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DHEA, Pregnenolone & Melatonin Replacement Therapy --John Crisler DO Lansing, MI USA MSU-COM 1 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… 2 3 DHEA “The Mother of all sex hormones” 4 DHEA decline in aging: “Adrenopause” • Produced in adrenal cortex and brain • Most abundant steroid hormone • Precursor to androgens and estrogens 5 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 7 DHEA and Immune Stimulation 8 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. 9 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. 10 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 11 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 12 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. 13 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 14 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 15 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 16 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 17 DHEA and Adrenal Function 18 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 20 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 21 DHEA and Brain Memory Mood Depression 22 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 23 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 24 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 25 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 26 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 28 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 29 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 30 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. 31 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. 32 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. 33 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. 34 SUMMARY 35 • 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 36 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 37 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 38 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 39 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 40 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 41 DHEA Administration 42 Cholesterol Pregnenolone Progesterone DHEA Dehydroepiandrosterone Androstenedione Estrone Testosterone Dihydrotestosterone Estradiol 43 Dr. Rothenberg’s DHEA Algorithm 44 7-keto DHEA 45 46 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 47 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 48 • 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. 49 50 51 52 Pregnenolone “Grandmother of All Steroids” 53 54 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 55 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. 56 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. 57 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 58 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 59 • 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 60 • 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 61 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) 62 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 63 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 64 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 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 65 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 66 67 Melatonin “The Pineal Gland is the seat of the soul.” --Rene Descartes (1596-1650) 68 Tryptophan Serotonin Brzezinski A. Mechanisms of Disease: Melatonin in Humans The New England Journal of Medicine -January 16, 1997 -- Vol. 336, No. 3 69 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 70 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. 71 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. 72 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 73 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 74 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 75 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 76 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 77 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 78 Cochrane Database Syst Rev 2001;1:CD001520 79 80