Peritraumatic 17β-estradiol levels influence chronic posttraumatic pain outcomes

Abstract

Biologic factors that predict risk for and mediate the development of common outcomes of trauma exposure such as chronic posttraumatic pain (CPTP) are poorly understood. In the current study, we examined whether peritraumatic circulating 17β-estradiol (E2) levels influence CPTP trajectories. 17β-estradiol levels were measured in plasma samples (n = 254) collected in the immediate aftermath of trauma exposure from 3 multiethnic longitudinal cohorts of men and women trauma survivors. Chronic posttraumatic pain severity was evaluated 6 weeks, 6 months, and 1 year after traumatic stress exposure. Repeated measures mixed models were used to test the relationship between peritraumatic E2 levels and prospective CPTP. Secondary analyses in a nested cohort assessed the influence of participant body mass index on the E2-CPTP relationship. In women, a statistically significant inverse relationship between peritraumatic E2 and CPTP was observed (β = -0.280, P = 0.043) such that higher E2 levels predicted lower CPTP severity over time. Secondary analyses identified an E2 * body mass index interaction in men from the motor vehicle collision cohort such that obese men with higher E2 levels were at greater risk of developing CPTP. In nonobese men from the motor vehicle collision cohort and in men from the major thermal burn injury cohort, no statistically significant relationship was identified. In conclusion, peritraumatic circulating E2 levels predict CPTP vulnerability in women trauma survivors. In addition, these data suggest that peritraumatic administration of E2 might improve CPTP outcomes for women; further research is needed to test this possibility.

Figure 1.. Relationship between peritraumatic levels of circulating 17β-estradiol and chronic posttraumatic pain (CPTP) severity in multiethnic women and men (n = 254).

17β-estradiol (E2) levels were measured in blood plasma collected from women and men enrolled following trauma exposure. E2 levels were subgrouped based on tertiles as defined in Supplementary Figure 1S. Pain levels were assessed (0–10 numeric rating scale) at the time of blood plasma collection (day 0) and at three additional timepoints over the course of a year (six weeks, six months, one year). (A) CPTP in trauma survivor women (n = 166) with high peritraumatic circulating levels of E2 (black circles, black lines) were compared with trauma survivor women with moderate (half-open circles, dashed line) and low peritraumatic circulating levels of E2 (open circles, dotted line), ^#p < 0.001. Significance of repeated measures mixed model trajectories indicated by horizontal line, *p < 0.05. (B) Trauma survivor men (n = 88) with high, medium, and low peritraumatic levels of E2 were compared, n.s. = not significant. Circles and error bars represent mean and SEM, respectively.

Figure 2.. Relationship between peritraumatic levels of circulating 17β-estradiol and chronic posttraumatic pain (CPTP) severity in women in three independent trauma cohorts.

17β-estradiol (E2) levels were measured in blood plasma collected from women enrolled following three types of trauma exposure: motor vehicle collision (MVC), sexual assault (SA), and major thermal burn injury (MThBI). E2 levels were subgrouped based on tertiles (MVC and SA) or median (MThBI) as defined in Supplementary Figure 1S. (A) CPTP in MVC survivor women (n = 88) with high peritraumatic circulating levels of E2 (black circles, black lines) were compared with MVC survivor women with moderate (half open circles, dashed lines) or low levels (open circles, dotted line). (B) Same as in A but in women SA survivors (n = 64). (C) Same as in A and B but in women MThBI survivors (n = 14). Significance of repeated measures mixed model trajectories indicated by horizontal line and significance at individual timepoints indicated with a symbol above relevant timepoints *p < 0.05, ^#p < 0.001. Circles and error bars represent mean and SEM, respectively.

Figure 3.. Relationship between peritraumatic levels of circulating 17β-estradiol and chronic posttraumatic pain (CPTP) severity in men in two independent trauma cohorts.

17β-estradiol (E2) levels were measured in blood plasma collected from men enrolled following two types of trauma exposure, motor vehicle collision (MVC) and major thermal burn injury (MThBI). E2 levels were subgrouped based on tertiles (MVC) or median (MThBI) as defined in Supplementary Figure 1S. (A) CPTP in MVC survivor men (n = 47) with high peritraumatic circulating levels of E2 (black circles, black lines) were compared with MVC survivor men with moderate (half open circles, dashed lines) or low levels (open circles, dotted line). (B) Same as in A but in MThBI survivor men (n = 41). Significance of repeated measures mixed model trajectories indicated by horizontal line and significance at individual timepoints indicated with a symbol above relevant timepoints *p < 0.05, ^#p < 0.001, n.s. = not significant. Circles and error bars represent mean and SEM, respectively.

Figure 4.. Relationship between peritraumatic levels of circulating 17β-estradiol and chronic posttraumatic pain (CPTP) severity in men from the motor vehicle collision cohort with low BMI and high BMI.

17β-estradiol (E2) levels were measured in blood plasma collected from men enrolled following motor vehicle collision (MVC). A median BMI cutoff of 30 was used to compare men with (A) low BMI (<30, n = 18) to men with (B) high BMI (≥30, n = 21). Scatterplots were generated using log transformed E2 values and representative six month CPTP levels. Correlation coefficients (r) and statistical significance (p value) were determined using Spearman’s rank order correlation.