Bibian van der Voorn

182 CHAPTER 11 According to the Developmental Origins of Health and Disease (DOHaD) hypothesis, disease susceptibility arises early in development 1 and might be mediated by HPA axis (re)activity. Dysfunctional (hypo- or hyperreactive) HPA axis responses have previously been associated with cardiovascular disease risk. 97 In addition, more subtle differences in early HPA axis settings can also contribute to sex-specific disease risks throughout life. 10,98 Sex differences in HPA axis reactivity might be due to interactions between the HPA- and HPG axes, and several mechanisms have been proposed. Estradiol has been shown to enhance, while testosterone inhibited CRH gene transcription in the hypothalamus. 9 In addition, estradiol has been found to sensitize the pituitary, thereby increasing the ACTH response, while progesterone seemed to oppose this effect. 9 Moreover, estrogen receptors (ERs) are widely expressed throughout the brain, especially in the limbic system. Although not unequivocal, the distribution of the ER subtypes α and β, which have opposing actions on the HPA axis, 99 is probably sex-dependent. 100 In rats, gender differences in the expression of ERs were already present early in life. 101 It is possible that sex differences in the balance and distribution of ERα and ERβ in the brain are already present before puberty as a result of priming 1 or genetics, which subsequently change after the onset of puberty. In addition, the sensitivity of the adrenal cortex to ACTH is suggested to be increased in young women, 9 while estrogens were found to increase the production of corticosteroid-binding globulin (CBG), 102 decrease glucocorticoid receptor (GR) expression and activitation 7 and lower hepatic clearance of cortisol by inhibition of A-ring reduction . 103 In contrast, testosterone was found to inhibit the release of ACTH, while progesterone possibly acts as a glucocorticoid antagonist. 9,47,104 However, estrogens seem to have different effects in (postmenopausal) women and men, 105-107 and ACTH responses to a TSST after two weeks of DHEA or placebo treatment was found to be equal for women treated with DHEA to those of men, but increased compared to women taking placebos. 4 These HPA/HPG axes interactions might explain why the sex differences in HPA axis reactivity that we found in children are not corroborated by studies in adults. Moreover, some of the included studies in this review took pubertal status into account, 13,24,30,33,34,36,37,39,45,48,50-52,64,65,67,84,95 . Although different (sex-specific) effects of pubertal status on cortisol reactivity were found, HPA/HPG axes interactions might nevertheless play a role in the possible sex-specific changes in HPA axis reactivity throughout puberty. The different natures and effects of the applied stressors are something to take into account when assessing HPA axis reactivity. Different types of stressors activate