Bibian van der Voorn

15 PRETERM GLUCOCORTICOID PROGRAMMING Children born very preterm or with a VLBWwere found to display more internalizing problem behavior and attention problems as well as reduced scores on various cognitive tests 62 . Furthermore, imaging studies showed that very preterm birth and VLBW were associated with permanent reductions in, among other brain structures, hippocampal volume 63 . These patterns resemble those of term-born children who were exposed antenatally to higher maternal cortisol levels 64,65 . Findings from studies addressing the long-term effect of prematurity on several aspects of HPA axis activity were contradictory ( table 2 ). One study found that basal cortisol was higher in adults born preterm than in normal controls 58 . Another study found that this was already evident from the corrected age of 8 mo. for children born in the extremely preterm range 66 . Evidence for sex-specific effects was provided by Walker et al. 67 , who compared adults born preterm, with or without IUGR, with normal controls. In women, plasma cortisol was not different, but the total urinary cortisol metabolite excretion was lower in the preterm non-IUGR group than in the other 2 groups, suggestive of impairedmetabolic clearance. In contrast, no differences in cortisol parameters were observed in men. Yet another study found that ELBWwas associated with higher excretion rates of adrenal steroid metabolites at age 10 yrs 68 . Two out of 4 studies that assessed the cortisol response to psychosocial stress found that preterm birth was associated with blunted rather than enhanced responses 69-72 . Preterm birth was also associated with a higher salivary cortisol at bedtime 72 or over 24h 73 , and with a greater CAR in childhood 69 . Furthermore, very preterm carriers of the 23K variant of the R23K polymorphism in the glucocorticoid receptor ( GR ) gene, which is associated with resistance to cortisol, were found to display complete CUG before the age of 1 yr, while in the noncarriers, the stature remained around the –0.5 SD line 74 . In summary, these observations suggest that very preterm survivors show features of increased HPA axis activity that persist beyond the neonatal phase and extend into adulthood, although some studies were negative, and others, especially the ones that assessed the cortisol response to psychosocial stress, reported the opposite results. Signs of increased glucocorticoid bioactivity, such as an unfavorable body composition, raised blood pressure and insulin resistance, are already present in childhood 52,60,61 . Apparently, there is a large increment in the adrenal androgen production after an age-appropriate adrenarche, contributing to an earlier initiation of the pubertal growth spurt and advancement of bone maturation at adolescent age and, hence, earlier epiphyseal closure and shorter adult stature. The growth pattern of subjects born very preterm suggests that the growth-inhibiting actions of cortisol are outweighed by the anabolic effects of excess insulin and androgen levels.