Caregiving Stress, Endogenous Sex Steroid Hormone Levels, and Breast Cancer Incidence

Candyce H. Kroenke1 , Susan E. Hankinson1,2, Eva S. Schernhammer1, Graham A. Colditz1,2, Ichiro Kawachi1,3 and Michelle D. Holmes1

1 Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA.
2 Department of Epidemiology, Harvard School of Public Health, Boston, MA.
3 Department of Health and Social Behavior, Harvard School of Public Health, Boston, MA.

Received for publication September 15, 2003; accepted for publication December 30, 2003.


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Stress is hypothesized to be a risk factor for breast cancer. The authors examined associations of hours of, and self-reported levels of stress from, informal caregiving with prospective breast cancer incidence. Cross-sectional analyses of caregiving and endogenous sex steroid hormones were also conducted. In 1992 or 1996, 69,886 US women from the Nurses’ Health Study, aged 46–71 years at baseline, answered questions on informal caregiving; 1,700 incident breast cancer cases accrued over follow-up to 2000. A subset of 665 postmenopausal women not taking exogenous hormones returned a blood sample in 1990. Numbers of hours of care provided to an ill adult or to a child were each summed and analyzed as 0 (reference), 1–14, and >=15 per week. Cox proportional hazards models were used in prospective analyses and linear models in cross-sectional analyses. High numbers of caregiving hours and self-reported stress did not predict a higher incidence of breast cancer. However, compared with women providing no adult care, women providing >=15 hours of adult care (median, 54) had significantly lower levels of estradiol (geometric mean, 9.21 pg/ml vs. 7.46 pg/ml (95% confidence interval: 6.36, 8.76)) and bioavailable estradiol (geometric mean, 1.86 pg/ml vs. 1.35 pg/ml (95% confidence interval: 1.00, 1.82)). Stress from caregiving did not appear to increase breast cancer risk.

breast neoplasms; caregivers; cohort studies; gonadal steroid hormones; stress, psychological


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Psychosocial stress has long been implicated in the development of breast cancer, although the empirical findings have been mixed (18). Most studies of stress and cancer risk have measured stress in terms of specific adverse life events (bereavement, job loss, divorce, disasters, or family illness or death) (9), but a meta-analysis by Petticrew et al. (10) concluded that recent adverse life events are not causative factors in the development of breast cancer. However, adverse life events differ from daily chronic stressors that may persist indefinitely (11). One study examining both acute and chronic stress found that chronic stress, but not acute stress, was related to breast cancer relapse (12).

Caregiving has been reported to be stressful (1315). Stress associated with caregiving can persist indefinitely and may have pronounced effects on health (1618). No prior study, to the authors’ knowledge, has examined stress from informal caregiving activities and cancer risk. Therefore, we hypothesized that chronic stress from prolonged, full-time, informal caregiving would be prospectively associated with an increased risk of breast cancer. Because subjective response to stress may be as or more relevant than the objective stressor to outcomes (19), we further hypothesized that high self-reported stress from caregiving would predict a higher risk of breast cancer. We also hypothesized that other potential psychosocial stressors such as full-time work, social isolation, and depressive symptoms would exacerbate the effects of caregiving stress on the rate of cancer incidence.

Endogenous reproductive hormones have been strongly implicated in the etiology of breast cancer; prospective studies of postmenopausal women show an increased risk with elevated estrogen levels (2022). Consistent with the above hypotheses, we hypothesized that women provid-ing high levels of caregiving would have higher levels of estrogens.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Nurses’ Health Study subjects and blood sample collection
The Nurses’ Health Study is a longitudinal study of 121,700 US female nurses, 30–55 years of age at baseline in 1976. At baseline and during biennial follow-up periods, participants provided detailed lifestyle and medical history information through a mailed questionnaire.

We included in this study women who answered questions on informal caregiving activities in 1992 or 1996. Women with prior cancer (n = 9,274) and cardiovascular disease (myocardial infarction, angina, stroke) (n = 6,080) were excluded from the study.

To ensure the proper time order between exposure and outcome, we attempted to exclude fatal breast cancer cases between 1992 and 1996; however, after other exclusions, no women with incident breast cancer died from the disease within this 4-year period. After exclusions, 55,395 women, aged 46–71 years in 1992, were included in the analysis (table 1). Of these women, 759 were diagnosed with breast cancer between 1992 and 1996.


View this table:
[in this window]
[in a new window]
 
TABLE 1. Selected characteristics, by categories of caregiving hours in 1992, of 55,395 women* from the US Nurses’ Health Study
 
For analyses with follow-up from 1996 to 2000, we also excluded 2,590 women who had cancer between 1992 and 1996, 2,172 women who had cardiovascular disease, 811 women who died in the interim, and two women who were diagnosed with breast cancer after 1996 and died within the 4-year follow-up period. A remaining 55,430 women were included in analyses, and 941 were diagnosed with invasive breast cancer between returning the 1996 questionnaire and June 2000. In total, 69,886 women were included in the study, and 1,700 new cases of primary invasive breast cancer accrued between 1992 and 2000.

Women included in the analysis of endogenous hormones (n = 665) were controls in a nested case-control study of plasma hormone levels and breast cancer risk and responded to questions on informal caregiving in 1992 (23). Women included were postmenopausal (no menses for at least 12 months before blood sampling) and had not used hormones for at least 3 months before the blood collection. Participants had no previously diagnosed cancer (except nonmelanoma skin cancer).

Data collection
Blood samples were collected in 1989–1990 from 32,826 Nurses’ Health Study participants 43–69 years of age at the time, as detailed previously (2426). Hormone levels for the plasma samples used in this analysis were assayed in four batches between 1990 and 1998.

We further measured hours of informal caregiving (unrelated to participants’ paid work as nurses) and self-reported caregiving stress. In 1992 and 1996, Nurses’ Health Study participants were asked how many hours per week they provided care for each of specific categories of kin including children, grandchildren, a disabled or ill spouse, a disabled or ill parent, or another disabled or ill person. Participants could respond that they provided care for each person 0 (reference category), 1–8, 9–20, 21–35, 36–72, or 73 or more hours per week.

Participants were further asked, "How stressful would you say it is to provide care to the individuals mentioned above?" Choices included not applicable, not at all, just a little bit, moderately, extremely, and don’t know.

In 1992 and 1996, depressive symptoms were assessed by using the five-item Mental Health Index (MHI-5) from the Medical Outcomes Study Short-Form 36 (SF-36) Health Status Survey. A score of 52 or less (on a scale of 0–100) on the short-form mental health scale was used to define the group with depressive symptoms (27). Social networks were measured by using the Berkman-Syme Social Networks Index (28). Responses to this index were categorized into four levels of social connection from low to high (29). Participants were also asked about their working status, indicating whether they were employed full time or part time (as a nurse or in another profession), worked as a homemaker, or were retired.

Data on other biomedical, lifestyle, and hormonal factors have also been assessed, including age, alcohol consumption, body mass index, physical activity, husband’s education, recent mammography, family history of breast cancer, benign breast disease, past oral contraceptive use, age at menarche, age at first birth, parity, age at menopause, type of menopause, and postmenopausal hormone use. We controlled for these variables in multivariate-adjusted analyses.

In the Nurses’ Health Study, incident breast cancer was ascertained by a biennial mailing of the questionnaire to participants. For any report of cancer (except basal cell skin cancer), written permission was obtained from study participants to review their medical records. Physicians, blinded to exposure information from questionnaires, subsequently reviewed medical records and pathology reports. Overall, 99 percent of self-reported breast cancers for which medical records are obtained have been confirmed.

Ascertainment of deaths in the Nurses’ Health Study cohort has included reporting by the family or postal authorities. Additionally, names of persistent nonresponders are searched in the National Death Index. More than 98 percent of deaths in the Nurses’ Health Study cohort have been identified by this method (30).

Laboratory analysis
Hormone fractions of estradiol, estrone, estrone sulfate, and testosterone were assayed in four different batches. Estrone sulfate from batches 1 and 2 was assayed in the laboratory of Dr. C. Longcope (University of Massachusetts Medical Center, Worcester, Massachusetts). All other analyses were performed by the Nichols Institute (San Juan Capistrano, California). Methods for plasma hormone assays and detailed information regarding laboratory precision and reproducibility have been published previously (23, 31, 32). Within-batch laboratory coefficients of variation were all 15 percent or less.

Statistical analyses
To obtain continuous caregiving hours for each kin group, the numerical values 0, 4.5, 14.5, 28, 54, and 73 were assigned to the respective categorical responses mentioned above (0, 1–8, 9–20, 21–25, 36–72, and >=73 hours per week). Total hours of care provided to an ill adult were then obtained by summing numbers of hours of informal care given to an ill spouse, parent, or other adult. Total hours of care provided to a child were correspondingly obtained by summing numbers of hours of informal care given to a child or grandchild. For categorical analyses of these new variables, continuous variables were collapsed to 0, 1–14, and 15 or more hours. We chose these categories because of the low frequency of women indicating more than 15 hours of caregiving per week.

When exploring combined effects of stress and other variables, hours were categorized as 0 and as more than 0 per week in stratified analyses. Social networks were divided into high networks (top two categories) and low networks (bottom two categories). We also computed the change in social networks between 1992 and 1996 and created three categories: declining networks, stable networks, and improving networks. Work status was collapsed to full-time work and other.

Different types of caregiving may have differential effects on health (33) and on stress levels. Therefore, we analyzed adult and child caregiving separately, adjusting simultaneously for numbers of adult and child caregiving hours. Furthermore, hours of care provided to different kinship groups (children, grandchildren, parent, spouse, other) were analyzed simultaneously in models.

We used Cox proportional hazards models (the SAS PROC PHREG procedure) (34) for failure-time data to simultaneously calculate point and interval estimates of hazard rate ratios for more than one exposure variable of interest and to evaluate and quantify interaction terms (35, 36). Person-months of follow-up were counted from the date a psychosocial questionnaire was returned (in 1992 or 1996) until the date of death, breast cancer event, or age at end of follow-up, whichever came first. Relative risk estimates were obtained by exponentiation of the fitted ß to a particular model; 95 percent confidence intervals were obtained by exponentiation of the 95 percent confidence bounds of ß. Departures from the proportional hazards assumption were tested by using likelihood ratio tests comparing models with and without the time-by-covariate interaction terms.

Because the latency period of a stress exposure is unknown, we first conducted analyses by assigning the most recent exposure status to subsequent outcomes (1992 caregiving with outcomes between 1992 and 1996, and 1996 caregiving with outcomes between 1996 and 2000). We subsequently conducted a lagged analysis of 1992 caregiving with breast cancer between 1996 and 2000. To evaluate whether chronic stress from caregiving was the relevant exposure, 1996–2000 cancer outcomes were regressed on cumulative exposure assessed as the average number of hours of adult or child caregiving provided in 1992 and 1996. This approach has the further advantage of reducing random error in the exposure (37).

We further regressed outcomes on self-reported stress from child or adult caregiving responsibilities represented in terms of indicator variables, collapsed to the following categories: not providing any care (reference); not at all or just a little bit stressful; moderately or extremely stressful; and missing, not applicable, or don’t know. We also explored stratified associations by levels of self-reported stress—high and moderate versus little or none.

In additional models, we stratified by levels of social networks, depressive symptoms, and employment status to examine possible effect modification. Interaction terms were computed for linear hours and the dichotomous versions of each of these variables. Because social support may be an important buffer of the stress response (38, 39), we also compared whether change in social support (increasing, decreasing, or staying the same), adjusted for baseline social support, buffered the association between caregiving hours and breast cancer outcome.

Age and age at menopause were analyzed continuously in models. Age-adjusted results were compared with those obtained by adjusting for multiple reproductive, lifestyle, and psychosocial factors (table 2). We also adjusted for birth index, a variable developed by Colditz and Rosner (40). The birth index =


View this table:
[in this window]
[in a new window]
 
TABLE 2. Relative risk (95% confidence interval) of incident breast cancer, by categories of caregiving hours, for 69,886 women* from the US Nurses’ Health Study
 
,

where t* = minimum(age, age at menopause); ti = age at the ith birth; i = 1, ..., s; and bit = 1 if parity >=i at age t or 0 otherwise. Adjustment for this variable enables fine adjustment for parity and age at each birth with the inclusion of a single, continuous variable.

To include women for whom information was missing and to reduce bias, we used the Greenland and Finkle (41) regression method in analyses of certain continuous caregiving variables and for continuously analyzed reproductive covariates. Missing values were assigned an arbitrary value, and a missing-value indicator was created; it took the value 1 wherever the original variable was missing and 0 otherwise. An advantage of this method is an improved ability to adjust for potential confounding. For categorical covariates, we also created indicator variables to represent missing covariate information.

For hormonal biomarker values that were less than the limit of sensitivity, we reset values to minimum plausible levels (estrone = 5, estrone sulfate = 20, testosterone = 1, progesterone = 1.5). Then, using linear regression (the SAS PROC GLM procedure; SAS Institute, Inc.), we regressed log mean levels of reproductive hormones including estradiol, bioavailable estradiol, estrone, and progesterone on categories of both adult and child caregiving hours. We included variable numbers of women in analyses since the number of those for whom data on specific hormones were available varied. These analyses were adjusted for age, body mass index, laboratory, time since blood draw, smoking, husband’s education, and age at menarche. All tests of statistical significance were two-sided.


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Age-adjusted distributions of multiple covariates are presented, by categories of adult and child caregiving hours, in table 1. In 1992, 11,971 (22 percent) women reported providing informal adult care, and 23,336 (42 percent) supplied informal child care. A total of 2,405 (4 percent) women provided 15 or more hours of adult care, and 5,750 (10 percent) provided 15 or more hours of care to a child. Those supplying 1–14 hours of care to a child or adult provided a median of 4.5 hours of care per week. Those providing 15 or more hours a week of adult care reported a median of 54 hours of care per week. Women providing adult care also tended to administer some child care (table 1).

Women providing 15 or more hours of care per week to an adult were older on average and therefore more likely to be postmenopausal. They were also less likely to have ever used oral contraceptives, although parity was no higher than for those providing less or no care. Because of their increased caregiving responsibilities, these women were less likely to be employed full-time outside of the home. They were also more likely to report high levels of stress and depressive symptoms and were more likely to smoke; however, their level of physical activity was slightly higher, they drank less per week, and they were less likely to be socially isolated. Family history of breast cancer was unrelated to caregiving. In contrast, compared with women providing no child care, those providing 15 or more hours of caregiving to a child were younger and had more children (table 1).

One fourth of the women in the cohort provided care to their own children in 1992, and another 25 percent indicated doing so for grandchildren. In 1996, about half as many (14 percent) provided care to their children, but slightly more (28 percent) provided care to grandchildren. Fewer supplied care to an ill adult, although the proportion providing care to an ill spouse (~5 percent), parent (~12 percent), or other adult (~9 percent) was approximately the same in both time periods (data not shown).

For those providing care, numbers of hours of care given to children, grandchildren, parents, or "other" ill adults remained approximately the same between 1992 and 1996 (median, 4.5 hours/week for each group at each time point). In contrast, spousal caregiving responsibilities increased from a median of 4.5 hours in 1992 to 14.5 hours in 1996. Among those at or above the 75th percentile of caregiving hours, the caregiving burden nearly doubled from 28.0 to 54.0 hours (data not shown).

In both age-adjusted and multivariate-adjusted analyses of caregiving, hours of care provided to an ill adult and to a child were not associated with breast cancer incidence (table 2). Results were generally similar whether the caregiving exposure was considered recent, lagged, or cumulative. The exception was that a lower incidence of breast cancer was found between 1996 and 2000 for those providing on average 1–14 hours of care to a child (0 hours: reference; 1–14 hours: hazard ratio = 0.85, 95 percent confidence interval: 0.72, 1.00; and >=15 hours: hazard ratio = 0.87, 95 percent confidence interval: 0.66, 1.16), although the trend was nonsignificant overall (p value, continuous variable = 0.69). Caregiving to specific kinship groups (child, grandchild, parent, spouse, or other ill adult) was also unrelated to the outcome (data not shown). Furthermore, no significant interactions were found between caregiving and other psychosocial variables.

High levels of self-reported stress from caring for a child were unrelated to breast cancer outcome. However, high levels of self-reported stress associated with adult care were related to a borderline lower incidence of breast cancer (hazard ratio = 0.82, 95 percent confidence interval: 0.68, 1.00) (table 3).


View this table:
[in this window]
[in a new window]
 
TABLE 3. Relative risk (95% confidence interval) of incident breast cancer, by categories of self-reported stress, for 69,886 women* from the US Nurses’ Health Study
 
Compared with women providing no adult care, women providing 15 hours or more per week of care had significantly lower mean levels of estradiol (9.21 pg/ml vs. 7.46 pg/ml, 95 percent confidence interval: 6.36, 8.76; p for trend < 0.01) and bioavailable estradiol (1.86 pg/ml vs. 1.35 pg/ml, 95 percent confidence interval: 1.00, 1.82; p for trend = 0.03) (table 4). They also had lower levels of testosterone. On the other hand, caregiving provided to children was positively associated with prolactin (p for trend < 0.01). Numbers of hours of caregiving provided to an adult or child were unrelated to levels of estrone or progesterone. Self-reported stress and depressive symptoms were unrelated to levels of any of the endogenous hormones (data not shown).


View this table:
[in this window]
[in a new window]
 
TABLE 4. Geometric mean values of several reproductive hormones, by category of caregiving hours (n = 422–645), for women from the US Nurses’ Health Study*
 

    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Contrary to our initial hypothesis, high numbers of caregiving hours and high self-reported stress did not predict a higher incidence of breast cancer. In cumulative analyses, moderate time spent providing caregiving to children and high self-reported stress from adult caregiving responsibilities were inversely related to prospective breast cancer incidence. Furthermore, high numbers of hours of adult caregiving were related to lower levels of certain endogenous sex steroid hormones, portending a possible lower future risk of breast cancer.

Stress is thought to influence development of cancer through immune down-regulation. Acting via the hypothalamic-pituitary-adrenal axis in a complex feedback loop between the central nervous and immune systems, stress increases cortisol levels (4244), which adversely affects immune function (14, 4556). Frequent cortisol release that occurs with chronic stress may lead to persistently high cortisol levels (57), thus leading to immune suppression. Caregiving has been linked to lower levels of interleukin-2, natural killer cell activity, and other immune parameters (5861). It has been hypothesized that because the immune system is invoked in eliminating mutated cells, reduced immunity could lead to more rapid development of cancer. Stress might also promote cancer through DNA damage, faulty DNA repair, inhibition of apoptosis, effects on endocrine parameters, or somatic mutation (62). These factors may be precursors to certain types of cancer such as hormonal (63, 64) and lymphatic (7, 9) cancers. However, despite the plausibility of these mechanisms, little epidemiologic evidence (65), including results from this study, exists to support the hypothesis that stress in a healthy population is related to breast cancer.

It is possible that life stress is of insufficient magnitude to affect cancer unless the immune system is already compromised (46), which may explain findings of stress and lowered survival after breast cancer diagnosis (12). This hypothesis is consistent with findings by Vitaliano et al. (66). These authors concluded that psychosocial stress was not associated with levels of natural killer cell activity in spousal caregivers of Alzheimer’s disease patients but was associated in the presence of a history of cancer. In our study, little evidence existed that a combination of stressors was any more predictive. Of course, the stressors we examined may be insufficient to lead to the kind of immune down-regulation found in those diagnosed with cancer.

Null associations of psychosocial stress with breast cancer outcomes could reflect competing effects of both reduced immunity and reduced exposure to estrogen. Recent studies have found that low socioeconomic status and depression suppress estrogen levels and lead to early menopause (6769), factors related to a lower risk of breast cancer. To the extent that immune down-regulation adversely affects breast cancer outcomes, a corresponding decline in estrogens could obscure apparent effects through this mechanistic pathway. Little research has examined the potential effects of stress per se on endogenous hormones, but our results are consistent with prior literature. The magnitude of the difference between women with and without a history of depression in Harlow et al.’s study (67) was similar to that in our study comparing women providing no adult caregiving with those providing high levels of care.

Despite the logic that reduced immune function may predict higher levels of breast cancer, the effects of immunosuppression on breast cancer etiology may be counterintuitive. Although not definitive, the findings from one study (70) showed that immunosuppression in women after organ transplant was associated with a lowered risk of breast cancer over a 1- to 11-year follow-up (relative risk = 0.75, p = 0.009); in another study (71), women with acquired immunodeficiency syndrome–related immunosuppression also had a lower risk of breast cancer (relative risk = 0.5, 95 percent confidence interval: 0.3, 0.8).

Rather than predicting an elevated risk of breast cancer, these findings and mechanistic data from previous studies suggest that high levels of stress could ultimately be associated with a lower rather than a higher risk of breast cancer. Our largely null findings for caregiving and breast cancer may therefore be due to the relatively short-term follow-up (8 years since the first psychosocial assessment and only 4 years since the 1996 assessment). From time of initiation, cancers are thought to progress to a diagnosable malignant tumor over 15–20 years. For breast cancer, the estimated median growth time to detection is 7–11 years (72, 73). We would expect to detect an association between stress and incident breast cancer if the effects of stress served to promote (or inhibit) a tumor from an earlier stage to diagnosable size within 4–8 years.

In this study, high stress from caregiving was not associated with increased prospective cumulative incidence of breast cancer. This finding does not preclude the possible role of stress earlier in life in breast cancer etiology.


    ACKNOWLEDGMENTS
 
This research was supported by grants AG14742 and CA87969 supplied by the National Institute on Aging and the National Cancer Institute, National Institutes of Health.


    NOTES
 
Correspondence to Dr. Candyce H. Kroenke, Channing Laboratory, 181 Longwood Avenue, 3rd Floor, Boston, MA 02115 (e-mail: candyce.kroenke{at}channing.harvard.edu). Back


    REFERENCES
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Chen CC, David AS, Nunnerley H, et al. Adverse life events and breast cancer: case-control study. BMJ 1995;311:1527–30.[Abstract/Free Full Text]
  2. Protheroe D, Turvey K, Horgan K, et al. Stressful life events and difficulties and onset of breast cancer: case-control study. BMJ 1999;319:1027–30.[Abstract/Free Full Text]
  3. Lillberg K, Verkasalo PK, Kaprio J, et al. Stressful life events and risk of breast cancer in 10,808 women: a cohort study. Am J Epidemiol 2003;157:415–23.[Abstract/Free Full Text]
  4. Li J, Johansen C, Hansen D, et al. Cancer incidence in parents who lost a child: a nationwide study in Denmark. Cancer 2002;95:2237–42.[CrossRef][ISI][Medline]
  5. Achat H, Kawachi I, Byrne C, et al. A prospective study of job strain and risk of breast cancer. Int J Epidemiol 2000;29:622–8.[Abstract/Free Full Text]
  6. Jacobs JR, Bovasso GB. Early and chronic stress and their relation to breast cancer. Psychol Med 2000;30:669–78.[CrossRef][ISI][Medline]
  7. Levav I, Kohn R, Iscovich J, et al. Cancer incidence and survival following bereavement. Am J Public Health 2000;90:1601–7.[Abstract/Free Full Text]
  8. Johansen C, Olsen JH. Psychological stress, cancer incidence and mortality from non-malignant diseases. Br J Cancer 1997;75:144–8.[ISI][Medline]
  9. Fox BH. The role of psychological factors in cancer incidence and prognosis. Oncology (Huntingt) 1995;9:245–56.[Medline]
  10. Petticrew M, Fraser JM, Regan MF. Adverse life events and risk of breast cancer: a meta-analysis. Br J Health Psychol 1999;4:1–17.[CrossRef][ISI]
  11. Gottlieb BH. Conceptual and measurement issues in the study of coping with chronic stress. In: Gottlieb B, ed. Coping with chronic stress. New York, NY: Plenum Press, 1997:3–40.
  12. De Brabander B, Gerits P. Chronic and acute stress as predictors of relapse in primary breast cancer patients. Patient Educ Counsel 1999;37:265–72.[CrossRef][ISI][Medline]
  13. Beach SR, Schulz R, Yee JL, et al. Negative and positive health effects of caring for a disabled spouse: longitudinal findings from the caregiver health effects study. Psychol Aging 2000;15:259–71.[CrossRef][ISI][Medline]
  14. Lutgendorf SK, Garand L, Buckwalter KC, et al. Life stress, mood disturbance, and elevated interleukin-6 in healthy older women. J Gerontol 1999;54a:M434–9.
  15. Stephens MA, Townsend AL. Stress of parent care: positive and negative effects of women’s other roles. Psychol Aging 1997;12:376–86.[CrossRef][ISI][Medline]
  16. Schulz R, Beach SR, Lind B, et al. Involvement in caregiving and adjustment to death of a spouse: findings from the caregiver health effects study. JAMA 2001;285:3123–9.[Abstract/Free Full Text]
  17. Cannuscio CC, Jones C, Kawachi I, et al. Reverberations of family illness: a longitudinal assessment of informal caregiving and mental health status in the Nurses’ Health Study. Am J Public Health 2002;92:1305–11.[Abstract/Free Full Text]
  18. Schulz R, Beach SR. Caregiving as a risk factor for mortality: the Caregiver Health Effects Study. JAMA 1999;282:2215–19.[Abstract/Free Full Text]
  19. Lazarus RS, Folkman S. Stress, appraisal, and coping. New York, NY: Springer Publishing Company, 1984.
  20. Endogenous Hormones and Breast Cancer Collaborative Group. Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies. J Natl Cancer Inst 2002;94:606–16.[Abstract/Free Full Text]
  21. Bernstein L, Ross RK. Endogenous hormones and breast cancer risk. Epidemiol Rev 1993;15:48–65.[ISI][Medline]
  22. Thomas HV, Reeves GK, Key TJ. Endogenous estrogen and postmenopausal breast cancer: a quantitative review. Cancer Causes Control 1997;8:922–8.[CrossRef][ISI][Medline]
  23. Hankinson SE, Willett WC, Manson JE, et al. Plasma sex steroid hormone levels and risk of breast cancer in postmenopausal women. J Natl Cancer Inst 1998;90:1292–9.[Abstract/Free Full Text]
  24. Hankinson SE, Willett WC, Manson JE, et al. Alcohol, height, and adiposity in relation to estrogen and prolactin levels in postmenopausal women. J Natl Cancer Inst 1995;87:1297–302.[Abstract]
  25. Hankinson SE, London SJ, Chute CG, et al. Effect of transport conditions on the stability of biochemical markers in blood. Clin Chem 1989;35:2313–16.[Abstract/Free Full Text]
  26. Holmes MD, Spiegelman D, Willett WC, et al. Dietary fat intake and endogenous sex steroid hormone levels in postmenopausal women. J Clin Oncol 2000;18:3668–76.[Abstract/Free Full Text]
  27. Berwick DM, Murphy JM, Goldman PA, et al. Performance of a five-item mental health screening test. Med Care 1991;29:169–76.[ISI][Medline]
  28. Berkman LF, Syme SL. Social networks, host resistance, and mortality: a nine-year follow-up study of Alameda County residents. Am J Epidemiol 1979;109:186–204.[Abstract]
  29. Kawachi I, Colditz GA, Ascherio A, et al. A prospective study of social networks in relation to total mortality and cardiovascular disease in men in the USA. J Epidemiol Community Health 1996;50:245–51.[Abstract]
  30. Stampfer MJ, Willett WC, Speizer FE, et al. Test of the National Death Index. Am J Epidemiol 1984;119:837–9.[ISI][Medline]
  31. Hankinson SE, Manson JE, Spiegelman D, et al. Reproducibility of plasma hormone levels in postmenopausal women over a 2–3-year period. Cancer Epidemiol Biomarkers Prev 1995;4:649–54.[Abstract]
  32. Hankinson SE, Willett WC, Michaud DS, et al. Plasma prolactin levels and subsequent risk of breast cancer in postmenopausal women. J Natl Cancer Inst 1999;91:629–34.[Abstract/Free Full Text]
  33. Fisher L, Lieberman MA. Alzheimer’s disease: the impact of the family on spouses, offspring, and inlaws. Fam Process 1994;33:305–25.[ISI][Medline]
  34. SAS Institute, Inc. I. SAS software, version 8.1 ed. Cary, NC: SAS Institute, Inc, 2000.
  35. Cox DR. Regression models and life tables (with discussion). J R Stat Soc (B) 1972;34:187–220.[ISI]
  36. Cupples LA, D’Agostino RB, Anderson K, et al. Comparison of baseline and repeated measure covariate techniques in the Framingham Heart Study. Stat Med 1988;7:205–22.[ISI][Medline]
  37. Willett WC, Lenart EB. Reproducibility and validity of food-frequency questionnaires. In: Willett WC, ed. Nutritional epidemiology. 2nd ed. New York, NY: Oxford University Press, 1998.
  38. Lepore S. Social environmental influences on the chronic stress process. In: Gottlieb B, ed. Coping with chronic stress. New York, NY: Plenum Press, 1997:133–60.
  39. Vedhara K, Addy L, Wharton L. The role of social support as a moderator of the acute stress response: in situ versus empirically-derived associations. Psychol Health 2000;15:297–307.[ISI]
  40. Colditz GA, Rosner B. Cumulative risk of breast cancer to age 70 years according to risk factor status: data from the Nurses’ Health Study. Am J Epidemiol 2000;152:950–64.[Abstract/Free Full Text]
  41. Greenland S, Finkle WD. A critical look at methods for handling missing covariates in epidemiologic regression analyses. Am J Epidemiol 1995;142:1255–64.[Abstract]
  42. Makara GB, Palkovits M, Szentagoithai J. The endocrine hypothalamus and the hormonal response to stress. In: Selye H, ed. Selye’s guide to stress research. Vol 1. New York, NY: Van Nostrand Reinhold, 1980:280–337.
  43. Mason JW. A review of the psychoendocrine research on the pituitary-adrenal cortisol system. Psychosom Med 1968;30:576–607.[ISI][Medline]
  44. Rose RM. Overview of endocrinology of stress. In: Brown GM, Koslow SH, Reichlin S, eds. Neuroendocrinology and psychiatric disorder. New York, NY: Raven Press, 1984:95–122.
  45. Kiecolt-Glaser JK, Glaser R, Gravenstein S, et al. Chronic stress alters the immune response to influenza virus vaccine in older adults. Proc Natl Acad Sci U S A 1996;93:3043–7.[Abstract/Free Full Text]
  46. Kiecolt-Glaser JK, Glaser R. Psychoneuroimmunology and health consequences: data and shared mechanisms. Psychosom Med 1995;57:269–74.[Abstract]
  47. Kiecolt-Glaser JK, Marucha PT, Malarkey WB, et al. Slowing of wound healing by psychological stress. Lancet 1995;346:1194–6.[ISI][Medline]
  48. Esterling BA, Kiecolt-Glaser JK, Bodnar JC, et al. Chronic stress, social support, and persistent alterations in the natural killer cell response to cytokines in older adults. Health Psychol 1994;13:291–8.[CrossRef][ISI][Medline]
  49. Herbert TB, Cohen S. Stress and immunity in humans: a meta-analytic review. Psychosom Med 1993;55:364–79.[Abstract]
  50. Marieb EN. Human anatomy and physiology. 3rd ed. Redwood City, CA: Benjamin/Cummings Publishing Co, 1998.
  51. Lacey K, Zaharia MD, Griffiths J, et al. A prospective study of neuroendocrine and immune alterations associated with the stress of an oral academic examination among graduate students. Psychoneuroendocrinology 2000;25:339–56.[CrossRef][ISI][Medline]
  52. Cohen S, Doyle WJ, Skoner DP. Psychological stress, cytokine production, and severity of upper respiratory illness. Psychosom Med 1999;61:175–80.[Abstract/Free Full Text]
  53. Guidi L, Tricerri A, Vangeli M, et al. Neuropeptide Y plasma levels and immunological changes during academic stress. Neuropsychobiology 1999;40:188–95.[CrossRef][ISI][Medline]
  54. Song C, Kenis G, van Gastel A, et al. Influence of psychological stress on immune-inflammatory variables in normal humans. Part II. Altered serum concentrations of natural anti-inflammatory agents and soluble membrane antigens of monocytes and T lymphocytes. Psychiatry Res 1999;85:293–303.[CrossRef][ISI][Medline]
  55. Dekaris D, Sabioncello A, Mazuran R, et al. Multiple changes of immunologic parameters in prisoners of war. Assessments after release from a camp in Manjaca, Bosnia. JAMA 1993;270:595–9.[Abstract]
  56. Kiecolt-Glaser JK, Dura JR, Speicher CE, et al. Spousal caregivers of dementia victims: longitudinal changes in immunity and health. Psychosom Med 1991;53:345–62.[Abstract]
  57. Kirschbaum C, Prussner JC, Stone AA, et al. Persistent high cortisol responses to repeated psychological stress in a subpopulation of healthy men. Psychosom Med 1995;57:468–74.[Abstract]
  58. Pariante CM, Carpiniello B, Orru MG, et al. Chronic caregiving stress alters peripheral blood immune parameters: the role of age and severity of stress. Psychother Psychosom 1997;66:199–207.[ISI][Medline]
  59. Glaser R, Sheridan J, Malarkey WB, et al. Chronic stress modulates the immune response to a pneumococcal pneumonia vaccine. Psychosom Med 2000;62:804–7.[Abstract/Free Full Text]
  60. Glaser R, Kiecolt-Glaser JK, Malarkey WB, et al. The influence of psychological stress on the immune response to vaccines. Ann N Y Acad Sci 1998;840:649–55.[Abstract/Free Full Text]
  61. Castle S, Wilkins S, Heck E, et al. Depression in caregivers of demented patients is associated with altered immunity: impaired proliferative capacity, increased CD8+, and a decline in lymphocytes with surface signal transduction molecules (CD38+) and a cytotoxicity marker (CD56+ CD8+). Clin Exp Immunol 1995;101:487–93.[ISI][Medline]
  62. Forlenza MJ, Baum A. Psychosocial influences on cancer progression: alternative cellular and molecular mechanisms. Curr Opin Psychiatry 2000;13:639–45.[CrossRef][ISI]
  63. Rowse GJ, Weinberg J, Bellward GD, et al. Endocrine mediation of psychosocial stressor effects on mouse mammary tumor growth. Cancer Lett 1992;65:85–93.[ISI][Medline]
  64. Riley V. Psychoneuroendocrine influences on immunocompetence and neoplasia. Science 1981;212:1100–9.[ISI][Medline]
  65. Dalton SO, Boesen EH, Ross L, et al. Mind and cancer. Do psychological factors cause cancer? Eur J Cancer 2002;38:1313–23.[CrossRef][ISI][Medline]
  66. Vitaliano PP, Scanlan JM, Ochs HD, et al. Psychosocial stress moderates the relationship of cancer history with natural killer cell activity. Ann Behav Med 1998;20:199–208.[ISI][Medline]
  67. Harlow BL, Wise LA, Otto MW, et al. Depression and its influence on reproductive endocrine and menstrual cycle markers associated with perimenopause: the Harvard Study of Moods and Cycles. Arch Gen Psychiatry 2003;60:29–36.[Abstract/Free Full Text]
  68. Wise LA, Krieger N, Zierler S, et al. Lifetime socioeconomic position in relation to onset of perimenopause. J Epidemiol Community Health 2002;56:851–60.[Abstract/Free Full Text]
  69. Young EA, Midgley AR, Carlson NE, et al. Alteration in the hypothalamic-pituitary-ovarian axis in depressed women. Arch Gen Psychiatry 2000;57:1157–62.[Abstract/Free Full Text]
  70. Stewart T, Tsai SC, Grayson H, et al. Incidence of de-novo breast cancer in women chronically immunosuppressed after organ transplantation. Lancet 1995;346:796–8.[ISI][Medline]
  71. Frisch M, Biggar RJ, Engels EA, et al. Association of cancer with AIDS-related immunosuppression in adults. JAMA 2001;285:1736–45.[Abstract/Free Full Text]
  72. Steel GG. Cytokinetics of neoplasia. In: Holland JF, Frei EI, eds. Cancer medicine. 2nd ed. Philadelphia, PA: Lea & Febiger, 1982.
  73. Fox BH. Premorbid psychological factors as related to cancer incidence. J Behav Med 1978;1:45–133.[Medline]