Abstract
BackgroundIn adults, hypothalamus–pituitary–adrenal (HPA) axis activity shows sexual dimorphism, and this is thought to be a mechanism underlying sex-specific disease incidence. Evidence is scarce on whether these sex differences are also present in childhood. In a meta-analysis, we recently found that basal (non-stimulated) cortisol in saliva and free cortisol in 24-h urine follow sex-specific patterns. We explored whether these findings could be extended with sex differences in HPA axis reactivity.MethodsFrom inception to January 2016, PubMed and EMBASE.com were searched for studies that assessed HPA axis reactivity in healthy girls and boys aged ≤18 years. Articles were systematically assessed and reported in the categories: (1) diurnal rhythm, (2) cortisol awakening response (CAR), (3) protocolled social stress tests similar or equal to the Trier Social Stress Test for children (TSST-C), (4) pharmacological (ACTH and CRH) stress tests, and (5) miscellaneous stress tests.ResultsTwo independent assessors selected 109 out of 6158 records for full-text screening, of which 81 studies (with a total of 14,591 subjects) were included. Studies showed that girls had a tendency towards a more variable diurnal rhythm (12 out of 29 studies), a higher CAR (8 out of 18 studies), and a stronger cortisol response to social stress tests (9 out of 21 studies). We found no evidence for sex differences in cortisol response after a pharmacological challenge or to miscellaneous stress tests.DiscussionSex differences in HPA axis reactivity appear to be present in childhood, although evidence is not unequivocal. For a better evaluation of sex differences in HPA axis reactivity, standardization of protocols and reports of stress tests is warranted.
Highlights
In adults, hypothalamus–pituitary–adrenal (HPA) axis activity shows sexual dimorphism, and this is thought to be a mechanism underlying sex-specific disease incidence
Martikainen et al [29] (n = 252, age 8.1 ± 0.3 years) reported a higher cortisol level at awakening in girls, while there was no difference between sexes at nadir, suggesting a steeper cortisol decline over the day in girls compared to boys
Netherton et al [37] (n = 129, age 12.8 ± 0.19 years) found higher morning cortisol levels in mid- to postpubertal girls compared to boys, but no sex differences were found in evening cortisol levels
Summary
Hypothalamus–pituitary–adrenal (HPA) axis activity shows sexual dimorphism, and this is thought to be a mechanism underlying sex-specific disease incidence. In a meta-analysis, we recently found that basal (non-stimulated) cortisol in saliva and free cortisol in 24-h urine follow sex-specific patterns We explored whether these findings could be extended with sex differences in HPA axis reactivity. Sexually dimorphic HPA axis reactivity has been reported in Hollanders et al Biology of Sex Differences (2017) 8:23 adulthood: men showed a greater cortisol response to acute real-life or controlled laboratory psychological stress compared to women [4]. Cortisol responses increased with age in both men and women, but the effect was threefold 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 hypothalamus–pituitary–gonadal (HPG) axis are thought to mediate sex-specific stress reactions as well as pathophysiology [7]
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