In healthy young and elderly adults, hypothalamic-pituitary-adrenocortical axis reactivity (HPA AR) varies with increasing pharmacological challenge and with age, but not with gender Martin Hatzinger a, * , Serge Brand b , Natalie Herzig b , Edith Holsboer-Trachsler b a Psychiatric Hospital, Solothurn, Switzerland Weissensteinstrasse 102, 4503 Solothurn, CH, Switzerland b Psychiatric Hospital of the University of Basel, Depression Research Unit, Switzerland article info Article history: Received 17 March 2011 Received in revised form 12 May 2011 Accepted 12 May 2011 Keywords: HPA activity Aging Corticosteroid receptors Cortisol DEX/CRH-test abstract Background: Hypothalamic-pituitary-adrenocortical axis reactivity (HPA AR) is the key indicator of the psychophysiological response to stress. The HPA AR may vary with age and gender. To investigate these factors concurrently, the aims of the present study were to observe HPA AR (plasma ACTH and plasma cortisol) in response to a pharmacological challenge (dexamethasone/corticotropin releasing hormone test: DEX/CRH-test) and as a function of age and gender. Method: 19 young (10 females and 9 males; mean age ¼ 24.05 years) and 23 elderly (11 females and 12 males; mean age ¼ 71.61 years) healthy volunteers took part in the study. To assess HPA AR, participants underwent the combined DEX/CRH test applied with the following DEX doses: 0.75, 1.5, and 3.0 mg, respectively. Results: A dose-dependent response was observed in young adult participants, but not in elderly participants. With increasing DEX doses, ACTH and cortisol values decreased in young adult participants, while the decrease was blunted among elderly compared to young adult participants. No differences were observed for gender. Conclusions: Results point to diminished HPA axis sensitivity as an effect of normal aging, irrespective of gender. Therefore, altered HPA regulation in old age should be taken into account for developing new therapeutic approaches acting on the HPA axis and its receptor mechanisms. Ó 2011 Elsevier Ltd. All rights reserved. 1. Introduction A hallmark of the neuroendocrine response to perceived and acute stress is the hypothalamic-pituitary-adrenocortical axis reactivity (HPA AR). Specifically, the secretion of glucocorticoids, namely cortisol in humans and corticosterone in animals, enables the organisms to adapt quickly and effectively to perceived stress (McEwen, 2007), that is to say, rapidly to adapt behavior and cognitive-emotional processes to altered conditions (Holsboer and Ising, 2010; Jezova and Hlavacova, 2008). The aim of a rapidly adapting HPA AR is to enable the organism to interact optimally with environmental demands and to protect itself from harm. However, prompt determination of the stress response is key to inhibiting detrimental effects of disproportionate CRH (cortico- tropin-releasing hormone) and glucocorticoids. Indeed, over- activity of the HPA axis and an inability to regulate the stress response are associated with an increased risk for psychiatric disorders. To illustrate, compelling evidence indicates that the HPA axis is compromised in major depressive disorders (Hatzinger et al., 2004; for review: Holsboer, 2007; Zimmermann and Stansbury, 2004; Holsboer and Ising, 2010; Wolkowitz et al., 2010), in anxiety disorders such as posttraumatic stress disorder (Kessler et al., 1995; Heim et al., 2001, 2008), and in separation anxiety disorder in children (Brand et al., 2011). Moreover, there is an evidence that early adverse experiences in childhood such as physical, sexual or psychological abuse, neglect or loss lead to a stable and long-lasting deterioration in HPA AR (Heim et al., 2000, 2008). To explain this deterioration, findings from animal studies lend support to the hypothesis that early adverse experience leads to functional impairment of the glucocorticoid receptor (GR) in the hippocampus and consequently to impaired feedback regulation and increased stress responsiveness (De Kloet et al., 1998; Heim et al., 2008; Weaver et al., 2004). With respect to aging, there is considerable evidence that normal aging has an influence on the neuroendocrine stress response, and altered HPA axis reactivity with aging is supposed to * Corresponding author. Tel.: þ41 32 627 14 50, fax: þ41 32 627 14 66. . E-mail address: martin.hatzinger@spital.so.ch (M. Hatzinger). Contents lists available at ScienceDirect Journal of Psychiatric Research journal homepage: www.elsevier.com/locate/psychires 0022-3956/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.jpsychires.2011.05.006 Journal of Psychiatric Research 45 (2011) 1373e1380