Psychological stress and risk of hormone-dependent cancers

Transcription

1 UNIVERSITY OF CALIFORNIA Los Angeles Psychological stress and risk of hormone-dependent cancers A dissertation submitted in partial satisfaction of the requirements for the degree Doctor of Philosophy in Epidemiology by Naja Rod Nielsen 2007

2 The dissertation of Naja Rod Nielsen is approved Abdelmonem A. Afifi Morten Grønbæk Beate Ritz Barbara Visscher Zuo-Feng Zhang, Committee Chair University of California, Los Angeles, 2007

3 TABLE OF CONTENTS I. Introduction 1 Objective and specific aims 2 Causal hypothesis 4 Outline 4 Definition of stress 5 Incidence and prevalence of hormone-dependent cancers 7 II. Material and methods 14 The Copenhagen City Heart Study 14 Measurement of perceived stress 15 Assessment of endpoints by linkage to national registers 16 Statistical methods 16 III. Stress and breast cancer: a current overview of prospective studies 23 Introduction 23 Assessment methods 24 Results 26 Discussion 29 Conclusion 33 IV. Stress and other hormone-dependent cancers: current knowledge 39 Endometrial cancer 39 Colorectal cancer 40 Prostate cancer 42 V. Self-reported stress and risk of breast cancer: a prospective cohort study 47 Introduction 47 Methods 47 Results 49 Discussion 50 Conclusions 53 VI. Self-reported stress and risk of endometrial cancer: a prospective cohort study 61 Introduction 61 Methods 62 Results 64 Discussion 66 ii

4 VII. Perceived stress and risk of colorectal cancer: a prospective cohort study 75 Introduction 75 Methods 76 Results 78 Discussion 80 VIII. Sociodemographic status, stress and risk of prostate cancer: a prospective cohort study 92 Introduction 92 Methods 93 Results 95 Discussion 97 Conclusion 100 IX. Perceived stress and sex steroid hormones: a cross-sectional study 106 Introduction 106 Methods 107 Results 109 Discussion 109 X. Stress and hormone-dependent cancers: a discussion of the evidence 117 Is there a relation between stress and hormone-dependent cancers? 117 The strength of the Copenhagen City Heart Study 120 Selection bias and external validity 121 Misclassification of perceived stress 121 Misclassification of outcome measures 123 Confounding 124 Random error 127 XI. Conclusion 128 XII. Public health implications 130 Is stress a public health problem? 130 Future population studies on stress and risk of hormone-dependent cancers 132 XIII. Bibliography 136 iii

5 LIST OF TABLES Chapter I Table 1-1. Overview of major stress theories and definition... 9 Table 1-2. Estimates of the incidence and mortality rate per 100,000 as well of the oneyear prevalence in the total population of hormone-dependent cancers in Denmark, USA, and the World Chapter II Table 2-1. Baseline characteristics of the 12,698 men and women who participated in the second examination of the Copenhagen City Heart Study in Table 2-2. Number of primary site-specific hormone-dependent cancer cases occurring during follow-up (year ) in the Copenhagen City Heart Study Chapter III Table 3-1. Summary of prospective studies on stress and breast cancer incidence Table 3-2. Summary of prospective studies on stress and breast cancer relapse Chapter IV Table 4-1. Summary of previous studies on stress and endometrial cancer Table 4-2. Summary of previous studies on stress and colorectal cancer Chapter V Table 5-1. Baseline characteristics of women who participated in the second examination of the Copenhagen City heart study in Values are numbers (percentages) unless stated otherwise Table 5-2. Incidence and hazard ratio of primary breast cancer associated with intensity and frequency of stress among 6689 Danish women participating in the second examination of the Copenhagen City heart study in Table 5-3. Incidence and hazard ratio of primary breast cancer associated with stress score among 6689 Danish women participating in the Copenhagen City heart study in Table 5-4.Incidence and hazard ratio of primary breast cancer associated with categorized stress score among 6689 Danish women participating in the Copenhagen City heart study in , according to time period of follow-up iv

6 Table 5-5.Hazard ratio of primary breast cancer associated with stress score among 6689 Danish women participating in the Copenhagen City heart study in , in subgroups of hormone therapy Chapter VI Table 6-1. Baseline characteristics of 6,760 women who participated in the second examination of the Copenhagen City Heart Study in Table 6-2. Incidence, hazard ratio (HR), and 95 % confidence interval (CI) for first-time incidence of primary endometrial cancer associated with perceived stress among 6,760 women who participated in the Copenhagen City Heart Study in Table 6-3. Incidence, hazard ratio (HR), and 95 % confidence interval (CI) for first-time incidence of primary endometrial cancer associated with perceived stress among 6,760 women who participated in the Copenhagen City Heart Study in by hormone status Table 6-4. Incidence, hazard ratio (HR), and 95 % confidence interval (CI) for first-time incidence of primary endometrial cancer associated with perceived stress among 6,760 women who participated in the Copenhagen City Heart Study in by body mass index Chapter VII Table 7-1. Baseline characteristics of the 6,488 women and 5,426 men who participated in the second examination of the Copenhagen City Heart Study in Table 7-2. Women. Incidence, hazard ratio (HR), and 95 % confidence interval (CI) for first-time incidence of primary colorectal, colon, and rectal cancer associated with perceived stress among 6,488 women who participated in the Copenhagen City Heart Study in Table 7-3. Hazard ratio (HR), and 95 % confidence interval (CI) for first-time incidence of primary colorectal, colon, and rectal cancer associated with a seven-unit stress score among 1,716 pre-menopausal and 4,772 post-menopausal women who participated in the Copenhagen City Heart Study in v

7 Table 7-4. Men. Incidence, hazard ratio (HR), and 95 % confidence interval (CI) for first-time incidence of primary colorectal, colon, and rectal cancer associated with perceived stress among 5,426 men who participated in the Copenhagen City Heart Study in Chapter VIII Table 8-1. Baseline characteristics of the 5,496 men who participated in the second examination of the Copenhagen City Heart Study in Table 8-2. Risk of primary prostate cancer associated with sociodemographic variables among 5,496 men who participated in the Copenhagen City Heart Study in Table 8-3. Risk of primary prostate cancer associated with perceived stress among 5,496 men who participated in the Copenhagen City Heart Study in Table 8-4. Risk of primary prostate cancer associated with perceived stress and sociodemographic variables according to period of follow-up Chapter IX Table 9-1. Median and relative difference in geometric mean of 17β-estradiol by category of stress among 832 postmenopausal women who did not use hormones Table 9-2. Median and relative difference in geometric mean of free testosterone by category of stress among 840 postmenopausal women who did not use hormones Table 9-3. Median and relative difference in geometric mean of cortisol by category of stress among 840 postmenopausal women who did not use hormones Chapter XII Table Estimates of the number of ischemic heart disease and breast cancer there can be attributed/ prevented by perceived stress among women in the Copenhagen City Heart Study vi

8 LIST OF FIGURES Chapter I Figure 1-1. Causal hypothesis for the relation between perceived stress and risk of hormone-dependent cancers Figure 1-2. Different approaches to stress research and their relation to hormonedependent cancers Figure 1-3. Age-standardized incidence and mortality rates of site-specific cancers in Denmark in year Chapter II Figure 2-1. Formation of the stress-score based on an additive approach. The numbers indicates the score on the seven-point stress-score and the numbers in parentheses indicates the proportion of the total study sample in each category. The lines indicate the categorization of the seven-point stress-score into low, medium, and high stress Chapter III Figure 3-1. Flow diagram of the data collection process Chapter V Figure 5-1. Causal diagram of the relation between perceived stress and risk of breast cancer Chapter VI Figure 6-1. Causal diagram for the relation between perceived stress and risk of endometrial cancer Chapter VII Figure 7-1. Causal diagram for the relation between perceived stress and risk of colorectal cancer Chapter VIII Figure 8-1. Causal diagram for the relation between socio-economic status, marital status, perceived stress, and risk of prostate cancer vii

9 Chapter IX Figure 9-1. Flow diagram of the data selection process Figure 9-2. Circadian pattern for 17β-estradiol, free testosterone, and cortisol Chapter XII Figure Questionnaire used for the Perceived Stress Scale viii

10 LIST OF ABBREVATIONS AND DEFINITIONS Allostasis: The process by which we actively adjust ourselves to predictable and unpredictable events, and thereby preserve the homeostatic stability of vital body systems. The primary mediators of allostasis are the sympathetic nervous system and hormones of the hypothalamus-pituitary-adrenal axis. CI: Confidence interval Distress: The mental and bodily reaction generated by a stressor. Such reactions may include neurobiological changes in cortisol and other hormones, physical changes in blood pressure, heart rate, and muscle tension, as well as varying mental states (e.g. anxiety, nervousness, depression). HR: Hazard ratio Hormone-dependent cancers: Cancers that have a hormonal component, so that their development to some degree depends on levels of sex steroid hormones. HPA-axis: Hypothalamic-Pituitary-Adrenal axis HPG-axis: Hypothalamic-Pituitary-Gonadal axis Perceived stress: An individual s appraisal of an imbalance between demands (stressors) and his or hers resources to cope with it. Stressor: An external stimuli that may increase the demand of the individual, for example adverse life events (e.g. divorce, death within the family), daily hassles (e.g. computer problems, being late for the bus), and characteristics of the job situation (e.g., demands, control, rewards). ix

11 AKNOWLEDGEMENTS Writing this dissertation has provided me with an opportunity to comprehensively address the relation between stress and cancer and combine it with an exploration of conventional and upcoming epidemiologic methods. Epidemiologic studies at the Department of Epidemiology at University of California, Los Angeles has inspired me to use alternative epidemiologic methods and has led me to see some of the flaws sometimes contained in conventional approaches. I thank my committee members, Drs. Zhang, Ritz, Visscher, Afifi, and Grønbæk for their support and guidance throughout my doctoral studies. I especially want to thank my advisor Dr. Zhang for encouraging me to do my doctoral studies at UCLA and for being a supportive and inspiring mentor. I had the pleasure of being able to write the dissertation at the Danish National Institute of Public Health surrounded by great colleagues. I am grateful for Dr. Grønbæk s openness to and sincere interest in my research as well as his detailed guidance during the writing process. I also want to thank Dr. Søndergaard Kristensen for his constructive comments and for sharing with me his broad knowledge on stress research, and Dr. Hansen for her help and support with the laboratory analyses. I am grateful that my good friends and colleagues Majken Karoline Jensen and Katrine Strandberg-Larsen took the time to comment on my dissertation, and I highly value the statistical comments and philosophical discussions with my father Jens Nielsen. Thanks to my friends and family for their support and love and a special thanks to Morten Hulvej Jørgensen for making it all worthwhile. I thank the steering committee and the staff of the Copenhagen City Heart Study for letting me use the data and for provided me with valuable help. Chapter 3 is a version of Nielsen NR, Grønbæk M. Stress and breast cancer: A systematic update on the current knowledge. Nat Clin Pract Oncol 2006; 3: Chapter 5 is a version of Nielsen NR, Zhang ZF, Kristensen TS, Netterstrøm B, Schnohr P, Grønbæk M. Selfreported stress and risk of breast cancer. BMJ 2005;331:548. This study was supported by funds from the Health Insurance Foundation. Chapter 6 is a version of Nielsen NR, Strandberg-Larsen K, Grønbæk M, Kristensen TS, Schnohr P, Zhang ZF. Is perceived stress associated with lower risk of endometrial cancer? A prospective cohort study. Psychosom Med (in press). The study was supported by funds from the Health Insurance x

12 Foundation and the Lundbeck Foundation. Chapter 7 is a version of Nielsen NR, Kristensen TS, Strandberg Larsen K, Zhang ZF, Schnohr P, Grønbæk M. Perceived stress and risk of colorectal cancer in men and women: a prospective cohort study (submitted). The study was supported by funds from the Lundbeck Foundation and the Danish Cancer Society. Chapter 8 is a version of Nielsen NR, Kristensen TS, Zhang ZF, Strandberg-Larsen K, Schnohr P, Grønbæk G. Sociodemographic status, stress and risk of prostate cancer: a prospective cohort study. Ann Epidemiol (in press). The study was supported by funds from the Health Insurance Foundation and the Lundbeck Foundation. Drs. Åse Marie Hansen, Jens Nielsen, and Morten Grønbæk contributed to the study on stress and sex steroid hormones presented in chapter 9. xi

13 VITA November 17, 1977 Born, Odense, Denmark 2001 Research assistant The Bandim Health Project Guinea-Bissau, West Africa Research assistant Institute of Preventive Medicine Copenhagen, Denmark 2002 B.S., Public Health Science University of Copenhagen Copenhagen, Denmark Graduate research assistant National Institute of Public Health Copenhagen, Denmark 2004 M.S., Public Health Science University of Copenhagen Copenhagen, Denmark 2006 Raymond D. Goodman Scholarship Award UCLA School of Public Health Los Angeles, California 2006 Teaching assistant Department of Social Medicine University of Copenhagen Copenhagen, Denmark xii

14 PUBLICATIONS AND PRESENTATIONS Nielsen NR (May 2003). Is the effect of alcohol on risk of stroke confined to highly stressed persons? Oral presentation at the 12 th European Stroke Conference, Valencia, Spain Nielsen NR, Schnohr P, Jensen G, Grønbæk M. (2004). Is the relationship between type of alcohol and mortality influenced by socio-economic status? J Intern Med, 255: Nielsen NR, Kjøller M, Jørgensen FK, Grønbæk M. (2004) [Stress among working population of Danes]. Ugeskr Laeger, 166: Nielsen NR (April, 2004). Stress reporting in a representative health interview study of Danes. Oral presentation at The 1 st Danish Stress Conference, Copenhagen, Denmark Nielsen NR, Thygesen LC, Johansen D, Jensen G, Grønbæk M. (2005). The influence of duration of follow-up on the interpretation of estimates from prospective studies. Alcohol and mortality in the Copenhagen City Heart Study. Ann Epidemiol, 15:44-55 Nielsen NR, Truelsen T, Barefoot J, Johnsen SP, Overvad K, Schnohr P, Grønbæk M. (2005). Is the association between alcohol and stroke modified by self-reported stress? Neuroepidemiology, 25: Nielsen NR, Zhang ZF, Kristensen TS, Netterstrøm B, Schnohr P, Grønbæk M. (2005). Self-reported stress and risk of breast cancer. BMJ, 331:548. Nielsen NR (June, 2005). Self-reported stress and risk of breast cancer. Oral presentation at the Society of Epidemiologic Research annual meeting, Toronto, Canada xiii

15 Nielsen NR (November, 2005). Perceived stress and risk of ischemic heart disease: Causation or bias? Oral presentation at the 2 nd Danish Stress Conference, Copenhagen, Denmark Nielsen NR, Kristensen TS, Prescott E, Strandberg Larsen K, Schnohr P, Grønbæk M. (2006). Perceived stress and risk of ischemic heart disease: Causation or bias? Epidemiology, 17: Nielsen NR (June, 2006). Interactions between intakes of alcohol and postmenopausal hormones on risk of breast cancer. Oral presentation at the 2 nd American Congress of Epidemiology, Seattle, Washington Nielsen NR (June, 2006). Is perceived stress associated with lower risk of endometrial cancer? Poster presentation at the IEA-EEF European Congress of Epidemiology, Utrecht, Holland Nielsen NR, Grønbæk M. (2006). Stress and breast cancer: A systematic update on the current knowledge. Nat Clin Pract Oncol, 3: Nielsen NR (November, 2006). Perceived stress and risk of colorectal cancer in men and women. Poster presentation at the International Congress of Behavioral Medicine, Bangkok, Thailand Nielsen NR, Strandberg Larsen K, Grønbæk M, Kristensen TS, Schnohr P, Zhang ZF (2007). Is perceived stress associated with lower risk of endometrial cancer? A prospective cohort study. Psychosom Med (in press) Nielsen NR, Kristensen TS, Zhang ZF, Strandberg-Larsen K, Schnohr P, Grønbæk M (2007). Sociodemographic status, stress and risk of prostate cancer. A prospective cohort study. Ann Epidemiol (in press) xiv

16 Strandberg Larsen K, Nybo Andersen A, Olsen J, Nielsen NR, Grønbæk M. (2006). Do women give the same information on binge drinking during pregnancy when asked repeatedly? Eur J Clin Nutr, 60: Truelsen T, Nielsen NR, Boysen G, Grønbæk M (2003). Self-reported stress and risk of stroke. Stroke, 34(4): xv

17 ABSTRACT OF THE DISSERTATION Psychological stress and risk of hormone-dependent cancers by Naja Rod Nielsen Doctor of Philosophy in Epidemiology University of California, Los Angeles, 2007 Professor Zuo-Feng Zhang, Chair Background and objective: Psychological stress is an increasing public health problem and may play a role in the etiology of hormone-dependent cancers by impairing the body s synthesis of and sensitivity towards sex steroid hormones. The objective of the dissertation is to address a potential relation between perceived stress and risk of primary breast, endometrial, colorectal, and prostate cancers as well as to address if perceived stress affects endogenous levels of sex steroid hormones. Material and methods: The 12,698 men and women who participated in the longitudinal Copenhagen City Heart Study were asked about their stress level in The participants were followed in a cancer registry until year 2000 and first-time incidence of primary hormone-dependent cancers were identified. Less than 0.1 % was lost to follow-up. Causal diagrams were used to visualize the assumed causal model and Cox proportional hazard models were used to analyze data. Plasma levels of sex steroid hormones were assayed in a sub-sample of postmenopausal women. Results: A one-unit change in perceived stress measured on a seven-point stress scale was consistently associated with lower risk of breast (hazard ratio: 0.92; 95 % confidence intervals: ), endometrial (0.88; ), and colon cancer (0.89; ) in a linear dose-response manner in women. Some sub-groups were more sensitive to the effect of stress than others, especially those women who received xvi

18 hormone therapy. However, no differences in endogenous sex steroid hormones were observed among postmenopausal women with varying stress levels. There were no evidence of a relation between perceived stress and risk of colorectal (0.99; ) or prostate cancer (0.99; ) in men. Discussion: We found perceived stress to be associated with a lower risk of hormonedependent cancers in women. However, it is important to emphasize that stress is not a healthy response and that the total burden of disease attributable to perceived stress most likely may exceed the few cases of hormone-dependent cancers that may be prevented by stress. xvii

19 I. Introduction Psychological stress is a public health problem in the Western world. Taking Denmark as an example, about one in every ten Danish adults report high levels of stress in their daily life, and the number is increasing. 1 This may imply adverse health consequences for the individual as well as lead to expenses at the societal level. Psychological stress may affect the immune system and the hormone system, as well as lead to changes in health behavior and may thereby affect the risk of cancer. 2 More than half of all incident cancers in women and more than one third of all incident cancers in men in the Western world seem to be related to endogenous levels of sex steroid hormones. 3 This includes common cancers such as breast, colorectal, and prostate cancers. 4-9 Each of these cancers constitute a major public health problem and known risk factors can only partly explain their incidence. In order to prevent these diseases, modifiable risk factors, which affect the cancer process directly via initiation or promotion of the carcinogenesis or indirectly through changes in hormone levels, should therefore be identified. The role of psychological stress in the etiology of hormone-dependent cancers has been an area of emerging interest, in part because of its suggested ability to alter endogenous levels of sex steroid hormones The sympathetic nervous system and the hypothalamic-pituitary-adrenal (HPA) axis are the main mediators of the stress response. 13 We use this system to adapt ourselves to unexpected and stressful situations. Stress hormones released by the HPA-axis might suppress the synthesis and metabolism of sex steroid hormones, which are important risk factors for hormone-dependent cancers. This hypothesised stress-induced suppression of sex steroid hormones may lead to a lower risk of hormone-dependent cancers. Conversely, persistent activation of the HPA-axis also seem capable of suppressing the function of the immune system, which may result in a reduced ability to recognize and destroy neoplastic cell growth. 2;14 This mechanism may increase the risk of cancer and thereby oppose the stress-induced suppression of sex steroid hormones. The importance of each of these mechanisms probably depends on the population and the type of cancer in question. Three distinct phenomena have been studied as aspects of the stress concept, that is, external stressors, perceived stress, and individual states of stress (distress). The 1

20 majority of stress research in relation to hormone-dependent cancers has focused on external stressors and especially stressful life events as a potential risk factor for breast cancer. 15 Perceived stress, on the other hand, arises when the individual finds there to be an imbalance between external stressors and his or her ability to cope with them. 16 This will often lead to distress, which is an individual state of stress ranging in severity from modest stress-reactions and sleep-problems to fatigue, vital exhaustion, burn out, and depression. Few studies have addressed the impact of perceived stress on risk of tumors of the mammary gland, the male and female reproductive system organs, or colorectal cancer. The physiological stress response is highly dependent on the type and the timing of the stressor, which makes it vital to distinguish between different types of stress. Several studies have reported that the physiological stress response resulting from acute stress differs markedly from the one resulting from chronic stress. 13;17 The physiological effects of acute stressors are in most cases reversible due to the remarkable ability of the human organism to re-establish homeostasis. In an acute stress situation, the body is prepared to use all its energy on survival and re-establishment of homeostasis, which is an appropriate response. The problems mainly arise if the stress-response is prolonged and becomes chronic in nature, which may result in permanent disturbances in the homeostasis of vital body systems. 17 My hypothesis is that perceived stress can lead to chronic disturbances in the homeostasis of sex steroid hormones and thereby be related to risk of hormone-dependent cancers. Objective and specific aims The main objective of the dissertation is to address a potential relation between perceived stress and risk of primary breast, endometrial, colorectal, and prostate cancers as well as to address if perceived stress affects endogenous levels of sex steroid hormones. The objectives are addressed in studies based on data from the Copenhagen City Heart Study, which is a cohort of 12,698 Danish men and women prospectively followed-up for 20 years. An approach combining the information obtained from the present studies with current biological, psychological, and epidemiological knowledge 2

21 will be used to address the posed questions in a valid manner. The dissertation has five specific aims: Specific aim 1. To examine the main effects of self-reported measures of stress intensity and stress frequency on first time incidence of primary breast cancer and to investigate whether the main effects of stress are altered by menopause and postmenopausal hormone therapy among the women who participated in the Copenhagen City Heart Study. Cox proportional hazard models are used to analyse data. Specific aim 2. To examine the main effects of self-reported measures of stress intensity and stress frequency on first time incidence of endometrial cancer and to investigate whether the main effects of stress are altered by menopause and postmenopausal hormone therapy among the women who participated in the Copenhagen City Heart Study. Cox proportional hazard models are used to analyse data. Specific aim 3. To examine the main effects of self-reported measures of stress intensity and stress frequency on incidence of first time primary colon and rectal cancers and to investigate whether the main effects of stress are altered by sex among the participants in the Copenhagen City Heart Study. Cox proportional hazard models are used to analyse data. Specific aim 4. To examine the main effects of socio-economic status, marital status and self-reported measures of stress intensity and stress frequency on first time incidence of primary prostate cancer among the men who participated in the Copenhagen City Heart Study. Cox proportional hazard models are used to analyse data. Specific aim 5. To assess if self-reported stress intensity and stress frequency were associated with plasma levels of estrogen, testosterone, and cortisol in a subset of 1,150 postmenopausal women randomly sampled from all the postmenopausal women who participated in the Copenhagen City Heart Study. Linear regression models are used to analyse data. 3

22 Causal hypothesis The underlying causal hypothesis is that perceived stress will affect the risk of hormonedependent cancers by direct pathophysical mechanisms and indirect behavioral mechanisms (figure 1-1). Perceived stress may directly lead to prolonged activation of the sympathetic nervous system and the hypothalamus-pituitary-adrenal axis, which through cortisol and other stress hormones can affect the synthesis and metabolism of sex steroid hormones as well as impair the immune system and thereby, depending on the etiology of each specific type of cancer, result in an altered risk of hormonedependent cancers. Further, high levels of perceived stress may lead to changes in health-related behavior, whereby stress contributes to a higher frequency of adverse health behaviors (e.g., smoking, high fat diet, physical inactivity, and high alcohol consumption), which may indirectly affect the risk of hormone-dependent cancers. Outline The dissertation is based on a review paper and four epidemiologic studies, which are either published in or submitted to peer reviewed journals (please refer to acknowledgements for references). The dissertation is divided into twelve chapters. The theoretical basis of the dissertation is presented in the current chapter. Chapter two is a detailed description of the material and methods used in the dissertation. The following chapter is a systematic review of the evidence from prospective studies on stress as a risk factor for breast cancer incidence or relapse. The fourth chapter is an overview over the relatively few studies that have assessed the association between stress and other hormone-dependent cancers. The following four chapters (five to eight) each include a prospective cohort study that addresses the association between perceived stress and risk of breast, endometrial, colorectal, and prostate cancer, respectively. A cross-sectional study on the association between perceived stress and sex steroid hormones is described in chapter nine. Chapter ten includes a critical discussion of the evidence of a relation between perceived stress and risk of hormone-dependent cancers. The degree to which the estimated quantitative measure of the association between perceived stress and risk of hormone-dependent cancers deviates from a possible causal relation by systematic and random processes is also addressed. The empirical evidence of a relation between 4

23 perceived stress and risk of hormone-dependent cancer and its causal implications is summarized in the conclusion in chapter eleven. The conclusion is put into a public health perspective in the final chapter, where the individual and social consequences of a relation between stress and risk of hormone-dependent cancers and other health outcomes are briefly addressed, and future studies on stress and hormone-dependent cancers are discussed. Definition of stress Theoretical background There is no clear consensus on how to define stress, and many different definitions have been suggested. Three distinct phenomena of the stress concept have primarily been studied, that is, external stressors, perceived stress, and distress. Stress theories, which provide the theoretical basis for the different definitions of stress, can at the very general level be divided into three major and quite distinct approaches: stimulus-oriented, response-oriented, and interactional theories. 18 The stimulus-oriented and responseoriented theories provide the theoretical background for the study of external stressors and the stress reaction (distress), respectively, while the interactional theories emphasize perceived stress (figure 1-2). The main characteristics of the different theories are summarized in table 1-1. The stimulus-oriented theories define stress in terms of external stimuli that may increase the demand of the individual (stressors). The main focus of the stimulusoriented theories is the number and amount of external stressors, such as adverse life events (e.g., divorce, death within the family), daily hassles (e.g., computer problems, being late for the bus), and characteristics of the job situation (e.g., demands, control, rewards). Response-oriented theories, on the other hand, define stress as the mental and bodily reaction generated by stressful stimuli. 18 Such reactions may include neurobiological changes in cortisol levels, physical changes in blood pressure, heart rate and muscle tension, as well as varying degrees of distress (e.g., anxiety, nervousness, depression). By emphasizing the individual as an important mediator between external stressors and the resulting stress response, the interactional theories provide a newer approach to 5

24 stress research. 18 Each individual has different capacity and ways of handling stressful situations, and the same external stressor may therefore result in different levels of stress depending on the individual s mental attitude and personal resources. 13 Early learning in concert with psychosocial and cultural influences may be important in determining the individual s attitude toward a potential stressful situation. 19 Not only the attitude toward stressful situations but also external resources play an important part in coping with stressful situations. While some individuals have a strong social network, which may act as a buffer against a detrimental behavioral or physiological stress response, others lack this kind of support. An individual s social network and personal resources seem to greatly influence the way the individual adapts to and resolves an encounter with a stressful situation. 20 The interactional theories emphasize the importance of taking individual differences in appraisal and coping into account when measuring stress. The theory on stress, appraisal and emotion developed by Richard S. Lazarus has been a cornerstone in the development of the interactional theories. 16 According to Lazarus, neither the stimulus- nor the response-oriented approaches succeed in explaining the stress experience. The traditional stimulus-oriented approach fails to explain why and how we respond differently to an external stimulus, which makes the stimulus alone insufficient to define stress. 16 Individual differences in stress response becomes more pronounced when addressing less acute stressors, like everyday stress, making the stimulus-approach even more insufficient for this type of research. The responseoriented approach does not provide any important additional information beyond that of the stimulus-approach because it is built on a circular reasoning, where the stressor is defined by the fact that it leads to a stress response, while the stress response, in turn, is defined in reference back to the stressor. 16 Further, some response-oriented theories have been used to try to describe the phenomenon (stress) by describing its parts (e.g. elevated blood pressure). A problem with this approach is that we cannot necessarily explain what happens on one level of analysis by referring to another level. The interactional theories are putting the person back in the equation by emphasizing the importance of the personal cognitive appraisal of how threatening an external stimulus seems to the specific person s values, beliefs and goals, and whether he or she will be able to successfully cope with it. 16 In the dissertation, stress will 6

25 therefore, in accordance with Lazarus, be defined as the individual s appraisal of an imbalance between demands and the individual s resources to cope with it. 16 Acute and chronic stress The concept of allostasis will be used to illuminate the subtle differences between acute and chronic stress in their effect on pathologies such as hormone-dependent cancers. Allostasis is central to the stress response and to survival in general, because it is the process by which we actively adjust ourselves to predictable and unpredictable events, and thereby preserve the homeostatic stability of vital body systems. 17 The primary mediators of allostasis are the sympathetic nervous system and hormones of the hypothalamus-pituitary-adrenal (HPA) axis. These mediators are altered in response to changing environments or other challenges to the individual and are therefore essential to the stress response. Most allostatic mediators have a biphasic role with protective effects in the short run and damaging effects over longer time periods. 17 Glucocorticoids are good examples of this biphasic role in that they can convert proteins and lipids to carbohydrates and thereby replenish energy reserves in an acute stress situation. At the same time, they can result in obesity and insulin resistance if they are chronically elevated in response to sustained stress. 17 Sustained stress is therefore important in terms of disease development and this type of stress will be the main focus of this dissertation. In sum, stress should ideally be assessed as an individual perception of prolonged stress. Incidence and prevalence of hormone-dependent cancers Breast cancer is the most common cancer in terms of incidence and the second most common cancer in terms of mortality among Danish women (figure 1-3). Colorectal cancer is the second most common cancer in both men and women in Denmark, closely followed by prostate cancer in terms of both incidence and mortality among Danish men. Other hormone-dependent cancers such as endometrial, ovarian, cervix, and testicular cancers are relatively rare both in terms of incidence and mortality. Fortunately, the incidence rates of even the most common hormone-dependent cancers are low, and the studies included in the dissertation will therefore be confined to the study of stress as a risk factor for the three most common hormone-dependent cancers, 7

26 namely breast-, colorectal-, and prostate cancer. Despite a low incidence rate, a potential relation between stress and risk of endometrial cancer will also be addressed, because endometrial cancer, together with breast cancer, shows the strongest dependency on sex steroid hormones, especially estrogens. Estimates of crude and age standardized incidence and mortality rates as well as the one-year prevalence of breast, endometrial, colorectal, and prostate cancer are shown in table 1-2. The world standardized incidence rates of all of these cancers are markedly higher in both Denmark and the U.S. compared to the world average. The age standardized incidence rates of the cancers in question were slightly lower in Denmark compared to the U.S., but the mortality rates were in general higher. Among the Danish population of about five million people, 3,792 women had prevalent breast cancer, 1,401 women had colorectal cancer, and 610 women had endometrial cancer in year These three types of cancer were estimated to account for 47.3 % of all new cancer cases among Danish women in the same year. 3 Among Danish men, 1,636 had prostate cancer and 1,405 had colorectal cancer, and these two types of cancer were estimated to account for 31.2 % of all new cancer cases in Danish men in Thus, hormone-dependent cancers seem to be a major public health issue. 8

27 Table 1-1. Overview of major stress theories and definition Stimulus-oriented theories Interactional theories Response-oriented theories Main focus External stressors Perceived stress The stress response Stress definition Stress is environmental stimuli Stress is the individual s appraisal of an imbalance between demands and the individual s resources to cope with it. Stress is the mental and bodily reaction generated by stressful stimuli Measures Stressful life events Daily hassles Job strain Effort-reward imbalances Harmful work conditions Perceived disparity between threats and coping resources Physical: Level of stress hormones, blood pressure reactivity, heart rate reactivity, muscle tension Degree of distress: Nervousness, anxiety, depression Measurement method Self-rated Assignment of mean score Independent count of external stressors Self-rated subjective appraisal Measurement of physical indicators of stress Measurement of stress-related behavior and emotions Examples of measuring tools Strengths Weaknesses The social readjustment rating scale The job content questionnaire Well-developed and validated Failure to account for the individual differences in appraisal of and coping with external stressors The Perceived Stress Scale Responsive to individual differences in appraisal of external stimuli A question on perceived stress may be understood differently by different individuals, leading to possible misclassification Beck Depression Inventory The SCL-90-R (a multidimensional self-report symptom inventory developed to assess symptomatic psychological distress) Standardized objective biological and physical measures. Validated scales The reasoning is circular, in that the stress stimuli is defined by the fact that is lead to a stress response, while the stress response, in turn, is defined by referring back to the stimuli.

28 Table 1-2. Estimates of the incidence and mortality rate per 100,000 as well of the one-year prevalence in the total population of hormonedependent cancers in Denmark, USA, and the World Denmark USA World Female breast cancer Crude incidence rate Age-standardized incidence rate Crude mortality rate Age-standardized mortality rate year prevalence in the population Endometrial cancer Crude incidence rate Age-standardized incidence rate Crude mortality rate Age-standardized mortality rate year prevalence in the population Colorectal cancer Female Crude incidence rate Age-standardized incidence rate Crude mortality rate in the population Age-standardized mortality rate year prevalence in the population Male Crude incidence rate Age-standardized incidence rate Crude mortality rate Age-standardized mortality rate year prevalence in the population Prostate cancer Crude incidence rate Age-standardized incidence rate Crude mortality rate Age-standardized mortality rate year prevalence in the population Source: Globocan 2002, the International Agency for Research on Cancer Age-standardized rate: a summary measure of the rate that a population would have had if it had had the age structure of the world.

29 Figure 1-1. Causal hypothesis for the relation between perceived stress and risk of hormone-dependent cancers Perceived stress Changes in health-related behavior High alcohol consumption, high fat diet, physical inactivity, and smoking Physical stress response Prolonged activation of the HPA-axis and the sympathetic nervous system Stress hormones Cortisol Hormone system Decreased synthesis of sex steroid hormones Immune system Impaired function Hormone-dependent cancers

30 Figure 1-2. Different approaches to stress research and their relation to hormone-dependent cancers External stressors Perceived stress Physiological stress response Cancer Behavioral changes Stimulus-oriented theories Interactional theories Response-oriented theories

31 Figure 1-3. Age-standardized incidence and mortality rates of site-specific cancers in Denmark in year