Cortisol levels after cold exposure are independent of adrenocorticotropic hormone stimulation

Abstract

2We previously showed that postmortem serum levels of adrenocorticotropic hormone 3 (ACTH) were significantly higher in cases of hypothermia (cold exposure) than other 4 causes of death. This study examined how the human hypothalamic-pituitary-adrenal axis, 5 and specifically cortisol, responds to hypothermia. Human samples: Autopsies on 205 6 subjects (147 men and 58 women; age 15-98 years, median 60 years) were performed 7 within 3 days of death. Cause of death was classified as either hypothermia (cold exposure, 8 n=14) or non-cold exposure (controls; n=191). Cortisol levels were determined in blood 9 samples obtained from the left and right cardiac chambers and common iliac veins using 10 a chemiluminescent enzyme immunoassay. Adrenal gland tissue samples were stained 11 for cortisol using a rabbit anti-human polyclonal antibi. Cell culture: AtT20, a mouse 12 ACTH secretory cell line, and Y-1, a corticosterone secretory cell line derived from a 13 mouse adrenal tumor, were analyzed in mono-and co-culture, and times courses of ACTH 14 (in AtT20) and corticosterone (in Y-1) secretion were assessed after low temperature 15 exposure mimicking hypothermia and compared with data for samples collected 16 postmortem for other causes of death. However, no correlation between ACTH 17 concentration and cortisol levels was observed in hypothermia cases. Immunohistologic 18 analyses of samples from hypothermia cases showed that cortisol staining was localized 19 primarily to the nucleus rather than the cytoplasm of cells in the zona fasciculata of the 20 adrenal gland. During both mono-culture and co-culture, AtT20 cells secreted high levels 21 of ACTH after 10-15 minutes of cold exposure, whereas corticosterone secretion by Y-1 22 cells increased slowly during the first 15-20 minutes of cold exposure. Similar to autopsy 23 results, no correlation was detected between ACTH levels and corticosterone secretion, 24 either in mono-culture or co-culture experiments. These results suggested that ACTH-25 independent cortisol secretion may function as a stress response during cold exposure. 26 27 31 etiologies of hypothermia include drug abuse, dementia, malnutrition, and infectious 32 disease, only a few studies have specifically examined pathologic findings after cold 33 exposure [8,9], especially from a biochemical perspective, such as the presence and levels 34 of ketone bodies [10-13]. Furthermore, only a few reports have estimated hormone levels 35 as part of the pathophysiologic findings of cold exposure [14-16]. 36The primary stress response system is the sympathetic/adrenomedullary (S/A) 37 system, which includes the chromogranin A [14] and hypothalamic-pituitary-adrenal 38 (HPA) axis [16, 18]. Previous studies have suggested that postmortem serum 39 adrenocorticotropic hormone (ACTH) concentration is a useful biomarker of death due 40 to cold exposure and the magnitude of physical stress responses during cold exposure 41 [17]. Increased serum concentrations of ACTH associated with activation of the HPA axis 42 and S...