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
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
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
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
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............................................................................................................. 10
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 1981-83............................. 20
Table 2-2. Number of primary site-specific hormone-dependent cancer cases occurring
during follow-up (year 1981-2000) in the Copenhagen City Heart Study ....................... 21
Chapter III
Table 3-1. Summary of prospective studies on stress and breast cancer incidence ......... 35
Table 3-2. Summary of prospective studies on stress and breast cancer relapse ............. 37
Chapter IV
Table 4-1. Summary of previous studies on stress and endometrial cancer..................... 44
Table 4-2. Summary of previous studies on stress and colorectal cancer ........................ 45
Chapter V
Table 5-1. Baseline characteristics of women who participated in the second
examination of the Copenhagen City heart study in 1981-3. Values are numbers
(percentages) unless stated otherwise ................................................................................. 55
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 1981-3 ............................................. 56
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
1981-3 ................................................................................................................................... 57
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 1981-3, according to time period of follow-up .................................. 58
iv
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 1981-3, in subgroups
of hormone therapy .............................................................................................................. 59
Chapter VI
Table 6-1. Baseline characteristics of 6,760 women who participated in the second
examination of the Copenhagen City Heart Study in 1981-83.......................................... 70
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 1981-83 ..................... 71
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 1981-83 by hormone
status...................................................................................................................................... 72
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 1981-83 by body mass
index...................................................................................................................................... 73
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 1981-83................... 85
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 1981-83 .................................................................................................................. 86
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 1981-83.................................................................... 88
v
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 1981-83............................................................................................................................. 89
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 1981-83........................................101
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 1981-83 .102
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 1981-83 ........................103
Table 8-4. Risk of primary prostate cancer associated with perceived stress and
sociodemographic variables according to period of follow-up .......................................104
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 ......112
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 ......113
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 ..........................114
Chapter XII
Table 12-1. 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. ........................................................................................................................134
vi
LIST OF FIGURES
Chapter I
Figure 1-1. Causal hypothesis for the relation between perceived stress and risk of
hormone-dependent cancers ................................................................................................ 11
Figure 1-2. Different approaches to stress research and their relation to hormonedependent cancers ................................................................................................................ 12
Figure 1-3. Age-standardized incidence and mortality rates of site-specific cancers in
Denmark in year 2002.......................................................................................................... 13
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........... 22
Chapter III
Figure 3-1. Flow diagram of the data collection process................................................... 38
Chapter V
Figure 5-1. Causal diagram of the relation between perceived stress and risk of breast
cancer .................................................................................................................................... 60
Chapter VI
Figure 6-1. Causal diagram for the relation between perceived stress and risk of
endometrial cancer ............................................................................................................... 74
Chapter VII
Figure 7-1. Causal diagram for the relation between perceived stress and risk of
colorectal cancer................................................................................................................... 91
Chapter VIII
Figure 8-1. Causal diagram for the relation between socio-economic status, marital
status, perceived stress, and risk of prostate cancer.........................................................105
vii
Chapter IX
Figure 9-1. Flow diagram of the data selection process ..................................................115
Figure 9-2. Circadian pattern for 17β-estradiol, free testosterone, and cortisol.............116
Chapter XII
Figure 12-1. Questionnaire used for the Perceived Stress Scale.....................................135
viii
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
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; 3:612-620. 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
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
VITA
November 17, 1977
Born, Odense, Denmark
2001
Research assistant
The Bandim Health Project
Guinea-Bissau, West Africa
2001-2002
Research assistant
Institute of Preventive Medicine
Copenhagen, Denmark
2002
B.S., Public Health Science
University of Copenhagen
Copenhagen, Denmark
2002-2006
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
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 12th 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, 255:280-8.
Nielsen NR, Kjøller M, Jørgensen FK, Grønbæk M. (2004) [Stress among working
population of Danes]. Ugeskr Laeger, 166:4155-4160.
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, 25:105-113
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
Nielsen NR (November, 2005). Perceived stress and risk of ischemic heart disease:
Causation or bias? Oral presentation at the 2nd 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, 17:391-397
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, 3:612-620.
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
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: 1294-1298
Truelsen T, Nielsen NR, Boysen G, Grønbæk M (2003). Self-reported stress and risk of
stroke. Stroke, 34(4):856-62.
xv
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 198183. 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: 0.85-0.99), endometrial (0.88; 0.76-1.01), and colon cancer (0.89;
0.81-0.99) 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
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; 0.90-1.09) or
prostate cancer (0.99; 0.90-1.09) 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
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.10-12 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, 10-12 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
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
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
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
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
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
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
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 2002.3
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 2002.3 Thus, hormone-dependent
cancers seem to be a major public health issue.
8
Table 1-1. Overview of major stress theories and definition
Stimulus-oriented theories
Main focus
Measurement
method
Examples of
measuring tools
Perceived stress
Stress is the individual’s appraisal of an
imbalance between demands and the
individual’s resources to cope with it.
The stress response
Stress is the mental and bodily
reaction generated by stressful
stimuli
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
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
The social readjustment rating scale
The job content questionnaire
The Perceived Stress Scale
Well-developed and validated
Responsive to individual differences in
appraisal of external stimuli
Failure to account for the individual
differences in appraisal of and
coping with external stressors
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.
Strengths
Weaknesses
Response-oriented theories
External stressors
Stress is environmental stimuli
Stress definition
Measures
Interactional theories
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
Female breast cancer
Crude incidence rate
Age-standardized incidence rate
Crude mortality rate
Age-standardized mortality rate
1-year prevalence in the population
Endometrial cancer
Crude incidence rate
Age-standardized incidence rate
Crude mortality rate
Age-standardized mortality rate
1-year prevalence in the population
USA
World
144.2
88.7
51.7
27.8
3 792
143.8
101.1
29.4
19.0
211 400
37.4
37.4
13.3
13.2
1 060 042
24.0
13.3
6.2
2.9
610
32.8
22.8
4.0
2.6
46 696
6.5
6.5
1.6
1.6
183 528
Colorectal cancer
Female
Crude incidence rate
Age-standardized incidence rate
Crude mortality rate in the population
Age-standardized mortality rate
1-year prevalence in the population
Male
Crude incidence rate
Age-standardized incidence rate
Crude mortality rate
Age-standardized mortality rate
1-year prevalence in the population
66.9
33.0
41.4
19.2
1401
55.1
33.1
20.3
11.6
69 939
15.4
14.6
8.1
7.6
362 911
69.3
41.0
40.1
23.3
1405
60.0
44.6
20.9
15.2
75 481
17.6
20.1
8.9
10.2
423 416
Prostate cancer
Crude incidence rate
Age-standardized incidence rate
Crude mortality rate
Age-standardized mortality rate
1-year prevalence in the population
69.8
39.3
40.7
22.6
1636
168.9
124.8
22.8
15.8
233 926
21.7
25.3
7.1
8.2
604 506
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.
Figure 1-1. Causal hypothesis for the relation between perceived stress and risk of hormone-dependent cancers
Perceived stress
Changes in health-related behavior
Physical stress response
High alcohol consumption, high fat diet,
physical inactivity, and smoking
Prolonged activation of the HPA-axis and the
sympathetic nervous system
Stress hormones
Cortisol
Hormone system
Immune system
Decreased synthesis of
sex steroid hormones
Impaired function
Hormone-dependent cancers
Figure 1-2. Different approaches to stress research and their relation to hormone-dependent cancers
Physiological stress
response
External stressors
Perceived stress
Cancer
Behavioral changes
Stimulus-oriented theories
Interactional theories
Response-oriented theories
Figure 1-3. Age-standardized incidence and mortality rates of site-specific cancers in Denmark in year
2002
13
II. Material and methods
The Copenhagen City Heart Study
The study objective will be addressed using data from the Copenhagen City Heart Study.
The Copenhagen City Heart Study is a longitudinal study initiated in 1976.21 An agestratified sample of 19,698 men and women aged 20 to 93 years who lived in the
Copenhagen area were randomly drawn from the Central Population Registry and
invited by letter to participate in the study. A physical examination was performed and
participants were asked to fill in a questionnaire regarding various risk factors. A blood
sample was drawn during the examination. In 1981-83 the study population was
supplemented with 500 men and women aged 20 to 29 years, and additional study
assessments were performed for both new and continuing study participants. The study
participants were asked about their stress level only at this second examination, which is
therefore used as baseline for the studies included in the dissertation. The 12,698 women
and men who participated in the second examination constituted a response proportion
of 70 %. The vast majority of the participants were Caucasians and all participants gave
written informed consent. The Danish ethics committee for the City of Copenhagen and
Frederiksberg approved the Copenhagen City Heart Study (# 01-144/01).
Table 2-1 shows the baseline characteristics of the participants in the second
examination of the Copenhagen City Heart Study. There are more women than men and
the average age was 57 for women and 56 for men. About 28 percent of the women and
20 percent of the men reported moderate to high stress intensity, and about the same
percentages experienced stress on a weekly or daily basis. A relatively high proportion
of the population had low education and low income. The male participants generally
had a higher weekly alcohol intake compared to their female counterparts. More than
half of the population was current smokers at baseline, while less than 20 percent were
physically inactive. The mean body mass index was in the normal range and few
participants had diabetes mellitus. Most women had gone trough menopause at baseline,
and only about one fifth of these women used postmenopausal hormone therapy.
14
Measurement of perceived stress
The study participants in the Copenhagen Heart Study were asked about their level of
stress in terms of intensity and frequency at baseline in 1981-83. In the questionnaire,
stress was exemplified as the sensation of tension, nervousness, impatience, anxiety, or
sleeplessness and no time frame was specified. To assess stress intensity, the participants
were asked: “Do you feel stressed?” The response categories were: (0) none, (1) light,
(2) moderate, or (3) high. To measure stress frequency the participants were asked:
“How often do you feel stressed?” The response categories were: (0) never/hardly ever,
(1) monthly, (2) weekly, or (3) daily.
In order to combine the two dimensions of stress intensity and frequency, we
chose to use an additive approach, where the values of the two questions were added and
combined into a seven-point stress score ranging from 0 (indicating low stress) to 6
(indicating high daily stress). How the score was formed is shown in figure 2-1. For
example, if a woman reported moderate, daily stress this woman would be given a stress
score of 5 (2 points for moderate at the intensity dimension plus 3 points for daily at the
frequency dimension). This stress-score was categorized into low (0-1 points), medium
(2-4 points), and high (5-6 points) stress.
An obvious alternative would have been to combine stress intensity and frequency
analogous to methods used in nutritional epidemiology, where the participants are often
asked about the average intake of a specific nutrient or food (intensity), which is then
multiplied with the frequency of the intake. If stress intensity was given the values 0
(none), 1 (low), 2 (medium), 3 (high), and stress frequency was measured as number of
days per month, so that monthly stress had the value 1, weekly stress had the value 4,
and daily stress had the value 30, using the nutritional approach to create an alternative
stress-score, we would multiply the values of stress intensity and stress frequency. This
scale would give considerably more weight to frequency than intensity (even with higher
values given to stress intensity), where the additive approach weighs them equally. An
intuitive problem with the multiplicative approach is that weekly high stress would be
given a score of 12, which is less than half the score of 30, which would be given to
daily low stress. However, most people would find it more straining to be exposed to
weekly high stress than daily low stress. This would be better resembled in the additive
approach, where weekly high stress has a higher score than daily low stress. We
15
therefore chose to use the additive instead of the multiplicative approach in the studies
included in the dissertation.
Assessment of endpoints by linkage to national registers
The participants of the Copenhagen City Heart Study were followed in national registers
from date of entry into the study till date of first diagnosis of a hormone-dependent
cancer, death, loss to follow-up, emigration, or end of follow-up between 2000 and
2003, depending on the study in question. In Denmark, every newborn citizen is
assigned a unique civil registry number, which is a ten-digit number consisting of the
date of birth and four unique digits. Using the civil registry number a complete hospital
discharge history was established for each individual and unambiguous record
linkage could be performed. Identification of site-specific cancer cases was obtained
through linkage to the Danish National Cancer Registry. Reporting of new cancer cases
to the registry is compulsory in Denmark and the Danish National Cancer Registry
contains, according to the National Board of Health, data on more than 95 percent of all
cancer diagnoses in Denmark. The Cancer Registry has consistently used the
International Classification of Disease codes revision seven (ICD-7). The vital status of
the study population was followed in the Civil Registration System. Assessment of
endpoints in central disease registries allowed for nearly complete follow-up (less than
0.1 percent were lost to follow-up). The number of cancer cases that occurred at each
site is shown in table 2-2.
Statistical methods
Building a conceptual model
Causal diagrams will be used to clarify the assumed causal models that constitute the
basis for the statistical analyses in each of the included studies. The use of causal
diagrams in epidemiology was suggested by Greenland, Pearl, and Robins as a useful
alternative to conventional statistical models, and as a way of elucidating assumptions
about the web of causation without incorporating strong parametric assumptions.22 In a
16
causal diagram, one’s assumptions about causal relations are graphically shown in a
diagram, where the variables are connected with arrows that represent assumed causal
relations. These assumed relations should always be based on the most updated scientific
knowledge. The main advantage of using causal diagrams is their ability to visualize
model assumptions and to include both measured and unmeasured variables. As opposed
to the conventional statistical methods, in which the underlying causal model is based
primarily on statistical associations assessed in a particular data material at hand, causal
diagrams have the advantage of making use of prior knowledge of causal relations. The
diagrams will be used in each study as a way to identify a set of potential confounders
that may create a spurious association between perceived stress and the hormonedependent cancer in question. The stated diagrams should not be taken as comprehensive
causal models, and should instead be understood as a graphical presentation of the
assumed causal model underlying the statistical model. Every statistical model is based
on an assumed causal model, whether stated or not, and by clearly stating our
assumption in causal diagrams we make the assumptions open to debate.
The Cox proportional hazard model
Cox proportional hazard models will be used to estimate the hazard ratios of hormonedependent cancers associated with perceived stress in the dissertation. The Cox
proportional hazard model is a log linear model where the log hazard function at time t
is given by
log(h(t)| X=x)) = log(h0(t)) + bx
where h0(t) is the baseline hazard function and X=x is the exposure level for a given
subpopulation. The regression coefficient b can be interpreted as the log relative hazard
associated with one unit increase in X. Thus, if X denotes the continuous stress score
with seven levels, the hazard ratio associated with a one-level increase in stress score
would be given by exp(b). The above model only includes one covariate, namely X, but
it can easily be extended to include multiple covariates
log(h(t)| X1=x1,…., Xk=xk) = log(h0(t)) + b1x1 + … + b kxk
17
If X1 is the continuous stress score, then exp(b1) will be the hazard ratio associated with
one unit increase in the stress score, adjusting for the other covariates.
The effect of stress intensity and stress frequently will be assessed separately as
well as combined in a stress score with seven levels. Stress intensity and stress
frequency were assessed in a multiple-choice form and are therefore naturally ordered
into four categories each. These categories will be added to the model, so that each level
of stress intensity is compared to the no stress category and each level of stress
frequency is compared to the never/hardly ever stress category. The combined stress
score will be included as a continuous variable and in categories of low, medium, and
high stress. By including the stress score as a continuous variable we maximize the
utility of the data available. By doing this however, we also assume that the hazard ratio
associated with one unit increase in stress score is constant. This is not necessarily a
valid assumption, because the hazard ratio associated with going from low stress on a
monthly basis to low stress on a weekly basis may be very different from the hazard
ratio associated with going from high stress on a weekly basis to high stress on a daily
basis. The stress score will therefore be included both as a continuous and as a
categorical variable in order to evaluate how these assumptions affect the results.
Age will be used as the underlying time scale in order to soundly adjust for
confounding by this variable. The proportional hazards assumption, stating that the
proportional hazards will be constant over the time-scale, will therefore apply to this
age-scale. The validity of this assumption will be evaluated graphically as well as by
testing an age-covariate interaction in data.
Linear regression models
Linear regression models will be used to address the association between perceived
stress and plasma levels of estrogen, testosterone, and cortisol. A simple linear
regression model is given by:
E(y│X=x) = a + bx + ε
18
where y denotes the dependent variable and X=x is the exposure level for a given
subpopulation. a and b are the parameter estimates and ε (the error term) is the
unexplained and unpredicted variance of y. The regression coefficient b can be
interpreted as the expected change in y with a one-unit increase in X. Thus, if X denotes
the continuous stress score with seven levels, b is the expected change in plasma levels
of, for example, estrogens associated with a one-level increase in stress score. The above
model only includes one covariate, namely X, but it can easily be extended to include
multiple covariates
E(y | X1=x1,…., Xk=xk) = a + b1x1 + … + b kxk + ε
If X1 is the continuous stress score then b 1 will be the expected change in y associated
with a one-unit increase in the stress score, adjusted for the other covariates.
A linear regression model is based on several assumptions: (1) The outcome is
continuous; (2) The effect of exposure is measured as differences in the mean of the
outcome variable; (3) The conditional mean of the outcome given the independent
variables included in the model are assumed to be a linear function of the independent
variables; (4) The outcome is assumed to be normally distributed for each of the
combinations of the independent variables; (5) Variance homogeneity. We used plasma
levels of estrogens, testosterone, and cortisol as outcome measures which are continuous
in nature (assumption 1). The distributions of the outcome measures were (skewed) nonnormal and we therefore log-transformed the outcome measures in order to make
assumptions 2 and 4 reasonable. We either assumed that the conditional mean of the
outcome was a linear function of the independent variables or we included the
independent variables as categorical variables (assumption 3). We plotted the residuals
(observed value minus expected value) against the fitted values to address variance
homogeneity (assumption 5). In a well-fitted model there should be no pattern to the
residuals plotted against the fitted values.
19
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 1981-83
Women
Men
Study population, n
7,018
5,680
Mean age, y (range)
57 (21-91)
56 (21-98)
Moderate to high stress intensity (%)
1,971 (28)
1,163 (20)
Weekly or daily stress (%)
1,933 (28)
1,163 (20)
<8 years of education (%)
3,249 (46)
2,539 (45)
Income of <$1000/month (%)
2,570 (37)
1,437 (25)
4 (7)
14 (16)
3,734 (53)
3,622 (64)
1,270 (18)
922 (16)
25 (5)
26 (4)
Diabetes mellitus (%)
125 (2)
197 (3)
Oral contraceptive use (%)
258 (4)
-
Menopause (%)
5,167 (74)
-
Hormone replacement therapy (%)
1,062 (15)
-
Mean alcohol consumption, drinks/wk (SD)
Current smoker (%)
Physical inactive (%)
2
Mean body mass index, kg/m (SD)
Table 2-2. Number of primary site-specific hormone-dependent cancer cases occurring during follow-up (year 1981-2000) in the Copenhagen
City Heart Study
Site-specific cancers
No. of primary cases
Breast
251
Female reproductive system organs
Ovary
Cervix
Endometrial
Other female genital organs
190
82
31
72
5
Male reproductive system organs
Prostate
Testis
Other male genital organs
157
157
0
0
Colorectal
Colon
Rectum
328
236
92
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 sevenpoint stress-score into low, medium, and high stress
Intensity
Frequency
No
Light
Medium
High
Never
0 (38 %)
1 (1 %)
2 (0 %)
3 (0 %)
Monthly
1 (9 %)
2 (21 %)
3 (5 %)
4 (1 %)
Weekly
2 (1 %)
3 (5 %)
4 (9 %)
5 (3 %)
Daily
3 (0 %)
4 (0 %)
5 (1 %)
6 (4 %)
III. Stress and breast cancer: a current overview of prospective
studies
Introduction
Breast cancer is the most common cancer among women both in terms of incidence and
prevalence.23 Psychological stress may affect the immune system and the hormonal
system, and may also lead to changes in risk behavior, which may again play a role in
breast cancer etiology and prognosis.2;10;12 Considerable research has been carried out in
an attempt to establish the type and strength of a relation between psychological stress
and breast cancer.15;24-29 The heterogeneity of the results reported in the individual
studies are reflected in the conflicting conclusions of previous reviews. 15;24-29 Stress
may also render the individual more susceptible to the progression or recurrence of
breast cancer either by disturbing recovery or by affecting treatment compliance. The
association between stress and breast cancer relapse has gained less attention than the
association with breast cancer incidence and the results are conflicting.30 We have
chosen to address breast cancer incidence and relapse as two distinct entities in order to
assess if stress affects development and progression of breast cancer differently.
Previous reviews assessing the relationship of stress and breast cancer have
included a range of studies based on different designs, which may explain some of the
heterogeneity in the results. In a recent meta-analysis of stressful life events and risk of
breast cancer, Duijts and colleagues found that the estimates from retrospective studies
differed from those of prospective ones.15 Diagnosis of cancer is stressful, which might
increase the likelihood for recall bias in retrospective studies. Therefore, we have chosen
to only include prospective studies in this review, where stress is measured before breast
cancer incidence and therefore is not affected by the diagnosis. The major limitation is
that prospective studies are often expensive and time-consuming, making only few
prospective studies on stress and breast cancer available.
How stress is defined and measured depends on the theoretical background
applied. Some researchers define stress in terms of external demands or stressors, while
others emphasize the importance of the individual’s appraisal of the demands, depending
23
on his or hers coping capacities (perceived stress). The majority of research on stress and
breast cancer has been concerned with major life events such as death of a spouse or
near relative.15 Life events are measures of major external demands (stressors) that have
gained popularity partly because of their objectivity and the fact that they can relatively
easily be measured retrospectively in case-control studies.31 Work-related stress, often
defined as a work situation with high demands and low control, is another popular
measure of external demands.32 However, a person’s appraisal of, and reaction to, a
major life event or a demanding work-situation might be just as crucial for breast cancer
onset and prognosis as the event per se. Several investigators have emphasized the
importance of also including subjective measures of stress, such as measures of
perceived stress, in addition to the more objective measures of life events and workrelated stress.16;24;33;34 Thus, we will include measures of stressful life events, workrelated stress, and measures of perceived stress in the present review to accommodate
these different theoretical views. The purpose of this review is to systematically address
if various measures of stress are risk factors for breast cancer incidence or breast cancer
relapse in prospective studies, and to identify sources of potential heterogeneity in the
results.
Assessment methods
Criteria for assessment
We used systematic and explicit methods to identify, select, and critically appraise
relevant studies as recommended by the Cochrane Collaboration.35 The articles included
in this analysis had to describe the relation between some measure of stress and breast
cancer incidence or breast cancer relapse. Furthermore, the articles had to describe
prospective studies, defined as studies in which stress was measured before disease
occurrence. Only the prospective parts of studies that included both retrospective and
prospective elements were included in this review. The association between stressful life
events has also been evaluated in so called limited prospective designs, where women
who undergo biopsies are interviewed about life events prior to the final diagnosis.36-42
These women may both be emotionally affected by the uncertainty of their final
diagnosis, and may also have a fairly good prediagnostic forecast of their diagnosis.43
24
Results from limited prospective studies might therefore be affected by recall bias and
cannot necessarily be applied to the general population. Therefore, such studies were
excluded from this review. Articles describing the association between stress and breast
cancer case-fatality or breast cancer mortality, and studies on stress arising in those
diagnosed with breast cancer were also excluded. Figure 3-1 shows a flow diagram of
the data collection process. The search strategy for this review was based on the
following five steps:
Step 1. The MEDLINE and PsycINFO databases were searched for publications until
November 2005, with no language restriction. The following terms were used in this
systematic search: the articles were selected if “stress” or “ life event” or “job strain” or
“effort reward” appeared in the Title; OR “stress” or “life event” or ” job strain” or
“effort reward” appeared in a keywords search, AND “stress” or “life event” or “job
strain” or “effort reward”, and “breast” or “mamma”, and “cancer” or “carcinoma” or
“neoplasms” appeared in the abstract. This search resulted in 258 potentially relevant
studies.
Step 2. After reading the abstracts of the 258 studies, studies that did not describe the
relation between some measure of stress and breast cancer incidence or breast cancer
relapse were excluded, which meant that 35 studies remained. Non-English language
studies were classified according to their title and abstract written in English.
Step 3. A total of 23 studies not describing prospective studies were excluded. Study
design was not used to limit the search, because not all studies are indexed by study
design.
Step 4. Assessment of reference lists of all relevant studies and previous reviews
identified eight potentially relevant prospective studies.44-51 The majority of these studies
were not identified in the general search because they focused primarily on overall
cancer risk and only included subgroup analyses on breast cancer. Seven of these studies
were included in our analysis, while the last study was excluded because of
methodological flaws.50
25
Step 5. Two of the papers included in this search reported on the association between
job strain and breast cancer incidence in the Nurses’ Health Study with varying followup.52;53 Only the paper with the longer follow-up was included in the review.53
Altogether, 18 prospective studies were included in our analysis.
Data extraction
Information on population, follow-up, exposure, outcome, confounding, and results were
extracted from each study. The analyses of the association between stress and breast
cancer incidence should ideally be adjusted for the following behavioral and lifestyle
factors: alcohol, physical activity, body mass index, postmenopausal hormone use; and
the following biological factors: family history of breast cancer, benign breast disease,
age at menarche, age at menopause, age at first birth, parity; as well as some measures of
socio-economic status (i.e., income and education). Because of the heterogeneity in the
measures of stress applied in the different studies, calculating a summary measure of
effect was neither feasible nor reasonable. Instead, we grouped the studies according to
the type of stress measure applied. We interpreted the evidence based on an evaluation
of both the point estimates and the statistical variability of the estimates, and the
assessment was therefore not restricted to an evaluation of statistical significance.
Whether a risk estimate is statistically significant depends both on the strength of the
association and the power of the analysis, and because some of the studies had low
statistical power we found it inappropriate to base our evaluation solely on statistical
significance.
Results
Study characteristics
Thirteen studies on stress and breast cancer incidence44-49;53-59 and five studies on stress
and breast cancer relapse were included in the review.51;60-63 The studies were either
from Europe, 44-47;49;54;56;57;59-63 North America,51;53;55;58 or Israel,48 and all of them were
published in English. These 18 studies included 15 prospective cohort studies44;47;48;51;53-
26
63
and three prospective case-control studies.45;46;49 Six of the studies were record linkage
studies based on national registers.44-49
Stress and breast cancer incidence
The association between stress and breast cancer incidence was addressed in ten
prospective cohort studies and three prospective case-control studies (table 3-1). The
association between ‘stressful life events’ and risk of breast cancer was evaluated in five
cohort studies and three nested case-control studies. 44-49;58;59 Six of these studies were
registry-linkage studies, which were based solely on information from national
registries. 44-49 The following events were used as measures of major life events: losing a
husband by death or divorce,45;49 parental death in childhood,58 death of a child,44;46
having a child with cancer,47 losing an adult son in war or accident,48 or the combination
of a range of stressful life events such as divorce, death of a husband, or death of a close
relative.59 Three registry-linkage studies assessed the risk of developing breast cancer
among parents who had a child with cancer or who had lost a child, and none of these
studies found a clear association between these major stress factors and breast cancer
incidence.44;46;47 A registry-linkage study from Denmark reported a slightly lower risk of
breast cancer among women who had lost a husband by death.49 This lower risk was not
supported in a Norwegian registry-linkage study, where loss of a husband by death was
not associated with breast cancer risk.45 Instead, loss of a husband by divorce was
associated with a slightly lower risk of breast cancer in this study. In another registrylinkage study Levav et al. reported a slightly higher risk of breast cancer incidence
among Israeli women who had experienced losing an adult child, but the risk estimates
were rather unstable.48 In contrast to the null results of the registry-linkage studies, the
death of ones mother, but not ones father, in childhood was associated with a doubling
of breast cancer risk in the Baltimore Epidemiologic Catchments Area Study.58 This
association was based on a relatively small sample of 1,213 women followed-up for 15
years during which only 29 cases of breast cancer occurred. An increased risk of breast
cancer associated with major life events was also reported in the larger Finnish Twin
Cohort Study, which included 10,808 female twins followed for 15 years.59 All of the
studies on stressful life events and risk of breast cancer lacked information on
postmenopausal hormone therapy and several of the other risk factors for breast cancer.
27
This may have hindered proper control of potential confounding from these factors. In
sum, major stressors such as death of a child or losing a husband by death or divorce did
not seem to be associated with higher incidence of breast cancer in large-scale registrylinkage studies. An accumulation of stressful life events may, however, increase the risk
of breast cancer.
The association between ‘work-related stress’ and risk of breast cancer has only
been prospectively assessed in the Nurses’ Health Study.53 Schernhammer and
colleagues reported a slightly lower risk of breast cancer among women with high strain
jobs, defined as jobs with high demands and low influence, compared to women with
low strain jobs in a questionnaire-based study, where job strain was measured in the 27item job content questionnaire.53 However, there may have been insufficient variation in
the exposure to work-related stressors among nurses because most of them work in very
similar jobs. To validly address the effect of work-related stress on breast cancer risk,
more prospective studies that include different types of professions are needed. Also,
there was no information on current night-shift work, which may both have led to higher
job strain as well as have disrupted the circadian rhythm of the hormonal system and
thereby predicted a higher risk of breast cancer.64 Such confounding would, however,
have resulted in an artificial increased risk of breast cancer contrary to what was
observed in the study by Schernhammer et al.
Four studies assessed the association between ‘perceived stress’ and incidence of
breast cancer.54-57 A Swedish study, which included 1,462 women followed for 24 years,
reported an increased risk of breast cancer among women who had experienced stress
occasionally or more often during the five years preceding baseline based on a simple
question describing the extent to which the women had previously experienced stress.54
These results contrast with those of the three other studies that have addressed the effect
of perceived stress, all of which included more women and more cases than the Swedish
study. In a Finish study including 10,519 female twins followed for 21 years, no
association between stress of daily activities and breast cancer incidence was found.56 A
different form of stress, namely stress from adult caregiving, was associated with a
slightly lower risk of breast cancer incidence in the Nurses’ Health Study after
appropriate adjustment for confounding.55 This inverse association was supported by the
fact that women with high levels of stress from caregiving also had lower levels of sex
28
steroid hormones.55 An inverse dose-response association between perceived stress and
incidence of breast cancer has also been found in a recent Danish study.57 Despite the
inconsistent results, perceived global stress does not seem to be associated with higher
risk of breast cancer. Whether perceived stress reduces the risk of breast cancer remains
to be confirmed and the underlying mechanisms need to be elaborated.
Stress and breast cancer relapse
Five prospective studies have evaluated the association between stress and breast cancer
recurrence (table 3-2). Four of these studies were conducted in Europe and one in
Canada. Breast cancer patients were followed from the date of diagnosis to first-time
recurrence. All studies included some measure of stress one year prior to diagnosis,
while only two studies included measures of the life events that occurred during followup.60;63 Breast cancer patients who had experienced any severe event or difficulty one
year prior to diagnosis were at lower risk of relapse in an English study with 3.5 years of
follow-up,60 while no association was reported in another English study of a similar size
but with five years of follow-up.63 Consistently, no association between relapse and
stress from recent life events prior to diagnosis was reported in the Canadian study.51 In
a smaller study from Finland, experience of life events 12 months prior to diagnosis was
associated with a markedly higher risk of relapse after eight years of follow-up.62
Chronic stress prior to diagnosis was also associated with a slightly higher risk of
relapse in a small study from Belgium.61 Experience of severe life events during followup was not associated with higher risk of breast cancer relapse in either of the two
English studies.60;63 In fact, one of the studies reported a lower risk of relapse five years
after diagnosis.63 All studies controlled for axillary-node involvement, which is one of
the main prognostic factors for relapse. Most of the studies also controlled for other
prognostic factors such as grade and stage of the tumor. However, none of the studies
had information on treatment history or treatment compliance.
Discussion
The relation between stress and breast cancer incidence and relapse were evaluated using
qualitative data from 18 prospective studies. All studies were conducted in Westernized
29
countries and the results were inconsistent. No higher risk of breast cancer was found in
large-scale registry linkage studies that addressed the effect of a major life event such as
death of a child or divorce. An accumulation of stressful life events may, however, be
associated with higher risk of breast cancer. Work-related stress and perceived stress
were either not associated with breast cancer risk or were associated with a slightly
lower risk of breast cancer. In general, a higher risk of breast cancer incidence was
mainly seen in the smaller studies, which could indicate some degree of publication bias;
we conclude that stress does not seem to be an important risk factor for breast cancer
incidence. By contrast, stress experienced one year prior to diagnosis of breast cancer
was associated with a higher risk of relapse in some, but not all, studies.51;60-63 Only two
studies addressed whether experience of life events after diagnosis affected the risk of
breast cancer relapse, and neither study reported a changed risk.60;63
Burke and Goodkin suggested a range of criteria when addressing the evidence of
a link between stress and cancer.33 First, they emphasized the importance of
distinguishing between stressors and stress. A stressor is an external stimulus that may
potentially cause stress depending on the individual’s perception of the threat the
stressor poses. Second, the association between stress and cancer should be assessed
prospectively to avoid recall bias from either attribution or emotional repression. Third,
according to Burke and Goodkin, a fair test of the association of cancer risk and stress
should examine a specific type of cancer, because cancer is a heterogeneous group of
diseases with multiple etiologies.33 In the present review we distinguished between
stressors (stressful life events and work-related stress) and stress (perceived stress) and
we only included prospective studies that addressed a specific type of cancer, namely
breast cancer. Furthermore, we used systematic methods to identify the literature. In
spite of this we found inconsistent results.
Sources of heterogeneity
The heterogeneity of the results observed in the present review could be ascribed to
several factors. First, a broad range of different exposures has been regarded to as
measures of stress, though they might not all express dimensions of the same underlying
concept. We have tried to categorize the different measures of stress into stressful life
events, work-related stress, and perceived stress in order to make the exposure groups
30
more homogenous. However, this resulted in few studies in each category, and even
within the categories different measures of stress were applied in the different studies.
Perceived stress of daily life is not necessarily the same as stress of daily activities.
Similarly, the death of one’s mother in childhood is different from losing a child later in
life. Thus, the heterogeneity in results might be a reflection of the variety in the
measures of stress as well as the lack for sufficient prospective studies to address the
effect of each stress measure on breast cancer risk and progression. Also, most of the
studies included only a single measure of stress assessed at baseline. Each of these
measures may therefore only account for a fraction of the individual stress burden. We
cannot exclude that an ideal study, in which the full stress burden for each individual
could have been comprehensively measured, might have come up with a different result.
Second, the physiological stress response is highly dependent on the type and the
timing of the stressor,17 which makes it important to distinguish between different types
of stress. Thus, by categorizing stress into stressful life events, work-related stress, and
perceived stress we implicitly assumed that these measures would affect the risk of
breast cancer differently. The results partly support this assumption in that they indicate
some differences in the effect of major acute life events and the more chronic exposures
to stress of everyday life. A lower risk of breast cancer was especially observed in the
studies that applied measures of perceived stress. Chronic impairment of estrogen
synthesis has been set forth as a possible explanation to this observed lower risk.55;57 The
reason why the lower risk is not also consistently observed in studies that use stressful
life events as measures of stress may be that perceived stress is simply a better measure
of prolonged exposure to stress. Alternatively, women who report high levels of stress
may be more accurately and adaptively handling their stress and thereby have fewer
health consequences.
Third, some of the studies lacked control for important risk factors for breast
cancer, which may have biased the results. Several of the registry-linkage studies on
stressful life events and breast cancer were not appropriately adjusted for potential
confounding. However, in order to affect the results, these risk factors should also be
associated with the stressful life event in question. For example, for an unmeasured
covariate to have distorted the association between the loss of a child and breast cancer,
this major life event would have to be associated with family history of breast cancer,
31
age at menarche and menopause, age at first birth, etc. Although there may be some
associations between the major life events and other risk factors, they are not expected to
be substantial enough to seriously have distorted the risk estimates in the large linkage
studies. Future studies that combine information from registries with information from
survey designs may be needed to fully adjust for potential confounding. Also, some of
the studies may have adjusted for factors on the causal path from stress to breast cancer.
An example; stress may effect alcohol consumption that may in turn affect the risk of
breast cancer. Adjustment for alcohol consumption would lead to an underestimate of
the effect of stress on breast cancer mediated through alcohol. This could possibly
explain the null findings in some of the studies, although not in the registry linkage
studies where no such adjustments were performed.
Fourth, even after restricting the review to only include prospective studies, the
methodology of the included studies might still vary to a degree that could affect the
results. Some of the studies used self-reported measures of breast cancer incidence,
while others identified breast cancer cases in validated cancer registries. This may have
led to differences in outcome assessment. Publication bias might also have affected the
results. Small studies with positive results are often more likely to be published than
those with negative results, either because of the reluctance to publish studies with no
significant results or because authors choose not to submit such studies. Interestingly,
only the two studies with the smallest number of participants found a markedly higher
risk of breast cancer incidence associated with stress.54;58 This could indicate some
degree of publication bias in the included studies. Further, the studies on breast cancer
relapse had insufficient sample sizes to warrant firm conclusions. These differences in
methodology might, to some extent, explain the heterogeneity in the results.
Finally, the length of follow-up differed between the studies; most studies only
included a baseline measure of stress, which may have changed over time in a manner
that is most likely independent of subsequent incidence of cancer. Thus, non-differential
exposure misclassification may have reduced the ability to detect a potential relation
between the different measures of stress and risk of breast cancer in studies with a long
follow-up.
32
Causal pathways
The human organism is in a state of dynamic equilibrium, whereby stability is
maintained throughout change, also known as allostasis.17 Allostasis is central to the
stress response and to survival in general in that 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 stress response is initiated when
external and internal forces, the stressors, challenge this allostasis. 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. This review does not support stress as an important etiologic
factor in breast cancer etiology, which may be due to the organism’s amazing ability to
re-establish allostasis.
Stress hormones released by the HPA-axis might suppress the synthesis and
metabolism of estrogen, which is an important risk factor for breast cancer. This
biological mechanism may be consistent with the lower risk of breast cancer incidence
associated with different measures of stress observed in several of the included studies.
Conversely, persistent activation of the HPA-axis and some of the mediators released by
the HPA-axis, such as corticosteroids and catecholamines, also seem capable of
suppressing immune function resulting in a reduced ability to recognize and destroy
neoplastic cell growth.2;14 This mechanism may increase the risk of breast cancer and
thereby oppose the stress-induced suppression of estrogens. Thus, stress may affect the
risk of breast cancer directly through biological processes or indirectly by affecting
health-related behavior, and the relation between stress and breast cancer is probably a
result of a complex system with different mechanisms working in opposite directions.
The importance of each mechanism probably depends on the population and the type of
breast cancer in question.
Conclusion
In spite of the heterogeneity of the results, the combined evidence from prospective
studies does not indicate that stress is an important risk factor for breast cancer
incidence. It is still unclear if stress prior to a breast cancer diagnosis may render women
33
more susceptible to an accelerated progression of the disease. Studies with more
homogenous measures of stress, more thorough adjustments for confounding, and larger
studies on stress and breast cancer relapse are required to pursue this issue further.
34
Table 3-1. Summary of prospective studies on stress and breast cancer incidence
First author,
Population and follow-up N (no. of cases)
Exposure
year
32
Ewertz M
Linkage study based on
1782 cases and 1738 Divorce or loss of a
Denmark,
national registries. Nested controls
husband by death
1986
case-control study. Age<70
yrs
Jacobs JR41
The Baltimore
1213 (29)
Parental death in
USA, 2000
Epidemiologic Catchment
childhood
Area Study. Mean age 43.
Follow-up=15 yrs
Johansen C30 Linkage study based on
5716 exposed women Cancer in a child
Denmark,
national registries. Mean (198 cases in the
1997
age? Follow-up=25 yrs
exposed)
Kvikstad A28 Linkage study based on
4547 cases and 34 470 Divorce or loss of a
Norway, 1994 national registries. Nested controls
husband by death
case-control study. Mean
age?
Kvikstad A29 Linkage study based on
4340 cases and 29 750 Death of a child
Norway, 1996 national registries. Nested controls
case-control study. Mean
age?
Levav I31
Linkage study based on
3299 exposed women Loss of an adult son
Israel, 2000 national registries. Mean (96 cases in the
in war or accident
age 55 yrs. Follow-up=20 exposed)
yrs
27
Li J
Linkage study based on
168 138 (?)
Death of a child
Denmark,
national registries. Mean
2002
age 33. Mean followup=10.5 yrs
Lillberg K42 The Finnish Twin Cohort 10 808 (180)
Stressful life events
Finland, 2003 Study. Mean age 41.
Follow-up=15 yrs
Confounding*
Results
No adjustment
Divorce:
OR=0.9 (0.7-1.2)
Loss of husband by death:
OR=0.8 (0.7-1.0)
No association between death of
father and breast cancer.
Death of a mother in childhood:
HR=2.13 (1.02-4.55)
Mothers whose child has cancer
compared to background population:
SIR=1.0 (0.9-1.1)
Divorce:
OR=0.84 (0.76-0.92)
Loss of a husband by death:
OR=1.15 (0.95-1.39)
Mothers who lost a child:
OR=0.93 (0.79-1.10)
Age, AL, HIS,
SES
No adjustment
BIR, PAR
Age, PAR
Age
Age, PAR, SES
Age, AL, PA,
BMI, BIR, PAR,
SES
Loss of a son in war:
OR=1.32 (0.86-2.02)
Loss of a son in accident:
OR=1.16 (0.92-1.46)
Mothers who lost a child:
HR=1.10 (0.89-1.35)
One-event increase in stressful life
events:
HR=1.07 (1.00-1.15
One-event increase in major events:
HR=1.35 (1.09-1.67)
Work-related stress
Schernhammer Nurses’ Health Study.
37 562 (1030)
ES 36
Mean age 55. Follow-up=8
USA, 2004
yrs
Job strain
Age, AL, PA,
BMI, HT, HIS,
BD, MA, MO,
BIR, PAR, SES
High strain jobs versus low strain
jobs
RR= 0.87 (0.73-1.04)
Stress during the
last five years
Age, AL, BMI,
HIS, MA, MO,
BIR, PAR, SES
Stress versus no stress:
HR=2.0 (1.1-3.5)
Perceived global stress
Helgesson Ö37 The Prospective Population 1462 (47)
Sweden, 2003 Study of Women in
Gothenburg. Age 38-60.
Follow-up=24 yrs
Kroenke CH38 Nurses’ Health Study.
69 886 (1700)
USA, 2004
Aged 46-71 yrs. Followup=8 yrs
Lillberg K39 The Finnish Twin Cohort 10 519 (205)
Finland, 2001 Study. Aged >18 yrs.
Follow-up=21 yrs
Nielsen NR40 The Copenhagen City
6 689 (251)
Denmark,
Heart Study. Mean age 57.
2005
Follow-up=18 yrs
Hours and stress of Age, AL, PA,
informal caregiving BMI, HT, HIS,
BD, MA, MO,
BIR, PAR, SES
Perceived stress of Age, AL, PA,
daily activities
BMI, BIR, PAR,
SES
Perceived stress
Age, AL, PA,
BMI, HT, MO,
PAR, SES
≥15 hrs to child: HR=1.19 (0.871.62)
≥15 hrs to adult: HR=0.87 (0.661.16)
Stress (child caregiving): HR=1.12
(0.92-1.36)
Stress (adult caregiving): HR=0.82
(0.68-1.00)
No stress: 1 (reference)
Some stress: 1.11 (0.78-1.57)
Severe stress: 0.96 (0.53-1.73)
Low stress: 1 (reference)
Medium stress: 0.80 (0.62-1.04)
High stress: 0.60 (0.37-0.97)
* Behavioural factors: alcohol (AL), physical activity (PA), body mass index (BMI), postmenopausal hormone therapy (HT);
Biological factors: family history of breast cancer (HIS), benign breast disease (BD), age at menarche (MA), age at menopause (MO), age at
first birth (BIR), parity (PAR);
Socio-economic status: Some measure of income or education
Table 3-2. Summary of prospective studies on stress and breast cancer relapse
First author,
N (no. of
Population and follow-up
Exposure
Confounding
year
cases)
Barraclough Women recruited from
204 (47)
Adverse life
Age, axillary lymph node
J43
breast cancer clinics in
events and social involvement
UK, 1992
Southampton and
difficulties (not
Portsmouth. Mean age 54.
incl. own health)
Follow-up=3 ½ yrs
Brabander
BD 44
Belgium,
1999
Women admitted to Free
44 (10)
University hospital of
Brussels. Median age 58 yrs.
Follow-up=3 ½ yrs
Chronic stress 1
y prior to
diagnosis / Acute
stress of
diagnosis
Forsén A45
Finland,
1991
Breast cancer patients from 86 (41)
Finnish hospitals.
Mean age 51 yrs. Followup=8 yrs
Stressful life
events 12 months
before diagnosis
Graham J46
UK, 2002
NHS breast clinic, London. 202 (54)
Age < 60. Follow-up= 5 yrs
Severe life
experiences 1 yr
prior and 5 yrs
after diagnosis
Hislop TG34 Women referred to the
124 (38)
Canada, 1987 AMEC clinic in Vancouver.
Age <55 yrs. Follow-up=4
yrs
Stress from
recent life events
prior to diagnosis
Results
Any severe event or difficulty 1 yr
before diagnosis
HR=0.43 (0.20-0.93)
Any severe event or difficulty during
follow-up
HR=0.88 (0.48-1.64)
Age, tumor size, lymph node Acute stress: N/S in a forward
invasion, estrogen receptor
stepwise model
positive, progesterone receptor Chronic stress:
positive, expression of neuOR=1.34 (1.00-1.80)
oncogen, expected result of
biopsy
Age, radiotherapy, axillary
2 SD increase in life events measured
node status, chemotherapy,
by the Social Readjustment Rating
estrogen receptor status,
Scale:
histological type of tumor,
HR=3.48 (1.72-7.04)
clinical stage
Tumor size, tumor histology, Severe life experiences 1 yr prior
axillary nodes with tumor
(y/n):
infiltration, age, social class, HR=1.01 (0.58-1.74)
marital status
Severe life experiences 5 yrs after
(y/n):
HR=0.52 (0.29-0.95)
Age, clinical stage, pathologic Stress from recent life events
nodal status, histologic grade, Low: HR=1 (reference)
estrogen receptor status
Medium: HR=0.83
P-value=0.82
High: HR=0.74
Figure 3-1. Flow diagram of the data collection process
258 studies from the search
223 studies did not address the
association between stress and
breast cancer incidence or
breast cancer relapse
35 studies on breast cancer
incidence or relapse
23 studies were not
prospective in design (8 were
limited prospective and 15
were retrospective)
4 studies on stress and
breast cancer relapse
8 studies on stress and
breast cancer incidence
7 studies were included
from scanning the
reference lists of
included studies and
previous reviews
5 studies on stress and
breast cancer relapse
14 studies on stress and
breast cancer incidence
2 studies described the
same association in the
same population
5 studies on stress and
breast cancer relapse
13 studies on stress and
breast cancer incidence
38
IV. Stress and other hormone-dependent cancers: current
knowledge
Most of the previous studies on stress and hormone-dependent cancers have been
confined to the study of breast cancer. Fewer studies have addressed the association
between stress and endometrial, colorectal, and prostate cancers. The evidence from
these studies will be summarized in this chapter. Only prospective studies were included
in the review on stress and breast cancer presented in the previous chapter, but the
limited number of studies on stress and other hormone-dependent cancers does not allow
for such a restriction. Furthermore, varying study designs may make it even harder to
compare the results from the different studies directly.
Endometrial cancer
Four studies have previously assessed the relation between stress and risk of endometrial
cancer (table 4-1).45-48 They have all studied the effect of a major stressful life event and
they were solely based on information from national registries. In a nested case-control
study based on information from national registries, Kvikstad and colleagues found a
slightly lower risk of endometrial cancer among women who had been divorced
compared to married women, but they found no association between loss of a husband
by death and risk of endometrial cancer.45 In another registry-linkage study, Kvikstad
and Vatten found no evidence of a higher risk of endometrial cancer among women who
had lost a child compared to those who had not experienced this severe stressor.46
Johansen and Olsen hypothesized that learning that one’s child has cancer is one
of the most severe stressors a parent can be exposed to.47 They compared the observed
incidence rate of endometrial cancer and a range of other malignancies among women
who had a child with cancer to the incidence rate that would have been expected based
on the incidence of this malignancy in the general population, and they found no
association between having a child with cancer and risk of endometrial cancer.
In a study from Israel also based on information from national registries, Levav
and colleagues found no association between loosing an adult child in war and risk of
39
uterine/ ovarian cancers.48 However, they found more than a doubling of the risk of
these cancers among women who had lost an adult son in an accident. Uterine and
ovarian cancers were combined as one endpoint in this study and we can therefore not
sort out the separate effect of loss of an adult son on risk of endometrial cancer from this
study.
The advantages of using registry-based information are that the exposure can be
assessed independently of the cancer diagnosis and that a large number of cases can be
included into the study. The disadvantage is that each stressful life event is seen as a
separate entity and that stress arising in daily life is not incorporated. This may lead to
serious underestimation of the total stress burden experienced by the individual. Also,
the individual differences in reactions to the life event are not taken into account. The
aim of the study presented in chapter five of this dissertation is to assess a potential
relation between more stress in daily life and risk of endometrial cancer.
Colorectal cancer
Eight previous studies have assessed the association between stress and colorectal cancer
(Table 4-2).45;46;48;65-69 The study designs included four case-control studies,65-68 three
registry linkage studies,45;46;48 and one cohort study.69 Different measures of stress were
applied in these studies including measures of perceived stress and stressful life events.
The case-control and the registry-linkage studies had colorectal cancer incidence as the
endpoint, while the cohort study assessed the risk of colorectal cancer mortality.
Five of the studies addressed the association between stressful life events and
colorectal cancer.45;46;48;65;67 In a population-based case-control study from Sweden,
Courtney et al. addressed the association between stressful life events and risk of
colorectal cancer in 569 cases and 510 controls.67 Stressful life events were assessed
retrospectively during the last 10 years in both cases and controls. They found a
relatively strong positive association between work-related problems or changes in
residence and risk of colorectal cancer. They also found a moderately increased risk of
colorectal cancer associated with death of a spouse, but they found no clear associations
with other stressful life events such as death of a child, divorce, or financial problems.
Kune and colleagues found recent life changes within five years prior to diagnosis as
40
well as the reporting of being extremely upset by these changes to be important risk
factors for colorectal cancer in a population-based case-control study including 715
cases and 727 age- and sex-matched controls.65The associations were strongest for men
as opposed to women and for colon cancer as opposed to rectal cancer. In contrast to
these results, Kvikstad et al. found a lower risk of colorectal cancer among divorced
women, but no association between the loss of a husband by death and risk of colorectal
cancer in a large registry-linkage study.45 Through the national registries, they obtained
information on marital status prior to diagnosis. In another registry-linkage study,
Kvikstad and Vatten report a slightly lower risk of colorectal cancer among women who
have lost a child.46 In a study from Israel also based on information from national
registries, Levav and colleagues found some evidence of a slightly higher risk of
colorectal cancer among fathers and mothers who had lost a son in an accident, but there
were few cases and the confidence intervals were broad.48 In the same study no
association was found between the loss of a son in war and colorectal cancer. In sum, the
evidence from studies on stressful life events and risk of colorectal cancer are
conflicting. In general, stress from acute severe stressors such as the loss of a child or a
spouse did not seem to markedly increase the risk of colorectal cancer, while more
prolonged stress such as major work-related problems may be associated with higher
risk of colorectal cancer.
Two studies have addressed the potential relation between work-related stress and
risk of colorectal cancer.66;68 In a population-based case-control study that included 744
matched case-control pairs, Courtney et al. assessed the association between perceived
job control, demands, and social support five and 30 years before the interview and the
risk of colon cancer.66 Control, demands, and social support in jobs held one year prior
to the interview were imputed for occupational categories. They found a weak positive
association between a self-reported lack of job control and risk of colon cancer, but a
similar association was not found for the imputed measures of job control. No consistent
association was found between job demands and colon cancer, and lower levels of social
support seemed to be linked to a lower risk of colon cancer. Spiegelman and colleagues
used data from the Third National Cancer Survey to assess the relation between workrelated stress and risk of colorectal cancer.68 They included 343 male cases and
compared them to 643 controls with cancers they assumed to be unrelated to
41
occupational exposures. They had no direct measure of stress and the measure of job
stress was therefore imputed from occupational categories. Based on this measure of
stress, they found men with high demands and low control to have more than twice the
risk of colorectal cancer than those with low demands and high control. Their use of
other cancer cases as controls as well as their imputation of individual measures of stress
from occupational categories that did not account for the within-occupation variance in
stress exposure may be problematic. Thus, there is no clear evidence of an association
between work-related stress and colorectal cancer, and prospective studies with
individual measures of work-related stress are needed to pursue this issue further.
Only one previous study has assessed the association between perceived stress in
daily life and colorectal cancer.69 In a cohort of 78,007 Japanese men and women,
Kojima and colleagues found women who reported high levels of daily stress to have a
1.64-fold higher risk of colon cancer mortality, while they reported no association
between stress and colorectal cancer in men or stress and rectal cancer in women.
Colorectal cancer mortality was assessed as the endpoint, which does not allow for a
distinction between etiologic and prognostic factors. The aim of the cohort study
presented in chapter six of this dissertation is to address the association between
perceived stress of daily life and incidence of colorectal cancer.
Prostate cancer
Only one study has previously addressed the association between stress and prostate
cancer.47 In a registry-linkage study from Denmark, Johansen and Olsen assessed the
relative incidence of a range of malignancies, one of them being prostate cancer, among
men who had been exposed to the severe stressor of having a child with cancer
compared to the incidence rate in the general population.47 They found no evidence of an
association between this severe stressor and risk of prostate cancer (Standardized
incidence rate =1.0; 95% CI: 0.8-1.2). Although cancer in a child is a severe stressor, it
may still just represent one dimension of the total stress burden experienced by the
individual. Fortunately, having a child with cancer is a rare event and the association
between the much more prevalent experience of stress in daily life and risk of prostate
42
cancer remains to be studied. The study presented in chapter seven of this dissertation is
aimed at addressing this question.
43
Table 4-1. Summary of previous studies on stress and endometrial cancer
First author, year
Study design
Population
Measure of stress
Endpoints
Johansen C47
Denmark, 1997
Registry-linkage
5716 exposed women Cancer in a child
study with 25 years compared to the
of follow-up
general population
Kvikstad A45
Norway, 1994
Registry-linkage
576 cases and 34 470
study. Nested case- controls
control study
Divorce and loss of Endometrial
a husband by death cancer
incidence
Kvikstad A46
Norway, 1996
Registry-linkage
study. Nested casecontrol study
Registry-linkage
study with 10.5
years of follow-up
Death of a child
Levav I48
Israel, 2000
488 cases and 29 750
controls
3299 exposed and
524 916 unexposed
Endometrial
cancer
incidence
(N=46)
Adjustment
Age
Age, parity
Endometrial Age, parity
cancer
incidence
Loss of an adult son Uterine/
Age, year of
in war or accident ovarian cancer birth, region
incidence
of origin,
(N=8235)
period of
immigration
Results
Mothers whose child had
cancer compared with the
background population:
SIR= 1.0 (95% CI: 0.71.3)
Divorce:
OR= 0.64 (95% CI: 0.480.85)
Loss of a husband by
death:
OR= 1.08 (95% CI: 0.661.80)
Death of a child:
OR= 0.84 (95% CI: 0.511.39)
Loss of son in war:
OR= 1.16 (95% CI: 0.821.64)
Loss of son in accident:
OR= 2.19 (95% CI: 1.323.63)
Table 4-2. Summary of previous studies on stress and colorectal cancer
First author, Study
Population
Measure of stress Endpoints
year
design
67
Courtney JG
Population- 569 cases and 510 Stressful life
Colorectal cancer
Sweden, 1993 based case- controls. Controls events within the incidence
control study were selected from last 10 years
the general
population
Courtney JG66
USA, 1996
Kojima M69
Japan, 2005
Adjustment
Results
Age, sex, diet, body Death of a spouse:
mass index, physical OR=1.5 (95% CI: 1.1-2.4)
activity, alcohol
Serious occupational problems:
OR=5.3 (95% CI: 2.2-13.0)
Change of residence of >200
km:
OR=3.2 (95% CI: 1.1-8.3)
No association with death of a
child/friend/relative, divorce,
unemployment, or financial
problems
Population- 744 matched case- Perceived job
Colon cancer
Age, sex,
Low vs. high control
based case- control pairs.
demand, control, incidence
neighborhood,
OR=1.3 (95% CI: 1.0-1.6)
control study Controls were
and social support
physical activity,
High vs. low demands
selected from the
family history,
OR=1.0 (95% CI: 0.8-1.3
general population
employment status, Low vs. high social support
weight, alcohol, diet, OR=0.6 (95% CI: 0.4-1.0)
pregnancies
No sex differences
Cohort study 78,007 men and
Perceived stress of Colorectal cancer Body mass index,
High vs. low stress
with an
women participating daily life
deaths (N=320)
family history,
Colon cancer:
average of in the Japan
smoking, alcohol,
Men: HR=0.95 (95% CI: 0.559.6 years of Collaborative
sleep duration, intake 1.66)
follow-up Cohort Study for
of green leafy
Women: HR=1.63 (95 % CI:
Evaluation of
vegetables, walking, 1.00-2.64)
Cancer Risk
constipation,
Rectal cancer:
education, marital
Men: HR=0.96 (95% CI: 0.53status, children,
1.73)
employment
Women: HR=1.27 (95% CI:
0.58-2.81)
Continues on next page
Kune S 65
Population- 715 cases and 727 Stressful life
Australia, 1991 based case- controls. Controls events with the
control study were selected from last 5 years
the general
population
Colorectal cancer Sex, age, diet, beer,
incidence
family history, age at
birth of first child,
number of children
Kvikstad A45 Registry918 cases and 34
Norway, 1994 linkage
470 controls.
study.
Females only
Nested casecontrol study
Kvikstad A46 Registry861 cases and 29
Norway, 1996 linkage
750 controls.
study.
Females only
Nested casecontrol study
Levav I48
Registry6284 exposed and
Israel, 2000
linkage
1 019 255
study with unexposed
10.5 years of
follow-up
Divorce and loss
of a husband by
death
Colorectal cancer Age
incidence
Death of a child
Colorectal cancer Age
incidence
Loss of an adult
son in war or
accident
Loss of son in war
Colorectal cancer Age, year of birth,
Fathers: OR=1.06 (0.81-1.38)
incidence (N=22 region of origin,
158)
period of immigration Mothers: OR= 1.12 (0.82-1.54)
Spiegelman D68 Case-control 343 cases and 626
USA, 1985
study
controls. Controls
were cancer cases
with no confirmed
occupational
association. Males
only
Major family illness:
OR=1.22 (95% CI: 1.01-1.47)
Major family problem:
OR=1.32 (95% CI: 1.08-1.61)
Major work problem:
OR=2.54 (95% CI: 1.74-3.72)
Extremely upsetting event:
OR=1.68 (95% CI: 1.30-2.17)
Divorce:
OR= 0.66 (95% CI: 0.53-0.83)
Loss of a husband by death:
OR= 1.01 (95% CI: 0.68-1.51)
Death of a child:
OR= 0.70 (95% CI: 0.48-1.02)
Loss of son in accident
Fathers: OR= 1.39 (0.90-2.16)
Mothers: OR= 1.62 (0.85-1.54)
High demands and low control
vs. low demands and high
control:
Imputed measure Colorectal cancer Age, race, marital
of job stress based incidence
status, region,
on occupation
ponderosity,
socioeconomic status,
diet
OR= 2.51 (P-value:0.03)
V. Self-reported stress and risk of breast cancer: a prospective
cohort study
Introduction
Breast cancer is the most common cancer in women in terms of both incidence and
prevalence.23 It is a hormone-dependent disease with a clear positive relation to high
endogenous concentrations of estrogen.70 The role of stress in the etiology of breast
cancer has been an area of emerging interest, partly because stress seem to affect the
hormonal system and especially estrogen synthesis.10-12;71 A potential relation between
stress and risk of breast cancer has been examined in studies with different designs and
with conflicting results.15;41;47;52;54-56;59 Different measures of stress, as applied in these
studies, may well have different physiological and psychological impacts. Death of a
spouse or near relative is a major acute stressor, whereas stress experienced in daily life
is more moderate and chronic in nature.
The risk of breast cancer associated with the acute stress of major life events has
been assessed in several studies,15;41;47;59 but less attention has been given to the effect of
perceived daily stress.54-56 Prolonged low key stress in everyday life results in a
persistent activation of stress hormones, which may impair estrogen synthesis,72 and
may thereby be related to a lower risk of breast cancer. Everyday stress may also
indirectly affect the risk of breast cancer through changes in health-related behavior. The
objective of this study is to explore the impact of everyday stress on the long term risk of
first time incidence of primary breast cancer among 6,689 women prospectively
followed up for 18 years.
Methods
Study population
Information from the second examination of the prospective Copenhagen City Heart
Study in 1981-83 was used to address the objective. The second examination of the
study included 7,018 women and we excluded women with breast cancer before baseline
47
(n=120) or lacking information on stress or other covariates (n=209), leaving 6,689
women. Twenty-six (<0.1%) women were lost to follow-up. Perceived stress was
assessed at baseline and included two questions on stress intensity and stress frequency.
A seven-point stress score was created based on these two questions. Please refer to the
material and methods chapter for a detailed description of the Copenhagen City Heart
study and the measurement of perceived stress.
Covariates
We considered the following variables as potential confounders for the analyses based
assumptions shown in the causal diagram in figure 5-1: current oral contraceptive use
(yes/no), other hormone therapy (yes/no), menopause at baseline (yes/no), body mass
index (continuous), number of children (0, 1-2, ≥3), physical activity in leisure time
(low, medium, high), alcohol consumption (0 drinks/week, 1-14 drinks/week, >14
drinks/week), and education (<8 years, 8-11 years, ≥12 years). All variables were
measured at baseline. Early menarche, age at first birth, family history of breast cancer,
ionizing radiation, benign breast cancer, mammographically dense breasts and mutations
in BRCA1/2 or p53 and contraceptive use were not expected to be strongly associated
with stress and were therefore also not included in the analyses.
Follow-up
We followed participants from the date of the second examination until the date of first
diagnosis of primary breast cancer (n=251), death (n=2,224), emigration (n=26), or the
end of follow-up on 31 December 1999 (n=4,188). We used the civil registry number,
which is unique to every Danish citizen, to identify primary breast cancer events through
linkage to the Danish National Cancer Registry, which contains data on all cancer
diagnoses in Denmark. We used ICD-7 codes170.0-170.5, 470.0-470.5, and 870.0-870.2
to identify cases of primary invasive breast cancer. We followed the vital status of the
study population in the Central Death Registry. Information on diagnosis of breast
cancer was updated until 1999, making it possible to follow the participants from the
second examination for 16-18 years for a primary diagnosis of breast cancer.
48
Statistical methods
We used Cox regression models (SAS/STAT software version 8.2) to analyse data with
age as the time scale. All included variables met the assumption of proportional hazards.
Initially, we estimated the age adjusted hazard ratio of primary breast cancer associated
with stress intensity, stress frequency, and stress score (continuous and in categories of
low, medium, and high stress). Subsequently, we fitted a multivariate Cox regression
model to adjust for potential confounding from baseline covariates. We used trend
analyses to assess dose-response relations between stress and breast cancer. A variable
was only included in the analyses as a continuous variable if a linear trend could be
confirmed in a likelihood ratio test. To estimate the effect of prolonged follow-up, we
assessed the association in the first and last nine years of follow-up. We also used these
analyses to address if the introduction of mammography screening for women aged 5069 years in 1991 in the Copenhagen area affected the results. Finally, we did subgroup
analyses to assess potential effect modification of the ratio measure.
Results
Baseline characteristics
Mean age at baseline was 57 (range 21-91) years. Ten percent of the women reported
high levels of stress (table 5-1). Mean age, number of children, and body mass index
seemed to be similar at the different stress levels. A lower proportion of highly stressed
women than less stressed women were premenopausal and used oral contraceptives. A
higher proportion of the women in the high stress group received hormone therapy, had
low education and high alcohol intake, and was physically inactive in their leisure time
compared with women with lower levels of stress. During follow-up, 251 cases of
primary breast cancer occurred. A higher percentage of women in the high stress group
(n=261, 39.3 %) than in the medium (n=972, 30.4 %) or low stress groups (n= 991, 35.1
%) died during follow-up.
49
Stress intensity, stress frequency, and risk of breast cancer
Seven percent of the women reported high stress intensity, and 10 % reported high
frequency of stress. The adjusted hazard ratio of primary breast cancer seemed to be
inversely associated with both stress intensity (test for trend, P=0.02) and stress
frequency (test for trend, P=0.06) (table 5-2).
Stress score and risk of breast cancer
After adjustment for potential confounders, an 8% lower risk (hazard ratio 0.92, 95%
confidence interval 0.85 to 0.99) of primary breast cancer occurred for each increase in
stress level on the six-point stress scale (table 5-3). Higher stress was inversely
associated with incidence of primary breast cancer (test for trend, P=0.02), and high
stress was associated with a hazard ratio of 0.60 (0.37 to 0.97) for breast cancer
compared with low stress.
Subgroup analyses
One hundred and fourteen first time primary breast cancers occurred in the first nine
years of follow-up and 137 cases occurred in the last nine years. The relative effect of
stress on incidence of breast cancer seemed to be similar in the two periods of follow-up
(table 5-4).
Sixteen percent (n=1045) of the women were receiving hormone therapy at
baseline, and the effect of stress on risk of breast cancer seemed to be mainly confined to
these women (table 5-5). The P-value for statistical interaction was 0.09. Among women
receiving hormone therapy, the hazard ratio for primary breast cancer was 0.83 (0.72 to
0.97) for each increase in stress level on the six-point stress scale. No notable effect
modification occurred in subgroups of menopausal status, physical activity, alcohol
consumption, oral contraceptive use, education, and number of children (data not
shown).
Discussion
Among 6,689 women followed-up for an average of 18 years, higher self-reported
everyday stress was associated with lower risk of breast cancer. Our results are similar to
50
those from the Nurses’ Health Study, in which Kroenke et al found self-reported stress
from adult caregiving to be associated with lower incidence of breast cancer.55 However,
our results contrast with the results of a Finnish cohort study, which found no
association between stress of daily activities and breast cancer, and a Swedish study in
which severe mental stress was associated with higher incidence of breast cancer.54;56
Some of the discrepancy may be explained by the fact that different measures of stress
were applied and that the Finnish and Swedish studies included all incident cases of
breast cancer, whereas we confined our analyses to first time incidence of primary breast
cancer. Apart from these studies, the main focus has been on stressful life events.
However, the nature of sustained everyday stress is different from stressful life events,
and an increased risk of breast cancer associated with stressful life events is not
necessarily in contrast with a lower risk of breast cancer associated with daily stress.
Strengths and weaknesses
The prospective design of the Copenhagen City Heart Study ensured temporality
between stress and incidence of breast cancer. The cohort is a large random sample of
the general population of Copenhagen. Furthermore, linkage of civil registry numbers to
nationwide population based registers enabled identification of virtually all cases of
breast cancer and allowed for nearly complete long-term follow-up.
Information on several important risk factors for breast cancer, such as family
history of breast cancer, age at menarche, and age at first full time pregnancy, was not
obtained. However, to confound the results these factors should also be related to stress.
We cannot exclude that having experienced breast cancer in a near family member may
act as a stressor and thereby lead to higher levels of stress, which would result in a
spurious positive association between stress and breast cancer. This is opposite to the
inverse association we observe in our study and therefore cannot explain it. Late age of
menarche would have to be relatively strongly related to high stress in order to explain
our results, but we know of no empirical evidence or biological explanation that would
support such an expectation. Late age at first full term pregnancy is a well-established
risk factor for breast cancer. More women with high stress had low education (55%
versus 47% in the low stress group), and women with low education tend to have their
first pregnancy earlier than other women. Thus, we cannot exclude that some of the
51
observed inverse association is due to uncontrolled confounding by age at first
pregnancy. However, adjustment for number of children, which also tends to be
correlated with age at first pregnancy, as well as adjustment for education only changed
the estimates slightly.
Mammographic screening for women aged 50-69 years was introduced in
Copenhagen in 1991.73;74 Stressed women may have been less likely to participate in the
screening program and may therefore have had invasive breast cancer diagnosed at a
later stage. According to Olsen et al., an expected increase in incidence of invasive
breast cancer occurred after the first screening round, but the incidence dropped to the
pre-screening level in the following screening rounds, indicating that over-diagnosis of
breast cancer was not a major problem.74 Furthermore, screening only took place in
women aged 50-69 years and in the last nine years of our study. The effect estimates
were similar in the first and last nine years of follow-up (table 5-4), so bias by screening
is unlikely to explain our results.
How stress is to be defined and measured remains a point of debate. So far the
literature has focused on external stressors with less emphasis given to how they are
perceived by the individual. However, each person has different capacity and ways of
coping with stressful situations, and the same external stressor may result in different
levels of perceived stress. A measure of perceived stress will therefore provide a better
measure of the actual level of stress experienced by the individual as opposed to a count
of potential stressful situations defined by the researcher.
More women in the high stress group (39.3%) than in the medium (30.4%) and
low stress (35.1%) groups died during follow-up. Although this indicates no systematic
difference, it may raise concern about how censoring has influenced the results. We
assumed, in the statistical model, that censoring was independent of breast cancer risk
within each stratum of stress. Competing causes, such as death from cardiovascular
disease, could, however, be associated with risk of breast cancer within strata of stress
owing to other common risk factors. Some of the common risk factors, such as
socioeconomic status, have opposite effects on the two diseases, whereas other risk
factors, such as low physical activity, increase the risk of both diseases.70;75 On average,
we would expect the bias to level out and the average risk of breast cancer among
women not censored to be similar to what it would have been if no such censoring had
52
occurred. Thus, although our results may have been influenced by bias from nonindependent censoring, we find it unlikely that this could completely explain them.
Possible causal pathways between perceived stress and breast cancer
In most cases, the physiological effects of acute stressors are reversible owing to the
amazing ability of the human organism to re-establish allostasis. The problems arise
when the stress response becomes chronic and results in permanent disturbances. In a
normally functioning female reproductive system, the hypothalamus releases luteinizing
hormone releasing hormone, which stimulates the pituitary gland to release luteinizing
hormone and follicle stimulation hormone. Luteinizing hormone stimulates the ovaries
to synthesize estrogens, whereas follicle stimulation hormone stimulates the ovaries to
release eggs. This is called the hypothalamic-pituitary-gonadal axis. Stress can affect the
signals of this axis by activating the hypothalamic-pituitary-adrenal axis and the
sympathetic nervous system. Several studies in mammals have found that activation of
the hypothalamic-pituitary-adrenal axis inhibits the function of the hypothalamicpituitary-gonadal axis and thereby decreases estrogen synthesis, but data on humans are
sparse.10-12;72 Still, in a recent study in which caregiving was used as an indicator of
chronic stress, significantly lower concentrations of bioavailable estradiol were found
among female caregivers than among non-caregivers.55 In essence, stress induced
suppression of estrogen secretion could explain a reduced risk of breast cancer.
An imbalance in the allostatic concentration of reproductive hormones may also
result in other reproductive disturbances and mood swings and initiate depression in
susceptible women.76;77 Some women may be more sensitive to hormonal disturbances
and therefore be more likely to receive hormone therapy to lessen their symptoms.
Hormone sensitive women are more likely to be susceptible to stress induced changes in
estrogen synthesis, which could explain why stress mainly seems to be associated with
lower risk of breast cancer among women receiving hormone therapy.
Conclusions
It is biologically plausible that the lower risk of breast cancer associated with stress
observed in this long term prospective cohort study might be due to stress induced
53
imbalances in normal concentrations of estrogens. However, stress induced disturbances
of allostasis cannot be considered a healthy response, and prolonged stress may have
harmful effects on a range of other diseases, especially cardiovascular diseases.
54
Table 5-1. Baseline characteristics of women who participated in the second examination of the Copenhagen City heart study in 1981-3. Values
are numbers (percentages) unless stated otherwise
Stress*
Study population
Participants
Low
Medium
High
6689
2823 (42)
3201 (48)
665 (10)
57 (12)
58 (12)
55 (12)
58 (12)
1766 (26)
672 (24)
978 (31)
116 (17)
250 (4)
99 (4)
143 (4)
8 (1)
1045 (16)
328 (12)
568 (18)
149 (22)
1.6 (1.3)
1.6 (1.4)
1.6 (1.3)
1.7 (1.4)
25 (5)
25 (5)
25 (4)
25 (5)
449 (7)
152 (5)
230 (7)
67 (10)
< 8 years of formal education
3096 (46)
1340 (47)
1388 (43)
368 (55)
Physically inactive
1179 (18)
442 (16)
520 (16)
217 (33)
Mean (SD) age (years)
Premenopausal
Current oral contraceptive users
Other hormone therapy
Mean (SD) No. of children
2
Mean (SD) body mass index (kg/m )
High alcohol consumption
*Participants reported stress intensity and frequency on a standard questionnaire with four multiple-choice categories (0-3 points) for each stress
measure. The scores of the two questions were added and combined into a continuous stress score from 0 to 6. This stress score was categorized
into low (0-1 points), medium (2-4 points), and high (5-6 points).
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 1981-3
No. of breast
Incidence per 100 000
Age adjusted hazard ratio
Multi-adjusted* hazard ratio
cancers
person years
(95% CI)
(95% CI)
None (n=2214)
96
292
1 (reference)
1 (reference)
Light (n=2608)
97
243
0.89 (0.67 to 1.18)
0.85 (0.64 to 1.13)
Moderate (n=1384)
44
210
0.74 (0.52 to 1.05)
0.68 (0.47 to 0.98)
High (n=483)
14
203
0.65 (0.37 to 1.13)
0.61 (0.35 to 1.07)
0.04
0.02
Stress intensity
P value for trend
Stress frequency
Never (n=2854)
119
282
1 (reference)
1 (reference)
Monthly (n=1994)
71
228
0.90 (0.67 to 1.20)
0.85 (0.64 to 1.15)
Weekly (n=1168)
40
227
0.83 (0.58 to 1.19)
0.78 (0.55 to 1.13)
Daily (n=673)
21
213
0.70 (0.44 to 1.11)
0.67 (0.42 to 1.07)
0.09
0.06
P value for trend
*Adjusted for age, current oral contraceptives use, other hormone therapy, menopausal status, number of children, body mass index, alcohol
consumption, physical activity in leisure time, and education.
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 1981-3
Stress score
No. of breast
Incidence per
Age adjusted hazard ratio
Multi-adjusted* hazard ratio
cancers
100 000 person years
(95% CI)
(95% CI)
0.93 (0.87 to 1.00)
0.92 (0.85 to 0.99)
Continuous
Categorised:
Low stress (n=2823)
120
285
1 (reference)
1 (reference)
Medium stress (n=3201)
112
229
0.84 (0.65 to 1.09)
0.80 (0.62 to 1.04)
High stress (n=665)
19
194
0.63 (0.39 to 1.02)
0.60 (0.37 to 0.97)
0.04
0.02
P value for trend
*Adjusted for age, current oral contraceptives use, other hormone therapy, menopausal status, number of children, body mass index, alcohol
consumption, physical activity in leisure time, and education.
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 1981-3, according to time period of follow-up
First nine years of follow-up
Last nine years of follow-up
Incidence per 100 000
person years
Multiple adjusted hazard
ratio* (95% CI)
Incidence per 100 000
person years
Multiple adjusted hazard
ratio* (95% CI)
Low stress
239
1 (reference)
339
1 (reference)
Medium stress
190
0.82 (0.55 to 1.21)
272
0.78 (0.55 to 1.11)
High stress
167
0.63 (0.31 to 1.28)
227
0.60 (0.30 to 1.16)
P-value for trend
0.14
0.07
*Adjusted for age, current oral contraceptives use, other hormone therapy, menopausal status, number of children, body mass index, alcohol
consumption, physical activity in leisure time, and education.
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 1981-3, in subgroups of hormone therapy
Stress score
No hormone therapy (n=5644)
Hormone therapy (n=1045)
Age adjusted hazard ratio
Multi-adjusted* hazard ratio
(95% CI)
(95% CI)
184
0.95 (0.87 to 1.04)
0.96 (0.88 to 1.05)
67
0.82 (0.71 to 0.95)
0.83 (0.72 to 0.97)
No. of breast cancers
*Adjusted for age, current oral contraceptive use, menopausal status, number of children, body mass index, alcohol consumption, physical
activity in leisure time, and education.
Figure 5-1. Causal diagram of the relation between perceived stress and risk of breast cancer
Oral contraceptive use
Family history of
breast cancer
Ionizing
radiation
Menopause
Time of menarche
Benign breast
cancer
Estrogens
Postmenopausal
hormone theraphy
Perceived stress
Breast cancer
Alcohol
Body mass index
Physical activity
Mammographically
dense breasts
Mutations in p53
Number of children
Age at first birth
Mutations in BRCA1/2
Socio-economic
status
VI. Self-reported stress and risk of endometrial cancer: a
prospective cohort study
Introduction
Endometrial cancer is the fourth most common cancer in Europe and North America.78
Some of the best known risk factors for endometrial cancer are endogenous
concentrations of estrogens and exposure to unopposed exogenous estrogens.79
Psychological stress may play a role in endometrial carcinogenesis by affecting
synthesis and metabolism of estrogens as well as by decreasing the sensitivity of the
uterus toward estrogen stimulation.10;80;81 Estradiol, which is the most active estrogen
metabolite, can bind to the estrogen receptors, activate gene expression, and thereby
increase cell proliferation. By this pathway, estrogens may promote growth of already
initiated cells. There is also some evidence that estrogens can be metabolized into more
reactive intermediates that can, in turn, lead to structural changes in the DNA and
thereby act as initiating agents.82 Chronic stress from caregiving has been associated
with lower levels of bioavailable estradiol among female nurses.55 If high levels of stress
hormones indeed result in lower levels of endogenous estradiol, we would expect
psychological stress to lower the incidence of endometrial cancer. However, a possible
relation between stress and endometrial cancer remains to be studied.
Stress may affect the risk of endometrial and breast cancer through the same
hormonal pathway, namely, by impairment of estrogen synthesis. For breast cancer risk,
several large registry-linkage studies have found no association with major life events
such as death of a spouse, divorce, or having a child with cancer,44-47;49 whereas some
cohort studies have suggested a lower risk in women exposed to chronic stress in
everyday life.53;55;57 In contrast, a higher risk of breast cancer associated with measures
of stress has also been reported in some prospective studies.48;54;58;59 However, these
studies were smaller than the ones reporting no association or a protective effect. Thus,
the combined evidence showed no increased or maybe even a decreased risk of breast
cancer associated with different measures of stress.
61
On the other hand, combined evidence from experimental and animal studies have
suggested that stress may promote the initiation and progression of cancer by
impairment of the elements involved in the immune surveillance of the cell.2 Stress
could, by this pathway, potentially increase the risk of cancer. However, cancer is a
heterogeneous group of diseases with multiple causes and the involvement of the
immune system may therefore depend on the specific cancer in question.
We aim to address the association between stress and endometrial cancer in a
prospective cohort study including 6,760 women prospectively followed up for 18 years.
Our hypothesis is that perceived stress may suppress synthesis of and sensitivity towards
estrogens and thereby be related to lower risk of endometrial cancer.
Methods
Study population
Information from the second examination of the prospective Copenhagen City Heart
Study in 1981-83 was used to address the objective. The second examination of the
study included 7,018 women, and we excluded women with endometrial cancer before
baseline (n=38) or with lacking information on stress (n=25) or other covariates
(n=195), leaving 6,760 women for the analyses. Perceived stress was assessed at
baseline and included two questions on stress intensity and stress frequency. A sevenpoint stress score was created based on these two questions. Please refer to the material
and methods chapter for a detailed description of the Copenhagen City Heart study and
the measurement of perceived stress.
Covariates
The confounder identification was based on a causal diagram, in which we included the
most current prior knowledge about causal relations between perceived stress,
covariates, and endometrial cancer (Figure 6-1).22 This served as a way to visualize and
explicitly elaborate the assumptions about the web of causation for the relation between
stress and endometrial cancer and to identify variables that must be measured and
controlled to obtain unconfounded estimates. According to the diagram the analyses
should be adjusted for the following covariates: age (continuous), education (less than 8
62
years, 8-11 years, or 12 or more years), physical activity in leisure time (none or very
little activity; 2-4 hours of light activity per week; more than 4 hours of light activity or
2-4 hours of high level activity; and competitional level or more than 4 hours of hard
level activity per week), body mass index (continuous), tobacco smoking (never-smoker,
ex-smoker, smokers of 1-14 grams per day, 15-24 grams per day, and more than 24
grams per day), diabetes mellitus (yes/no), number of children (0, 1-2, 3 or more),
menopause (yes/no), and hormone therapy (yes/no). Alcohol intake, dietary patterns,
hypertension, late menopause, and stress hormones are possible intermediates on the
pathway from perceived stress and endometrial cancer and will therefore not be included
in the analyses. Also, early menarche and contraceptive use are not included in the
analyses, as they were not assumed to be strongly associated with stress.
Follow-up
The women were followed from date of the second examination until date of first
diagnosis of primary endometrial cancer (n=72), death (n=2,418), emigration out of
Denmark (n=28), or end of follow-up on December 31, 2000 (n=4,242). Thus, fewer
than 0.1% were lost to follow-up due to emigration. Using the civil registry number,
which is unique to every Danish citizen, primary endometrial cancer events were
identified through linkage to the Danish National Cancer Registry, which contains data
on all cancer diagnoses in Denmark since 1942. The following ICD7-codes were used to
identify primary invasive endometrial cancer cases: 172.0-172.2. The vital status of the
women was followed in the Central Death Registry. Information on diagnosis of
endometrial cancer has been updated until December 31, 2000, making it possible to
follow the women for 17 to 19 years.
Statistical methods
Data were analyzed by means of Cox proportional hazards models with age as the time
variable. Stress intensity, stress frequency, and the combined stress score all met the
assumption of proportional hazards. Initially, we estimated the age-adjusted hazard ratio
of endometrial cancer associated with stress intensity, stress frequency, and the
combined stress score in separate models. By including age as the time variable the
estimates were soundly adjusted for age. Secondly, a multivariate Cox proportional
63
hazards model was fitted to adjust for potential confounding from baseline covariates.
Trend tests were used to test for linear dose-response trends in the associations between
stress and endometrial cancer. Thirdly, statistical interactions between stress and all
variables included in the multivariate model were addressed and subgroup analyses were
conducted for interactions with a P-value below 0.20. Thus, subgroup analyses were
done for hormone therapy (P-value for interaction: 0.08) and body mass index (P-value
for interaction: 0.09). No cases of endometrial cancer occurred among underweight
women (BMI≤ 18.5) so the analyses were only stratified into normal weight (BMI≤ 25)
and overweight (BMI>25). Finally, separate analyses for the first and last nine years of
follow-up were done in order to address the possible effect of prolonged follow-up.
Results
Baseline characteristics
The median age at baseline was 58 years ranging from 21 to 91 years. Ten percent of the
women reported high levels of stress (table 6-1). Women reporting medium stress were
slightly younger and had lower body mass index than women reporting both low and
high levels of stress. A higher proportion of women who reported high stress used
hormone therapy, were current smokers, were physically inactive in their leisure time,
and had low education compared to women with lower levels of stress. A lower
proportion of highly stressed women were pre-menopausal and were nulliparous. The
percentage with diabetes mellitus was similar at the different stress levels.
Perceived stress and incidence of endometrial cancer
At the end of follow-up, 72 incident cases of primary endometrial cancer had occurred.
The adjusted hazard ratios of endometrial cancer were 0.52 (95 % CI: 0.26-1.04) and
0.72 (95 % CI: 0.28-1.89) for women reporting medium and high stress intensity,
respectively, compared to women who did not perceive their life as stressful (table 6-2).
In terms of stress frequency, women reporting daily stress had a hazard ratio of 0.40 (95
% CI: 0.14-1.15) compared to women who reported to never experience stress. There
appeared to be an inverse dose-response association between stress frequency and risk of
endometrial cancer (P-value for trend: 0.07). For the combined stress score, the hazards
64
ratio for endometrial for each unit change on the seven-point stress-scale was 0.88 (95 %
CI: 0.76-1.01). Adjustment for potential confounders made the associations slightly
stronger.
Stratified analyses
Fifteen percent (n=1,041) of the women received hormone therapy at baseline and these
women had a more than four-fold higher risk of endometrial cancer (HR=4.15; 95 % CI:
2.54 - 6.78) compared to women who did not receive such treatment (data not shown).
The association between stress and endometrial cancer was only apparent in women who
received hormone therapy (table 6-3). Among women receiving hormone therapy, stress
intensity (P-value for trend: 0.06) and stress frequency (P-value for trend: 0.01) were
both inversely associated with risk of endometrial cancer, and the hazard ratio for
primary endometrial cancer was 0.77 (0.61 to 0.96) for each unit increase in stress level
on the seven-point stress scale among these women. No associations between perceived
stress and risk of endometrial cancer were observed among women who did not receive
hormone therapy.
A body mass index of more than 25 kg/m2 was associated with a hazard ratio of
1.27 (95 % CI: 0.79 – 2.04) compared to those with a lower body mass index (data not
shown). Among the 4,004 women with a body mass index of less than or equal to 25,
there was a clear inverse association between both stress intensity (P-value for trend:
0.01) and stress frequency (P-value for trend: 0.005) and risk of endometrial cancer
(Table 6-4). The hazard ratio for primary endometrial cancer was 0.73 (0.58 to 0.91) for
each unit increase in stress level on the seven-point stress scale among these women. No
clear association between stress and risk of endometrial cancer was noted among women
with a BMI above 25 kg/m2.
No notable effect modification of the ratio measure occurred in subgroups of
menopausal status, physical activity, smoking, education, and number of children (data
not shown). Half the cases of endometrial cancer (n=36) occurred in the first nine years
of follow-up, while the other 36 cases occurred in the last nine years of follow-up. The
association between stress score and endometrial cancer was stronger in the first nine
years (HR=0.85, 95 % CI: 0.70-1.04) compared to the last nine years (0.91, 0.75-1.10)
of follow-up.
65
Discussion
Among the 6,760 women followed up for 18 years, perceived stress appeared to be
associated with lower risk of primary endometrial cancer in an inverse dose-response
manner. The association was confined to women who received hormone therapy and
women of normal weight. No studies have, to our knowledge, previously addressed the
relation between stress and endometrial cancer. Both breast and endometrial cancers are
estrogen-dependent cancers with a clear relation to endogenous concentrations of
estrogens.70;79 If stress in fact affects the risk of endometrial cancer through a hormonal
pathway, then our results are in accordance with the lower risk of breast cancer
previously observed among stressed women in the same cohort.57 Other studies that have
addressed the effect of chronic stress, such as that arising from caregiving or from high
strain jobs, have also reported a lower risk of breast cancer among stressed women,53;55
In studies that have applied other measures of stress, such as stressful life events, the
results have been more conflicting.15
Strengths and weaknesses
The prospective design of the Copenhagen City Heart Study ensured temporality
between self-reported stress and incidence of endometrial cancer. Linkage of civil
registry numbers to nationwide population-based registers enabled identification of
virtually all cases of diagnosed endometrial cancer and allowed for nearly complete
long-term follow-up.
How stress is defined and measured remains a point of debate. In this study, stress
was defined as an individual state of high arousal and displeasure, sometimes referred to
as distress.83 By using a measure of perceived stress we accounted for the fact that each
individual has different capacities and ways to cope with stressful situations.16 Perceived
stress was assessed by combining two questions on stress intensity and stress frequency
asked at baseline. Since these two questions are not yet validated against a more
extensive scale, such as the Perceived Stress Scale,84 we cannot fully determine the
magnitude of the misclassification and an even stronger relation between perceived
stress and risk of endometrial may have been blurred. Perceived stress was only assessed
66
at baseline and may have changed over time in a manner that is most likely independent
of subsequent development of endometrial cancer. In another Danish cohort study85 that
included a question on perceived stress, the majority of the participants (62%) reported
the same level of stress in 1994 as in 2000 (Nielsen, unpublished data, 2006). Although
this finding indicates that a measure of perceived stress may be relatively stable over
time, a considerable minority changed stress levels. The association between stress and
risk of endometrial cancer was strongest in the first nine years compared to the last nine
years of follow-up. This may either be due to changes in stress levels over time and thus
exposure misclassification, or it may be due to a differential effect of stress depending
on whether it affects the multistage carcinogenesis early as an initiating agent or later as
a promoting agent.
Women with breast cancer are often treated with tamoxifen, a non-steroidal
compound with partially estrogenic and anti-estrogenic effects depending on the target
tissue. Such treatment seems to increase the risk of second primary endometrial cancer
among women with breast cancer.79 Women who had breast cancer before baseline may
also report higher levels of stress; thus, confounding from history of breast cancer could
arise. However, even though 126 of the women included in this study were diagnosed
with breast cancer before baseline, none of them developed primary endometrial cancer
during follow-up, and confounding from breast cancer history is therefore unlikely.
An inverse association between tobacco smoking and risk of endometrial cancer
has previously been reported.86 More women with high levels of stress also engaged in
tobacco smoking in this study, which may raise concern about residual confounding
from smoking. We adjusted our analyses for smoking in five categories and such
adjustment only slightly changed the risk estimates.
We assumed that hypertension was a possible intermediate on the pathway
between stress and endometrial cancer. We also assumed that use of oral contraceptives
was unrelated to stress. Neither of these variables was therefore included in the
statistical analyses. However, it could be argued that these factors may have been
associated with stress because of unmeasured confounding and thus should have been
included in the analyses. However, adjustment of hypertension and oral contraceptive
use did not change the risk estimates (data not shown).
67
Possible pathways between stress and endometrial cancer
A stress-induced distortion of estrogen synthesis may explain the lower incidence of
endometrial cancer among women with high levels of stress. The hypothalamicpituitary-gonadal (HPG) axis regulates the synthesis of estrogens in a normally
functioning female reproductive system. Stress can affect the signals of this axis by
activating the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous
system. Several experimental studies have found that the activation of the HPA axis can
inhibit the function of the HPG axis and thereby decrease the synthesis of estrogen.1012;72;81
Although human evidence is sparse, significantly lower levels of bioavailable
estradiol was also found among female caregivers compared to non-caregivers in a
recent epidemiologic study.55 These mechanisms may explain the lower risk of
endometrial cancer observed among normal-weight women. In overweight women,
peripheral conversion of androgens to estrogens in adipose tissue is another important
source of estrogens.87 No evidence indicates that stress hormones have an effect on this
extra-gonadal synthesis of estrogens. Also, overweight women seem to be in a proinflammatory state that facilitates carcinogenesis by creating an environment susceptible
to tumor initiation and promotion as well as increased estrogen production.88 This may
counteract the stress-induced suppression of estrogens and thus explain the less
pronounced effect of stress on endometrial cancer among overweight women. Because
of the long delay between the development and the detection of the disease and the fact
that we were only able to follow the study participants in registries, we cannot determine
whether stress, through its effect on estrogen synthesis and metabolism, hinders
initiating and/or interrupts promotion of already initiated cells.
Experimental evidence shows that stress may also produce a direct effect on the
uterus by changing the response of its structures toward estrogen.89-91 It is well known
that unopposed estrogens increase the proliferative activity of uterine tissues as well as
lead to morphogenetic changes, which may increase the risk of developing tumors in
these tissues. Chronic exposure to glucocorticoids, a major end-point in a physiologic
stress response, has been shown to produce a complex anti-estrogenic effect in the uterus
of mice by turning the estrogen-dependent changes from the direction of pre-cancerous,
atypical hyperplasia formation to the more favorable development of simple and cystic
hyperplasia.89 Acute stress and administration of glucocorticoids in doses normally
68
experienced during a stress response have both been reported to decrease the uterus’
sensitivity toward estrogen stimulation and decrease estrogen receptor concentration in
ovariectomized rats treated with estrogen.90;91 In these studies, the effects of stress on the
uterine structures depended on the presence of estrogens. The majority of the women in
the Copenhagen City Heart Study was post-menopausal at baseline and therefore had a
relatively low ovarian synthesis of estrogens. If the effect of stress on the sensitivity of
the uterine structures to estrogens depends on the presence of estrogen, then it may
explain the stronger effect of stress observed among women receiving hormone therapy
in the present study.
This is the first prospective cohort study to address an association between stress
and endometrial cancer. Perceived stress seemed to be associated with lower incidence
of endometrial cancer in women receiving hormone therapy and in women of normal
weight. These results are biologically plausible and are in agreement with the lower risk
of breast cancer previously observed in the same cohort.
69
Table 6-1. Baseline characteristics of 6,760 women who participated in the second examination of the Copenhagen City Heart Study in 1981-83
Stress*
Study population
Low
Medium
High
P-value
Persons, n (% of study sample)
6760
2848 (42)
3234 (48)
678 (10)
57 (12)
58 (12)
55 (12)
58 (11)
<0.001
Pre-menopausal, n (%)
1775 (26)
676 (24)
979 (30)
120 (18)
<0.001
Hormone therapy, n (%)
1041 (15)
330 (12)
564 (17)
147 (22)
<0.001
1661 (25)
741 (26)
766 (24)
154 (23)
0.07
Mean body mass index, kg/m (SD)
24.9 (4.6)
25.2 (4.6)
24.6 (4.4)
24.8 (5.1)
<0.001
Current smokers, n (%)
3616 (53)
1398 (49)
1796 (56)
422 (62)
<0.001
Low education, n (%)
3116 (46)
1348 (47)
1396 (43)
372 (55)
<0.001
Physically inactive, n (%)
1200 (18)
446 (16)
527 (16)
227 (33)
<0.001
119 (2)
49 (2)
59 (2)
11 (2)
0.92
Mean age (SD)
Nulliparous, n (%)
2
Diabetes mellitus, n (%)
* Participants were asked to report their stress intensity and frequency in a standard questionnaire with four multiple-choice categories (0-3
points) for each stress measure. The scores of the two questions were added and combined into a continuous stress-score from 0 to 6. This stressscore was categorized into low (0-1 points), medium (2-4 points), and high (5-6 points) stress.
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 1981-83
Cancers, n
Incidence per
100 000 years
Age-adjusted HR
(95 % CI)
Multi-adjusted HR*
(95 % CI)
None (n=2,233)
30
86
1 (reference)
1 (reference)
Light (n=2,627)
26
61
0.79 (0.47-1.34)
0.71 (0.42-1.21)
Moderate (n=1,406)
11
49
0.61 (0.31-1.23)
0.52 (0.26-1.04)
High (n=494)
5
68
0.78 (0.30-2.00)
0.72 (0.28-1.89)
0.22
0.10
Stress intensity
P-value for trend
Stress frequency
Never (n=2,879)
36
81
1 (reference)
1 (reference)
Monthly (n=2,010)
20
60
0.90 (0.52-1.55)
0.77 (0.44-1.34)
Weekly (n=1,190)
12
63
0.86 (0.45-1.66)
0.73 (0.38-1.42)
Daily (n=681)
4
38
0.47 (0.17-1.32)
0.40 (0.14-1.15)
0.18
0.07
0.91 (0.80-1.04)
0.88 (0.76-1.01)
P-value for trend
Stress score (continuous)
72
* Adjusted for age, education, physical activity during leisure time, body mass index, tobacco smoking, diabetes mellitus, number of children,
menopause at baseline, and hormone therapy.
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 1981-83 by hormone status
Women receiving hormone therapy at baseline
Cancers,
n
Incidence per
100 000 years
Age-adjusted HR
(95 % CI)
Multi-adjusted HR*
(95 % CI)
Stress intensity
None (n=256)
Light (n=412)
Moderate (n=274)
High (n=99)
P-value for trend
13
11
5
2
312
165
112
121
1 (reference)
0.53 (0.24-1.18)
0.37 (0.13-1.03)
0.41 (0.09-1.80)
0.05
1 (reference)
0.54 (0.24-1.21)
0.36 (0.13-1.02)
0.44 (0.10-2.00)
0.06
Stress frequency
Never (n=338)
Monthly (n=335)
Weekly (n=224)
Daily (n=144)
P-value for trend
16
10
4
1
303
178
109
42
1 (reference)
0.62 (0.28-1.37)
0.39 (0.13-1.17)
0.14 (0.02-1.07)
0.01
1 (reference)
0.58 (0.26-1.30)
0.42 (0.14-1.26)
0.14 (0.02-1.09)
0.01
0.76 (0.61-0.95)
0.77 (0.61-0.96)
Stress score
(continuous)
31
Women not receiving hormone therapy at baseline
Cancers,
n
Incidence per
100,000 years
Age-adjusted HR
(95 % CI)
Multi-adjusted HR*
(95 % CI)
Stress intensity
None (n=1,977)
Light (n=2,215)
Moderate (n=1,132)
High (n=395)
P-value for trend
17
15
6
3
55
42
33
52
1 (reference)
0.88 (0.44-1.77)
0.67 (0.27-1.71)
0.95 (0.28-3.23)
0.56
1 (reference)
0.89 (0.44-1.80)
0.68 (0.27-1.75)
1.09 (0.31-3.81)
0.66
Stress frequency
Never (n=2,541)
Monthly (n=1,675)
Weekly (n=966)
Daily (n=537)
P-value for trend
20
10
8
3
51
36
52
37
1 (reference)
0.91 (0.43-1.96)
1.17 (0.52-2.67)
0.74 (0.22-2.47)
0.86
1 (reference)
0.91 (0.42-1.97)
1.23 (0.54-2.83)
0.82 (0.24-2.80)
0.98
0.97 (0.81-1.15)
0.98 (0.82-1.17)
Stress score
(continuous)
41
* Adjusted for age, education, physical activity during leisure time, body mass index, tobacco smoking,
diabetes mellitus, number of children, and menopause at baseline.
72
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 1981-83 by body mass index
Body mass index ≤ 25 kg/m2 at baseline
Cancers,
n
Incidence per
100,000 years
Age-adjusted HR
(95 % CI)
Multi-adjusted HR*
(95 % CI)
Stress intensity
None (n=1,218)
Light (n=1,638)
Moderate (n=844)
High (n=304)
P-value for trend
16
14
4
2
83
52
29
43
1 (reference)
0.70 (0.34-1.43)
0.37 (0.12-1.10)
0.49 (0.11-2.14)
0.07
1 (reference)
0.54 (0.26-1.13)
0.26 (0.09-0.80)
0.37 (0.08-1.63)
0.01
Stress frequency
Never (n=1,607)
Monthly (n=1,250)
Weekly (n=727)
Daily (n=420)
P-value for trend
20
12
3
1
79
57
26
15
1 (reference)
0.87 (0.42-1.78)
0.35 (0.10-1.19)
0.18 (0.02-1.36)
0.02
1 (reference)
0.64 (0.31-1.34)
0.29 (0.08-0.97)
0.14 (0.02-1.05)
0.005
0.79 (0.64-0.97)
0.73 (0.58-0.91)
Stress score
(continuous)
36
Body mass index > 25 kg/m2 at baseline
Cancers,
n
Incidence per
100,000 years
Age-adjusted HR
(95 % CI)
Multi-adjusted HR*
(95 % CI)
Stress intensity
None (n=1,015)
Light (n=989)
Moderate (n=562)
High (n=190)
P-value for trend
14
12
7
3
90
77
80
109
1 (reference)
0.92 (0.43-2.00)
0.98 (0.39-2.42)
1.26 (0.36-4.41)
0.85
1 (reference)
0.89 (0.41-1.94)
0.90 (0.36-2.26)
1.37 (0.38-4.89)
0.89
Stress frequency
Never (n=1,272)
Monthly (n=760)
Weekly (n=463)
Daily (n=261)
P-value for trend
16
8
9
3
82
66
123
78
1 (reference)
0.93 (0.40-2.19)
1.66 (0.73-3.77)
0.98 (0.28-3.36)
0.53
1 (reference)
0.86 (0.36-2.04)
1.56 (0.68-3.57)
0.93 (0.26-3.25)
0.63
1.04 (0.87-1.25)
1.03 (0.86-1.24)
Stress score
(continuous)
36
* Adjusted for age, education, physical activity during leisure time, body mass index, tobacco smoking,
diabetes mellitus, number of children, and menopause at baseline.
73
Figure 6-1. Causal diagram for the relation between perceived stress and risk of endometrial cancer
History of
breast cancer
Tamoxifen
Problematic
menopause
Postmenopausal
hormone therapy
Late menopause
Nulliparity
Early menarche
Stress hormones
Estrogens
Combined estrogen-progestin contraceptive
Perceived stress
Endometrial cancer
Cigarette smoking
Hypertension
Diet high in fat and low in
fiber and vegetables
Diabetes
Obesity
Physical activity
Education
Alcohol
Age
VII. Perceived stress and risk of colorectal cancer: a prospective
cohort study
Introduction
Colorectal cancer is the third most common cancer worldwide and the age-adjusted
incidence rate of colorectal cancer for Danish men and women are more than two times
as high as the world average.3;92 Psychological stress may directly affect the risk of
colorectal cancer by suppressing immune function,2 which might lead to increased
neoplastic growth. Stress may also indirectly affect the risk of colorectal cancer by
altering physical activity levels and dietary habits, which are some of the major risk
factors for colorectal cancer.93;94 In addition, colorectal cell lines express both functional
estrogen receptors that mediate the proliferative activity of estradiol and enzymes
capable to synthesize and metabolize estrogens, suggesting that sex steroid hormones
may also increase the risk of colorectal cancer.8;95-98 This is supported by the fact that
women with primary breast cancer, especially those receiving tamoxifen treatment, as
well as men with primary testicular cancer are at higher risk of developing colorectal
cancer.99;100 Persistent activation of stress hormones seems to impair the gonadal
synthesis of estrogens and thereby reduce bioavailable estradiol and testosterone.10
Stress-induced impairment of estrogen synthesis and metabolism may therefore protect
against colorectal cancer.
Only a few studies have addressed a potential relation between stress and
colorectal cancer and a majority of these studies have focused on stressful life events or
work-related stress and have been applied in case-control designs. 65-68 The
physiological reaction to acute stress of stressful life events may be very different from
the reaction to a more chronic state of stress in everyday life. Thus, the health
consequences of these two measures are not directly comparable. Further, it is stressful
to be diagnosed with cancer, which may render it difficult for cancer patients to recall
their stress level prior to the diagnosis without recall bias, and thereby to validly assess
the association between stress and risk of colorectal cancer in a case-control design.
Only one previous prospective cohort study has addressed the association between stress
75
and colorectal cancer.69 However, they used colorectal cancer mortality as their outcome
measure, which does not allow for a distinction between causal and prognostic factors.
We aim to address the association between perceived stress of everyday life and
incidence of primary colorectal cancer in a prospective design.
Methods
Study population
Information from the second examination of the prospective Copenhagen City Heart
Study in 1981-83 was used to address the objective. The second examination of the
study included 12,698 participants. Individuals with colorectal cancer before baseline
(n=49) or with lacking information on stress (n=42) or other covariates (n=605) were
excluded. Women with lacking information on reproductive and hormonal factors
(n=88) were also excluded, leaving 6,488 women and 5,426 men for the analyses.
Perceived stress was assessed at baseline and included two questions on stress intensity
and stress frequency. A seven-point stress score was created based on these two
questions. Please refer to the material and methods chapter for a detailed description of
the Copenhagen City Heart study and the measurement of perceived stress.
Covariates
The confounder identification was based on a causal diagram (figure 7-1) in which we
included the most current prior knowledge about causal relations between perceived
stress, covariates, and colorectal cancer:22 According to the diagram, the analyses should
be controlled for: age (continuous), education (less than 8 years, 8-11 years, or 12 or
more years), income (<$1,000, $1,000 to $2,500, or more than $2,500), cohabitation
(living with partner and/or children, or living alone), physical activity in leisure time
(none or very little activity, 2-4 hours of light activity per week, more than 4 hours of
light activity or 2-4 hours of high level activity, and competitional level or more than 4
hours of hard level activity per week), alcohol consumption (<1, 1-14, >14 drinks/week),
tobacco smoking (never-smoker, ex-smoker, smokers of 1-14 grams per day, 15-24
grams per day, and more than 24 grams per day), body mass index (< 18.5, 18.5-30, >30
kg/m2) and diabetes mellitus (yes/no). Analyses conducted in women were also adjusted
76
for current oral contraceptive use (yes/no), hormone therapy (yes/no), menopause
(yes/no) and number of children (0, 1-2, 3 or more). All variables were measured at
baseline in 1981-83. Fruit and vegetable intake, dietary fibers, folate, vitamins, and
stress hormones were assumed to be intermediates on the pathway between stress and
colorectal cancer and were therefore not included in the analyses. Family history of
colorectal cancer, red meat consumption, calcium intake, use of NSAIDS or aspirins,
and inflammatory bowls disease or Chronhn’s disease were assumed not to be strongly
associated with stress and were therefore not included in the analyses.
Follow-up
Participants were followed from date of the second examination till date of first
diagnosis of primary colorectal cancer (162 in women and 166 in men), death from other
causes (n=4,816), emigration (n=55), or end of follow-up on December 31, 2000
(n=6,715). Thus, less than 0.1 % of the participants were lost to follow-up due to
emigration. Using the civil registry number, which is unique to every Danish citizen,
diagnoses of primary colorectal cancer were identified through linkage to the Danish
National Cancer Registry, which contains data on all cancer diagnoses in Denmark since
1942. The following ICD7-codes were used to identify primary invasive colon cancer
cases: 153.0, 153.4,153.5,154.9, 253.0-253.4, 453.0-453.5,453.8, 454.9, 853.0-853.5,
and 854.9. The following ICD7-codes were used to identify primary invasive rectal
cancer cases: 154.0, 454.0, and 854.0. The vital status of the study population was
followed in the Central Death Registry.
Statistical methods
Data were analyzed by means of proportional hazards regression models with age as the
time scale using SAS/STAT software version 8.2. Stress intensity, stress frequency, and
the stress score all met the assumption of proportional hazards. We estimated the ageadjusted and multi-adjusted hazard ratio of colorectal cancer associated with stress
intensity, stress frequency, and the stress-score. By including age as the time scale, the
estimates were soundly adjusted for confounding by age. The analyses were also done
separately for colon and rectal cancer. Trend analyses were used to address doseresponse associations between stress and colorectal cancer. There appeared to be sex-
77
differences in the associations and all analyses were therefore conducted separately for
men and women. The associations between stress and risk of colorectal cancer in women
were also assessed in subgroups according to menopausal status at baseline. Finally, to
address the possible effect of prolonged follow-up we conducted the analyses between
stress score and colorectal cancer separately for the first and last nine years of follow-up.
Results
Baseline characteristics
The median age at baseline was 58 years for women and 57 years for men ranging from
21 to 98 years. Ten percent of the women and six percent of the men reported high
levels of stress (Table 7-1). Individuals with medium stress were slightly younger than
individuals with both low and high stress levels. Mean body mass index and percentage
with diabetes mellitus were similar at the different stress levels in both men and women.
A higher proportion of men and women at the high stress level had low education, low
income, high alcohol intake, were current smokers, and were physically inactive in their
leisure time compared to men and women with low levels of stress. A lower proportion
of highly stressed women were nulliparous, pre-menopausal, and used oral
contraceptives compared to less stressed women, while a higher proportion received
hormone therapy.
Perceived stress and risk of colorectal cancer in women
During follow-up, 162 cases of primary colorectal cancer (125 colon and 37 rectal
cancers) occurred in women. Women reporting moderate and high stress intensity had a
hazard ratio of 0.60 (95 % CI: 0.37-0.98) and 0.52 (0.23-1.14) for colorectal cancer,
respectively, compared to women who reported no stress intensity (table 7-2), and there
appeared to be a linear trend in the dose-response association (p-value for trend: 0.02).
For stress frequency, monthly and weekly stress were not associated with risk of
colorectal cancer, but women reporting daily stress were at lower risk of developing
colorectal cancer (HR=0.28, 95 % CI: 0.11-0.67) compared to women who never
experienced stress. For each unit increase in the combined seven-point stress score,
women were 10 percent less likely to develop colorectal cancer (HR=0.90, 95 % CI:
78
0.82-0.98). Dividing colorectal cancer into colon and rectal cancer made it clear that the
association between high stress and lower risk of colorectal cancer was strongest for
colon cancer.
Stress intensity was associated with lower risk of colon cancer in an inverse doseresponse manner (test for trend: p= 0.03). Daily stress was also associated with lower
risk of colon cancer (HR=0.23, 95% CI: 0.07-0.73), while monthly and weekly stress
were not associated with colon cancer. The association between perceived stress and risk
of rectal cancer in women was based on few cases. Even though stress frequency and
the stress score seemed to be associated with lower risk of rectal cancer, no clear picture
emerged. In general, adjustment for potential confounders only changed the risk
estimates slightly.
One hundred and forty-six colorectal cancer cases occurred in postmenopausal
women, while only 33 cases occurred among pre-menopausal women. The inverse
association between stress and risk of colon cancer appeared to be strongest in postmenopausal women, while a stronger association between stress and rectal cancer was
suggested in pre-menopausal women (table 7-3). Sixty-five cases of colorectal cancer
occurred in women during the first nine years of follow-up and 97 cases occurred during
the last nine years of follow-up. The association between the stress score and colorectal
cancer was stronger in the first nine years (HR=0.84, 95 % CI: 0.72-0.97) than in the last
nine years (HR=0.94, 95 % CI: 0.83-1.05) of follow-up (data not shown).
Perceived stress and risk of colorectal cancer in men
During follow-up, 166 cases of primary colorectal cancer (111 colon and 55 rectum
cancers) occurred in men. High stress intensity was associated with a higher risk of
colorectal cancer among men (HR=1.96, 95 % CI: 1.03-3.74) while moderate stress
intensity appeared to be associated with lower risk of colorectal cancer (HR=0.64, 95 %
CI: 0.37-1.10) compared to no stress (table 7-4). There was no notable association
between neither stress frequency nor the combined stress score and risk of colorectal
cancer in men. A similar picture emerged when studying colon cancer alone. High stress
intensity was associated with a hazard ratio of 2.94 (95 % CI: 1.09-7.93) for rectal
cancer compared to no stress, while there was no association between neither stress
frequency nor stress score and risk of rectal cancer. The risk estimates for rectal cancer
79
were rather unstable because of the low number of cases. Sixty-three cases of colorectal
cancer in men occurred during the first nine years of follow-up, while the other 103
cases occurred during the last nine years of follow-up. The impact of a one-unit change
in stress score on colorectal cancer risk was quite similar in the first nine years
(HR=0.97, 95 % CI: 0.82-1.14) and the last nine years (HR=0.99, 95 % CI: 0.88-1-12)
of follow-up (data not shown).
Discussion
We found sex-differences in the associations between perceived stress and incidence of
colorectal cancer among 11,914 men and women prospectively followed for 18 years. In
women, higher stress intensity and daily stress were associated with lower incidence of
colon cancer in particular, while there was no clear association between these measures
of stress and rectal cancer. Although high stress intensity appeared to be associated with
a higher incidence of rectal cancer in men, this result was based on few cases and there
was no clear evidence of a relation between stress and colorectal cancer. While we
addressed incidence of colon and rectal cancer, sex-differences in the effect of stress has
previously been noted for colorectal cancer mortality in a cohort of Japanese men and
women prospectively followed-up for nine years.69 Contrary to our results, perceived
psychological stress, assessed by the question “Do you feel stressed in your daily life?”
with two response categories, was weakly associated with higher colon cancer mortality
in women, but not in men, while stress was not associated with rectal cancer mortality in
neither women nor men. There were no clear trends in these associations and the
analyses were based on mortality alone, which as already mentioned does not allow for a
distinction between causal and prognostic factors. Other studies have primarily focused
on stressful life events or stressors at work and have been conducted as case-control
studies.65-68 Different measures of stress have been applied in these studies and the
results are conflicting.
Strengths and weaknesses of the study
The prospective design of the Copenhagen City Heart Study ensured temporality
between self-reported stress and incidence of colorectal cancer, and linkage of civil
80
registry numbers to population-based registers with nationwide coverage enabled
identification of virtually all cases of colorectal cancer and allowed for nearly complete
long-term follow-up.
Stress was defined as an individual state of high arousal and displeasure,83 and by
using a measure of perceived stress, we accounted for the fact that each individual has
different capacity and ways to cope with stressful situations.16 Stress was assessed by
combining two questions on stress intensity and stress frequency asked at baseline.
Using these two questions instead of a more extensive scale, such as the Perceived Stress
Scale,84 may have blurred an even stronger relation between perceived stress and risk of
colorectal cancer. However, in a recent study, two single-item measures on stress were
found to be just as reliable and valid as three fully validated multi-item measures on
perceived stress.101 This may provide some assurance that the single-item measurements
used in the present study actually provided a reasonably valid measure of stress. Also,
the same measure of stress have previously been found to be predictive of a range of
other diseases in the same cohort.57;102;103 In the questionnaire, stress was exemplified as
impatience, anxiety, and sleeplessness. Based on the two simple questions of stress
applied in this study, we cannot fully exclude the possibility that we have also partly
measured the effect of depressive symptoms or personality traits, which may be closely
related to stress as it is measured in this study. Stress was only assessed at baseline and
the participants may have changed stress level over time in a manner that is most likely
independent of subsequent development of colorectal cancer. The association between
stress and risk of colorectal cancer in women was strongest in the first nine years
compared to the last nine years of follow-up, while there was virtually no difference for
men. Thus, the long follow-up period may partly have blurred the associations,
especially in women. In another Danish cohort study85 that included a question on
perceived stress, the majority of the participants (62%) reported the same level of stress
in 1994 as in 2000 (Nielsen, unpublished data, 2006). Although this finding indicates
that a measure of perceived stress may be relatively stable over time, a large minority
changed stress levels over time. Thus, we cannot exclude the possibility that the relation
between stress and risk of colorectal cancer may have been partly blurred by nondifferential misclassification from changes in stress levels over time.
81
Information on some important risk factors for colorectal cancer such as family
history of colorectal cancer and diet were not obtained in the Copenhagen City Heart
Study. However, to confound the results, these factors would also have to be related to
stress. We cannot exclude that having experienced colorectal cancer in the near family
may act as a stressor and thereby lead to higher levels of stress, which would result in a
spurious positive association between stress and colorectal cancer. This is opposite to the
inverse association between perceived stress and colon cancer observed among women,
but it may explain some of the positive association between stress and rectal cancer in
men. In order to determine potential confounding from dietary factors, it is important to
determine whether dietary habits are a cause or consequence of stress. Some evidence
indicates that during chronic stress, individuals tend to eat smaller, but more frequent,
amounts of energy-dense, fatty, low-protein foods.93 Thus, diet is more likely to be an
intermediate factor in the causal path from stress to colorectal cancer than a confounder.
Men and women with high levels of stress smoked more, drank more alcohol, and
did less exercise. Also, they had lower income and education than those with lower
levels of stress. We adjusted our analyses for baseline differences in these factors to
avoid confounding, but one may still be concerned about residual confounding. The
amount of residual confounding is, however, proportional to the confounding originally
present,104 and adjustment for confounding only slightly changed the risk estimates,
making residual confounding less of a concern.
The age range of the study participants was relatively broad and one may be
concerned that the perceptions of stress in the general adult population may be different
from that of the very old. To address this question, we reanalyzed data after excluding
all persons above the age of 75 at baseline. This only led to minor changes in the risk
estimates (data not shown).
More women in the high stress group (42 %) than in the medium (31 %) and low
(37 %) stress group died during follow-up. The pattern was similar in men and the
proportions that died during follow-up were 58 %, 41 %, 51 % for high, medium, and
low stress, respectively. Although this indicates no systematic difference, it may raise
concern about how censoring has influenced the results. We assumed, in the statistical
model, that censoring was independent of colorectal cancer risk within strata of stress.
However, it is possible that competing causes, such as death of cardiovascular disease,
82
could be associated with risk of colorectal cancer within strata of stress due to other
common risk factors. Some of the common risk factors, such as alcohol consumption,
have opposite effects on the two diseases, while other risk factors, such as low physical
activity, increase the risk of both diseases. To some degree, we would expect the bias to
level out and the average risk of colorectal cancer among women not censored to be
similar to what it would have been if no such censoring had occurred. Also, both a
higher proportion of men and of women in the high stress group died during follow-up,
and we therefore find it unlikely to explain the sex-differences observed in the present
study. Thus, while our results may have been influenced by bias from non-independent
censoring, we find it unlikely to fully explain them.
Possible pathway from perceived stress to colorectal cancer
Stress may affect the risk of colorectal cancer directly through biological processes or
indirectly by affecting health-related behavior. Several possible pathways between
perceived stress and incidence of colorectal cancer may be identified. The importance of
each of these pathways may be sex-specific and explain the observed sex-differences in
the present study.
First, the hypothalamic-pituitary-gonadal (HPG) axis regulates the synthesis of sex
steroid hormones in a normally functioning reproductive system. Stress can affect the
signals of this axis by activating the hypothalamic-pituitary-adrenal (HPA) axis and the
sympathetic nervous system. Several experimental studies have found that the activation
of the HPA axis inhibits the function of the HPG axis and thereby decrease estrogen and
testosterone synthesis.10-12;72 In a recent epidemiologic study, significantly lower levels
of bioavailable estradiol was also found among female caregivers compared to noncaregivers.55 In vitro treatment of a human colon cancer cell line with estradiol was
found to rapidly stimulate intermediates in a signal transduction pathway that is known
to trigger cell proliferation.96 Further, the intensity of the stimulatory effect of estradiol
in human colon cancer cells is similar to the estradiol responsiveness of human
mammary cancer cell lines, which are classical estradiol sensitive cells.96 A stressinduced distortion of estrogen synthesis may therefore explain the lower incidence of
colon cancer among women with high levels of stress.
83
Secondly, long-term stress may lead to a persistent activation of the HPA-axis.
Some of the mediators released by the HPA-axis, like corticosteroids and
catecholamines, seem to be capable of suppressing the immune function and are thereby
reduce its ability to recognize and destroy neoplastic cell growth.2;105 A decrease in
cytotoxic T-cell and natural-killer-cell activity and in the general cellular immune
response has been found in laboratory animals exposed to stress.2 Thus, by affecting the
immune system and the DNA repair system, perceived stress may promote the initiation
and progression of colorectal cancer. Men seem to respond to psychological stress with
greater increases in cortisol than women,106 which may explain the higher incidence of
colorectal cancer observed among men reporting high levels of stress.
Thirdly, there is growing evidence that chronic stress may lead to the development
of obesity and insulin resistance either by a behavioral pathway with altered dietary and
activity patterns or through an abnormal diurnal cortisol rhythm induced by the
activation of the HPA-axis.107 Obesity, insulin resistance, and insulin growth factor are
all potential metabolic mediators for tumor progression and may thereby increase the
risk of colorectal cancer.107 We adjusted the analyses for body mass index at baseline,
but high levels of stress may still have led to weight changes in some individuals during
follow-up. Experimental studies have also suggested that stress may alter bowel
movement,93;94;108 and thereby indirectly affect the risk of colorectal cancer.
Finally, stress may affect health-related behavior. The participants with high levels
of perceived stress were more likely to also have a high alcohol intake, be current
smokers, and be physically inactive at baseline. We adjusted our analyses for such
differences in health-related behavior at baseline in order to control for confounding, but
we would also expect some of the effect of stress on colorectal cancer risk to be
mediated through such changes in health-related behavior occurring during follow-up. In
addition, some of the effect of stress on risk of colorectal cancer may be mediated
through mental processes such as depression or burnout.
In conclusion, the relation between perceived stress and risk of colorectal cancer
seems to be a result of a complex system with different mechanisms working in opposite
directions. In this cohort study we found high stress to be associated with lower risk of
colon cancer in women, while there is no clear evidence of a relation between stress and
risk of colorectal cancer in men.
84
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 1981-83
Stress score
Study population
Low
Medium
High
Women
Persons, N (% of study sample)
Mean age (SD)
Low education (%)
Low income (%)
Physically inactive (%)
High alcohol consumption (%)
Mean body mass index, kg/m2 (SD)
Current smokers (%)
Diabetes mellitus (%)
Nulliparous (%)
Hormone replacement therapy, %
Pre-menopausal, %
Current oral contraceptive users, %
6,488
57 (12)
2,961 (45)
2,431 (37)
1,124 (17)
445 (7)
25 (5)
3,468 (53)
114 (2)
1,608 (25)
995 (15)
1,716 (26)
249 (4)
2,745 (42)
58 (13)
1,286 (47)
1,080 (39)
417 (15)
150 (5)
25 (5)
1,343 (49)
48 (2)
726 (26)
315 (11)
655 (24)
99 (4)
3,101 (48)
55 (12)
1,322 (43)
996 (32)
494 (16)
228 (7)
25 (4)
1,727 (56)
56 (2)
739 (24)
539 (17)
949 (31)
143 (5)
642 (10)
58 (11)
353 (55)
355 (55)
213 (33)
67 (10)
25 (5)
398 (62)
10 (2)
143 (22)
141 (22)
112 (17)
7 (1)
Men
Persons, N (% of study sample)
Mean age (SD)
Low education (%)
Low income (%)
Physically inactive (%)
High alcohol consumption (%)
Mean body mass index, kg/m2 (SD)
Current smokers (%)
Diabetes mellitus (%)
5,426
56 (13)
2,122 (45)
1,345 (25)
854 (16)
1,791 (33)
26 (4)
3,466 (64)
187 (3)
2,984 (55)
58 (13)
1,405 (47)
774 (26)
425 (14)
911 (31)
26 (4)
1,870 (63)
99 (3)
2,984 (39)
53 (12)
845 (40)
439 (21)
323 (15)
760 (36)
26 (4)
1,362 (64)
77 (4)
329 (6)
57 (11)
172 (52)
132 (40)
106 (32)
120 (36)
26 (4)
234 (71)
11 (3)
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 1981-83
Cancers,
n
Incidence per
100,000 years
Age- and sex-adjusted
HR (95 % CI)
Multi-adjusted HR*
(95 % CI)
Colorectal cancer
Stress intensity
None (n=2144)
Light (n=2535)
Moderate (n=1345)
High (n=464)
P-value for trend
62
71
22
7
185
173
103
101
1 (reference)
1.08 (0.77-1.52)
0.62 (0.38-1.02)
0.55 (0.25-1.20)
0.03
1 (reference)
1.06 (0.75-1.49)
0.60 (0.37-0.98)
0.52 (0.23-1.14)
0.02
Stress frequency
Never (n=2772)
Monthly (n=1947)
Weekly (n=1122)
Daily (n=647)
P-value for trend
77
52
28
5
180
163
158
50
1 (reference)
1.16 (0.81-1.65)
1.01 (0.66-1.56)
0.29 (0.12-0.71)
0.05
1 (reference)
1.14 (0.80-1.63)
0.98 (0.63-1.51)
0.28 (0.11-0.67)
0.04
0.91 (0.83-0.99)
0.90 (0.82-0.98)
Stress score
(continuous)
162
Colon cancer
Stress intensity
None (n=2144)
Light (n=2535)
Moderate (n=1345)
High (n=464)
P-value for trend
50
53
18
4
150
130
84
58
1 (reference)
1.01 (0.69-1.49)
0.64 (0.38-1.10)
0.39 (0.14-1.09)
0.03
1 (reference)
0.99 (0.67-1.47)
0.63 (0.37-1.09)
0.39 (0.14-1.08)
0.03
Stress frequency
Never (n=2772)
Monthly (n=1947)
Weekly (n=1122)
Daily (n=647)
P-value for trend
59
41
22
3
137
128
124
30
1 (reference)
1.22 (0.82-1.82)
1.06 (0.65-1.73)
0.23 (0.07-0.73)
0.09
1 (reference)
1.21 (0.81-1.81)
1.04 (0.64-1.71)
0.23 (0.07-0.73)
0.09
0.90 (0.81-1.00)
0.89 (0.81-0.99)
Stress score
(continuous)
125
Continues on next page
86
Rectal cancer
Stress intensity
None (n=2144)
Light (n=2535)
Moderate (n=1345)
High (n=464)
P-value for trend
12
18
4
3
36
44
19
43
1 (reference)
1.35 (0.65-2.81)
0.56 (0.18-1.74)
1.17 (0.33-4.14)
0.68
1 (reference)
1.29 (0.62-2.71)
0.49 (0.16-1.52)
0.94 (0.26-3.41)
0.43
Stress frequency
Never (n=2772)
Monthly (n=1947)
Weekly (n=1122)
Daily (n=647)
P-value for trend
18
11
6
2
42
34
34
20
1 (reference)
0.97 (0.45-2.05)
0.87 (0.34-2.19)
0.47 (0.11-2.02)
0.36
1 (reference)
0.95 (0.44-2.02)
0.77 (0.30-1.96)
0.38 (0.09-1.68)
0.21
37
0.93 (0.78-1.12)
0.90 (0.75-1.09)
Stress score
(continuous)
* Adjusted for age, education, income, physical activity in leisure time, alcohol consumption, body mass
index, tobacco smoking, diabetes mellitus, cohabitation, number of children, hormone replacement
therapy, menopause at baseline, and oral contraceptive use. Women with lacking information on any of
these variables were excluded from the analyses.
87
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 1981-83
Colorectal cancer
Cancers, n
Multi-adjusted HR*
(95 % CI)
Colon cancer
Cancers, n
Multi-adjusted HR*
(95 % CI)
Rectal cancer
Cancers, n
Multi-adjusted HR*
(95 % CI)
Pre-menopausal
Stress score
(per one-unit change)
16
0.97 (0.70-1.35)
12
1.12 (0.78-1.62)
4
0.56 (0.21-1.46)
146
0.89 (0.81-0.98)
113
0.88 (0.79-0.98)
33
0.92 (0.76-1.12)
Post-menopausal
Stress score
(per one-unit change)
* Adjusted for age, education, income, physical activity in leisure time, alcohol consumption, body mass index, tobacco smoking, diabetes
mellitus, cohabitation, number of children, hormone replacement therapy, and oral contraceptive use.
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 1981-83
Cancers,
n
Incidence per
100 000 years
Age- and sex-adjusted
HR (95 % CI)
Multi-adjusted
HR* (95 % CI)
Colorectal cancer
Stress intensity
None (n=2559)
Light (n=1779)
Moderate (n=892)
High (n=196)
P-value for trend
91
48
16
11
258
181
123
472
1 (reference)
0.94 (0.66-1.34)
0.67 (0.39-1.14)
2.13 (1.14-3.99)
0.84
1 (reference)
0.93 (0.65-1.32)
0.64 (0.37-1.10)
1.96 (1.03-3.74)
0.96
Stress frequency
Never (n=2984)
Monthly (n=1352)
Weekly (n=747)
Daily (n=343)
P-value for trend
106
31
19
10
256
150
176
234
1 (reference)
0.82 (0.55-1.24)
0.98 (0.60-1.61)
1.03 (0.54-1.96)
0.85
1 (reference)
0.81 (0.54-1.22)
0.94 (0.57-1.55)
0.98 (0.51-1.89)
0.69
1.00 (0.91-1.10)
0.99 (0.90-1.09)
Stress score
(continuous)
166
Colon cancer
Stress intensity
None (n=2559)
Light (n=1779)
Moderate (n=892)
High (n=196)
P-value for trend
65
30
10
6
184
113
77
258
1 (reference)
0.84 (0.54-1.30)
0.60 (0.30-1.16)
1.65 (0.71-3.81)
0.54
1 (reference)
0.82 (0.53-1.27)
0.57 (0.29-1.13)
1.51 (0.64-3.56)
0.42
Stress frequency
Never (n=2984)
Monthly (n=1352)
Weekly (n=747)
Daily (n=343)
P-value for trend
70
24
12
5
169
116
111
117
1 (reference)
1.00 (0.62-1.59)
0.97 (0.53-1.81)
0.79 (0.32-1.96)
0.69
1 (reference)
0.97 (0.60-1.55)
0.94 (0.50-1.75)
0.76 (0.30-1.90)
0.59
0.97 (0.86-1.09)
0.96 (0.85-1.08)
Stress score
(continuous)
111
Continues on next page
89
Rectal cancer
Stress intensity
None (n=2559)
Light (n=1779)
Moderate (n=892)
High (n=196)
26
18
6
5
74
68
46
215
36
7
7
5
87
34
65
117
1 (reference)
1.18 (0.64-2.16)
0.84 (0.34-2.05)
3.27 (1.25-8.55)
0.23
P-value for trend
1 (reference)
1.19 (0.65-2.19)
0.80 (0.32-1.95)
2.94 (1.09-7.93)
0.32
Stress frequency
Never (n=2984)
Monthly (n=1352)
Weekly (n=747)
Daily (n=343)
P-value for trend
1 (reference)
0.51 (0.23-1.16)
0.99 (0.44-2.26)
1.45 (0.57-3.69)
0.84
1 (reference)
0.52 (0.23-1.18)
0.92 (0.40-2.11)
1.34 (0.51-3.49)
0.99
55
1.06 (0.91-1.24)
1.04 (0.89-1.22)
Stress score
(continuous)
* Adjusted for age, education, income, physical activity in leisure time, alcohol consumption, body mass
index, tobacco smoking, diabetes mellitus, and cohabitation.
90
Figure 7-1. Causal diagram for the relation between perceived stress and risk of colorectal cancer
Family history of
colorectal cancer
Oral contraceptive use
Body mass index
Reproductive history
Red meat consumption
Stress hormones
Diabetes mellitus
Estrogen
Problematic
menopause
Postmenopausal
hormone therapy
Perceived stress
Colorectal cancer
Age
Smoking
Calcium
Social
network
Physical activity
Alcohol
Dietary fibers
Fruits and vegetables
NSAIDS and aspirin
Infection
Folate
Vitamins
Socio-economic status
Immune system
Inflammatory Bowls
diseases / Chronhn’s
disease
VIII. Sociodemographic status, stress and risk of prostate cancer:
a prospective cohort study
Introduction
Prostate cancer is among the most common malignancies in men and the incidence of
the disease is increasing worldwide.109 Little is known about the etiology of prostate
cancer and modifiable risk factors for the disease are essentially unknown. There are
remarkable racial and geographic variations in the incidence of and mortality from
prostate cancer,109 indicating the existence of both genetic and environmental risk
factors. Prostate cancer is also a disease of striking social disparities. Men of higher
socio-economic status seem to have an elevated incidence of prostate cancer compared
to those of lower socio-economic status.110-112 For prostate cancer mortality, the picture
is reversed with lower prostate cancer mortality rates among men with higher socioeconomic status.112 These differences in incidence and mortality patterns have mainly
been ascribed to differential access to medical care and thereby also to prostate-specific
antigen (PSA) testing in the different socio-economic and racial groups.
Socio-economic disadvantages can lead to psychological stress. Animal models
have provided evidence that stress affects tumor growth and development,2 but few
epidemiologic studies have assessed the relation between stress and risk of prostate
cancer.47 In a large registry linkage study, no increased risk of prostate cancer was
observed among men who had experienced losing a child to cancer.47 However, the
manner in which a stressor is perceived and coped with may be important to the
magnitude of the stress response and thereby also to the resulting health consequences.16
In addition, the bodily reactions to acute stress from major life events such as losing a
child or a spouse may be very different from those resulting from the chronic “low-key”
stress of everyday life. Repeated episodes of stress or chronic stress may weaken the
immune system and render the individual susceptible to malignancies.2
Marital status, as an indicator of social support, may be an important way of
coping with socio-economic disadvantages or stress and may thereby also affect prostate
cancer risk. One study found that divorced and separated men had a higher risk of
92
prostate cancer than married men.113 In the present study, we include information on
socio-economic status, perceived stress of everyday life, and marital status. We aim to
assess if the social disparity in prostate cancer incidence prevail in a racially
homogenous population of Caucasians with free access to medical care. We also aim to
assess if perceived stress of everyday life is associated with risk of prostate cancer, and
to address differences in prostate cancer incidence according to marital status in a
prospective study with 20 years of follow-up.
Methods
Study population
Information from the second examination of the prospective Copenhagen City Heart
Study in 1981-83 was used to address the objective. Of the 12,698 participants in the
second examination 5,680 were men, and men with prostate cancer before baseline
(n=19) and men who lacked information on stress (n=15), educational level (n=12),
income (n=47), marital status (n=5), or other covariates (n=86) were excluded, leaving
5,496 men for the analyses. Perceived stress was assessed at baseline and included two
questions on stress intensity and stress frequency. A seven-point stress score was created
based on these two questions. Please refer to the material and methods chapter for a
detailed description of the Copenhagen City Heart study and the measurement of
perceived stress.
Sociodemographic variables
All sociodemographic variables were based on self-reported information at baseline in
1981-83. Educational level was reported in categories of: low (less than 8 years),
medium (8-11 years), and high (12 or more years) education. Income was divided into
categories of: low (<$1,000 per month), medium ($1,000-2,500 per month), and high
(>$2,500 per month) income. Marital status categories were: married, unmarried,
divorced/ separated, and widowed.
Covariates
Potential confounders was identified according to the methods of causal diagrams
developed by Greenland, Pearl, and Robins.22 The causal diagram that we have specified
93
is shown in figure 8-1 and it served as a way to visualize and explicitly elaborate our
assumptions about the web of causation for the relation of interest as well as to help
identify variables that must be controlled for to obtain unconfounded estimates.
According to the diagram, age (continuous) was the main possible confounder of the
associations of interest. The associations between the sociodemographic variables and
risk of prostate cancer will therefore only be adjusted for age. Socio-economic status and
marital status were also possible confounders for the relation between stress and risk of
prostate cancer and the association will be adjusted for these factors. Physical activity,
body mass index, and alcohol intake were either possible intermediates on the pathway
between stress and risk of prostate cancer (as they are presented in the diagram), but they
may also be potential confounders for the association between stress and prostate cancer.
The analysis of stress will therefore be presented both with adjustment for age alone and
with adjustment for age as well as sociodemographic factors, physical activity in leisure
time (none or very little activity; 2-4 hours of light activity per week; more than 4 hours
of light activity or 2-4 hours of high level activity; and competitional level or more than
4 hours of high level activity per week), body mass index (continuous), and alcohol
intake (<1, 1-7, 8-14, 15-21, 22+ drinks/wk). Lucopene, fish intake, selenium/vitamin E,
and foods high in animal fat are possible intermediates on the pathway from stress to
prostate cancer and will therefore not be included in the analysis. Insulin-like growth
factor (IGF-1), BRCA1/2 mutations, family history of prostate cancer, and sexually
transmitted diseases were also not included in the analysis, as they were assumed not to
be strongly associated with the socio-demographic factors or stress.
Follow-up
The participants were followed from the date of the second examination until the date of
first diagnosis of primary prostate cancer (n=157), death (n=2,889), emigration out of
Denmark (n=31), or end of follow-up on December 31, 2002 (n=2,419). Thus, less than
0.1% were lost to follow-up due to emigration. Using the civil registry number, which is
unique to every Danish citizen, primary prostate cancer events were identified through
linkage to the Danish National Cancer Registry, which contains data on all cancer
diagnoses in Denmark since 1942. The following ICD7-codes were used to identify
94
primary invasive prostate cancer cases: 177.0, 477.0, and 877.0. The vital status of the
participants was followed in the Central Person Registry.
Statistical methods
Data were analyzed by means of Cox proportional hazards models with age as the time
variable. Stress and the sociodemographic variables met the assumption of proportional
hazards. Initially, we estimated the age-adjusted hazard ratio of prostate cancer
associated with the sociodemographic variables and stress. By including age as the time
variable, the estimates were adjusted for confounding by age. A trend test was used to
test for linear dose-response trends in the associations between the sociodemographic
variables or stress and prostate cancer. Secondly, a multivariate Cox proportional
hazards model was fitted to adjust the association between stress and prostate cancer for
potential confounding from the sociodemographic variables as well as for alcohol,
physical activity in leisure time, and body mass index. Finally, PSA screening is less
common in Denmark than in the US and Canada, but introduction of PSA testing in the
late 1980s may still have affected the diagnosis pattern in this population. Thus, we
divided the follow-up period into two periods, before and after 1990, and conducted
separate analyses for these periods in order to address whether the introduction of PSA
testing affected our estimates.
Results
Baseline characteristics
The median age at baseline was 57 years ranging from 21 to 98 years. Forty-five percent
of the study participants had low education (table 8-1). In the total study population, 25
% had low income, 22 % were unmarried or divorced, and six percent reported high
levels of stress. As expected, income and education were correlated, so that men with
low education were more likely to also have low income. Men with high education
appeared to be somewhat more likely to be unmarried or divorced, while a slightly
higher proportion of men with low education reported high levels of stress. A higher
proportion of men with low education were physically inactive than observed among
95
men with higher educational levels. Mean body mass index and mean alcohol
consumption were similar over the different educational levels.
Sociodemographic status and risk of prostate cancer
With an incidence rate of 317 per 100,000 years, men with low income had markedly
higher incidence of prostate cancer than men with higher income (table 8-2). This
difference in risk could, in large part, be explained by age, so that no clear association
between income and risk of prostate cancer remained after adjusting for age. Men with
more than 12 years of formal education seemed to be at a slightly higher risk of prostate
cancer (HR=1.22; 95 % CI: 0.76-1.96), but the estimates were unstable and there was no
dose-response effect (P-value for trend: 0.42). Widowed men had a markedly higher
incidence of prostate cancer than any other marital group, but this could again be
explained by age, as there seemed to be no association between marital status and
prostate cancer risk after adjusting for age.
Stress and risk of prostate cancer
The incidence of prostate cancer was highest among men who reported no stress
intensity and was lowest among men with high stress (table 8-3). High stress intensity
seemed to be associated with a lower risk of prostate cancer (HR=0.38; 95 % CI: 0.091.57), but the estimate was only based on two prostate cancer cases and there was no
trend in the dose-response effect (P-value for trend: 0.84). The association between
stress frequency and prostate cancer risk was similar to that of stress intensity. A oneunit change in the stress score was not associated with risk of prostate cancer (HR=0.99;
95 % CI: 0.90-1.09).
Different periods of follow-up
During the 1980s, 41 men developed prostate cancer, while 116 men developed prostate
cancer from 1990 and until the end of the study in 2002 (table 8-4). Men with high
income, with high education, or who were widowed all seemed to have a slightly higher
incidence of prostate cancer in the first follow-up period. Stress seemed to be weakly
associated with prostate cancer in an inverse manner in the first follow-up period
(HR=0.92, 95 % CI: 0.75-1.14 per one unit increase in the seven-point stress score).
96
However, the associations during this period were based on few cases and no clear
trends were found. Prostate cancer incidence did not seem to be associated with neither
stress nor any of the sociodemographic variables in the last period of follow-up.
Discussion
In this racially homogenous population of Caucasians with free access to health care, we
found no evidence of social disparities in the incidence of prostate cancer, nor that the
risk of prostate cancer was associated with marital status or perceived stress. The fact
that we found no social gradient in the incidence of prostate cancer is in contrast to the
results from several other large studies.111 In a registry linkage study from Finland,
Pukkala and Weiderpass found a higher incidence of prostate cancer among the higher
social classes than the lower. The results were consistent over time and most pronounced
for localized prostate cancers.114 A social gradient was also found in another large
registry-based study from the UK, in which aggregated data on socio-economic factors
were used to calculate a deprivation score.112 The authors found that men in the most
affluent group had an about 50 percent higher incidence of prostate cancer compared to
men in the most deprived group, while prostate cancer survival displayed a negative
association with deprivation. In a study of 11,896 prostate cancer cases derived from a
cancer surveillance system in Detroit, Schwartz and colleagues found that cases from the
highest socio-economic group were more likely to have local stage disease than those
from the lowest socio-economic group.110
Access to PSA testing became widely available in most westernized countries in
the late 1980s. Socio-economic status distinguishes subgroups within a population from
each other by economic opportunities and health awareness, which may affect the access
and utilization of the health care system including PSA testing. Dutta and colleagues
found that the incidence trend between socio-economic groups primarily started to
diverge after PSA testing became widely available.112 Health insurance is strongly
associated with undergoing prostate cancer screening. A plausible reason for the lack of
a social gradient in the observed prostate cancer incidence in the present study is that
Denmark has a free access health care system accessible to all Danes. This supports the
hypothesis that the social gradient in prostate cancer observed in some populations is
97
due to differential access and utilization of the health care system, and is not a result of
socio-economic status per se.
We found no association between stress and risk of prostate cancer in spite of the
fact that prolonged stress may affect both the immune2 and hormonal systems,10 both of
which could be expected to alter the risk of prostate cancer. Although we used a very
different measure of stress, our results are in agreement with the null result of the
previously mentioned registry-based study on prostate cancer risk among men who had
lost a child to cancer.47 Both breast and prostate cancers are assumed to be hormonedependent diseases, and the findings from breast cancer studies may therefore also be
relevant to prostate cancer. In general, major life events such as the death of a child or a
divorce have not been associated with a higher risk of breast cancer in large-scale
registry linkage studies.44;46;47;49 More chronic exposures to stress, such as work-related
stress and perceived stress, have either not been associated with breast cancer or have
been associated with a slightly lower risk of breast cancer.53;55;56 We have previously
found that the same measure of perceived stress, as the one applied in this study, was
inversely associated with the risk of breast cancer among the female participants in the
Copenhagen City Heart Study.57
Strengths and weaknesses
The prospective design of the Copenhagen City Heart Study ensured temporality
between assessment of the exposures of interest and incidence of prostate cancer.
Linkage of civil registry numbers to nationwide population-based registers enabled the
identification of virtually all cases of diagnosed prostate cancer and allowed for nearly
complete long-term follow-up.
Several previous studies on social disparities in prostate cancer risk have used
ecological measures of socio-economic status derived from census-registries.110;112 This
becomes problematic if an individual is assigned to a socio-economic group different
from his actual socio-economic position. We used individual measures to avoid this
problem. We used self-reported measures of income and education as proxy measures of
socioeconomic status, and one may argue that these are only crude measures of a much
more complex concept. We agree that a more comprehensive measure of socioeconomic status would be required to reveal a modest social gradient in prostate cancer
98
incidence. However, we still expect that the measures of socio-economic status in this
study are sufficient to reveal any major social disparities in prostate cancer incidence.
In this study, stress was defined as an individual state of high arousal and
displeasure, sometimes referred to as distress.83 By using a measure of perceived stress,
we accounted for the fact that each individual has different capacities and ways to cope
with stressful situations.16 We assessed perceived stress by combining a question on
stress intensity and a question on stress frequency asked at baseline. Using these two
questions instead of a more extensive scale may have resulted in some conceptual
exposure misclassification. Since the two questions we used as a measure of perceived
stress has not yet been validated against a more extensive scale such as the Perceived
Stress Scale,84 we cannot fully determine the magnitude of this conceptual
misclassification. A disparity between the ideal and the operational measure will have
reduced our ability to address the relation between perceived stress and prostate cancer
and could possibly explain why we found no such association. However, the same
measure of perceived stress has previously been found to be associated with breast
cancer57 as well as cardiovascular disease,103 making it less likely that the null finding
was due to exposure misclassification.
The sociodemographic variables and stress were measured at baseline, and we can
therefore not exclude that the association between these variables and risk of prostate
cancer may have been partly blurred by non-differential misclassification from changes
in socio-economic position, marital status, or stress levels over time.
We lacked information on family history of prostate cancer, which is an important
risk factor for prostate cancer. However, in order to confound the associations between
the exposures of interest and prostate cancer, family history of prostate cancer would
have to also affect the person’s sociodemographic position or stress level. We find it
unlikely that a family history of prostate cancer would affect a person’s education,
income, or marital status, but the awareness of the hereditability of the disease could
possibly increase the person’s stress level. Such confounding would create an artificial
positive association between stress and prostate cancer, which cannot explain the lack of
an association observed in the present study.
Even though prostate cancer is the most common cancer in men, only 157 of the
5,496 men developed prostate cancer during the 20 years of follow-up. Lacking power
99
of the statistical analyses may have resulted in unstable risk estimates and could be a
possible explanation to the null findings. However, the risk estimates did not indicate
any trends or strong associations, and we would therefore not expect more statistical
power to have changed our conclusions considerably.
Some studies have found that higher socio-economic status was associated with
lower stages and grades of prostate cancers at the time of diagnosis.111 We derived
information on prostate cancer cases from a national cancer registry and information on
the histopathological characteristics of the disease at the time of diagnosis was not
available. Thus, we cannot exclude a possible social inequality in the stage of the disease
at the time of diagnosis.
Conclusion
We found no evidence of a social gradient in the incidence of prostate cancer in a
population with free access to medical care. Thus, the social gradient observed in other
studies is most likely a result of differential usage of PSA testing. If early detection of
prostate cancer indeed has an effect on prostate cancer mortality, breaking down barriers
for health care utilization and PSA screening may be a major public health issue in
populations without free access to medical care. Also, prostate cancer risk did not seem
to be associated with either perceived stress of everyday life or with marital status.
100
Table 8-1. Baseline characteristics of the 5,496 men who participated in the second examination of the Copenhagen City Heart Study in 1981-83
Education
Study population
Low
Medium
High
Persons, n (% of study sample)
5496
2462 (45)
2175 (40)
859 (16)
56 (13)
59 (11)
55 (12)
50 (15)
Low income, n (%)
1366 (25)
887 (36)
351 (16)
128 (15)
Divorced or unmarried, n (%)
1224 (22)
538 (23)
454 (21)
232 (27)
338 (6)
175 (7)
117 (5)
46 (5)
26 (4)
27 (4)
26 (4)
25 (3)
872 (16)
518 (21)
269 (12)
85 (10)
14 (16)
13 (16)
14 (16)
13 (15)
Mean age (SD)
High stress, n (%)
2
Mean body mass index, kg/m (SD)
Physically inactive, n (%)
Mean alcohol consumption, drinks/wk (SD)
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 1981-83
Cancers, n
Incidence per
100 000 years
Age-adjusted HR
(95 % CI)
Low (n=1366)
51
317
1 (reference)
Medium (n=2719)
60
139
0.72 (0.49-1.05)
High (n=1411)
46
193
1.17 (0.78-1.76)
Income
P-value for trend
0.51
Education
Low (n=2462)
71
207
1 (reference)
Medium (n=2175)
63
183
1.07 (0.76-1.50)
High (n=859)
23
160
1.22 (0.76-1.96)
P-value for trend
0.42
Marital status
Married (n=4035)
122
197
1 (reference)
Unmarried (n=639)
12
119
1.03 (0.57-1.86)
Divorced/ separated (n=585)
12
145
0.92 (0.51-1.67)
Widowed (n=237)
11
419
1.09 (0.59-2.03)
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 1981-83
Cancers, n
Incidence per
100 000 years
Age-adjusted HR
(95 % CI)
Multi-adjusted HR*
(95 % CI)
None (n=2586)
88
233
1 (reference)
1 (reference)
Light (n=1800)
38
132
0.80 (0.55-1.18)
0.78 (0.53-1.15)
Moderate (n=909)
29
206
1.33 (0.87-2.04)
1.30 (0.85-2.00)
2
79
0.41 (0.10-1.68)
0.38 (0.09-1.57)
0.99
0.84
Stress intensity
High (n=201)
P-value for trend
Stress frequency
Never (n=3020)
99
223
1 (reference)
1 (reference)
Monthly (n=1366)
29
130
0.88 (0.58-1.34)
0.85 (0.56-1.30)
Weekly (n=759)
24
205
1.45 (0.92-2.27)
1.41 (0.89-2.23)
Daily (n=351)
5
108
0.57 (0.23-1.40)
0.54 (0.22-1.33)
0.97
0.81
1.00 (0.91-1.10)
0.99 (0.90-1.09)
P-value for trend
Stress score (continuous)
157
* Adjusted for age, income, educational level, marital status, alcohol intake, physical activity in leisure time, and body mass index.
Table 8-4. Risk of primary prostate cancer associated with perceived stress and sociodemographic variables according to period of follow-up
Baseline -1989
1990-2002
Cancers,
n
Multi-adjusted
HR*(95 % CI)
Cancers,
n
Multi-adjusted
HR*(95 % CI)
Low
19
1 (reference)
32
1 (reference)
Medium
10
0.55 (0.25-1.23)
50
0.69 (0.43-1.09)
High
12
1.49 (0.70-3.18)
34
0.96 (0.58-1.59)
Income
P-value for trend
0.46
0.98
Education
Low
20
1 (reference)
51
1 (reference)
Medium
15
1.07 (0.55-2.08)
48
1.05 (0.71-1.55)
6
1.37 (0.55-3.41)
17
1.15 (0.66-1.99)
High
P-value for trend
0.55
0.63
Marital status
Married
30
1 (reference)
92
1 (reference)
Unmarried
3
1.14 (0.35-3.73)
9
0.97 (0.49-1.92)
Divorced/ separated
3
0.90 (0.27-2.96)
9
0.92 (0.46-1.82)
Widowed
5
1.36 (0.52-3.56)
6
1.07 (0.46-2.46)
41
0.92 (0.75-1.14)
116
1.00 (0.89-1.12)
Stress score (continuous)
* The associations between income, education, or marital status and prostate cancer are adjusted for age. The association between stress and
prostate cancer is adjusted for age, income, educational level, marital status, alcohol intake, physical activity in leisure time, and body mass
index.
Figure 8-1. Causal diagram for the relation between socio-economic status, marital status, perceived stress, and risk of prostate cancer
Age
BRCA1/2
mutations
Lucopene
Fish intake
IGF-1
Selenium/ Vitamin E
Socio-economic
status
Perceived stress
Prostate cancer
Androgens
Marital status
Physical activity
Alcohol
Body mass index
Foods high in animal fat
Family history of prostate cancer
Sexually transmitted
diseases
IX. Perceived stress and sex steroid hormones: a cross-sectional
study
Introduction
Estrogens and other reproductive hormones play an important role in the etiology of
several human cancers.4-6;70;97;115-117 Estrogen-induced proliferation appears to be partly
responsible for tumor formation in organs that express estrogen receptors, such as those
found in the reproductive system organs and the mammary gland.21;116 Estradiol, the
most active estrogen metabolite, can bind to the estrogen receptors, activate gene
expression, and thereby increase cell proliferation. By this pathway, estrogens promote
growth of already initiated cells. There is also some evidence that estrogens can act as
initiating agents themselves by being metabolized into more reactive intermediates that,
in turn, may lead to structural changes in the DNA.82
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.10-12 Prolonged low-key stress of everyday
life results in a persistent activation of stress-hormones such as glucocorticoids, which
have been suggested to participate in the down-regulation of the synthesis of
endogenous sex steroid hormones.72 Our hypothesis is that stress leads to lower levels of
sex steroid hormones and thereby explain the lower risk of hormone-dependent cancers
previously observed among women with chronic stress in some studies.53;55;57 The
objective of the present study is to examine a potential association between perceived
stress and plasma levels of sex steroid hormones in postmenopausal women. We also
aim to assess if a questionnaire-based measure of perceived stress is associated with
cortisol, which is often referred to as one of the major stress hormones.
106
Methods
Study population
Information from the second examination of the prospective Copenhagen City Heart
Study in 1981-83 was used to address the objective. Hormone levels were assayed in a
random sample of women (n=1,150) drawn from the base population in 1981-1983. A
flow diagram of the data selection process is shown in figure 9-1. Women with
hormone-dependent cancer prior to baseline, women who took exogenous hormones,
and pre-menopausal women were excluded from the analyses. The final analyses
included 832 women for the 17β-estradiol analysis and 840 women for the analyses of
free testosterone and cortisol. Perceived stress was assessed at baseline and included
two questions on stress intensity and stress frequency. A seven-point stress score was
created based on these two questions. Please refer to the material and methods chapter
for a detailed description of the Copenhagen City Heart study and the measurement of
perceived stress.
Laboratory analyses
The hormone analyses were conducted at a laboratory at the Danish National Research
Center for Working Environment during 2006. All blood samples were taken after 30
minutes rest and the date and time for each blood sample were recorded. All samples for
the hormone analysis were stored frozen at –20°C. Endogenous hormone levels were
measured in serum and all hormones were measured in duplicate and the mean of the
two measurements was used in the statistical analyses. The Radio Immune Assays (RIA)
used for determination of free testosterone and 17ß-estradiol in serum was Coat-a-count
kits purchased from Diagnostic Products Corporation (DPC, Los Angeles, CA). The
analyses were carried out according to the manufacturer’s specifications. A 1470 Wizard
gamma counter (Wallac, Turku, Finland) was used for measurement of radioactivity. A
method evaluation of free testosterone and 17ß-estradiol was performed by use of Con6
Immunoassay Tri-level Controls from DPC at three levels. The method evaluation for
free testosterone showed no bias of the method, recovery 97.7 [CI95%: 87.0%;108.3%].
Limit of detection (LOD) was 1.2 pmol/l. The method evaluation for 17ß-estradiol
showed no bias of the method, recovery 103.7 [CI95%: 99.0%;108.3%]. Limit of detection
(LOD) was 9.8 pmol/l. The assay used for the determination of cortisol in serum was a
107
competitive Radio Immuno Assay (RIA) (Spectria Cortisol Coated Tube RIA)
purchased from Orion Diagnostica, Espoo, Finland. A method evaluation of certified
reference material in water showed a bias of the method, recovery was 88.8% [CI95%:
79.1%; 98.6%]. LOD was 4.7 nmol/l.
To show equivalence between the different runs, reference materials were analysed
together with the samples.118;119 Westgard control charts were used to document that the
analytical method remained in analytical and statistical control, that is, the trueness and
the precision of the analytical methods remained stable. Con6 Immunoassay Tri-level
Controls from DPC were used for cortisol, free testosterone, and 17ß-estradiol.
Statistical analyses
The association between perceived stress and levels of endogenous sex steroid hormones
(17β-estradiol and free testosterone) and cortisol was addressed in a cross-sectional
study design using blood samples and data on perceived stress from the second
examination of the Copenhagen City Heart Study in 1981-1983. Cortisol and the sex
steroid hormones are known to have a circadian rhythm, making it important to control
for the time of day at which the blood is drawn. We graphically examined the circadian
pattern of each hormone and included both a linear and a quadratic term of time of day
for the blood draw to adjust for the observed patterns. First, we assessed the median and
the 10th and 90th percentiles for each of the hormones for categories of stress intensity,
stress frequency, and the combined stress score. Secondly, we regressed levels of sex
steroid hormones and cortisol on categories of stress in a linear regression model. Due to
non-normal (skewed) distributions and heteroscedastic variances (proportional to level
of measurements) in the biomarker data, all concentrations of the biomarkers were
analysed on logarithmic scales. The regression models were adjusted for age, body mass
index, physical activity, alcohol consumption, tobacco smoking, education, and time of
day for blood draw. We included age as linear splines with two knots at ages 55 and 70
in order to adjust for changing associations between age and hormone levels.
108
Results
The majority of the women had their blood drawn in the morning between 8 AM and
noon (76 %). The median 17β-estradiol value was 24.9 pmol/L with 10th and 90th
percentiles of 7.4 pmol/L and 122.5 pmol/L. Estradiol did not show any clear circadian
pattern in this study (figure 9-2). The median value of 17β-estradiol was similar in the
different categories of stress intensity, stress frequency, and the stress score (table 9-1).
After adjustment for age and time of blood draw, women who reported no stress
intensity or to never experience stress had the highest level of 17β-estradiol, while
women who reported light or monthly stress had the lowest levels. There were no doseresponse associations and the differences were most likely due to chance. Adjustment
for a range of potential confounders only slightly changed the risk estimates.
The median value of free testosterone was 4.9 pmol/L with 10th and 90th
percentiles of 2.3 pmol/L and 9.0 pmol/L and there were also no clear circadian patterns
(figure 9-2). Mean levels of free testosterone were not dependent on categories of stress
intensity, stress frequency, or the combined stress score (table 9-2).
The median cortisol value was 239 nmol/L with 10th and 90 th percentiles of 134
nmol/L and 392 nmol/L. Cortisol showed a circadian pattern with declining values over
time during the morning after which it levelled off (figure 9-2). The analyses of stress
and cortisol are controlled for this circadian pattern. After adjustment for a range of
potential confounders, there were no clear associations between any of the stress
measures and cortisol levels (table 9-3).
Discussion
We found no associations between perceived stress in daily life and endogenous levels
of sex steroid hormones in postmenopausal women. Also, perceived stress did not seem
to be associated with cortisol, which is hypothesized to be one of the main
neuroendocrine mediators of the stress response.13 In contrast to our results, Kroenke
and colleagues used caregiving as an indicator of chronic stress, and they found lower
levels of estradiol and testosterone among postmenopausal women who provided more
than 15 hours of caregiving to an adult per week.55 However, in line with the results
from the present study, they also found no relation between self-reported stress and
109
levels of endogenous sex steroid hormones. We have previously found perceived stress
to be associated with lower risk of breast cancer in the Copenhagen City Heart Study
and we suggested lower levels of endogenous sex steroid hormones among stressed
women to a be possible explanation.57 This mechanistic explanation is not supported by
the present study.
The ovarian synthesis of estrogens is low among postmenopausal women, which
may be one reason why we do not observe an association between stress and estrogen
levels in this study. If stress indeed impairs estrogen synthesis, it may have been more
relevant to address this hypothesis in premenopausal women who have a much higher
ovarian synthesis of estrogens. However, it would have been difficult to disentangle the
effects of stress from the large fluctuations in estrogen levels during the menstrual cycle
among these women.
Even though we find no associations between stress and sex steroid hormones,
stress hormones may still affect the responsiveness of the target tissues toward estrogen
stimulation so that similar levels of estrogen may lead to different rates of cell
proliferation depending on the level of stress hormones. For example, experimental
evidence has shown that stress may produce a direct effect on the uterus by changing the
response of its structures to estrogen.89-91 This hypothesis cannot be addressed in the
present study, but may be important to keep in mind when addressing the relation
between stress and hormone-dependent cancers.
Estradiol, testosterone, and cortisol all have intrinsic biological variability and
cortisol also shows a clear circadian pattern. This may have decreased the reliability of
single measurements of hormonal levels, as the one included in this study, and may have
blurred a possible weak association between stress and hormonal levels. Several
measures of hormones at different times of the day in each individual would have been
preferable. On the other hand, such an approach would have been much more time
consuming and expensive and would possibly not have been feasible to accomplish in a
large population study such as the one at hand. In support of the validity of the results,
we found body mass index to be associated with higher levels of estradiol levels (data
not shown), similar to what would be expected based on results from other studies.120
The blood samples were first assayed more than 20 years after collection. During
this period they have been stored at -20°C. Steroid hormones, in general, seem to be
110
relatively stable over time at this temperature,121 and we therefore do not expect this
time span to have seriously distorted our internal comparisons of hormone levels
between stress categories. However, due to the long-term storing, a higher proportion of
the sex steroid hormones maybe in an unbound form compared to other studies.122
Perceived stress was assessed by two questions on stress intensity and stress
frequency measured at baseline. This may not be the optimal way to assess a complex
phenomenon such as stress and we cannot exclude the possibility that other measures of
stress could be associated with sex steroid hormones. However, in a recent study, two
single-item questions on stress were found to be just as valid as three fully validated
multi-item measures on perceived stress.101 Also, perceived stress has been related to
other health outcomes in the present study population.57;102;103 However, perceived stress
was not associated with cortisol levels in this study. One reason may be that we only had
a single measure of cortisol, which is not necessarily a valid presentation of an
individual’s cortisol profile. If stress for examples leads to a blunted circadian cortisol
rhythm, this will not be captured by a single measure.
Hormone levels were only assayed in a random sample of the total study
population, and one may be concerned that lacking statistical power is a possible
explanation to the null findings. Both the estradiol and testosterone analyses indicated
lower levels of these hormones among stressed women. However, there were no doseresponse trends and the observed differences were only modest.
In conclusion, we found no evidence of a relation between perceived stress and
levels of sex steroid hormones among postmenopausal women. In spite of measurement
problems, which may have blurred a relation between stress and hormone levels, stressinduced impairment of estrogen synthesis is not supported as a possible etiologic link
between psychological stress and risk of hormone-dependent cancers in this study.
111
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
Age-and-time adjusted relative difference
Multi-adjusted relative difference in
No.
Median 17β-estradiol,
in geometric mean of 17β-estradiol,
geometric mean of 17β-estradiol*,
(10 -90 percentiles)
% (95% CI)
% (95% CI)
pmol/L
th
th
Stress
intensity
None
312
26 (8; 150)
Ref
Ref
Light
283
22 (8; 114)
-17 (-31; -1)
-18 (-32; -1)
Moderate
179
25 (7; 126)
-12 (-28; 9)
-12 (-29; 9)
58
24 (8; 89)
-11 (-35; 23)
-12 (-36; 22)
Never
403
26 (8; 113)
Ref
Ref
Monthly
198
22 (8; 128)
-13 (-29; 6)
-17 (-32; 1)
Weekly
147
25 (7; 142)
-8 (-26; 14)
-11 (-29; 10)
84
26 (6; 124)
-3 (-26; 27)
-5 (-27; 25)
Low
388
26 (8; 113)
Ref
Ref
Medium
360
24 (7; 129)
-9 (-23; 8)
-11 (-25; 5)
84
25 (7; 123)
-3 (-26; 28)
-4 (-27; 26)
High
Stress
frequency
Daily
Stress score
High
* Adjusted for age, body mass index, physical activity, alcohol consumption, tobacco smoking, education, and time of day for blood draw
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
Age-and-time adjusted relative difference
Multi-adjusted relative difference in
No.
Median free testosterone,
in geometric mean of free testosterone,
geometric mean of free testosterone*,
(10 -90 percentiles)
% (95% CI)
% (95% CI)
pmol/L
th
th
Stress
intensity
None
315
4.9 (2.4; 9.4)
Ref
Ref
Light
284
4.9 (2.4; 9.2)
-2 (-11; 9)
-3 (-12; 9)
Moderate
179
4.6 (2.1; 8.7)
-9 (-19; 3)
-11 (-21; 0)
62
5.0 (2.5; 7.5)
-6 (-21; 12)
-9 (-23; 8)
Never
405
4.8 (2.3; 9.0)
Ref
Ref
Monthly
199
5.0 (2.5; 9.0)
1 (-10; 13)
0 (-10; 12)
Weekly
149
4.6 (2.2; 8.8)
-6 (-17; 6)
-7 (-17, 5)
87
5.0 (2.5; 9.3)
2 (-12; 18)
-1 (-14; 15)
Low
391
4.8 (2.3; 9.0)
Ref
Ref
Medium
361
4.8 (2.2; 8.8)
-4 (-12; 5)
-5 (-13; 4)
88
5.0 (2.5; 9.3)
0 (-14; 16)
-2 (-16; 13)
High
Stress
frequency
Daily
Stress score
High
* Adjusted for age, body mass index, physical activity, alcohol consumption, tobacco smoking, education, and time of day for blood draw
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
Age-and-time adjusted relative difference
Multi-adjusted relative difference in
No.
Median cortisol, nmol/L
(10 th-90 th percentiles)
in geometric mean of cortisol,
geometric mean of cortisol*,
% (95% CI)
% (95% CI)
Stress
intensity
None
315
230 (135; 389)
Ref
Ref
Light
285
258 (149; 403)
7 (0; 14)
5 (-1; 13)
Moderate
180
231 (124; 382)
-2 (-9; 6)
-3 (-9; 5)
60
234 (132; 387)
-1 (-11; 11)
-1 (-11; 11)
Never
404
230 (137; 392)
Ref
Ref
Monthly
200
248 (139; 392)
4 (-4; 11)
2 (-5; 10)
Weekly
150
262 (131; 383)
5 (-3; 13)
4 (-4; 12)
86
234 (140; 406)
3 (-7; 13)
2 (-7; 12)
Low
391
234 (139; 392)
Ref
Ref
Medium
362
248 (133; 391)
2 (-4; 8)
1 (-5; 7)
87
234 (138; 395)
-1 (-10; 8)
-2 (-11; 8)
High
Stress
frequency
Daily
Stress score
High
* Adjusted for age, body mass index, physical activity, alcohol consumption, tobacco smoking, education, and time of day for blood draw
Figure 9-1. Flow diagram of the data selection process
12698 participants in the Copenhagen City Heart Study
7018 women
- 207 women with hormone-dependent
cancer prior to baseline
6811 women
- 1716 premenopausal women
5095 women
- 86 women with no blood samples
5009 women
- 127 women without information on
stress or other covariates
4882 women
Random sample of 1150 women
- 86 blood samples not found
1064 women
- 214 women who used hormone theraphy
850 women
- 10 (-18) because ofinsuffient material for the analyses
Estradiol: 832 women
Testosterone: 840 women
115
Cortisol: 840 women
Figure 9-2. Circadian pattern for 17β-estradiol, free testosterone, and cortisol
0
Fitted values/S_Estradiol
100
200
300
400
500
Estradiol
5
6
7
8
9
10
11 noon 1
2
Time of day, hour
Fitted values
3
4
5
6
7
4
5
6
7
4
5
6
7
S_Estradiol
0
Fitted values/S_testosteron
5
10
15
20
25
Free testosterone
5
6
7
8
9
10
11 noon 1
2
Time of day, hour
Fitted values
3
S_testosteron
0
Fitted values/S_kortisolnmolL
200
400
600
800
Cortisol
5
6
7
8
9
10
11 noon 1
2
Time of day, hour
Fitted values
116
3
S_kortisolnmolL
X. Stress and hormone-dependent cancers: a discussion of the
evidence
Is there a relation between stress and hormone-dependent cancers?
Perceived stress and breast cancer
Previous prospective studies on stress and breast cancer have reported inconsistent
results. In general, exposure to major stressors such as death of a child or divorce was
not associated with a higher risk of breast cancer in large-scale registry-linkage
studies.44-49 It is unclear whether an accumulation of stressful life events is associated
with higher risk of breast cancer.59 Previous prospective studies that addressed the effect
of work-related stress or perceived stress either did not find an association with breast
cancer risk or found indications of a lower risk of breast cancer among stressed
women.53;55;56 In the Copenhagen City Heart Study, we found high levels of perceived
stress to be associated with a lower risk of breast cancer in an inverse dose-response
manner. We found that women who reported high levels of stress in their daily life were
almost half as likely to develop breast cancer compared to women who reported no
stress. It was hypothesized that stress could lead to a suppression of estrogen synthesis
and thereby reduce the risk of breast cancer, which is highly dependent on endogenous
levels of estrogens.70 Given that this hypothesis is correct, we would expect to also see a
lower risk of other hormone-dependent cancers among stressed women.
Perceived stress and endometrial cancer
Endometrial cancer is another clearly estrogen-dependent cancer in women. Previous
studies on stress and endometrial cancer have only addressed the effect of major
stressful life events and these studies have solely been based on information from
national registries. None of the studies found any clear evidence of an association
between stressful life events and risk of endometrial cancer. 45-48 As argued in the
introduction chapter, the health consequences of acute severe stress from stressful life
events can differ considerably from the health consequences of the more chronic stress
117
experienced in daily life. We therefore found it relevant to address the association
between perceived stress and risk of endometrial cancer in the Copenhagen City Heart
Study. Although few women in the cohort developed endometrial cancer during followup, we still found an inverse dose-response association between stress and risk of
endometrial cancer similar to the one observed for breast cancer. This association was
particularly strong among women who received hormone therapy and in women of
normal weight. Some experimental studies have shown that stress hormones may impair
both estrogen synthesis, as hypothesized in the breast cancer study, as well as make the
target organs less responsive to estrogen stimulation.10;81 In this cohort of middle-aged
women where most were postmenopausal and therefore had a low ovarian synthesis of
estrogens, the lower responsiveness of the target organs toward estrogen stimulation
may explain the stronger effect of stress in women who received hormone therapy.
Overweight women, on the other hand, may be in a pro-inflammatory state that
facilitates carcinogenesis. This alternative pathway would counteract the stress-induced
suppression of estrogens and thereby explain the less pronounced effect of stress among
overweight women. The similar results found for breast and endometrial cancer provide
some support to the hormone hypothesis stating that impairment of estrogen synthesis
and metabolism may be an etiological explanation to the lower risk of these two
malignancies observed among stressed women.
Perceived stress and colorectal cancer
Colorectal cancer seems to also have a hormonal component, although less pronounced
than in breast and endometrial cancers. In previous studies on stress and colorectal
cancer, stress from acute severe stressors such as the loss of a child or a spouse did not
markedly increase the risk of colorectal cancer, while there were some evidence to
support that more prolonged stressors such as major work-related problems was
associated with higher risk. 45;46;48;65;67 The association between perceived stress and
colorectal cancer has only been addressed in a cohort study once before.69 This earlier
study assessed colorectal cancer mortality as the endpoint, which did not allow for a
distinction between etiologic and prognostic factors. We addressed the association
between perceived stress and risk of colorectal cancer in the Copenhagen City Heart
Study and found sex-differences in the results. In women, higher stress was associated
118
with a lower risk of colon cancer in particular, while there was no clear relation between
perceived stress and colon or rectal cancer in men. This may indicate different etiologic
pathways for colorectal cancer in men and women, and it may again lend some support
to the hormone hypothesis in women. Such sex-differences have, however, not
previously been reported and the analyses should be replicated in other cohorts before
conclusions can be drawn.
Perceived stress and prostate cancer
Prostate cancer is assumed to be the primary hormone-dependent cancer in men,
although a clear relation between testosterone levels and prostate cancer risk still
remains to be established.9 One previous registry-linkage study found no increased risk
of prostate cancer among men who had experienced having a child with cancer.47
Similarly, we did not find any support of a relation between stress and risk of prostate
cancer in the Copenhagen City Heart Study.
Perceived stress and endogenous sex steroid hormones
In the Copenhagen City Heart Study, perceived stress was associated with lower risk of
breast, endometrial, and colon cancer in women, while there was no clear evidence of a
relation between perceived stress and colorectal or prostate cancer in men. This lower
risk of hormone-dependent cancers consistently observed among stressed women
provide some support to the hypothesis that stress hormones may impair estrogen
synthesis as well as make the target organs less sensitive to estrogen stimulation.
Following in the line of this hypothesis, we investigated whether women who reported
high levels of stress also had lower endogenous levels of estrogens or other sex steroid
hormones at baseline compared to less stressed women. We therefore measured estradiol
and testosterone in a sub-sample of the postmenopausal women from the Copenhagen
City Heart Study. Women with high levels of stress did not have lower endogenous
levels of sex steroid hormones. This may either be due to methodological flaws in the
measurement or it may question the underlying hormone hypothesis. If stress indeed
impairs estrogen synthesis it may have been more relevant to address the hormone
hypothesis in premenopausal women. However, this would have led to difficulties in
disentangling the effect of stress from the large fluctuations in estrogen levels during the
119
menstrual cycle, especially as only one measurement of estrogens was available in the
present study population.
Summary
Perceived stress seems to be associated with lower risk of hormone-dependent cancers
among women in the Copenhagen City Heart Study, but the findings remain to be
confirmed in other cohort studies and the underlying mechanisms need to be further
explored.
The strength of the Copenhagen City Heart Study
The Copenhagen City Heart Study is one of few cohort studies that contains both
information on perceived stress and has a sufficient follow-up time to address specific
cancer types separately. In addition, there were blood samples available on the majority
of the participants. The prospective design of the Copenhagen City Heart Study also
ensured temporality between self-reported stress and incidence of hormone-related
cancers, which is very important in stress research where recall problems may constitute
a major problem. The cohort is a large random sample of the general population of
Copenhagen, and the attendance rate was relatively high. Linkage of civil registry
numbers to nationwide population-based registers enabled identification of virtually all
hormone-dependent cancer cases and allowed for nearly complete long-term follow-up.
This made the Copenhagen City Heart Study a valuable data-source for the study of
stress and risk of hormone-dependent cancers. In this cohort, we found perceived stress
to be associated with lower risk of hormone-dependent cancer in women, but not in men.
Despite the strength of the Copenhagen City Heart Study, the observed associations may
still deviate from the causal relations of interest by systematic processes, such as
selection bias, misclassification of exposure or disease, and confounding, as well as by
random processes (random errors). The goal was to measure the associations as
accurately as possible, but errors in estimation are unavoidable and will therefore be
given attention in the following sections.
120
Selection bias and external validity
In cohort studies, as the ones applied in the dissertation, loss to follow-up is the main
source of selection bias, whereas non-participation in the study at time of initiation
constitutes a question of external validity. A small proportion (less than 0.1 %) of the
women were lost to follow-up, and strong selection bias is therefore unlikely. Seventy
percent of the originally invited cohort participated in the second examination of the
Copenhagen City Heart Study. A decision not to participate could well be related to
stress level, since high stress may limit the time available for participating in surveys.
Thus, the results of the included studies on stress and hormone-dependent cancers
cannot necessarily be generalized to groups with extremely high levels of stress, as these
individuals may not be represented in the study population. Also the results cannot
necessarily be generalized to younger age groups or to other ethnical groups.
We studied the relation between perceived stress and risk of hormone-dependent
cancers in the Copenhagen City Heart Study. The associations observed in this cohort
may differ from what might have been observed in another cohort. We tried to integrate
evidence from other cohorts before drawing conclusions in each of the studies, but we
cannot completely refuse that some of the results may be specific to this cohort. There is
a need to replicate the studies in other study populations.
Misclassification of perceived stress
The impact and magnitude of misclassification of perceived stress will be addressed by
various means. None of these can fully determine the exact amount of exposure
misclassification, but they can, in concert, provide a picture of the magnitude and
direction of this type of bias. There are two ways by which the ideal and the operational
measure of exposure can deviate from one another.104 The first, conceptual exposure
misclassification arises when the operational measure addresses something different
from what is intended. That is, the ascertained measure does not resemble what is of
etiological interest (the ideal measure). The other way is more often addressed in
traditional approaches to evaluate exposure misclassification, and it deals with errors in
implementing the chosen operational measure. This includes concerns about recall bias,
121
underreporting, technical imprecision, etc. Both types of misclassification need equal
attention.
Perceived stress has been the construct of etiological interest (the ideal measure) in
the dissertation. Every disparity between this ideal measure and the way it is
operationalized and measured may have biased the assessment of the causal relations of
interest. The question is how widespread this kind of bias has been. Two different
measures of perceived stress (intensity and frequency) were obtained in the Copenhagen
City Heart Study, both resembling different aspects of the concept of interest. Neither of
the two measures can be said to be better than the other, but by combining them into one
stress-score we hoped to create a measure with less conceptual error. On the other hand,
one of the measures may be measured with less precision than the other, which would
result in the combined score being less precise than at least one of the measures alone. In
each of the studies we therefore chose to both present the results for each of the
measures alone as well as for the combined score.
Using the two questions on stress intensity and stress frequency instead of a more
extensive scale may have resulted in some conceptual exposure misclassification. The
question is whether the two questions on stress intensity and stress frequency did capture
the intended ideal measure of perceived stress to an acceptable degree. Since the two
questions used as an operational measure of perceived stress has not yet been validated
against a more extensive scale such as the Perceived Stress Scale,84 we cannot fully
determine the magnitude of this conceptual misclassification. A disparity between the
ideal and the operational measure will have reduced our ability to address the
hypothesized etiologic relations between perceived stress and hormone-dependent
cancers, and by using only two measures of stress intensity and stress frequency instead
of a more extensive scale an even stronger relation between perceived stress and risk of
hormone-dependent cancers may have been blurred.
The ability to retrieve known health consequences of perceived stress in the
Copenhagen City Heart Study would give some idea about the degree of exposure
misclassification. Perceived stress is a relatively new measure of interest in stress
research, and known health consequences of perceived stress therefore remain to be
established. However, we have previously found perceived stress to be associated with
higher risk of stroke and ischemic heart disease in the same cohort,102;103 which provide
122
some modest confidence that the operational measure applied in this cohort resembled
the ideal measure of perceived stress. Further, a dose-response gradient may support a
causal relation between the operational measure and disease and thereby support a
relation between the ideal measure of etiological interest and the applied operational
measure, while the opposite is not necessarily the case.104 An inverse dose-response
relation was found for the associations between perceived stress and risk of breast
cancer, endometrial cancer, and colon cancer in women.
One also has to identify the etiologically relevant time window for exposure,
because inclusion of irrelevant periods of exposure would also constitute exposure
misclassification.104 Perceived stress was the measure of etiologic interest in this study,
but whether this includes stress experienced until shortly before diagnosis or only
prolonged stress, for example ten years prior to diagnosis, is unclear. In order to address
this question, we have assessed the relation between perceived stress and risk of
hormone-dependent cancer in different intervals of follow-up in each of the sub-studies.
In most of the studies the associations were strongest in first nine years of follow-up.
One of two explanations, or a combination of both, may apply. The etiologically
relevant time frame for stress exposure is primarily within the nine years prior to
diagnosis. Alternatively, perceived stress was only assessed at baseline and may have
changed over time in a manner that is most likely independent of subsequent incidence
of cancer. Such non-differential exposure misclassification may have reduced our ability
to detect a potential relation between stress and risk of hormone-dependent cancers and
thereby explain the attenuated associations observed in the last period of follow-up.
Which explanation that applies cannot be clarified from the present data, but it is
probably a combination of both.
Misclassification of outcome measures
In countries with nationwide morbidity and mortality registries, like the Danish, it is
often assumed that disease misclassification is a minor problem. It may indeed be a
much smaller problem than in studies where disease status is obtained by, for example,
self-report, but it may still exist. Sources of disease misclassification may, analogue to
exposure misclassification, be divided into being conceptual or practical in nature.
123
Conceptual error may arise in the very definition of the disease, while errors in
registration and in the actual process by which individuals come to be identified as cases
arises in the implementation of the case definition.104 We have chosen to address each of
the site-specific types of hormone-dependent cancers separately in order not to combine
subsets of disease with different etiologies. This approach has hopefully reduced the
problem of conceptual disease misclassification. Reporting of new cancer cases to the
registry is compulsory in Denmark and, according to the Danish National Board of
Health, the Danish National Cancer Registry contains data on more than 95 percent of
all cancer diagnoses in Denmark.123 Disease misclassification is therefore unlikely to
have severely affected our results.
Estradiol, testosterone, and cortisol all have an intrinsic biological variability,
which may have decreased the reliability of single measurements of hormonal levels, as
the one applied in the study that assessed the association between stress and sex steroid
hormones. This may also be a likely explanation to the finding of no association between
stress and sex steroid hormones in this study. Several measures of hormones at different
times of the day in each individual should be the aim of future studies on this relation.
Confounding
In this and most other epidemiologic studies, an unexposed group is chosen to provide
an estimate of what the experience of the exposed group would have been, had they not
been exposed. Confounding is said to be present whenever the disease experience of the
unexposed group differs from what it would have been in the exposed group, had they
not been exposed.104 Thus, a central question in the present study is: Did individuals
with low levels of stress (the reference group) have the risk of cancer that individuals
with higher levels of stress would have had, if their stress level had been low? In other
words, is the observed baseline risk of hormone-dependent cancers in the unexposed
group exchangeable with the hypothetical counterfactual baseline risk of hormonedependent cancers in the exposed groups? If not, the measure of association comparing
the exposed and unexposed groups would not have been a valid estimate of the causal
effect of interest. In order to address this possible non-exchangeability, we tried to
identify covariates that could serve as markers of this non-exchangeability (potential
124
confounders) in each of the studies.104 A covariate cannot be a confounder unless 1) it
can causally affect disease risk within exposure groups, 2) it is distributed differentially
among the compared groups, and 3) it is not an intermediate variable in the causal
pathway between exposure and disease.124 These necessary conditions for a confounder
apply to a source population of individuals at risk of becoming cases. Identification of
potential confounders, using these necessary conditions, is commonly achieved by a
stepwise selection procedure, where covariate-disease associations are observed in data.
This is not automatically a sound approach because we cannot be sure that the observed
associations themselves are not confounded or otherwise biased. According to
Greenland and Morgenstern, we should therefore rely on prior knowledge of causal
effects when identifying confounders in a study.124
There are various ways by which to control for potential confounding.
Confounding can either be controlled directly in the study design (e.g., restriction,
randomization) or in the statistical analysis (e.g., stratification, using regression models).
The last approach was applied in the present studies, where the estimated associations
between perceived stress and risk of hormone-dependent cancers were controlled for
confounding effects of other covariates in multivariate regression models. The statement
that the adjusted measure of association is a valid estimate of the causal effect depends
on two assumptions; 1) that the variables available for the analysis were sufficient, and
2) that they were adequately measured and categorized.124 Neither of the assumptions
can be proven to be true, but we used sensitivity analyses and evaluation of residual
confounding to evaluate the impact of these assumptions in each of the studies.
A set of confounders was identified based on causal diagrams in each of the
studies. However, the proposed set of potential confounders would not be adequate if the
assumed causal model was wrong. It is, unfortunately, never possible to be completely
certain about the assumed model, but by explicitly stating the assumptions made either
in a causal diagram or by verbalizing them, it is possible for other investigators to
acknowledge and discuss the assumptions. Further, alternative assumptions and their
effect on the relation of interest can be addressed in sensitivity analyses and thereby
provide important information on the impact of the assumptions. Such sensitivity
analyses were performed in several of the studies in order to address the impact of our
assumptions. As an example, we assumed that hypertension was a possible intermediate
125
on the pathway from perceived stress to endometrial cancer, and hence we did not adjust
our analyses for this variable. Some investigators may not agree with this assumption,
and in order to address the impact of this assumption we performed a sensitivity analysis
where we adjusted for hypertension. Such adjustment did not change the risk estimates,
which suggests that the results were not very sensitive to this particular assumption.
Information on several important risk factors for hormone-dependent cancers was
not obtained in the Copenhagen City Heart Study. The fact that we did not have
information on family history of the specific hormone-dependent cancers in first-degree
relatives may be especially of concern. However, we would not expect perceived stress
to be strongly associated with family history of hormone-dependent cancers, and strong
confounding from this important risk factor is therefore unlikely. We also lacked
information on other important risk factors for the site-specific hormone-related cancers.
We have discussed the impact of this lacking information in each of the studies and in
general, we concluded that confounding from unmeasured covariates were unlikely to
explain the inverse relations between perceived stress and hormone-dependent cancers
observed in women.
Misclassification of confounders may result in incomplete statistical control from
covariates included in the analysis and thereby lead to residual confounding.104 Some
variables are more prone to this kind of misclassification than others. Day of birth was
derived from the nationwide Central Person Registry, and a variable like age is therefore
unlikely to be subject to a great amount of misclassification. The same is evident for sex.
On the contrary, a concept like socio-economic status is more prone to both conceptual
and measurement error. We used self-reported education and income as proxy-measures
for socio-economic status. Undoubtedly, these proxy-measures did not fully capture the
underlying concept of etiologic interest, and residual confounding was inevitable. Socioeconomic status could just as well have included measures of wealth, position, etc., and
omission of such aspects of the concept makes the assessment incomplete. The amount
of residual confounding from a variable is, however, often proportional to the amount of
confounding originally present by the specific factor in question, and evaluating the
change in effect estimates after adjustment for the incomplete operational measure can
give us some idea of the magnitude of distortion.104 Adjustment for socio-economic
126
status did not substantially change the results in any of the studies and thereby make
residual confounding from this variable less of a concern.
Random error
Even in as large a cohort study as the Copenhagen City Heart Study where the
participants were followed for almost two decades, the number of hormone-dependent
cancer cases was limited. We found inverse dose-response associations between
perceived stress and risk of breast, endometrial, and colon cancers in women. This may
provide some comfort that the studies were sufficiently powerful to address our main
hypothesis, namely that the risk of hormone-dependent cancers differed between stress
groups. However, power problems arose as soon as we wanted to conduct subgroup
analyses in order to identify susceptible subgroups, and the results of these analyses
should therefore be interpreted with caution.
127
XI. Conclusion
Perceived stress was consistently associated with lower risk of breast, endometrial, and
colon cancer in a dose-response manner among women participating in the Copenhagen
City Heart Study. This supports the existence of a common causal pathway between
perceived stress and these hormone-dependent cancers. We proposed a hormone
hypothesis, where stress impairs the synthesis of estrogens, as a possible explanation.
This hypothesis was not supported in a cross-sectional study conducted in a subset of the
women, where we found no differences in endogenous levels of sex steroid hormones
among women with different stress levels. We could not determine if the lacking
association between stress and sex steroid hormones was in fact valid or a consequence
of an insufficient measurement of the hormone levels. Alternatively, stress may also
render the target tissues less sensitive toward estrogen stimulation. This part of the
hormone hypothesis was not tested in the dissertation. Further, there were no clear
evidence of a relation between perceived stress and risk of colorectal or prostate cancers
in men. Prior biological, psychological, and epidemiological knowledge was used to
identify causal models for the statistical analysis. Such an approach ensured
transparency of the applied assumptions and increased the efficiency of the statistical
model by making it possible to identify a minimum sufficient set of confounders based
on the stated causal model. Due to almost complete follow-up, selection bias was
unlikely to have distorted the results of the studies. However, misclassification of
perceived stress may be of concern. The applied measure of stress intensity and stress
frequency may not have fully captured the concept of etiologic interest, namely
perceived stress. This misclassification of perceived stress is likely to have resulted in an
underestimation of possibly stronger relations between perceived stress and risk of
hormone-dependent cancers. Further, the magnitude of the effect was diluted by the long
period of follow-up and possible changes in stress levels during follow-up. Only a few
participants developed hormone-dependent cancer during follow-up, which resulted in
the lack of sufficient statistical power in some of the studies and especially in the
subgroup analyses. Drawing firm causal conclusions from epidemiological studies are
problematic because the empirical results will always be on a continuum of uncertainty.
128
We tried to integrate the empirical evidence from this study with prior scientific
knowledge about the relation between stress and risk of hormone-dependent cancer.
Based on this approach we can conclude that perceived stress seems to affect the risk of
hormone-dependent cancers in women, but the findings from the Copenhagen City Heart
Study remain to be confirmed in other cohort studies and the underlying causal
mechanisms need to be further explored.
129
XII. Public health implications
Is stress a public health problem?
Perceived stress is quite prevalent in most western societies and even a relatively small
change in risk could therefore have a large public health impact at the population level.
We found perceived stress to be associated with lower risk of hormone-dependent
cancers in women. Hopefully, these results may prevent some women from blaming
their own stressful life style if they are diagnosed with cancer. However, it is also
important to emphasize that stress cannot be considered a healthy response. Stress is not
a desirable state to be in neither mentally nor physically and it may lead to the
development of diseases other than hormone-dependent cancers, such as cardiovascular
diseases.
Whether stress affects the risk of non-hormone-dependent cancers is still an area
of debate. There is considerable experimental evidence indicating that stress plays a role
in the development, course, and outcome of tumors in animals.125 An increased secretion
of glucocorticoids in an acute stress situation is found to suppress the function of the
immune system and thereby reduce its ability to recognize and destroy neoplastic cell
growth.14 The evidence of a relation between stress and cancer is less consistent in
humans,125 which may partly be due to different mechanisms working in opposite
directions.
Apart from cancer, stress in its varying kinds may have a range of other health
consequences. An association between stress and risk of cardiovascular diseases is both
biologically plausible and empirically supported in a range of observational
studies.105;126-128 In a recent large case-control study that included cases and controls
from 52 countries, a higher risk of myocardial infarction was reported among individuals
who experienced stress at home or at work, were under severe financial stress, had
experienced stressful life events in the past year, or were depressed.126 Stress seems to
activate the sympathetic nervous system, with various metabolic effects: increased blood
pressure, pulse rate, and platelet aggregation; reduction in insulin sensitivity; and
promotion of endothelial dysfunction.105 Stress may also lead to changes in smoking,
130
diet, alcohol consumption, and level of physical activity, and thereby indirectly
influence the risk of cardiovascular diseases.93;129-131
It is well established that stress measured by both self-report and objective life
events is associated with increased susceptibility to infectious diseases.132 This risk is
mediated by both direct modulation of functional and enumerative aspects of immunity
as well as by indirect changes in health-related behavior. However, a marked variability
among individuals in immune response to stress has been noted. This has primarily been
ascribed to the fact that each individual has different abilities to cope with stressors,
which again makes stress appraisal more predictive than external stressors.132
Stress is also associated with a higher risk of depression.133;134 Chronic stress
decreases the brains sensitivity to circulating glucocorticoids and thereby its normal role
in down-regulating increased levels. The neurotransmitters serotonin, norepinephrine,
and dopamine are all suspected to play a part in the etiology of depression.
Glucocorticoids can alter the synthesis, the breaking-down process, and the number of
receptors for each of these neurotransmitters, which may explain a link between
prolonged stress and depression. By itself, depression is a major public health problem
because of its severity, prolonged impact on quality of life, and relatively high
prevalence in the population. Further, epidemiologic studies evaluating the relation
between depression and ischemic heart disease have consistently found a positive
association between major depression episodes and incidence of cardiac events.135
In sum, stress is associated with an increased risk of common diseases such as
colds and other infectious diseases, depression, cardiovascular disease, and probably
some types of non-hormone-dependent cancers. Even if stress is only related to a
modestly increased risk of each of these diseases, the impact of stress on these may more
than counteract the possible protective effect of stress on hormone-dependent cancers
among women. To illustrate this, I calculated the absolute impact of perceived stress on
ischemic heart disease and breast cancer, respectively, among women in the Copenhagen
City Heart Study (table 12-1). I found that perceived stress prevented about 14 percent
of all the breast cancer cases that would have occurred among women in the study and
that only seven percent of all cases of ischemic heart disease were attributable to
perceived stress. However, since ischemic heart disease is a more common disease than
breast cancer, this amounts to about 71 cases of ischemic heart disease being attributable
131
to perceived stress, while only about 35 cases of breast cancer were prevented by
perceived stress among women in the Copenhagen City Heart Study. These calculations
are based on the assumptions that the effect estimates represented valid estimates of
causal effects, and that removing exposure to stress would not have affected the size of
the population at risk. These assumptions are seldom completely valid and the example
should therefore only be used to illustrate that a modestly increased risk of a common
disease like ischemic heart disease may more than counteract a markedly lower risk of a
relatively seldom disease like breast cancer, when we address the actual caseload. In
general, I would expect the total burden of disease attributable to perceived stress to far
exceed the relatively few cases of hormone-dependent cancers that may be prevented by
stress. Superimposed on the health consequences of stress come economic
considerations such as days lost through sickness, lost earnings, and hospital
expenditures. This makes stress a major public health problem and emphasizes the
importance of public health initiatives to remedy the problem.
Future population studies on stress and risk of hormone-dependent cancers
In the Introduction section, stress was defined as the individual’s appraisal of an
imbalance between demands and the individual’s resources to cope with it.16 This
measure of etiologic interest was probably not fully captured by the self-reported
information on stress intensity and stress frequency in the Copenhagen City Heart Study.
Using only two questions may have resulted in more conceptual misclassification than if
a more extensive scale of stress perception had been applied. One scale that would be
relevant to include in future studies of the relation between perceived stress and risk of
hormone-dependent cancer is the Perceived Stress Scale (PSS). Cohen and colleagues
proposed this scale in 1983 as an attempt to develop a psychometrically valid measure of
perceived stress.84 The scale is aimed at measuring the degree to which situations in
one’s life are perceived as stressful. Items are designed to measure how unpredictable,
uncontrollable, and overloaded respondents find their life.84 The original scale included
14 items, but a shorter version including 10 items has been validated in a probability
sample of the US population and appears to provide at least as good a measure as does
the longer one.136 The questions included in the PSS10 are shown in figure 12-1. The
132
PSS10 has good construct validity and high internal reliability (Cronbach’s alpha
coefficient = 0.78). It can be administered in few minutes and is easy to score. The total
score is just the sum of the score of each question with positive questions scored
reversed. Further, the Perceived Stress Scale provided better predictions of
psychological and physical symptoms than did life-event scales in the validation study
conducted by Cohen and Williamson.136 One problem with using this scale in future
prospective studies is that level of perceived stress will be influenced by changes in
daily hassles, major life events, and changes in coping resources, and that the predictive
value of the scale is therefore expected to fall over time.136 This is, however, also a
problem if one measures “objective” stressors, such as daily hassles, and should
therefore be considered an inherited problem in stress research in general and not a
problem specific to measuring perceived stress. One way to address this problem would
be to use repeated measures of perceived stress during follow-up. In order to get a more
accurate assessment of the relation between perceived stress and risk of hormonedependent cancers, future studies should ideally be prospective in design, be large
enough to ensure sufficient statistical power, include repeated measures of perceived
stress using the Perceived Stress Scale or another comprehensive stress measure, and
include a better measurement of the sex steroid hormones in order to address a possible
hormonal pathway between stress and hormone-dependent cancers. In an ideal study
with information on stressors and perceived stress at different time-points in life, it
would also be interesting to address the health consequences of stress in a life course
perspective. Some of the studies indicated that the effect of perceived stress might be
confined to specific groups and these differences should be more directly addressed in
future studies with more statistical power. This dissertation has mainly focused on stress
as a potential risk factor for hormone-dependent cancers, but in future studies it may also
be interesting to assess whether stress affects the prognosis of these cancers.
133
Table 12-1. 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.
Breast cancer**
Ischemic heart disease*
Cases
Multi-adjusted HR (95 % CI)
Cases
Multi-adjusted HR (95 % CI)
Low stress
447
1 (reference)
120
1 (reference)
Medium stress
435
1.08 (0.94-1.23)
112
0.80 (0.62-1.04)
High stress
129
1.41 (1.16-1.72)
19
0.60 (0.37-0.97)
Attributable/ prevented fraction in
the population
Attributable/ prevented number
AF = 1 – ((447/1011)/1 + (435/1011)/1.08 +
PF = 1 – (1/((120/251)/1 + (112/251)/0.80 +
(129/1011)/1.41) = 0.07
(19/251)/0.60) = 0.14
a = 0.07 (1011) = 71
a(0) = 0.14 (251) = 35
* The risk estimates are taken from a study on perceived stress and ischemic heart disease in the Copenhagen City Heart Study, which has
previously been published. Reference: Nielsen NR, Kristensen TS, Prescott E, Strandberg Larsen K, Schnohr P, Grønbæk M. Perceived stress and
risk of ischemic heart disease: Causation or bias? Epidemiology 2006;17:391-397
** The risk estimates are taken from the study on perceived stress and breast cancer in the Copenhagen City Heart Study, which is included in
the dissertation. Reference: Nielsen NR, Zhang ZF, Kristensen TS, Netterstrøm B, Schnohr P, Grønbæk M. Self-reported stress and risk of breast
cancer. BMJ 2005;331:548.
Figure 12-1. Questionnaire used for the Perceived Stress Scale
The questions in this scale ask you about your feelings and thoughts during the last month. In each
case, you will be asked to indicate by circling how often you felt or thought a certain way.
0 = Never 1 = Almost Never 2 = Sometimes 3 = Fairly Often 4 = Very Often
1. In the last month, how often have you been upset
because of something that happened unexpectedly? ................................... 0
1
2
3
4
2. In the last month, how often have you felt that you were unable
to control the important things in your life?..................................................0
1
2
3
4
3. In the last month, how often have you felt nervous and “stressed”? ........... 0
1
2
3
4
4. In the last month, how often have you felt confident about your ability
to handle your personal problems? ............................................................... 0
1
2
3
4
5. In the last month, how often have you felt that things
were going your way?.................................................................................... 0
1
2
3
4
6. In the last month, how often have you found that you could not cope
with all the things that you had to do? .......................................................... 0
1
2
3
4
7. In the last month, how often have you been able
to control irritations in your life?................................................................... 0
1
2
3
4
8. In the last month, how often have you felt that you were on top of things?.. 0
1
2
3
4
9. In the last month, how often have you been angered
because of things that were outside of your control? .................................... 0
1
2
3
4
10. In the last month, how often have you felt difficulties
were piling up so high that you could not overcome them?......................... 0
1
2
3
4
135
XIII. Bibliography
1. Nielsen NR, Kjoller M, Kamper-Jorgensen F, Gronbaek MN. [Stress among
working population of Danes]. Ugeskr Laeger 2004;166:4155-60.
2. Reiche EM, Nunes SO, Morimoto HK. Stress, depression, the immune system,
and cancer. Lancet Oncol 2004;5:617-25.
3. Globocan 2002 [database on the internet]. Lyon: International Agency for
Research on Cancer [Cited 2006 October 10]. Available from: www.iarc.fr
4. Lukanova A, Lundin E, Micheli A, Arslan A, Ferrari P, Rinaldi S et al.
Circulating levels of sex steroid hormones and risk of endometrial cancer in
postmenopausal women. Int J Cancer 2004;108:425-32.
5. Kaaks R, Berrino F, Key T, Rinaldi S, Dossus L, Biessy C et al. Serum sex
steroids in premenopausal women and breast cancer risk within the European
Prospective Investigation into Cancer and Nutrition (EPIC). J Natl Cancer Inst
2005;97:755-65.
6. Missmer SA, Eliassen AH, Barbieri RL, Hankinson SE. Endogenous estrogen,
androgen, and progesterone concentrations and breast cancer risk among
postmenopausal women. J Natl Cancer Inst 2004;96:1856-65.
7. Singh S, Sheppard MC, Langman MJ. Sex differences in the incidence of
colorectal cancer: an exploration of oestrogen and progesterone receptors. Gut
1993;34:611-5.
8. Talamini R, Franceschi S, Dal Maso L, Negri E, Conti E, Filiberti R et al. The
influence of reproductive and hormonal factors on the risk of colon and rectal
cancer in women. Eur J Cancer 1998;34:1070-6.
9. Severi G, Morris HA, MacInnis RJ, English DR, Tilley W, Hopper JL et al.
Circulating steroid hormones and the risk of prostate cancer. Cancer Epidemiol
Biomarkers Prev 2006;15:86-91.
10. Rivier C. Luteinizing-hormone-releasing hormone, gonadotropins, and gonadal
steroids in stress. Ann N Y Acad Sci 1995;771:187-91.
11. Negro-Vilar A. Stress and other environmental factors affecting fertility in men
and women: overview. Environ Health Perspect 1993;101:59-64.
136
12. Breen KM, Karsch FJ. Does cortisol inhibit pulsatile luteinizing hormone
secretion at the hypothalamic or pituitary level? Endocrinology 2004;145:692-8.
13. Plante GE. Vascular response to stress in health and disease. Metabolism
2002;51:25-30.
14. Luecken LJ, Compas BE. Stress, coping, and immune function in breast cancer.
Ann Behav Med 2002;24:336-44.
15. Duijts SF, Zeegers MP, Borne BV. The association between stressful life events
and breast cancer risk: a meta-analysis. Int J Cancer 2003;107:1023-9.
16. Lazarus R. Stress and emotion. A new synthesis. London: Free Association
Books; 1999.
17. McEwen BS, Wingfield JC. The concept of allostasis in biology and
biomedicine. Horm Behav 2003;43:2-15.
18. Derogatis L. Self-reported measures of stress. In: Goldberger L, Breznitz S,
editors. Handbook on stress. Theoretical and clinical aspects. New York: The
Free Press; 1993. p. 200-33.
19. Soufer R, Arrighi JA, Burg MM. Brain, behavior, mental stress, and the
neurocardiac interaction. J Nucl Cardiol. 2002;9:650-62.
20. Moos R, Schaefer J. Coping resources and processes: current concepts and
measures. In: Goldberger L, Breznitz S, editors. Handbook of stress. Theoretical
and clinical aspects. New York: The Free Press; 1993. p. 234-57.
21. Appleyard M, Hansen AT, Schnohr P, Jensen G, Nyboe J. The Copenhagen City
Heart Study. A book of tables with data from the first examination (1976-78) and
a five year follow-up (1981-83). Scand J Soc Med 1989;170:1-160.
22. Greenland S, Pearl J, Robins JM. Causal diagrams for epidemiologic research.
Epidemiology 1999;10:37-48.
23. Parkin DM, Bray FI, Devesa SS. Cancer burden in the year 2000. The global
picture. Eur J Cancer 2001;37:S4-66.
24. Dalton SO, Boesen EH, Ross L, Schapiro IR, Johansen C. Mind and cancer. Do
psychological factors cause cancer? Eur J Cancer 2002;38:1313-23.
137
25. Bleiker EM, van der Ploeg HM. Psychosocial factors in the etiology of breast
cancer: review of a popular link. Patient Educ Couns 1999;37:201-14.
26. Gerits P. Life events, coping and breast cancer: state of the art. Biomed
Pharmacother 2000;54:229-33.
27. Petticrew M, Fraser J, Regan M. Adverse life-events and risk of breast cancer: A
meta-analysis. Br J Health Psychol 1999;4:1-17.
28. Hilakivi-Clarke L, Rowland J, Clarke R, Lippman ME. Psychosocial factors in
the development and progression of breast cancer. Breast Cancer Res Treat.
1994;29:141-60.
29. Garssen B. Psychological factors and cancer development: evidence after 30
years of research. Clin Psychol Rev 2004;24:315-38.
30. De Boer MF, Ryckman RM, Pruyn JF, Van den Borne HW. Psychosocial
correlates of cancer relapse and survival: a literature review. Patient Educ Couns
1999;37:215-30.
31. Holmes TH, Rahe RH. The Social Readjustment Rating Scale. J Psychosom Res
1967;11:213-8.
32. Karasek RA. Job demands, job decision latitude, and mental strain: Implications
for job redesign. Adm Sci Q 1979;24:285-308.
33. Burke MA, Goodkin K. Stress and the development of breast cancer: a persistent
and popular link despite contrary evidence. Cancer 1997;79:1055-9.
34. Cox T, Mackay C. Psychosocial factors and psychophysiological mechanisms in
the aetiology and development of cancers. Soc Sci Med 1982;16:381-96.
35. Jackson N, Waters E. Guidelines for systematic reviews in health promotion and
public health taskforce. Health Promot Int 2005;20:367-74.
36. Geyer S. Life events, chronic difficulties and vulnerability factors preceding
breast cancer. Soc Sci Med 1993;37:1545-55.
37. Geyer S. Life events prior to manifestation of breast cancer: a limited prospective
study covering eight years before diagnosis. J Psychosom Res 1991;35:355-63.
138
38. Chen CC, David AS, Nunnerley H, Michell M, Dawson JL, Berry H et al.
Adverse life events and breast cancer: case-control study. BMJ 1995;311:152730.
39. Price MA, Tennant CC, Butow PN, Smith RC, Kennedy SJ, Kossoff MB et al.
The role of psychosocial factors in the development of breast carcinoma: Part II.
Life event stressors, social support, defense style, and emotional control and their
interactions. Cancer 2001;91:686-97.
40. Ollonen P, Lehtonen J, Eskelinen M. Stressful and adverse life experiences in
patients with breast symptoms; a prospective case-control study in Kuopio,
Finland. Anticancer Res 2005;25:531-6.
41. Protheroe D, Turvey K, Horgan K, Benson E, Bowers D, House A. Stressful life
events and difficulties and onset of breast cancer: case-control study. BMJ
1999;319:1027-30.
42. Cooper CL, Faragher EB. Psychosocial stress and breast cancer: the interrelationship between stress events, coping strategies and personality. Psychol
Med 1993;23:653-62.
43. Schwarz R, Geyer S. Social and psychological differences between cancer and
noncancer patients: cause or consequence of the disease? Psychother Psychosom.
1984;41:195-9.
44. Li J, Johansen C, Hansen D, Olsen J. Cancer incidence in parents who lost a
child: a nationwide study in Denmark. Cancer 2002;95:2237-42.
45. Kvikstad A, Vatten LJ, Tretli S, Kvinnsland S. Widowhood and divorce related
to cancer risk in middle-aged women. A nested case-control study among
Norwegian women born between 1935 and 1954. Int J Cancer 1994;58:512-6.
46. Kvikstad A,.Vatten LJ. Risk and prognosis of cancer in middle-aged women who
have experienced the death of a child. Int J Cancer 1996;67:165-9.
47. Johansen C, Olsen JH. Psychological stress, cancer incidence and mortality from
non-malignant diseases. Br J Cancer 1997;75:144-8.
48. Levav I, Kohn R, Iscovich J, Abramson JH, Tsai WY, Vigdorovich D. Cancer
incidence and survival following bereavement. Am J Public Health
2000;90:1601-7.
49. Ewertz M. Bereavement and breast cancer. Br J Cancer 1986;53:701-3.
139
50. Jones DR, Goldblatt PO, Leon DA. Bereavement and cancer: some data on
deaths of spouses from the longitudinal study of Office of Population Censuses
and Surveys. BMJ (Clin Res Ed) 1984;289:461-4.
51. Hislop TG, Waxler NE, Coldman AJ, Elwood JM, Kan L. The prognostic
significance of psychosocial factors in women with breast cancer. J Chronic Dis
1987;40:729-35.
52. Achat H, Kawachi I, Byrne C, Hankinson S, Colditz G. A prospective study of
job strain and risk of breast cancer. Int J Epidemiol 2000;29:622-8.
53. Schernhammer ES, Hankinson SE, Rosner B, Kroenke CH, Willett WC, Colditz
GA et al. Job stress and breast cancer risk: the nurses' health study. Am J
Epidemiol 2004;160:1079-86.
54. Helgesson O, Cabrera C, Lapidus L, Bengtsson C, Lissner L. Self-reported stress
levels predict subsequent breast cancer in a cohort of Swedish women. Eur J
Cancer Prev 2003;12:377-81.
55. Kroenke CH, Hankinson SE, Schernhammer ES, Colditz GA, Kawachi I,
Holmes MD. Caregiving stress, endogenous sex steroid hormone levels, and
breast cancer incidence. Am J Epidemiol 2004;159:1019-27.
56. Lillberg K, Verkasalo PK, Kaprio J, Teppo L, Helenius H, Koskenvuo M. Stress
of daily activities and risk of breast cancer: a prospective cohort study in Finland.
Int J Cancer 2001;91:888-93.
57. Nielsen NR, Zhang ZF, Kristensen TS, Netterstrom B, Schnohr P, Gronbaek M.
Self reported stress and risk of breast cancer: prospective cohort study. BMJ
2005;331:548.
58. Jacobs JR, Bovasso GB. Early and chronic stress and their relation to breast
cancer. Psychol Med 2000;30:669-78.
59. Lillberg K, Verkasalo PK, Kaprio J, Teppo L, Helenius H, Koskenvuo M.
Stressful life events and risk of breast cancer in 10,808 women: a cohort study.
Am J Epidemiol 2003;157:415-23.
60. Barraclough J, Pinder P, Cruddas M, Osmond C, Taylor I, Perry M. Life events
and breast cancer prognosis. BMJ 1992;304:1078-81.
61. De Brabander B, Gerits P. Chronic and acute stress as predictors of relapse in
primary breast cancer patients. Patient Educ Couns 1999;37:265-72.
140
62. Forsen A. Psychosocial stress as a risk for breast cancer. Psychother Psychosom
1991;55:176-85.
63. Graham J, Ramirez A, Love S, Richards M, Burgess C. Stressful life experiences
and risk of relapse of breast cancer: observational cohort study. BMJ
2002;324:1420.
64. Schernhammer ES, Laden F, Speizer FE, Willett WC, Hunter DJ, Kawachi I et
al. Rotating night shifts and risk of breast cancer in women participating in the
nurses' health study. J Natl Cancer Inst 2001;93:1563-8.
65. Kune S, Kune GA, Watson LF, Rahe RH. Recent life change and large bowel
cancer. Data from the Melbourne Colorectal Cancer Study. J Clin Epidemiol
1991;44:57-68.
66. Courtney JG, Longnecker MP, Peters RK. Psychosocial aspects of work and the
risk of colon cancer. Epidemiology 1996;7:175-81.
67. Courtney JG, Longnecker MP, Theorell T, Gerhardsson V. Stressful life events
and the risk of colorectal cancer. Epidemiology 1993;4:407-14.
68. Spiegelman D, Wegman DH. Occupation-related risks for colorectal cancer. J
Natl Cancer Inst 1985;75:813-21.
69. Kojima M, Wakai K, Tokudome S, Tamakoshi K, Toyoshima H, Watanabe Y et
al. Perceived psychologic stress and colorectal cancer mortality: findings from
the Japan Collaborative Cohort Study. Psychosom Med 2005;67:72-7.
70. Hankinson S, Hunter D. Breast Cancer. In: Adami H, Hunter D, Trichopoulos D,
editors. Textbook of cancer epidemiology. New York: Oxford University Press;
2002. p. 301-39.
71. McEwen BS. Protective and damaging effects of stress mediators. N Engl J Med
1998;338:171-9.
72. Ferin M. Clinical review 105: Stress and the reproductive cycle. J Clin
Endocrinol Metab 1999;84:1768-74.
73. Olsen AH, Jensen A, Njor SH, Villadsen E, Schwartz W, Vejborg I et al. Breast
cancer incidence after the start of mammography screening in Denmark. Br J
Cancer 2003;88:362-5.
141
74. Olsen AH, Njor SH, Vejborg I, Schwartz W, Dalgaard P, Jensen MB et al. Breast
cancer mortality in Copenhagen after introduction of mammography screening:
cohort study. BMJ 2005;330:220.
75. The World Health Organization MONICA Project (monitoring trends and
determinants in cardiovascular disease): a major international collaboration.
WHO MONICA Project Principal Investigators. J Clin Epidemiol 1988;41:10514.
76. Halbreich U. Role of estrogen in postmenopausal depression. Neurology
1997;48:S16-S19.
77. Birkhauser M. Depression, menopause and estrogens: is there a correlation?
Maturitas 2002;41:S3-S8.
78. Amant F, Moerman P, Neven P, Timmerman D, Van Limbergen E, Vergote I.
Endometrial cancer. Lancet 2005;366:491-505.
79. Persson I, Adami H. Endometrial cancer. In: Adami H, Hunder D, Trichopoulos
D, editors. Textbook of cancer epidemiology. New York: Oxford University
Press; 2002. p. 359-77.
80. Gunin AG. Effect of chronic stress on estradiol action in the uterus of
ovariectomized rats. Eur J Obstet Gynecol Reprod Biol 1996;66:169-74.
81. Kam K, Park Y, Cheon M, Son GH, Kim K, Ryu K. Effects of immobilization
stress on estrogen-induced surges of luteinizing hormone and prolactin in
ovariectomized rats. Endocrine 2000;12:279-87.
82. Pitot H, Dragan Y. Chemical carcinogenesis. In: Klaassen C, editor. Toxicology:
the basic science of poisons. New York: McGraw-Hill; 2001. p. 241-320.
83. Warr P. The measurement of well-being and other aspects of mental-health. J
Occup Health 1990;63:193-210.
84. Cohen S, Kamarck T, Mermelstein R. A global measure of perceived stress. J
Health Soc Behav. 1983;24:385-96.
85. Helweg-Larsen K, Kjoller M, Davidsen M, Rasmussen NK, Madsen M. The
Danish National Cohort Study (DANCOS). Dan Med Bull 2003;50:177-80.
142
86. Viswanathan AN, Feskanich D, De Vivo I, Hunter DJ, Barbieri RL, Rosner B et
al. Smoking and the risk of endometrial cancer: results from the Nurses' Health
Study. Int J Cancer 2005;114:996-1001.
87. Kaaks R, Lukanova A, Kurzer MS. Obesity, endogenous hormones, and
endometrial cancer risk: a synthetic review. Cancer Epidemiol Biomarkers Prev
2002;11:1531-43.
88. Modugno F, Ness RB, Chen C, Weiss NS. Inflammation and endometrial cancer:
a hypothesis. Cancer Epidemiol Biomarkers Prev 2005;14:2840-7.
89. Gunin AG, Mashin IN, Zakharov DA. Proliferation, mitosis orientation and
morphogenetic changes in the uterus of mice following chronic treatment with
both estrogen and glucocorticoid hormones. J Endocrinol 2001;169:23-31.
90. Gunin A. Realization of estradiol effects in the uterus of ovariectomized rats
under acute stress. Eur J Obstet Gynecol Reprod Biol 1995;60:69-74.
91. Rabin DS, Johnson EO, Brandon DD, Liapi C, Chrousos GP. Glucocorticoids
inhibit estradiol-mediated uterine growth: possible role of the uterine estradiol
receptor. Biol Reprod 1990;42:74-80.
92. Weitz J, Koch M, Debus J, Hohler T, Galle PR, Buchler MW. Colorectal cancer.
Lancet 2005;365:153-65.
93. Wardle J, Gibson EL. Impact of stress on diet: processes and implications. In:
Stansfeld S, Marmot M, editors. Stress and the heart. Psychosocial pathways to
coronary heart disease. London: BMJ Books; 2002. p. 124-49.
94. Pohorecky LA. Stress and alcohol interaction: an update of human research.
Alcohol Clin Exp Res 1991;15:438-59.
95. Singh S, Sheppard MC, Langman MJ. Sex differences in the incidence of
colorectal cancer: an exploration of oestrogen and progesterone receptors. Gut
1993;34:611-5.
96. Di Domenico M, Castoria G, Bilancio A, Migliaccio A, Auricchio F. Estradiol
activation of human colon carcinoma-derived Caco-2 cell growth. Cancer Res
1996;56:4516-21.
97. Fiorelli G, Picariello L, Martineti V, Tonelli F, Brandi ML. Functional estrogen
receptor beta in colon cancer cells. Biochem Biophys Res Commun
1999;261:521-7.
143
98. Singh S, Langman MJ. Oestrogen and colonic epithelial cell growth. Gut
1995;37:737-9.
99. Newcomb PA, Solomon C, White E. Tamoxifen and risk of large bowel cancer
in women with breast cancer. Breast Cancer Res Treat 1999;53:271-7.
100. Travis LB, Curtis RE, Storm H, Hall P, Holowaty E, Van Leeuwen FE et al. Risk
of second malignant neoplasms among long-term survivors of testicular cancer. J
Natl Cancer Inst 1997;89:1429-39.
101. Littman AJ, White E, Satia JA, Bowen DJ, Kristal AR. Reliability and validity of
2 single-item measures of psychosocial stress. Epidemiology 2006;17:398-403.
102. Truelsen T, Nielsen N, Boysen G, Gronbaek M. Self-reported stress and risk of
stroke: the Copenhagen City Heart Study. Stroke 2003;34:856-62.
103. Nielsen NR, Kristensen TS, Prescott E, Larsen KS, Schnohr P, Gronbaek M.
Perceived Stress and Risk of Ischemic Heart Disease: Causation or Bias?
Epidemiology 2006;17:391-7.
104. Savitz D. Interpreting epidemiologic evidence. Strategies for study design and
analysis. New York: Oxford University Press; 2003.
105. Stratakis CA, Chrousos GP. Neuroendocrinology and pathophysiology of the
stress system. Ann N Y Acad Sci 1995;771:1-18.
106. Kudielka BM, Kirschbaum C. Sex differences in HPA axis responses to stress: a
review. Biol Psychol 2005;69:113-32.
107. Boyd DB. Insulin and cancer. Integr Cancer Ther 2003;2:315-29.
108. Monnikes H, Tebbe JJ, Hildebrandt M, Arck P, Osmanoglou E, Rose M et al.
Role of stress in functional gastrointestinal disorders. Evidence for stressinduced alterations in gastrointestinal motility and sensitivity. Dig Dis
2001;19:201-11.
109. Hsing AW, Tsao L, Devesa SS. International trends and patterns of prostate
cancer incidence and mortality. Int J Cancer 2000;85:60-7.
110. Schwartz KL, Crossley-May H, Vigneau FD, Brown K, Banerjee M. Race,
socioeconomic status and stage at diagnosis for five common malignancies.
Cancer Causes Control 2003;14:761-6.
144
111. Gilligan T. Social disparities and prostate cancer: mapping the gaps in our
knowledge. Cancer Causes Control 2005;16:45-53.
112. Dutta RS, Philip J, Javle P. Trends in prostate cancer incidence and survival in
various socioeconomic classes: a population-based study. Int J Urol
2005;12:644-53.
113. Lund Nilsen TI, Johnsen R, Vatten LJ. Socio-economic and lifestyle factors
associated with the risk of prostate cancer. Br J Cancer 2000;82:1358-63.
114. Pukkala E, Weiderpass E. Socio-economic differences in incidence rates of
cancers of the male genital organs in Finland, 1971-95. Int J Cancer
2002;102:643-8.
115. Riman T, Nilsson S, Persson IR. Review of epidemiological evidence for
reproductive and hormonal factors in relation to the risk of epithelial ovarian
malignancies. Acta Obstet.Gynecol.Scand. 2004;83:783-95.
116. Thomas M, Thomas J. Toxic responses of the reproductive system. In: Klaassen
C, editor. Toxicology: The basic science of poisons. New York: McGraw-Hill;
2001. p. 673-710.
117. Di Leo A, Messa C, Cavallini A, Linsalata M. Estrogens and colorectal cancer.
Curr Drug Targets Immune Endocr Metabol Disord 2001;1:1-12.
118. Christensen S, Anglov J, Christensen J, Olsen E, Poulsen O. Application of a
new AMIQAS computer program for integrated quality control, method
evaluation and proficiency testing. Fresen J Anal Chem 1993;345:343-50.
119. Westgard JO, Barry PL, Hunt MR, Groth T. A multi-rule Shewhart chart for
quality control in clinical chemistry. Clin Chem 1981;27:493-501.
120. Hankinson SE, Willett WC, Manson JE, Hunter DJ, Colditz GA, Stampfer MJ et
al. Alcohol, height, and adiposity in relation to estrogen and prolactin levels in
postmenopausal women. J Natl Cancer Inst 1995;87:1297-302.
121. Kley HK, Schlaghecke R, Kruskemper HL. Stability of steroids in plasma over a
10-year period. J Clin Chem Clin Biochem 1985;23:875-8.
122. Bolelli G, Muti P, Micheli A, Sciajno R, Franceschetti F, Krogh V et al. Validity
for epidemiological studies of long-term cryoconservation of steroid and protein
hormones in serum and plasma. Cancer Epidemiol Biomarkers Prev 1995;4:50913.
145
123. Cancer Registry [homepage on the internet]. Copenhagen: Danish National
Board of Health [cited 2007 January 15]. Available from: www.sst.dk
124. Greenland S, Morgenstern H. Confounding in health research. Annu Rev Public
Health 2001;22:189-212.
125. Stein M, Miller A. Stress, the immune system, and health and illness. In
Goldberger L, Breznitz S, eds. Handbook on stress. Theoretical and clinical
aspects, pp 127-41. New York: The Free Press, 1993.
126. Rosengren A, Hawken S, Ounpuu S, Sliwa K, Zubaid M, Almahmeed WA et al.
Association of psychosocial risk factors with risk of acute myocardial infarction
in 11119 cases and 13648 controls from 52 countries (the INTERHEART study):
case-control study. Lancet 2004;364:953-62.
127. Rosengren A, Tibblin G, Wilhelmsen L. Self-perceived psychological stress and
incidence of coronary artery disease in middle-aged men. Am J Cardiol
1991;68:1171-5.
128. Iso H, Date C, Yamamoto A, Toyoshima H, Tanabe N, Kikuchi S et al.
Perceived mental stress and mortality from cardiovascular disease among
Japanese men and women: the Japan Collaborative Cohort Study for Evaluation
of Cancer Risk Sponsored by Monbusho (JACC Study). Circulation
2002;106:1229-36.
129. Pohorecky LA. Interaction of alcohol and stress at the cardiovascular level.
Alcohol 1990;7:537-46.
130. Bhui K. Physical activity and stress. In Stansfeld S, Marmot M, eds. Stress and
the heart. Psychosocial pathways to coronary heart disease, pp 158-67. London:
BMJ books, 2002.
131. Jarvis M. Smoking and stress. In Stansfeld S, Marmot M, eds. Stress and the
heart. Psychosocial pathways to coronary heart disease, pp 150-7. London: BMJ
books, 2002.
132. Marsland A, Bachen E, Cohen S, Manuck S. Stress, immunity, and susceptibility
to infectious disease. In: Baum A, Revenson T, Singer J, editors. Handbook of
health psychology. Mahwah, NJ: Erlbaum; 2001.
133. Rugulies R, Bultmann U, Aust B, Burr H. Psychosocial Work Environment and
Incidence of Severe Depressive Symptoms: Prospective Findings from a 5-Year
146
Follow-up of the Danish Work Environment Cohort Study. Am J Epidemiol
2006;16:877-87
134. Wang J, Patten SB. Perceived work stress and major depression in the Canadian
employed population, 20-49 years old. J Occup Health Psychol 2001;6:283-9.
135. Rozanski A, Blumenthal JA, Kaplan J. Impact of psychological factors on the
pathogenesis of cardiovascular disease and implications for therapy. Circulation
1999;99:2192-217.
136. Cohen S, Williamson GM. Perceived stress in a probability sample of the United
States. In: Spacapan OS, editor. The social psychology of health. Newbury Park:
Sage; 1988.
147