Self reported stress and risk of breast cancer: prospective cohort stu
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《英国医生杂志》
1 National Institute of Public Health, ?ster Farimagsgade 5A, DK-1399 Copenhagen K, Denmark, 2 Department of Epidemiology, UCLA School of Public Health, Los Angeles, CA, USA, 3 National Institute of Occupational Health, Copenhagen, 4 Clinic of Occupational Medicine, Hiller?d Hospital, Hiller?d, Denmark, 5 Copenhagen City Heart Study, Epidemiological Research Unit, Bispebjerg University Hospital, Copenhagen
Correspondence to: N R Nielsen nrn@niph.dk
Objective To assess the relation between self reported intensity and frequency of stress and first time incidence of primary breast cancer.
Design Prospective cohort study with 18 years of follow-up.
Setting Copenhagen City heart study, Denmark.
Participants The 6689 women participating in the Copenhagen City heart study were asked about their perceived level of stress at baseline in 1981-3. These women were followed until 1999 in the Danish nationwide cancer registry, with < 0.1% loss to follow-up.
Main outcome measure First time incidence of primary breast cancer.
Results During follow-up 251 women were diagnosed with breast cancer. After adjustment for confounders, women with high levels of stress had a hazard ratio of 0.60 (95% confidence interval 0.37 to 0.97) for breast cancer compared with women with low levels of stress. Furthermore, for each increase in stress level on a six point stress scale an 8% lower risk of primary breast cancer was found (hazard ratio 0.92, 0.85 to 0.99). This association seemed to be stable over time and was particularly pronounced in women receiving hormone therapy.
Conclusion High endogenous concentrations of oestrogen are a known risk factor for breast cancer, and impairment of oestrogen synthesis induced by chronic stress may explain a lower incidence of breast cancer in women with high stress. Impairment of normal body function should not, however, be considered a healthy response, and the cumulative health consequences of stress may be disadvantageous.
Breast cancer is the most common cancer in women in terms of both incidence and prevalence.1 It is a hormone dependent disease with a clear positive relation to high endogenous concentrations of oestrogen.2 The role of stress in the aetiology of breast cancer has been an area of emerging interest, partly because of the ability of stress to affect the hormonal system and especially oestrogen synthesis.3-7 A potential relation between stress and risk of breast cancer has been examined in studies with different designs and with conflicting results.8-15 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,9-11 13 but less attention has been given to the effect of perceived daily stress.12 14 15 Prolonged low key stress of everyday life results in a persistent activation of stress hormones, which may impair oestrogen synthesis,16 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 behaviour. This study provides an important opportunity to explore the impact of everyday stress on the long term risk of first time incidence of primary breast cancer among 6689 women prospectively followed up for 18 years.
Methods
Study population—The Copenhagen City heart study is a longitudinal study initiated in 1976. An age stratified random sample of 19 698 Danish men and women were invited to participate. All participants gave written informed consent. In 1981-3 the same population had additional examinations. The second examination of 7018 women included questions on stress and is therefore used as baseline for the study reported here. The response rate was 70%. We excluded women with breast cancer before baseline (n = 120) or lacking information on stress or other covariates (n = 209), leaving 6689 women. Twenty six (< 0.1%) women were lost to follow-up. A detailed description of the Copenhagen City heart study has previously been published.17
Everyday stress—The study participants were asked about their level of stress in terms of intensity and frequency. In the questionnaire, stress was exemplified as the sensation of tension, nervousness, impatience, anxiety, or sleeplessness. Participants were asked to report their stress intensity as none (0), light (1), moderate (2), or high (3). Frequency of stress was reported as never/hardly ever (0), monthly (1), weekly (2), or daily (3).18 We added the scores of the two questions and combined them into a continuous stress score from 0 to 6. We categorised the stress score into low (0-1 points), medium (2-4 points), and high (5-6 points) stress in order to examine differences in incidence of breast cancer for low and high levels of stress.
Covariates—We considered the following variables as potential confounders for the analyses: 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).
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 = 2224), emigration (n = 26), or the end of follow-up on 31 December 1999 (n = 4188). 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.
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 according to the "change in estimate" method,19 with a cut-off point of 5% change, to adjust for potential confounding from baseline covariates. We used trend analyses to assess dose-response relations between stress and breast cancer. We did a 2 test for goodness of fit before including any variables as continuous and also used it to test for linear trends. To estimate the effect of prolonged follow-up, we assessed the association in the first and last nine years of follow-up. Finally, we did subgroup analyses to assess potential effect modification.
Results
Baseline characteristics—Mean age at baseline was 57 (range 21-91) years. Ten per cent of the women reported high levels of stress (table 1). Mean age, number of children, and body mass index were 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 were 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 (n = 261, 39.3%) than in the medium stress (n = 972, 30.4%) or low stress group (n = 991, 35.1%) died during follow-up.
Table 1 Baseline characteristics of women participating in the second examination of the Copenhagen City heart study in 1981-3. Values are numbers (percentages) unless stated otherwise
Stress intensity, stress frequency, and risk of breast cancer—Seven per cent 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 2).
Table 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
Stress score and risk of breast cancer—After adjustment for potential confounders, an 8% reduction (hazard ratio 0.92, 95% confidence interval 0.85 to 0.99) in risk of primary breast cancer occurred for each increase in stress level on the six point stress scale (table 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.
Table 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
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 4). Sixteen per cent (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). The P value for effect modification 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).
Table 4 Incidence and hazard ratio of primary breast cancer associated with categorised stress score among 6689 Danish women participating in the Copenhagen City heart study in 1981-3, according to time period of follow-up
Table 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
Discussion
Parkin DM, Bray FI, Devesa SS. Cancer burden in the year 2000: the global picture. Eur J Cancer 2001;37: S4-66.
Hankinson S, Hunter D. Breast cancer. In: Adami H, Hunder D, Trichopoulos D, eds. Textbook of cancer epidemiology. New York: Oxford University Press, 2002: 301-39.
Rivier C. Luteinizing-hormone-releasing hormone, gonadotropins, and gonadal steroids in stress. Ann N Y Acad Sci 1995;771: 187-91.
Sapolsky R. Sex and reproduction. In: Sapolsky R, ed. Why zebras don't get ulcers. New York: W H Freeman and Company, 1998: 101-25.
Negro-Vilar A. Stress and other environmental factors affecting fertility in men and women: overview. Environ Health Perspect 1993;101: 59-64.
Breen KM, Karsch FJ. Does cortisol inhibit pulsatile luteinizing hormone secretion at the hypothalamic or pituitary level? Endocrinology 2004;145: 692-8.
McEwen BS. Protective and damaging effects of stress mediators. N Engl J Med 1998;338: 171-9.
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.
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.
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.
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.
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.
Johansen C, Olsen JH. Psychological stress, cancer incidence and mortality from non-malignant diseases. Br J Cancer 1997;75: 144-8.
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.
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.
Ferin M. Clinical review 105: stress and the reproductive cycle. J Clin Endocrinol Metab 1999;84: 1768-74.
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.
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.
Greenland S, Rothman K. Introduction to stratified analysis. In: Rothman K, Greenland S, eds. Modern epidemiology. Philadelphia: Lippincott Williams & Wilkins, 1998: 253-300.
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.
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.
Halbreich U. Role of estrogen in postmenopausal depression. Neurology 1997;48: S16-9.
Birkhauser M. Depression, menopause and estrogens: is there a correlation? Maturitas 2002;41: S3-8.(Naja Rod Nielsen, student and research a)
Correspondence to: N R Nielsen nrn@niph.dk
Objective To assess the relation between self reported intensity and frequency of stress and first time incidence of primary breast cancer.
Design Prospective cohort study with 18 years of follow-up.
Setting Copenhagen City heart study, Denmark.
Participants The 6689 women participating in the Copenhagen City heart study were asked about their perceived level of stress at baseline in 1981-3. These women were followed until 1999 in the Danish nationwide cancer registry, with < 0.1% loss to follow-up.
Main outcome measure First time incidence of primary breast cancer.
Results During follow-up 251 women were diagnosed with breast cancer. After adjustment for confounders, women with high levels of stress had a hazard ratio of 0.60 (95% confidence interval 0.37 to 0.97) for breast cancer compared with women with low levels of stress. Furthermore, for each increase in stress level on a six point stress scale an 8% lower risk of primary breast cancer was found (hazard ratio 0.92, 0.85 to 0.99). This association seemed to be stable over time and was particularly pronounced in women receiving hormone therapy.
Conclusion High endogenous concentrations of oestrogen are a known risk factor for breast cancer, and impairment of oestrogen synthesis induced by chronic stress may explain a lower incidence of breast cancer in women with high stress. Impairment of normal body function should not, however, be considered a healthy response, and the cumulative health consequences of stress may be disadvantageous.
Breast cancer is the most common cancer in women in terms of both incidence and prevalence.1 It is a hormone dependent disease with a clear positive relation to high endogenous concentrations of oestrogen.2 The role of stress in the aetiology of breast cancer has been an area of emerging interest, partly because of the ability of stress to affect the hormonal system and especially oestrogen synthesis.3-7 A potential relation between stress and risk of breast cancer has been examined in studies with different designs and with conflicting results.8-15 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,9-11 13 but less attention has been given to the effect of perceived daily stress.12 14 15 Prolonged low key stress of everyday life results in a persistent activation of stress hormones, which may impair oestrogen synthesis,16 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 behaviour. This study provides an important opportunity to explore the impact of everyday stress on the long term risk of first time incidence of primary breast cancer among 6689 women prospectively followed up for 18 years.
Methods
Study population—The Copenhagen City heart study is a longitudinal study initiated in 1976. An age stratified random sample of 19 698 Danish men and women were invited to participate. All participants gave written informed consent. In 1981-3 the same population had additional examinations. The second examination of 7018 women included questions on stress and is therefore used as baseline for the study reported here. The response rate was 70%. We excluded women with breast cancer before baseline (n = 120) or lacking information on stress or other covariates (n = 209), leaving 6689 women. Twenty six (< 0.1%) women were lost to follow-up. A detailed description of the Copenhagen City heart study has previously been published.17
Everyday stress—The study participants were asked about their level of stress in terms of intensity and frequency. In the questionnaire, stress was exemplified as the sensation of tension, nervousness, impatience, anxiety, or sleeplessness. Participants were asked to report their stress intensity as none (0), light (1), moderate (2), or high (3). Frequency of stress was reported as never/hardly ever (0), monthly (1), weekly (2), or daily (3).18 We added the scores of the two questions and combined them into a continuous stress score from 0 to 6. We categorised the stress score into low (0-1 points), medium (2-4 points), and high (5-6 points) stress in order to examine differences in incidence of breast cancer for low and high levels of stress.
Covariates—We considered the following variables as potential confounders for the analyses: 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).
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 = 2224), emigration (n = 26), or the end of follow-up on 31 December 1999 (n = 4188). 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.
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 according to the "change in estimate" method,19 with a cut-off point of 5% change, to adjust for potential confounding from baseline covariates. We used trend analyses to assess dose-response relations between stress and breast cancer. We did a 2 test for goodness of fit before including any variables as continuous and also used it to test for linear trends. To estimate the effect of prolonged follow-up, we assessed the association in the first and last nine years of follow-up. Finally, we did subgroup analyses to assess potential effect modification.
Results
Baseline characteristics—Mean age at baseline was 57 (range 21-91) years. Ten per cent of the women reported high levels of stress (table 1). Mean age, number of children, and body mass index were 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 were 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 (n = 261, 39.3%) than in the medium stress (n = 972, 30.4%) or low stress group (n = 991, 35.1%) died during follow-up.
Table 1 Baseline characteristics of women participating in the second examination of the Copenhagen City heart study in 1981-3. Values are numbers (percentages) unless stated otherwise
Stress intensity, stress frequency, and risk of breast cancer—Seven per cent 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 2).
Table 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
Stress score and risk of breast cancer—After adjustment for potential confounders, an 8% reduction (hazard ratio 0.92, 95% confidence interval 0.85 to 0.99) in risk of primary breast cancer occurred for each increase in stress level on the six point stress scale (table 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.
Table 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
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 4). Sixteen per cent (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). The P value for effect modification 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).
Table 4 Incidence and hazard ratio of primary breast cancer associated with categorised stress score among 6689 Danish women participating in the Copenhagen City heart study in 1981-3, according to time period of follow-up
Table 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
Discussion
Parkin DM, Bray FI, Devesa SS. Cancer burden in the year 2000: the global picture. Eur J Cancer 2001;37: S4-66.
Hankinson S, Hunter D. Breast cancer. In: Adami H, Hunder D, Trichopoulos D, eds. Textbook of cancer epidemiology. New York: Oxford University Press, 2002: 301-39.
Rivier C. Luteinizing-hormone-releasing hormone, gonadotropins, and gonadal steroids in stress. Ann N Y Acad Sci 1995;771: 187-91.
Sapolsky R. Sex and reproduction. In: Sapolsky R, ed. Why zebras don't get ulcers. New York: W H Freeman and Company, 1998: 101-25.
Negro-Vilar A. Stress and other environmental factors affecting fertility in men and women: overview. Environ Health Perspect 1993;101: 59-64.
Breen KM, Karsch FJ. Does cortisol inhibit pulsatile luteinizing hormone secretion at the hypothalamic or pituitary level? Endocrinology 2004;145: 692-8.
McEwen BS. Protective and damaging effects of stress mediators. N Engl J Med 1998;338: 171-9.
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.
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.
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.
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.
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.
Johansen C, Olsen JH. Psychological stress, cancer incidence and mortality from non-malignant diseases. Br J Cancer 1997;75: 144-8.
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.
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.
Ferin M. Clinical review 105: stress and the reproductive cycle. J Clin Endocrinol Metab 1999;84: 1768-74.
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.
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.
Greenland S, Rothman K. Introduction to stratified analysis. In: Rothman K, Greenland S, eds. Modern epidemiology. Philadelphia: Lippincott Williams & Wilkins, 1998: 253-300.
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.
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.
Halbreich U. Role of estrogen in postmenopausal depression. Neurology 1997;48: S16-9.
Birkhauser M. Depression, menopause and estrogens: is there a correlation? Maturitas 2002;41: S3-8.(Naja Rod Nielsen, student and research a)