DHEA, Pregnenolone & Melatonin Replacement Therapy

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DHEA, Pregnenolone MelatoninReplacement Therapy

• --John
  Crisler DO
• 
  Lansing, MI USA
• 
  MSU-COM

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IN APPRECIATION

• I want to thank Dr. Ronald Rothenberga true
  doctors doctor, and, in my professional opinion,
  the finest Anti-Aging Medicine physician in
  Americafor 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
Progesterone
Estrone
Estradiol
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• 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 Oct84 Suppl 2S605-12
• Du C J Administration of dehydroepiandrosterone
  suppresses experimental allergic
  encephalomyelitis in SJL/J mice.Immunol. 2001
  Dec 15167(12)7094-101.

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Dehydroepiandrosterone-sulfate inhibits
nuclear factor-kappaB-dependent transcription in
hepatocytes, possibly through antioxidant
effect. Iwasaki Y et al. J Clin Endocrinol
Metab. 2004 Jul89(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 200059
  Suppl 2II/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 Nov143(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 3148(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 20013(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
  Dec25(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
  Mar8(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-Dec33(7-8)897-910

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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 MemoryMood 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 2066(1-2)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
  Nov26(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 time

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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 1153(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 1153(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 May311(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 Sep89(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
  Jul88(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. (P0.02).
• Increased the frequency of sexual thoughts
  (P0.006), sexual interest (P0.002), and
  satisfaction with both mental and physical
  aspects of sexuality (P0.009 and P0.02,
  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 1197(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 dont use it ?????????
• Wolfgang Oelkers, M.D. Dehydroepiandrosterone
  for Adrenal Insufficiency The New England Journal
  of Medicine -- September 30, 1999 -- Vol. 341,
  No. 14

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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 30123(8)1101-6

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DHEA Administration
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Progesterone
Estrone
Estradiol
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Dr. Rothenbergs 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
  Oct23(5)300-10.
• Zenk JL, Kuskowski MA. The use of
  3-acetyl-7-oxo-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.
  200061(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 1940s

• 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
  2394(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
  Oct2(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
  13396-398

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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
  Sep4(3)259-64

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• Low levels of Pregnenolone in Social Phobia
  and Depression
• Mayo W, Le Moal M, Abrous DN. Pregnenolone
  sulfate and aging of cognitive functions
  Behavioral, neurochemical, and morphological
  investigations. Horm Behav. 2001 Sep40(2)215-7.
• 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
  1535(10)775-80.
• 14. Heydari B, Le Melledo JM. Low preg- nenolone
  sulfate plasma concentrations in patients with
  generalized social phobia. Psychol Med. 2002
  Jul232(5)929-33.

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Pregnenolone

• Dose
• 50-200 mg in men and women
• Consider other cognitive enhancement
  neutraceuticals as well
• Acetyl-L-Carnitine
• Phosphatidyl serine/choline
• Vinpocetine
• DeprenylEldeprylSeligiline
• HydergineErgyloid 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-Apr56(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 amyloid-beta
  peptide in rat brain a comparative, in vivo
  study versus vitamin C and E.J Pineal Res. 2003
  Sep35(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 2000917404
• Kriegsfeld LJ In vitro melatonin treatment
  enhances cell-mediated immune function in male
  prairie voles J Pineal Res 2001 May30(4)193-8

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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 Mar34(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 dont feel good
• Others well rested, bright eyed and bushy tailed

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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 sleep at
  low dose 0.3 mg

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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 AMs 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 Jun54(3)377-8
• Herxheimer A Melatonin for preventing and
  treating jet lag Cochrane Database Syst Rev
  20011CD001520

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