Neuroendocrine pathways underlying risk and resilience to PTSD in women

Abstract

Women are twice as likely than men to suffer from posttraumatic stress disorder (PTSD). While women have increased exposure to traumatic events of many types and have greater prevalence of comorbid psychiatric disorders compared to men, these differences do not account for the overall sex difference in the prevalence of PTSD. The current review summarizes significant findings that implicate the role of estradiol, progesterone, and allopregnanolone in female risk for PTSD symptoms and dysregulation of fear psychophysiology that is cardinal to PTSD. We also discuss how these steroid hormones influence the stress axis and neural substrates critical for the regulation of fear responses. Understanding the role of ovarian steroid hormones in risk and resilience for trauma-related adverse mental health outcomes across the lifespan in women has important translational, clinical, and intergenerational implications for mitigating the consequences of trauma exposure.

Keywords: Estrogen; Fear psychophysiology; Neuroimaging; PTSD; Progesterone; Women.

Figure 1.. Illustration of fear conditioning paradigms and fear responses related to PTSD.

Classical fear conditioning paradigms typically consist of a (A) conditioning (acquisition) phase, an (B) extinction phase, and sometimes an (C) extinction recall phase. In the conditioning phase (acquisition), a neutral stimulus (conditioned stimulus; CS) is paired with an aversive unconditioned stimulus (US; such as a mild shock or aversive air blast). Some paradigms have multiple neutral stimuli, where only one (CS+; danger cue) is paired with the aversive US while the other (CS−; safety cue) is not. In the extinction phase, the CS+ is no longer presented with the aversive US, and participants should learn to dissociate the CS from danger. In some paradigms, recall of the extinction memory (dissociation of the CS+ from danger) is assessed at a later time (extinction retention phase). Fear potentiated startle is another paradigm used, in which the startle response is measured in response to a loud but harmless tone (startle probe) in the presence of the CS+ and CS−. Deficits in fear inhibition during fear conditioning are analogous to the increased fear and fear generalization symptoms seen in PTSD, while deficits in extinction and extinction recall point to the re-experiencing and hyperarousal symptoms characteristic of PTSD.

Figure 2.. Relationship between cycle phase, ovarian hormones, and fear conditioning.

Existing studies in women indicate no relationship between menstrual cycle phase/ovarian hormone levels on acquisition or extinction processes. Low E2/P4 concentrations (as seen in the early follicular phase) are associated with impaired extinction recall and fear inhibition. High E2 concentrations (seen in the late follicular phase) and high E2/P4 concentrations (seen in the early to mid luteal phase) are associated with enhanced extinction recall and fear inhibition. The effects of declining E2/P4 concentrations during the late luteal phase on fear conditioning processes remain to be assessed.