Inhibition of fear is differentially associated with cycling estrogen levels in women

Abstract

Background: Although the prevalence of posttraumatic stress disorder (PTSD) is twice as high in women as it is in men, the role of estrogen in the risk for PTSD is not well understood. Deficits in fear inhibition and impaired safety signal learning may be biomarkers for PTSD. We examined menstrual cycle phase and serum estradiol levels in naturally cycling women while they were undergoing a novel conditioned inhibition procedure that measured their ability to discriminate between cues representing danger versus safety and to inhibit fear in the presence of safety cues. Methods: Sample 1 included healthy participants in whom we compared inhibition of fearpotentiated startle during the follicular (lower estrogen) and luteal (higher estrogen) phases of the menstrual cycle. We used the same paradigm in a traumatized clinical population (sample 2) in whom we compared low versus high estradiol levels. Results: In both samples, we found that lower estrogen in cycling women was associated with impaired fear inhibition. Limitations: In the clinical sample, the low estradiol group was on average older than the high estradiol group owing to the random recruitment approach; we did not exclude participants based on hormonal status or menopause. Conclusion: Our results suggest that the lower estrogen state during normal menstrual cycling may contribute to risk for anxiety disorders through dysregulated fear responses.

Estrogen and Extinction of Fear Memories:Implications for Posttraumatic Stress Disorder Treatment

“…Schematic summarizing risk factors related to estrogen levels in PTSD vulnerability and severity based on preclinical and clinical investigations (9-10; 45-51). Although not depicted in the figure, it is understood that these factors operate within the context of a larger gene by environment perspective and that the beneficial “dose” range of estrogen must be further explored.…”

Diagnostic Biomarkers for Posttraumatic Stress Disorder: Promising Horizons from Translational Neuroscience Research

“…For example, menstrual cycle phase (46, 47) and pregnancy (48) influence PTSD symptom expression profile and psychophysiology in women, suggesting that ovarian steroid hormones are important modulators of PTSD susceptibility and symptom presentation. Indeed, low levels of estradiol are associated with impaired fear extinction in PTSD (49), and high levels of pituitary adenylate cyclase-activating polypeptide (PACAP), a peptide implicated in stress-related behavior and physiology (50–52), are associated with PTSD only in women (53).…”

Sex differences in conditioned stimulus discrimination during context-dependent fear learning and its retrieval in humans: the role of biological sex, contraceptives and menstrual cycle phases

“…At the same time, low levels have been shown to be disadvantageous for these processes 7,8,[13][14][15][16] and associated with impaired fear inhibition. 17 These studies suggest that the consolidation of extinction memory is critically modulated by fluctuating estrogen levels through the menstrual cycle and may be medi ated through facilitation of (hippocampal) neuronal plasticity. 8 If estrogen in fact modulates the success of experimental fear extinction, this might be of high clinical relevance.…”