Gender differences in hypothalamic–pituitary–adrenal (HPA) axis reactivity
Introduction
Activation of the hypothalamic–pituitary–adrenal (HPA) axis is an essential adaptive mechanism that enables the human body to maintain physiological stability in response to stressful stimuli (Herman and Cullinan, 1997, Chrousos, 1997, Tsigos and Chrousos, 2002). Following the perception of stress, corticotropin-releasing hormone (CRH) neurons in the hypothalamus receive regulatory impulses from several major neurotransmitter systems, including direct and indirect inhibitory signals from β-endorphin-producing neurons (Jackson et al., 1990, Calogero, 1995, Jessop, 1999). CRH release stimulates the synthesis and release of adrenocorticotropin (ACTH) by the anterior pituitary, which in turn stimulates the synthesis and release of cortisol by the adrenal cortex. There is evidence that healthy individuals react differently to stressful stimuli (Berger et al., 1987; Kirschbaum et al., 1995a), and that both enhanced and attenuated hormonal responses to stress are maladaptive. Chronic HPA axis dysregulation is associated with the development of mood and anxiety disorders, such as depression (Sapolsky, 2000, Gold and Chrousos, 2002, Sherwood Brown et al., 2004). Moreover, excess cortisol exposure is related to a variety of medical conditions including hypertension, atherosclerosis, obesity, insulin resistance, dyslipidemia, bone demineralization, and impaired immunity (McEwen, 1998, Tsigos and Chrousos, 2002). Likewise, it contributes to the development and maintenance of substance use disorders, such as alcohol dependence (Gianoulakis, 1998). Interestingly, pronounced differences in the prevalence of several of these disorders have been shown between men and women (Boyd and Weissman, 1981, Grant et al., 2002).
Previous studies suggest that gender influences the HPA axis hormonal responses to stress. In preclinical models, ACTH and corticosterone levels in response to stress have been shown to be consistently greater in females compared with males (Kitay, 1961, Handa et al., 1994, Armario et al., 1995). However, in human studies, no such clear-cut gender differences have been established. In response to psychological stressors in young subjects, certain studies have shown higher cortisol and ACTH responses in male subjects compared to females (Kirschbaum et al., 1992, Kirschbaum et al., 1995a, Kirschbaum et al., 1995b). Nevertheless, other studies have suggested that there are no significant gender differences in young subjects in response to stress (Collins and Frankenhaeuser, 1978, Frankenhaeuser et al., 1978). In a study of healthy young adults, Kirschbaum et al. (1999) showed that ACTH responses were elevated in men compared to women and that free cortisol responses were similar between men and women in the luteal phase of their menstrual cycle whereas women in the follicular phase or taking oral contraceptives showed lower free cortisol responses compared to males. The same gender effect was demonstrated in elderly subjects, with higher ACTH and cortisol responses in male subjects compared to females (Kudielka et al., 1998, Traustadottir et al., 2003). Conversely, higher HPA axis hormonal responses to stress in elderly females compared to males have also been reported (Seeman et al., 1995, Seeman et al., 2001). Thus, the impact of gender on the HPA axis hormonal response to stressful events remains inconclusive.
Activation of the HPA axis can be evoked by numerous methods that act at different levels of the HPA system. Removing the endogenous inhibitory opioid tone on CRH neurons using naloxone, a non-selective opioid receptor antagonist, induces a rise in ACTH and cortisol (Volavka et al., 1979, Morley et al., 1980, Wand et al., 1998) and thus provides an assessment strategy for the functional evaluation of the hypothalamic opioid tone. Although several studies have evaluated effects of opioid blockade on the HPA axis (Cohen et al., 1983, Kreek, 1996, Wand et al., 1999, Wand et al., 2001), little research has addressed gender differences in the opioid–HPA axis interactions in healthy subjects.
The aim of the present study was to determine whether there are gender differences in HPA axis hormonal response patterns to two different methods of HPA axis activation: a standardized psychological stress test and a pharmacological challenge with naloxone.
Section snippets
Subjects
One hundred and eleven healthy subjects between the ages of 18 and 50 (mean age 23.4 years, SD 7.0 years) from the Baltimore area were recruited by newspaper advertisements and posted fliers. Persons who appeared to qualify for research participation based on a telephone screen were invited to the laboratory for an interview. After being given complete description of the study, volunteers provided written informed consent for the protocol approved by the Johns Hopkins Medicine Institutional
Demographics
Demographic characteristics for the subjects undergoing the TSST (n=80) and the naloxone challenge (n=72) are in Table 1. Subjects were healthy and predominantly Caucasian, and all subjects were non-smokers. The groups differed in racial composition (TSST, χ2=6.76, p=0.034; naloxone, χ2=6.70, p=0.035), and race was adjusted for in our statistical models. There were no statistically significant differences between gender groups in terms of age and BMI. In the TSST group, males were 18–50 years
Discussion
In the present study, we observed that healthy male subjects demonstrate a more robust ACTH and cortisol response to a psychological stress compared to females. In contrast, healthy females had a higher cortisol and marginally higher ACTH response to naloxone compared to males. Overall, our findings were consistent whether our analysis was conducted using a between-subject or within-subject design.
Our findings in response to the TSST lend further support to a number of studies that have shown
Acknowledgements
This work was supported by NIH grants AA 10158 (GSW), AA 12303 (GSW) and AA 12837 (MEM), and a gift from the Kenneth A. Lattman Foundation (GSW).
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