Flattened cortisol rhythms in metastatic breast cancer patients
Introduction
In most healthy individuals, cortisol typically shows marked diurnal variation, peaking in early morning, and declining throughout the day (Stone et al., 2001). The health consequences of flattened cortisol rhythms or aberrant peaks and troughs have not yet been precisely delineated, but alteration in rhythmicity of cortisol has been associated with various negative outcomes, including tumor growth, early mortality in cancer, (Sapolsky and Donnelly, 1985, Sephton et al., 2000, Filipski et al., 2002) and obesity and disrupted glucose metabolism (e.g., Rosmond et al., 1998). Although women with metastatic breast cancer have been shown to maintain circadian cycling of cortisol (Touitou et al., 1995, Haus et al., 2001), data in previous studies were not compared to control groups to determine whether the rhythms were as pronounced as in healthy individuals. Furthermore, Touitou and colleagues (1995) showed that breast cancer patients with the most severe metastases (in the liver) showed flattened rhythms of several bioactive substances, including cortisol. Thus, women with severe metastatic breast cancer appear to have disrupted circadian rhythmicity. Circadian abnormalities also appear to have prognostic value in regard to the initial occurrence of breast cancer. Patients at high risk show abnormal circadian patterns among an array of hormones including cortisol (Ticher et al., 1996). In addition, the circadian rhythmicity of cortisol appears to have long-term prognostic value for women already diagnosed with metastatic disease. Our laboratory reported that loss of normal diurnal variation in cortisol predicts early mortality in metastatic breast cancer for at least seven years later. The divergence in survival as a function of cortisol rhythm emerged approximately one year after cortisol assessment and extended at least six years after (Sephton et al., 2000).
A limitation of our prior study examining the relation between diurnal cortisol rhythm and mortality in breast cancer was the lack of a healthy control group. Thus, it was impossible to determine whether the patient group as a whole showed abnormal cortisol rhythmicity compared to healthy individuals. In order to address this issue, we conducted this cross-sectional study on a separate sample.
We were also interested in relations between cortisol rhythmicity and other aspects of physiological as well as psychological functioning. In a review of the human stress literature, McEwen and Seeman (1999) document the adverse health effects of cumulative stressors which can lead to failure of the body to effectively terminate stress responses. “Allostatic load” occurs when external demands and/or adaptation efforts are excessive, leading to dysregulation of the HPA axis, impairing negative feedback and diurnal rhythmicity, and eventually leading to dysregulation across multiple physiological systems—including the immune and cardiovascular systems, and metabolic regulation of energy balance and fat deposition.
HPA axis dysregulation is hypothesized to be an early indicator of allostatic load, and is sensitive to psychosocial factors such as stress and social support (Chrousos and Gold, 1998, Turner-Cobb et al., 2000, Gunnar and Vazquez, 2001). Cortisol is also known to have direct effects on memory (e.g., Abercrombie et al., 2003), and chronic cortisol dysregulation causes hippocampal dysfunction and memory impairment (cf. Lupien and McEwen, 1997, Lupien and Lepage, 2001), although no studies have yet linked declarative memory performance to aberrations in diurnal rhythmicity.
Dysregulation in the HPA axis can also disrupt glucose homeostasis and energy balance, resulting in greater overall or abdominal adiposity. Bjorntorp and colleagues have linked a flattened diurnal rhythm to aspects of the Metabolic Syndrome (Rosmond et al., 1998, Rosmond et al., 2000), which is a cluster of inter-related factors, including abdominal and general obesity, insulin resistance, glucose intolerance, hyperlipidemia, and hypertension, and strongly predicts cardiovascular disease (CVD) and type II diabetes (Lapidus et al., 1984, Kissebah and Krakower, 1994). Newer studies have linked indices of the Metabolic Syndrome, such as increased abdominal fat distribution (Ballard-Barbash and Swanson, 1996, Kaaks et al., 1998) as well as high levels of circulating insulin (independent of obesity) (Del Giudice et al., 1998), to incidence of breast cancer (Kaaks et al., 1998). However, the relationship between adiposity and health status in breast cancer patients is complex. Whereas obesity is a risk factor for breast cancer incidence and more rapid progression (Zumoff et al., 1982, Stoll, 1996, Chlebowski et al., 2002), advancing cancer is often associated with wasting. Furthermore, not all studies support the connection between obesity and cancer progression (Rock and Demark-Wahnefried, 2002, Dignam et al., 2003), and one study even shows that low body mass index is a predictor of local recurrence (Marret and Perrotin, 2001). Therefore, it is un clear whether a flattened diurnal rhythm would be linked with excess adiposity or weight loss in metastatic breast cancer patients, although stage of disease may be critical.
In order to better understand the salience to breast cancer of the syndromal aspects of disrupted rhythmicity of cortisol, it is important to examine both physiological and psychological correlates of altered rhythms. We therefore hypothesized that 1) metastatic breast cancer patients would show flattened diurnal slope of cortisol compared to controls, and that the patients with the most severe metastatic disease would show the flattest rhythms, and 2) relations would be apparent between diurnal slope of cortisol and adiposity and memory functioning, as well as psychosocial factors—perceived stress and social support.
Section snippets
Participants
Participants included 17 metastatic breast cancer patients and 31 healthy female controls. Nine other breast cancer patients were excluded on the basis of exclusionary criteria (see below) or unwillingness to complete the protocol. Likewise, nine other potential control subjects were excluded because unwillingness to initiate or complete the protocol. Patients were recruited by letter of request through breast cancer clinics at Stanford University, and healthy controls were recruited through
Comparison of patients vs. controls on biological indicators
Patients had flatter diurnal slope of cortisol than controls, t(46) = −2.19, p < 0.05. (See Table 2 for means, and see Fig. 1 for log cortisol by time point.) The effect size for the group difference in diurnal slope was 0.67, which is a medium effect size (Cohen, 1977). The groups did not differ on mean cortisol levels, t(46) = 0.4, n.s. Furthermore, no group differences emerged in cortisol levels for any particular time of day, all t’s < 1.06, p’s > 0.29. Thus, the significant group
Discussion
In the current study diurnal cortisol rhythms were flattened in metastatic breast cancer patients compared to healthy controls. We also found that within the group of breast cancer patients, individuals with more severe metastatic spread showed higher mean cortisol levels and a tendency toward flatter diurnal slopes of cortisol. In addition, we previously found in a separate sample that flatter diurnal slope of cortisol was predictive of earlier death in women with metastatic breast cancer (
Summary
We found that women with metastatic breast cancer had significantly flatter diurnal cortisol rhythms than did healthy controls. Patients with greater disease severity showed higher mean cortisol levels, smaller waist circumference, and a tendency toward flatter diurnal cortisol rhythms. Thus, we found that metastatic disease is associated with dysregulated cortisol functioning, and the most ill, advanced patients have greatest cortisol dysregulation and most progressive cachexia.
No relations
Acknowledgements
This research was supported by Charles A. Dana foundation grants 176D003 and 176C530. Heather C. Abercrombie was supported by NIMH postdoctoral training grant MH19938-08. We would also like to acknowledge the support of the NIA Program Project Grant AG18784, which has contributed to the knowledge base for this paper. The authors would like to thank Frank Villa and Laurel Hill for their help with data collection, Eric Neri, Sue DiMiceli, and Helena C. Kraemer for their statistical consultation,
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