living longer presentation 2012

LEAD, ‘10LEAD, ‘10

Aging and Hormone Replacement: The Aging and Hormone Replacement: The Latest in Disease PreventionLatest in Disease Prevention

Craig S. Atwood, Ph.D.

Associate Professor, Section of Geriatrics and Gerontology

University of Wisconsin School of Medicine and Public Health

Geriatrics, Education and Clinical Center, VA HospitalMadison, Wisconsin

From: beautyanalysis.com From: Pilates Reforming NY

LEAD ‘10LEAD ‘10

Jacques: All the world's a stage, And all the men and women merely players;

They have their exits and their entrances, And one man in his time plays many parts,

His acts being seven ages. At first, the infant, Mewling and puking in the nurse's arms.

Then the whining schoolboy, with his satchel And shining morning face, creeping like snail

Unwillingly to school. And then the lover, Sighing like furnace, with a woeful ballad

Made to his mistress' eyebrow. Then a soldier, Full of strange oaths and bearded like the pard, Jealous in honour, sudden and quick in quarrel,

Seeking the bubble reputation Even in the canon's mouth. And then the justice,

In fair round belly with good capon lined, With eyes severe and beard of formal cut, Full of wise saws and modern instances;

The Seven Acts of Life


And so he plays his part. The sixth age shifts Into the lean and slippered pantaloon

With spectacles on nose and pouch on side; His youthful hose, well saved, a world too wide For his shrunk shank, and his big manly voice,

Turning again toward childish treble, pipes And whistles in his sound. Last scene of all,

That ends this strange eventful history, Is second childishness and mere oblivion,

Sans teeth, sans eyes, sans taste, sans everything.

(As You Like It, Act II, Scene VII, lines 139-166)


Decreasingfunction

Mild

Moderate

Severe

Function Changes During the Life CycleFunction Changes During the Life CycleF

un

ctio

n

Increasingfunction

Stablefunction

0 20 40 8060 100Lifespan in Years


Slow decreasingfunction

Mild

Moderate

Severe

Function Changes During the Life Cycle: Function Changes During the Life Cycle: Extending LifespanExtending Lifespan

Fu

nct

ion Cognitive function

Vascular functionImmune function

Bone functionReproductive functionAthletic performance

Increasingfunction

Stablefunction

0 20 40 8060 100

Increasinglifespan

Lifespan in Years


Delaydecreasing

function

Mild

Moderate

Severe

Function Changes During the Life Cycle: Function Changes During the Life Cycle: Extending Lifespan and HealthspanExtending Lifespan and Healthspan

Fu

nct



Bone functionReproductive function

Athletic function

Increasingfunction

Increase stablefunction

0 20 40 8060 100

IncreasingLifespan and Healthspan

Lifespan in Years


• The Reproductive-Cell Cycle Theory of Aging•Bowen, R.L. and Atwood, C.S., 2004, Gerontology, 50, 265-290

•Atwood, C.S. and Bowen, R.L., 2011, Experimental Gerontology,

in press.

How and Why Do We Age? How and Why Do We Age?

The hormones that regulate reproduction in mammals act in an antagonistic pleiotrophic manner to control aging via cell cycle

signaling

How we can halt the aging process

Provides a credible reason for why and how aging occurs at the evolutionary, physiological and molecular levels


Reproductive Hormones Regulate Cell Growth, Development and Death

fetal hCG

LH (male and female)

LH (adult female)

LH (adult male)

mitogenicity index

Gestation Infancy Childhood Puberty Adult-reproductive period

Senescence

Mito

gen

icity Ind

exH

um

an C

ho

rio

nic

Go

nad

otr

op

in/

Lu

tein

izin

g H

orm

on

e


Hypothalamic-Pitutiary-Gonadal Axis: Hypothalamic-Pitutiary-Gonadal Axis: The Reproductive AxisThe Reproductive Axis

Feedback mechanisms keep axis in Feedback mechanisms keep axis in balance during reproductive periodbalance during reproductive period

LH, FSH, GnRH – mitogenic hormonesLH, FSH, GnRH – mitogenic hormonesSex steroids, activins – differentiative hormonesSex steroids, activins – differentiative hormones

Receptors for these Receptors for these hormones are hormones are

expressed in all expressed in all tissues of the bodytissues of the body


Feedback Feedback Regulatory LoopsRegulatory Loops

HYPOTHALAMUS

GnRH

LHFSH

Ovaries

OestrogenProgesterone

Pituitary

Negative feedback

luteal phase

Positive feedbackFollicular

phase

HYPOTHALAMUS

GnRH

LHFSH

Ovaries

OestrogenProgesterone

Pituitary

Negative feedback

luteal phase

Positive feedbackFollicular

phase

- pubertypuberty- menstrual cyclemenstrual cycle- pregnancypregnancy- castrationcastration- polycystic ovary syndromepolycystic ovary syndrome- disease statedisease state- menopause/andropausemenopause/andropause

When and Why Do Sex Steroid Levels When and Why Do Sex Steroid Levels ChangeChange


Feedback mechanisms keep axis in Feedback mechanisms keep axis in balance during reproductive periodbalance during reproductive period

LH, FSH, GnRH – mitogenic hormonesLH, FSH, GnRH – mitogenic hormonesSex steroids, activins – differentiative hormonesSex steroids, activins – differentiative hormones

Receptors for these Receptors for these hormones are hormones are

expressed in all expressed in all tissues of the bodytissues of the body



Endocrine Dyscrasia in Women and Endocrine Dyscrasia in Women and Age-Age-related Diseasesrelated Diseases

Dyotic Signaling: decreased sex steroid signaling, but increased gonadotropin, GnRH and activin signaling


Dyotic Signaling: decreased sex steroid signaling, but increased gonadotropin, GnRH and activin signaling

Endocrine Dyscrasia in Men and Endocrine Dyscrasia in Men and Age-Age-related Diseasesrelated Diseases


The Balance Between Mitogenic and The Balance Between Mitogenic and Differentiation Hormones Dictates Cell FateDifferentiation Hormones Dictates Cell Fate

Mitogenic SignalshCG/LH/FSH

GnRH

Differentiation SignalsSex steroids

ActivinsCellular

Homeostasis

Aberrant Cell Division and Death/Dysfunction

Equilibrium becomes dysregulated, initiating dyosis which drives senescence

Endocrine dyscrasia


Aberrant re-entry of cells into the cell cycle

Tissues with differentiated cell types

• Brain – neurons – Alzheimer’s disease

• Heart – endothelial cells/cardiomyocytes – CHD

Tissues with totipotent stem cell types

• Lung, liver, colon, reproductive tissues – cancer

• Vasculature – SMC/endothelial cells – stroke

• Bone – osteoclasts/osteoblast – osteoporosis

• Metabolism – diabetes mellitus

Consequences of HPG DysregulationConsequences of HPG Dysregulation


Global and pervasive deterioration in bodily function – explains why we develop our age-related diseases

Rate at which degenerative changes occurs depends on how

dysregulated the HPG axis becomes

Organs involved is dependent upon the influence of both

environmental and genetic factors

These factors determine who will age faster and who will age slower

But, we all eventually die

Consequences of HPG Dysregulation: Consequences of HPG Dysregulation: Endocrine DyscrasiaEndocrine Dyscrasia


Leading Causes of Death in the USALeading Causes of Death in the USA

Table 1. Leading causes of death in the USCause of Death All AgesTotal Number of Deaths 2,426,264 100%Diseases of the heart 631,636 26.0%Malignant Neoplasms (Cancer) 559,888 23.1%Cerebrovascular diseases 137,119 5.7%Chronic Lower Respiratory Disease 124,583 5.1%Accidents (unintentional injuries) 121,599 5.0%Diabetes Mellitus 72,449 3.0%Alzheimer’s disease 72,432 3.0%Influenza and Pneumonia 56,326 2.3%

Table 1. Leading causes of death in the USCause of Death All AgesTotal Number of Deaths 2,426,264 100%Diseases of the heart 631,636 26.0%Malignant Neoplasms (Cancer) 559,888 23.1%Cerebrovascular diseases 137,119 5.7%Chronic Lower Respiratory Disease 124,583 5.1%Accidents (unintentional injuries) 121,599 5.0%Diabetes Mellitus 72,449 3.0%Alzheimer’s disease 72,432 3.0%Influenza and Pneumonia 56,326 2.3%

CDC National Vital Statistics Report, Vol. 57, No. 14, April 17, 2009

Osteoporosis/low bone massOsteoporosis/low bone mass 55% by 50 years of age55% by 50 years of age

45% by 85 years of age45% by 85 years of ageDementia/cognitive lossDementia/cognitive loss

→→→

→

→→


1. Epidemiological evidence

2. Clinical evidence

3. Experimental evidence

Evidence that Endocrine Dyscrasia Evidence that Endocrine Dyscrasia Leads to Aging-related DiseasesLeads to Aging-related Diseases

This evidence provides clues as to how to halt the aging process that leads to our age-

related diseases


Age-related Reproductive Endocrine Age-related Reproductive Endocrine DyscrasiaDyscrasia Initiates Senescence and Age-related Diseases Initiates Senescence and Age-related Diseases

Epidemiological Evidence (>10 studies)

The longer the HPG axis is in balance, the less likely The longer the HPG axis is in balance, the less likely you are to develop an age-related diseaseyou are to develop an age-related disease

Disease risk in women with later menopause:

↓ cardiovascular disease

↓ calcifications in the aorta

↓ atherosclerosis

↓ dementia/cognitive decline

↓ osteoporosis/bone fractures

↓ colorectal and breast cancer

↑ uterine and ovarian cancer



Epidemiological Evidence (>16 studies) Disease risk in women with early reproductive endocrine dyscrasia (oophorectomy or natural):

↑ cardiovascular disease (fatal and non-fatal)

↑ stroke

↑ dementia/cognitive decline/Parkinsonism

↑ osteoporosis/bone fractures

↑ lung cancer

↑ depression and anxiety

↓ breast and ovarian cancer

Earlier endocrine dysrasia is associated with earlier onset Earlier endocrine dysrasia is associated with earlier onset of age-related diseaseof age-related disease



Experimental Evidence

Coronary heart disease Stroke (except women) Alzheimer’s disease/dementia/cognitive loss Osteoporosis/bone fractures Cancer Obesity, metabolic syndrome/diabetes mellitis II Frailty (men)

Positive relationships between age-related diseases and decreased circulating sex steroids and

increased gonadotropins in both men and women

The more dysregulated your HPG axis, the more likely you are to develop age-related diseases


Sex Hormones and Age-related Disease RiskSex Hormones and Age-related Disease Risk

Low T but elevated LH is associated with-Specific symptoms:

• frailty• increased prostate cancer• decreased sexual desire, shrinkage of testes• low sperm count• height loss• hot flushes, sweats

Other less specific symptoms:• decreased energy• poor concentration and memory• sleep disturbances• reduced muscle bulk and strength• increased body fat

MalesMales



All hormones of the axis have All hormones of the axis have important physiological functionsimportant physiological functions


Reproductive Hormones are Required for Growth Reproductive Hormones are Required for Growth and Development, and Maintenance of Tissues and Development, and Maintenance of Tissues

During AdulthoodDuring Adulthood

Embryonic and fetal growth and development:Embryonic and fetal growth and development:hCG – proliferative functionshCG – proliferative functionsProgesterone – promotes neurogenesis and differentiationProgesterone – promotes neurogenesis and differentiation

Adult tissue maintenance:Adult tissue maintenance:LH –LH – induces neurogenesis in the adult braininduces neurogenesis in the adult brainEstradiol – promotes neuritogenesis - neurite extension, Estradiol – promotes neuritogenesis - neurite extension,

dendritic spine formation, synaptogenesisdendritic spine formation, synaptogenesisProgesterone – promotes angiogenesis, mammary gland Progesterone – promotes angiogenesis, mammary gland

developmentdevelopmentSex hormones are required for normal adult tissue Sex hormones are required for normal adult tissue

maintenancemaintenance


Sex Steroid Hormones Are Synthesized by the Sex Steroid Hormones Are Synthesized by the Gonads and the Brain: Feedback Regulatory Gonads and the Brain: Feedback Regulatory

LoopsLoops

11

2233

1122334455

44

55

Sex steroids are made by the brain, for the brain


1. Modulating Reproductive Parameters1. Modulating Reproductive Parameters later menopauselater menopause later pubertylater puberty pregnancy and lactational amenorrheapregnancy and lactational amenorrhea stress: caloric restriction or coldstress: caloric restriction or cold

~5-20 years~5-20 years

Life Extension Strategies Through Hormone Life Extension Strategies Through Hormone Supplementation or SuppressionSupplementation or Suppression


Suppressing the HPG Axis as a Means to Suppressing the HPG Axis as a Means to Extend LongevityExtend LongevityLife-extending modalities

• caloric restriction (fasting, inadequate or inconsistent food supply)

• cold• stress

- all modalities suppress HPG axis hormones

- decrease fertility

- sparing of ovarian and testicular reserves

- offset the reproductive clock to a later time when the environment might be better for reproducing and raising offspring

- suppressing gonadotropins with GnRH agonists halves the risk of death from Alzheimer’s disease


2. Pharmacological solutions2. Pharmacological solutions

Hormone replacement therapies (physiological hormones)Hormone replacement therapies (physiological hormones) Sex steroids – 1Sex steroids – 1-estradiol, progesterone and testosterone-estradiol, progesterone and testosterone Currently we cannot replace all hormones lostCurrently we cannot replace all hormones lost Partial replacementPartial replacement

Hormone suppression therapiesHormone suppression therapies GnRH agonists and antagonistsGnRH agonists and antagonists Comes with some negative issues – osteoporosis, heart disease Comes with some negative issues – osteoporosis, heart disease

but appears positive for Alzheimer’s diseasebut appears positive for Alzheimer’s disease

5-20 years5-20 years These above strategies are the best we can do currentlyThese above strategies are the best we can do currently Focus on sex steroid replacement otherwise known as hormone Focus on sex steroid replacement otherwise known as hormone

replacement therapyreplacement therapy



Hormone Replacement TherapyHormone Replacement Therapy

Compelling evidence for endocrine dyscrasia as promoting age-related diseases comes from HRT studies

Sex steroids used to supplement those sex steroids no longer produced by the gonads

Women: estrogen, progesterone, or both given to women after menopause to replace the hormones no longer produced by the ovaries (~50 years of age)

Men: testosterone given to men with hypogonadism to replace testosterone no longer produced by testes

Sources vary: Physiologically (bio)identical human hormones Unphysiological hormones - hormones extracted from horse

urine plus synthetic analogs


Reversing Endocrine Dyscrasia as a Reversing Endocrine Dyscrasia as a Means to Extend LongevityMeans to Extend Longevity


Reversing Endocrine Dyscrasia: Reversing Endocrine Dyscrasia: Restoring Some Balance to the HPG AxisRestoring Some Balance to the HPG Axis

It’s not perfect, but it’s the best we can do for now


What are Sex SteroidsWhat are Sex Steroids

Sex steroid synthesis begins in the embryo and continues throughout life

Decreases in sex steroid synthesis with menopause and andropause

ProgesteroneCholesterol



Human sex steroids are made by:- ovaries and testes - adrenal glands- brain- adipose tissue



Human sex steroids are made by:- ovaries or testes - adrenal glands- brain- adipose tissue

Classes of sex steroids- androgens (testosterone)- estrogens (17-estradiol)- progestagens (progesterone)

All hormones are found in males and females


Steroid Biosynthesis Cholesterol

StAR followed by P450 side chain cleavage

Pregnenolone 17αOH Pregnenolone DHEA

Androstenedione

17αHSD 17,20 lyase3βHSD 3βHSD3βHSD

Progesterone 17αOH Progesterone

Testosterone

17βHSD

17-Estradiol

17βHSD

+

aromatase

DHT

5α reductase

21 & 11β hydroxylase

Corticosterone Cortisol18 hydroxylase & 18 HSD

Aldosterone Physiologically important steroids


Age-related Reproductive Endocrine Age-related Reproductive Endocrine Dyscrasia and Age-related Diseases Dyscrasia and Age-related Diseases

Clinical and Epidemiological Evidence

Alzheimer’s disease/dementia/cognitive loss Coronary heart disease* Stroke (except women)* Osteoporosis/bone fractures Obesity, metabolic syndrome/diabetes mellitis II* Cancer*

Supplementation with physiological sex steroid post-menopause and during andropause delays the onset, decreases the incidence and often improves

the course of age-related diseases


William Utermohlen’s self-portraits reveal his

descent into dememtia over the span of nearly

four decades. Left, a self-portrait from 1967.

When he learned in 1995 that he had Alzheimer’s

disease, William Utermohlen, an American

artist in London, responded in

characteristic fashion.

©2006 Galerie Beckel-Odille-Boicos


1996




1997



1998



1999



2000


William Utermohlen’s self-portraits reveal his descent into dememtia over the span of nearly four decades.

First picture, a self-portrait from 1967.

1996 1996 1996 1996 1996 1996 1996 1996

1997 1997 1997 1997 1998 1998 1999 1999 2000 2000


Macroscopic Differences Between AD Macroscopic Differences Between AD and Control Brainsand Control Brains

• narrowing of gyri (blue arrow)

• widening of sulci (yellow arrow)

(Adapted from Kisilevsky, 1994)

Alzheimer’s DiseaseAged Control Brain

• Neurodegenerative disorder of the elderlyNeurodegenerative disorder of the elderly• Memory loss and impairments of behavioral, language and visuo-spatial skillsMemory loss and impairments of behavioral, language and visuo-spatial skills


Alzheimer’s disease attacks nerve cells in several regions of the brain.

A. Cerebral Cortex: Involved in conscious thought and language.B. Basal forebrain: Has large numbers of

neurons containing acetylcholine, a

chemical important in memory and learning.

C. Hippocampus: Essential to memory storage.

The earliest signs of Alzheimer's are found in the nearby entorhinal cortex (not shown).

The Brain and Alzheimer DiseaseThe Brain and Alzheimer Disease

• Neurons loss/dysfunction• Synapse loss/dysfunction• Neurofibillary tangles – P-tau• Amyloid plaques – amyloid-• Microgliosis

Overt Neuropathology:


The Biochemical and Pathological Changes The Biochemical and Pathological Changes Associated with ADAssociated with AD

Cell Cycle Related EventsCell Cycle Related Events

• Cell cycle proteinsCell cycle proteins

• Chromosome replication Chromosome replication

• Elevated mtDNA/Cox-1 levelsElevated mtDNA/Cox-1 levels

• Oxidative stress Oxidative stress

• APP processingAPP processing

• Tau phosphorylation Tau phosphorylation

• Mitotic signal transduction pathwaysMitotic signal transduction pathways


Why is the Cell Cycle Reactivated in Why is the Cell Cycle Reactivated in Alzheimer’s Disease?Alzheimer’s Disease?

Certain HPG hormones are mitogenicCertain HPG hormones are mitogenic(cell proliferation)(cell proliferation)

- LH, FSH, GnRH- LH, FSH, GnRH- increase amyloid-- increase amyloid- deposition, tau phosphorylation deposition, tau phosphorylation

Certain HPG hormones are differentiativeCertain HPG hormones are differentiative(specify cell function)(specify cell function)

- sex steroids, activins- sex steroids, activins- reduce amyloid-- reduce amyloid- deposition, tau phosphorylation deposition, tau phosphorylation

Loss of balance in the reproductive hormonal axis leads to Loss of balance in the reproductive hormonal axis leads to aberrant reactivation of the cell cycle leading to aberrant reactivation of the cell cycle leading to

neuron deathneuron death


Epidemiological and Clinical Evidence for Epidemiological and Clinical Evidence for Sex Hormones as the Cause of ADSex Hormones as the Cause of AD

• female predominance (general population)female predominance (general population)• 2:1 ratio of women to men2:1 ratio of women to men• abrupt earlier loss of gonadal function in womenabrupt earlier loss of gonadal function in women

• increased risk of dementia in women who had increased risk of dementia in women who had oophorectomy (ovaries removed)oophorectomy (ovaries removed)

• positive relationships between AD and decreased positive relationships between AD and decreased sex steroids and increased LH/FSH levels after sex steroids and increased LH/FSH levels after menopause/andropausemenopause/andropause

• hormones regulate biochemical and hormones regulate biochemical and neuropathological changes associated with ADneuropathological changes associated with AD• physiological hormone replacement therapies delay physiological hormone replacement therapies delay onset and decrease incidenceonset and decrease incidence


Clinical Trials Demonstrate Importance of Clinical Trials Demonstrate Importance of Physiological Sex Steroids for CognitionPhysiological Sex Steroids for Cognition

Intervention (treatment) trialsIntervention (treatment) trials– 1717-estradiol -estradiol improvesimproves cognitive performance in women with cognitive performance in women with

AD (3 controlled studies and 5 uncontrolled studies)AD (3 controlled studies and 5 uncontrolled studies)– testosterone testosterone improvesimproves cognitive performance in men with AD cognitive performance in men with AD

(1 controlled study)(1 controlled study)

Prospective cohort studiesProspective cohort studies– 1717-estradiol -estradiol reducesreduces the incidence (1 study) and the incidence (1 study) and delaysdelays the the

onset (4 studies) of AD in older women onset (4 studies) of AD in older women – 1717-estradiol -estradiol improvesimproves cognitive performance in cognitively cognitive performance in cognitively

healthy post-menopausal women (12 of 15 studies; 3 studies healthy post-menopausal women (12 of 15 studies; 3 studies showed no benefit)showed no benefit)

2626 different studies indicate physiological forms of different studies indicate physiological forms of estrogens and testosterone are beneficial for estrogens and testosterone are beneficial for cognitive healthcognitive health


Estradiol Halts Cognitive Decline and Estradiol Halts Cognitive Decline and Enhances CognitionEnhances Cognition

Estradiol study, elderly women, 5 yearsEstradiol study, elderly women, 5 years No estradiol - 16% developed ADNo estradiol - 16% developed AD Estradiol - 1.7% developed AD Estradiol - 1.7% developed AD

Other studiesOther studies Women who suffered only moderate memory Women who suffered only moderate memory

problems from Alzheimer's disease improved problems from Alzheimer's disease improved their memory while on HRTtheir memory while on HRT


Compelling Evidence that Sex Steroids Compelling Evidence that Sex Steroids are Important for Brain Healthare Important for Brain Health

Why are we not all taking human estradiol and Why are we not all taking human estradiol and progesterone post-menopause to supplement for the progesterone post-menopause to supplement for the loss of these hormones with aging?loss of these hormones with aging?

And testosterone during andropause in men to And testosterone during andropause in men to supplement for the loss of these hormones with supplement for the loss of these hormones with aging? aging?


Unphysiological Sex Steroids and Unphysiological Sex Steroids and Disease RiskDisease Risk

1. Women Health Initiative Studies 1. Women Health Initiative Studies Human versus non-human sex hormonesHuman versus non-human sex hormones Non-human sex hormones developed initially for Non-human sex hormones developed initially for

treatment of menopausal symptoms (profit from treatment of menopausal symptoms (profit from patented sex steroids)patented sex steroids)

Analogs/non-human forms developed for human Analogs/non-human forms developed for human useuse

Long-term use led to health issuesLong-term use led to health issues

2. Risk of cancer, stroke and heart disease2. Risk of cancer, stroke and heart disease


1. Women’s Health Initiative Studies1. Women’s Health Initiative Studies

PREMARIN – conjugated PREMARIN – conjugated equine estrogens (estrone equine estrogens (estrone sulfate)sulfate)

PREMPRO – CEE plus PREMPRO – CEE plus medroxyprogesterone acetatemedroxyprogesterone acetate

Horse-derived and synthetic analogs:Horse-derived and synthetic analogs:

Let’s compare estradiol Let’s compare estradiol with CEE…..with CEE…..


Clinical and Observational Studies of Natural and Clinical and Observational Studies of Natural and Unnatural Sex Steroids on Cognitive OutcomeUnnatural Sex Steroids on Cognitive Outcome

1717-estradiol:-estradiol: 100% of studies show improvement in cognition in AD subjects100% of studies show improvement in cognition in AD subjects 80% of studies show improvement in cognitive performance in 80% of studies show improvement in cognitive performance in

healthy older womenhealthy older women

Conjugated equine estrogens: Conjugated equine estrogens: ~50% of studies show a delay in onset and halting of the ~50% of studies show a delay in onset and halting of the

progression of ADprogression of AD ~50% of studies show an improvement in cognitive ~50% of studies show an improvement in cognitive

performance in healthy older womenperformance in healthy older women One study, the Women’s Health Initiative – Memory Study One study, the Women’s Health Initiative – Memory Study

(WHIMS) showed that women taking CEE (Premarin) or CEE (WHIMS) showed that women taking CEE (Premarin) or CEE with medroxyprogesterone (Prempro) were more likely to show with medroxyprogesterone (Prempro) were more likely to show cognitive cognitive declinedecline

Different forms of estrogen vary in their effects, and side effects, Different forms of estrogen vary in their effects, and side effects, on the brain and other tissueson the brain and other tissues


Undoing the ‘Scientific’ DamageUndoing the ‘Scientific’ DamageNatural Forms of Sex Steroids


Undoing the ‘Scientific’ DamageUndoing the ‘Scientific’ Damage

Progesterone Testosterone

Natural Forms of Sex Steroids





Major differences in biological action




Medroxyprogesterone (MPA)


Synthetic/Animal Forms of Sex Steroids

Biologically – we might expect major differences, and we do






Unlike progesterone, medroxyprogesterone:

DOES NOT protect against glutamate-induced neuronal toxicity (Nilsen et al., 2006, Gynecol Endocrinol.; Jodhka et al., 2009, Endocrinology)

DOES NOT protect against the neuro-degeneration induced by traumatic brain injury (Wright et al., 2008; Brain)

DOES prevents neurogenesis (Nilsen and Brinton, 2003, PNAS; Brinton, 2009)





17-estradiol







17-estradiol

Estrone sulfate



Biologically – major differences in function

Major estrogen from horse urine

found in Premarin



Progesterone Testosterone 17-estradiol

Estrone sulfate


Biologically – major differences in action

CEE – different signaling pathways? major CEE = estrone sulfate contain ~ 15 different estrogens excretory products decreased ER binding conjugation - hormonal inactivation to limit signaling (sulfation or glucuronidation)

Major estrogen from horse urine

found in Premarin


We need to be supplementing our body with sex steroids that are physiologically relevant!

For Women: 17-estradiol and progesterone

For Men: testosterone and progesterone

Undoing the ‘Scientific’ DamageUndoing the ‘Scientific’ DamageThe Bottom Line

No study has ever shown a No study has ever shown a negative cognitive outcome from negative cognitive outcome from the use of human sex steroids.the use of human sex steroids.

Predominantly a US problemPredominantly a US problem


Small Changes Can Lead to Big Small Changes Can Lead to Big Differences!Differences!

Synthetic sex steroids- anabolic steroids – androgenic (T and DHT)

- synthetic estrogens and progestagens used in hormone replacement therapies, oral contraceptives and other reproductive conditions or diseases


2. Cancer Risk for Hormone Replacement 2. Cancer Risk for Hormone Replacement Therapies (HRT)Therapies (HRT)

There is an indisputable increase in the risk of breast, uterine There is an indisputable increase in the risk of breast, uterine and ovarian cancer with CEE and estradiol supplementationand ovarian cancer with CEE and estradiol supplementation

CancerCancer UsageUsage

(years)(years)Incidence Incidence (/1000)(/1000)

BreastBreast >10>10 3-63-6

OvarianOvarian >10>10 3-113-11

UterineUterine >10>10 7-157-15

TotalTotal ~23/1000~23/1000

CEECEE EstradiolEstradiol

CancerCancer UsageUsage

(years)(years)Incidence Incidence (/1000)(/1000)

BreastBreast >10>10 1-131-13

OvarianOvarian >10>10 1-31-3

UterineUterine >10>10 1-51-5

TotalTotal ~12/1000~12/1000

~1-2 women per 100 will develop a reproductive cancer~1-2 women per 100 will develop a reproductive cancer


Cancer Risk for Hormone Replacement Cancer Risk for Hormone Replacement Therapies (HRT)Therapies (HRT)

But estradiol replacement therapy decreases But estradiol replacement therapy decreases the risk of other diseases: heart disease, AD, the risk of other diseases: heart disease, AD, stroke, osteoporosis, diabetes mellitus II, etcstroke, osteoporosis, diabetes mellitus II, etc

Does the risk of cancer or other diseases Does the risk of cancer or other diseases from HRT outweigh the risk from developing from HRT outweigh the risk from developing other diseases of aging?other diseases of aging?


2. Cancer Risk for Hormone Replacement 2. Cancer Risk for Hormone Replacement Therapies (HRT)Therapies (HRT)

But HRT decreases the risk of nearly every But HRT decreases the risk of nearly every other disease: heart disease, AD, stroke, other disease: heart disease, AD, stroke, osteoporosis, diabetes mellitus II, etcosteoporosis, diabetes mellitus II, etc

Does the risk of cancer or other diseases Does the risk of cancer or other diseases from HRT outweigh the risk from developing from HRT outweigh the risk from developing other diseases of aging?other diseases of aging?

NONO


Humans: Estrogen Replacement Humans: Estrogen Replacement Therapy Decreases MortalityTherapy Decreases Mortality

Consistently show a 20-50% decrease in mortality among estrogen (CEE) users

Paganini-Hill et al., 2006


Higher Age at Menopause Increases Female Higher Age at Menopause Increases Female Post-Reproductive Post-Reproductive LifespanLifespan

Advanced age at last reproduction is associated with improved longevity

~ 2.4% reduced mortality per year increase in age at menarche

Age at menopause (years)

9 studies demonstrate advanced age at menopause - ↑ longevity

Ossewaarde et al., (2005)


Cancer Risk for Hormone Cancer Risk for Hormone Replacement Therapies (HRT)Replacement Therapies (HRT)

Example 1: I am 80 years of age and have no family history of Example 1: I am 80 years of age and have no family history of cancer, but my cognition is declining. May consider risk of cancer, but my cognition is declining. May consider risk of cancer unimportant in the face of memory loss.cancer unimportant in the face of memory loss.




Example 2: I am 65 years of age and have cognitive decline. Example 2: I am 65 years of age and have cognitive decline. May consider risk of cancer unimportant in the face of memory May consider risk of cancer unimportant in the face of memory loss.loss.





Example 3: I am 70 years of age without cognitive loss, but a Example 3: I am 70 years of age without cognitive loss, but a family history of cancer. May consider risk of cancer family history of cancer. May consider risk of cancer outweighs risks of memory loss.outweighs risks of memory loss.





Example 3: I am 70 years of age without cognitive loss, but a Example 3: I am 70 years of age without cognitive loss, but a family history of cancer. May consider risk of cancer family history of cancer. May consider risk of cancer outweighs risks of memory loss.outweighs risks of memory loss.

Example 4: I am 70 years of age and have cognitive decline. Example 4: I am 70 years of age and have cognitive decline. I also have a family history of cancer. I also have a family history of cancer.


Summary: Sex Hormones and Age-Summary: Sex Hormones and Age-related Disease Riskrelated Disease Risk

Maintaining sex steroid levels reduces the risk of:Maintaining sex steroid levels reduces the risk of:

Alzheimer’s diseaseAlzheimer’s disease

Stroke*Stroke*

Coronary heart disease*Coronary heart disease*

OsteoporosisOsteoporosis

Obesity, metabolic syndrome/diabetes mellitis II*Obesity, metabolic syndrome/diabetes mellitis II*

Depression and anxietyDepression and anxiety

Menopausal symptomsMenopausal symptoms

Maintaining sex steroid levels increase the risk of:Maintaining sex steroid levels increase the risk of:

CancerCancer

Quality of lifeQuality of life

Living longer!Living longer!

Partial hormone Partial hormone replacement therapyreplacement therapy


Female Hormone Replacement Therapy:Female Hormone Replacement Therapy:

What Should I Take?What Should I Take?• WomenWomen

– 1717-estradiol (USP) - patch (Climara or Vivelle)-estradiol (USP) - patch (Climara or Vivelle)

– progesterone (USP) - Pro Gest (cream) – preferable; Prometrium (pill) – progesterone (USP) - Pro Gest (cream) – preferable; Prometrium (pill) – first pass changes in liverfirst pass changes in liver

• DoseDose

– 1717-estradiol (USP) - 0.025 mg/day-estradiol (USP) - 0.025 mg/day

– progesterone (USP) - 30 mg/dayprogesterone (USP) - 30 mg/day

• Route?Route?

– Varies for hormoneVaries for hormone

• Opposed or unopposed?Opposed or unopposed?

– 1717-estradiol + progesterone-estradiol + progesterone

– decreased uterine cancerdecreased uterine cancer

• Timing, duration and cyclicity?Timing, duration and cyclicity?

– during menopause – for relief of menopausal symptomduring menopause – for relief of menopausal symptom

– post-menopause: window – 5 years versus foreverpost-menopause: window – 5 years versus forever

– continuous progesterone to avoid breakthrough bleedingcontinuous progesterone to avoid breakthrough bleeding


Male Hormone Replacement Therapy:Male Hormone Replacement Therapy:

What Should I Take?What Should I Take?• MenMen

– testosterone (USP) - gel or underarm topicaltestosterone (USP) - gel or underarm topical

– progesterone (USP) - Pro Gest (cream) – preferable; Prometrium progesterone (USP) - Pro Gest (cream) – preferable; Prometrium (pill) – first pass changes in liver(pill) – first pass changes in liver

• DoseDose

– testosterone (USP) – 10 mg/day testosterone (USP) – 10 mg/day

– progesterone (USP) - 30 mg/dayprogesterone (USP) - 30 mg/day

• Route?Route?

– Transdermal to avoid oral first pass effects through liverTransdermal to avoid oral first pass effects through liver

• Opposed or unopposedOpposed or unopposed

– testosterone + progesterone?testosterone + progesterone?

• Timing, duration and cyclicityTiming, duration and cyclicity

– Starting at andropause (30-50 years)Starting at andropause (30-50 years)

– Starting when hypogonadal (i.e. low serum T) and phenotypic Starting when hypogonadal (i.e. low serum T) and phenotypic changes menopause – for relief of menopausal symptomchanges menopause – for relief of menopausal symptom

– Continuous? Continuous?


3. Replacing gonadal cells3. Replacing gonadal cells Ovarian and testicular implants?Ovarian and testicular implants? Would provide Would provide completecomplete hormone replacement hormone replacement Would eliminate the negative consequences resulting from partial Would eliminate the negative consequences resulting from partial

hormone replacement???hormone replacement???

Ovary replacement shown to increase longevityOvary replacement shown to increase longevity Human embryonic stem cell technologiesHuman embryonic stem cell technologies Not currently a possibility for humansNot currently a possibility for humans

20-40 years20-40 years



Healthy Lifespan Extension Following Healthy Lifespan Extension Following Ovary TransplantationOvary Transplantation

Cargill et al., (2003)

40% increase in life expectancy

Rebalancing the HPG Axis Increases Longevity


Delaydecreasing

function

Mild

Moderate

Severe

Restoration of the HPG Axis Extends Restoration of the HPG Axis Extends Lifespan and HealthspanLifespan and Healthspan

Fu

nct



Bone functionReproductive function

Athletic function

Increasingfunction

Increase stablefunction

0 50 100 150

IncreasingLifespan and Healthspan

Lifespan in Years


Laboratory of Endocrinology, Laboratory of Endocrinology, Aging and Disease (LEAD)Aging and Disease (LEAD)

Post-doctoral Students• Giuseppe Verdile, Ph.D. • Glenda M. Bishop, Ph.D.• Sivan Vadakkadath Meethal, Ph.D.• Prashob Porayette, M.B.B.S., M.S.

Graduate Students• Tianbing Liu, M.Sc.• Hsien Chan, B.Sc.• Andrea C. Wilson, B.S.• Miguel Gallego, B.S.• Kentaro Hayashi, M.Sc.

Duke University, Raleigh, NCRichard L. Bowen, M.D.

Research Staff• Hong Zeng, M.S.• Zvezdana Kubats, M.S., • Patrick F. Lyon, M.S. • John Wung, B.S.• Sandra L. Siedlak, M.S.• Ryan Haasl, M.Sc.• Jon Sweeney, B.S.• Derek Simon • Jacob Basson, B.S.


Life and Death is About Balance:Life and Death is About Balance:Hormonal Balance!Hormonal Balance!

Live Longer Foundation, Inc.Live Longer Foundation, Inc.

www.livelongerfoundation.org

living longer presentation 2012

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