1. Aging and Hormone Replacement: The
Latest in Disease Prevention
From: beautyanalysis.com From: Pilates Reforming NY
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 Hospital
Madison, Wisconsin
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2. The Seven Acts of Life
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;
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3. 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)
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4. Function Changes During the Life Cycle
Increasing Stable Decreasing
function function function
Mild
Function
Moderate
Severe
0 20 40 60 80 100
Lifespan in Years
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5. Function Changes During the Life Cycle:
Extending Lifespan
Increasing Stable Slow decreasing
function function function
Cognitive function Increasing
Mild
Function
Vascular function lifespan
Immune function Moderate
Bone function
Reproductive function
Severe
Athletic performance
0 20 40 60 80 100
Lifespan in Years
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6. Function Changes During the Life Cycle:
Extending Lifespan and Healthspan
Increasing Increase stable Delay
function function decreasing
function
Increasing
Cognitive function Mild Lifespan and
Function
Vascular function Healthspan
Immune function Moderate
Bone function
Reproductive function
Severe
Athletic function
0 20 40 60 80 100
Lifespan in Years
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7. How and Why Do We Age?
• 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.
The hormones that regulate reproduction in mammals act in an
antagonistic pleiotrophic manner to control aging via cell cycle
signaling
Provides a credible reason for why and how aging occurs
at the evolutionary, physiological and molecular levels
How we can halt the aging process
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8. Reproductive Hormones Regulate Cell Growth,
Development and Death
fe ta l h C G L H (a d u lt fe m a le ) m ito g e n ic ity in d e x
L H (m a le a n d fe m a le ) L H (a d u lt m a le )
Human Chorionic Gonadotropin/
Luteinizing Hormone
Mitogenicity Index
G e s t a t i o n I n f a n c y C h i l d h o o d P u b e r t y Adult-reproductive Senescence
period
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9. Hypothalamic-Pitutiary-Gonadal Axis:
The Reproductive Axis
Receptors for these
hormones are
expressed in all
tissues of the body
Feedback mechanisms keep axis in
balance during reproductive period
LH, FSH, GnRH – mitogenic hormones
Sex steroids, activins – differentiative hormones
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10. When and Why Do Sex Steroid Levels
Change
- puberty
- menstrual cycle
- pregnancy
- castration
- polycystic ovary syndrome
- disease state
- menopause/andropause
Feedback
Regulatory Loops
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11. Hypothalamic-Pitutiary-Gonadal Axis:
The Reproductive Axis
Receptors for these
hormones are
expressed in all
tissues of the body
Feedback mechanisms keep axis in
balance during reproductive period
LH, FSH, GnRH – mitogenic hormones
Sex steroids, activins – differentiative hormones
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12. Endocrine Dyscrasia in Women and Age-
related Diseases
Dyotic Signaling: decreased sex steroid signaling, but
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increased gonadotropin, GnRH and activin signaling

13. Endocrine Dyscrasia in Men and Age-
related Diseases
Dyotic Signaling: decreased sex steroid signaling, but
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increased gonadotropin, GnRH and activin signaling

14. The Balance Between Mitogenic and
Differentiation Hormones Dictates Cell Fate
Mitogenic Signals Differentiation Signals
hCG/LH/FSH Cellular Sex steroids
GnRH Homeostasis Activins
Aberrant Cell Division and
Death/Dysfunction
Endocrine dyscrasia
Equilibrium becomes
dysregulated, initiating dyosis
which drives senescence
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15. Consequences of HPG
Dysregulation
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 – SM C/endothelial cells –
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16. Consequences of HPG
Dysregulation: Endocrine Dyscrasia
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
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17. Leading Causes of Death in the USA
Table 1. Leading causes of death in the US
Cause of Death All Ages
Total 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%
→ Osteoporosis/low bone mass 55% by 50 years of age
→ Dementia/cognitive loss 45% by 85 years of age
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CDC National Vital Statistics Report, Vol. 57, No. 14, April 17, 2009

18. Evidence that Endocrine Dyscrasia
Leads to Aging-related Diseases
1. Epidemiological evidence
2. Clinical evidence
3. Experimental evidence
This evidence provides clues as to how to
halt the aging process that leads to our age-
related diseases
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19. Age-related Reproductive Endocrine Dyscrasia
Initiates Senescence and Age-related Diseases
Epidemiological Evidence (>10 studies)
 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
The longer the HPG axis is in balance, the less likely
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20. Age-related Reproductive Endocrine Dyscrasia
Initiates Senescence and Age-related Diseases
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
of age-related disease
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21. Age-related Reproductive Endocrine Dyscrasia
Initiates Senescence and Age-related Diseases
Experimental Evidence
Positive relationships between age-related diseases
and decreased circulating sex steroids and
increased gonadotropins in both men and women
 Coronary heart disease
 Stroke (except women)
 Alzheimer’s disease/dementia/cognitive loss
 Osteoporosis/bone fractures
 Cancer
 Obesity, metabolic syndrome/diabetes mellitis II
 Frailty (men)
The more dysregulated your HPG axis, the more likely you
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are to develop age-related diseases

22. Sex Hormones and Age-related Disease Risk
Males
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
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• increased body fat

23. Hypothalamic-Pitutiary-Gonadal Axis:
The Reproductive Axis
All hormones of the axis have
important physiological functions
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24. Reproductive Hormones are Required for Growth
and Development, and Maintenance of Tissues
During Adulthood
Embryonic and fetal growth and development:
hCG – proliferative functions
Progesterone – promotes neurogenesis and differentiation
Adult tissue maintenance:
LH – induces neurogenesis in the adult brain
Estradiol – promotes neuritogenesis - neurite extension,
dendritic spine formation, synaptogenesis
Progesterone – promotes angiogenesis, mammary gland
development
Sex hormones are required for normal adult tissue
maintenance
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25. Sex Steroid Hormones Are Synthesized by the
Gonads and the Brain: Feedback Regulatory
Loops
1
5
1
2
3
3 4
2 5
4
Sex steroids are made by the
brain, for the brain
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26. Life Extension Strategies Through
Hormone Supplementation or
Suppression
1. Modulating Reproductive Parameters
 later menopause
 later puberty
 pregnancy and lactational amenorrhea
 stress: caloric restriction or cold
 ~5-20 years
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27. Suppressing the HPG Axis as a Means to
Extend Longevity
Life-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
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halves the risk of death from Alzheimer’s disease

28. Life Extension Strategies Through
Hormone Supplementation or
Suppression
2. Pharmacological solutions
Hormone replacement therapies (physiological hormones)
 Sex steroids – 17β -estradiol, progesterone and testosterone
 Currently we cannot replace all hormones lost
 Partial replacement
Hormone suppression therapies
 GnRH agonists and antagonists
 Comes with some negative issues – osteoporosis, heart disease
but appears positive for Alzheimer’s disease
 5-20 years
 These above strategies are the best we can do currently
 Focus on sex steroid replacement otherwise known as hormone
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29. Hormone 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
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30. Reversing Endocrine Dyscrasia as a
Means to Extend Longevity
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31. Reversing Endocrine Dyscrasia:
Restoring Some Balance to the HPG
Axis
It’s not perfect, but it’s the best we can do for now
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32. What are Sex Steroids
Cholesterol Progesterone
Sex steroid synthesis begins in the embryo and
continues throughout life
Decreases in sex steroid synthesis with menopause and
andropause
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33. What are Sex Steroids
Human sex steroids are made by:
- ovaries and testes
- adrenal glands
- brain
- adipose tissue
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34. What are Sex Steroids
Human sex steroids are made by:
- ovaries or testes
- adrenal glands
- brain
- adipose tissue
Classes of sex steroids
- androgens (testosterone)
- estrogens (17β-estradiol)
- progestagens (progesterone)
All hormones are found in males and females
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35. Cholesterol
Steroid Biosynthesis
StAR followed by P450 side chain cleavage
Pregnenolone 17αOH Pregnenolone DHEA
17αHSD 17,20
3βHSD 3βHSD lyase 3βHSD
Progesterone 17αOH Progesterone Androstenedione
21 & 11β 17βHSD 17βHSD
hydroxylase
+
Testosterone
Corticosterone Cortisol aromatase
18 hydroxylase 5α
& 18 HSD reductase 17β-Estradiol
Aldosterone Physiologically
DHT
important steroids
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36. Age-related Reproductive Endocrine
Dyscrasia and Age-related Diseases
Clinical and Epidemiological Evidence
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
 Alzheimer’s disease/dementia/cognitive loss
 Coronary heart disease*
 Stroke (except women)*
 Osteoporosis/bone fractures
 Obesity, metabolic syndrome/diabetes mellitis II*
 Cancer*
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37. 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.
LEAD, ‘10 ©2006 Galerie Beckel-Odille-Boicos

38. 1996
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39. 1996
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40. 1996
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41. 1997
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42. 1997
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©2006 Galerie Beckel-Odille-Boicos

43. 1998
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44. 1999
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45. 2000
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46. 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
1997 1997 1998 1999 2000
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47. Macroscopic Differences Between AD
and Control Brains
Aged Control Brain Alzheimer’s Disease
• narrowing of gyri (blue arrow)
• widening of sulci (yellow arrow
(Adapted from Kisilevsky, 1994)
• Neurodegenerative disorder of the elderly
• Memory loss and impairments of behavioral, language and visuo-spatial skills
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48. The Brain and Alzheimer Disease
Alzheimer’s disease attacks nerve cells in several regions
of the brain. Overt Neuropathology:
• Neurons loss/dysfunction
• Synapse loss/dysfunction
• Neurofibillary tangles – P-tau
• Amyloid plaques – amyloid-β
• Microgliosis
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
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shown).

49. The Biochemical and Pathological Changes
Associated with AD
Cell Cycle Related Events
• Cell cycle proteins
• Chromosome replication
• Elevated mtDNA/Cox-1 levels
• Oxidative stress
• APP processing
• Tau phosphorylation
• Mitotic signal transduction pathways
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50. Why is the Cell Cycle Reactivated in
Alzheimer’s Disease?
Certain HPG hormones are mitogenic
(cell proliferation)
- LH, FSH, GnRH
- increase amyloid-β deposition, tau phosphorylation
Certain HPG hormones are differentiative
(specify cell function)
- sex steroids, activins
- reduce amyloid-β deposition, tau phosphorylation
Loss of balance in the reproductive hormonal axis leads to
aberrant reactivation of the cell cycle leading to
neuron death
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51. Epidemiological and Clinical Evidence
for Sex Hormones as the Cause of AD
• female predominance (general population)
• 2:1 ratio of women to men
• abrupt earlier loss of gonadal function in women
• increased risk of dementia in women who had
oophorectomy (ovaries removed)
• positive relationships between AD and decreased
sex steroids and increased LH/FSH levels after
menopause/andropause
• hormones regulate biochemical and
neuropathological changes associated with AD
• physiological hormone replacement therapies delay
onset and decrease incidence
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52. Clinical Trials Demonstrate Importance of
Physiological Sex Steroids for Cognition
 Intervention (treatment) trials
– 17β -estradiol improves cognitive performance in women with
AD (3 controlled studies and 5 uncontrolled studies)
– testosterone improves cognitive performance in men with AD
(1 controlled study)
 Prospective cohort studies
– 17β -estradiol reduces the incidence (1 study) and delays the
onset (4 studies) of AD in older women
– 17β -estradiol improves cognitive performance in cognitively
healthy post-menopausal women (12 of 15 studies; 3 studies
showed no benefit)
 26 different studies indicate physiological forms of
estrogens and testosterone are beneficial for
cognitive health
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53. Estradiol Halts Cognitive Decline and
Enhances Cognition
 Estradiol study, elderly women, 5 years
 No estradiol - 16% developed AD
 Estradiol - 1.7% developed AD
 Other studies
 Women who suffered only moderate memory
problems from Alzheimer's disease improved
their memory while on HRT
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54. Compelling Evidence that Sex Steroids
are Important for Brain Health
 Why are we not all taking human estradiol and
progesterone post-menopause to supplement for the
loss of these hormones with aging?
 And testosterone during andropause in men to
supplement for the loss of these hormones with
aging?
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55. Unphysiological Sex Steroids and
Disease Risk
1. Women Health Initiative Studies
 Human versus non-human sex hormones
 Non-human sex hormones developed initially for
treatment of menopausal symptoms (profit from
patented sex steroids)
 Analogs/non-human forms developed for human
use
 Long-term use led to health issues
2. Risk of cancer, stroke and heart disease
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56. 1. Women’s Health Initiative Studies
Horse-derived and synthetic analogs:
PREMARIN – conjugated
equine estrogens (estrone
sulfate)
PREMPRO – CEE plus
medroxyprogesterone
acetate
Let’s compare estradiol
with CEE…..
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57. Clinical and Observational Studies of Natural and
Unnatural Sex Steroids on Cognitive Outcome
 17β -estradiol:
 100% of studies show improvement in cognition in AD subjects
 80% of studies show improvement in cognitive performance in
healthy older women
 Conjugated equine estrogens:
 ~50% of studies show a delay in onset and halting of the
progression of AD
 ~50% of studies show an improvement in cognitive
performance in healthy older women
 One study, the Women’s Health Initiative – Memory Study
(WHIMS) showed that women taking CEE (Premarin) or CEE
with medroxyprogesterone (Prempro) were more likely to show
cognitive decline
 Different forms of estrogen vary in their effects, and side effects,
on the brain and other tissues
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58. Undoing the ‘Scientific’ Damage
Natural Forms of Sex
Steroids
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59. Undoing the ‘Scientific’ Damage
Natural Forms of Sex
Steroids
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60. Undoing the ‘Scientific’ Damage
Natural Forms of Sex
Steroids
Progesterone Testosterone
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61. Undoing the ‘Scientific’ Damage
Natural Forms of Sex
Steroids
Progesterone Testosterone
Major differences in biological action
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62. Undoing the ‘Scientific’ Damage
Natural Forms of Sex
Steroids
Progesterone Testosterone
Synthetic/Animal Forms of
Medroxyprogesteron Sex Steroids
e (MPA)
Biologically – we might expect major
differences, and we do
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63. Undoing the ‘Scientific’ Damage
Natural Forms of Sex
Steroids
Progesterone Testosterone
Unlike progesterone, medroxyprogesterone:
 DOES NOT protect against glutamate-induced
Medroxyprogesteron neuronal toxicity (Nilsen et al., 2006, Gynecol
e (MPA) 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
LEAD ‘10 Brinton, 2003, PNAS; Brinton, 2009)

64. Undoing the ‘Scientific’ Damage
Natural Forms of Sex
Steroids
Progesterone Testosterone 17β-estradiol
Synthetic/Animal Forms of
Medroxyprogesteron Sex Steroids
e (MPA)
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65. Undoing the ‘Scientific’ Damage
Natural Forms of Sex
Steroids
Progesterone Testosterone 17β-estradiol
Synthetic/Animal Forms of
Medroxyprogesteron Sex Steroids
e (MPA) Estrone sulfate
Major estrogen
from horse urine
found in
Premarin
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66. Undoing the ‘Scientific’ Damage
Natural Forms of Sex
Steroids
Progesterone Testosterone 17β-estradiol
CEE – different signaling pathways?
Estrone sulfate
 major CEE = estrone sulfate
 contain ~ 15 different estrogens Major estrogen
 excretory products from horse urine
 decreased ER binding found in
 conjugation - hormonal inactivation to limit Premarin
signaling (sulfation or glucuronidation)
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67. Undoing the ‘Scientific’ Damage
The Bottom Line
We need to be supplementing
our body with sex steroids that
are physiologically relevant!
For Women: 17β-estradiol and
progesterone
For Men: testosterone and
progesterone
No study has ever shown a
negative cognitive outcome
from the use of human sex
steroids.
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Predominantly a US problem

68. Small Changes Can Lead to Big
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
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69. 2. Cancer Risk for Hormone Replacement
Therapies (HRT)
 There is an indisputable increase in the risk of breast, uterine
and ovarian cancer with CEE and estradiol supplementation
CEE Estradiol
Cancer Usage Incidence Cancer Usage Incidence
(years) (/1000) (years) (/1000)
Breast >10 3-6 Breast >10 1-13
Ovarian >10 3-11 Ovarian >10 1-3
Uterine >10 7-15 Uterine >10 1-5
Total ~23/1000 Total ~12/1000
~1-2 women per 100 will develop a reproductive cancer
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70. Cancer Risk for Hormone Replacement
Therapies (HRT)
 But estradiol replacement therapy decreases
the risk of other diseases: heart disease, AD,
stroke, osteoporosis, diabetes mellitus II, etc
 Does the risk of cancer or other diseases
from HRT outweigh the risk from developing
other diseases of aging?
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71. 2. Cancer Risk for Hormone Replacement
Therapies (HRT)
 But HRT decreases the risk of nearly every
other disease: heart disease, AD, stroke,
osteoporosis, diabetes mellitus II, etc
 Does the risk of cancer or other diseases
from HRT outweigh the risk from developing
other diseases of aging?
NO
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72. Humans: Estrogen Replacement
Therapy Decreases Mortality
Consistently show a 20-50% decrease in mortality among
estrogen (CEE) users
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73. Higher Age at Menopause Increases
Female Post-Reproductive Lifespan
9 studies demonstrate advanced age at menopause - ↑ longevity
Ossewaarde et al., (2005)
Age at menopause (years)
Advanced age at last reproduction is associated with improved
longevity
~ 2.4% reduced mortality per year increase in age at menarche
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74. Cancer Risk for Hormone
Replacement Therapies (HRT)
 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 unimportant in the face of memory loss.
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75. Cancer Risk for Hormone
Replacement Therapies (HRT)
 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 unimportant in the face of memory loss.
 Example 2: I am 65 years of age and have cognitive decline.
May consider risk of cancer unimportant in the face of memory
loss.
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76. Cancer Risk for Hormone
Replacement Therapies (HRT)
 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 unimportant in the face of memory loss.
 Example 2: I am 65 years of age and have cognitive decline.
May consider risk of cancer unimportant in the face of memory
loss.
 Example 3: I am 70 years of age without cognitive loss, but a
family history of cancer. May consider risk of cancer
outweighs risks of memory loss.
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77. Cancer Risk for Hormone
Replacement Therapies (HRT)
 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 unimportant in the face of memory loss.
 Example 2: I am 65 years of age and have cognitive decline.
May consider risk of cancer unimportant in the face of memory
loss.
 Example 3: I am 70 years of age without cognitive loss, but a
family history of cancer. May consider risk of cancer
outweighs risks of memory loss.
 Example 4: I am 70 years of age and have cognitive decline.
I also have a family history of cancer.
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78. Summary: Sex Hormones and Age-
related Disease Risk
Maintaining sex steroid levels reduces the risk of:
Alzheimer’s disease
Stroke*
Coronary heart disease*
Osteoporosis
Obesity, metabolic syndrome/diabetes mellitis II*
Depression and anxiety
Menopausal symptoms
Maintaining sex steroid levels increase the risk of:
Cancer
Quality of life Partial hormone
replacement therapy
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Living longer!

79. Female Hormone Replacement Therapy:
What Should I Take?
• Women
– 17β -estradiol (USP) - patch (Climara or Vivelle)
– progesterone (USP) - Pro Gest (cream) – preferable; Prometrium (pill) –
first pass changes in liver
• Dose
– 17β -estradiol (USP) - 0.025 mg/day
– progesterone (USP) - 30 mg/day
• Route?
– Varies for hormone
• Opposed or unopposed?
– 17β -estradiol + progesterone
– decreased uterine cancer
• Timing, duration and cyclicity?
– during menopause – for relief of menopausal symptom
– post-menopause: window – 5 years versus forever
– continuous progesterone to avoid breakthrough bleeding
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80. Male Hormone Replacement Therapy:
What Should I Take?
• Men
– testosterone (USP) - gel or underarm topical
– progesterone (USP) - Pro Gest (cream) – preferable; Prometrium
(pill) – first pass changes in liver
• Dose
– testosterone (USP) – 10 mg/day
– progesterone (USP) - 30 mg/day
• Route?
– Transdermal to avoid oral first pass effects through liver
• Opposed or unopposed
– testosterone + progesterone?
• Timing, duration and cyclicity
– Starting at andropause (30-50 years)
– Starting when hypogonadal (i.e. low serum T) and phenotypic
changes menopause – for relief of menopausal symptom
– Continuous?
LEAD ‘10

81. Life Extension Strategies Through
Hormone Supplementation or
Suppression
3. Replacing gonadal cells
 Ovarian and testicular implants?
 Would provide complete hormone replacement
 Would eliminate the negative consequences resulting from partial
hormone replacement???
 Ovary replacement shown to increase longevity
 Human embryonic stem cell technologies
 Not currently a possibility for humans
 20-40 years
LEAD ‘10

82. Healthy Lifespan Extension Following
Ovary Transplantation
40% increase in life
expectancy
Rebalancing the HPG Axis Increases Longevity
LEAD ‘10 Cargill et al., (2003)

83. Restoration of the HPG Axis Extends
Lifespan and Healthspan
Increasing Increase stable Delay
function function decreasing
function
Increasing
Cognitive function Mild Lifespan and
Function
Vascular function Healthspan
Immune function Moderate
Bone function
Reproductive function
Severe
Athletic function
0 50 100 150
Lifespan in Years
LEAD ‘10

84. Laboratory of Endocrinology,
Aging and Disease (LEAD)
Post-doctoral Students
• Giuseppe Verdile, Ph.D. Research Staff
• Glenda M. Bishop, Ph.D. • Hong Zeng, M.S.
• Sivan Vadakkadath Meethal, Ph.D. • Zvezdana Kubats, M.S.,
• Prashob Porayette, M.B.B.S., M.S. • Patrick F. Lyon, M.S.
• John Wung, B.S.
Graduate Students • Sandra L. Siedlak, M.S.
• Tianbing Liu, M.Sc. • Ryan Haasl, M.Sc.
• Hsien Chan, B.Sc. • Jon Sweeney, B.S.
• Andrea C. Wilson, B.S. • Derek Simon
• Miguel Gallego, B.S. • Jacob Basson, B.S.
• Kentaro Hayashi, M.Sc.
Duke University, Raleigh, NC
Richard L. Bowen, M.D.
LEAD ‘10

85. Life and Death is About Balance:
Hormonal Balance!
Live Longer Foundation, Inc.
www.livelongerfoundation.org
LEAD ‘10