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Beyond the HPA Axis: Progesterone-Derived Neuroactive Steroids in Human Stress and Emotion

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      Stress and social isolation are well-known risk factors for psychopathology. However, more research is needed as to the physiological mechanisms by which social support buffers the impacts of stress. Research in animal models suggests important roles for progesterone (P) and its product, the neuroactive steroid allopregnanolone (ALLO), in stress and psychopathology. These hormones are produced in brain and periphery during stress in rodents, and down-regulate anxiety behavior and hypothalamic-pituitary–adrenal axis activity. Human clinical populations, including depressed patients, have alterations in ALLO levels, but it is unclear whether these basal hormone level differences have clinical import. To begin to address this question, this review examines the role of P and ALLO in stress physiology, and the impact of these hormones on mood, in healthy humans. Evidence largely supports that P and ALLO increase during stress in humans. However, P/ALLO administration appears to cause only mild effects on mood and subjective anxiety, while exerting effects consistent with gamma-aminobutyric acid receptor modulation. Additionally, P is linked to motivation for affiliation/social contact; P (and ALLO) release may be especially responsive to social rejection. These observations lead to the novel hypothesis that stress-related P/ALLO production functions not only to down-regulate stress and anxiety, but also to promote social contact as a long-term coping strategy. Malfunctioning of the P/ALLO system could therefore underlie depression partly by decreasing propensity to affiliate with others.

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      Most cited references 124

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      Acute stressors and cortisol responses: a theoretical integration and synthesis of laboratory research.

      This meta-analysis reviews 208 laboratory studies of acute psychological stressors and tests a theoretical model delineating conditions capable of eliciting cortisol responses. Psychological stressors increased cortisol levels; however, effects varied widely across tasks. Consistent with the theoretical model, motivated performance tasks elicited cortisol responses if they were uncontrollable or characterized by social-evaluative threat (task performance could be negatively judged by others), when methodological factors and other stressor characteristics were controlled for. Tasks containing both uncontrollable and social-evaluative elements were associated with the largest cortisol and adrenocorticotropin hormone changes and the longest times to recovery. These findings are consistent with the animal literature on the physiological effects of uncontrollable social threat and contradict the belief that cortisol is responsive to all types of stressors.
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        Social support and oxytocin interact to suppress cortisol and subjective responses to psychosocial stress.

        The presence of social support has been associated with decreased stress responsiveness. Recent animal studies suggest that the neuropeptide oxytocin is implicated both in prosocial behavior and in the central nervous control of neuroendocrine responses to stress. This study was designed to determine the effects of social support and oxytocin on cortisol, mood, and anxiety responses to psychosocial stress in humans. In a placebo-controlled, double-blind study, 37 healthy men were exposed to the Trier Social Stress Test. All participants were randomly assigned to receive intranasal oxytocin (24 IU) or placebo 50 min before stress, and either social support from their best friend during the preparation period or no social support. Salivary free cortisol levels were suppressed by social support in response to stress. Comparisons of pre- and poststress anxiety levels revealed an anxiolytic effect of oxytocin. More importantly, the combination of oxytocin and social support exhibited the lowest cortisol concentrations as well as increased calmness and decreased anxiety during stress. Oxytocin seems to enhance the buffering effect of social support on stress responsiveness. These results concur with data from animal research suggesting an important role of oxytocin as an underlying biological mechanism for stress-protective effects of positive social interactions.
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          The trier social stress test –a tool for investigating psychosocial stress responses in a laboratory setting


            Author and article information

            1simpleDepartment of Psychology, University of Notre Dame Notre Dame, IN, USA
            Author notes

            Edited by: Hubert Vaudry, University of Rouen, France

            Reviewed by: Rafael Vazquez-Martinez, University of Cordoba, Spain; Nicolas Vitale, CNRS, France

            *Correspondence: Michelle M. Wirth, Department of Psychology, University of Notre Dame, 123B Haggar Hall, Notre Dame, IN 46556, USA. e-mail: mwirth@

            This article was submitted to Frontiers in Neuroendocrine Science, a specialty of Frontiers in Endocrinology.

            Front Endocrinol (Lausanne)
            Front Endocrinol (Lausanne)
            Front. Endocrin.
            Frontiers in Endocrinology
            Frontiers Research Foundation
            11 August 2011
            : 2
            Copyright © 2011 Wirth.

            This is an open-access article subject to a non-exclusive license between the authors and Frontiers Media SA, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and other Frontiers conditions are complied with.

            Figures: 3, Tables: 0, Equations: 0, References: 130, Pages: 14, Words: 13743
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