Bio-Identical Hormone Optimization and The Unified Theory of Wellness

Ron Rothenberg MDThe following potential conflict of interest relationships

are germane to my presentation.

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Bio-Identical Hormone Optimization and The Unified

Theory of Wellness

Ron Rothenberg MD

Aging is a disease which can be prevented or reversed

We are not prisoners of our genetic destiny

Chronic Inflammation is the cause and the effect of the diseases of aging

Balanced hormone optimization decreases chronic inflammation

We age because our hormones decline, our hormones don’t decline because we age

Treatment of Adult GH deficiency is necessary for healthy adult life and GH Replacement Therapy can prevent and reverse some aspects of aging

Testosterone replacement therapy for treatment of testosterone deficiency is safe and provides dramatic benefits in men and women

Bio-identical Estrogens/Progesterone replacement is safe and has dramatic benefits in women

Progestins are not ProgesteroneEquine estrogen is not humanOral estrogen is not transdermalEstriol (E3) is an important

protective hormoneMany people with “euthyroid” lab

values are clinically hypothryoid

Treating “mild” hormone deficiencies can dramatically improve quality of life

Adrenal fatigueMild HypothyroidsmGrowth HormoneProgesteroneTestosterone

Treat a “deficiency disease” Improve Quality of LifeDecrease InflammationDo not increase cancer riskDo not increase heart disease riskAre a matter of personal choiceMust be given by the correct routeAre a “work in progress”

Bio-Identical hormones

Bio-identical hormone optimization Is a clinical specialtyOptimal range not reference rangeWhen lab and clinical do not agree -

clinical winsEvolutionary Biology

Hormone decline does not serve any positive biological function

Evolution is blind to events after reproductive age

Bio-identical hormones to optimize

Growth HormoneTestosterone for men and womenDHEA, Pregnenolone, MelatoninEstrogens: E1, E2, E3Progesterone Thyroid: T3, T4CortisolVitamin DOptimal replacement considers levels

and “How do you feel?”

Eicosanoid hormones–Regulated by Lifestyle, Diet, Insulin, Omega 3’s, Endocrine Hormones, Mind-Body connection, Vitamins and Neutraceuticals

AutocrineParacrineEndocrineLifestyle impacts hormone levels

and actionsLifestyle decreases inflammation

Inflammatorycytokines

NF Kappa Beta

Inflammatory EnzymesCOX, LOX

InflammatoryCytokines

Arachidonicacid

Bad EicosanoidsTXA2. ASCVD

PGE2, LRC4 - CAPain PGE2, LTB4

Chronic Illness

Acute phaseproteins

CRP, Fibrinogen

EPA

EPA

Control insulin.Less omega 6

Less DietArachadonic

StressInfection

DepressionHigh Glucose and Insulin

Hormone DeclineLack of Exercise

AgingHigh Homocysteine

Trans Fats

EPA

Pro-oxidantsViral Infections

Anti-oxidantsGlutathioneAnti-Inflammatory

Cytokines

Adhesionmolecules

VCAM1, ICAM1,MCP1, MadCAM1

PGI2=prostacyclingood eicosanoids

Coxibs blockvioxx

WellnessEPA, DHAGood

Eicosanoids

DHEA,Testosterone

Melatonin

HighGlucose

NutritionGlucose and Insulin

control

ASCVD

ASCVD

ASCVD

HighHomocysteine

B vits

cancer

cancer

DiabeticRetinopathy

Adipocytes

GH

GH

IBD

SRIFAnti-Inflam

Diet

ASA

aging

E2P4

Resveratrol

Red inhibits

Yellow activates

Harmonic Theory of Wellness:

Chronic Inflammation Is the Cause and the Effect of the Diseases of Aging

Pain

EPA, DHA from Fish OIL

© Ron Rothenberg 2010

PGE2:PainCancerSkin aging

Angio-tensin II

p53

CRP

ResveratrolEPC’s

Vitamin D

TXA2Athero-sclerosis

ProstaglandinsThromboxanes

Leucotrienes

LipoxinsHydroxylatedFatty acids

Pain

Vasoconstriction, Atherosclerosis. Plaque formation

Viralreplication

Atherosclerosis

cancer

Prostacyclin, Vasodilation,

Breast Cancer

PGI2, PGA2 cytoprotectiveBlocked by COX2 inhibitionNot all “bad” Eicosanoids are bad

COX, LOX are key enzymes for eicosanoid synthesis

LTB4, PGE2

Pain

Inflammation

Basics still apply Hormone optimization is the finishing touch

on lifestyle: Nutrition, Exercise, Stress Reduction, Anti-oxidants and Nutraceuticals

Use hormones when necessary to treat a deficiency disease

Bio-identical Titrate to youthful levels and clinical

response - control metabolites when needed Advanced treatments are backed up by

current medical literature More than any other field of medicine

• Chronic Inflammation is the cause and the effect of most illnesses and of the diseases of aging.

• Anti-inflammation = Wellness• Hormone optimization is

necessary for anti-inflammation

“Unified Theory of Wellness”

®© Ron Rothenberg MD, 2010

Cytokines, GH, aging, and death Age 72-92 Death associated with higher IL-6 1.27 x TNF alpha 1.30 x Life associated with higher IGF-1 0.70 x

Harris, et al. Cytokines, insulin-like growth factor 1, sarcopenia, and mortality in very old community-dwelling men and women: the Framingham Heart Study. Am J Med. 2003 Oct 15;115(6):429-35 .

If a shark bites you, you need inflammation right now

Blood vessels constrict to stop bleeding

Fibrinogen and clotting factors increase to stop bleeding

White blood cells fight infection Pain reminds you “Don’t swim with

sharks”

Acute inflammation keeps us alive

Chronic inflammation kills us slowly

Why do we have all this inflammation anyway?

Antagonistic Evolutionary Benefit What helped our Paleolithic ancestors make it

to reproductive age…is killing us now Insulin Resistance – helped store fat and

survive famine Anti-inflammation resistance – helped survive

acute infectious disease and trauma Thyroid resistance

– reverse T3 increased in times of famine or stress

NFkBNuclear Factor kappa Beta

Transcription factor in inflammationLives in cytoplasm and enters

nucleus and turns on inflammation genes

Barnes PJ et al. Nuclear factor-kappa: a pivotal transcription factor in chronic inflammatory diseases.N Engl J Med. 1997 Apr 10; 336(15):1066-71.

Positive regulatory loop

COXLOX

VCAMICAM

NFkB and cancer

Inhibiting NF-kappaB results in apoptosis of abnormal cells and no progress to cancer

NF-kappaB is essential for promoting inflammation-associated cancer

Pikarsky E et al. NF-kappaB functions as a tumor promoter in inflammation-associated cancer. Nature. 2004 Sep 23;431(7007):461-6.

Omega 3’s and NFkBEPA inhibits NFkB EPA decreases TNF alpha and other

pro-inflammatory cytokinesZhao Y et al. Eicosapentaenoic acid

prevents LPS-induced TNF-alpha expression by preventing NF-kappaB activation. J Am Coll Nutr. 2004 Feb;23(1):71-8.

Resveratrol inhibits NFKBBhardwaj A et al. Resveratrol inhibits

proliferation, induces apoptosis, and overcomes chemo resistance through down-regulation of STAT3 and nuclear factor-kappaB-regulated antiapoptotic and cell survival gene products in human multiple myeloma cells. Blood. 2007 Mar 15;109(6):2293-302.

Turns on Sirtuin genes

Vitamin D and inflammation

Inversely associated with CRP and fraility

Inhibits NFKB Boxer RS et al. The Association Between

Vitamin D and Inflammation with the 6-Minute Walk and Frailty in Patients with Heart Failure. J Am Geriatr Soc. 2008 Jan 5

Szeto, FL et al. Involvement of the vitamin D receptor in the regulation of NF-kappaB activity in fibroblasts. J Steroid Biochem Mol Biol. 2007, March

Inflammatory cytokines produced by white blood cells and other tissues

Cytokines cause liver to produce Acute Phase proteins

Gets animal ready for “combat” with enemies or micro-organisms

SAA

Aging causes inflammationYouthful hormones protect

IL-6 proinflammatory cytokineStays low in youth except for

trauma, infection, stressTestosterone and Estrogens down

regulate IL-6 gene expression

Ershler, WB et al. Age-associated Increased Interleukin-6 Gene Expression, Late-Life Diseases and Frailty. Annu. Rev. Med. 2000. 51:245–270

Neuroendocrine theory

We age because our hormones decline, our hormones don’t decline because we age

Declining hormones increase chronic inflammation

Hormones to Optimize for Wellness and Decreased Inflammation Melatonin DHEA Pregnenolone Cortisol Thyroid Testosterone Growth Hormone Estrogens Progesterone Vitamin D

Thyroid

Treat the patient not the lab testOrder the right lab testKnow which is the active

hormone, the pro-hormone and the anti-hormone

“Euthyroid” is not Optimal thyroid

TESTOSTERONE

Andropause is a deficiency disease

Half of healthy men between the ages of 50–70 yr will have a Bioavailable Testosterone level below the lowest level seen in healthy men who are 20–40 yr of age

Korenman SG, Morley JE, Mooradian AD, et al. 1990 Secondary hypogonadism in older men: its relationship to impotence. J Clin Endocrinol Metab. 71:963–969.

Andropause is a lethal disease

Diabetes, Metabolic syndromeBrainHeartFrailty syndromeBone InflammationCancer

High T = Low Mortality 10 year prospective study 11,606 men – 40-79 years old High Endogenous T = low mortality

from CV disease and cancer Low T predicts CV disease High T = no increase in Prostate Cancer “Paradoxically” fear of Prostate Ca has

keep men from T treatment Khaw KT. et al. Endogenous testosterone and

mortality due to all causes, cardiovascular disease, and cancer in men. Circulation. 2007;116:2694-2701

41% decrease in chance of dying in men with T >564 compared to 350

For each increase in 173, chance of dying went down 14%

Extrapolating:Comparing T 300 to 100057% decrease in chance of dyingThis study was of endogenous T

not treatment

Prostate CA and Hormones 3886 men with prostate cancer, 6438

controls No associations were found between the

risk of prostate cancer Testosterone, calculated free testosterone,

dehydroepiandrosterone sulfate, androstenedione, androstanediol,estradiol, calculated free estradiol

Endogenous Sex Hormones and Prostate Cancer: A Collaborative Analysis of 18 Prospective Studies Endogenous Hormones and Prostate Cancer CollaborativeGroup . J Natl Cancer Inst 2008 100: 170-183

Morgentaler conclusion

“There is not now--nor has there ever been a scientific basis for the belief that T causes PC to grow”

Morgentaler A. Testosterone and Prostate Cancer: An Historical Perspective on a Modern Myth. Eur Urol. 2006 Jul 26

TRT benefits from head to toe–Improved mood, cognitive, function, Alzheimer's prevention

–Improved Body composition, more muscle, less fat, reversal of osteoporosis

–Improved libido and erectile function–Reverses Insulin Resistance and type 2 diabetes

–Less inflammation, pain, osteo and rheumatoid arthritis

TRT decreases inflammation–CRP, IL-6, TNF alpha decreased

Female Hormones

EstrogensProgesteroneTestosterone

“Delicate balance between E and P both antagonistic and complimentary” –Thierry Hertoghe

TRT in Women T needed for sense of well being Strength especially upper body Libido Nipple and clitoral sensitivity T usually decreased in perimenopausal and

menopausal women Body composition Bone density DHEA can increase T in women but not in men “Relative Androgen Deficiency” with normal

levels Goldstat R. et al. Transdermal testosterone therapy improves

well-being, mood, and sexual function in premenopausal women. Menopause. 2003 Sep-Oct;10(5):390-8

Estradiol

EstrogensE1=Estrone

–May be more than she needs–Get some anyway through conversion of E2

E2=Estradiol– Protective Estrogen via catechol and methoxy metabolites

E3=Estriol–cancer protective, weak

Controversies

Does Bio-identical E and P increase rates of breast cancer and cardiovascular disease?

Lab tests vs. clinical picture?Why not use bio-identical oral E?Does she need Progesterone after

hysterectomy?

Progesterone = P4

Antagonism E and P4Estrogen Progesterone___

Fluid retention DiureticAldosterone blocker

Sympathetic Parasympathetic Energy Tranquility

________________________________ Synthetic “Progestins” are more

androgenic lack diuretic and many other beneficial effects of P4

Block many P4 receptor sites and act as anti-progesterone

Some Problems with WHIWrong Estrogen

–Premarin is not a human hormone–Mostly Equillin– Low Estradiol (E2)–No Estriol (E3)

Wrong “Progesterone”–Provera blocks progesterone receptors

and is not a human hormoneWrong route

–Oral Estrogens increase inflammationWrong women

–Older with established CV disease

Oral vs. Transdermal Estrogens

Oral Estrogens (especially Premarin) increase inflammation as measured by CRP

Transdermal Estrogens do not

Decensi A et al. Effect of transdermal estradiol and oral conjugated estrogen on C-reactive protein in retinoid-placebo trial in healthy women Circulation 2002 Sep 3;106(10):1224-8

Oral CEECRP increased 192% IGF-1 decreased 30%

Shifren J et al. A Comparison of the Short-Term Effects of Oral Conjugated Equine Estrogens vs. Transdermal Estradiol on C-Reactive Protein, Other Serum Markers of Inflammation and Other Hepatic Proteins in Naturally Menopausal Women. J Clin Endocrinol Metab 26 February 2008

Transdermal E2 decreases IL-6, TNF

Inflammatory cytokines implicated in autoimmune, cardiovascular, osteoporosis, Alzheimer’s

E2 may protect above diseases

Puder JJ et al. Estrogen modulates the hypothalamic-pituitary-adrenal and inflammatory cytokine responses to endotoxin in women. J Clin Endocrinol Metab. 2001 Jun;86(6):2403-8.

E3 safe and effective Provides some of the protection without

the risks associated with stronger estrogens

Effective at controlling symptoms of menopause: hot flashes Insomnia vaginal dryness frequent urinary tract infections. Head KA. Estriol: safety and efficacy.

Altern Med Rev. 1998 Apr;3(2):101-13

E2 protects thru Methoxyestradiols

Premenopausal women protected against cardiovascular and renal disease

WHI shows no protection, even worseWhy “striking disconnect” between basic

science and animal studies who consistently show CV protection?

Dubuy, Raghvendra K. et al. Cardiovascular Pharmacology of Estradiol Metabolites. The Journal of Pharmacology and Experimental Therapeutics. 308:403–409, 2004

2-MeO-E2 has strong antiproliferative, apoptotic, and antiangiogenic action

Liu ZJ et al. Selective insensitivity of ZR-75-1 human breast cancer cells to 2-methoxyestradiol: evidence for type II 17beta-hydroxysteroid dehydrogenase as the underlying cause. Cancer Res. 2005 Jul 1;65(13):5802-11.

COMT

CYP 1A1

Bio-Identical Hormone Replacement in Women

Balance Estrogens, Progesterone and Testosterone

Every woman needs a unique balance

Progesterone protects against breast cancer

Results from the E3N cohort study- Fournier 2007.

80,377 postmenopausal women No increase or decrease in breast cancer in

women on E2 and Progesterone. RR 1.0 E2 plus MPA (Provera) had RR of 1.69 or 69%

increase in risk of breast cancer. Bioidentical hormones: safer, no increased risk

of breast cancerFournier A . Unequal risks for breast cancer associated

with different hormone replacement therapies: results from the E3N cohort study. Breast Cancer Res Treat. 2007 Feb 27

Progesterone decreases Breast Cancer risk - Campagnoli

Synthetic progestins increase BC riskProgesterone decreases BC riskHigher P4 in pregnancy 50%

reduction in riskHigher P4 during menstrual cycle

premenopausal, 78% reduction in risk

Campagnoli C et al. Pregnancy progesterone and progestins in relation to breast cancer risk. Journal of Steroid Biochemistry and Molecular Biology 97 (2005)441-450

Estrogen replacement -No increased mortality from

cancer 23000 women Estradiol- (E2 and CEE) and Estriol E3

with or without progestins RR- 0.72- Breast Ca mortality RR- 0.77 – All cause mortality

Schairer C et al. Epidemiology, Jan 1997, Volume 8 Number 1

Estrogen decreased risk of mortality in patients with

Breast CA history

Batur, P et al. Menopausal Hormone Therapy in Women with Breast CA. Maturitas 53(2006)123-132

Durna, E et al. Breast Cancer in Premenopausal Women: recurrence and survival rates and relationship to hormone replacement therapy. Climacteric 2004; 7:284-291.

Testosterone

Androstenedione

E2

E1

Aromatase

Aromatase

E2S17Beta HSD17Beta HSD

Sulfotransferase

Sulfotransferase

Sulfatase

Sulfatase

Estrogen Metabolism - Breast

E2, P4 sulfatase inhibitorsE2 aromatase inhibitor

GROWTH HORMONE

Exponential decline in GH release after 18-21

50% decline every 7 years Negative correlation of GH release and

BMI GH has half life of 15 minutes IGF-1 has half life of 15 minutes Ternary Complex has half life of 15 hours

IGFBP’s

6 IGF Binding ProteinsInhibit and Enhance IGF ActionsIGF-1 + IGFBP-3 + Acid Labile Subunit = Ternary ComplexHalf-Life of Ternary Complex = 15 hoursIGFBP-3 has independent actions and inhibits cancer through p53

“Life without GH is poor both in quantity and quality.”- R. Savine

“GH peaks at puberty and begins to decrease at 21.”

“At age of 60 most adults have total 24-hour secretion rates indistinguishable from those of hypopituitary patients with organic lesions in the pituitary gland.”

“If IGF-1 of 300 is mean normal for 20-30 almost all > 40 have IGF-1 deficit”

Savine R. et al. Growth hormone replacement for the somatopause. Horm Res 2000;53 Suppl 3:37-41

GH deficiency = decreased longevity in humans

Patients with absent GH-1 gene compared to siblings

Males, 56 vs. 75 yr (P < 0.0001)Females, 46 vs. 80 yr (P < 0.0001)

Besson A et al. Reduced longevity in untreated patients with isolated growth hormone deficiency. J Clin Endocrinol Metab. 2003 Aug;88(8):3664-7.

GHRT for AGHD Improves Inflammation Brain Bone Atherosclerosis Heart Function Immune System Body Composition Exercise Capacity Wound healing Well Being Quality of Life Cosmetic Appearance

Does GH cause cancer? “Extensive studies of the outcome

of GH replacement in childhood cancer survivors show no evidence of an excess of de novo cancers, and more recent surveillance of children and adults treated with GH has revealed no increase in observed cancer risk .”

Jenkins PJ et al. Does growth hormone cause cancer? Clin Endocrinol (Oxf). 2006 Feb;64(2):115-21.

GH and CRP

GH deficiency = Increased CRPGH treatment = Decreased CRP

Andreassen et al. Concentrations of the acute phase reactants high-sensitive C-reactive protein and YKL-40 and of interleukin-6 before and after treatment in patients with acromegaly and growth hormone deficiency. Clin Endocrinol (Oxf). 2007 Aug 28

Know your Inflam-aging numbers

CRP <1Fasting Insulin <7Homocysteine <7AA/EPA Ratio <1.525-OH-D >65Cytokines

IL-6 <12 pg/lTNF alpha <8 pg/lIL-1 beta <15 pg/l

Optimize stem cells

Optimized hormones and neutraceuticals increase quantity and quantity of endogenous adult stem cells

Kawakita E, et al. Docosahexaenoic acid promotes neurogenesis in vitro and in vivo. Neuroscience2006:139:991-997

Sinha-Hikim, I et al. Effects of testosteronesupplementation on skeletal muscle fiber hypertrophy and satellite cells in community-dwelling older men. J Clin Endocrinol Metab. 2006 Aug;91(8):3024-33

Chakravarthy MV et al. Insulin-like growth factor-I extends in vitro replicative life span of skeletal muscle satellite cells by enhancing G1/S cell cycle progression via the activation of phosphatidylinositol 3'-kinase/Akt signaling pathway.J Biol Chem. 2000 Nov17;275(46):35942.

Stem cells optimization through nutraceuticals

• Blueberry• Green tea• Vitamin D3• Carnosine

Bickford PC et al. Nutraceuticals synergistically promote proliferation of human stem cells. Stem Cells Dev. 2006 Feb;15(1):118-23.

Resveratrol and stem cells

J.G. et al. Effects of resveratrol on endothelial progenitor cells and their contributions to reendothelialization in intima-injured rats. J Cardiovasc Pharmacol. 2006 May;47(5):711-21

Unified Theory of Wellness

Control Inflam-AgingOptimize hormones Increased quality of lifeWe all have to die sometimeWhat will the journey be like?RectangularizeAnd if we delay, intervene and

reverse the diseases of aging…. Increased quantity of life as well

Inflammatorycytokines

NF Kappa Beta

Inflammatory EnzymesCOX, LOX

InflammatoryCytokines

Arachidonicacid

Bad EicosanoidsTXA2. ASCVD

PGE2, LRC4 - CAPain PGE2, LTB4

Chronic Illness

Acute phaseproteins

CRP, Fibrinogen

EPA

EPA

Control insulin.Less omega 6

Less DietArachadonic

StressInfection

DepressionHigh Glucose and Insulin

Hormone DeclineLack of Exercise

AgingHigh Homocysteine

Trans Fats

EPA

Pro-oxidantsViral Infections

Anti-oxidantsGlutathioneAnti-Inflammatory

Cytokines

Adhesionmolecules

VCAM1, ICAM1,MCP1, MadCAM1

PGI2=prostacyclingood eicosanoids

Coxibs blockvioxx

WellnessEPA, DHAGood

Eicosanoids

DHEA,Testosterone

Melatonin

HighGlucose

NutritionGlucose and Insulin

control

ASCVD

ASCVD

ASCVD

HighHomocysteine

B vits

cancer

cancer

DiabeticRetinopathy

Adipocytes

GH

GH

IBD

SRIFAnti-Inflam

Diet

ASA

aging

E2P4

Resveratrol

Red inhibits

Yellow activates

Harmonic Theory of Wellness:

Chronic Inflammation Is the Cause and the Effect of the Diseases of Aging

Pain

EPA, DHA from Fish OIL

© Ron Rothenberg 2010

PGE2:PainCancerSkin aging

Angio-tensin II

p53

CRP

ResveratrolEPC’s

Vitamin D

TXA2Athero-sclerosis