Identifying patterns in cortisol secretion in an older population. Findings from the Whitehall II study
Introduction
The use of salivary sampling as a noninvasive tool for the assessment of free cortisol and therefore as a marker for activity of the hypothalamic-pituitary-adrenal (HPA) axis is well established in human stress research (Kirschbaum and Hellhammer, 1989). This sampling method captures the diurnal variations in cortisol secretion with the large rise associated with the awakening response and the subsequent decline in levels across the day and has provided the opportunity to examine predictors of variation in these patterns in a naturalistic setting.
A number of ‘patterns’ in cortisol release have been described. For instance, studies of serum cortisol variations in patients with severe long lasting psychiatric depression have shown that these patients have raised evening levels of cortisol which correspond to an inability to lower appropriately serum cortisol during the dexamethasone test (Rubin et al., 1987). Conversely, those with pronounced symptoms of exhaustion such as the chronic fatigue syndrome are unable to raise their cortisol level in challenging situations and they also show very small diurnal variation (“low flat curves”) (Demitrack et al., 1991). Cortisol hyposecretion is associated with post traumatic stress disorder (Yehuda et al., 1991) and a ‘flat pattern’ is associated with fatigue in cancer patients (Abercrombie et al., 2004) and in mal-treatment in childhood (Tarullo and Gunnar, 2006). These patterns in cortisol secretion may reflect disturbances of the capacity to regulate cortisol secretion. Flatter patterns in cortisol secretion, in which evening levels of cortisol secretion are raised, may occur due to impaired feedback in the hypothalamic-pituitary-adrenal (HPA) axis or to hypersensitivity to cortisol stimulation later in the day with evidence suggesting a role for the former rather than latter mechanism (Spiegel et al., 2006).
Patterns in the diurnal release of cortisol secretion are usually described from visual inspection of means or population specific arbitrary cut points in slope of cortisol levels (Smyth et al., 1997, Ice et al., 2004, Ranjit et al., 2005, Cohen et al., 2006). A recent study used growth curve modelling and described three curves in cortisol secretion in children aged 3 years (van Rysin et al., 2009). Previous analyses have not formally described how the different patterns of diurnal cortisol secretion group or cluster together in older groups because few studies have assessed diurnal cortisol secretion in populations sufficiently large enough, that is, with many hundreds of participants, to examine clustering of these patterns.
Cortisol secretion is hypothesized to be etiological in the development of a number of conditions including heart disease (Rosmond et al., 2003), osteoporosis (Raff et al., 1999), cognitive decline (Karlamangla et al., 2005) and recently with frailty (Varadhan et al., 2008). These are conditions that are manifest in older age groups, and understanding how the patterns of diurnal cortisol secretion group together in an older population and also the predictors of these groups could help us identify normative and “abnormal” patterns of diurnal cortisol secretion and hence help identify the role of changes in cortisol secretion in the development of these morbidities and disease. Correlates of cortisol secretion in older age groups are mixed for basic descriptive correlates such as age in community dwelling populations. For example, previous reported associations of cortisol secretion with age and gender have been equivocal. Thus, associations with age are reported to be positive (Deuschle et al., 1997, Powell et al., 2002) or null (Van Cauter et al., 1996). Others have suggested that an association is apparent for those with depression only (Kudielka et al., 2000). Ice et al., describe a flatter slope in cortisol secretion associated with increasing age in 48 community dwelling volunteers aged 65 years and older. In this study, 2% of participants were described as having flat slopes in cortisol secretion, while Smyth et al. (1997) describe ‘flat’ patterns in 17% of younger participants.
Here we examine patterns of cortisol secretion in a large community dwelling population use a latent variable mixture modelling (LVMM) approach. The primary objective of LVMM is to uncover groups of individuals who share similar characteristics on a set of observed variables (in this paper cortisol). The unobserved patterns of cortisol release are described by a mixture of components, identified by categorical latent variables (latent classes): the object of the analysis is to find the smallest number of latent classes that can describe the associations among the set of observed continuous cortisol values observed across the day. The analysis adds classes stepwise until the model fits the data well.
We use the LVMM to examine whether different patterns in the diurnal variation of salivary cortisol can be identified in the population. Specifically,
- 1.
What are the patterns (clusters) of diurnal cortisol secretion?
- 2.
With which variables are the LVMM patterns associated? The predictors examined are those which have been demonstrated to modulate cortisol secretion in nonclinical studies and include biological (age and sex), behavioural factors (current smoking (Badrick et al., 2007), waking up time (Williams et al., 2005) and sleep duration (Spiegel et al., 1999), psychosocial (perceptions of stress) and a physical measure of functioning relevant to older age groups, gait/walking speed (Melzer et al., 2003).
Section snippets
Study population
Data reported here are from phase 7 (2002–2004) of the Whitehall II study. The cohort was initially recruited between 1985 and 1988 (phase 1) from 20 London-based civil service departments, 10,308 people participated. Eight phases of the study have been completed, details of the study have been reported elsewhere (Marmot and Brunner, 2005). The number participating at phase 7 was 6968, of these 6484 had a clinical assessment. The collection of saliva samples was instigated part way through
Results
Compared to all those who were asked to complete sample collection at phase 7, the subsample of 2802 participants that were analyzed were very similar (Table 1).
Discussion
We find two common curves in this large community dwelling population using a latent class analysis approach. These curves represent a ‘normative curve’, and a ‘raised curve’. The raised curve was composed of an increased CAR and higher day time cortisol and flatter slope compared to normative curve.
The epidemiology of the HPA axis is relatively unexplored in large community dwelling populations, here we find in nearly 3000 participants, that those with a raised cortisol profile tend to be
Role of the funding source
The Whitehall II study has been supported by grants from the Medical Research Council; Economic and Social Research Council; British Heart Foundation (RG/02/005; PG/03/029); Health and Safety Executive; Department of Health; National Heart Lung and Blood Institute (HL36310), US, NIH: National Institute on Aging (AG13196), US, NIH; Agency for Health Care Policy Research (HS06516); and the John D. and Catherine T. MacArthur Foundation Research Networks on Successful Midlife Development and
Conflict of interest
The authors have no conflicts of interests to declare.
Acknowledgements
We thank all participating Civil Service departments and their welfare, personnel, and establishment officers; the Occupational Health and Safety Agency; the Council of Civil Service Unions; all participating civil servants in the Whitehall II study; all members of the Whitehall II study team. The Whitehall II Study team comprises research scientists, statisticians, study coordinators, nurses, data managers, administrative assistants and data entry staff, who make the study possible.
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