11

DHEA, Pregnenolone DHEA, Pregnenolone &&MelatoninMelatoninReplacement Replacement TherapyTherapy

--John Crisler DO--John Crisler DO Lansing, MI USALansing, MI USA MSU-COMMSU-COM

22

IN APPRECIATIONIN APPRECIATION I want to thank Dr. Ronald Rothenberg—a I want to thank Dr. Ronald Rothenberg—a

true true doctor’s doctordoctor’s doctor, and, in my , and, in my professional opinion, the finest Anti-Aging professional opinion, the finest Anti-Aging Medicine physician in America—for Medicine physician in America—for providing most of the material for this providing most of the material for this lecture. We all owe Dr. Rothenberg our lecture. We all owe Dr. Rothenberg our respect, appreciation and gratitude for his respect, appreciation and gratitude for his years of relentless service to our industry years of relentless service to our industry and our craft. I have learned more from and our craft. I have learned more from him than any other doctor I have studied him than any other doctor I have studied under. My friend, my mentor, my goal…under. My friend, my mentor, my goal…

33

44

DHEADHEA

““The Mother of all sex hormones”The Mother of all sex hormones”

55

DHEA decline in aging: DHEA decline in aging: “Adrenopause”“Adrenopause”

• Produced in adrenal cortex and Produced in adrenal cortex and brainbrain

• Most abundant steroid Most abundant steroid hormonehormone

• Precursor to androgens and Precursor to androgens and estrogensestrogens

Gonadal and Adrenal Steroid Biosynthesis

Gonadal and Adrenal Steroid BiosynthesisCholesterol

Dihydrotestosterone

Testosterone

Androstenedione

DHEADehydroepiandrosterone

Pregnenolone

Estrone

Estradiol

Progesterone

77

LOW LEVELS ASSOCIATED WITH:LOW LEVELS ASSOCIATED WITH:– Obesity, Type 2 diabetesObesity, Type 2 diabetes– Immune dysfunctionImmune dysfunction– Autoimmune diseaseAutoimmune disease– CancerCancer– HypertensionHypertension– Cardiovascular diseaseCardiovascular disease– Depression, loss of well-beingDepression, loss of well-being– Low libido, Erectile dysfunctionLow libido, Erectile dysfunction– OsteoporosisOsteoporosis

88

DHEA

and

Immune Stimulation

99

DHEA and InflammationDHEA and InflammationDHEA and InflammationDHEA and Inflammation•DHEA can lower the levels of DHEA can lower the levels of

interleukin-6 (IL-6) and tumor interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-necrosis factor alpha (TNF-alpha)alpha)

•DHEA administration decreases DHEA administration decreases pro-inflammatory cytokinespro-inflammatory cytokines

Leowattana WLeowattana W DHEA(S): the fountain of DHEA(S): the fountain of youth.youth. J Med Assoc Thai 2001 Oct;84 Suppl J Med Assoc Thai 2001 Oct;84 Suppl 2:S605-122:S605-12

Du CDu C J J Administration of Administration of dehydroepiandrosterone suppresses dehydroepiandrosterone suppresses experimental allergic encephalomyelitis experimental allergic encephalomyelitis in SJL/J mice.in SJL/J mice.Immunol. 2001 Dec 15;167(12):7094-101. Immunol. 2001 Dec 15;167(12):7094-101.

1010

Dehydroepiandrosterone-sulfate Dehydroepiandrosterone-sulfate inhibits nuclear factor-kappaB-inhibits nuclear factor-kappaB-dependent transcription in dependent transcription in hepatocytes, possibly through hepatocytes, possibly through antioxidant effect.antioxidant effect.

Iwasaki Y et al. Iwasaki Y et al. J Clin Endocrinol J Clin Endocrinol Metab. Metab.

2004 Jul;89(7):3449-54.2004 Jul;89(7):3449-54.

1111

DHEA and InflammationDHEA and Inflammation•DHEA is a potent inhibitor of IL-6DHEA is a potent inhibitor of IL-6 •DHEA (DHEA-S) was significantly DHEA (DHEA-S) was significantly

lower in patients with chronic lower in patients with chronic inflammatory diseasesinflammatory diseases

•Lack of DHEA leads to a significant Lack of DHEA leads to a significant sex hormone deficiency in the sex hormone deficiency in the peripheryperiphery

Straub RH et al. Replacement therapy with DHEA Straub RH et al. Replacement therapy with DHEA

plus corticosteroids in patients with chronic plus corticosteroids in patients with chronic inflammatory diseases--substitutes of adrenal and inflammatory diseases--substitutes of adrenal and sex hormones.sex hormones.Z Rheumatol 2000;59 Suppl 2:II/108-18Z Rheumatol 2000;59 Suppl 2:II/108-18

1212

DHEA and Immune FunctionDHEA and Immune Function

• DHEA counteracts Glucocorticoid DHEA counteracts Glucocorticoid (GC) effects on monocytes(GC) effects on monocytes

• Increased T cell productionIncreased T cell production

Canning MO et al. Opposing effects Canning MO et al. Opposing effects of Dehydroepiandrosterone and of Dehydroepiandrosterone and dexamethasone on the generation dexamethasone on the generation of monocyte-derived dendritic cells.of monocyte-derived dendritic cells. Eur J Endocrinol 2000 Nov;143(5):687-95Eur J Endocrinol 2000 Nov;143(5):687-95

1313

DHEA lowers TNF alphaDHEA lowers TNF alphaDHEA lowers TNF alphaDHEA lowers TNF alpha

•Improves Glucose toleranceImproves Glucose tolerance•Improves lipidsImproves lipids•Complimentary with exerciseComplimentary with exercise

Yang SC et al. Yang SC et al. Interactive effect of an acute Interactive effect of an acute bout of resistance exercise and bout of resistance exercise and dehydroepiandrosterone administration dehydroepiandrosterone administration on glucose tolerance and serum lipids in on glucose tolerance and serum lipids in middle-aged women.middle-aged women.Chin J Physiol. 2005 Mar 31;48(1):23-9. Chin J Physiol. 2005 Mar 31;48(1):23-9.

1414

DHEA in Inflammatory DHEA in Inflammatory ArthritisArthritisDHEA in Inflammatory DHEA in Inflammatory ArthritisArthritis

• Low DHEAS in Inflammatory ArthritisLow DHEAS in Inflammatory Arthritis• Especially in womenEspecially in women• DHEA for treatment?DHEA for treatment?

Dessein PH et al. Hyposecretion of the Dessein PH et al. Hyposecretion of the adrenal androgen dehydroepiandrosterone adrenal androgen dehydroepiandrosterone sulfate and its relation to clinical variables sulfate and its relation to clinical variables in inflammatory arthritis.in inflammatory arthritis. Arthritis Res Arthritis Res 2001;3(3):183-82001;3(3):183-8

1515

DHEA and LupusDHEA and LupusDHEA and LupusDHEA and Lupus

• Statistically significant Statistically significant improvements were found in all improvements were found in all lupus outcomes over 6 months. lupus outcomes over 6 months. • Optimal serum level of DHEAS was Optimal serum level of DHEAS was

1000 microg/dl. 1000 microg/dl.

Barry NN, McGuire JL, van Vollenhoven RF. Barry NN, McGuire JL, van Vollenhoven RF. Dehydroepiandrosterone in systemic lupus Dehydroepiandrosterone in systemic lupus erythematosus: relationship between erythematosus: relationship between dosage, serum levels, and clinical response.dosage, serum levels, and clinical response.J Rheumatol 1998 Dec;25(12):2352-6J Rheumatol 1998 Dec;25(12):2352-6

1616

DHEA, Stress, Immune DHEA, Stress, Immune FunctionFunctionDHEA, Stress, Immune DHEA, Stress, Immune FunctionFunction

• Immunosenescence may be closely Immunosenescence may be closely related to both psychological related to both psychological distress and stress hormonesdistress and stress hormones

• Neuroendocrine hypothesis of Neuroendocrine hypothesis of immunosenescenceimmunosenescence

• Age-related increase in the Age-related increase in the cortisol/DHEA ratio is major cortisol/DHEA ratio is major determinant of immunological determinant of immunological changes observed during ageing.changes observed during ageing.

Bauer ME et al.Bauer ME et al. Stress, Glucocorticoids and Stress, Glucocorticoids and ageing of the immune system.ageing of the immune system.Stress. 2005 Mar;8(1):69-83Stress. 2005 Mar;8(1):69-83

1717

SUMMARYSUMMARY• DHEA inhibits IL-6 and chronic DHEA inhibits IL-6 and chronic

inflammationinflammation• DHEA may be necessary for immune DHEA may be necessary for immune

responseresponse• Autoimmune diseases may benefit from Autoimmune diseases may benefit from

DHEA RTDHEA RT• Since aging is a state of cortisol excess, Since aging is a state of cortisol excess,

patients with adrenopause should have patients with adrenopause should have DHEA RT to balance CortisolDHEA RT to balance Cortisol

• Patients in corticosteroids should have Patients in corticosteroids should have DHEA RTDHEA RT

1818

DHEA and DHEA and Adrenal Adrenal FunctionFunction

1919

Aging Adrenal CortexAging Adrenal Cortex• Increased GC secretion, decreased DHEAIncreased GC secretion, decreased DHEA• Cortisol excess leads to cognitive Cortisol excess leads to cognitive

impairment due to damage to neurons in impairment due to damage to neurons in the hippocampusthe hippocampus

• DHEAS alters liver fatty acid metabolism DHEAS alters liver fatty acid metabolism and may be protective against cancerand may be protective against cancer

• Aging produces cortisol/DHEA excessAging produces cortisol/DHEA excess

Yen SS. Yen SS. Aging and the adrenal cortex.Aging and the adrenal cortex. Exp Gerontol 1998 Nov-Dec;33(7-8):897-Exp Gerontol 1998 Nov-Dec;33(7-8):897-910910

2020

2121

USE DHEA with GlucocorticoidsUSE DHEA with Glucocorticoids• ACTH stimulates release of Cortisol and ACTH stimulates release of Cortisol and

DHEA from the adrenal cortexDHEA from the adrenal cortex• Catabolic effects of Glucocorticoids (GC) Catabolic effects of Glucocorticoids (GC)

are counteracted by anabolic effects of are counteracted by anabolic effects of DHEADHEA•DHEA ameliorates some deleterious DHEA ameliorates some deleterious

effects of GC, such as diabetes, amino effects of GC, such as diabetes, amino acid deamination, fattiness, acid deamination, fattiness, hypertension and susceptibility to hypertension and susceptibility to viraemia. viraemia.

• Decreased DHEA in aging, Rheumatoid Decreased DHEA in aging, Rheumatoid Arthritis and LupusArthritis and Lupus

2222

DHEA and Brain DHEA and Brain MemoryMemoryMood Mood DepressionDepression

2323

DHEA Protects Hippocampal DHEA Protects Hippocampal NeuronsNeurons

• Protects hippocampal neurons from Protects hippocampal neurons from oxidative damage in vitro neurons from oxidative damage in vitro neurons from Alzheimer's DiseaseAlzheimer's Disease

• Hippocampal damage is a cause of age Hippocampal damage is a cause of age associated memory impairmentassociated memory impairment

• Neuoprotection from DHEA?Neuoprotection from DHEA?

Bastianetto SBastianetto S Dehydroepiandrosterone Dehydroepiandrosterone (DHEA) protects hippocampal cells from (DHEA) protects hippocampal cells from oxidative stress-induced damage.oxidative stress-induced damage.Brain Res Mol Brain Res 1999 Mar 20;66(1-Brain Res Mol Brain Res 1999 Mar 20;66(1-2):35-412):35-41

2424

• 22 Men & Women, Major 22 Men & Women, Major depressiondepression

• Dose up to 90 mg/dayDose up to 90 mg/day

• Hamilton depression rating scaleHamilton depression rating scale

• 6 weeks6 weeks

• Double blind / Placebo controlledDouble blind / Placebo controlled

DHEA/DepressionDHEA/Depression

Wolkowitz et al, UCSF, AJ PSY 4/99

2525

WolkowitzWolkowitz et alet al,, UCSF, AJY, 4/99UCSF, AJY, 4/99WolkowitzWolkowitz et alet al,, UCSF, AJY, 4/99UCSF, AJY, 4/99

• 50% or greater reduction in 50% or greater reduction in symptoms occurred in 5/11 symptoms occurred in 5/11 (45%) with DHEA, 0/11 with (45%) with DHEA, 0/11 with placeboplacebo

DHEA/Depression

Results

DHEA/Depression

Results

2626

DHEA and Well-Being in DHEA and Well-Being in WomenWomen

• Double blind, placebo, crossover studyDouble blind, placebo, crossover study• 50 mg/day50 mg/day

•Significantly improvedSignificantly improved– WellbeingWellbeing– DepressionDepression– AnxietyAnxiety– Sexual interest, sexual satisfactionSexual interest, sexual satisfaction

Arlt W et al. DHEA replacement in women with adrenal Arlt W et al. DHEA replacement in women with adrenal insufficiency--pharmacokinetics, bioconversion and insufficiency--pharmacokinetics, bioconversion and clinical effects on well-being, sexuality and cognition.clinical effects on well-being, sexuality and cognition.Endocr Res 2000 Nov;26(4):505-11Endocr Res 2000 Nov;26(4):505-11

2727

SUMMARYSUMMARY• DHEA is a neurosteroidDHEA is a neurosteroid• May protect the brain against May protect the brain against

neurodegenerationneurodegeneration• No proven improvement on memory in No proven improvement on memory in

humanshumansMakes old mice as smart as young miceMakes old mice as smart as young mice

• Mood enhancement, increased well being Mood enhancement, increased well being and anti-depressant effect usually foundand anti-depressant effect usually found

• Increased libido in womenIncreased libido in women• Improves menopausal Sx in womenImproves menopausal Sx in women• Glucocorticoid balancing could improve Glucocorticoid balancing could improve

memory and neurodegeneration over timememory and neurodegeneration over time

2828

DHEA and DHEA and Cardiovascular Cardiovascular

DzDz

2929

Low DHEA-S Predicts Ischemic Low DHEA-S Predicts Ischemic Heart DzHeart Dz

• Prospective study 1700 men 40-70 years oldProspective study 1700 men 40-70 years old• Lowest quartile of DHEA and DHEAS had Lowest quartile of DHEA and DHEAS had

most ischemic heart diseasemost ischemic heart disease• Independent of other risk factorsIndependent of other risk factors• Is DHEA protective against IHD?Is DHEA protective against IHD?

Feldman HA et al. Low DHEAe and ischemic Feldman HA et al. Low DHEAe and ischemic heart disease in middle-aged men: prospective heart disease in middle-aged men: prospective results from the Massachusetts Male Aging results from the Massachusetts Male Aging Study. Study. Am J Epidemiol 2001 Jan 1;153(1):79-89Am J Epidemiol 2001 Jan 1;153(1):79-89

3030

DHEA and Ischemic Heart DHEA and Ischemic Heart diseasediseaseDHEA and Ischemic Heart DHEA and Ischemic Heart diseasedisease• Is DHEA protective against IHD?Is DHEA protective against IHD?• Lowest quartile DHEA and DHEAS– highest Lowest quartile DHEA and DHEAS– highest

IHDIHD• ““Independent of a comprehensive set of Independent of a comprehensive set of

known risk factors including age, obesity, known risk factors including age, obesity, diabetes, hypertension, smoking, serum diabetes, hypertension, smoking, serum lipids, alcohol intake, and physical lipids, alcohol intake, and physical activity”activity”

Feldman HA et al.Feldman HA et al. Low DHEA and ischemic Low DHEA and ischemic heart disease in middle-aged men: heart disease in middle-aged men: prospective results from the Massachusetts prospective results from the Massachusetts Male Aging Study.Male Aging Study. Am J Epidemiol 2001 Jan Am J Epidemiol 2001 Jan 1;153(1):79-891;153(1):79-89

3131

DHEA-S and CV DiseaseDHEA-S and CV Disease

DHEAS concentration is DHEAS concentration is independently and inversely independently and inversely related to death from any related to death from any cause and death from cause and death from cardiovascular disease in men cardiovascular disease in men over age 50.over age 50.

3232

Dehydroepiandrosterone Dehydroepiandrosterone reduces plasma plasminogen reduces plasma plasminogen activator inhibitor type 1 and activator inhibitor type 1 and tissue plasminogen activator tissue plasminogen activator antigen in men.antigen in men.

Beer NA, Jakubowicz DJ, Matt DW, Beer Beer NA, Jakubowicz DJ, Matt DW, Beer RM, Nestler JE.RM, Nestler JE.Am J Med Sci. 1996 May;311(5):205-10. Am J Med Sci. 1996 May;311(5):205-10.

3333

Dehydroepiandrosterone Dehydroepiandrosterone increases endothelial cell increases endothelial cell proliferation in vitro and proliferation in vitro and improves endothelial function improves endothelial function in vivo by mechanisms in vivo by mechanisms independent of androgen and independent of androgen and estrogen receptors.estrogen receptors.

Williams MR, Dawood T, Ling S, Dai A, Lew R, Williams MR, Dawood T, Ling S, Dai A, Lew R, Myles K, Funder JW, Sudhir K, Komesaroff PA.Myles K, Funder JW, Sudhir K, Komesaroff PA.J Clin Endocrinol Metab. 2004 Sep;89(9):4708-15. J Clin Endocrinol Metab. 2004 Sep;89(9):4708-15.

3434

Dehydroepiandrosterone Dehydroepiandrosterone supplementation improves supplementation improves endothelial function and endothelial function and insulin sensitivity in men.insulin sensitivity in men.

Kawano H, Yasue H, Kitagawa A, Hirai N, Kawano H, Yasue H, Kitagawa A, Hirai N, Yoshida T, Soejima H, Miyamoto S, Nakano M, Yoshida T, Soejima H, Miyamoto S, Nakano M, Ogawa H.Ogawa H.J Clin Endocrinol Metab. 2003 Jul;88(7):3190-5. J Clin Endocrinol Metab. 2003 Jul;88(7):3190-5.

3535

SUMMARYSUMMARY

3636

• Double blind, placebo, 50 mg x 4 monthsDouble blind, placebo, 50 mg x 4 months• Increased DHEA, DHEAS, T, A to normal Increased DHEA, DHEAS, T, A to normal

rangerange• SHBG, Total Cholesterol, HDL decreasedSHBG, Total Cholesterol, HDL decreased• Improved overall well-being ,depression Improved overall well-being ,depression

and anxiety. (P=0.02). and anxiety. (P=0.02). • Increased the frequency of sexual Increased the frequency of sexual

thoughts (P=0.006), sexual interest thoughts (P=0.006), sexual interest (P=0.002), and satisfaction with both (P=0.002), and satisfaction with both mental and physical aspects of sexuality mental and physical aspects of sexuality (P=0.009 and P=0.02, respectively). (P=0.009 and P=0.02, respectively).

Wiebke Arlt, Wiebke Arlt, Dehydroepiandrosterone Replacement in Dehydroepiandrosterone Replacement in Women with Adrenal InsufficiencyWomen with Adrenal Insufficiency The New England The New England Journal of Medicine -- September 30, 1999 -- Vol. Journal of Medicine -- September 30, 1999 -- Vol. 341, No. 14341, No. 14

3737

DHEA 50 mg QD in Older Men and DHEA 50 mg QD in Older Men and WomenWomen• ““Young” levels of DHEASYoung” levels of DHEAS

• No “harmful” levels of DHEAS adverse effectsNo “harmful” levels of DHEAS adverse effects

• Increase in T and E2 in women but not menIncrease in T and E2 in women but not men

• Improved libido, bone turnover, skin in women Improved libido, bone turnover, skin in women but not menbut not men

Baulieu EE et al.Baulieu EE et al. Dehydroepiandrosterone Dehydroepiandrosterone (DHEA), DHEA sulfate, and aging: (DHEA), DHEA sulfate, and aging: contribution of the DHEAge Study to a contribution of the DHEAge Study to a sociobiomedical issue.sociobiomedical issue. Proc Natl Acad Sci U S AProc Natl Acad Sci U S A 2000 Apr 11;97(8):4279-842000 Apr 11;97(8):4279-84

3838

NEJM Editorial - DHEANEJM Editorial - DHEA• Benefits:Benefits:

– BoneBone– Vaginal LubricationVaginal Lubrication– Mood and well-beingMood and well-being– DepressionDepression– Counteracts GlucocorticoidsCounteracts Glucocorticoids

•Protects against catabolism, bone lossProtects against catabolism, bone loss– LupusLupus

• But don’t use it ?????????But don’t use it ?????????

Wolfgang Oelkers, M.D. Wolfgang Oelkers, M.D. Dehydroepiandrosterone for Dehydroepiandrosterone for Adrenal Insufficiency Adrenal Insufficiency The New England Journal of Medicine The New England Journal of Medicine -- September 30, 1999 -- Vol. 341, No. 14-- September 30, 1999 -- Vol. 341, No. 14

3939

SummarySummarySummarySummary• DHEA may be necessary for immune DHEA may be necessary for immune

responseresponse• Patients on corticosteroids should have Patients on corticosteroids should have

DHEA RTDHEA RT• Autoimmune diseases may benefit from Autoimmune diseases may benefit from

DHEA RTDHEA RT• Since aging is a state of cortisol excess, Since aging is a state of cortisol excess,

patients with adrenopause should have patients with adrenopause should have DHEA RT to balance CortisolDHEA RT to balance Cortisol

• DHEA inhibits IL-6 and chronic DHEA inhibits IL-6 and chronic inflammationinflammation

4040

SummarySummarySummarySummary• Raises T and Free T in womenRaises T and Free T in women• Usually No change in T menUsually No change in T men• Increases libido in womenIncreases libido in women• May or may not improve body composition May or may not improve body composition

in womenin women• Improves body composition in menImproves body composition in men• Conflicting data on strength in menConflicting data on strength in men• Reverses osteoporosisReverses osteoporosis• Raises IGF-1Raises IGF-1• No significant adverse effectsNo significant adverse effects

4141

DHEA: Anti-aging steroidDHEA: Anti-aging steroidDHEA: Anti-aging steroidDHEA: Anti-aging steroidBased on both in vitro and in vivoBased on both in vitro and in vivo•Stimulatory effect of immune Stimulatory effect of immune

systemsystem•Anti-diabetes mellitusAnti-diabetes mellitus•Anti-atherosclerosisAnti-atherosclerosis•Anti-dementia (neurosteroid)Anti-dementia (neurosteroid)•Anti-obesityAnti-obesity•Anti-osteoporosisAnti-osteoporosis Nawata Het al. Mechanism of action of anti-Nawata Het al. Mechanism of action of anti-

aging DHEA-S and the replacement of DHEA-S.aging DHEA-S and the replacement of DHEA-S.Mech Ageing Dev 2002 Apr 30;123(8):1101-6Mech Ageing Dev 2002 Apr 30;123(8):1101-6

4242

DHEA DHEA AdministrationAdministration

4343

Cholesterol

Dihydrotestosterone

Testosterone

Androstenedione

DHEADehydroepiandrosterone

Pregnenolone

Estrone

Estradiol

Progesterone

4444

Dr. Rothenberg’s DHEA Dr. Rothenberg’s DHEA AlgorithmAlgorithm

4545

7-keto7-keto DHEADHEA

4646

4747

7-keto DHEA7-keto DHEA7-keto DHEA7-keto DHEA

• 3-acetyl-7-oxo-dehydroepiandrosterone 3-acetyl-7-oxo-dehydroepiandrosterone

• Does not biotransform to andogenic and Does not biotransform to andogenic and estrogenic metabolitesestrogenic metabolites

• Associated with thermogenesis and Associated with thermogenesis and weight lossweight loss

Hanpl et al. Hanpl et al. Steroids and Steroids and thermogenesis.thermogenesis. Physiol Res. 2005 May Physiol Res. 2005 May 2424

4848

7-Keto DHEA7-Keto DHEA7-Keto DHEA7-Keto DHEA

• Decline contributes to fat gainDecline contributes to fat gain

• Weight loss without side effects Weight loss without side effects (Kalman)(Kalman)

• Improves Immune functionImproves Immune function

• Improves lipidsImproves lipids

• Improves memory in ratsImproves memory in rats

• Dose: 50-100 mg in AMDose: 50-100 mg in AM

• Can use alone or combine with DHEACan use alone or combine with DHEA

4949

• Davidson M, Marwah A, Sawchuk RJ, et al. Davidson M, Marwah A, Sawchuk RJ, et al. Safety and pharmacokinetic study with Safety and pharmacokinetic study with escalating doses of 3-acetyl-7-oxo-escalating doses of 3-acetyl-7-oxo-dehydroepiandrosterone in healthy male dehydroepiandrosterone in healthy male volunteers. Clin Invest Med. 2000 volunteers. Clin Invest Med. 2000 Oct;23(5):300-10. Oct;23(5):300-10.

• Zenk JL, Kuskowski MA. The use of 3-acetyl-Zenk JL, Kuskowski MA. The use of 3-acetyl-7-oxo-dehydroepiandrosterone for 7-oxo-dehydroepiandrosterone for augmenting immune response in the augmenting immune response in the elderly. Presented at meeting of FASEB, elderly. Presented at meeting of FASEB, April 17, 2004. April 17, 2004.

• Kalman DS, Colker CM, Swain MA, Torina Kalman DS, Colker CM, Swain MA, Torina GC, Shi Q. A randomized, double-blind, GC, Shi Q. A randomized, double-blind, placebo-controlled study of 3-acetyl-7-oxo-placebo-controlled study of 3-acetyl-7-oxo-dehydroepiandrosterone in healthy dehydroepiandrosterone in healthy overweight adults. Curr Therap Res. overweight adults. Curr Therap Res. 2000;61(7):435-42. 2000;61(7):435-42.

5050

5151

5252

5353

PregnenolonePregnenolone

““Grandmother of All Steroids”Grandmother of All Steroids”

5454

5555

PREGNENOLONEPREGNENOLONE

• Precursor to DHEAPrecursor to DHEA

• Produced in adrenals and brainProduced in adrenals and brain

• Can raise levels of steroids, lower Can raise levels of steroids, lower them or they can remain samethem or they can remain same

• Neurosteroid for peak brain Neurosteroid for peak brain functionfunction– found in highest concentrations in the found in highest concentrations in the

brainbrain

5656

PREGNENOLONEPREGNENOLONE

• Initiates the memory storage process by Initiates the memory storage process by stimulating neuronal stimulating neuronal adenylate cyclaseadenylate cyclase

• Regulates the timed-sequential flow of Regulates the timed-sequential flow of calcium ions through the cell membrane.calcium ions through the cell membrane.

• Calcium ion exchange may determine Calcium ion exchange may determine how memory is encoded by neurons. how memory is encoded by neurons.

5757

PREGNENOLONEPREGNENOLONE• Modulates calcium-protein bindings, gene Modulates calcium-protein bindings, gene

activation, protein turnover, and the intra-cellular activation, protein turnover, and the intra-cellular distribution of compounds and enzyme reactions distribution of compounds and enzyme reactions involved in the storage and retrieval of memory. involved in the storage and retrieval of memory.

• As stores of As stores of pregnenolonepregnenolone (and (and DHEADHEA) are ) are depleted with advancing age there is a marked depleted with advancing age there is a marked and often dramatic decline in the neuronal and often dramatic decline in the neuronal synchronization required for optimal mental synchronization required for optimal mental function. function.

5858

PregnenolonePregnenolone

• Levels decrease with ageLevels decrease with age

• Serum levels Serum levels – Men 10-230 ng/dlMen 10-230 ng/dl– Women 50-350 ng/dlWomen 50-350 ng/dl

• Serum levels thought not to be Serum levels thought not to be very useful or reliablevery useful or reliable

• No adverse effects reported No adverse effects reported

5959

Used for arthritis in the Used for arthritis in the 1940’s1940’s

• Less painLess pain

• Greater energyGreater energy

• Improved strength and Improved strength and mobilitymobility

• Also used for osteoarthritis, Also used for osteoarthritis, scleroderma and psoriasisscleroderma and psoriasis

• Lost favor with the Lost favor with the introduction of cortisoneintroduction of cortisone

6060

• Pregnenolone is necessary for Pregnenolone is necessary for hippocampal function in older rats. hippocampal function in older rats.

• Memory restored by replacement.Memory restored by replacement.

Vallee MVallee M Neurosteroids: deficient cognitive Neurosteroids: deficient cognitive performance in aged rats depends on low performance in aged rats depends on low pregnenolone sulfate levels in the hippocampuspregnenolone sulfate levels in the hippocampus Proc Natl Acad Sci U S A 1997 Dec 23;94(26):14865-70Proc Natl Acad Sci U S A 1997 Dec 23;94(26):14865-70

6161

• There is accumulating evidence that some There is accumulating evidence that some neurosteroids, in particular pregnenolone neurosteroids, in particular pregnenolone sulfate, have strong influences on sulfate, have strong influences on learning and memory processes, most learning and memory processes, most likely by regulating neurotransmission in likely by regulating neurotransmission in the hippocampusthe hippocampus

Schumacher MSchumacher M Neurosteroids in the Neurosteroids in the Hippocampus: Neuronal Plasticity Hippocampus: Neuronal Plasticity and Memoryand Memory Stress 1997 Oct;2(1):65-78 Stress 1997 Oct;2(1):65-78

6262

Pregnenolone and MemoryPregnenolone and Memory

• Cerebral Preg-S correlated to cognitive Cerebral Preg-S correlated to cognitive performanceperformance

• Improved with Preg-SImproved with Preg-S• Preg-S increases Acetylcholine in amygdala, cortex Preg-S increases Acetylcholine in amygdala, cortex

and hippocampusand hippocampus• Preg-S increases neurogenesis in hippocampusPreg-S increases neurogenesis in hippocampus

Mayo M et al. Pregnenolone Sulfate and Aging of Mayo M et al. Pregnenolone Sulfate and Aging of Cognitive Functions: Behavioral, Neurochemical Cognitive Functions: Behavioral, Neurochemical and Morphological Investigations. Hormones and and Morphological Investigations. Hormones and Behavior 40, 215-217 (2001)Behavior 40, 215-217 (2001)

6363

Neuroactive Steroid Levels in Neuroactive Steroid Levels in Patients with Generalized Anxiety Patients with Generalized Anxiety DisorderDisorder

• Patients with Generalized Anxiety DisorderPatients with Generalized Anxiety Disorder– Lower Preg-SLower Preg-S– Lower AlloPreg (not significant)Lower AlloPreg (not significant)– No difference in DHEASNo difference in DHEAS

• Preg-S is GABA A (benzodiazepine) receptor Preg-S is GABA A (benzodiazepine) receptor Agonist in low dosesAgonist in low doses

Semeniuk, T et al. The Journal of Neuropsychiatry Semeniuk, T et al. The Journal of Neuropsychiatry

and Clinical Neurosciences 2001; 13:396-398and Clinical Neurosciences 2001; 13:396-398

6464

Neurosteroids and ADHDNeurosteroids and ADHD Inverse correlation between Inverse correlation between clinical symptoms and levels of clinical symptoms and levels of DHEA and Pregnenolone in DHEA and Pregnenolone in young male subjects aged 7-15 young male subjects aged 7-15 years with DSM-IV criteria of years with DSM-IV criteria of ADHD. ADHD.

Strous RD et al. Analysis of neurosteroid Strous RD et al. Analysis of neurosteroid levels in attention deficit hyperactivity levels in attention deficit hyperactivity disorder. Int J Neuropsychopharmacol disorder. Int J Neuropsychopharmacol 2001 Sep;4(3):259-642001 Sep;4(3):259-64

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Low levels of Pregnenolone in Low levels of Pregnenolone in Social Phobia and DepressionSocial Phobia and Depression

• Mayo W, Le Moal M, Abrous DN. Mayo W, Le Moal M, Abrous DN. Pregnenolone sulfate and aging of cognitive Pregnenolone sulfate and aging of cognitive functions: Behavioral, neurochemical, and functions: Behavioral, neurochemical, and morphological investigations. Horm Behav. morphological investigations. Horm Behav. 2001 Sep;40(2):215-7.2001 Sep;40(2):215-7.

• 13. George M, Guidotti A, Rubinow D, Pan B, 13. George M, Guidotti A, Rubinow D, Pan B, Mikalauskas K, Post R. CSF neuroactive Mikalauskas K, Post R. CSF neuroactive steroids in affective disorders: steroids in affective disorders: pregnenolone, progesterone and DBI. Biolog pregnenolone, progesterone and DBI. Biolog Psychiatry. 1994 May 15;35(10):775-80.Psychiatry. 1994 May 15;35(10):775-80.

• 14. Heydari B, Le Melledo JM. Low preg- 14. Heydari B, Le Melledo JM. Low preg- nenolone sulfate plasma concentrations in nenolone sulfate plasma concentrations in patients with generalized social phobia. patients with generalized social phobia. Psychol Med. 2002 Jul2;32(5):929-33.Psychol Med. 2002 Jul2;32(5):929-33.

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PregnenolonePregnenolone

• DoseDose– 50-200 mg in men and women50-200 mg in men and women

• Consider other cognitive Consider other cognitive enhancement neutraceuticals as wellenhancement neutraceuticals as well– Acetyl-L-CarnitineAcetyl-L-Carnitine– Phosphatidyl serine/cholinePhosphatidyl serine/choline– VinpocetineVinpocetine– Deprenyl=Eldepryl=SeligilineDeprenyl=Eldepryl=Seligiline– Hydergine=Ergyloid MesylateHydergine=Ergyloid Mesylate

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MelatoninMelatonin

““The Pineal Gland is the seat of the The Pineal Gland is the seat of the soul.” --Rene Descartes soul.” --Rene Descartes

(1596-1650)(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 - Melatonin - N-acetyl-5-N-acetyl-5-methoxytryptaminemethoxytryptamine

• Secreted by pineal gland Secreted by pineal gland

• Produced in darkness, suppressed Produced in darkness, suppressed by lightby light

• Levels decline with aging - 10-15% Levels decline with aging - 10-15% per decadeper decade– All studies but one show thisAll studies but one show this

• Manages circadian rhythm of inner Manages circadian rhythm of inner clockclock– Lowers body temperatureLowers body temperature– Controls sleep wake cycleControls sleep wake cycle

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The Ultimate Anti-oxidant?The Ultimate Anti-oxidant?

• Protects lipids, proteins, DNAProtects lipids, proteins, DNA• Stimulates glutathioneStimulates glutathione• Protects mitochondriaProtects mitochondria• Protects against ischemia-Protects against ischemia-

reperfusion injuryreperfusion injury• Protects against ionizing radiationProtects against ionizing radiation

Reiter RJ et al. Pharmacological utility of Reiter RJ et al. Pharmacological utility of melatonin in reducing oxidative cellular and melatonin in reducing oxidative cellular and molecular damage.molecular damage. Pol J Pharmacol. 2004 Mar- Pol J Pharmacol. 2004 Mar-Apr;56(2):159-70. Apr;56(2):159-70.

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MELATONINMELATONIN•Free Radical ScavengerFree Radical Scavenger•Decreases pro-inflammatory Decreases pro-inflammatory

cytokinescytokines•Decreases damage from beta Decreases damage from beta

amyloidamyloid

Rosales-Corral S et al. Orally administered Rosales-Corral S et al. Orally administered melatonin reduces oxidative stress and melatonin reduces oxidative stress and proinflammatory cytokines induced by proinflammatory cytokines induced by amyloid-beta peptide in rat brain: a amyloid-beta peptide in rat brain: a comparative, in vivo study versus vitamin C comparative, in vivo study versus vitamin C and E.and E.J Pineal Res. 2003 Sep;35(2):80-4. J Pineal Res. 2003 Sep;35(2):80-4.

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Enhances Immune FunctionEnhances Immune Function• Inhibits tumor growthInhibits tumor growth• Counteracts stress induced immunodepressionCounteracts stress induced immunodepression• Increases in CD4 cells, natural killer cellsIncreases in CD4 cells, natural killer cells• Activates cytokine system when neededActivates cytokine system when needed• Decreases pro-inflammatory cytokinesDecreases pro-inflammatory cytokines• Increases immune function in winter when there are Increases immune function in winter when there are

more environmental stressorsmore environmental stressors Nelson RJ Melatonin mediates seasonal changes in immune Nelson RJ Melatonin mediates seasonal changes in immune

function function Ann N Y Acad Sci 2000;917:404Ann N Y Acad Sci 2000;917:404Kriegsfeld LJKriegsfeld LJ In vitro melatonin treatment enhances cell-In vitro melatonin treatment enhances cell-

mediated immune function in male prairie voles mediated immune function in male prairie voles J Pineal Res J Pineal Res 2001 May;30(4):193-82001 May;30(4):193-8

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CANCERCANCER• Inhibits tumor growth in humansInhibits tumor growth in humans

– Anti-mitotic activityAnti-mitotic activity– Down regulate activity of receptorsDown regulate activity of receptors

•Decreased Estrogen binding to cells in breast caDecreased Estrogen binding to cells in breast ca

– Enhanced Immune ResponseEnhanced Immune Response– Free Radial scavengingFree Radial scavenging– Anti-angiogenesisAnti-angiogenesis

• Improved outcome in glioblastoma, malignant Improved outcome in glioblastoma, malignant melanoma, breast cancermelanoma, breast cancer– Used along with chemo, radiationUsed along with chemo, radiation– Large doses used 20-700 mg /dayLarge doses used 20-700 mg /day

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Melatonin and BoneMelatonin and Bone

•Reverses osteoporosisReverses osteoporosis•Improves deep sleep and GH Improves deep sleep and GH

releaserelease

Cardinali DPCardinali DP et al. et al. Melatonin effects on Melatonin effects on Bone: experimental facts and clinical Bone: experimental facts and clinical perspectives.perspectives.J Pineal Res 2003 Mar;34(2):81-7J Pineal Res 2003 Mar;34(2):81-7

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Melatonin Replacement Melatonin Replacement TherapyTherapy

• No serious adverse effects (NEJM Review)No serious adverse effects (NEJM Review)– Usually produces drowsiness and decreased sleep Usually produces drowsiness and decreased sleep

latency and increased total sleeplatency and increased total sleep– Occasional paradoxical stimulationOccasional paradoxical stimulation– Can produce vivid dreams which are interesting to Can produce vivid dreams which are interesting to

some and distressing to otherssome and distressing to others– Can produce “hangover”Can produce “hangover”

•This effect usually resolves after a few daysThis effect usually resolves after a few days

– Some people “just don’t feel good”Some people “just don’t feel good”– Others: well rested, bright eyed and bushy tailedOthers: well rested, bright eyed and bushy tailed

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Melatonin Dose - 1/2 hr before Melatonin Dose - 1/2 hr before sleepsleep• Try small dose 0.5 mg at firstTry small dose 0.5 mg at first

• If no unpleasant reaction can increase dose in If no unpleasant reaction can increase dose in increments to 3-10 mgincrements to 3-10 mg

• Time release for people who wake up in middle of nightTime release for people who wake up in middle of night

• Sublingual lozenge or drops for people who have Sublingual lozenge or drops for people who have trouble falling asleeptrouble falling asleep

• Some tolerance develops but usually levels off at 3-10 Some tolerance develops but usually levels off at 3-10 mgmg

• For some people, less in more and better sleep at low For some people, less in more and better sleep at low dose 0.3 mgdose 0.3 mg

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JET LAGJET LAG• Improves recovery and prevents jet Improves recovery and prevents jet

laglag

• Take 3-6 mg on airplane at the time Take 3-6 mg on airplane at the time of bedtime of your destinationof bedtime of your destination

• Expose yourself to bright light in Expose yourself to bright light in AM’s upon arrivalAM’s upon arrival

• Take 3-6 mg at bedtime at Take 3-6 mg at bedtime at destinationdestination

Takahashi TTakahashi T Effect of 3 mg melatonin on jet lag syndrome in Effect of 3 mg melatonin on jet lag syndrome in an 8-h eastward flight.an 8-h eastward flight. Psychiatry Clin Neurosci 2000 Psychiatry Clin Neurosci 2000 Jun;54(3):377-8Jun;54(3):377-8

Herxheimer AHerxheimer A Melatonin for preventing and treating jet lag Melatonin for preventing and treating jet lag Cochrane Database Syst Rev 2001;1:CD001520Cochrane Database Syst Rev 2001;1:CD001520

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