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 HPAA response to psychosocial stress in late adulthood.

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

Participants: 287 men and women born between 1934 and 1944 whose birth measurements and gestational age came from hospital records.

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 birthweight and low plasma ACTH but no linear relationship with cortisol. There were, however, quadratic relationships between birthweight 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/L (95% CI of mean 11.2–15.0), compared with 17.1 nmol/L (14.8–19.8) in the middle and 14.1 nmol/L (12.6–15.7) in the highest third or birth weights. Corresponding figures for plasma cortisol were 246 nmol/L (221–273), 271 nmol/L (244–302) and 166 nmol/L (227–289), and for plasma ACTH 4.02 pmol/L (3.51–4.61), 4.78 pmol/L (4.24–5.38) and 4.89 (4.30–5.57), 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.