Glucocorticoid regulation throughout childhood: developmental aspects

Background The topic of this thesis is inter-individual variability in the activity of the hypothalamic pituitary adrenal (HPA) axis. In literature, a large variability has been demonstrated for both basal and peak cortisol levels. Examining the sources of this variability is important, since activity of the HPA axis may have consequences for long-term outcomes. Summary of the results Part 1: Glucocorticoid regulation throughout puberty Inter-individual variability of cortisol production and metabolism is a consequence of both genetic and environmental factors. In chapter 2 we explored the relative contribution of genetic and environmental factors to variability in HPA axis activity in children aged 9 to 17 years. We found that the environment plays a key role in the production of cortisol. This lends support to previous observations, suggesting that the settings of the HPA axis are mainly determined by individual circumstances. In chapter 3 we researched the stability of the HPA axis over time and found a low stability for both cortisol metabolite excretion rate and cortisol metabolism activity indices, indicating that the processes underlying the genetic and environmental contributions are dynamic over time. Inter-individual variability in HPA axis activity might partially be explained by sex dimorphism, which has been described in adulthood, and, interaction between gonadal steroids and cortisol metabolism has been suggested by several studies. In chapter 4 we assessed the contribution of pubertal development to sex dimorphism in HPA axis activity and found that sexes were similar in cortisol parameters before the onset of puberty. During puberty, differences in cortisol metabolism pathways emerged. In chapter 5 we demonstrated that body mass index predicted cortisol metabolite excretion rate later in puberty. Alterations in HPA axis activity as observed among children and adolescents with obesity may therefore be a consequence rather than a cause of increase body mass index. Part 2: Glucocorticoid regulation in early life In addition to sex differences during puberty, we focused on differences between boys and girls in early life. Among preterm infants, sex differences in morbidity and mortality have previously been demonstrated. For example, neonatal mortality risk is higher in boys compared to girls. Sex-specific differences in HPA axis activity might offer an explanation for these differences in clinical outcomes. In chapter 6 we did not find sex differences in adrenocortical function at 10 days postnatal age in preterm born infants. However, sex differences in adrenocortical function became manifest under stressful circumstances. These differences might offer an explanation for the male disadvantage following preterm birth. Early-life experiences may permanently alter the settings of the HPA axis. There is emerging evidence demonstrating that nutrition during early-life stress exposure may ameliorate the long-term consequences of dysregulation of the HPA axis, but the possible mechanistic insights in this process are sparsely reported. In chapter 7 we discussed the programming effects of early-life stress and its underlying mechanisms. Moreover, we discussed how nutrition could impact these processes. Part 3: Specific genetic influences Chapter 8 describes the disease course of a girl with a rare neurological syndrome, caused by a homozygote pathogenic mutation in NGLY1. For unknown reasons, mortality is increased in patients with this condition. This chapter provides adrenal insufficiency as a possible explanation for this increased mortality. An inadequate stress response due to adrenal insufficiency may lead to a life-threatening situation. Patients with NGLY1 deficiency may develop adrenal insufficiency as a consequence of impaired proteostasis, and proteotoxis stress-induced cell death. In this chapter we recommend an annual evaluation of adrenal function in all patients with NGLY1 mutations in order to prevent unnecessary deaths.