reproductive hormones and -...
TRANSCRIPT
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ReproductiveHormones andDepression…Huh?A Rational Basis for HormonalPsychopharmacotherapeutics
David R. Rubinow, MDUniversity of NorthCarolina
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David R. Rubinow, MDDisclosures
Research/Grants: Foundation of Hope; NationalInstitutes of Health; National Institute of MentalHealth
Speakers Bureau: None Consultant: Azevan Pharmaceutical, Inc.;
Dialogues in Clinical Neuroscience Stockholder: Amgen Inc.; Vanguard Special
Health Mutual Fund Other Financial Interest: None Advisory Board: None
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LearningObjectiveName 2 ways in whichestrogen levelinfluences neuralfunction in women
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ReproductiveSteroids:Sources ofVariance andContextDependency
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Conversion of Cholesterolto Steroid Hormones
Rubinow DR, et al. Am J Psychiatry 1996;153:974-984.
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Estradiol Dihydrotestosterone
Androsterone Etiocholanolone5αAndrostanediol
Metabolism Determines Function
Rubinow DR, et al. Am J Psychiatry 1996;153:974-984.
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E2
E R
ERE
Hormones
E2 = estrogen; ER = estrogen receptor; ERE = estrogen-responsive elementsKushner PJ, et al. J Steroid Biochem Mol Biol 2000;74:311-317; Wu RC, et al.Endocr Rev 2005;26:393-399; McEwen BS. J Appl Physiol 2001;91:2785-2801.
ER Signaling Pathway
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E2
E R
ERE
HormonesGrowth Factors
NT
EGFTGFaIGF-1
DA
G R
CBP P300 CoReg
PREAP-1CRE
MAPK
c-Jun/c-Fos
CREB
SRC-1
cAMP
Pl 2
Ca++
E R
Akt
Kushner PJ, et al. J Steroid Biochem Mol Biol 2000;74:311-317; Wu RC, et al.Endocr Rev 2005;26:393-399; McEwen BS. J Appl Physiol 2001;91:2785-2801.
Estradiol and ERManifold Regulators of Transcription
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E R
ERE
Hormones
CoReg
PREAP-1CRE
Kushner PJ, et al. J Steroid Biochem Mol Biol 2000;74:311-317; Wu RC, et al.Endocr Rev 2005;26:393-399; McEwen BS. J Appl Physiol 2001;91:2785-2801.
Coregulators DetermineEffects of ER
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Brzozowski AM, et al. Nature 1997;389:753-758.
Agonist-Induced Conformation Antagonist-Induced Conformation
Shape of Hormone SelectsReceptor Coregulator
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Available at: http://universe-review.ca/I10-33-epigenetic.jpg. Accessed July 10, 2009.
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Available at: http://www.molecularstation.com/molecular-biology-images/502-dna-pictures/60-nucleosome.html. Accessed July 10, 2009.
Nucleosome
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Bauer U-M. Available at: http://www.imt.uni-marburg.de/bauer/research.html.Accessed July 10, 2009.
Histone Modifications ModulateChromatin Structure
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1. Pfaff D, et al. Trends Neurosci 2002;25:45-50.2. Krezel W, et al. Proc Natl Acad Sci USA 2001;98:12278-12282.3. Lund TD, et al. Endocrinology 2005;146:797-807.4. Walf AA, Frye CA. Neuropsychopharmacology 2005;30:1598-1609.5. Rocha BA, et al. Psychopharmacology (Berl) 2005;179:637-643.
Estrogen Receptorsand Depression
E2-induced arousal1
ER-beta knockout mouse – anxious2
Selective ER-beta modulators areanxiolytic3,4
ER-beta mediates antidepressant effects ofE2 in forced-swim test5
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CRH = corticotropin-releasing hormone (cortisol)
Models of Depression
Neurotransmitter deficiency Neuroplasticity Cellular energetics Stress/CRH Signal trafficking (e.g., p11) Inflammation Network dysregulation
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Endocrinology of…Fat?
Hammarstedt A, et al. Biochem Biophys Res Commun 2007;357:700-706.
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FatOrchestrator of Systemic Illness
Hammarstedt A, et al. Biochem Biophys Res Commun 2007;357:700-706.
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CVD = cardiovascular disease; IL-6 = interleukin-6; MCP-1 = monocytechemoattractant protein-1; TNF-α = tumor necrosis factor alpha;VEGF = vascular endothelial growth factor
Relationship Between Inflammation,Disease, and Hormone Level
CVD Diabetes Obesity Depression Stress
TNF-α
IL-6
MCP-1
InsulinSensitivity
VEGF
Estrogen
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Models of Depression
Neurotransmitter deficiency Neuroplasticity Cellular energetics Stress/CRH Signal trafficking (e.g., p11) Inflammation Network dysregulation
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Conceptual Proposalfor RelationshipBetween AnatomicalSites, NeuralComputations, andBehaviors
Pessoa L. Nat Rev Neurosci 2008;9:148-158.
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rCBF = regional cerebral blood flowBerman KF. Proc Natl Acad Sci USA 1997;94:8836-8841.
Working Memory Activation
Primary Motor & Visual Activation
Leuprolide Alone Leuprolide + Estrogen Leuprolide + Progesterone
rCBF Activation DuringHormonal Manipulation
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NoGoNE = negative no-go; NoGoNU = neutral no-go; NoGoPO = positive no-go;OFC = orbitofrontal cortexProtopopescu X, et al. Proc Natl Acad Sci USA 2005;102:16060-16065.
b
OFC Activity in Response to EmotionalStimuli in the Context of BehavioralInhibition Across the Menstrual Cycle
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Dreher JC, et al. Proc Natl Acad Sci USA 2007;104:2465-2470.
Anticipation ofReward andReward-InducedActivation AreGreater in theFollicular Phase
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Dreher JC, et al. Proc Natl Acad Sci USA 2007;104:2465-2470.
Bilateral amygdalo-hippocampal complex Hypothalamus
Positive correlation with estradiol Negative correlation with estradiol
Estradiol Level (pg/mL)
Estradiol Level (pg/mL) Estradiol Level (pg/mL)
Par
amet
er E
stim
ates
Par
amet
er E
stim
ates
Par
amet
er E
stim
ates
T-va
lue
Follicular PhaseCorrelations with Estradiol Level DuringAnticipation of Uncertain Rewards
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Dreher JC, et al. Proc Natl Acad Sci USA 2007;104:2465-2470.
Bilateral dorsolateral prefrontal cortex Bilateral fronto-polar cortex
Estradiol Level (pg/mL)Par
amet
er E
stim
ates
Par
amet
er E
stim
atesLeft DLPFC
Estradiol Level (pg/mL)
Left fronto-polar cx
T-va
lue
Follicular PhasePositive Correlation with Estradiol Levelat the Time of Rewarded Outcome
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1. Schmidt PJ, et al. Am J Obstet Gynecol 2000;183:414-420.2. Morrison MF, et al. Biol Psychiatry 2004;55:406-412.
Antidepressant Efficacyof Estradiol
Estradiol is effective in perimenopausalwomen1
Estradiol is NOT effective inpostmenopausal women2
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Hormone Psychopharmacology
Psychotropic neuropharmacology
Formulation
Administration
Indication
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Hormone Psychopharmacology
Psychotropic neuropharmacology
Formulation
Administration
Indication
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Hormone Formulation
Functional implications of structuraldifferences– E2 vs. conjugated estrogens– Progesterone vs. medroxyprogesterone
Measures of action: single tissuesin isolation
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Hormone Psychopharmacology
Psychotropic neuropharmacology
Formulation
Administration
Indication
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Hormone Administration
Implications of route of administration Bioavailability
– Absorption, distribution, protein binding,metabolism
Individual differences, gender, and age
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Hormone Psychopharmacology
Psychotropic neuropharmacology
Formulation
Administration
Indication
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Women’s HealthInitiativeThe Good, the Bad,and the Ugly
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CHD = coronary heart diseaseRossouw JE, et al. JAMA 2002;288:321-333.
Women’s Health Initiative
16,608 apparently healthypostmenopausal women (50-79)– ½ receive conjugated estrogens and
medroxyprogesterone
CHD = primary outcome Invasive breast cancer = primary adverse
outcome
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“This is the finalnail in the coffinfor hormonereplacementtherapy.”Lori Mosca, MD, MPH, PhDDirector, PreventiveCardiology, New York-Presbyterian HospitalScience, March 5, 2004
Science 2004;303:1449.
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If E2 is so “goodfor you,” why arethey saying suchterrible thingsabout it?
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1. Timing
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Time-Dependent Protective Effectsof E2 Against Ischemic Brain Injury
MCAO = middle cerebral artery occlusion; OVX = ovariectomized femalesSuzuki S, et al. PNAS 2007;104:6013-6018.
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Immediate E2 Treatment AttenuatedProinflammatory Responses in the Brain
VEGF = vascular endothelial growth factorSuzuki S, et al. PNAS 2007;104:6013-6018.
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2. Healthy CellHypothesis
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How Do We Get from Gene toGonadal Steroids to Depression?
Animal models: the ER in depression Brain imaging: functional effects of E2
E2: antidepressant efficacy Modulation of gene expression by
gonadal steroids– Change in hormone as trigger– Genetic predispositions modified by gonadal
steroids Stress, gonadal steroids, and epigenesis
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Paracelsus, 1493-1541.
A drug can be an inert substance, a poison,or a therapeutic agent depending upon how itis used and the dosage in which it is given.
Alle Ding' sind Gift und nichts ohn' Gift; alleindie Dosis macht, dass ein Ding kein Gift ist.
"All things are poison and nothing is withoutpoison, only the dose permits something notto be poisonous."
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CC-EPT = continuous-combined estrogen-progestogen therapy;CS-EPT = continuous-sequential estrogen-progestogen therapy;DM = diabetes mellitus; HT = hypertension
We Don’t Know…
Optimal combo of formulation, route, regimen, dose Mechanisms of harm Long-term risks Usefulness of protectors (e.g., statins) Risk to benefit of CS-EPT vs. CC-EPT Interactions with antidepressants Role in DM or HT Impact of different progestins Predictors of benefit or risk…………..
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an educational series offered byCME Outfitters, LLC
This CME/CE activity isco-sponsored by
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Reproductive Hormones and Depression…Huh? A Rational Basis for Hormonal Psychopharmacotherapeutics David R. Rubinow, MD Available at: http://universe-review.ca/I10-33-epigenetic.jpg. Accessed July 10, 2009.
Available at: http://www.molecularstation.com/molecular-biology-images/ 502-dna-pictures/60-nucleosome.html. Accessed July 10, 2009.
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