxidant properties and reactive oxygen species (ROS) scavenger effects of curcumin

The health-promoting effects of lipophilic curcumin in healthy individuals

Longvida curcumin lowered

b-amyloid protein: a marker of brain ageing, especially in relation to Alzheimer’s disease

Lowered triglycerides: related to increased risk of poor cardiovascular health

Soluble intercellular adhesion molecule (sICAM): linked to atherosclerosis

Salivary amylase: a marker of sympathetic nervous system stress

Alanine aminotransferase (ALT): a marker of liver injury

Longvida curcumin increased

Catalase activity: an antioxidant enzyme

Antioxidant status: linked to lower levels of damaging free radicals

DiSilvestro RA, Joseph E, Zhao S, Bomser J. Diverse effects of a low dose supplement of lipidated curcumin in healthy middle aged people. Nutr J. 2012 Sep 26;11:79. doi: 10.1186/1475-2891-11-79.

In a 30 day, randomised placebo-controlled trial, daily supplementation with 400 mg Longvida curcumin in healthy, middle-aged individuals (40-60 years) led to significant (p<0.05) improvements (versus placebo) in the following markers:

© CNELM

Hirsutism The primary androgen responsible for hair growth is dihydrotestosterone (DHT), which is synthesized from testosterone by the activity of 5α-reductase type II

Hirsute females have increased 5α-reductase-activity in hair follicles

There are two drugs finasteride and dutasteride that used successfully as alpha-5 reductase inhibitors in the treatment of enlarged prostate (and to reduce the risk of prostate cancer)

Finasteride is known as a selective type II inhibitor as it reduces the activity of just one form of alpha-5 reductase (and only really works for men - prostate health) whereas dutasteride is known as a dual inhibitor as is acts on both forms of alpha-5 reductase (so works for men and women)

In addition there are a number of natural (non-phamaceutical) alpha-5 reductase inhibitors (some more effective than others) that include:

Serenoa repens, commonly known as saw palmetto is a well established 5α-reductase type II and commonly used to treat benign prostatic hyperplasia (enlarged prostate) because it inhibits testosterone’s action on the prostate

EGCG - has type I 5-alpha-reductase activity b-sterol Genistein Gamma-linolenic acid Ginkgo Biloba

Rossi A, Mari E, Scarno M, Garelli V, Maxia C, Scali E, Iorio A, Carlesimo M. Comparitive effectiveness of finasteride vs Serenoa repens in male androgenetic alopecia: a two-year study. Int J ImmunopatholPharmacol. 2012 Oct-Dec;25(4):1167-73. Hiipakka RA, Zhang HZ, Dai W, Dai Q, Liao S. Structure-activity relationships for inhibition of human 5alpha-reductases by polyphenols.Biochem Pharmacol. 2002 Mar 15;63(6):1165-76.Liao S, Hiipakka RA. Selective inhibition of steroid 5 alpha-reductase isozymes by tea epicatechin-3-gallate and epigallocatechin-3-gallate. Biochem Biophys Res Commun. 1995 Sep 25;214(3):833-8.

Excess sebum production by the sebaceous gland

Colonisation of the follicle by the bacterium propionibacterium acnes (p acnes) - the primary pathogenic agent responsible for acne

Alteration in keratinisation processes

Release of inflammatory mediators into the skin

Diet, hormone balance, inflammation, insulin levels, digestion, allergies and intolerances, liverfunction, adrenal function, SHBG levels, sebum quality, cell function and turnover, nutrientdeficiencies can all affect these 4 primary pathogenic factors

4 primary factors interact to produce acne lesions:

Vegetable oils and intensively farmed

animal products

Grains (gluten)

Micronutrient deficiency

Leaky gut DysbiosisDairy from intensively

farmed animals

Hypochlorhydria

Refined grains/sugars &

protein rich dairy foods

High omega-6 to omega-3 ratio

Low SHBG

Impaired methylation & sulfuration/low glutathione

Proteins disrupt gut/immune/barrier function and enter the blood stream

Elevated insulin/insulin

resistance

Inhibition of key enzymes involved in dissolving cell

adhesion molecules

Elevated testosterone

IGFBP-3: Insulin-like growth factor-binding protein 3IGF-1: insulin growth factor-1SHBG: sex hormone binding globulin

High omega-6 to omega-3 ratio

drives inflammatory processes

Inflammation/ROS

Pore blockage Excess sebum productionBacterial colonisation leads to infection

ACNE

Skin cells fail to shed at normal rate

Skin cells clump together

Low IGFBP-3

Elevated IGF-1

Insulin-sensitising compounds have been proposed as potential treatments to solve the hyperinsulinemia-induced dysfunction of ovarian response to endogenous gonadotropins

Inositol is a component of inositolphosphoglycans (IPGs) which act as second messengers in insulin signalling

In PCOS women, a defect in tissue availability or altered metabolism of Inositol or IPGs mediators are thought to contribute to insulin resistance

Studies have demonstrated that myo-inositol (2-4 g/day for 12-16 weeks) is capable of restoring spontaneous ovarian activity, and consequently fertility, in many patients with PCOS

The LH/FSH ratio is restored Testosterone levels reduce Restores normal ovulatory activity and fertilisation rate Improves insulin sensitivity Reduces total cholesterol and LDL (increasing HDL) Reduces triglycerides

Inositol for the management of PCOS

Unfer V, Nestler JE, Kamenov ZA, Prapas N, Facchinetti F. Effects of Inositol(s) in Women with PCOS: A Systematic Review of Randomized Controlled Trials. Int J Endocrinol. 2016;2016:1849162. Epub 2016 Oct 23.

Under conditions of low insulin, most GLUT4 is sequestered in intracellular vesicles in muscle and fat cells and insulin induces a rapid increase in the uptake of glucose by inducing the translocation of GLUT4 from these vesicles to the plasma membrane

Dietary omega-3 increases insulin binding by changing the fatty acid composition of phospholipid surrounding the insulin receptor, and this might be the mechanism by which dietary fatty acids modify insulin action

Albert, B. B., J. G. Derraik, et al. (2014). "Higher omega-3 index is associated with increased insulin sensitivity and more favourable metabolic profile in middle-aged overweight men." Scientific reports 4: 6697. Tsitouras, P. D., F. Gucciardo, et al. (2008). "High omega-3 fat intake improves insulin sensitivity and reduces CRP and IL6, but does not affect other endocrine axes in healthy older adults." Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme 40(3): 199-205.Liu S, Baracos VE, Quinney HA, Clandinin MT.Dietary omega 3 and polyunsaturated fatty acids modify fatty acyl composition and insulin binding in skeletal-muscle sarcolemma. Biochem J. 1994 May 1;299 ( Pt 3):831-7.

Image source: http://i0.wp.com/www.namrata.co/wp-content/uploads/2012/09/In4.jpg

P:S ratio and insulin resistance

Higher omega-3 index (EPA & DHA) is associated with increased insulin sensitivity, lower omega-6 to omega-3 ratio and lower CRP levels in middle-aged overweight men (Albert et al., 2014)

Dietary intervention with omega-3 fatty acids (as both fish and fish oil) improves insulin sensitivity and decreases CRP and IL-6 (Tsitouras et al., 2008)

Improves symptoms in treatment-resistant

depression

Increases insulin sensitivity

Reduces activation of PLA2 and the release of

AA and PGE2

Lowers cortisol levels

Normalisation of BDNF levels

Improved cell survival via increased neurotrophin

receptor expression

Decreased pro-inflammatory cytokine

production

Reduces hippocampal atrophy

EPA and/or DHA

Increased production of pro resolving mediators & anti-inflammatory eicosanoids

Lowers cholesterol, triglycerides and blood

pressure

Lowers CRP

Increases adiponectin

Omega-3 in the management of PCOS

45 non-obese PCOS women were treated with daily oral 1,500 mg of omega-3 for 6 months (Oneret al. 2013)

Significant improvements in:

Oner G, Muderris II. Efficacy of omega-3 in the treatment of polycystic ovary syndrome. J Obstet Gynaecol. 2013 Apr;33(3):289-91

Mohammadi E, Rafraf M, Farzadi L, Asghari-Jafarabadi M, Sabour S. Effects of omega-3 fatty acids supplementation on serum adiponectin levels and some metabolic risk factors in women with polycystic ovary syndrome. Asia Pac J Clin Nutr. 2012;21(4):511-8.

LH Testosterone (total and free) SHGB

Adiponectin Insulin Glucose HOMA-IR:r TC HDL LDL Triglycerides CRP*

32 obese PCOS women were treated with daily oral 1,200 mg of omega-3 for 8 weeks (Mohammadi et al. 2012)

Significant improvements in:

HOMA-IR: homeostatic model assessment for insulin resistance, TC: total cholesterol, TG: triglyceride, LDL-C: low density lipoprotein, HDL-C: high density lipoprotein, CRP: high sensitive C-reactive protein

*CRP – lower but not significant

Homocysteine lowering methylation supporting agents

• N-Acetyl –L-cysteine 1-3 g daily

• Creatine 2-5 g daily

• Choline 0.5-1 g daily (which is also the estimated daily intake)

– ~11g soybean lecithin is required to provide ~0.85 g choline [TUL = 3.5g/d] as phosphatidylcholine

– Sunflower oil derived phosphatidylcholine! 10 g = 2.7 g PC?

• Betaine 500mg/daily

– Can be synthesised from choline

– Betaine intake from foods is estimated at 0.5-2 g/d

• Folate ([6S]-5-methyltetrahydrofolate) / folic acid 3-5 mg

• Vitamin B12 (as methylcobalamin) 10 mcg – 1 g

• Vitamin B6 ( as pyridoxal-5-phosphate) 2-25 mg

• S- adenosyl methionine (SAM) 100-200 mg

Non enzymic antioxidants Vitamins A, C, & EPolyphenols- flavanoids- isothiocyanates- stilbenes- phenolic acids- lignans- carotenoids- resveratrol

Enzymatic antioxidantsSuperoxide dismutaseGlutathione peroxidaseGlutathione reductaserequire: SeleniumVitamin DCopperManganeseMagnesiumZincAmino acids (i.e. taurine)

Brain proteins, lipids and DNA are vulnerable to

oxidative damage

Prevent, inhibit, repair ROS damage

Metabolism and exogenous damage contribute to the

formation of ROS

Parletta N, Milte CM, Meyer BJ. Nutritional modulation of cognitive function and mental health. J Nutr Biochem. 2013 May;24(5):725-43.

• Astaxanthin’s lipophilic nature means it is able to penetrate the cell membrane and the keto [C=O] and hydroxyl group [OH] attached to the end rings make them hydrophilic so that the two ring ends become embedded into the inner and outer cell membranes

• This unique orientation gives it a bridge-like structure that adds stability to the cell membrane

• Because of Astaxanthin’s unique shape, it offers protection against free radicals on the outside of the cell membrane, on the inside of the cell membrane (as free radicals are generated) and within the membrane lipid bi-layer itself where it protects fatty acids from oxidation

Vitamin E & β-carotene – protect from inner layerVitamin C – protects only from outer layerAstaxanthin – protects both layers

http://truazta.com/for-business/no-astaxanthin/what-is-astaxanthin/

Supporting antioxidant defences

Alpha lipoic acid is an endogenous antioxidant and essential cofactor for many enzyme complexes that interrupt cellular oxidative processes

Increases acetylcholine production by activation of choline acetyl-transferase Increases glucose uptake Acts as a metal chelator Down-regulates the expression of redox-sensitive pro-inflammatory proteins including TNF-a

and inducible nitric oxide synthase Scavenges lipid peroxidation products such as 4-hydroxynonenal (HNE) and acrolein

Vitamin EAntioxidant protection

Vitamin C Further supports detoxification,

provides antioxidant protection against free radicals

Reduces tiredness and fatigueNecessary for the proper

functioning of the CNS and psychological functioning

Samimi M, Zarezade Mehrizi M, Foroozanfard F, Akbari H, Jamilian M, Ahmadi S, Asemi Z. The effects of coenzyme Q10 supplementation on glucose metabolism and lipid profiles in women with polycystic ovary syndrome: a randomized, double-blind, placebo-controlled trial. Clin Endocrinol (Oxf). 2017 Apr;86(4):560-566.

Randomized, double-blind, placebo-controlled trial was conducted on 60 women diagnosed with PCOS

Subjects were randomly assigned into two groups to intake either 100 mg CoQ10 supplements (N = 30) or placebo (N = 30) per day for 12 weeks

After 12 weeks of intervention, compared to the placebo, subjects who received CoQ10 supplements had significantly decreased fasting plasma glucose, decreased serum insulin concentrations and improved insulin sensitivity

Effect of CoQ10 supplementation on metabolic profiles among women with PCOS

In addition, changes in serum total and LDL-cholesterol concentrations in supplemented women were significantly different from those of women in the placebo group

Effects of coenzyme Q10 supplementation on inflammatory markers

Meta- analysis of nine RCTs involving 428 subjects (Zhai et al, 2017)

The results showed that compared with control group, CoQ10 supplementation significantly improved the serum level of CoQ10 and significantly decreased TNF-α

No significant difference was observed between CoQ10 and placebo with regard to CRP or IL-6

CoQ10 supplementation may partly improve the process of inflammatory state

Meta-analysis of seventeen RCTs (Fan et al., 2017)

CoQ10 supplementation significantly reduced the levels of circulating CRP, IL-6 and TNF-α

Changes of CRP were independent of baseline CRP, treatment duration, dosage, and patients characteristics

A higher baseline IL-6 level was significantly associated with greater effects of CoQ10 on IL-6 levels

Significant lowering effects of CoQ10 on CRP, IL-6 and TNF-α - buy results should be interpreted with caution because of the evidence of heterogeneity and limited number of studies

Fan L, Feng Y, Chen GC, Qin LQ, Fu CL, Chen LH Effects of coenzyme Q10 supplementation on inflammatory markers: A systematic review and meta-analysis of randomized controlled trials. Pharmacol Res. 2017 May;119:128-136. Zhai J, Bo Y, Lu Y, Liu C, Zhang L. Effects of Coenzyme Q10 on Markers of Inflammation: A Systematic Review and Meta-Analysis. PLoS One. 2017 Jan 26;12(1):e0170172

N-Acetyl –L-cysteineN-Acetyl –L-cysteine (NAC) has a direct antioxidant capacity (via its sulfhydryl groups) and through its promotion of glutathione synthesis

• Glutathione levels decrease with increasing age, with markedly reduced glutathione levels observed in a number of inflammatory driven diseases

• Glutathione is a tri-peptide [L-cysteine, L-glutamine and L-glycine] with L-cysteine the limiting amino acid

Why not supplement directly with L-cysteine?

• L-cysteine loses the majority [~85%] of its sulphur groups (the active part of glutathione) during digestion, while NAC is more stable and only loses ~15%

• NAC inhibits the oxidation of LDL, increases HDL cholesterol and reduces homocysteine levels

For optimum efficacy NAC needs synergists. Alpha lipoic acid, L-glutamine, vitamin C and vitamin E play an important role in the regeneration of glutathione (vitamin C converts oxidised glutathione into its reduced form, vitamin E has the same effect on vitamin C)

Wiklund O, Fager G, Andersson A, Lundstam U, Masson P, Hultberg B. N-acetylcysteine treatment lowers plasma homocysteine but not serum lipoprotein(a) levels. Atherosclerosis. 1996 Jan 5;119(1):99-106.

Textbook of Functional Medicine. Gig Harbor, Wash: The Institute for Functional Medicine, 2005, p 278. © 2005 The Institute of Functional Medicine.

In humans, ~90% of the gut bacteria

are represented by two phyla

Firmicutes (60–80%) and Bacteroidetes

(15–30%)

Firmicutes phylum encompasses more than 250 genera, including Lactobacillus and Clostridium

Bacteroidetes includes around 20 genera, the most abundant being Bacteroides

Both phyla produce beneficial SCFA from indigestible carbohydrates that reach the colon

– Firmicutes being the main butyrate-producers

– Bacteroidetes producing mainly acetate and propionate

Studies have consistently shown that the Firmicutes to Bacteroidetes ratio, in particular, is increased in obesity and reduces with weight loss

Gut microbiome dysbiosis is common in obese PCOS women

https://salveodiagnostics.com/test-guides/firmicutesbacteroidetes-ratio-test-summary/

Firmicutes to bacteroidetes

A shift in the Firmicutes to Bacteroidetes ratio (F/B ratio) may be influenced by various factors and conditions:

• Various factors such as changes in nutrition, digestive secretions, use of prescription medications, and alterations in gut transit time all contribute to a decrease in the F/B ratio and microbial diversity with age

• The F/B ratio is affected by diet and Bacteroidetes communities can shift according to dietary modulation and weight change, whereas Firmicutes numbers are more dependent on individual genetic makeup

• Antibiotic-associated diarrhoea, Crohn’s disease, and ulcerative colitis have been correlated with decreases in Firmicutes strains, a concomitant increase in Bacteroidetes (low F/B ratio), and a reduced gut biodiversity

• Dysbiosis has been suggested to play a role in the development of type II diabetes

• Patients with type II diabetes have a lower F/B ratio than non-diabetic controls with worsening glucose tolerance as the F/B ratio decreases

Lena K Brahe, Arne Astrup, Lesli H Larsen Can We Prevent Obesity-Related Metabolic Diseases by Dietary Modulation of the Gut Microbiota? Adv Nutr. 2016 Jan; 7(1): 90–101.

Valdés L, Cuervo A, Salazar N, Ruas-Madiedo P, Gueimonde M, González S. The relationship between phenolic compounds from diet and microbiota: impact on human health. Food Funct. 2015 Aug;6(8):2424-39.

Improving gut health

Several probiotic strains such as Lactobacillus Bacteroides thetaiotaomicron, Bifidobacterium longum and Lactobacillus rhamnosus, Bifidobacterium infantis, Lactobacillus plantarum shown to have beneficial impacts on tight junction- and intestinal barrier function

Increasing zonula occludens-1 (ZO-1) Increased transcription of occludin and cingulin genes Decreased faecal zonulin levels (a marker indicating enhanced gut permeability) Decreased proinflammatory cytokines

Short-chain non-digestible carbohydrates (inulin-type fructans, fructo-oligosaccharides (FOS) and galacto-oligosaccharides (GOS)) are the quintessential prebiotics (occurring naturally in cereals, fruits and vegetables) and the target bacterial groups are typically Bifidobacterium and Lactobacillus

Fermented foods like sauerkraut, kimchi, yogurt, kefir

Ulluwishewa D, Anderson RC, McNabb WC, Moughan PJ, Wells JM, Roy NC Regulation of tight junction permeability by intestinal bacteria and dietarycomponents. Nutr. 2011 May;141(5):769-76.

Lamprecht M, Bogner S, Schippinger G, Steinbauer K, Fankhauser F, Hallstroem S, Schuetz B, Greilberger JF Probiotic supplementation affects markers of intestinal barrier, oxidation, and inflammation in trained men; a randomized, double-blinded, placebo-controlled trial. J Int Soc Sports Nutr. 2012 Sep 20;9(1):45.

Strategies for the management of PCOS and associated conditions

Ameliorating inflammation and ROS Up-regulates SHBG

Insulin resistanceImproved glycaemic control increases adiponectin & SHBG

SHBGIncreased SHBG improves hormone regulation

AdiponectinIncreasing adiponectin will increase SHBG and lower total triglyceride and free fatty acids Increasing adiponectin decreases ROS and inflammation

Homocysteine Regulating homocysteine supports methylation, transsulfuration & sulfation pathways

Weight lossImproves glycaemic control/insulin signalling, lowers IGF-1, improves hormone regulation - as little as 5% of initial weight has resulted in lower circulating androgen levels, and decreased levels of circulating insulin

Synergistic nutrients

Studies are beginning to show that targeted combination interventions elicit greater benefits over single nutrients

Addressing multiple factors/pathways involved in disease onset and progression simultaneously helps overcome clinical paradox effect

“Combining nutrients acting on converging anti-inflammatory pathways leads to enhanced anti-inflammatory properties as compared to the action of a single nutrient” Kurtys et al. 2016

Kurtys E, Eisel UL, Verkuyl JM, Broersen LM, Dierckx RA, de Vries EF. The combination of vitamins and omega-3 fatty acids has an enhanced anti-inflammatory effect on microglia. Neurochem Int. 2016 Oct;99:206-14

Brain structure & function with anti-inflammatory

benefits

Potent antioxidant

Supports methylation, transsulfation

etc

Comprehensive support

Synergistic nutrients

Serving size: 1 capsule Per serving % RI*

Longvida® optimised curcumin extract

from turmeric root

(min. 20% curcuminoids)

500 mg n/a

DIRECTIONS FOR USEAdults: take 1 capsule daily with food. For intensive support, take 2 capsules daily as a split dose. Do not exceed the dose unless advised by a healthcare practitioner.

NUTRITIONAL INFORMATION

INGREDIENTS: Longvida® optimised curcumin extract; capsule shell (emulsifier: hydroxypropyl methylcellulose); stearic acid; soy lecithin; maltodextrin; ascorbyl palmitate; silicon dioxide.

Free from: dairy, gluten, lactose, soya protein, wheat, yeast, artificial colours and flavours; not tested on animals; non-GMO; suitable for vegetarians & vegans; halal & kosher.

* % Reference Intake

Product information

Education Technical

Sophie TullyNutrition Education Manager

sophiet@igennus.com

Dr Nina Bailey Head of Nutrition

ninab@igennus.comTwitter @DrNinaBailey