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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2005-2077
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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 5 1868-1871
Copyright © 2006 by The Endocrine Society

BRIEF REPORT

Fetal Growth and the Adrenocortical Response to Psychological Stress

Alexander Jones, Keith M. Godfrey, Peter Wood, Clive Osmond, Peter Goulden and David I. W. Phillips

Medical Research Council, Southampton General Hospital, Southampton SO16 6YD, United Kingdom

Address all correspondence and requests for reprints to: Dr. Alex Jones, Medical Research Council, Southampton General Hospital, Tremona Road, Southampton SO16 6YD, United Kingdom. E-mail: aj{at}mrc.soton.ac.uk.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Context: Experimental studies in animals show that adverse prenatal environments lead to lifelong alterations in the activity of the hypothalamic-pituitary-adrenal axis, which mediates the stress response through secretion of glucocorticoid hormones. The extent to which such prenatal hypothalamic-pituitary-adrenal axis adaptations occur in humans is unknown.

Objective: The objective of the study was to determine whether smaller but otherwise healthy term babies are more likely to demonstrate increased glucocorticoid responses to psychological stress in childhood.

Design and Participants: This was a cross-sectional study of 68 boys and 72 girls (aged 7–9 yr) who have been followed up since 12 wk gestation when their mothers took part in a study of healthy children born in Southampton, United Kingdom.

Main Outcome Measure: Salivary cortisol responses to psychological stress were measured.

Results: In boys, birth weight was inversely related to salivary cortisol responses to stress (r = –0.56, P < 0.001) but not morning cortisol levels, whereas in girls, morning peak cortisol was inversely related to birth weight (r = –0.36, P < 0.05). These associations were independent of gestational age and potential confounding factors including obesity, social class, and educational achievement.

Conclusions: This study suggests that processes occurring during fetal life, resulting in smaller newborns, have a lasting effect on adrenocortical responses to stress in boys and on basal adrenocortical activity in girls. Given the known associations between small alterations in adrenocortical activity and features of the metabolic syndrome such as raised blood pressure and glucose intolerance, these effects warrant further investigation of their potential impact on the future health of prepubertal children.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
LOW BIRTH WEIGHT is associated with the metabolic syndrome and cardiovascular disease in adult life. These associations are thought to result from adverse prenatal environmental influences that reduce fetal growth and induce thrifty developmental responses in the fetus. These responses may be beneficial if the offspring continue to live in adverse environments but are inappropriate and predispose to disease if the postnatal environment is one of nutritional excess (1). Animal studies demonstrate that changes in the set point of several hormonal systems, particularly the hypothalamic-pituitary-adrenal axis (HPAA), may have an important role in developmental adaptation to harsh environments (2). These changes may be induced prenatally by nutrient restriction, maternal adversity, and glucocorticoid exposure or postnatally by neonatal handling, maternal deprivation, and infection, for example (3).

In humans, although lower birth weight is linked to increased fasting cortisol concentrations (4), it does not appear to relate to cortisol secretion in the unstressed state (5). We hypothesized that induction of psychological stress by venesection for fasting cortisol may account for this disparity (6). Therefore, we examined the relationship between birth weight and HPAA stress responsivity. Reliable induction of HPAA responses to psychological stimuli requires motivation of the subject to perform well in a task with elements of uncontrollability and social evaluative threat that occurs when an important aspect of self-identity is, or could be, negatively judged by others (7). Ensuring such factors in adults is often difficult due to the confounding influences of expectation and prior experience. Consequently, we studied children using the Trier Social Stress Test for Children (TSST-C) (8) and increased motivation by offering toys as a potential reward for high performance. Because they were unaccompanied by their parents during the TSST-C, uncontrollability was also enhanced. It is increasingly apparent that many of these factors alter HPAA activity in a gender-specific manner (9). Therefore, we studied both genders separately.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
We recruited healthy children (68 boys and 72 girls, aged 7–9 yr) who have been followed up since 12 wk gestation when their mothers took part in a study of children born in Southampton, UK (10). Birth weight was recorded, and duration of gestation was estimated from menstrual history and ultrasound scan data.

To assess their baseline adrenocortical function, the children were asked to use a home-testing kit to collect salivary cortisol at five time points [on awakening, 30 min later, 1230 h (before lunch), 1530 h, and 1830 h (before evening meal)] on a restful day (usually a weekend or holiday) when the children were taking no part in activities.

On a different day, the children attended a clinical research facility for the TSST-C, which was timed to occur in the afternoon (1330–1430 h) when diurnal secretion of cortisol is leveling out. Lunch times were arranged to be at least 11/2 h before the test to avoid postprandial effects on cortisol. During their visit, a dual-energy x-ray absorptiometry scan was performed to measure body composition. Parents were asked to change their appointment if stressful events or illness occurred in their family in the preceding week. Parents and children gave written informed consent.

The children were asked to stand in front of a video camera and microphone and perform an exciting story of their own invention followed by a serial subtraction task for an audience of three adult strangers. They had 5 min to prepare before the stress test, which lasted 10 min. The original TSST-C protocol (8) was modified to reduce task difficulty appropriately for our younger age group, and motivation was increased by offering toys as potential rewards for high performance. These modifications were tested in a pilot study of 20 subjects of the same age and shown to stimulate HPAA responses comparable with those reported previously (8). Saliva samples were collected at seven time points during their visit (on arrival, 1 h later, just before the TSST-C, and then at 10-min intervals after the stress test). The local research ethics committee approved the study.

Assay

Salivary cortisol concentrations were measured using a time-resolved immunofluorescent assay (DELFIA) (11). This assay has a lower limit of detection of 0.4 nmol/liter and an interassay coefficient of variation of 5–10% between 2 and 15 nmol/liter.

Statistical methods

Baseline values corresponding to the period of the clinic visit were calculated by linear interpolation of the home data using time of awakening as a common reference point for the home and clinic series (Fig. 1Go, main graphs). The difference between the area under the clinic curve and the area under the equivalent time period of the home curve was used to estimate the stress-induced change in cortisol concentration. Because this measure might be biased by variations in the interval between first and last salivary sampling, we divided area under the curve by this interval to yield time-weighted mean. Because season (12) and time of day (7) affect HPAA function, we adjusted for their confounding influence. Associations with birth weight were also adjusted for gestational age to examine the effects of growth restriction on our outcome measures and not prematurity. Skewed data were log transformed. Differences in cortisol between genders or between pre- and poststress measures were assessed using t tests. All other analyses were performed using multiple linear regression, and results are presented as normalized regression coefficients, analogous to correlation coefficients.


Figure 1
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  		FIG. 1. Geometric mean (± SEM) salivary cortisol profiles during a restful day (dashed line) and a clinic visit (solid line) for the TSST-C (shaded vertical bar) in boys (upper panel) and girls (lower panel). The inset graphs show the relationship between time-weighted mean cortisol responses (comparing home and clinic visit cortisol concentrations) and birth weight adjusted for gestational age. Linear regression and 95% confidence interval lines are shown.

 

   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Figure 1Go shows comparisons between cortisol profiles at home with those obtained during the clinic visit in both boys (Fig. 1Go, upper main graph) and girls (Fig. 1Go, lower main graph). Home profiles did not differ significantly between genders with the exception of the awakening response, which was evident in boys but not girls (P = 0.04 for difference in increment between awakening and 30 min later). During the clinic visit, cortisol profiles were similar in boys and girls until the poststress measures, which were greater in the girls (P < 0.05 for last three samples). In both genders, cortisol had risen in anticipation of the stress test (P < 0.001 for comparison of second and third samples). In girls, the further rise was significant (P < 0.001 for comparisons of third sample with all following samples), whereas boys showed no further increment in cortisol.

Table 1Go shows the birth weight relationships with home and clinic cortisol measurements. In boys, we found a strong inverse relationship between birth weight adjusted for gestational age and HPAA stress responsivity (Fig. 1Go, upper inset graph) when home cortisol profiles were used as a baseline but not when prestress clinic levels were used. In boys, birth weight was not related to the home baseline cortisol values or to morning peak cortisol levels but was positively associated with evening nadir levels (1830 h). By contrast, birth weight of girls was not associated with HPAA responsivity (Fig. 1Go, lower inset graph) or evening nadir levels but was inversely associated with morning peak cortisol. On additional multiple regression analysis, all of our findings were found to be independent of social class, educational achievements, and markers of obesity such as body mass index and percentage body fat derived by dual-energy x-ray absorptiometry.


View this table:
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  		TABLE 1. Normalized regression coefficients showing associations between birth weight and salivary cortisol measures during a restful day at home and a clinic visit for a stress study in boys and girls

 

   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
These data suggest that the effects of the prenatal environment on the HPAA are significant and lasting but gender specific. Lower birth weight in boys, but not girls, is associated with greater HPAA stress responsivity, and, because this is seen with adjustment for gestational age, this reflects the effect of growth restriction rather than prematurity. Less expected were the associations between birth weight and morning peak cortisol in girls and evening nadir cortisol in boys. These findings are also at variance with data from adults (5, 6), which found no such associations, and therefore require confirmation. In animals, females appear to be generally more susceptible to programing of HPAA stress responsivity, which also stands in contrast to our findings. However, to our knowledge, there have been no previous studies examining the role of gender in programming of HPAA stress responsivity in humans, which may differ between species.

We also found gender differences in the pattern of both home and clinic cortisol profiles. In comparison with girls, boys had a clear postawakening rise of cortisol and similar anticipation of the stress task and did not show a significant further increment of cortisol after stress (Fig. 1Go, main graphs). Although there is still much debate about the biological meaning of morning peak cortisol, several authors (13) have suggested that this acts to prepare individuals for expected metabolic and psychosocial demands of the day. One interpretation of these findings is that, in this age group, the HPAA plays a greater preparatory role in boys and a more reactive role in girls, but this requires confirmation in future studies.

An important decision in the design of our study was to use measures of cortisol at home as a baseline for comparison with measures during stress. Previous stress studies have generally used prestress cortisol measures from the clinic setting as a baseline. However, there is increasing evidence that HPAA function is altered well in advance of arrival for such studies by the anticipated threat of the visit itself. For example, a study of 9-yr-old girls showed that laboratory baseline cortisol measures were 40% greater than measures at home, and several animal studies show that relocation alone is a stimulus for increased HPAA activity (14). This may explain why the association between birth weight and HPAA responsivity was stronger in our study than in the only previously reported study of programing of HPAA responsivity, which was carried out in adult male twins (15). Because birth weight did not relate significantly to either time-weighted mean home or clinic cortisol concentrations (Table 1Go), it is likely that our result represents an association between birth weight and stress responsivity (clinic – home) rather than differences in underlying basal cortisol production.

It has been noted that studies of preschool children in which home baselines were obtained almost universally report significantly lower cortisol levels during the clinic visit than at home, whereas in adults and older children, the opposite is generally true (14). A proportion of high birth weight boys appear to have higher home cortisol levels than those measured during the stress visit (Fig. 1Go, upper inset graph), which is similar to the pattern observed in preschool children. Although little is known about HPAA maturation, this similarity raises the possibility that an inverse association between rate of HPAA maturation and birth weight might explain our findings in the boys.

This study suggests that processes occurring during fetal life, resulting in smaller newborns, have a lasting effect on adrenocortical responses to stress in boys and basal adrenocortical activity in girls. Given the known associations between small alterations in adrenocortical activity and features of the metabolic syndrome such as raised blood pressure and glucose intolerance, these effects warrant further investigation of their potential impact on the future health of prepubertal children.


   Acknowledgments
 
We are extremely grateful to Tracey Tudball and the staff of the Wellcome Trust Clinical Research facility for their work on this study; John Kerslake at Cadbury-Schwepps for donation of Trident sugar-free gum; and Toys R’Us, Tomy, Mattel, and Bandai for their generous donation of toys. We also thank Megan Gunnar, Bonny Donzella, Carol Worthman, and Clemens and Angelika Kirschbaum for helpful discussion in setting up the study.


   Footnotes
 
This work was supported by the National Institute of Child Health and Human Development Grant 1 R01 HD41107-01.

A.J., K.M.G., P.W., C.O., P.G., and D.I.W.P. have nothing to declare.

First Published Online February 7, 2006

Abbreviations: HPAA, Hypothalamic-pituitary-adrenal axis; TSST-C, Trier Social Stress Test for Children.

Received September 20, 2005.

Accepted February 1, 2006.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

  1. Bateson P, Barker DJP, Clutton-Brock T, Deb D, D’Udine B, Foley RA, Gluckman PD, Godfrey KM, Kirkwood T, Lahr MM, McNamara J, Metcalfe NB, Monaghan P, Spencer HG, Sultan SE 2004 Developmental plasticity and human health. Nature 430:419–421[CrossRef][Medline]
  2. Wingfield JC, Maney DL, Breuner CW, Jacobs JD, Lynn S, Ramenofsky M, Richardson RD 1998 Ecological bases of hormone-behavior interactions: the "emergency life history stage." Am Zool 38:191–206
  3. Matthews SG 2002 Early programming of the hypothalamo-pituitary-adrenal axis. Trends Endocrinol Metab 13:373–380[CrossRef][Medline]
  4. Phillips DIW, Barker DJP, Fall CHD, Seckl JR, Whorwood CB, Wood PJ, Walker BR 1998 Elevated plasma cortisol concentrations: a link between low birth weight and the insulin resistance syndrome? J Clin Endocrinol Metab 83:757–760[Abstract/Free Full Text]
  5. Fall CH, Dennison E, Cooper C, Pringle J, Kellingray SD, Hindmarsh P 2002 Does birth weight predict adult serum cortisol concentrations? Twenty-four-hour profiles in the United Kingdom, 1920–1930; Hertfordshire Birth Cohort. J Clin Endocrinol Metab 87:2001–2007[Abstract/Free Full Text]
  6. Kajantie E, Eriksson J, Osmond C, Wood PJ, Forsen T, Barker DJ, Phillips DI 2004 Size at birth, the metabolic syndrome and 24-h salivary cortisol profile. Clin Endocrinol (Oxf) 60:201–207[CrossRef][Medline]
  7. Dickerson SS, Kemeny ME 2004 Acute stressors and cortisol responses: a theoretical integration and synthesis of laboratory research. Psychol Bull 130:355–391[CrossRef][Medline]
  8. Buske-Kirschbaum A, Jobst S, Wustmans A, Kirschbaum C, Rauh W, Hellhammer DH 1997 Attenuated free cortisol response to psychosocial stress in children with atopic dermatitis. Psychosom Med 59:419–426[Abstract/Free Full Text]
  9. O’Regan D, Kenyon CJ, Seckl JR, Holmes MC 2004 Glucocorticoid exposure in late gestation in the rat permanently programs gender-specific differences in adult cardiovascular and metabolic physiology. Am J Physiol Endocrinol Metab 287:E863–E870
  10. Godfrey KM, Walker-Bone K, Robinson S, Taylor P, Shore S, Wheeler T, Cooper C 2001 Neonatal bone mass: influence of parental birthwieght, maternal smoking, body composition, and activity during pregnancy. J Bone Miner Res 16:1694–1703[CrossRef][Medline]
  11. Wood PJ, Kilpatrick K, Barnard G 1997 New direct salivary cortisol and cortisone using the ‘DELFIA’ system. J Endocrinol 155:71 (Abstract)
  12. Maes M, Mommen K, Hendrickx D, Peeters D, D’Hondt P, Ranjan R, De Meyer F, Scharpe S 1997 Components of biological variation, including seasonality, in blood concentrations of TSH, TT3, FT4, PRL, cortisol and testosterone in healthy volunteers. Clin Endocrinol (Oxf) 46:587–598[CrossRef][Medline]
  13. Clow A, Thorn L, Evans P, Hucklebridge F 2004 The awakening cortisol response: methodological issues and significance. Stress 7:29–37[Medline]
  14. Gunnar MR 2003 Integrating neuroscience and psychological approaches in the study of early experiences. Ann NY Acad Sci 1008:238–247[CrossRef][Medline]
  15. Wust S, Entringer S, Federenko IS, Schlotz W, Hellhammer DH 2005 Birth weight is associated with salivary cortisol responses to psychosocial stress in adult life. Psychoneuroendocrinology 30:591–598[CrossRef][Medline]



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