This article is part of the Research Topic Neurosteroids


Front. Endocrinol., 11 August 2011 | doi: 10.3389/fendo.2011.00019

Beyond the HPA axis: progesterone-derived neuroactive steroids in human stress and emotion

  • Department of Psychology, University of Notre Dame, Notre Dame, IN, USA

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.

Keywords: progesterone, allopregnanolone, 3α-hydroxy-5α-pregnan-20-one, stress, affiliation, social motivation, psychopathology, depression

Citation: Wirth MM (2011) Beyond the HPA axis: progesterone-derived neuroactive steroids in human stress and emotion. Front. Endocrin. 2:19. doi: 10.3389/fendo.2011.00019

Received: 17 June 2011; Accepted: 28 July 2011;
Published online: 11 August 2011.

Edited by:

Hubert Vaudry, University of Rouen, France

Reviewed by:

Rafael Vazquez-Martinez, University of Cordoba, Spain
Nicolas Vitale, CNRS, France

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.

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

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