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

Michelle M Wirth

doi:10.3389/fendo.2011.00019

Abstract

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.

Highlights

THE IMPORTANCE OF PROGESTERONE-DERIVED HORMONES IN HUMAN EMOTION AND PSYCHOPATHOLOGY Stress is a part of life for all vertebrate animals
While the fields of behavioral and cognitive neuroscience tackle the neural pathways of stress and the effects of stress hormones on the brain, researchers in clinical psychology and psychiatry have been exploring the links between stress physiology and psychopathology; social and personality psychologists increasingly study human stress hormones in the context of various social situations
Evidence is accumulating for a link between P and motivation to affiliate. These findings suggest the hypotheses that: (1) P/ALLO increases during stress function in part to promote affiliation and bonding as a long-term coping strategy; and (2) diminished P/ALLO responses to stress could be a risk factor for depression, and/or could underlie certain features of depressive disorders, such as less propensity to seek out social contact (Figure 3)

Summary

INTRODUCTION

THE IMPORTANCE OF PROGESTERONE-DERIVED HORMONES IN HUMAN EMOTION AND PSYCHOPATHOLOGY Stress is a part of life for all vertebrate animals. P is metabolized to other steroid hormones, including allopregnanolone (ALLO), which have actions on neurons, causing effects that are relevant for stress, emotion, and behavior As evidence for their importance to the brain, P and ALLO are produced by peripheral glands (e.g., ovary; adrenal gland), and in the brain itself (Paul and Purdy, 1992). The role of these hormones in stress, along with their effects on neuronal transmission, have been studied for decades in animal models. P and ALLO have been implicated in mood and anxiety disorders, most notably major depressive disorder (MDD), and Premenstrual Dysphoric Disorder (PMDD), Generalized Anxiety Disorder, Post-Traumatic Stress Disorder (PTSD), and other illnesses

Neuroactive steroids in human emotion

AVP gene transcription

Findings

CONCLUSION