ReproductiveHormones andDepression…Huh?A Rational Basis for HormonalPsychopharmacotherapeutics

David R. Rubinow, MDUniversity of NorthCarolina

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

LearningObjectiveName 2 ways in whichestrogen levelinfluences neuralfunction in women

ReproductiveSteroids:Sources ofVariance andContextDependency

Conversion of Cholesterolto Steroid Hormones

Rubinow DR, et al. Am J Psychiatry 1996;153:974-984.

Estradiol Dihydrotestosterone

Androsterone Etiocholanolone5αAndrostanediol

Metabolism Determines Function

Rubinow DR, et al. Am J Psychiatry 1996;153:974-984.

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

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

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

Brzozowski AM, et al. Nature 1997;389:753-758.

Agonist-Induced Conformation Antagonist-Induced Conformation

Shape of Hormone SelectsReceptor Coregulator

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.

Nucleosome

Bauer U-M. Available at: http://www.imt.uni-marburg.de/bauer/research.html.Accessed July 10, 2009.

Histone Modifications ModulateChromatin Structure

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

CRH = corticotropin-releasing hormone (cortisol)

Models of Depression

Neurotransmitter deficiency Neuroplasticity Cellular energetics Stress/CRH Signal trafficking (e.g., p11) Inflammation Network dysregulation

Endocrinology of…Fat?

Hammarstedt A, et al. Biochem Biophys Res Commun 2007;357:700-706.

FatOrchestrator of Systemic Illness

Hammarstedt A, et al. Biochem Biophys Res Commun 2007;357:700-706.

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

Models of Depression

Neurotransmitter deficiency Neuroplasticity Cellular energetics Stress/CRH Signal trafficking (e.g., p11) Inflammation Network dysregulation

Conceptual Proposalfor RelationshipBetween AnatomicalSites, NeuralComputations, andBehaviors

Pessoa L. Nat Rev Neurosci 2008;9:148-158.

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

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

Dreher JC, et al. Proc Natl Acad Sci USA 2007;104:2465-2470.

Anticipation ofReward andReward-InducedActivation AreGreater in theFollicular Phase

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

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

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

Hormone Psychopharmacology

Psychotropic neuropharmacology

Formulation

Administration

Indication

Hormone Psychopharmacology

Psychotropic neuropharmacology

Formulation

Administration

Indication

Hormone Formulation

Functional implications of structuraldifferences– E2 vs. conjugated estrogens– Progesterone vs. medroxyprogesterone

Measures of action: single tissuesin isolation

Hormone Psychopharmacology

Psychotropic neuropharmacology

Formulation

Administration

Indication

Hormone Administration

Implications of route of administration Bioavailability

– Absorption, distribution, protein binding,metabolism

Individual differences, gender, and age

Hormone Psychopharmacology

Psychotropic neuropharmacology

Formulation

Administration

Indication

Women’s HealthInitiativeThe Good, the Bad,and the Ugly

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

“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.

If E2 is so “goodfor you,” why arethey saying suchterrible thingsabout it?

1. Timing

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.

Immediate E2 Treatment AttenuatedProinflammatory Responses in the Brain

VEGF = vascular endothelial growth factorSuzuki S, et al. PNAS 2007;104:6013-6018.

2. Healthy CellHypothesis

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

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."

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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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.

Bauer U-M. Available at: http://www.imt.uni-marburg.de/bauer/research.html. Accessed July 10, 2009.

Berman KF, Schmidt PJ, Rubinow DR, et al. Modulation of cognition-specific cortical activity by gonadal steroids: a positron-emission tomography study in women. Proc Natl Acad Sci U S A 1997;94:8836-8841.

Brzozowski AM, Pike AC, Dauter Z, et al. Molecular basis of agonism and antagonism in the oestrogen receptor. Nature 1997;389:753-758.

Dreher JC, Schmidt PJ, Kohn P, Furman D, Rubinow D, Berman KF. Menstrual cycle phase modulates reward-related neural function in women. Proc Natl Acad Sci U S A 2007;104:2465-2470.

Hammarstedt A, Isakson P, Gustafson B, Smith U. Wnt-signaling is maintained and adipogenesis inhibited by TNFalpha but not MCP-1 and resistin. Biochem Biophys Res Commun 2007;357:700-706.

Krezel W, Dupont S, Krust A, Chambon P, Chapman PF. Increased anxiety and synaptic plasticity in estrogen receptor beta -deficient mice. Proc Natl Acad Sci U S A 2001;98:12278-12282.

Kushner PJ, Agard DA, Greene GL, et al. Estrogen receptor pathways to AP-1. Steroid Biochem Mol Biol 2000;74:311-317.

Lund TD, Rovis T, Chung WC, Handa RJ. Novel actions of estrogen receptor-ß on anxiety-related behaviors. Endocrinology 2005;146:797-807.

McEwen BS. Invited eeview: estrogen’s effects on the brain: multiple sites and molecular mechanisms. J Appl Physiol 2001;91:2785-2801.

Morrison MF, Kallan MJ, HaveLack TT et al. Lack of efficacy of estradiol for depression in postmenopausal women: a randomized, controlled trial. Biol Psychiatry 2004;55:406-412.

Pessoa L. On the relationship between emotion and cognition. Nat Rev Neurosci 2008;9:148-158.

Pfaff D, Frohlich J, Morgan M. Hormonal and genetic influences on arousal--sexual and otherwise. Trends Neurosci 2002;25:45-50.

Protopopescu X, Pan H, Altemus M, et al. Orbitofrontal cortex activity related to emotional processing changes across the menstrual cycle. Proc Natl Acad Sci U S A 2005;102:16060-16065.

Rocha BA, Fleischer R, Schaeffer JM, Rohrer SP, Hickey GJ. 17 Beta-estradiol-induced antidepressant-like effect in the forced swim test is absent in estrogen receptor-beta knockout (BERKO) mice. Psychopharmacology (Berl) 2005;179:637-643.

Rossouw JE, Anderson GL, Prentice RL,et al; Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA 2002;288:321-333.

Rubinow DR, Schmidt PJ. Androgens, brain, and behavior. Am J Psychiatry 1996;153:974-984.

Schmidt PJ, Nieman L, Danaceau MA, et al. Estrogen replacement in perimenopause-related depression: a preliminary report. Am J Obstet Gynecol 2000;183:414-420.

Suzuki S, Brown CM, De la Cruz CD. Timing of estrogen therapy after ovariectomy dictates the efficacy of its neuroprotective and antiinflammatory actions. PNAS 2007;104:6013-6018.

Walf AA, Frye CA. ER-selective estrogen receptor modulators produce antianxiety behavior when administered systemically to ovariectomized rats. Neuropsychopharmacology 2005;30:1598–1609.

Wu RC, Smith CL, O'Malley BW. Transcriptional regulation by steroid receptor coactivator phosphorylation. Endocr Rev 2005;26:393-399.