Gender differences in hypothalamic–pituitary–adrenal (HPA) axis reactivity

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Summary

The present study was designed to determine whether there are gender differences in hormonal response patterns to HPA axis activation. To this end, two methods of activating the HPA axis were employed: a standardized psychological stress test and a pharmacological challenge.

Healthy subjects (mean age 23.4 years, SD 7.0 years) completed a naloxone challenge and/or the modified Trier Social Stress Test (TSST). For the naloxone challenge, two baseline blood samples were obtained. Placebo was then administered (0 min), followed by increasing doses of intravenous naloxone (50, 100, 200 and 400 μg/kg) at 30-min intervals. Post-placebo blood samples were collected at 15-min intervals for 180 min. The TSST consisted of 5 min of public speaking followed by 5 min of mental arithmetic exercises. Three baseline and five post-TSST blood samples were drawn.

Eighty subjects (53 male, 27 female) underwent the TSST. Following the psychological stressor, adrenocorticotropin (ACTH) and cortisol responses were significantly greater in male subjects compared to female subjects (z=−2.34, p=0.019 and z=−2.12, p=0.034, respectively). Seventy-two subjects (52 male, 20 female) underwent HPA axis activation induced by naloxone. In contrast to the TSST, cortisol responses to the naloxone challenge were significantly greater in female subjects compared to male subjects (z=4.11, p<0.001). Forty-one subjects (25 male, 16 female) completed both the TSST and naloxone challenge. In this subset, ACTH and cortisol responses to the TSST did not differ significantly by gender, although the effect size was moderate to large. Adrenocorticotropin and cortisol responses to the naloxone challenge were significantly greater in female subjects compared to male subjects (z=2.29, p=0.022 and z=4.34, p<0.001, respectively).

In summary, male subjects had greater HPA axis responses to a psychological stressor than female subjects, and females had greater hormonal reactivity than males to pharmacological stimulation with naloxone. Such differences are of interest as potential contributors to gender differences in health risks.

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).

References (60)

  • D. Mangold et al.

    Plasma adrenocorticotropin responses to opioid blockade with naloxone: generating a dose–response curve in a single session

    Biol. Psychiatry

    (2000)
  • L.M. Oswald et al.

    Opioids and alcoholism

    Physiol. Behav.

    (2004)
  • E.C. Petrie et al.

    Effects of Alzheimer's disease and gender on the hypothalamic–pituitary–adrenal axis response to lumbar puncture stress

    Psychoneuroendocrinology

    (1999)
  • C.A. Priest et al.

    Estrogen regulates preproenkephalin-A mRNA levels in the rat ventromedial nucleus: temporal and cellular aspects

    Brain Res. Mol. Brain Res.

    (1995)
  • T.E. Seeman et al.

    Gender differences in patterns of HPA axis response to challenge: macarthur studies of successful aging

    Psychoneuroendocrinology

    (1995)
  • T.E. Seeman et al.

    Gender differences in age-related changes in HPA axis reactivity

    Psychoneuroendocrinology

    (2001)
  • L.R. Stroud et al.

    Sex differences in stress responses: social rejection versus achievement stress

    Biol. Psychiatry

    (2002)
  • C. Tsigos et al.

    Hypothalamic–pituitary–adrenal axis, neuroendocrine factors and stress

    J. Psychosom. Res.

    (2002)
  • J. Born et al.

    Effects of age and gender on pituitary–adrenocortical responsiveness in humans

    Eur. J. Endocrinol.

    (1995)
  • J.H. Boyd et al.

    Epidemiology of affective disorders. A reexamination and future directions

    Arch. Gen. Psychiatry

    (1981)
  • K.K. Bucholz et al.

    A new, semi-structured psychiatric interview for use in genetic linkage studies: a report on the reliability of the SSAGA

    J. Stud. Alcohol

    (1994)
  • L.H. Burgess et al.

    Chronic estrogen-induced alterations in adrenocorticotropin and corticosterone secretion, and glucocorticoid receptor-mediated functions in female rats

    Endocrinology

    (1992)
  • A.E. Calogero

    Neurotransmitter regulation of the hypothalamic corticotropin-releasing hormone neuron

    Ann. NY Acad. Sci.

    (1995)
  • G.P. Chrousos

    Stressors, stress, and neuroendocrine integration of the adaptive response. The 1997 hans selye memorial lecture

    Ann. NY Acad. Sci.

    (1997)
  • Cohen, J. 1988. Statistical power analysis for the behavioral sciences, 2nd ed. Hillsdale,...
  • A. Collins et al.

    Stress responses in male and female engineering students

    J. Human Stress

    (1978)
  • C.B. Eckersell et al.

    Estrogen-induced alteration of μ-opioid receptor immunoreactivity in the medial preoptic nucleus and medial amygdala

    J. Neurosci.

    (1998)
  • M. Frankenhaeuser et al.

    Sex differences in psychoneuroendocrine reactions to examination stress

    Psychosom. Med.

    (1978)
  • W.T. Gallucci et al.

    Sex differences in sensitivity of the hypothalamic–pituitary–adrenal axis

    Health Psychol.

    (1993)
  • C. Gianoulakis

    Alcohol-seeking behavior: the roles of the hypothalamic–pituitary–adrenal axis and the endogenous opioid system

    Alcohol Health Res. World

    (1998)
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