Download PathoLOGIC Hgh Deficiency and Somatopause

DHEA, Pregnenolone &
Melatonin
Replacement Therapy
--John Crisler DO
Lansing, MI USA
MSU-COM
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IN APPRECIATION
I want to thank Dr. Ronald Rothenberg—a
true doctor’s doctor, and, in my
professional opinion, the finest Anti-Aging
Medicine physician in America—for
providing most of the material for this
lecture. We all owe Dr. Rothenberg our
respect, appreciation and gratitude for his
years of relentless service to our industry
and our craft. I have learned more from
him than any other doctor I have studied
under. My friend, my mentor, my goal…
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DHEA
“The Mother of all sex hormones”
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DHEA decline in aging: “Adrenopause”
• Produced in adrenal cortex and
brain
• Most abundant steroid hormone
• Precursor to androgens and
estrogens
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Gonadal and Adrenal Steroid Biosynthesis
Cholesterol
Pregnenolone
Progesterone
DHEA
Dehydroepiandrosterone
Androstenedione
Estrone
Testosterone
Dihydrotestosterone
Estradiol
LOW LEVELS ASSOCIATED WITH:
– Obesity, Type 2 diabetes
– Immune dysfunction
– Autoimmune disease
– Cancer
– Hypertension
– Cardiovascular disease
– Depression, loss of well-being
– Low libido, Erectile dysfunction
– Osteoporosis
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DHEA
and
Immune Stimulation
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DHEA and Inflammation
• DHEA can lower the levels of
interleukin-6 (IL-6) and tumor
necrosis factor alpha (TNF-alpha)
• DHEA administration decreases
pro-inflammatory cytokines
Leowattana W DHEA(S): the fountain of
youth. J Med Assoc Thai 2001 Oct;84 Suppl
2:S605-12
Du C J Administration of
dehydroepiandrosterone suppresses
experimental allergic encephalomyelitis in
SJL/J mice.
Immunol. 2001 Dec 15;167(12):7094-101.
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Dehydroepiandrosterone-sulfate
inhibits nuclear factor-kappaBdependent transcription in hepatocytes,
possibly through antioxidant effect.
Iwasaki Y et al. J Clin Endocrinol Metab.
2004 Jul;89(7):3449-54.
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DHEA and Inflammation
• DHEA is a potent inhibitor of IL-6
• DHEA (DHEA-S) was significantly
lower in patients with chronic
inflammatory diseases
• Lack of DHEA leads to a
significant sex hormone
deficiency in the periphery
Straub RH et al. Replacement therapy with DHEA
plus corticosteroids in patients with chronic
inflammatory diseases--substitutes of adrenal
and sex hormones.
Z Rheumatol 2000;59 Suppl 2:II/108-18
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DHEA and Immune Function
• DHEA counteracts Glucocorticoid (GC)
effects on monocytes
• Increased T cell production
Canning MO et al. Opposing effects of
Dehydroepiandrosterone and
dexamethasone on the generation of
monocyte-derived dendritic cells. Eur J
Endocrinol 2000 Nov;143(5):687-95
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DHEA lowers TNF alpha
• Improves Glucose tolerance
• Improves lipids
• Complimentary with exercise
Yang SC et al. Interactive effect of an acute
bout of resistance exercise and
dehydroepiandrosterone administration on
glucose tolerance and serum lipids in
middle-aged women.
Chin J Physiol. 2005 Mar 31;48(1):23-9.
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DHEA in Inflammatory Arthritis
• Low DHEAS in Inflammatory Arthritis
• Especially in women
• DHEA for treatment?
Dessein PH et al. Hyposecretion of the
adrenal androgen dehydroepiandrosterone
sulfate and its relation to clinical variables
in inflammatory arthritis. Arthritis Res
2001;3(3):183-8
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DHEA and Lupus
• Statistically significant
improvements were found in all
lupus outcomes over 6 months.
• Optimal serum level of DHEAS was
1000 microg/dl.
Barry NN, McGuire JL, van Vollenhoven RF.
Dehydroepiandrosterone in systemic lupus
erythematosus: relationship between
dosage, serum levels, and clinical response.
J Rheumatol 1998 Dec;25(12):2352-6
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DHEA, Stress, Immune Function
• Immunosenescence may be closely
related to both psychological distress
and stress hormones
• Neuroendocrine hypothesis of
immunosenescence
• Age-related increase in the
cortisol/DHEA ratio is major
determinant of immunological
changes observed during ageing.
Bauer ME et al. Stress, Glucocorticoids and ageing
of the immune system.
Stress. 2005 Mar;8(1):69-83
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SUMMARY
• DHEA inhibits IL-6 and chronic
inflammation
• DHEA may be necessary for immune
response
• Autoimmune diseases may benefit from
DHEA RT
• Since aging is a state of cortisol excess,
patients with adrenopause should have
DHEA RT to balance Cortisol
• Patients in corticosteroids should have
DHEA RT
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DHEA and
Adrenal Function
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Aging Adrenal Cortex
• Increased GC secretion, decreased DHEA
• Cortisol excess leads to cognitive
impairment due to damage to neurons in
the hippocampus
• DHEAS alters liver fatty acid metabolism
and may be protective against cancer
• Aging produces cortisol/DHEA excess
Yen SS. Aging and the adrenal cortex.
Exp Gerontol 1998 Nov-Dec;33(7-8):89719
910
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USE DHEA with Glucocorticoids
• ACTH stimulates release of Cortisol and
DHEA from the adrenal cortex
• Catabolic effects of Glucocorticoids (GC)
are counteracted by anabolic effects of
DHEA
• DHEA ameliorates some deleterious
effects of GC, such as diabetes, amino
acid deamination, fattiness,
hypertension and susceptibility to
viraemia.
• Decreased DHEA in aging, Rheumatoid
Arthritis and Lupus
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DHEA and Brain
Memory
Mood
Depression
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DHEA Protects Hippocampal Neurons
• Protects hippocampal neurons from
•
•
oxidative damage in vitro neurons from
Alzheimer's Disease
Hippocampal damage is a cause of age
associated memory impairment
Neuoprotection from DHEA?
Bastianetto S Dehydroepiandrosterone
(DHEA) protects hippocampal cells from
oxidative stress-induced damage.
Brain Res Mol Brain Res 1999 Mar 20;66(12):35-41
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Wolkowitz et al, UCSF, AJ PSY 4/99
DHEA/Depression
•
•
•
•
•
22 Men & Women, Major depression
Dose up to 90 mg/day
Hamilton depression rating scale
6 weeks
Double blind / Placebo controlled
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Wolkowitz et al, UCSF, AJY, 4/99
DHEA/Depression
Results
• 50% or greater reduction in
symptoms occurred in 5/11 (45%)
with DHEA, 0/11 with placebo
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DHEA and Well-Being in Women
• Double blind, placebo, crossover study
• 50 mg/day
• Significantly improved
–Wellbeing
–Depression
–Anxiety
–Sexual interest, sexual satisfaction
Arlt W et al. DHEA replacement in women with adrenal
insufficiency--pharmacokinetics, bioconversion and
clinical effects on well-being, sexuality and cognition.
Endocr Res 2000 Nov;26(4):505-11
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SUMMARY
• DHEA is a neurosteroid
• May protect the brain against
neurodegeneration
• No proven improvement on memory in
humans
Makes old mice as smart as young mice
• Mood enhancement, increased well being
and anti-depressant effect usually found
• Increased libido in women
• Improves menopausal Sx in women
• Glucocorticoid balancing could improve
memory and neurodegeneration over time27
DHEA and
Cardiovascular Dz
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Low DHEA-S Predicts Ischemic Heart Dz
• Prospective study 1700 men 40-70 years old
• Lowest quartile of DHEA and DHEAS had most
•
•
ischemic heart disease
Independent of other risk factors
Is DHEA protective against IHD?
Feldman HA et al. Low DHEAe and ischemic heart
disease in middle-aged men: prospective results
from the Massachusetts Male Aging Study. Am J
Epidemiol 2001 Jan 1;153(1):79-89
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DHEA and Ischemic Heart disease
• Is DHEA protective against IHD?
• Lowest quartile DHEA and DHEAS– highest
IHD
• “Independent of a comprehensive set of
known risk factors including age, obesity,
diabetes, hypertension, smoking, serum
lipids, alcohol intake, and physical
activity”
Feldman HA et al. Low DHEA and ischemic
heart disease in middle-aged men:
prospective results from the Massachusetts
Male Aging Study. Am J Epidemiol 2001 Jan
1;153(1):79-89
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DHEA-S and CV Disease
DHEAS concentration is
independently and inversely
related to death from any cause
and death from cardiovascular
disease in men over age 50.
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Dehydroepiandrosterone reduces
plasma plasminogen activator
inhibitor type 1 and tissue
plasminogen activator antigen in
men.
Beer NA, Jakubowicz DJ, Matt DW, Beer
RM, Nestler JE.
Am J Med Sci. 1996 May;311(5):205-10.
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Dehydroepiandrosterone increases
endothelial cell proliferation in vitro
and improves endothelial function in
vivo by mechanisms independent of
androgen and estrogen receptors.
Williams MR, Dawood T, Ling S, Dai A, Lew R, Myles K,
Funder JW, Sudhir K, Komesaroff PA.
J Clin Endocrinol Metab. 2004 Sep;89(9):4708-15.
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Dehydroepiandrosterone
supplementation improves
endothelial function and insulin
sensitivity in men.
Kawano H, Yasue H, Kitagawa A, Hirai N,
Yoshida T, Soejima H, Miyamoto S, Nakano M,
Ogawa H.
J Clin Endocrinol Metab. 2003 Jul;88(7):3190-5.
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SUMMARY
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• Double blind, placebo, 50 mg x 4 months
• Increased DHEA, DHEAS, T, A to normal
range
• SHBG, Total Cholesterol, HDL decreased
• Improved overall well-being ,depression
and anxiety. (P=0.02).
• Increased the frequency of sexual thoughts
(P=0.006), sexual interest (P=0.002), and
satisfaction with both mental and physical
aspects of sexuality (P=0.009 and P=0.02,
respectively).
Wiebke Arlt, Dehydroepiandrosterone Replacement in
Women with Adrenal Insufficiency The New England
Journal of Medicine -- September 30, 1999 -- Vol.
341, No. 14
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DHEA 50 mg QD in Older Men and Women
•
•
•
•
“Young” levels of DHEAS
No “harmful” levels of DHEAS adverse effects
Increase in T and E2 in women but not men
Improved libido, bone turnover, skin in women but
not men
Baulieu EE et al. Dehydroepiandrosterone
(DHEA), DHEA sulfate, and aging: contribution
of the DHEAge Study to a sociobiomedical
issue. Proc Natl Acad Sci U S A 2000 Apr
11;97(8):4279-84
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NEJM Editorial - DHEA
• Benefits:
•
– Bone
– Vaginal Lubrication
– Mood and well-being
– Depression
– Counteracts Glucocorticoids
• Protects against catabolism, bone loss
– Lupus
But don’t use it ?????????
Wolfgang Oelkers, M.D. Dehydroepiandrosterone for
Adrenal Insufficiency The New England Journal of
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Medicine -- September 30, 1999 -- Vol. 341, No. 14
Summary
• DHEA may be necessary for immune
response
• Patients on corticosteroids should have
DHEA RT
• Autoimmune diseases may benefit from
DHEA RT
• Since aging is a state of cortisol excess,
patients with adrenopause should have
DHEA RT to balance Cortisol
• DHEA inhibits IL-6 and chronic inflammation
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Summary
• Raises T and Free T in women
• Usually No change in T men
• Increases libido in women
• May or may not improve body composition
in women
• Improves body composition in men
• Conflicting data on strength in men
• Reverses osteoporosis
• Raises IGF-1
• No significant adverse effects
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DHEA: Anti-aging steroid
Based on both in vitro and in vivo
• Stimulatory effect of immune
system
• Anti-diabetes mellitus
• Anti-atherosclerosis
• Anti-dementia (neurosteroid)
• Anti-obesity
• Anti-osteoporosis
Nawata Het al. Mechanism of action of anti-aging
DHEA-S and the replacement of DHEA-S.
Mech Ageing Dev 2002 Apr 30;123(8):1101-6
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DHEA
Administration
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Cholesterol
Pregnenolone
Progesterone
DHEA
Dehydroepiandrosterone
Androstenedione
Estrone
Testosterone
Dihydrotestosterone
Estradiol
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Dr. Rothenberg’s DHEA Algorithm
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7-keto DHEA
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7-keto DHEA
• 3-acetyl-7-oxo-dehydroepiandrosterone
• Does not biotransform to andogenic and
estrogenic metabolites
• Associated with thermogenesis and weight
loss
Hanpl et al. Steroids and
thermogenesis. Physiol Res. 2005 May 24
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7-Keto DHEA
• Decline contributes to fat gain
• Weight loss without side effects (Kalman)
• Improves Immune function
• Improves lipids
• Improves memory in rats
• Dose: 50-100 mg in AM
• Can use alone or combine with DHEA
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• Davidson M, Marwah A, Sawchuk RJ, et al. Safety
•
•
and pharmacokinetic study with escalating doses
of 3-acetyl-7-oxo-dehydroepiandrosterone in
healthy male volunteers. Clin Invest Med. 2000
Oct;23(5):300-10.
Zenk JL, Kuskowski MA. The use of 3-acetyl-7oxo-dehydroepiandrosterone for augmenting
immune response in the elderly. Presented at
meeting of FASEB, April 17, 2004.
Kalman DS, Colker CM, Swain MA, Torina GC, Shi
Q. A randomized, double-blind, placebo-controlled
study of 3-acetyl-7-oxo-dehydroepiandrosterone
in healthy overweight adults. Curr Therap Res.
2000;61(7):435-42.
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Pregnenolone
“Grandmother of All Steroids”
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PREGNENOLONE
• Precursor to DHEA
• Produced in adrenals and brain
• Can raise levels of steroids, lower them
or they can remain same
• Neurosteroid for peak brain function
– found in highest concentrations in the brain
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PREGNENOLONE
• Initiates the memory storage process by
•
•
stimulating neuronal adenylate cyclase
Regulates the timed-sequential flow of
calcium ions through the cell membrane.
Calcium ion exchange may determine
how memory is encoded by neurons.
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PREGNENOLONE
• Modulates calcium-protein bindings,
gene activation, protein turnover, and
the intra-cellular distribution of
compounds and enzyme reactions
involved in the storage and retrieval of
memory.
• As stores of pregnenolone (and DHEA)
are depleted with advancing age there
is a marked and often dramatic decline
in the neuronal synchronization required
for optimal mental function.
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Pregnenolone
• Levels decrease with age
• Serum levels
– Men 10-230 ng/dl
– Women 50-350 ng/dl
• Serum levels thought not to be very
useful or reliable
• No adverse effects reported
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Used for arthritis in the 1940’s
• Less pain
• Greater energy
• Improved strength and mobility
• Also used for osteoarthritis,
scleroderma and psoriasis
• Lost favor with the introduction
of cortisone
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• Pregnenolone is necessary for hippocampal
function in older rats.
• Memory restored by replacement.
Vallee M Neurosteroids: deficient cognitive
performance in aged rats depends on low
pregnenolone sulfate levels in the hippocampus
Proc Natl Acad Sci U S A 1997 Dec 23;94(26):14865-70
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• There is accumulating evidence that some
neurosteroids, in particular pregnenolone
sulfate, have strong influences on learning
and memory processes, most likely by
regulating neurotransmission in the
hippocampus
Schumacher M Neurosteroids in the
Hippocampus: Neuronal Plasticity
and Memory Stress 1997 Oct;2(1):65-78
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Pregnenolone and Memory
• Cerebral Preg-S correlated to cognitive
•
•
•
performance
Improved with Preg-S
Preg-S increases Acetylcholine in amygdala,
cortex and hippocampus
Preg-S increases neurogenesis in hippocampus
Mayo M et al. Pregnenolone Sulfate and Aging
of Cognitive Functions: Behavioral,
Neurochemical and Morphological Investigations.
Hormones and Behavior 40, 215-217 (2001)
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Neuroactive Steroid Levels in Patients
with Generalized Anxiety Disorder
• Patients with Generalized Anxiety Disorder
– Lower Preg-S
– Lower AlloPreg (not significant)
– No difference in DHEAS
• Preg-S is GABA A (benzodiazepine) receptor
Agonist in low doses
Semeniuk, T et al. The Journal of
Neuropsychiatry and Clinical Neurosciences
2001; 13:396-398
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Neurosteroids and ADHD
 Inverse
correlation between
clinical symptoms and levels of
DHEA and Pregnenolone in
young male subjects aged 7-15
years with DSM-IV criteria of
ADHD.
Strous RD et al. Analysis of neurosteroid
levels in attention deficit hyperactivity
disorder. Int J Neuropsychopharmacol
2001 Sep;4(3):259-64
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Low levels of Pregnenolone in
Social Phobia and Depression
• Mayo W, Le Moal M, Abrous DN. Pregnenolone
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•
sulfate and aging of cognitive functions:
Behavioral, neurochemical, and morphological
investigations. Horm Behav. 2001 Sep;40(2):2157.
13. George M, Guidotti A, Rubinow D, Pan B,
Mikalauskas K, Post R. CSF neuroactive steroids in
affective disorders: pregnenolone, progesterone
and DBI. Biolog Psychiatry. 1994 May
15;35(10):775-80.
14. Heydari B, Le Melledo JM. Low preg- nenolone
sulfate plasma concentrations in patients with
generalized social phobia. Psychol Med. 2002
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Jul2;32(5):929-33.
Pregnenolone
• Dose
– 50-200 mg in men and women
• Consider other cognitive
enhancement neutraceuticals as well
– Acetyl-L-Carnitine
– Phosphatidyl serine/choline
– Vinpocetine
– Deprenyl=Eldepryl=Seligiline
– Hydergine=Ergyloid Mesylate
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Melatonin
“The Pineal Gland is the seat of the soul.”
--Rene Descartes (1596-1650)
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Tryptophan
Serotonin
Brzezinski A. Mechanisms
of Disease: Melatonin in
Humans The New England
Journal of Medicine -January 16, 1997 -- Vol.
336, No. 3
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Melatonin -
N-acetyl-5-methoxytryptamine
• Secreted by pineal gland
• Produced in darkness, suppressed by
light
• Levels decline with aging - 10-15%
per decade
– All studies but one show this
• Manages circadian rhythm of inner
clock
– Lowers body temperature
– Controls sleep wake cycle
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The Ultimate Anti-oxidant?
• Protects lipids, proteins, DNA
• Stimulates glutathione
• Protects mitochondria
• Protects against ischemia-reperfusion
injury
• Protects against ionizing radiation
Reiter RJ et al. Pharmacological utility of melatonin
in reducing oxidative cellular and molecular
damage. Pol J Pharmacol. 2004 Mar-Apr;56(2):159-70.
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MELATONIN
• Free Radical Scavenger
• Decreases pro-inflammatory
cytokines
• Decreases damage from beta
amyloid
Rosales-Corral S et al. Orally administered
melatonin reduces oxidative stress and
proinflammatory cytokines induced by amyloidbeta peptide in rat brain: a comparative, in vivo
study versus vitamin C and E.
J Pineal Res. 2003 Sep;35(2):80-4.
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Enhances Immune Function
• Inhibits tumor growth
• Counteracts stress induced
immunodepression
• Increases in CD4 cells, natural killer cells
• Activates cytokine system when needed
• Decreases pro-inflammatory cytokines
• Increases immune function in winter when
there are more environmental stressors
Nelson RJ Melatonin mediates seasonal changes in
immune function Ann N Y Acad Sci 2000;917:404
Kriegsfeld LJ In vitro melatonin treatment enhances
cell-mediated immune function in male prairie
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voles J Pineal Res 2001 May;30(4):193-8
CANCER
• Inhibits tumor growth in humans
– Anti-mitotic activity
– Down regulate activity of receptors
• Decreased Estrogen binding to cells in breast ca
– Enhanced Immune Response
– Free Radial scavenging
– Anti-angiogenesis
• Improved outcome in glioblastoma,
malignant melanoma, breast cancer
– Used along with chemo, radiation
– Large doses used 20-700 mg /day
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Melatonin and Bone
• Reverses osteoporosis
• Improves deep sleep and GH
release
Cardinali DP et al. Melatonin effects
on Bone: experimental facts and
clinical perspectives.
J Pineal Res 2003 Mar;34(2):81-7
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Melatonin Replacement Therapy
• No serious adverse effects (NEJM Review)
– Usually produces drowsiness and decreased
sleep latency and increased total sleep
– Occasional paradoxical stimulation
– Can produce vivid dreams which are interesting
to some and distressing to others
– Can produce “hangover”
• This effect usually resolves after a few days
– Some people “just don’t feel good”
– Others: well rested, bright eyed and bushy
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tailed
Melatonin Dose - 1/2 hr before sleep
• Try small dose 0.5 mg at first
• If no unpleasant reaction can increase dose
in increments to 3-10 mg
• Time release for people who wake up in
middle of night
• Sublingual lozenge or drops for people who
have trouble falling asleep
• Some tolerance develops but usually levels
off at 3-10 mg
• For some people, less in more and better
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sleep at low dose 0.3 mg
JET LAG
• Improves recovery and prevents jet
lag
• Take 3-6 mg on airplane at the time
of bedtime of your destination
• Expose yourself to bright light in
AM’s upon arrival
• Take 3-6 mg at bedtime at
destination
Takahashi T Effect of 3 mg melatonin on jet lag syndrome in
an 8-h eastward flight. Psychiatry Clin Neurosci 2000
Jun;54(3):377-8
Herxheimer A Melatonin for preventing and treating jet lag
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Cochrane Database Syst Rev 2001;1:CD001520
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