Bibian van der Voorn

169 GENDER-SPECIFIC HPA AXIS REACTIVITY IN CHILDHOOD BACKGROUND Marked gender differences exist in the incidence of several diseases. While men are more prone to obesity, cardiovascular disease and infectious diseases, women are more susceptible to anxiety, depression and autoimmune diseases. Sex-specific risks for chronic, non-communicable diseases are thought to result from a combination of genotype, phenotype and environmental influences during life. Whereas adjustment to environmental challenges is healthy in the short term, developmental plasticity can cause sex-specific adverse effects in the long term. 1 One of the possible explanations for this sexual dimorphism in disease is a sex-specific reactivity of the hypothalamic-pituitary-adrenal (HPA) axis. HPA axis functioning can be distinguished by on the one hand the maintenance of homeostasis by controlling basal activity as well as the sensitivity to stressors, and on the other hand coping with, adapting to and recovery from reactions to stressors. These processes are controlled by mineralocorticoid and glucocorticoid receptors (MRs and GRs). MRs are mainly involved with basal HPA axis activity, whereas GRs predominantly regulate HPA axis reactivity. 2 In animals, receptor expression patterns appear to develop in a sex- specific manner, with sex differences already present at birth. 3 In humans, sexually dimorphic HPA axis reactivity has also been reported in adulthood: men showed a greater cortisol response to acute real-life or controlled laboratory psychological stress compared to women. 4 Additionally, cortisol responses increased with age in both men and women, but the effect was three-fold stronger in women compared to men, which could possibly be attributed to menopause. 5 These patterns closely resemble those of cardiovascular disease mortality and morbidity. 6 While the setting of HPA axis functioning results from the balance between MR and GR expression, 2 interactions with the hypothalamic–pituitary–gonadal (HPG) axis are thought to mediate sex-specific stress reactions as well as pathophysiology. 7 It has previously been hypothesized that disease susceptibility can originate in childhood, possibly through permanent alterations in HPA axis activity to environmental challenges. 1 We recently showed that basal HPA axis activity, represented by non-stimulated cortisol concentrations in saliva and free cortisol in 24h-urine, show sexual dimorphism, with a sex-specific change induced by puberty. 8 In addition, gender differences in the reactivity of the HPA axis have also been described in children, 4,9,10 although evidence is scarce and not systematically reviewed. Therefore, we aimed to examine whether sex-specific differences in HPA axis reactivity are present in childhood. To study this sex-specific reactivity of the HPA axis, we performed a systematic review of the literature. Reactivity of the HPA axis was defined as the response to either