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

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


J Psychiatry Neurosci 2013; 38(5): 341-348

Ebony M. Glover, PhD; Kristina B. Mercer, MPH; Seth D. Norrholm, PhD; Michael Davis, PhD; Erica Duncan, MD; Bekh Bradley, PhD; Kerry J. Ressler, MD, PhD; Tanja Jovanovic, PhD

Glover, Mercer, Norrholm, Davis, Duncan, Bradley, Ressler, Jovanovic — Department of Psychiatry & Behavioral Sciences, Emory University School of Medicine, Atlanta, Ga.; Mercer, Ressler — Howard Hughes Medical Institute, Chevy Chase, Md.; Norrholm, Duncan, Bradley — Atlanta VA Medical Center, Mental Health Service, Decatur, Ga.; Davis, Ressler — Yerkes National Primate Research Center, Atlanta, Ga., USA


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.

Submitted July 6, 2012; Revised Dec. 20, 2012, Feb. 15, 2013; Accepted Feb. 20, 2013.

Acknowledgements: This research was supported by the Mental Health Service, Atlanta DVA Medical Center; the STC Program Center for Behavioral Neuroscience of the National Science Foundation under Agreement No. IBN-9876754 (venture grant, PI, E. Duncan); the American Psychiatric Association/GlaxoSmithKline (PI, E. Duncan); National Institute of Mental Health Grants MH47840 (PI, M. Davis), MH071537 (PI, K.J. Ressler) and MH070129 (PI, T. Jovanovic); IRACDA grant number K12-GM000680 (PI, E.M. Glover); Howard Hughes Medical Institute (PI, K.J. Ressler); the Department of Defense/ Congressionally Directed Medical Research Program Award # W81XWH-08-2-0170 (PI, S.D. Norrholm); the Atlanta Clin ical Translational Science Institute; the NIH National Centers for Research Resources (M01 RR00039); and the Emory University General Clinical Research Center at Grady Hospital. We thank Allen Graham, Angelo Brown and Nineequa Blanding for their assistance with participant recruitment and data collection.

Competing interests: None declared for K.B. Mercer. As above for E.M. Glover, S.D. Norrholm, M. Davis, E. Duncan, B. Bradley, K.J. Ressler and T. Jovanovic.

Contributors: All authors contributed to study design, reviewed the article and approved its publication. E.M. Glover and T. Jovanovic acquired the data and wrote the article. They analyzed the data with S.D. Norrholm.

DOI: 10.1503/jpn.120129

Correspondence to: E.M. Glover, Emory University School of Medicine, Department of Psychiatry and Behavioral Sciences,
49 Jesse Hill Jr. Dr. Suite, Atlanta GA 30303, USA;