Estradiol is associated with mortality in critically ill trauma and surgical patients

Abstract

Objective: Sexual dimorphism (variation in outcome related to sex) after trauma-hemorrhage and sepsis is well documented in animals, with the pro-estrus state being proinflammatory and associated with a survival advantage. Although some observational studies confirm this pattern in humans, others demonstrate no difference in mortality. Estrogens are important modulators of the inflammatory response and insulin resistance in humans and have been linked to increased mortality during sepsis. Our objective was to determine whether sex hormone levels were associated with outcomes in critically ill surgical patients. Design: Prospective cohort.Patients: A total of 301 adult critically ill or injured surgical patients remaining in the intensive care unit for ≥48 hrs at two academic medical centers. Interventions: None.Measurements: Blood was collected 48 hrs after intensive care unit admission and assayed for sex hormones (estradiol, testosterone, prolactin, and progesterone) and cytokines (tumor necrosis factor-α and interleukin-1, -2, -4, -6, -8, and -10). Demographic and outcome data were also collected.Main Results: Estradiol was significantly higher in nonsurvivors (p < .001). Analysis by quartiles of estradiol demonstrated greater than a three-fold increase in the mortality rate for the highest vs. the lowest estradiol quartiles (29% vs. 8%, p < .001). Estradiol was also higher in nonsurvivors. An estradiol level of 100 pg/mL was associated with an odds ratio for death of 4.60 (95% confidence interval, 1.56-13.0) compared with a reference estradiol level of 45 pg/mL. Conclusions:We conclude that serum estradiol correlates with mortality in critically ill and injured surgical patients and discuss potential mechanisms for this observation. Keywordsestradiol; mortality; trauma; critical care; sexual dimorphism; aromatase For information regarding this article, E-mail: addison.may@vanderbilt.eduThe authors have not disclosed any potential conflicts of interest.This work was performed at Vanderbilt University Medical Center, Nashville, TN, and the Hospitals of the University of Virginia Health System, Charlottesville, VA. All authors took part in the interpretation of the findings and contributed to the preparation of the manuscript. In-hospital death after a severe traumatic, surgical, or septic insult often results from the sequential development of organ dysfunction (multiple organ dysfunction syndrome, or MODS). Although progression to MODS largely depends on the magnitude of tissue injury, considerable variation exists in an individual's susceptibility to this syndrome (1-3). Sex has been suggested as one determinant of this variability. NIH Public AccessIn animal models, the pro-estrous state is proinflammatory, with improved survival after untreated trauma-hemorrhage and sepsis, whereas the proandrogenic state leads to immune depression and decreased survival (4-10). Observational studies in humans have been less conclusive (9,. Although a number of human observational studies confirm this pattern, othe...

Impact of Aromatase Genetic Variation on Hormone Levels and Global Outcome after Severe TBI

“…30,31 In our study characterizing serum hormones acutely after TBI, elevated estradiol in particular was associated with mortality and poor outcomes 6 months postinjury. 10 These findings suggest that tissuespecific aromatase activity significantly influences the hormone profiles, and there are different mechanisms of hormone physiology at play in the CSF versus serum compartments.…”

Serum biomarkers as predictors of long-term outcome in severe traumatic brain injury: analysis from a randomized placebo-controlled Phase II clinical trial

“…5,15,23,25,29 However, this presumed benefit has not been consistently translated from animal (rodent) models to patients in clinical trials, partly due to a difference between the two groups in production of Eg via peripheral aromatization, which is selectively present in primates only. 5,15,23,25,29 Up to 80% of patients with sTBI have suppression of the hypothalamic-pituitary-gonadal axis and activation of stress hormones produced by the adrenal gland; therefore, Eg production is predominantly under the control of peripheral aromatization in adipose tissue, which in turn is positively affected by proinflammatory cytokines like TNF-a. 29 Because there is a surge of systemic proinflammatory chemokines immediately following sTBI, the injury increases Eg levels as a byproduct of ongoing inflammatory response, thereby reflecting a global illness rather than a causal role.…”

“…29 Because there is a surge of systemic proinflammatory chemokines immediately following sTBI, the injury increases Eg levels as a byproduct of ongoing inflammatory response, thereby reflecting a global illness rather than a causal role. 5,29 Few studies have shown a capacity of serum Eg levels at 48 hours to predict mortality, 5,15 but their model failed to incorporate proinflammatory cytokines, a major confounder in the primate TBI model. As expected, we failed to observe any statistically significant impact of admission Eg levels on mortality in the adjusted binary logistic model, despite a weak association evident with survival status (p = 0.09 and p = 0.07 at 6 and 12 months, respectively).…”

“…1,2,6,8,9,[11][12][13]22,26,27,30,36 More recently, posttraumatic suppression of the hypothalamic-pituitary-adrenal axis and an increase in cytokine-mediated peripheral aromatase activity, leading to an imbalance in sex steroid (estrogen [Eg], progesterone [Pg], and testosterone) serum levels, have been areas of active interest for precise understanding of the mechanisms involved. 5,15,23,25,29 Most of the recent literature deals with these biomarkers in isolation, and there is a paucity of existing literature for establishing a comprehensive model dealing with all 3 domains together. To this end, we serially analyzed serum biomarkers (S100-B, GFAP, NSE, TNF-a, IL-6, Eg, and Pg) as part of a randomized placebo-controlled Phase II trial of progesterone with or without hypothermia in patients with severe TBI (sTBI), and analyzed the long-term predictive value of these biomarkers on Glasgow Outcome Scale (GOS) score, functional independence measure (FIM), and survival status at 6 and 12 months.…”

Sex Hormones and Bacterial Infections

“…It has been also found that increased levels of estrogens are especially marked in males with sepsis (Fourrier et al, 1994;Majetschak et al, 2000). In addition, high circulating levels of estrogens seem efficient predictors of death in sepsis (Christeff et al, 1988;Dossett et al, 2008;May et al, 2008). The mortality of elderly patients with severe infections is related to increased estradiol levels in both men and women, whereas increased testosterone levels are found in females who do not survive (Angstwurm et al, 2005).…”