ORIGINAL ARTICLE Blunted hypothalamic-pituitary-adrenal axis and insulin response to psychosocial stress in young adults born preterm at very low birth weight Nina Kaseva* , †, Karoliina Wehkalampi* , †, Riikka Pyha ¨ la ¨ ‡, Elena Moltchanova* , §, Kimmo Feldt‡, Anu-Katriina Pesonen‡, Kati Heinonen‡, Petteri Hovi* , †, Anna-Liisa Ja ¨ rvenpa ¨a ¨ †, Sture Andersson†, Johan G. Eriksson* , ¶ , ** , †† , ‡‡, Katri Ra ¨ ikk€ onen‡ and Eero Kajantie* , † *Department of Chronic Disease and Diabetes Prevention, National Institute for Health and Welfare, †Children’s Hospital, Helsinki University Central Hospital and University of Helsinki, ‡Institute of Behavioral Sciences, University of Helsinki, Helsinki, Finland, §Department of Mathematics and Statistics, University of Canterbury, Christchurch, New Zealand, ¶Department of General Practice and Primary Health Care, University of Helsinki, **Unit of General Practice, Helsinki University Central Hospital, Helsinki, ††Vasa Central Hospital, Vasa and ‡‡Folkha ¨lsan Research Centre, Helsinki, Finland Summary Background Young adults born preterm at very low birth weight (VLBW, ≤1500 g) have higher levels of cardiovascular risk factors, including impaired glucose regulation, than their term-born peers. This could be mediated through altered hypo- thalamic-pituitary-adrenal axis (HPAA) response to stress. Objective To compare HPAA, glucose and insulin responses provoked by psychosocial stress in VLBW subjects versus a com- parison group of term-born controls. Design and participants We studied 54 unimpaired young adults, aged 19–27 years, born at VLBW and a comparison group of 40 adults born at term, group-matched for age, sex and birth hospital, from one regional centre in southern Fin- land. The participants underwent a standardized psychosocial stress test (Trier Social Stress Test, TSST). Measurements In conjunction with TSST, we measured sali- vary cortisol, plasma ACTH, cortisol, glucose and insulin. Data were analysed with mixed-effects model and multiple linear regression analyses. Results Baseline concentrations for cortisol, ACTH, insulin and glucose were similar in VLBW and comparison groups. During TSST, analysed with mixed-effects model, overall concentrations of plasma cortisol were 17Á2% lower (95% CI; 3Á5 to 28Á9) in the VLBW group. The VLBW group also had lower salivary (P = 0Á04) and plasma cortisol (P = 0Á02) responses to TSST. Insulin and glu- cose concentrations correlated with changes in cortisol concentra- tions. Accordingly, VLBW subjects had 26Á5% lower increment in insulin (95% CI; 9Á8–40Á1). Analyses were adjusted for age, sex, body mass index, hormonal contraception, menstrual cycle phase, time of day and parental education. Conclusions VLBW adults have lower HPAA responses to psy- chosocial stress than term-born controls. This is accompanied by a lower insulin response. (Received 27 March 2013; returned for revision 17 April 2013; finally revised 20 May 2013; accepted 22 May 2013) Introduction Individual reactions to psychosocial stressors vary. The stress response, including that of the hypothalamic-pituitary-adrenal axis (HPAA), is an important determinant of health and disease. For example, a hyperactive HPAA has been linked with depres- sion 1 , type 2 diabetes 2 and cardiovascular disease. 2 Hyporespon- siveness of the HPAA has been linked with several conditions, including fibromyalgia, post-traumatic stress disorder, burnout and depression. 3 It has been postulated that a hyporeactive HPAA might develop after prolonged periods of stress, characterized by hyperactivity of the HPAA. 4 Neonatal intensive care after preterm birth could represent such stress. Thus, preterm birth may be a risk factor, adversely affecting the future functioning of the HPAA. People born preterm at very low birth weight (VLBW, ≤1500 g) have, as adults, elevated risk factors for chronic non- communicable diseases, including impaired glucose regulation, 5,6 higher blood pressure 7–12 and lower bone mineral density. 13 Pre- term birth, especially when combined with intrauterine growth restriction, also constitutes a single independent risk factor for a range of psychiatric disorders such as depression, nonaffective psychosis, bipolar affective disorder and eating disorders. 14,15 However, preterm birth may also be associated with protective factors. Despite risk factors in young adults, studies have failed to show any association between preterm birth and coronary Correspondence: Nina Kaseva, Department of Chronic Disease and Diabetes Prevention, National Institute for Health and Welfare, P.O. Box 30, 00271 Helsinki, Finland. Tel.: +358 400 837526; Fax: +358 29 5248661; E-mail: nina.kaseva@fimnet.fi © 2013 John Wiley & Sons Ltd 1 Clinical Endocrinology (2013) doi: 10.1111/cen.12251