Psychological health throughout life and adultcortisol patterns at age 45 y

Chris Power a,*, Leah Li a, Kate Atherton a, Clyde Hertzman b

aCentre for Paediatric Epidemiology and Child Health, UCL Institute of Child Health, 30 Guilford Street,London, WC1N 1EH, United Kingdomb Early Human Learning Partnership, University of British Columbia, Canada

Received 16 February 2010; received in revised form 27 June 2010; accepted 27 June 2010

Psychoneuroendocrinology (2011) 36, 87—97

KEYWORDSExternalising;Internalising behaviour;Cortisol;Birth cohort;Psychological health

Summary Population-based studies of cortisol and psychological health over long periods arerare. This study aims to establish whether cortisol levels in mid-adulthood are associated withchronicity and life-stage of psychological ill-health onset. We used data from the 1958 British birthcohort (3209 males; 3315 females) with cortisol measures 45 min post-waking (t1) and 3 h later (t2)on the same day at 45 y. Lifetime psychological health was identified from child and adult measures(ages 7,11, 16, 23, 33, 42, 45 y). t1cortisolwas lowerby3—4% in thosewith lifetime (childandadult)ill-health thanthosewithno ill-health,after adjustment for socio-economicpositionandsmoking. t1cortisol was similarly lowered in those with adult onset of ill-health, but not among the groupwhoseill-healthwas of recent onset. t2 cortisolwas elevatedamong all lifetime ill-health groups, by6—9%,except for those whose ill-health did not extend beyond childhood. Simple analyses across theseparate ages of follow-up suggest that elevations in t2 cortisol reflect associations for adultill-health. Our study suggests that psychological ill-health over years and decades ‘‘blunts’’ post-awakening cortisol secretion, possibly reflecting HPA dysregulation due to social stressors.# 2010 Elsevier Ltd. All rights reserved.

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1. Introduction

The hypothalamic-pituitary—adrenal (HPA) axis is thought toplay a role in socio-emotional development and psychological

Abbreviations: HPA axis, hypothalamic-pituitary—adrenal axis;SEP, socio-economic position; AUC, area-under-the-curve; BSAG,Bristol Social Adjustment Score; CIS-R, revised Clinical InterviewSchedule; OR, odds ratio; CI, 95% confidence intervals; t1, time 1;t2, time 2.* Corresponding author. Tel.: +44 0207 905 2106;

fax: +44 0207 905 2381.E-mail address: c.power@ich.ucl.ac.uk (C. Power).

0306-4530/$ — see front matter # 2010 Elsevier Ltd. All rights reservedoi:10.1016/j.psyneuen.2010.06.010

state (Goodyer et al., 2001; Herbert et al., 2006). In infancy(Gunnar and Nelson, 1994; van Bakel and Riksen-Walraven,2004; Lewis and Ramsay, 2005), childhood (McBurnett et al.,2000; Shirtcliff et al., 2005; Herbert et al., 2006), andadulthood through to later life (Bremmer et al., 2007),associations between emotional state and cortisol have beenobserved, suggesting the need to understand their inter-playover the life-course. Differential regulation of the HPA sys-tem and elevated cortisol is thought to be associated with,and possibly contribute to, depression (Cohen et al., 2006b)and persistent HPA hyperactivity may set persons at risk forrecurrence (Anisman and Zacharko, 1992; Bouhuys et al.,2006; Halligan et al., 2007). Prospective investigation in well-adolescents at high risk of psychopathology found significant

d.

88 C. Power et al.

associations between morning peak cortisol and subsequentmajor depressive disorder (Goodyer et al., 2000). However,from the evidence to date, mostly based on cross-sectionalstudies, it is not always clear whether emotional stateinfluences cortisol secretion or vice versa.

A further observation in the literature is that cortisollevels may be either elevated or blunted in association withemotional development and psychological state. Associa-tions have been reported for HPA axis hyperactivity andmental health problems, with elevated cortisol associatedwith major depressive disorder (Goodyer et al., 2001)negative affect (Polk et al., 2005) and distress (Decker,2000). Hypo-secretion has also been documented, forexample, in relation to positive affect (Polk et al., 2005)post-traumatic stress (Heim et al., 2000) childhood aggres-sion, externalising and internalising behaviour (McBurnettet al., 2000; Shirtcliff et al., 2005) and higher neuroticismin women or low extraversion in men (Oswald et al., 2006).In some instances, U-shaped relationships have beenreported, with higher risk of major or recurrent depressionamong those with either hyper- and hypo-secretion thanamong those with cortisol in the mid-range (Bremmer et al.,2007). This research uses a diverse range of approaches toassessment of cortisol secretion, including a single salivarycortisol measure (e.g. McBurnett et al., 2000), diurnalrhythm as indicated by repeat measures throughout theday (e.g. Polk et al., 2005), awakening levels (e.g. Chidaand Steptoe, 2009) or response to a stressor (e.g. Oswaldet al., 2006). In summary, a diverse range of psychologicalhealth states and cortisol measurements have been exam-ined, but a coherent pattern of associations has yet toemerge.

One potential explanation for lack of coherence andinconsistencies across studies is the complexity of cortisolregulation. Cortisol typically follows a diurnal rhythm, with apeak soon after waking in the morning and a gradual declinethroughout the day (Stone et al., 2001). Other patterns havebeen observed, including absence, or alternatively, prolon-gation of the high awakening level or rises later in the day(Gunnar and Vazquez, 2001; Rohleder et al., 2004; Buchananet al., 2004). The literature suggests also that either acutepsychological trauma or chronic distress may change theregulation of the HPA axis, and lead to either hyper- orhypo-secretory states (Anisman and Zacharko, 1992; McE-wen, 1998, 2000; Miller et al., 2007) which may in turn affectpsychological state. McEwen (1998) outlined the long-termeffects of physiologic response to stress as ‘wear and tear’resulting from chronic over- or under-activity of allostaticsystems. He speculated that this ‘allostatic load’ over alifetime could cause the allostatic systems to wear out orbecome exhausted. Elsewhere, others have suggested thatthe HPA axis may become activated in the short-term follow-ing a stressor, resulting in elevated cortisol output, and thena counter-regulatory response is mounted such that cortisolrebounds below normal (Miller et al., 2007). If there is anevolution from hyper- to hypo-secretory states with chroni-city of distress (burnout), the direction of associationbetween cortisol and distress at any given life-stage willbe difficult to predict. Proper investigation of time sinceonset of distress has been limited by a dearth of prospectivestudies, but a recent meta-analysis of chronic distress andcortisol associations that relied heavily on cross-sectional

data has identified timing as a critical element: morningcortisol levels were elevated at stressor onset, but reducedwith time to a flatter diurnal secretion profile (Miller et al.,2007).

One challenge confronting research on cortisol and psy-chological health and distress in long-term follow-upstudies is the commensurability of measurable psychologicalhealth constructs between childhood and adulthood. Pre-vious longitudinal studies have identified homotypic conti-nuities, i.e. continuity of the same disorder, for examplebetween internalising disorders in childhood and early adult-hood (Costello et al., 2003). Heterotypic continuities (i.e.continuity from one disorder to another, such as from child-hood externalising disorders to adult affective/anxiety dis-orders) have also been demonstrated (Kim-Cohen et al.,2003) justifying studies of psychological health trajectoriesthat encompass both homotypic and heterotypic constructs.Here, we consider both homotypic and heterotypiccontinuities.

Another challenge is to determine the relationshipbetween psychological health and cortisol levels with pro-spective data and taking account of the timing of ill-healthonset. Our expectation is that cortisol levels will be ele-vated in association with ill-health of recent onset, andblunted with ill-health of long duration. Specifically, weexamine whether cortisol levels in mid-adulthood are asso-ciated with: (i) childhood psychological ill-health, repre-sented by internalising and externalising behaviour; (ii)psychological ill-health in early to mid-adulthood; (iii)chronicity and life-stage of ill-health onset. Also, we exam-ine whether associations are explained by main childhoodand adult covariates, namely child and adult socio-eco-nomic position or smoking. These covariates have pre-viously been found to be associated with psychologicalill-health and with cortisol in this population (Poweret al., 2002; Li et al., 2007) and elsewhere (Cohenet al., 2006a; Badrick et al., 2007). We use data fromthe 1958 British birth cohort wherein psychological healthwas ascertained in childhood and adulthood, but cortisolwas first measured in mid-adulthood (Power and Elliott,2006). Although we cannot fully disentangle the temporalsequence between cortisol and psychological ill-health, ourinvestigation provides insights into the magnitude anddirection of association between cortisol and the onsetand chronicity of psychological ill-health.

2. Methods

The 1958 cohort includes all born in England, Scotland andWales, in one week in March 1958. A population of about17,000 live-births were followed-up at ages 7, 11, 16, 23, 33,42 y (Power and Elliott, 2006). During 2002—2004, at 44—45 y,a target of 11,971 participants still in contact with the study,and at 42 y had not required a proxy interview (e.g. due tolearning disability) were invited to an examination by atrained nurse; 9377 (78%) participated. Most (n = 9165) con-sented to saliva collection for cortisol measurement: usabledata were obtained from 6524 (3209 males; 3315 females,i.e. 54% of the target for 45 y) (Atherton et al., 2008). Thediscrepancy between the number consenting and providingsaliva was probably due to reliance on the participant to

Lifetime psychological health and adult cortisol 89

return saliva samples after the interview. Compared with theoriginal birth sample (excluding deaths and emigrations),those with cortisol data were less likely to have had exter-nalising (9.7% vs 13.0%, respectively) or internalising (11.8%vs 14.2%) behaviour at 7 y; andmore likely to originate from anon-manual class (30.1% vs 26.5%). Ethical approval for the45 y survey was given by the South East Multi-CentreResearch Ethics Committee and written consent for theuse of information in medical studies was obtained fromstudy participants.

2.1. Measures

Salivary cortisol: At the end of the nurse interview, partici-pantswere requested to collect two saliva samples on the nextconvenient day, the first at 45 min after awakening (time 1)(Pruessner et al., 1997) and the second, 3 h later on the sameday (time2). A reminderwas sent to 53% of those consenting toreturn a sample, if they had not done so within two weeks ofthe interview. Samples were received from 6568 participants,6524 yielding information on at least one cortisol measure(6467 with time 1; 6506 with time 2 measure).

Participants were instructed to avoid brushing/flossingtheir teeth, or eating or drinking for 15 min before takingeach sample. They were asked to chew on a salivette untilit was soaked, record date and time of collection, andstore the sample at room temperature until mailed to thelaboratory. Salivary cortisol is stable at room temperaturefor up to 30 days but samples were frozen after reachingthe laboratory to reduce microbial growth. Cortisol levelswere measured at the University of Dresden with a com-mercial immunoassay kit with chemiluminescence detec-tion (CLIA, IBL-Hamburg, Hamburg, Germany). The lowersensitivity of this assay is 0.44 nmol/l, with intraassay andinterassay precision of <10% for a wide range of cortisolconcentrations. High levels (>50 nmol/l) were rerun in asecond assay for confirmation. On the day of samplecollection, participants also reported (i) the times ofawakening and saliva collection, (ii) regular night-work(shift-work), (iii) wakefulness during the previous night(i.e. 24.00—06.00 h), (iv) dental work within three days,(v) cuts inside their mouth that may bleed, and (vi) currentmedications.

Childhood psychological health was assessed by teachersusing the Bristol Social Adjustment Score (BSAG) at 7 y and11 y, and Rutter Behaviour Scale at 16 y (Rutter, 1967; Stott,1969). The BSAG consists of 146 phrases describing beha-viours representing 12 syndromes, grouped into internalis-ing (items such as ‘miserable’ and ‘fearful’) andexternalising (e.g. ‘resentful/aggressive’ and ‘bullies’)scores. The Rutter Scale consists of 26 behaviours, five ofwhich were used to derive an internalising score and ninefor an externalising score; participants had a score of 2 if anitem applied ‘definitely’, 1 for ‘somewhat’, and 0 if it didnot apply. Scores for internalising (or externalising) beha-viour were summed for each age. These total scores tend tohave a skewed distribution with a large percentage ofindividuals having a low score. Thus, categorisations usedpreviously (Clark et al., 2007) were derived: high (�top 13%of the original childhood sample); low (bottom 50%); andintermediate (remaining 37%) score. (The proportion cate-gorised as ‘high’ was <13% in the participating sample at

45 y.) Based primarily on the child’s behaviour, the scalesare commonly used to indicate emotional disturbance or(mal)adjustment (Stott, 1969; Clark et al., 2007) and arebest suited to large, long-term population studies (Elanderand Rutter, 1996).

Adult psychological health: was measured at ages 23, 33,and 42 y using the Malaise Inventory (Rodgers et al., 1999)which assesses 24 psychological and somatic symptoms ofvarying prevalence: for example, 40% of women and 24% ofmen at 33 y reported positively to ‘‘do you often get worriedabout things?’’; 14%and 9%, respectively for ‘‘do you often feelmiserable or depressed?’’; 3% and 2% for ‘‘have you ever had anervous breakdown?’’ (Rodgers et al., 1999). We used the 15psychological symptoms (i.e. excluding somatic symptoms),identifying participants with>4 as high scores. At 45 y, symp-toms of depression and anxiety in the previous week weremeasured by the revised Clinical Interview Schedule (Lewiset al., 1992) administered by a survey nurse: those with >2symptoms of depression or anxiety were identified.

Summary scoreswere derived in order to distinguish thoseidentified with psychological ill-health at any point in child-hood from those never with ill-health. Accordingly, a sum-mary score was based on �1 instance of a high score forexternalising behaviour at 7, 11 or 16 y. A similarly con-structed summary was derived for childhood internalisingbehaviour; whilst a separate summary score for adulthoodwas defined as �1 instance of high malaise symptoms (23—42 y), or depressive/anxiety symptoms at 45 y.

Lifetime psychological ill-health was classified as: ‘‘no ill-health’’ in childhood or adulthood; ‘‘childhood only’’ forthose with internalising behaviour in childhood but no ill-health in adulthood; ‘‘adult onset’’ for participants with nochildhood problems but high symptoms at 23, 33 or 42 y;‘‘recent onset’’ for a first report of symptoms at 45 y; finally,‘‘lifetime (both child and adult)’’ ill-health for those withinternalising behaviour in childhood and adult ill-health. Asimilar classification was created for externalising (ratherthan internalising) childhood behaviour.

Potential confounding factors: We identified smoking,child and adult socio-economic position (SEP) as confound-ing factors, because of their previously demonstratedassociations with psychological distress and cortisol (Poweret al., 2002; Cohen et al., 2006a; Badrick et al., 2007; Liet al., 2007). Smoking at 42 y was defined as current (�1cigarette/day), ever or never. Childhood SEP was based onfather’s social class at birth (7 y if data were missing);adult SEP was based on current or most recent occupationat 42 y (33 y if data were missing). SEP was categorisedwith the Registrar General’s classification (Office of Popu-lation Censuses and Surveys, 1990): professional (I); man-agerial/technical (II); skilled non-manual (IIInm); skilledmanual (IIIm); semi-skilled (IV); unskilled (V); andunknown.

2.2. Analysis

Extreme outliers for time 1 (t1) and time 2 (t2) were trun-cated: at 2 nmol/l for <2 nmol/l (n = 24 at t1; n = 123 at t2)and at 100 nmol/l for >100 nmol/l (n = 22 at t1; n = 20 at t2)in order that extreme values did not exert a disproportionateinfluence on analyses. The truncated cortisol values werethen transformed using log 10 to reduce skewness. Not all

90 C. Power et al.

samples were collected at the specified period after wakingand 3 h interval, leading to variation around the target timefor t1 (mean(S.D.) = 49(15) min) and t2 (mean(S.D.) = 3 h5 min (23 min)). Cortisol level was influenced by both timeof awaking and time since awaking, thus we centred the logtransformed cortisol values for each individual at 0808 h(45 min after mean waking time of 0723 h) and t2 at1108 h (3 h 45 min after mean awakening time) based onpredictions from linear regression models at these time-points and back-transformed to nmol/l. Thus, t1 and t2cortisols in all analyses are adjusted for both time of awakingand time since awaking.

We examined potential confounding factors in relation tot1 cortisol, including gender, night-work (8%), awake duringthe previous night (37.3%), cuts inside mouth (3.3%), recentdental treatment (1.5%), current medication, and day of theweek. Of these factors, current medication was associated( p < 0.05) with a lower t1 cortisol value (by 10.2% in men and5.9% in women), and previous night sleep disturbance wasassociated with a lower t1 cortisol (by 5.4% in women). Thus,medication and sleep disturbance were added to models thatassessed associations between lifetime psychological ill-health and cortisol measures.

To investigate the association with psychological ill-health, we analysed several cortisol measures derived fromcentred values: (1) (log 10) transformed t1 and t2 cortisollevels; (2) the highest and lowest 5% extremes of the t1cortisol distribution: using cut-offs for the highest 5% at40.73 nmol/l (males) and 41.69 nmol/l (females); and at7.24 and 7.94 nmol/l, respectively for the lowest 5%; (3)(log 10) transformed area-under-the-curve (AUC), derived asthe sum of t1 and t2 cortisol values multiplied by 3 h, anddivided by 2 (thus, AUC represents the 3 h average of t1 andt2 values, allowing for variation in collection times, usedhere to indicate total 3 h exposure); (4) cortisol patterns,represented by (i) t1—t2 slope; (ii) flat t1—t2. The latteridentified individuals who lacked the common pattern ofsteep t1—t2 decline. Flat t1—t2 was defined as a t2 cortisolwithin 20% of t1 cortisol, or when the t1 value was<7.5 nmol/l, a t2 value <120% of t1.

Log t1 and t2 cortisol, slope and log AUC were analysedas continuous variables and associations with psychologicalill-health were examined using linear regression. Thus,relative change (in percent) in these measures was calcu-lated from the regression coefficient (b) as 100 � (10b � 1).For example, t1 cortisol changes from value X1 to 10b X1when the factor of interest changes from low to intermedi-ate or high childhood score, or from �4 to >4 malaisesymptoms in adulthood. Logistic regression was used forextremes of t1 cortisol and flat t1—t2 change, from whichodds ratios (OR) and 95% confidence intervals (CI) wereobtained.

The univariate associations of internalising and externa-lising scores at 7, 11, 16 y, and adult symptoms at 23, 33, 42and 45 y with each cortisol measure were analysed usingsimple regression models. These models were conducted formen and women separately, given known sex differences incortisol patterns (Kirschbaum et al., 1992; Herbert et al.,2006) and in psychological status (Mirowsky, 1996; Clarket al., 2007). We use effect sizes and their confidenceintervals to identify likely patterns of association at differentlife-stages. We examined the associations of t1 and t2 corti-

sol levels with the summary psychological health measures.Gender interactions with summary psychological measures(childhood and adulthood and lifetime) were tested andfound to be non-significant ( p > 0.05). Thus, we combinedboth sexes with adjustment for gender, medications andprevious night waking. We further added covariates childand adult SEP (both four category variables) and smoking(three categories) to the models to establish whether theassociations were confounded by these factors. Each lifetimeill-health category was compared to the no lifetime ill-health(reference) group. Thus there were four pairs of comparisonsfor each lifetime measure (internalising or externalising). Weadjusted for multiple comparisons using Bonferroni methodto assess associations between lifetime ill-health and (t1 andt2) cortisol levels.

Because the sample was known to be biased in relation tochildhood internalising and externalising behaviour, analyseswere adjusted for non-response by inverse probabilityweighting. Several factors associated with non-response at45 y (internalising behaviour at 7 y, externalising behaviourat 11 y, social class at birth, sex, maths test scores at 11 y)were used to estimate the weights. We repeated analysesusing the sample with complete data and results were similarto those from weighted analyses; the latter are presentedhere.

3. Results

Men had a lower t1 but higher t2 cortisol (medians 18.8 and7.1 nmol/l, respectively) at 45 y than women (19.6 and6.6 nmol/l) (Table 1). For most individuals cortisol levelsdeclined from t1 to t2, with women having a greaterdecline than men (Table 1), but a small proportion ofparticipants (4.2%) had a t2 cortisol �4 nmol/l higher thant1. Males had more internalising behaviours at 7 and 11 y,and externalising behaviours at 7, 11, and 16 y thanfemales; whereas in adulthood, malaise and depressive/anxiety symptoms were more prevalent among women(Table 2). Our measure of lifetime psychological healthidentified a minority as ‘recent ill-health’ (<5%) or ‘ill-health in both child and adulthood’ (�7%), a higher pre-valence for those with ill-health in childhood only (�13%)or adult onset (�18%); with more than half of the popula-tion not identified as having psychological ill-health inchild or adulthood.

In univariate sex-specific analyses, t1 cortisol tended tobe reduced with internalising and externalising behaviour inchildhood and with malaise symptoms in adulthood (Table 3).t2 cortisol was elevated for males with childhood externalis-ing behaviour (11 and 16 y) and malaise in adulthood; simi-larly, for females, t2 cortisol was elevated from 11 y onwardsfor externalising behaviour and for adult malaise, with ele-vated t2 levels also seen for internalising behaviour at 16 y. t1cortisol was significantly reduced and t2 increased for womenbut not men with symptoms of depression/anxiety at 45 y.Associations with psychological ill-health were observed forthe lowest and top 5% of the t1 cortisol distribution, flat t1—t2, slope and AUC. In general, patterns of association areconsistent with those seen for t1 and t2 cortisol and hence,are not repeated here. For example, these further analysessuggested that those with ill-health had a flatter t1—t2 slope,especially in females in adulthood.

Table 1 Cortisol values and times of measurement at age 45 y.

Males Females pa

N N

Time of measures h:min (mean, S.D.)Waking-up time 7:22 (1:22) 3004 7:24 (1:12) 3192 0.46Time 1 8:12 (1:22) 3160 8:13 (1:12) 3290 0.45Time since waking 0:49 (0:15) 3004 0:49 (0:15) 3189 0.89Time 2 11:17 (1:26) 3048 11:17 (1:13) 3162 0.86

Interval (time 2—time 1) (h:min) 3:05 (0:27) 3046 3:04 (0:18) 3158 <0.001

Cortisol measuresTime 1 cortisol nmol/l (median)b 18.80 (11.94) 3185 19.60 3282 0.05Time 2 cortisol nmol/l (median)b 7.10 3198 6.60 3308 0.35AUC (nmol/l) (median)c 40.12 3174 40.67 3275 0.87Flat t1—t2 cortisol (%)d 11.2 354 8.7 285 0.001Lowest 5% t1 cortisol (%) 4.9 156 5.2 170 N/AHighest 5% t1 cortisol (%) 5.2 164 5.2 171 N/A

N/A not appropriate: cut-offs were gender specific.a For male and female difference; chi-squared test for categorical variables.b Truncated at 2 and 100 nmol/l.c Calculated using centred t1 and t2 cortisol values, i.e. allowing for measurement time.d Flat = t2 cortisol is within 20% of t1 value, or t2 value <120% of t1 value if t1 value is <7.5 nmol/l.

Lifetime psychological health and adult cortisol 91

Lifetime psychological health: Those with ‘ill-health inboth child and adulthood’, irrespective of whether lifetimemeasures were based on internalising or externalising child-hood behaviour, had a t1 cortisol 3—4% lower than those withno lifetime ill-health, after adjustment for SEP and smoking(Table 4). There was a lower t1 cortisol by 3.6% in those withill-health of adult (23—42 y) and ‘childhood only’ onset forthe lifetime measure based on externalising childhood beha-viour. No reduction in t1 cortisol was found for recent (45 y)onset ill-health. Similar patterns were observed for thelifetime measure based on internalising childhood behaviour.t2 cortisol was elevated in all ill-health groups, except‘childhood only’, after adjustment for SEP and smoking, withincreases ranging from 6% to 9% (Table 4). Effects of adjust-ment for SEP and smoking were modest, but with a tendencyto weaken associations for t2 and strengthen those for t1cortisol.

4. Discussion

Our findings resonate with a body of research suggestingthat cortisol hyper- and hypo-secretory patterns reflectdifferent durations of the experience of distress (Milleret al., 2007). t1 cortisol was lower for psychological ill-health of ‘adult onset’ and in ‘both child and adulthood’,whilst, among those with recent adult onset ill-healththere was no evidence of a lowered t1 cortisol. Thisobservation is consistent with a transition from hyper- tohypo-secretion with increasing duration of psychologicaldistress, whereby the HPA axis is dysregulated over time,leading to blunting of the morning peak, as might beexpected with ‘‘burnout’’. ‘Recent onset’ of psychologicalill-health implies a maximum of 3 y (42—45 y) since onset,whereas ‘both child and adulthood’ implies a minimum of29 y since onset (from 16 y). Findings for t2 cortisol differfrom those for t1, in that t2 cortisol levels were elevated

among those with ill-health in adulthood (recent and ear-lier) but not among those with ‘childhood only’ ill-health.This suggests that t2 cortisol is influenced by psychologicalill-health in the short-term, rather than the long-term, andthe weakening of the associations for t2 cortisol afteradjustment for smoking provides further support this argu-ment. The effect of adjustment implies either that smokingacts to elevate t2 cortisol (Badrick et al., 2007) or that it isa form of self-medication for psychological distress (Al’absiet al., 2007). We note that t2 cortisol was elevated inassociation with externalising behaviour at age 11, beforethis cohort started to smoke, arguing for the self-medica-tion hypothesis.

4.1. Methodological considerations

A major strength of this study is the availability of psycho-logical health measures in both child and adulthood in anunselected nationwide sample, not restricted to at-risk orclinical groups. A limitation is the lack of a childhood cortisolmeasure and therefore we are unable to provide a definitiveconclusion on the causal direction underlying the associationsobserved. Establishing the direction of association is notstraightforward, for example, those with depressive symp-toms may take samples later relative to awaking than others,leading to a flatter cortisol pattern and there was somesuggestion for this, at least among women (those with 45 ysymptoms woke 7.8 min later than others). Whilst cortisolvalues were centred to allow for differences in samplecollection times, this may not entirely overcome such biases.Our measures of psychological health do not equate topsychiatric diagnoses and are not entirely comparable overtime; measures at 45 y differed from earlier adulthood andno adult measure included externalising behaviour. More-over, it is difficult to disentangle state from trait with ourmeasures and it remains a possibility that associations

Table 2 Psychological health measures, 7—45 y.

Psychological health measures Males Females

% n % n

Internalising score7 ya Low 52.8 1505 63.5 1899

Intermediate 33.5 955 26.5 791High 13.7 391 10.0 300

11 ya Low 54.7 1532 62.9 1801Intermediate 33.2 929 27.6 791High 12.2 341 9.5 272

16 yb Low 47.8 1181 49.6 1276Intermediate 45.4 1123 43.6 1121High 6.8 168 6.9 177

Externalising score7 ya Low 42.9 1224 54.6 1631

Intermediate 44.7 1274 38.2 1143High 12.4 353 7.2 216

11 ya Low 48.5 1359 63.1 1809Intermediate 38.9 1091 30.4 872High 12.6 352 6.4 184

16 yb Low 65.7 1610 72.3 1862Intermediate 22.4 549 20.2 520High 12.0 293 7.5 192

Malaise symptomsc

23 y Low 95.0 2600 83.9 2444High 5.0 138 16.1 469

33 y Low 94.5 2664 88.8 2685High 5.5 155 11.2 340

42 y Low 85.0 2630 78.7 2533High 15.0 464 21.3 684

Depressive/anxiety symptoms <2 90.1 2874 87.0 286345 y �2 9.9 317 13.0 427

Childhood (7,11 or 16 y) behaviour(i) Internalisinge Never 76.7 2432 80.7 2643

>Once 23.3 737 19.4 634(ii) Externalisinge Never 75.8 2403 85.2 2791

>Once 24.2 766 14.8 485

Adult psychological ill-healthd,e Never 76.9 2457 63.7 2098>Once 23.1 737 36.3 1198

Lifetime ill-health(i) Internalising No ill-health 60.2 1896 53.2 1729

Childhood only 16.8 529 10.5 342Adult onset (23—42 y) 12.6 398 22.9 743Recent onset (45 y) 4.0 125 4.6 150Both child and adult 6.5 204 8.8 287

(ii) Externalising No ill-health 59.3 1869 56.0 1821Childhood only 17.6 556 7.7 250Adult onset (23—42 y) 12.5 393 24.4 794Recent onset (45 y) 4.0 126 4.8 156Both child and adult 6.6 208 7.1 229

a Bristol Social Adjustment Scale.b Rutter Scale.c Low = � 4; high >4 symptoms.d High malaise at 23, 33, 42 ys or depression or anxiety at 45 y.e Never ‘‘high’’; at least one ‘‘high’’.

92 C. Power et al.

Table 3 Psychological ill-health in childhood and adulthood and cortisol (t1 and t2) at age 45 y.

Socio-emotional status Males Females

t1 cortisol% differencea (95% CIs)

t2 cortisol% differencea (95% CIs)

t1 cortisol% differencea (95% CIs)

t2 cortisol% differencea (95% CIs)

Internalising score7 yIntermediate �4.72 (�7.68,�1.66) * �1.37 (�4.87, 2.25) 3.04 (�0.17, 6.35) �3.39 (�6.40, �0.29) *High �4.28 (�8.09,�0.31) * �3.62 (�7.87, 0.83) �2.28 (�6.59, 2.24) �3.62 (�7.87, 0.83)

11 yIntermediate �3.62 (�6.61, �0.52) * �0.46 (�3.99, 3.20) �4.28 (�7.26, �1.21) * 0.23 (�2.89, 3.45)High �3.39 (�7.24, 0.61) �2.50 (�7.22, 2.46) 0.93 (�3.53, 5.58) 0.46 (�3.97, 5.10)

16 yIntermediate 4.47 (1.22, 7.83) * �0.69 (�4.21, 2.96) �2.05 (�5.10, 1.09) 3.75 (0.53, 7.08) *

High �1.14 (�6.78, 4.83) �0.92 (�7.40, 6.02) �1.60 (�7.21, 4.35) 4.23 (�2.15, 11.03)

Externalising score7 yIntermediate �4.06 (�7.04, �0.98) * �2.28 (�5.74, 1.32) �2.28 (�4.89, 0.41) 1.62 (�1.09, 4.41)High �7.10 (�10.80, �3.25) * 1.39 (�3.52, 6.55) �8.38 (�12.82, �3.71) * 0.46 (�4.83, 6.05)

11 yIntermediate 0.23 (�2.89, 3.45) 3.28 (�0.39, 7.07) �0.92 (�4.00, 2.26) 0.69 (�2.44, 3.92)High �1.37 (�5.30, 2.72) 8.39 (3.61, 13.40) * �2.50 (�7.22, 2.46) 6.41 (1.26, 11.83) *

16 yIntermediate 7.15 (3.35, 11.09) * 3.28 (�1.28, 8.04) 1.39 (�2.20, 5.12) 4.71 (0.54, 9.05) *

High �0.23 (�4.63, 4.38) 13.76 (7.77, 20.09) * 0.46 (�4.83, 6.05) 3.51 (�1.94, 9.27)

Malaise symptoms23 yHigh �8.59 (�14.19, �2.63) * 12.4 (4.63, 20.88) * �11.90 (�15.02, �8.66) * 8.14 (3.84, 12.63) *

33 yHigh �2.73 (�8.68, 3.62) 10.66 (2.95, 18.95) * �6.67 (�10.79, �2.37) * 7.40 (2.66, 12.36) *

42 yHigh �5.38 (�8.73, �1.90) * 7.40 (2.66, 12.36) * �7.10 (�9.99, �4.12) * 6.66 (3.34, 10.08) *

Depressive/anxiety45 yHigh �0.12 (�4.55, 4.51) 5.05 (�0.31, 10.71) �5.45 (�9.19, �1.56) * 9.90 (5.54, 14.45) *

All analyses weighted by inverse probability (see Section 2).a % difference or OR (95% CIs) relative to reference, i.e. low score for 7, 11, 16 y; low (�4) symptoms 23—42 y; <2 symptoms at 45 y.* p < 0.05.

Lifetime psychological health and adult cortisol 93

between cortisol levels in adulthood and our psychologicalmeasures are due to a common underlying explanation(s)(such as inherited biological or social causes). Nonetheless,relating longitudinal measures of psychological symptoma-tology (that capture child—adult homotypic and heterotypiccontinuities) to cortisol patterns represents a novelapproach. Our lifetime measure based on childhood inter-nalising behaviour and adult symptoms is probably indicativeof homotypic continuities because measures include relateditems. Our heterotypic phenotype, externalising-to-affec-tive disorders, advances the simple analyses of externalisingbehaviour by indicating whether associations with cortisoldiffer between those with and without adult symptoms.Moreover, this lifetime psychological health measure pro-vides a useful comparison for that based on affective symp-tomatology.

Salivary measures are relatively easy and inexpensive tocollect and well-suited for population studies. Salivary cor-tisol is strongly correlated with serum cortisol (r = 0.71—0.96) and with the ‘‘free’’ cortisol fraction (Kirschbaumand Hellhammer, 1994). Ideally, an individual’s diurnal cor-tisol rhythm is obtained from multiple saliva collections, butin our large population two samples on one day was feasibleand affordable. Because of the study size precision in esti-mation of effects is gained at the group level whilst estimatesfor individuals may be less reliable. The literature has estab-lished a normative diurnal rhythm of decline in cortisol levelwithin the first few hours of the day (Stone et al., 2001). Weselected a measure soon (45 min) after waking (Pruessneret al., 1997) followed by a pre-lunch measure (3 h later) tocapture the typical morning peak and subsequent decline ofcortisol levels or deviations from that pattern. A systematic

Table

4Chronicityan

dag

eofonsetofpsych

ologica

lill-health:associationwitht1

andt2

cortisol.

Lifetimepsych

ologica

lill-health

at1

cortisol(%

difference

from

baselined;95

%CI)

t2co

rtisol(%

difference

from

baselined;95

%CI)

Model1b

Model2c

Model1b

Model2c

(i)Internalising

N=5721

N=57

21N=57

57N=57

57Childhoodonly

2.13

(�0.73

,5.06

)1.73

(�1.14

,4.76

)�0.59

(�3.66

,2.57

)�1.85

(�4.89

,1.27

)Adult

onset(23—

42y)

�1.32(�

4.07

,1.52

)�2.06

(�4.81

,0.77

)10

.27(6.88,

13.77)

*7.91

(4.60,

11.33)

*Rece

ntonset(45y)

5.24(0.10,

10.65)

5.03

(�0.10

,10

.42)

6.83

(1.06,

12.93)

*6.29

(�0.59

,12

.32)

*Both

childan

dad

ult

�3.59(�

7.05

,0.00

)�4.26

(�7.74

,�0.64

)^10

.09(5.76,

14.62)

*7.01

(2.75,

11.45)

*

(ii)Externalising

N=57

20

N=57

20N=57

56N=57

56Childhoodonly

�2.13(�

4.93

,0.75

)�3.54

(�6.36

,�0.64

)*

4.39

(1.10,

7.79

)*

0.17

(�3.04

,3.49

)Adult

onset(23—

42y)

�2.91(�

5.56

,�0.18

)�3.66

(�6.31

,�0.93

)*

9.76

(6.46,

13.16)

7.54

(4.30,

10.88)

*Rece

ntonset(45y)

1.66(�

3.34,

6.91

)1.59

(�3.40

,6.84

)8.33

(2.46,

14.54)

8.01

(2.19,

14.16)

*Both

childan

dadult

�1.73(�

5.42

,2.10

)�3.45

(�7.15

,�0.39

)14

.50(9.79,

19.42)

8.69

(4.15,

13.44)

*

Allan

alysesareweightedbyinve

rseprobab

ility(seeSe

ction2).

p-valuesad

justedformultiple

comparisons:

*p<

0.05

^p<

0.10

.aTw

omeasures,

basedon(i)internalisingan

d(ii)externalisingch

ildhoodbehav

iour.

bModel1includesad

justmentforge

nder,medicationan

dnightaw

aking.

cModel2includesad

justmentforge

nder,medication,nightaw

aking,

childan

dad

ult

SEP,

andsm

okingstatus.

dBaselinereference

group=noill-health.

94 C. Power et al.

review of cortisol awakening response published after thetime of our data collection gives a range of 20—45 min afterwaking as the period of peak concentration (Chida andSteptoe, 2009). Whilst sample collection at 30 min post-waking is now common, like us several other studies haveused 45 min. Our reliance on morning cortisol measures is acommon limitation of research in the field (Miller et al.,2007). Despite these limitations, associations are observablehere with t1 and t2 cortisol, treated as independent vari-ables, which is justified because within-individual correlationof these measures was low (r = 0.2) and variation in cortisolbetween t1 and t2 was larger than between individuals ateither time-point. Finally, due to attrition the sample withcomplete data was less than half of the original cohort andunder-representative of participants with childhood beha-vioural problems. We therefore presented a weighted ana-lysis using factors associated with non-participation(Atherton et al., 2008) to allow for differential loss tofollow-up.

4.2. Comparison with other studies

Our results are consistent with other studies of psychologicalhealth at specific life-stages over shorter periods of follow-up. For example, our finding of reduced t1 cortisol asso-ciated with childhood externalising and internalising beha-viours is consistent with another study in which thesebehaviours predicted low cortisol 1—2 y later in 6—16-year-old boys, although not girls (Shirtcliff et al., 2005).Elsewhere in the literature, it has been observed thatdepressed men show no evidence of basal cortisol hyper-secretion 8—10 am whilst depressed women do (Young,1995). This is consistent with our findings for current depres-sive/anxiety symptoms at 45 y (Table 3). However, our dis-tinction between longstanding psychological ill-health thatpersists into current time, and that of recent onset, allowedus to demonstrate that relationships with current ill-healthdepend on duration.

There was no evidence that associations for t1 and t2cortisol and lifetime ill-health differed for males andfemales, suggesting common explanations. Those with ill-health in both child and adulthood had a lower t1 and anincreased t2 cortisol than those with no lifetime ill-health,but this pattern was absent among those with recent adultill-health. The pattern we observed of ‘‘blunted’’ post-awakening cortisol rise and elevated cortisol later in theday, has been observed previously (Cohen et al., 2006b).Explanations for how the HPA axis becomes dysregulated toproduce this particular diurnal rhythm have yet to beelucidated.

Our study adds weight to the evidence base for theburnout hypothesis, as demonstrated in a meta-analysisfinding that duration of distress is a determinant of HPAresponse (Miller et al., 2007). A variation on this theme isthat the HPA axis becomes dysregulated over time, due tosocial stressors, suggested by studies of low SEP or mal-treatment in childhood (Carlson and Earls, 1997; Lupienet al., 2000; Gunnar and Vazquez, 2001; Gunnar et al.,2001; Cicchetti and Rogosch, 2001; Lupien et al., 2005;Ranjit et al., 2005; O’Connor et al., 2009). In turn, dysre-gulation of the HPA axis can lead to either hypo- or hyper-secretion of cortisol, both carrying increased risk of

Lifetime psychological health and adult cortisol 95

depression (Bremmer et al., 2007). Our results suggest thatboth can occur. It should be noted that the magnitude ofdifferences between lifetime psychological ill-healthgroups are not large, about 3—4% for t1 and 6—9% fort2, possibly due to methodological aspects intrinsic toour study or to other factors affecting cortisol levels.The general health implications of such differences haveyet to be fully understood as there may be harmful orbeneficial adaptive effects of HPA axis responses to pro-longed stress. Potential damaging effects on the brain havebeen identified in relation to excess or disturbed patternsof circulating corticosteroids (McEwen, 1998; Herbertet al., 2006) and there are suggestions elsewhere thatbreast cancer survival is reduced among women with flat-tened diurnal cortisol cycles compared to those with moretypical cycles (Sephton et al., 2000). Our study has notaddressed explanations for psychological ill-health, such asparental loss (Luecken and Appelhans, 2006); being raisedin an orphanage (Carlson and Earls, 1997); disruption ofmaternal care (Herbert et al., 2006); chronic unemploy-ment (Ockenfels et al., 1995); perceived stress (Hellham-mer et al., 2004); and acute trauma (Heim et al., 2000).Nor have we considered other personal and contextualfactors (Miller et al., 2007). Further long-term studiesare essential to better understand how dysregulation ofthe HPA axis is affected by and contributes to psychologicaldistress.

Appendix A

Correlation coefficients between measures of psychological heal

Internalisingscore

Externalising score

11 y 16 y 7 y 11 y 16 y

Internalising score7 y 0.32* 0.17* 0.25* 0.10* 0.10*

11 y 0.19* 0.13* 0.34* 0.14*

16 y 0.11* 0.13* 0.32*

Externalising score7 y 0.36* 0.23*

11 y 0.34*

16 y

Malaise symptoms23 y33 y42 y

* All correlations are significant with p < 0.05.y All variables are categorical measures. Males and females are comb

samples with complete information on each two variables considered.

Role of the funding source

Funding for data collection at 45 y was provided by theMedical Research Council grant G0000934 and for analysisby the MRC and the Human Early Learning Partnership (HELP),Vancouver, Canada. This work was undertaken at GOSH/UCLInstitute of Child Health who received a proportion of fundingfrom the Department of Health’s NIHR Biomedical ResearchCentres funding scheme. The funders had no further role instudy design; in the collection, analysis and interpretation ofdata; in the writing of the report; and in the decision tosubmit the paper for publication.

Conflict of interest

None declared.

Acknowledgments

We are grateful to participants in the 2002—2004 biomedicalfollow-up of the 1958 birth cohort. Cortisol levels weremeasured under the direction of Professor Kirschbaum (Bio-logical Psychology, Department of Psychology, University ofDresden, Germany).

thy.

Malaise symptoms Depressive symptoms

23 y 33 y 42 y 45 y

0.10* 0.08* 0.07* 0.07*

0.12* 0.08* 0.09* 0.07*

0.10* 0.10* 0.08* 0.08*

0.09* 0.08* 0.06* 0.06*

0.12* 0.10* 0.10* 0.06*

0.13* 0.12* 0.09* 0.07*

0.36* 0.30* 0.16*

0.34* 0.20*

0.25*

ined with adjustment for gender. Correlations are calculated using

96 C. Power et al.

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