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.

Fig. 1

Typical estrogen and progesterone fluctuations across the 28-day human menstrual cycle. The solid line represents estrogen levels, which peak at ovulation and remain relatively elevated during the luteal phase. The dashed line represents progesterone level, which peaks after ovulation and is high during the luteal phase. The data for this study were collected 2–12 days since the last menstrual period for the follicular group, and 17–25 days since the last menstrual period for the luteal group.

Fig. 2

Effects of menstrual cycle phase on conditioned discrimination in a healthy community sample. (A) Percent startle potentiation to the different trial types across groups. The women in the luteal phase showed significant discrimination between AX+ and BX− (p < 0.05) and significant inhibition on AB compared with AX+ trials (p < 0.01). On the other hand, women in the follicular phase showed neither discrimination nor inhibition. (B) Aversive unconditioned stimulus (US) expectancy. Women in the luteal phase showed robust discrimination between AX+ and BX− (p < 0.001) and significant inhibition on AB compared with AX+ trials. However, unlike their startle data, results of women in the follicular phase also demonstrated significant discrimination and significantly less US expectancy on the AB trials compared with AX+. AX+ > BX− = discrimination; AX+ > AB = inhibition.

Fig. 3

Effects of estradiol (E₂) levels on conditioned discrimination in a traumatized clinical sample. (A) Percent startle potentiation to the different trial types across groups. The women in the high E₂ group showed significant discrimination between AX+ and BX− (p < 0.05) and significant inhibition on AB compared with AX+ trials. On the other hand, women in the low E₂ group showed neither discrimination nor inhibition. (B) Aversive unconditioned stimulus (US) expectancy. Women in the high E₂ group showed robust discrimination between AX+ and BX− (p < 0.01) and significant inhibition on AB compared with AX+ trials. However, unlike their startle data, women in the low E₂ phase also demonstrated significant discrimination and inhibition (p < 0.001). AX+ > BX− = discrimination; AX+ > AB = inhibition.