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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2007-1539
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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 11 4094-4100
Copyright © 2007 by The Endocrine Society

Body Size at Birth Predicts Hypothalamic-Pituitary-Adrenal Axis Response to Psychosocial Stress at Age 60 to 70 Years

Eero Kajantie, Kimmo Feldt, Katri Räikkönen, David I. W. Phillips, Clive Osmond, Kati Heinonen, Anu-Katriina Pesonen, Sture Andersson, David J. P. Barker and Johan G. Eriksson

Department of Health Promotion and Chronic Disease Prevention (E.K., J.G.E.), National Public Health Institute, 00300 Helsinki, Finland; Hospital for Children and Adolescents (E.K., S.A.), Helsinki University Central Hospital, 00029 HUS, Helsinki, Finland; Departments of Psychology (K.F., K.R., K.H., A.-K.P.) and Public Health (J.G.E.), University of Helsinki, 00014 Helsinki, Finland; Medical Research Council Epidemiology Resource Centre and Developmental Origins of Health and Disease Division (D.I.W.P., C.O., D.J.P.B.), University of Southampton, Southampton SO16 6YD, United Kingdom; and Department of Medicine (D.J.P.B.), Heart Research Center, Oregon Health and Sciences University, Portland, Oregon 97201-3098

Address all correspondence and requests for reprints to: Eero Kajantie, M.D., Ph.D., National Public Health Institute, Department of Health Promotion and Chronic Disease Prevention, Mannerheimintie 166, 00300 Helsinki, Finland. E-mail: eero.kajantie{at}helsinki.fi.


   Abstract
Top
 Abstract
Introduction
 Participants and Methods
 Results
 Discussion
 References
 
Background: Studies in humans and animals have suggested intrauterine programming of hypothalamic-pituitary-adrenal axis (HPAA) function as an important mechanism in linking fetal life conditions with adult disease.

Objective: Our aim was to assess how body size at birth, a marker of intrauterine conditions, is associated with hypothalamic-pituitary-adrenal axis response to psychosocial stress in late adulthood.

Design and Setting: We conducted a clinical study in the Helsinki Birth Cohort.

Participants: Two hundred eighty-seven men and women born between 1934 and 1944 whose birth measurements and gestational age came from hospital records participated in the study.

Measurements: We measured salivary cortisol and, for 215 individuals, plasma cortisol and ACTH concentrations in conjunction with a standardized psychosocial stressor (Trier Social Stress Test).

Results: There was a linear relationship between low birth weight and low plasma ACTH but no linear relationship with cortisol. There were, however, quadratic relationships between birth weight and salivary (mixed model P = 0.001) and plasma cortisol (P = 0.005) but not with plasma ACTH (P = 0.1). The lowest peak salivary cortisol concentrations were seen in the lowest third of birth weights (adjusted for gestational age and sex): 12.9 nmol/liter (95% confidence interval of mean 11.2–15.0), compared with 17.1 nmol/liter (14.8–19.8) in the middle and 14.1 nmol/liter (12.6–15.7) in the highest third of birth weights. Corresponding figures for plasma cortisol were 418 nmol/liter (380–459), 498 nmol/liter (455–545), and 454 nmol/liter (428–482), and for plasma ACTH 8.17 pmol/liter (6.98–9.57), 12.42 pmol/liter (10.64–14.51), and 11.50 (10.06–13.14), respectively. Results for areas under the curve were similar.

Conclusions: We found an inverse U-shaped relationship between birth weight and cortisol concentrations during psychosocial stress. The lowest cortisol and ACTH concentrations were seen in subjects with the lowest birth weights. These results support the hypothesis that both hyper- and hypocortisolism may be programmed during the fetal period.


   Introduction
Top
 Abstract
 Introduction
Participants and Methods
 Results
 Discussion
 References
 
DURING THE PAST decade, it has become increasingly clear that circumstances during the fetal period may have a substantial impact on susceptibility to several common adult disorders such as cardiovascular disease (1, 2), type 2 diabetes (3, 4, 5), and depression (6, 7). Lifelong programming of the hypothalamic-pituitary-adrenal axis (HPAA) is a key candidate in mediating this link (8, 9, 10). Accordingly, many epidemiological observations in humans have linked small body size or early gestational age at birth with increased HPAA activity in adult life (10, 11, 12, 13, 14, 15, 16, 17, 18).

However, not all findings have been consistent (10, 17, 19, 20, 21, 22), and there are reports of opposite relationships as well (17, 19, 23). The complexity is further increased by observations that link hypoactive HPAA (24) with a number of disorders such as posttraumatic stress disorder (25, 26), fibromyalgia (27), and chronic fatigue syndrome (27, 28). One reason for the discrepant findings may be that most studies have assessed HPAA at a resting stage (11, 12, 16, 17, 18, 19, 20, 22) or after a biochemical stimulation or suppression (13, 14, 15, 18, 19, 23, 29). Indeed, many animal observations show that early life manipulations may have dissimilar effects on HPAA function at a resting stage and during stress (8). This is consistent with a study in young adult twins (30) and another study in 7- to 9-yr-old children (31) showing that whereas birth weight is unrelated to baseline salivary cortisol concentration, at least in males, it has a strong inverse relationship with the cortisol response to a standardized psychosocial stressor. Stress responsiveness, however, varies with age (32), and it is not known whether these relationships are sustained in later life. A study in 58-yr-old subjects in the Dutch Famine Cohort (33) showed no relationship between birth weight and salivary cortisol responsiveness, but the stress scenario used in that study produced only modest cortisol responses.

We set out to study whether body size at birth is related to HPAA responsiveness to a standardized psychosocial stressor in a well-characterized cohort of men and women aged 60–70 yr. In line with previous work (29), our particular focus was on subjects in the lower end of the distribution of birth weight for gestational age.


   Participants and Methods
Top
 Abstract
 Introduction
 Participants and Methods
Results
 Discussion
 References
 
Participants

The participants came from the Helsinki Birth Cohort, which consists of 4630 men and 4130 women who were born at Helsinki University Central Hospital during 1934–1944 and attended child welfare clinics in Helsinki. During years 2001–2004, a subset of 2003 randomly selected men (n = 928) and women (n = 1075) participated in a clinical examination (2, 4). From this subset, we then invited 407 subjects who had appropriate early life data, who did not use oral or inhaled glucocorticoids, and who were able to stand during the duration of the test; 287 subjects (144 men and 143 women) agreed to participate. The invited subjects were selected by random-number tables, except, because of our focus on the life span consequences of slow intrauterine growth, we overrepresented by 33% participants whose birth weight adjusted for gestational age was below the 10th percentile of the entire birth cohort. Their gestational age (P = 0.4) and length (P = 0.3) at birth and current age (P = 0.1) and body mass index (P = 0.9) were similar to the rest of the study cohort, although by design their mean birth weight was lower [93 g; 95% confidence interval (CI) 32–154 g; P = 0.003], as was ponderal index (0.52 kg/m3; 0.25–0.80 kg/m3; P = 0.0002) and social class at birth (P = 0.0004) and in adult life (P = 0.003). There was no difference in these variables between the study participants and those 120 who were invited but not willing to participate (all P > 0.2). When the subjects were asked whether they had been diagnosed with a chronic disease by a physician, 106 reported a history of hypertension, 25 coronary heart disease, four stroke, 28 depression, and seven panic disorder. In addition, 46 had been diagnosed with type 2 diabetes by an oral glucose tolerance test during the previous visit on average 2.1 yr earlier (2, 4). The subjects were invited in random order. We were able to use a study nurse for blood sampling after the study had commenced, and thus, blood samples could be obtained for 113 men and 102 women. The study protocol was approved by the Ethics Committee of Epidemiology and Public Health Research at the Helsinki University Central Hospital. Written informed consent was obtained from each participant.

Neonatal characteristics

Data on newborns’ date of birth, weight (grams), length (centimeters), head circumference (centimeters), and the date of the mother’s last menstrual period as well as childhood social class (lower, 78.0%; lower middle, 14.6%; upper, 7.0%; data missing for one subject) based on the father’s occupation, were extracted from birth records. Ponderal index was calculated as: (birth weight [kilograms])/(length at birth [meters])3.

Clinical visit

The subjects reported to the clinic between 0945 and 1300 h. Despite the circadian rhythm of cortisol concentrations, time of day has been shown to have a negligible effect on stress reactivity (34), and it was adjusted for in the data analysis. The subjects were instructed to abstain from caffeine, cigarettes, and eating for 2 h before arrival. On arrival their body weight was measured to the nearest 0.1 kg. For height and adult educational attainment (middle school, 36.9%; vocational school, 22.3%; senior high school, 27.9%; college/university degree, 12.2%; data missing for two subjects), we used data obtained during the previous visit to the clinic (2, 4). Body mass index (BMI) was calculated as: [weight (kilograms)/[height (meters)]2. An iv catheter was inserted for blood sampling for those 215 subjects who had blood samples obtained.

Experimental stress protocol

After resting for 45 min, the subject was led to the laboratory, where he/she remained standing throughout the experimental stress protocol. We used the Trier Social Stress Test (TSST), which is a well-standardized stress challenge known to elicit a powerful HPAA response (35) and have a high ecological validity via ego involvement and natural setting of the experiment (35, 36). Details of this protocol have been described (36, 37). Briefly, the subject was asked to convince a committee of two persons that his/her personal abilities make him/her the best candidate for a self-selected confidential post. After 5 min, the subject was asked to perform a series of serial subtractions for another 5 min. The committee minimized all verbal and nonverbal communication with the subject. After the completion of both tasks, the subject was led to another room for follow-up and debriefing. We obtained saliva (by Salivette) and blood at baseline and 0, 10, 20, 30, 45, 60, and 90 min after the end of the stressor.

Biochemical analyses

Salivary and plasma cortisol were measured from all samples and ACTH, which returns more rapidly to prestress levels, from the four first samples. Salivary cortisol concentrations were determined using a competitive solid-phase, time-resolved fluorescence immunoassay with fluorometric end point detection (DELFIA; Wallac, Turku, Finland). Plasma cortisol concentrations were determined by ELISA (ImmunoBiological Laboratories, Hamburg, Germany) and ACTH by chemiluminescence immunofluorometric assay (Nichols Institute Diagnostics, San Clemente, CA).

Data analysis

Cortisol and ACTH concentrations were log transformed to attain normality. We first analyzed the responses of these hormones to the TSST by linear mixed model with unstructured covariance structure (SPSS 13.0; SPSS Inc., Chicago, IL). We assessed quadratic relationships by including a squared variable in the model and reactivity by including an interaction term with sampling time. In further analyses we used linear regression to demonstrate effect sizes of statistically significant associations with commonly used indicators of HPAA function during stress testing: baseline and poststress peak concentrations, their relative increments (ratio of peak to baseline value), and time-weighted areas under the curve (AUCs, calculated by the trapezoidal rule) as dependent variables. Peak value was set as missing if no sample was available for 0, 10, and 20 min after stress, which was the case for salivary samples of three subjects. If two or more cortisol concentrations or one or more ACTH concentrations were missing for a subject, a missing value was set for the AUC. All analyses were adjusted for variables known to be associated with HPAA reactivity: sex (32), current age (32) and BMI (38), time of day (dummy coded) (34), and, except for analyses of sex differences, the use of oral estrogen therapy (32).


   Results
Top
 Abstract
 Introduction
 Participants and Methods
 Results
Discussion
 References
 
Birth data and results of the TSST are shown in Table 1Go. Birth weight ranged from 2070 to 4920 g, length at birth from 42.0 to 56.5 cm, and gestational age from 36.1 to 43.9 wk.


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  		TABLE 1. Descriptive data of the study subjects and their salivary and plasma cortisol and plasma ACTH concentrations during the TSST

 
Stress response

Figure 1Go shows that the TSST produced significant salivary and plasma cortisol and plasma ACTH responses as indicated by the significant main effects of time in the mixed model analysis (P < 0.0001). In comparison with the baseline value, salivary cortisol increased at least 10% in 80.9% of subjects and at least 50% in 65.6% of subjects. Corresponding figures for plasma cortisol were 88.8 and 66.0% and for plasma ACTH 94.0 and 76.7%, respectively. By 10 min after stress, salivary cortisol had reached its peak in 50.7% and plasma cortisol in 84.6% of subjects; by 20 min salivary cortisol had peaked in 89.8% and plasma cortisol in 96.7% of subjects. Plasma ACTH peak occurred by immediately after stress in 94.0% of subjects. Correlation coefficient between plasma and salivary cortisol AUC was 0.73, and between plasma cortisol and plasma ACTH AUC it was 0.49.


Figure 1
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  		FIG. 1. Salivary and plasma cortisol and plasma ACTH concentrations in groups according to thirds of birth weight adjusted for sex and gestational age. The concentrations are presented in geometric means, adjusted for sex, age, time of the day, BMI, and the use of oral estrogen treatment. The bars represent 95% CIs.

 
Sex differences

Mixed-model analyses showed that, as compared with women, men had 27.6% higher salivary (95% CI 12.6–44.6; P = 0.0002) and 10.9% higher plasma (1.6–21.9% P = 0.02) cortisol and 38.5% higher plasma ACTH (22.1–57.1%; P < 0.0001) concentrations during the TSST. There were similar sex differences in responsiveness of salivary (P = 0.005) and plasma (P = 0.01) cortisol. Table 1Go shows that these are reflected by higher concentrations and AUCs in men and a higher ratio of cortisol to ACTH AUC and higher increment of plasma cortisol in women.

We then analyzed whether the relationships between body size or gestational age at birth on cortisol and ACTH are different in men and women. Mixed-model analyses showed no statistically significant interactions between the effects of sex and any of these variables on levels of cortisol or ACTH (P values for interaction ≥ 0.2). Neither was there any interaction on cortisol to ACTH AUC ratio in linear regression (P values > 0.06). The only statistically significant interactions on plasma cortisol responsiveness were found between the effects of sex and birth weight (P = 0.01) and sex and length at birth (P = 0.01). However, separate analyses in both sexes showed no statistically significant relationships between these measurements and plasma cortisol responsiveness (P values > 0.1). We therefore present a pooled analysis adjusted for sex and other covariates described in the data analysis section.

Linear associations between body size at birth and HPAA function during psychosocial stress

We performed mixed model analyses to assess linear relationships of body size and gestational age at birth with HPAA function. There were no relationships with salivary or plasma cortisol concentrations or response to stress. Plasma ACTH concentrations were associated with birth weight (approaching statistical significance; 1 kg higher birth weight corresponded to 12.1% higher ACTH; 95% CI –1.5 to 27.5; P = 0.08) and length at birth (for each cm, 4.5% higher plasma ACTH; 95% CI 1.2–8.0%; P = 0.008). These relationships were further illustrated by linear regression showing that a 1 kg higher birth weight was associated with 24.9% (95% CI 4.2–49.8%) higher peak ACTH and with 19.2% higher (95% CI 2.1–39.2%) ACTH AUC (Fig. 2Go) and that longer length at birth was also associated with higher baseline (P = 0.02) and peak (P = 0.002) ACTH and ACTH AUC (P = 0.002). No associations were seen with ponderal index (mixed model P > 0.7) or gestational age (P > 0.6) at birth, and birth data were not related to ACTH stress response (P > 0.2).


Figure 2
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  		FIG. 2. Salivary and plasma cortisol and plasma ACTH time-weighted AUCs and the ratio of plasma cortisol to ACTH AUCs in relation to birth weight, adjusted for gestational age and sex. The lines show regression coefficients with 95% CIs. Quadratic (parabolic) lines are shown for cortisol and linear for ACTH and cortisol to ACTH ratio.

 
Nonlinear associations between size at birth and HPAA function during psychosocial stress

Mixed-model analyses showed quadratic relationships between birth weight and salivary (P = 0.001) and plasma cortisol (P = 0.005) but not with plasma ACTH (P = 0.1). Similar quadratic relationships were seen between length at birth and salivary (P = 0.005) and plasma cortisol (P = 0.01) but not with plasma ACTH (P = 0.5). No quadratic relationships were seen with ponderal index or gestational age. These relationships are illustrated in Fig. 1Go and Table 2Go, which show salivary and plasma cortisol and plasma ACTH concentrations before and after the TSST according to thirds of birth weight adjusted for sex and gestational age (less than 3124 g; 3125–3496 g; ≥3497 g). Relationships between birth weight and the AUCs are also shown in Fig. 2Go.


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  		TABLE 2. Geometric means (95% CI) of cortisol and ACTH concentrations, their relative increment, and AUC according to birth weight

 
Effect of disease and social class

Cortisol and ACTH concentrations or reactivity were not associated with social class in childhood or in adulthood. Adjusting for social class had little effect on the results. Consistent with previous studies in the source cohort (4, 39), a history of hypertension was present in 43.1% of subjects in the lowest birth weight third, 39.6% in the middle third, and 29.2% in the highest third (P for linear trend = 0.06, adjusted for age, sex, and gestational age), and diabetes had been diagnosed in 22.1, 15.8, and 11.4%, respectively (P = 0.2). Hypertension was related to 12.3% (95% CI –1.5 to 28.0%; P = 0.07) higher levels of salivary and 14.7% (4.8–25.5%; P = 0.003) higher plasma cortisol but not with ACTH (P = 0.7), whereas diabetes was associated with 17.8% (95% CI 4.8–32.5%; P = 0.006) higher plasma but not with salivary cortisol (P = 0.5) or plasma ACTH (P = 0.9). Hypertension and diabetes were not related to cortisol or ACTH reactivity (P values > 0.3). Depression was not related to cortisol or ACTH levels, but its effects on plasma cortisol showed a time interaction (P < 0.0001), suggesting higher reactivity in depressed subjects. Adjustment for these disorders had little effect on the results. When subjects with a history of depression were excluded from the mixed models, all statistically significant relationships with birth measurements remained so. This was also the case when subjects with diabetes were excluded. A history of coronary heart disease, stroke, or panic disorder was not related to cortisol or ACTH concentrations or reactivity.


   Discussion
Top
 Abstract
 Introduction
 Participants and Methods
 Results
 Discussion
References
 
We found that HPAA function during a standardized psychosocial stress challenge at age 60–70 yr is predicted by birth weight. The highest ACTH and cortisol concentrations were seen in individuals whose birth weight was in the middle third and lowest concentrations in individuals with low birth weight. The relationships were similar with hormone measurements at baseline, after stress and during recovery. Low birth weight was also associated with reduced cortisol to ACTH ratio, indicating attenuated responsiveness of the adrenal cortex to stimulation by ACTH.

Whereas standard biochemical HPAA tests such as the ACTH, CRH, and dexamethasone tests are important tools when assessing the function of specific levels of the HPAA, a standardized psychosocial stressor measures how social challenges an individual is likely to face from day to day affect HPAA function. The TSST has been carefully developed to include components of social-evaluative threat and uncontrollability, which are key elements in initiating an HPAA response (35), and produces robust ACTH and cortisol responses that are on average of similar magnitude than, for example, those after a 100-µg human CRH test (29).

Our results confirmed previous findings linking body size at birth with HPAA function in adult life (10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 21, 29). They add to previous literature by showing that this relationship exists in late middle-aged men and women in conjunction with a psychosocial stress challenge resembling stressful events encountered in everyday life. To our knowledge this has previously been shown only in prepubertal boys and young adult men: Jones et al. (31) found an inverse association between birth weight and salivary cortisol response in 7- to 9-yr-old boys but not girls. Wüst et al. (30) studied young adult male twin pairs and also showed an inverse relationship between birth weight and salivary cortisol response. No females were included in that study. The lack of relationship between birth weight and salivary cortisol response in 58-yr-old subjects of the Dutch Famine Birth Cohort (33) should be interpreted with caution because of the modest cortisol responses in that study.

The inverse U-shaped relationship we observed may reflect two different patterns/mechanisms of programing operating in this population. The higher birth weight part of the U parallels previous reports linking lower birth weight with increased HPAA activity (11, 12, 13, 14, 15). These findings are consistent with a hypothesis that had arisen from animal studies, suggesting that low birth weight is a sign of increased glucocorticoid exposure during the fetal period, leading to permanent resetting of the HPAA (40), perhaps in part through reducing feedback inhibition (9, 41). Increased HPAA activity is well known to be associated with risk factors of cardiovascular disease such as impaired glucose regulation, hypertension, and depression, and HPAA programing is an important putative mechanism in linking these disorders with low birth weight.

With this background, our observation of lower ACTH and cortisol concentrations in subjects in the lowest third of birth weights seems counterintuitive. This may represent an effect specific to the lower end of the birth weight spectrum: because of our focus on the lower end of the birth weight distribution, by design the lowest third of the birth weights represents the lowest tenth of birth weight adjusted for sex and gestational age in the original cohort. Low birth weight has indeed been associated with reduced HPAA activity in a number of previous studies. A study that compared 60- to 69-yr-old men in the bottom and top quartiles of birth weight (29) showed lower ACTH and cortisol responses to a dexamethasone-human CRH test in the low birth weight group. In another study of 65- to 75-yr-old subjects, we found lower morning fasting (17) or dexamethasone-suppressed (19) cortisol concentrations in subjects of lower birth weight, albeit only in those who were born after term. A study in adult twins of a wide age range showed lower morning fasting cortisol in the twin of lower birth weight (23). Although these findings differ in detail, a common feature is that the association between low birth weight and reduced HPAA activity would easily have been missed if assessing only linear effects throughout the normal variation of birth weights.

We do not know whether the lower HPAA response to psychosocial stress represents an intrinsic characteristic of the individuals in the low birth weight group or whether it developed later during life. Apart from the study in twins (23), associations between low birth weight and reduced HPAA function have been observed in people aged 60 yr or older (17, 19, 29). Although on average HPAA responses to psychosocial stress increase with age (32, 42), a hyporeactive HPAA may develop in a subset of individuals after exposure to prolonged periods of stress together with HPAA hyperreactivity (24). People born at term with low birth weight may be more likely to experience psychosocial stress in middle age (43). Given the large body of animal and human evidence discussed above (9, 10, 11, 12, 13, 14, 31, 40, 41), one might expect that individuals with lower birth weight are more likely to develop HPAA hyperactivity if confronted by chronic stress and consequently more likely to develop a hypoactive HPAA when approaching older age.

Another possibility is that HPAA hypoactivity is a lifelong characteristic programmed by prenatal conditions. There is evidence for this phenomenon in animal studies (44).

Hypoactive HPAA is a key feature of disorders such as posttraumatic stress disorder (24, 25, 45), fibromyalgia (24, 27), and chronic fatigue syndrome (24, 27, 28). The hypocortisolism characteristic of these disorders may be a consequence of enhanced global tissue sensitivity to glucocorticoids in the men and women with low birth weight. The lower circulating glucocorticoid concentrations may then be interpreted as a central adaptation to limit glucocorticoid action in target tissues. There is good clinical evidence for substantial individual differences in glucocorticoid sensitivity and evidence at least in animal models that this can be enhanced by early nutritional or pharmacological interventions (8). Our findings thus raise the question whether a subset of individuals with low birth weight are more susceptible to various hypocortisolism-related disorders, at least at an older age. We are unaware of any study that would have assessed this directly.

In accordance with most previous studies (10), we found higher cortisol and ACTH concentrations in men than women. However, the association between birth weight and cortisol and ACTH concentrations was similar in men and women. Previous observations have not been uniform: in a study of prepubertal children, birth weight was related to cortisol stress response in boys but not girls (31), whereas a recent study showed a relationship between birth weight and hippocampal size, a proposed marker of glucocorticoid exposure, in a group of women but not men (46). The dissimilarities in the patterns of sex differences may reflect the different age and hormonal status of the groups studied (10).

There are limitations to this study. Anticipation of stress may have affected baseline values and reduced our ability to find relationships with stress reactivity, i.e. differences from baseline, in particular because no samples obtained during a nonstressful day were available. Moreover, a random sample in this age group inevitably includes subjects with chronic disorders that may affect HPAA function. However, although this may introduce heterogeneity, our results remained similar when subjects with diabetes or depression were excluded.

In conclusion, we found an inverse U-shaped relationship between birth weight and cortisol concentrations during a psychosocial stress challenge at age 60–70 yr. The lowest cortisol and ACTH concentrations were seen in men and women with lowest birth weights. These results reinforce previous suggestions that both hyper- and hypocortisolism may be programmed during the fetal period and prompt further studies on early life origins of hypocortisolism and associated disorders.


   Acknowledgments
 
We are indebted to our research nurses Leena Järvinen and Paula Nyholm and research assistants Mauri Niiniaho, Riikka Pyhälä, and Jarkko Volanen. We also thank the researchers and staff at the Department of Psychology, University of Helsinki, who gave their time in the TSST committee.


   Footnotes
 
This work was supported by the Academy of Finland, British Heart Foundation, Finnish Foundation for Cardiovascular Research, Finnish Foundation for Pediatric Research, Finnish Diabetes Foundation, Finnish Medical Societies (Duodecim and Finska Läkaresällskapet), Juho Vainio Foundation, Novo Nordisk Foundation, Päivikki and Sakari Sohlberg Foundation, Signe and Ane Gyllenberg Foundation, University of Helsinki, and Yrjö Jahnsson Foundation.

Disclosure Statement: The authors have nothing to disclose.

First Published Online September 11, 2007

Abbreviations: AUC, Area under the curve; BMI, body mass index; CI, confidence interval; HPAA, hypothalamic-pituitary-adrenal axis; TSST, Trier Social Stress Test.

Received July 11, 2007.

Accepted August 30, 2007.


   References
Top
 Abstract
 Introduction
 Participants and Methods
 Results
 Discussion
 References
 

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