psychosocial stress and addison's disease

269 Pages·2006·4.84 MB·English

by  Nicolas Rohleder

PSYCHOSOCIAL STRESS AND ADDISON’S DISEASE

A NEW APPROACH TO EVALUATE THE RELEVANCE OF
ENDOCRINE STRESS RESPONSES FOR HEALTH AND DISEASE

DISSERTATIONSSCHRIFT

zur Erlangung des akademischen Grades

Doctor rerum naturalium
(Dr. rer nat.)

vorgelegt

der Fakultät Mathematik und Naturwissenschaften
der Technischen Universität Dresden

von

Dipl. Psych. Wolf, Jutta Manuela

geboren am 23.05.1974 in Waldshut-Tiengen

Gutachter: Prof. Dr. C. Kirschbaum
Prof. Dr. S. Bornstein
Prof. Dr. O. T. Wolf

Eingereicht am: 19.01.2006

Tag der Verteidigung: 06.03.2006

to Nic

to my and Nic’s family

I would like to thank Prof. Dr. C. Kirschbaum and Prof. Dr. O. T. Wolf. Without their ongoing
support and their scientific advice during the conception and conduction of the experiments,
this work would not have been possible.

Thanks go to my coworkers in Düsseldorf and Dresden, especially to Serkan Het, Gudrun
Ramlow, Stefanie Holdmann, and Marcel Piel for their assistance in data acquisition, and to
Simone M. Kern, Denise Dörfel, Johannes Müller, Tilman Hensch, Sirko Rabe, and Anke
Karl for being there at work and after work.

I am very grateful to Gregory E. Miller and Edith Chen for comments on the English language
in this thesis.

Finally, I would like to thank Nicolas Rohleder for providing the emotional framework during
completion of this thesis. Thank you for everything!

CONTENTS I
CONTENTS
1 INTRODUCTION 1
2 THEORETICAL BACKGROUND 3
2.1 THE NEUROENDOCRINE STRESS RESPONSE 3
2.1.1 STRESS CONCEPTS: HISTORICAL DEVELOPMENT 3
2.1.1.1 Claude Bernard 4
2.1.1.2 Walter Bradford Cannon 4
2.1.1.3 Hans Selye 4
2.1.1.4 John W. Mason 5
2.1.1.5 Richard S. Lazarus 6
2.1.1.6 Seymour Levine and Holger Ursin 7
2.1.1.7 Summary 9
2.1.2 CENTRAL AND PERIPHERAL STRESS SYSTEMS 9
2.1.2.1 HPA Axis 9
2.1.2.2 Sympathetic Nervous System 18
2.1.3 ACTIVATION OF STRESS SYSTEMS 22
2.1.3.1 Laboratory Stressors 22
2.1.3.2 Real-Life Stressors 23
2.1.3.3 Physical Exercise 23
2.1.4 PROTECTIVE EFFECTS OF STRESS MEDIATORS 24
2.1.4.1 Cardiovascular Effects 28
2.1.4.2 Metabolic Effects 28
2.1.4.3 Neurobiological Effects 30
2.1.4.4 Effects on Immunity and Inflammation 32
2.1.5 DAMAGING EFFECTS OF STRESS MEDIATORS 33
2.1.6 SUMMARY 39
2.2 ADDISON’S DISEASE 40
2.2.1 DEFINITION 41
2.2.2 PREVALENCE 42
2.2.3 SIGNS, SYMPTOMS, DISEASE PROGRESSION 42
2.2.4 LABORATORY ASSESSMENT OF PRIMARY ADRENAL INSUFFICIENCY 43
2.2.4.1 Basal Hormone Measurements 43
2.2.4.2 Pharmacological Stimulation tests 43
2.2.4.3 Radiologic Evaluation 45
2.2.4.4 Adrenal Autoantibody Tests 45
2.2.5 TREATMENT 45
2.2.6 ETIOLOGY OF ADDISON’S DISEASE 46
2.2.6.1 Infectious Addison’s Disease 47
2.2.6.2 Autoimmune Adrenalitis 48
2.2.7 SUMMARY 64
II CONTENTS
2.3 PSYCHONEUROIMMUNOLOGY 66
2.3.1 THE IMMUNE RESPONSE 67
2.3.1.1 First Line of Defense 67
2.3.1.2 Second Line of Defense: Innate immunity 68
2.3.1.3 Third Line of Defense: Adaptive Immunity 73
2.3.2 PSYCHONEUROIMMUNOLOGY: BRAIN – TO – IMMUNE SYSTEM COMMUNICATION 81
2.3.3 ROLE OF STRESS MEDIATORS 85
2.3.3.1 Effects of Glucocorticoids on Immune Functions 85
2.3.3.2 Effects of Catecholamines on Immune Functions 91
2.3.3.3 Immune System – to – Brain Communication 97
2.3.4 MECHANISMS AND MODULATION OF HORMONE-TO-IMMUNE SYSTEM SIGNALING 97
2.3.4.1 Mechanisms of Hormone-to-Immune System Signaling 97
2.3.4.2 Modulation of Hormone-to-Immune System Signaling 104
3 PROBLEM FORMULATIONS 110
3.1 ADDISON’S DISEASE: A METHOD 111
3.2 PROBLEM FORMULATIONS 112
3.2.1 STUDY 1: BASAL ENDOCRINE STATE 112
3.2.2 STUDY 2: STRESS EFFECTS IN ADDISON’S DISEASE 112
3.2.2.1 Psychosocial Stress: Endocrine and Cardiovascular Response 112
3.2.2.2 Psychosocial Stress: Immunological Consequences 113
3.2.2.3 Psychoneuroimmunology: Mediative Role of NF-(cid:1)B 114
4 RESULTS 115
4.1 ADDISON’S DISEASE: BASAL ENDOCRINE STATE 115
4.1.1 ABSTRACT 115
4.1.2 INTRODUCTION 116
4.1.3 METHODS 119
4.1.3.1 Subjects 119
4.1.3.2 Experimental Protocol 120
4.1.3.3 Biochemical Analysis 120
4.1.3.4 Statistical Analysis 120
4.1.4 RESULTS 121
4.1.4.1 Courses of Salivary Cortisol Levels 121
4.1.4.2 Salivary Cortisol Levels: Etiology, Gender, and Time Interval 122
4.1.4.3 Salivary Cortisol Levels: Glucocorticoid Replacement 122
4.1.5 DISCUSSION 124
4.2 ADDISON’S DISEASE: ENDOCRINOLOGICAL RESPONSE TO PSYCHOSOCIAL
STRESS 127
4.2.1 ABSTRACT 127
CONTENTS III
4.2.2 INTRODUCTION 127
4.2.2.1 Stress Response in Healthy Subjects 127
4.2.2.2 Stress Response in Patients with Addison’s Disease 129
4.2.2.3 Aim of the Study 131
4.2.3 METHODS 131
4.2.3.1 Subjects 131
4.2.3.2 Experimental Protocol 132
4.2.3.3 Fatigue Assessment 132
4.2.3.4 Biochemical Analyses 133
4.2.3.5 Statistical Analysis 133
4.2.4 RESULTS 133
4.2.4.1 Fatigue Assessment 133
4.2.4.2 Baseline Differences 134
4.2.4.3 Salivary Free Cortisol Stress Response 134
4.2.4.4 Effects of Treatment on Salivary Free Cortisol Levels 135
4.2.4.5 Catecholamine Stress Response 135
4.2.4.6 Cardiovascular Stress Response 136
4.2.5 DISCUSSION 137
4.3 ADDISON’S DISEASE: PSYCHOSOCIAL STRESS AND IMMUNOLOGICAL
CONSEQUENCES 140
4.3.1 ABSTRACT 140
4.3.2 INTRODUCTION 141
4.3.2.1 Aim of the Study 142
4.3.3 METHODS 144
4.3.3.1 Subjects 144
4.3.3.2 Experimental Protocol 144
4.3.3.3 Biochemical Analyses 145
4.3.3.4 Statistical Analysis 146
4.3.4 RESULTS 147
4.3.4.1 Stress Effects in Healthy Subjects 147
4.3.4.2 Baseline Differences (AD vs. HS) 148
4.3.4.3 Stress-Induced Changes in Blood Cell Counts 149
4.3.4.4 Stress-Induced Changes in LPS-Stimulated IL-6 Production and Glucocorticoid
Sensitivity of LPS-Stimulated IL-6 Production 150
4.3.4.5 Stress-Induced Changes in PHA-Stimulated Cell Proliferation and Glucocorticoid
Sensitivity of PHA-Stimulated Cell Proliferation 153
4.3.4.6 Summary of Results 154
4.3.5 DISCUSSION 154
4.3.5.1 Blood Cell Counts 155
4.3.5.2 LPS-Stimulated IL-6 Production 156
4.3.5.3 PHA-Stimulated Cell Proliferation 159
4.3.5.4 Conclusion and Outlook 160
4.4 ADDISON’S DISEASE: PSYCHONEUROIMMUNOLOGY AND THE MEDIATIVE
ROLE OF NF-(cid:1)B 162
4.4.1 ABSTRACT 162
IV CONTENTS
4.4.2 INTRODUCTION 163
4.4.2.1 NF-(cid:1)B is Central to Immune System Activation 163
4.4.2.2 Glucocorticoid Effects are Mediated by Inhibition of NF-(cid:1)B Activity 164
4.4.2.3 Catecholamines Interfere with NF-(cid:1)B Activity 166
4.4.2.4 Aim of the Present Study 167
4.4.3 METHODS 167
4.4.3.1 Subjects 167
4.4.3.2 Experimental Protocol 168
4.4.3.3 Biochemical Analyses 169
4.4.3.4 Statistical Analysis 170
4.4.4 RESULTS 172
4.4.4.1 Baseline Differences 172
4.4.4.2 Salivary Free Cortisol Levels: Effects of Stress and Treatment 172
4.4.4.3 Catecholamine Levels: Effects of Stress 172
4.4.4.4 NF-(cid:1)B Binding Activity: Effects of Stress, Disease, and Treatment 173
4.4.4.5 Endocrine Variables: Indices of Variation 174
4.4.4.6 Regression Analyses: Predictors of NF-(cid:1)B Binding Activity Variations 175
4.4.5 CONCLUSION 176
5 SUMMARY, GENERAL DISCUSSION, AND OUTLOOK 179
5.1 SUMMARY OF RESULTS 179
5.1.1 INITIAL ENDOCRINOLOGICAL CONDITIONS IN ADDISON’S DISEASE 179
5.1.2 EFFECTS OF ALTERED ENDOCRINE STRESS RESPONSES ON THE IMMUNE SYSTEM 181
5.1.2.1 Blood Cell Counts 182
5.1.2.2 LPS-Stimulated IL-6 Production and its Glucocorticoid Sensitivity 182
5.1.2.3 PHA-Stimulated Cell Proliferation and its Glucocorticoid Sensitivity 183
5.1.2.4 NF-(cid:1)B Activity 184
5.2 GENERAL DISCUSSION 185
5.2.1 INITIAL ENDOCRINOLOGICAL CONDITIONS 185
5.2.1.1 Initial Basal Conditions 185
5.2.1.2 Initial Stress-Related Conditions 187
5.2.1.3 Summary 190
5.2.2 EFFECTS OF ALTERED ENDOCRINE STRESS RESPONSES ON THE IMMUNE SYSTEM 191
5.2.2.1 Baseline Differences 191
5.2.2.2 Stress-Related Differences 192
5.2.3 SUMMARY OF GENERAL DISCUSSION 195
5.3 OUTLOOK 196
6 REFERENCES 198