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Age-RelatedEndocrine Changes
and the Role ofSupplementation
with GH, DHEA, andMelatonin
National Center for Complementary and
Alternative Medicine, NIH, DHHS
Marc. R. Blackman, M.D.
Director, Division of IntramuralResearch
Dietary Supplement Use in theElderly, 1/14/2003
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Dietary Supplements:
DSHEA Definition
Product intended to supplement the diet
Contains one or more of the following:
A vitamin
A mineral An herb or other botanical (not tobacco)
An amino acid
Any other dietary substance For oral intake as a concentrate, metabolite,
extract, constituent, or combination
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0
10
20
30
40
50
60
70
80
90
100
110
0 10 20 30 4050
60 70 80 90 100 110 120 130 140
Projected Future?
Present USA1600's
50,000 BC?
Age (Years)
PercentSurvival
Rectangularization vs Extension
of the Human Survival Curve
Maximum lifespan potential
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To What Extent are the Observed Changes
in Body Composition and Function with Aging
Due to Decreases in GH and IGF-I?
Somatopause?
Courtesy of Michael Thorner, MD
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24 Hour GH Secretory Profiles: Means (+ SDs) at 20 min
Intervals in 9 Young and 11 Healthy Old Men
8:00 am 12:00 pm 4:00 pm 8:00 pm 12:00 am 4:00 am 8:00 am
Time
0
5
10
15
GrowthHormon
e(ng/ml)
Young
0
5
10
15
Old
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0 20 40 60 80 100 120
0
5
10
15
20
Young
Old
Age-Related Blunting of Serum GH in Response to a
Single Bout of Resistive Exercise in Healthy Men
Exercise Recovery
Time (min)
S
erumG
H(n
g/ml)
*
**
* *
* *
*
( Marcel l , et a l ., 1999 )
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Serum IGF-I Levels vs. Age in
Healthy Women and Men in the BLSA
0
100
200
300
400
500
IGF-I(ng/ml)
20 40 60 80 100
r = 0.639 p < 0.001
Women
20 40 60 80 100
r = 0.546 p < 0.0001
Men
Age (years)
(n=131) (n=258)
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Linear Segment Plots by Decade; Longitudinal Effects
of Aging on Date-adjusted T and Free T Index.
30 40 50 60 70 80 9010
12
14
16
18
20
Age (years)
TotalTestosteron
e(nMol/L)
FreeTIndexn
Mol/nMol
(144) (151)
(158)
A
(109)
(43)
(177)
(144)(151)
(158)
(109)
(43)
(177) B
30 40 50 60 70 80 90
0.6
0.5
0.4
0.3
0.2
Age (years)
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Percentage of Group Hypogonadal by Decade Using
Total vs Free T Index Criteria (n in group above bars)
18 201 279
332
350
251
94
0
20
40
60
80
100
Percentage
20-29 30-39 40-49 50-59 60-69 70-79 80+
Age Decade
Free T Index
Testosterone
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Similarities of Changes in Body Composition,
Muscle Strength, Aerobic Capacity and Metabolic Variables
with Aging and in Hormone Deficiency/Excess States
Aging Low GHLow T or
DHEA Low E2
Lean Body Mass
Muscle Strength
Aerobic Capacity
Percent Body Fat
Total and LDLCholesterol
Insulin sensitivityGlucose tolerance
High
Cortisol
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-20
-15
-10
-5
0
5
10
Percen
tChange
GH Treated
Placebo
Weight LBM FatMass SkinThicknessTrochanter FemoralNeck LumbarSpine DistalRadius
0
200
400
600
800
1000
PlasmaIGF-I(U/L)
2 4 6 8Month
Treated
Placebo
Effects of hGH Treatment on Body Composition, Skin
Thickness and BMD in Men >60 Years of Age
Rudman, et al, 1990
*
**
*
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The plural of anecdoteThe plural of anecdote
is not evidenceis not evidence
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Study Design - Subjects and Interventions
Subjects: Healthy women (n=53) and men (n=72), ages 65-88 y(mean, 72 y) with baseline age-related reductions in serum IGF-I(
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Hormone Levels in Men and Women Before and During Treatment
0
100
200
300
400
IGF-I(g/L)
Women
PlaceboHRT
GHGH+HRT
0
100
200
300
400
Men
PlaceboT
GHGH+T
0
5
10
15
20
25
30
Testosterone
(nM/L)
-4 0 4 8 12 16 20 24 280
100
200
300
400
500
Estradiol(pM/L)
-4 0 4 8 12 16 20 24 28
Weeks
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Effects of Hormone Administration on Lean Body Mass
(DEXA) in Healthy Elderly Women and Men
GROUP
0.09
0.0010.0002
0
2
4
6
8
10
12
PercentChange
Placebo HRT GH GH+HRT
Women
0.059
0.0001
0.0001
0
2
4
6
8
10
12
Placebo T GH GH+T
Men
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Effects of Hormone Administration on Total Body Strength
in Healthy Elderly Women and Men
GROUP
0.86
0.28
0.053
-4
-2
0
2
4
6
8
10
Placebo T GH GH+T
Men
0.09
0.29
0.14
-4
-2
0
2
4
6
8
10
PercentChange
Placebo HRT GH GH+HRT
Women
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Effects of Hormones on Maximum Aerobic Capacity
(ml O2/min/kg BW) in Healthy Elderly Women and Men
GROUP
0.49
0.11
0.0001
-10
-5
0
5
10
15
Placebo T GH GH+T
Men
1.000
0.073 0.058
-10
-5
0
5
10
15
Percent
Change
Placebo HRT GH GH+HRT
Women
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Effects of Hormone Administration on Body Fat
(DEXA) in Healthy Elderly Women and Men
GROUP
0.12
0.0001
0.0001
-25
-20
-15
-10
-5
0
5
Placebo T GH GH+T
Men
0.69
0.001 0.006
-25
-20
-15
-10
-5
0
5
PercentCh
ange
Placebo HRT GH GH+HRT
Women
ff f Ad i i i Ch i S b d
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Effects of Hormone Administration on Change in Subcutaneous and
Visceral Abdominal Fat (MRI) in Healthy Elderly Women and Men
Percent
Change
-20
-15
-10
-5
0
510
SubcutaneousFat
Women Men
-30
-25
-20
-15-10
-5
0
510
Viscera
lFat
Placebo GH HRT GH +HRT
Placebo GH T GH + T
GROUP
0.0010.008
0.046
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Effects of Hormone Administration on Serum Levels of Total
Cholesterol and Triglycerides in Healthy Elderly Women and Men
GROUP
Percent
Change
-20
-15
-10
-5
0
510
SerumCholesterol Women Men
-20
0
20
40
60
80
SerumTrig
lycerides
Placebo GH HRT GH + HR Placebo GH T GH + T
.008 .006 .004
.042.046
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-25
-20
-15
-10-5
0
5
1015
LDLC
holesterol
Effects of Hormone Administration on Serum Levels of LDL
and HDL Cholesterol in Healthy Elderly Women and Men
PercentC
hange
GROUP
Women Men
HDLCho
lesterol
-20
-15
-10
-5
0
5
10
15
20
Placebo GH HRT GH +
HRT
Placebo GH T GH + T
0.0340.0060.001 0.008
0.0380.045
S I
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Summary I
GH (and testosterone) can:
Increase lean body mass
Increase muscle strength
Increase exercise capacity
Decrease body fat
Combination of GH and sex steroids
Effects of GH and testosterone tend to beadditive
Female hormones (HRT) and GH are not
additive
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Potential Risks of Hormone Treatments
Testosterone
Prostate
Hyperplasia (BPH) Cancer
Coronary Heart Disease
Decreased HDL Increased LDL
Polycythemia
Minor Acne Sleep apnea
Growth Hormone Arthritis
Carpal tunnel syndrome Fluid retention
Hypertension
Diabetes
Cancers (?)
Accelerated Aging (?)
Female HRT Mastodynia Vaginal Bleeding
Thrombosis
Cholelithiasis Breast Cancer
Frequency of Adverse Effects During Hormone
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Frequency of Adverse Effects During Hormone
Administration in Healthy Elderly Women
0% 20% 40% 60% 80%
Percent of Group with Adverse Effect
vaginal bleeding
edema
carpal tunnel
breast tenderness
arthralgias
headaches
rash
abdominal painWomen
GH + HRT
HRT
GH
Placebo
*
**
*
*
Fishers exact test vs placebo: * p < 0.05; p < 0.01; p < 0.0001
F f Ad Eff t D i H
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Frequency of Adverse Effects During Hormone
Administration in Healthy Elderly Men
0% 10% 20% 30% 40% 50%
Percent of Group with Adverse Effect
Edema
Carpal tunnel
Rash
Arthralgias
Gynecomastia
Impotence
Transient Diabetes Men
GH + T
T
GH
Placebo
*
Fishers exact test vs placebo: * p < 0.05; p < 0.01
Effects of Hormone Administration on S stolic and
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Effects of Hormone Administration on Systolic and
Diastolic BP Levels in in Healthy Elderly Women and Men
GROUP
PercentChange
-15
-10
-5
0
5
10
Diasto
licBP
Placebo GH HRT GH + HR Placebo GH T GH + T
-15
-10
-5
0
5
10
SysstolicBP
Women Men
a
Effects of Hormone Administration on Serum Glucose and
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-10
0
10
20
30
40
Gluco
se
Women
-40
0
40
80
120
160
200
240
Insu
lin
Placebo GH HRT GH +
HRT
Placebo GH T GH + T
Effects of Hormone Administration on Serum Glucose and
Insulin Levels (GTT120 ) in Healthy Elderly Women and Men
Percent
Change
aa*
Group
Men
c d
Percent of Women and Men by Group with Fasting Glucose Values
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0%
25%
50%
75%
100%
PercentofSubjectsinGroup
Women
GH+HRT
HRT
GH
Placebo
0%
25%
50%
75%
100%
126Fasting Glucose Values (mg/dL)
Men
GH+TE
TE
GH
Placebo
Percent of Women and Men by Group with Fasting Glucose Values
During Treatment Indicating Glucose Intolerance or Diabetes
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What Are the Gaps in Clinical Knowledge?
Are the declines in GH and DHEA with agingadaptive or maladaptive?
Whom to study and treat? Healthy elderly
Frail elderly
Disease Groups - CAD/CHF, Hip Fracture,hip/knee replacement, cancer cachexia, etc.
Patterns of treatment Prevention vs therapy
When to initiate, how long to continue?
Pattern - continuous vs discontinuous
Route - oral vs parenteral agents
Mode of Rx - GH, GHRH, GH secretagogues, DHEA(S)
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Summary and Conclusions Treatment of older adults with GH has
significant adverse effects which need to bebalanced against potential benefits
GH may be a pro-aging hormone (mice)
Down-regulation of oxidative defense enzymes
Increase in oxidative tissue damage
The true risk/benefit ratio and the treatmentregimen to optimize this ratio are unknown
Ad l St id i
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Adrenal Steroidogenesis
Cholesterol
Progesterone
DHEA
Androstenedione
Testosterone Estrone
Pregnenolone
Legal Definition of Androgenic
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Legal Definition of Androgenic
Anabolic Steroids (1990)
Chemical structure like testosterone
Not an estrogen, progestin, orcorticosteroid
Pharmacological activity liketestosterone
Must promote muscle growth
DHEA d A i
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DHEA and Aging
Weak adrenal androgen
DHEA most abundant steroid in humans Levels decrease 80% with aging; may contribute
to many age-related declines
In animal models, DHEA reverses features ofaging
Widely used as dietary supplement
Safety and efficacy not established
Adverse Effects of
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Adverse Effects of
Androgenic Anabolic Steroids
Feedback inhibition of testosterone and sperm function
Acne, male pattern hair distribution
Prostate enlargement
Increases in blood pressure, red blood cells, and clotting
Decreased HDL/LDL, liver and cardiac dysfunction
Virilization (women)
Increased libido, aggressiveness, and appetite
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DHEA: Background
DHEA levels decrease after birth, and increasedramatically during puberty. DHEA is the most
abundant steroid in adults. Non human primates haveless DHEA than do humans and non primates have littleor none.
DHEA-S is conjugated by the liver.
DHEA t1/2 15-30 min, levels 2-4 ng/ml
DHEAS t1/2 7-10 hr, levels 2-6 g/ml
DHEA is converted from -4 to -3 androstenedione
and then to active androgens and estrogens in liver, fat,muscle, prostate, bone, skin, and brain
No definite DHEA receptor has been identified, BUT a
compelling candidate has recently been reported (J BiolChem 277: 21379, 2002)
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DHEA: Background
A weak adrenal androgen that exerts its effects afterconversion to androgen and/or estrogen
Most abundant steroid in humans; receptor not defined
Levels decrease by 80% with aging, and maycontribute to age-related declines in body composition,
endocrine-metabolic, immune, neuropsychological,and cardiovascular functions
Administration to old rats reverses or attenuates many
features of aging Widely used as a dietary supplement for anti-aging and
athletic enhancement purposes, efficacy and safety notestablished
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Melatonin: Background
Melatonin, N-acetyl-5-methoxytryptamine, issynthesized from serotonin in many tissues, primarily
the pineal gland Circulating melatonin is inactivated in the liver, and its
conjugates are excreted by the kidney
The pineal gland is regulated by a circadian rhythm-generating system located in the hypothalamic SCN
Measurement of melatonin in plasma and saliva is ameasure of the biological clock
Capillary GC-MS is gold standard assay
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Melatonin: Background
Numerous prior reports suggest that melatonin isproduced during the dark phase of the day-night cycle
and that there is an age-related diminution in nocturnalmelatonin secretion
The bioavailability of melatonin in humans has not
been well characterized Use of an improved GC-MS assay, and PK studies,
suggest that melatonin secretion occurs at a constantrate rather than in peaks, with onset in the evening untilpineal synthesis ends in the early AM, does notcorrelate with the duration of the dark phase, and doesnot differ by gender or with advanced age
(Fourtillan et al, Am J Physiol 280:E11, 2001)
Biological Research
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Biological Research -
Its All Natural!
People can beinduced toswallowanything,provided it is
sufficientlyseasoned with
praise.Jean Moliere
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Skepticism is the chastity of theSkepticism is the chastity of the
intellect, and it is shameful to surrenderintellect, and it is shameful to surrender
it too soon or to the first comer.it too soon or to the first comer.
G. Santayana (1923)
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National Center for Complementary and Alternative Medicine
National Institutes of HealthDepartment of Health and Human Services
www.nccam.nih.gov
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