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Metabolism and Common Urological Diseases - Prostate and StonesMr. Noor NP Buchholz

U-merge Ltd. London/ UK & SVMC Dubai/ UAE

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• Benign prostate hyperplasia (BPH)

• Prostate Cancer (PCa)

• Urolithiasis

• Benign prostate hyperplasia (BPH)

• Prostate Cancer (PCa)

• Urolithiasis

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BPH

• 50% of men over 50y

symptoms

• 20-30% of men reaching

80y need surgery

• Economic burden

• direct medical costs

• Loss of work time

• Loss of QoL

BPH

• Hyperplastic nodules

• Mainly peri-urethral

region

• Enlarging prostate

• Obstructing urethra

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BPH

BPH

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BPH

• 1st line drugs

• Alpha-blockers

• 5-alpha-reductase

inhibitors

BPH

• Surgery

• TUR-P

• Lasers

• Waterjet

• Stents

• Injections

• Microwave

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BPH • Age and hormone dependent • Estrogen

increases androgen receptors

• Testosterone promotes growth

• Concurrent inflammatory changes

• Adrenergic stimulation

• Regional differences

• Common Europe and USA

• Less Asia

• Low China

• Natural hormones?

• Hormone-pathway modulators?

• Neuromodulators?

• Environment?

• Climate

• Pollution

• Diet

• Lifestyle

• Endemic genetics

• Genome modulators

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BPH

• Metabolic syndrome

• Diabetes mellitus

• Obesity

• Race

• Cardiovascular disease

• Family Hx

BPH – general lifestyle

• -ve

• High calories

• High protein

• High polyunsaturated

fatty acids

• +ve• Fruits

• Vegetables

• Whole grains

• Physical exercise• Lower insulin

• Lower IGF1

• Lower inflammatory cytokines

• Downregulation RAS oncogene

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BPH - soy

• non-fermented

• 5-alpha-reductase inhibitor

• Block of androgen receptors

• Low-potency estrogen

• Blocks estrogen receptors for

stronger estrogens

• Decrease of androgen

receptors

BPH - cholesterol

• Metabolite epoxycholesterol in BPH

• Foods high in cholesterol and saturated fats also rich in arachidonic acid (main precursor of inflammation)

• Statins reduce risk of BPH

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BPH – Omega 3 fatty acid

• Cold water fish, veggies, flaxseed

• Helps to reduce influence of prostaglandines and leukotrienes on inflammatory component of BPH

• In addition, flaxseed has lignan fibres that bind estrogens in gut

BPH – onion & garlic

• Garlic inhibits key enzymes in cholesterol and fatty acid synthesis

• Onion and garlic rich in phytochemical antioxydants

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BPH - micronutrients

• Zinc

• reduces Pvol and BPH symptoms

• Inhibits 5-alpha-reductase

• Pumpkin seeds rich

• Cadmium

• Increases 5-alpha-reductase activity

• inconclusive

BPH - micronutrients

• Amino acids

• Glycine, alanine + glutamic acid relieve BPH symptoms

• May act as inhibitory neurotransmitters

• Only symptomatic

• Vitamin D

• Attaches to receptors in prostate & bladder

• Lowers prostate growth

• Lowers excessive contractility (bladder, urethra)

• Reduces infammation

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BPH - micronutrients

• Phenols

• Cranberry

• Reduce symptoms of BPH

BPH – alcohol, smoking, coffee

• Alcohol: inconclusive

• Smoking: inconclusive

• Coffee

• decreases Zinc absorption by 50%

• Stimulates adrenergic nerves (smooth muscle prostate)

• Worsens BPH symptoms

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BPH – dietary supplements• Beta-sitosterol

• Phytosterol

• Similar to cholesterol

• Not converted to testosterone

• Inhibits 5-alpha reductase

• Improves flow & RU

BPH – dietary supplements

• Saw palmetto (serenoa repens)

• Anti-androgenic

• Anti-proliferative

• Anti-inflammatory

• Weak 5-alpha-RI

• Reduces number of androgen & estrogen receptors

• Main beta-sitosterol

• Improve BPH symptoms

• Does not reduce PVol

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BPH - dietary supplements

• Rye grass pollen

• Inhibits prostate cell growth

• Reduces inflammation

• (inhibits prostaglandines & leucotrienes)

• Pygeum Africanum

• Reduces inflammation

• Inhibits prostaglandines

• Reduces prostatic cholesterol levels

• Precursors testosterone

BPH – dietary supplements

• Stinging nettle (urticadioica)

• Main beta-sitosterol

• Reduces BPH symptoms

• Reduces Pvol

• Compared to placebo

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BPH – therapeutic goals

• Normalize P-nutrient levels

• Restore normal steroid hormone levels

• Inhibit overproduction of DHT

• Reduce inflammation

• Limit promoters of hyperplasia

BPH - conclusions

• Moderate exercise

• Rich veggie protein

• Low animal protein

• Zinc & Vit D

• Saw palmetto, Rye grass, Pygeumextracts

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• Benign prostate hyperplasia (BPH)

• Prostate Cancer (PCa)

• Urolithiasis

PCa

• Most commonly diagnosed Ca in men

• 1.6 Mio cases/ y

• 366.000 death/ y

• PSA screening led to localized disease

• Patients can live many years with disease

• Risks

• Age

• Race

• Genetics (family history)

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PCa

• Localised PCa

• Radical PE (lap/ robot)

• Radical RRX

• Brachytherapy

• Non-localized PCa

• LHRH-antagonists

• Anti-androgens

• Metastatic PCa

• Chemotherapy

• Estrogens

25-40% of PCa patients use CAM*

* Complimentary & Alternative Medicine

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PCa – some key facts

• Increased risk in Asians using Western diet

• Conflicting evidence about red meat and red wine

• Increased risk with high intake of grilled red meat

• No relationship between red meat/ fish intake and Pca progression

• Possible connection between milk-based diet and an increased risk (Ca+?)

• Increased risk with alcohol or non-advanced PCa

• Folate deficiency: 2.6 x increased risk for progression after RPE

• Increased risk of Pca-specific death with more saturated fat

PCa – some key facts• No scientific evidence for protective

effect fruits and vegetables - some of the ingredients are thought to reduce risk

• Reduced risk associated with lycopene (carotenes - antioxidants)

• Reduced risk in Asians with Soy, but no such effect in Western men

• Reduced risk with coffee > 6x / 24h

• Reduced risk with green tea only in Asians

• Reduced risk with highly unsaturated fatty acids (EPA/ DHA)

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PCa – Calcium

• Ca+ is required for:

• vascular contraction and vasodilation

• muscle function

• nerve transmission

• intracellular signaling

• hormonal secretion

• Major sources in USA food and dietary supplements.

• Studies of the association between Ca+ and PCa have been limited to nutritional sources, such as dairy products.

• Some studies suggest that high total Ca+ intake may be associated with increased risk of advanced and metastatic prostate cancer, compared with lower intake of calcium.

PCa – green tea

• Originates from Camellia sinensis; leaves are steamed and dried.

• Green tea may have protective effect against CVD and various cancers, incl. PCa

• Catechins are polyphenol compounds in tea associated with tea’s health benefits.

• Green tea catechins (GTCs) include

• epigallocatechin3gallate (EGCG),

• epicatechin (EC)

• epigallocatechin (EGC)

• epicatechin3gallate (ECG)

• oligomeric proanthocyanidins derived from catechin monomers.

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PCa – green tea

• Laboratory, preclinical, and earlyphaseclinical trials identified EGCG as one of the most potent modulators of molecular pathways relevant to prostate carcinogenesis.

• EGCG

• acts as an androgen antagonist

• can suppress PCa cell proliferation

• suppresses PSA production by PCacells

• demonstrates potent and selective pro-apoptotic activity in prostate cancer cell lines in vitro

Pca – green tea

• EGCG intake associated with significant reductions in tumor size, reduced multiplicity, and reduced development of prostate cancer in mouse studies

• In Asian countries with a high per capita consumption of green tea, prostate cancer mortality rates are among the lowest in the world

• Risk of PCa appears to be increased among Asian men who abandon their original dietary habits upon migrating to the US

• At least two RCT show an overall decreased rate of progression by GTC from high grade intraepithelial neoplasia (PIN) to PCa

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PCa - lycopene• Carotenoid, a natural pigment made by plants

and various fruits and vegetables, including tomatoes, apricots, guavas, and watermelon

• Absorption improved with concurrent fat intake

• Inhibits androgen receptor expression in PCacells in vitro

• Reduces PCa cell proliferation

• May modulate cellcycle progression

• May also affect the insulinlike growth factor (IGF) intracellular pathway in PCa cells

• Chemopreventive effects for cancers of the prostate, skin, breast, lung, and liver in vitro and in animals

• Human trials have been inconsistent in their findings.

PCa - pomegranate

• Punica granatum native to Asia

• Minerals and bioactive polyphenolic compounds

• ellagitannins

• Derivatives (alpha/betapunicalagin, punicalin, punigluconin)

• Inhibit proliferation of various PCa cell lines in vitro and induce apoptotic cell death in a dosedependentmanner

• Cytochrome P450 enzyme inhibition and effects on insulinlike growth factor binding protein3 (IGFBP3) have been identified

• In rodents pomegranate juice can decrease development, growth, and spread of PCa

• Only one fully reported clinical trial pomegranate juice in PCa men - increase in PSA doubling time

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PCa - selenium

• Essential trace mineral involved in kinase regulation, gene expression, and immune function

• Animal and epidemiological studies suggested inverse relationship between selenium supplementation and cancer risk

• Epidemiologic studies suggest some association between blood levels of selenium and the risk of PCa

• The Selenium and Vitamin E Cancer Prevention Trial (SELECT), a large multicenter clinical trial, was initiated to examine the effects of selenium and/or vitamin E on the development of prostate cancer.

• Initial results of SELECT showed no statistically significant difference in the rate of PCa with selenium

• In 2014, an analysis of SELECT results showed that men who had high selenium status at baseline and who were randomly assigned to receive selenium supplementation had an increased risk of highgrade PCa

PCa – vitamin E

• Most dietary vitamin E comes from gammatocopherol. Food sources of vitamin E include vegetable oil, nuts, and egg yolks

• Vitamin E may protect against a number of chronic diseases, such as CVD

• Alphatocopherol–associated protein (TAP) may act as a tumor suppressor in PCa

• In 2011, updated results from SELECT showed that men who took vitamin E alone had a 17% increase in prostate cancer risk compared with men who took placebo.

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PCa - soy• Soy foods (e.g., soy milk, miso, tofu, and soy flour) contain

phytochemicals that may have health benefits

• Soy isoflavones are phytoestrogens

• genistein (the most abundant)

• daidzein,

• glycitein.

• Genistein affects multiple growth and proliferationrelatedpathways in PCa cells:

• COX2/prostaglandin,

• epidermal growth factor (EGF)

• insulinlike growth factor (IGF)

• Combined effect of multiple isoflavones may be greater than that of a single isoflavone

• Animal studies conflicting results regarding beneficial effects of genistein on PCa

• Epidemiologic studies generally high consumption of nonfermented soy foods associated with a decreased risk of PCa

PCa - soy

• Early phase clinical trials with isoflavones, soy, and soy products for the prevention and treatment of PCa

• short durations of intervention

• sample sizes with low statistical power

• target heterogeneous prostate cancer patient populations (high risk, early and later stage disease)

• varying doses of isoflavones, soy, and soy products

• no evidence of reducing PCa progression

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PCa - other

• Modified Citrus Pectin

• Vitamin D

PCa - conclusions

• Green tea

• Lycopenes

• Pomegranate

• Ca+ (diary)

• Selenium

• Vitamin E

• Soy

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• Benign prostate hyperplasia (BPH)

• Prostate Cancer (PCa)

• Urolithiasis

Stones

• Multifactorial genesis

• Genetics

• Lifestyle (i.e. women catching up)

• Environment (i.e. climate)

• Diet (i.e. meat, fluid, salt)

• others

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Stones

• Prevalence 12% in lifetime

• Highly recurrent

• 1st SF 30%

• 2nd + SF 70%

• UA SF 100%

• Main RF

• High Ca, Ox, P, UA

• Low Uvol, Cit, Mg

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Stones & metabolic syndrome

• Risk doubled in MS patients

• Prevalence• 3.8% 1 trait

• 7.5% 3 traits

• 9.8% 5 traits

• Risk reciprocal (MS Stones)

• Mostly CaOx and UA

• pH = favorable environment

Stones & MS: treatment

• General

• Treat MS

• Specific

• Low urine volume

• Hyperuricosuria

• Low pH

• Drink > 2l/ day

• Reduce animal protein

• Reduce Na

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Stones & antioxydants

• RSF urine

• Higher level of ROS (reactive oxygen species = free radicals)

• Lower level of antioxydants

• Oxydative stress

• Cell inflammation & injury (i.e. Randall plaque)

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Compound* origin action effect

Vit E Lipid-rich food ROS scavengerImmune booster

NephroprotectiveReduce CaOx

Phycocyanin Spirulina (cyanobacteria) ROS scavengerdiuretic

Reduce UOx & UCa

Gallotannin Green tea Reduces ROS activityEnhances AO enzymes

Inhibits COM crystal growth and adhesion

Berberine Plant alkaloid AO activitydiuretic

Lowers UCaIncreases UpH

Apocynin Picrorhiza kurroa AO activity nephroprotective

Rottlerin Mallotus phillippinensis AO activity nephroprotective

Curcumin Turmeric ROS scavenger nephroprotective

Thymoquinone Nigella sativa ROS scavengerAO activity

Antibacterial (struvite)Reduces UOx

Fucoidans Brown algae AO activityanti-inflammatory

Nephroprotective

Taurine Natural amino sulphonic acid AO activity Lowers crystal deposits nephroprotective

Atorvastatin Anti-cholesterol drug AO activity Inhibits tubular crystal retention

*All animal studies

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Stones & vitamins

• Main players Ca and Ox

• 80% stones CaOx

• Ox more powerful binder

• Hyperoxaluria risk factor

Stones & vitamins

• Hyperoxaluria

• Dietary intervention

• Vitamin B6 lowers UOx

• Vit B6 (pyridoxine) might be supportive in CaOx prevention

• Note: >500mg/d neurotoxic

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Stones & vitamins

• Vit A inhibits degradation of crystallization inhibitors

• Vit C: increases UOx !

Stones & probiotics

• Oxalobacter formigenes

• Human microbiome

• Uses Ox as sole energy

• Reduces Ox absorption & stimulates Ox gut secretion

• Reduces urinary Ox secretion

• Lactobacillus acidophilus & Bifidobacter infantis less effective

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Stones & supplements

• Calcium

• Low Ca

• no gut binding of Ox

• Ox absorption up

• Ox urinary excretion up

• CaOx stones

• Normal to high Ca

• Avoid Ca supplementation

• Maintain normal input 1000mg/ d

Stones & supplements

compound action effect

Citrate Chelating UCaalkalinizing

Reduces UCaIncreases UpH

Mg Inhibits formation Ca crystals

Reduce UCacrystals

Omega 3 FA ReducesProstaglandin E2

Lowers UCaexcretion

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Stones & plants

• Danshen (Salvia miltiorrhiza, red sage)

• Reduces CaOx in Drosophila

• Clinically reduced stone interventions

• Chickpea (Cicer arietinum)

• Recent RCT n=74/ 6-10mm renal stones

• 70 days

• 24% complete dissolution

• 44% reduction stone size

• Increased UVol & UMg

Bladder stones

• Endemic with malnourishment (or obstructive)

• Ammonium, urate, uric acid

• Dehydration, protein & vitamin deficiencies

• Recommended mixed cereal diet, milk, vit A & B

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Stones - summary

• There is a definite link between MS and stones

• Antioxydants can reduce stone RF and protect kidney

• Vit B6 helpful in hyperoxaluria

• Probiotic with Oxalobacter formigenes can reduce UOx

• No more low Ca diet. Supplement low Ca.

• Citrate, Mg, Omega 3 reduce risk of SF

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