10/19/12. David R. Rubinow, MD Disclosures. Hormones, Heart Disease, and Health of the Perimenopausal Woman

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1 10/19/12 Hormones, Heart Disease, and Health of the Perimenopausal Woman David R. Rubinow, MD University of North Carolina at Chapel Hill School of Medicine Chapel Hill, NC David R. Rubinow, MD Disclosures Research/Grants: National Institute of Mental Health; Foundation of Hope Other: Editorial Board, Dialogues in Clinical Neuroscience 1

2 10/19/12 Learning Objective Counsel patients on the role of estradiol in cardiovascular disease and depression Questions to Consider Why do we think that 17-beta estradiol (E2) has anything to do with heart disease or depression? What are the mechanisms by which E2 can modify the heart or brain? Isn t hormone therapy (HT) bad for you? How do we explain the variability (across individuals) in the response to E2? Depression, Cardiovascular Disease (CVD), and the Perimenopause CVD and depression are separate and related sources of morbidity and mortality Patients with CVD: Increased risk of depression; if depressed, increased risk of death Patients with depression (or history of depression): Increased risk of CVD Ovarian failure is associated with: Increased risk of CVD and coronary artery atherosclerosis Increased risk of depression Rubinow DR, Girdler SS. Depress Anxiety. 2011;28(6):E1-E15. PMID:

3 Models of Depression Neurotransmitter deficiency, signal transduction, and scaffolding proteins Stress and corticotropin-releasing hormone (CRH) Neuroplasticity Cellular energetics Signal-trafficking Network dysregulation Inflammation Rubinow DR, Girdler SS. Depress Anxiety. 2011;28(6):E1-E15. PMID: Nestler EJ, et al. Biol Psychiatry. 2002;52(6): PMID: Estradiol Reverses Adverse Profile of Soluble Risk Factors CVD Diabetes Obesity Depression Stress Estrogen Tumor necrosis factoralpha (TNF-α) Interleukin 6 (IL-6) Monocyte chemotactic protein 1 (MCP-1) Insulin sensitivity Vascular endothelial growth factor (VEGF) See reference list at the end of this slide set. E2 Deficiency: Not So Great For Your CV System Endothelial dysfunction Impaired nitric oxide bioactivity Autonomic dysfunction Renin-angiotensin activation Increased oxidative stress Alteration in inflammatory and coagulation cascades Rubinow DR, Girdler SS. Depress Anxiety. 2011;28(6):E1-E15. PMID:

4 E2 Deficiency, CVD, and Depression Share Common Pathophysiological Disturbances Immune activation Endothelial dysfunction Platelet-clotting dysfunction Cardiac autonomic dysfunction (sympathetic dominance; decreased heart rate variability or baroreflex sensitivity) Metabolic risk: visceral adiposity, insulin resistance Rubinow DR, Girdler SS. Depress Anxiety. 2011;28(6):E1-E15. PMID: Evidence for a Role of E2 in Depression The ER in Depression (Animal Models) Functional Effects of E2 (Brain Imaging) E2 Antidepressant Efficacy Modulation of Gene Expression by Gonadal Steroids Evidence for a Role of E2 in Depression The ER in depression (Animal Models) Functional Effects of E2 (Brain Imaging) E2 Antidepressant Efficacy Modulation of Gene Expression by Gonadal Steroids 4

5 Steroids Regulate Prefrontal Cortex (PFC) Regional Cerebral Blood Flow (rcbf) During Cognitive Activation Leuprolide Alone Leuprolide + Estrogen Leuprolide + Progesterone WORKING MEMORY ACTIVATION PRIMARY MOTOR & VISUAL ACTIVATION Berman KF, et al. Proc Natl Acad Sci U S A. 1997;94(16): PMID: Decreased rcbf in BA 25 During Hypogonadism Compared With Hormone Replacement Oxygen-15 H 20 Resting regional cerebral blood flow Hormone Replacement vs. Lupron relative rcbf Hormone Replacement Hormone Conditions Lupron Hormone Hypogonadism Replacement p =.001, uncorrected; n = 28; rcbf = regional cerebral blood flow Schmidt PJ, et al. Unpublished data. Steroids Regulate Prefrontal Cortex Functional Correlations With Hippocampal Formation Activity Leuprolide Alone Progesterone Add-Back Estrogen Add-Back Berman KF, et al. Proc Natl Acad Sci U S A. 1997;94(16): PMID:

6 Orbitofrontal Cortex (OFC) Activity in Response to Emotional Stimuli Protopopescu X, et al. Proc Natl Acad Sci U S A. 2005;102(44): PMID: Greater reward circuitry activation in the follicular phase: anticipation of uncertain rewards Dreher JC, et al. Proc Natl Acad Sci U S A. 2007;104(7): PMID: Dreher JC, et al. Proc Natl Acad Sci U S A. 2007;104(7): PMID:

7 Evidence for a Role of E2 in Depression The ER in depression (Animal Models) Functional Effects of E2 (Brain Imaging) E2 Antidepressant Efficacy Modulation of Gene Expression by Gonadal Steroids E2 Efficacy in Treatment of Perimenopausal Depression CES-D Score Depression ± Hot Flushes (n = 34) p <.01 Baseline Placebo E 2 0 Baseline Weeks 2 4 Baseline Weeks 2 4 CES-D = Center for Epidemiologic Studies Depression Scale Schmidt PJ, et al. Am J Obstet Gynecol. 2000;183(2): PMID: Effect of E2 on Perimenopausal Symptoms CES-D Score Depression No Hot Flushes (n = 18) p <.01 Baseline Placebo E 2 0 Baseline Weeks 2 4 Baseline Weeks 2 4 CES-D = Center for Epidemiologic Studies Depression Scale Schmidt PJ, et al. Am J Obstet Gynecol. 2000;183(2): PMID:

8 Antidepressant Efficacy of Estradiol Estradiol is effective in perimenopausal women 1 Estradiol is NOT effective in postmenopausal women 2,3 1. Schmidt PJ, et al. Unpublished data. 2. Cohen LS, et al. Am J Psychiatry. 2003;160(8): PMID: Morrison MF, et al. Biol Psychiatry. 2004;55(4): PMID: Women s Health Initiative (WHI) The Good, The Bad, The Ugly 16,608 apparently healthy postmenopausal women (50-79); ½ receive estrogen + progestin Primary outcome Coronary heart disease (CHD) Primary adverse outcome Invasive breast cancer Rossouw JE, et al. JAMA. 2002;288(3): PMID: National Institutes of Health End Estrogen Study This is the final nail in the coffin for hormone replacement therapy Rubinow DR, et al. Sagecrossroads Website

9 If E2 Is So Good for You, Why Are They Saying Such Terrible Things About It? 1. Timing 2. Healthy cell hypothesis 3. Failure to consider individual differences in steroid sensitivity Neuroprotective Effects of Estradiol Dictated by Timing of Administration Post-Ovariectomy (OVX) Suzuki S, et al. Proc Natl Acad Sci U S A. 2007;104(14): PMID: Anti-Inflammatory Actions of Estradiol: Effects of Timing E2 exerted anti-inflammatory actions only when administered immediately after ovariectomy Suzuki S, et al. Proc Natl Acad Sci U S A. 2007;104(14): PMID:

10 Cardiovascular Disease No significant increased risk of coronary heart disease in women who are within 10 years of the onset of menopause 1 In women within 10 years of menopause: 29% increased risk in first two years 47% decreased risk thereafter 2 1. Rossouw JE, et al. JAMA. 2007;297(13): PMID: Toh S, et al. Ann Intern Med. 2010;152(4): PMID: Breast Cancer Both hormone therapy (HT) and estrogen therapy (ET) increase the risk of breast cancer: probably affected by duration and timing of therapy Estrogen use alone has been shown to reduce risk for breast cancer by a factor of four, in comparison with combined HT 1 Considering the worst-case scenario, the risk in a 50- to 54-year-old woman taking estradiol alone for five years increases from 13 per thousand (in women with no ET) to per thousand 2 1. Beral V, et al. Lancet. 2003;362(9382): PMID: Surveillance, Epidemiology and End Results (SEER) data Website. Effects of E2 Dictated by Gap After Menopause Condition Gap Duration ET vs. HT Route Regimen CVD 1,2 Beneficial short gap effect hazard ratio (HR) = 0.89 to 1.71,for women <10 years vs. > 20 years since menopause, CEE + progesterone For CEE (HR = 0.56, age 50-59) for young women or short gap (HR = 0.48) For CEE + progesterone, 25% - 30% decrease in mortality (young women) CEE = conjugated equine estrogen; HR = hazard ratio; ET = estrogen therapy; HT = hormone therapy 1. Rossouw JE, et al. JAMA. 2007;297(13): PMID: Salpeter SR, et al. Am J Med. 2009;122(1):42-52, e42. PMID:

11 Effects of E2 Dictated by Gap After Menopause Table (cont d) Condition Gap Duration ET vs. HT Route Regimen Breast Benefit seen with long Cancer 2,3 gap time only (> 5 years; CEE) RR = 0.58; same for CEE + progesterone; HR vs. 1, < 2 years vs. >3 years Long duration increases risk; no increased risk 2 years after discontinuation CEE alone RR = 0.80 Prog increases risk 2x - 4x No diff Sequential prog smaller RR CEE = conjugated equine estrogen; HR = hazard ratio; RR = relative risk; ET = estrogen therapy; HT = hormone therapy 2. Fournier A, et al. J Clin Oncol. 2009;27(31): PMID: Salpeter SR, et al. Am J Med. 2009;122(1):42-52 e42. PMID: Effects of E2 Dictated by Gap After Menopause Table (continued) Condition Gap Duration ET vs. HT Route Regimen Stroke 4 No effect No effect Dementia 5 Midlife HT has lowest prevalence, and latelife the highest prevalence Venous thromboem bolism 6 No effect; 40% increase for both -- Positive dose effect (0.932 to 1.62 for 0.3 to 1.25 mg of CEE) No difference RR of 2.5 oral vs 1.2 TDE CEE = conjugated equine estrogen; RR = relative risk; ET = estrogen therapy; HT = hormone therapy; TDE = transdermal estrogen 4. Grodstein F, et al. Arch Intern Med. 2008;168(8): PMID: Whitmer RA, et al. Ann Neurol. 2011;69(1): PMID: Canonico M. BMJ. 2008;336(7655): PMID: Neuroprotective Effects of E2 on Brain in Young Rats Neuroprotective Effects of E2 Rat Studies in Hippocampal CA1 Region in Young and Middle-Aged Rats After Global Ischemia Zhang QG, et al. Proc Natl Acad Sci Sci U S A. 2011;108(35):E PMID:

12 Absent Neuroprotective Effects of E2 in Old Rats Neuroprotective Effects of E2 Rat Studies in Hippocampal CA1 Region in Young and Middle-Aged Rats After Global Ischemia Zhang QG, et al. Proc Natl Acad Sci U S A. 2011;108(35):E PMID: If E2 Is So Good for You, Why Are They Saying Such Terrible Things About It? 1. Timing 2. Healthy cell hypothesis 3. Failure to consider individual differences in steroid sensitivity The Way the Steroid is Metabolized Determines Its Action Estradiol Dihydrotestosterone Androsterone Etiocholanolone 5αAndrostanediol 12

13 Hormones E 2 Estrogen Receptor ERE Courtesy of David Rubinow, MD Growth Factors Epdermal growth factor Tumor necrossis factor Insulin-like growth factor Neurotransmitter Dopamine Hormones E 2 Pl 2 E R Ca ++ camp G R SRC-1 Estrogen Receptors r Akt Mitogen-activated protein kinase (MAPK) CREB CBP P300 Co Regulator CRE AP-1 ERE PRE Courtesy of David Rubinow, MD Growth Factors Epdermal growth factor Tumor necrossis factor Insulin-like growth factor Neurotransmitter Dopamine Hormones E 2 Pl 2 E R Ca ++ camp G R SRC-1 Estrogen Receptors r Akt Mitogen-activated protein kinase (MAPK) CREB CBP P300 c-jun/c- Fos c-jun/c- Fos Co Regulator CRE AP-1 ERE PRE Courtesy of David Rubinow, MD 13

14 ER Alpha and Beta: A Physiological Tug of War NHD DBD Hinge LBD F herα herβ Gustaffson JA, et al. Biochem Pharmacol. 1979;28(4): PMID: What Is a Drug? A drug can be an inert substance, a poison, or a therapeutic agent, depending on how it is used and the dose in which it is given. Alle Ding' sind Gift und nichts ohn' Gift; allein die Dosis macht, dass ein Ding kein Gift ist. [Translation] All things are poison and nothing is without poison, only the dose permits something not to be poisonous. ~ Paracelsus SNPs Genotyped in ESR1 (6q25.1) Exons marker L0017 L0018 L0019 L0020 L0024 L0058 L0026 L0021 L0059 L0025 L0056 L0055 L0060 L0057 L0061 L0023 L0022 Intermarker distance (kb) Huo L, et al. Biol Psychiatry. 2007;62(8): PMID:

15 Premenstrual Syndrome: Significant Associations With SNPs Genotyped in ESR1 (6q25.1) Exons marker L0017 L0018 L0019 L0020 L0024 L0058 L0026 L0021 L0025 L0060 L0056 L0023 L0055 L0057 L0061 L0022 Intermarker distance (kb) Target region:16.7kb Huo L, et al. Biol Psychiatry. 2007;62(8): PMID: DLPFC Overactivation in PMDD Correlated With Symptom-Related Impairment A B PET PET-GAF fmri fmri-gaf DLPFC = dorsolateral prefrontal cortex; PMDD = premenstrual dysphoric disorder Baller E, et al. Am J Psychiatry. In press. Evidence for a Role of E2 in Depression The ER in depression (Animal Models) Functional Effects of E2 (Brain Imaging) E2 Antidepressant Efficacy Modulation of Gene Expression by Gonadal Steroids 15

16 10/19/12 Pregnancy Unmasks GABA Receptor Mutation * 25 * Τ Τ 0 WT WT δ-/thip Mothers (n) Pups (n) δ+/- δ+/thip Pups Cannibalized/ Neglected (%) Pups Cannibalized/ Neglected (%) Postpartum Depression and Infanticide 50 * 75 Τ * 50 Τ 25 0 WT Mothers (n) 9 Pups (n) 53 δ-/- δ+/ WT = Wild type THIP = a selective agonist (THIP) of GABAARs containing δ subunits δ = GABAA receptor δ subunit Maguire J, Mody I. Neuron. 2008;59(2): PMID: Clinical Connections Ovarian failure is associated with increased risk of CVD and of depression E2 has neuroprotective effects E2 deficiency, CVD, and depression share common pathophysiologic disturbances E2 has shown efficacy in treatment of perimenopausal depression Co-sponsored by 16

17 References for Slide 12 Correlates of Risk for Conditions and Cytokines Goldberg RB. J Clin Endocrinol Metab. 2009;94(9): PMID Chou E, et al. Circulation. 2002;105(3): PMID Cesari M, et al. Am J Cardiol. 2003;92(5): PMID Hanley AJ, et al. Diabetes Care. 2002;25(7): PMID Felmeden DC, et al. Am J Cardiol. 2003;92(4): PMID Hoogeveen RC, et al. Atherosclerosis. 2005;183(2): PMID Leonard BE. Neurochem Res. 2007;32(10): PMID Warner-Schmidt JL, et al. Curr Opin Pharmacol. 2008;8(1): PMID Vaccarino V, et al. Psychosom Med. 2008;70(1): PMID References for Slide 12 (cont d) Correlates of Risk for Conditions and Cytokines Mikova O, et al. Eur Neuropsychopharmacol. 2001;11(3): PMID Yudkin JS, et al. Atherosclerosis. 2000;148(2): PMID Berg AH, et al. Circ Res. 2005;96(9): PMID Yudkin JS, et al. Atherosclerosis. 2000;148(2): PMID Åsberg M, et al. PLoS One. 2009;4(1):e3590. PMID Wakatsuki A, et al. Arterioscler Thromb Vasc Biol. 2004;24(3): PMID Lindheim SR. Fertil Steril. 1993;60(4): PMID Cenci S, et al. J Clin Invest. 2000;106(10): PMID Pervin S, et al. Arterioscler Thromb Vasc Biol. 1998;18(10): PMID Losordo DW, et al. Arterioscler Thromb Vasc Biol. 2001;21(1):6-12. PMID References for Slide 16 Estrogen Receptors and Depression 1. Morgan MA, Pfaff DW. Behav Brain Res. 2002;132(1): PMID: Krezel W, et al. Proc Natl Acad Sci U S A. 2001;98(21): PMID: Tomihara K, et al. Physiol Behav. 2009;96(2): PMID: Lund TD, et al. Endocrinology. 2005;146(2): PMID: Walf AA, Frye CA. Neuropsychopharmacology. 2005;30(9): PMID: Imwalle DB, et al. Physiol Behav. 2005;84(1): PMID: Rocha BA, et al. Psychopharmacology (Berl). 2005;179(3): PMID: Walf AA, et al. Pharmacol Biochem Behav. 2004;78(3): PMID:

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