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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2005-2258
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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 7 2548-2554
Copyright © 2006 by The Endocrine Society

Dissociation of Serum Dehydroepiandrosterone and Dehydroepiandrosterone Sulfate in Septic Shock

Wiebke Arlt, Fabian Hammer, Petra Sanning, Stephen K. Butcher, Janet M. Lord, Bruno Allolio, Djillali Annane and Paul M. Stewart

Division of Medical Sciences (W.A., F.H., P.M.S.) and Medical Research Council Centre for Immune Regulation (J.M.L., S.K.B.), Institute of Biomedical Research, University of Birmingham, Birmingham B15 2TT, United Kingdom; Department of Medicine, Endocrine and Diabetes Unit (P.S., B.A.), University of Würzburg, 97080 Würzburg, Germany; and Critical Care Department (D.A.), Université de Versailles Saint-Quentin en Yvelines, 92380 Garches, France

Address all correspondence and requests for reprints to: Dr. Wiebke Arlt, Medical Research Council Senior Clinical Fellow, Division of Medical Sciences, University of Birmingham, Institute of Biomedical Research, Room 233, Birmingham B15 2TT, United Kingdom. E-mail: w.arlt{at}bham.ac.uk.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Context: Dehydroepiandrosterone (DHEA) replacement in sepsis has been advocated because of the sepsis-associated decrease in serum DHEA sulfate (DHEAS). However, experimental sepsis in rodents leads to down-regulation of DHEA sulfotransferase, which inactivates DHEA to DHEAS, theoretically resulting in higher DHEA levels.

Objective: The objective of the study was to test whether serum DHEA and DHEAS are dissociated in septic shock and to determine their association with circulating cortisol in the context of severity of disease and mortality.

Design, Setting, and Participants: This was a cross-sectional study consisting of 181 patients with septic shock, 31 patients with acute trauma, and 60 healthy controls.

Main Outcome Measures: Serum cortisol, DHEA, and DHEAS were measured before and 60 min after ACTH stimulation.

Results: Serum cortisol was increased and DHEAS was decreased in both septic shock and trauma patients (all P < 0.001). However, compared with healthy controls, DHEA was significantly increased in sepsis but decreased after trauma (all P < 0.001). In sepsis, neither cortisol nor DHEA increased significantly after ACTH. Most severely ill patients had higher cortisol (P = 0.069) and lower DHEA (P = 0.076) and a significantly higher cortisol to DHEA ratio (P = 0.004). Similarly, the cortisol to DHEA ratio was significantly increased in nonsurvivors of septic shock (P = 0.026), whereas survivors did not differ from controls (P = 0.322).

Conclusions: The observed dissociation of DHEA and DHEAS in septic shock contradicts the previous concept of sepsis-associated DHEA deficiency. Increased DHEA levels may maintain the balance between glucocorticoid- and DHEA-mediated immune and vascular effects. However, most severe disease and mortality is associated with an increased cortisol to DHEA ratio, which may represent a novel prognostic marker in septic shock.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
SEVERE SEPSIS REMAINS the most common cause of death in noncoronary intensive care unit patients. Sepsis accounts for 2% of all hospital admissions and severe sepsis and septic shock for 10% of admissions to intensive care units (1), with even more patients developing sepsis after admission, e.g. during the early postoperative course. Importantly, the 28-d mortality is 40–60% for severe sepsis and 60–80% for septic shock (1).

Adrenal insufficiency has been implicated as an important factor contributing to this poor outcome (2, 3). The normal endocrine response to severe sepsis is characterized by a significant increase in circulating cortisol (4). Exogenous ACTH stimulation often fails to elicit a further increase in cortisol production in sepsis, and patients exposed to acute surgical stress may fail a short synacthen test in up to 60%, depending on defined pass-fail criteria (5). There is an ongoing debate whether this attenuated cortisol response to ACTH reflects an already maximal and sufficient activation of the hypothalamus-pituitary-adrenal axis or a true impairment of adrenal function. An ACTH-induced cortisol increase of less than 9 µg/dl (248 nmol/liter) has been suggested to be a prognostic marker for higher mortality (3). Treatment of this subgroup with hydrocortisone yielded significant beneficial effects with regard to catecholamine requirements and, most importantly, the probability of survival (6). However, others have reported beneficial effects of hydrocortisone in septic shock irrespective of the ACTH-induced increase in serum cortisol (7, 8, 9).

Whereas serum cortisol increases in response to septic shock, circulating levels of dehydroepiandrosterone sulfate (DHEAS), the most abundant adrenal steroid in the human circulation, decrease (10, 11, 12). This has been interpreted as a stress-induced intraadrenal shift from adrenal androgen toward glucocorticoid biosynthesis (10, 12, 13), possibly explained by a partial inhibition of steroidogenic pathways leading to dehydroepiandrosterone (DHEA) production (14). Such a shift may have a negative impact on the immune response to stress by disrupting the balance between cortisol- and DHEA-induced immune effects (13). Furthermore, DHEA administration has beneficial effects on experimental-induced sepsis in rodents (15, 16, 17, 18, 19, 20, 21). On this basis, DHEA deficiency in septic shock in man may warrant DHEA replacement therapy (12, 22, 23).

The adrenals secrete both DHEA and DHEAS, but only DHEA is considered biologically active, mediating its action mainly indirectly via downstream conversion to sex steroids and intermediate steroids with potentially distinct properties (24, 25). We have recently shown that the conversion of DHEA sulfotransferase (SULT2A1) is the rate-limiting step regulating the equilibrium between DHEA and DHEAS (26). This suggests that circulating DHEAS may not appropriately reflect the biologically active DHEA pool, in particular if SULT2A1 activity is impaired. A recent study in rodents has demonstrated a significant down-regulation of SULT2A1 after lipopolysaccharide-induced sepsis (27).

Only one previous study (28) measured baseline DHEA and DHEAS levels in septic patients, but results were largely inconclusive due to the small sample size (15 survivors and 15 nonsurvivors of severe sepsis). Experimental endotoxinemia in healthy human volunteers has been shown to increase circulating DHEA, without affecting circulating DHEAS (29).

Here we analyzed a large sample of septic shock patients (n = 181), comparing them with healthy controls (n = 60) and an acute trauma cohort (n = 31). We set out to challenge the concept of severe DHEA deficiency in septic shock, hypothesizing that low circulating DHEAS in septic shock may not indicate true DHEA deficiency. Furthermore, we evaluated the interplay between glucocorticoids and adrenal androgens (cortisol to DHEA ratio) in the context of severity of disease and mortality in septic shock.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Study population

In a cross-sectional study, we analyzed serum samples obtained from three different cohorts. First, we studied 181 patients with septic shock as defined by the presence of the following criteria: 1) documented site of infection, as evidenced by the presence of polymorphs in a normally sterile body fluid (except blood), positive culture, or Gram stain of a normally sterile body fluid, clinical focus of infection, wound with purulent discharge, pneumonia, or other clinical evidence of systemic infection; 2) temperature higher than 38.3 C or lower than 35.6 C; 3) heart rate greater than 90 beats per minute; 4) systolic arterial pressure lower than 90 mm Hg for at least 1 h despite adequate fluid replacement and more than 5 µg/kg body weight of dopamine or current treatment with epinephrine or norepinephrine; 5) urinary output of less than 0.5 ml/kg body weight for at least 1 h or ratio of arterial oxygen tension to the fraction of inspired oxygen of less than 280 mm Hg or arterial lactate levels higher than 2 mmol/liter; and 6) need for mechanical ventilation. Severity of disease was assessed by the Simplified Acute Physiology Score II (SAPS II) (30), and mortality was recorded according to survival status on d 28 after admission. The patients with septic shock had been recruited for a previously published study carried out at 19 intensive care units (6). The original study cohort had consisted of 300 patients, and we included serum samples from all patients for whom sufficient amounts of serum were still available. Thus, we were able to analyze the serum samples obtained from 181 patients with septic shock, 118 men, and 63 women with a median age of 61 yr (age range 20–85 yr). This subcohort did not differ from the entire study cohort with regard to age, sex distribution, severity of disease, cortisol response to ACTH, or survival. Serum samples at baseline and 60 min after stimulation with 250 µg ACTH1–24 had been obtained within 6 h of onset of septic shock.

Second, we analyzed serum samples obtained from 60 healthy individuals, 34 women, and 26 men, median age 26 yr, age range 19–63 yr. They had volunteered for a previously published study on the normal cortisol response to the short synacthen test (31). All volunteers had been free of chronic or acute disease and were not taking any medication or oral contraceptives or postmenopausal hormone replacement therapy. Serum was available at baseline and 60 min after the administration of 250 µg ACTH1–24. All short synacthen tests had been carried out in the morning, with samples drawn between 0900 and 1200 h after a 30-min period of rest before baseline.

In addition, we analyzed baseline serum samples from a cohort of 31 acute trauma patients (24 women, seven men; median age 82 yr, age range 65–96 yr), who underwent blood sampling between 0900 and 1200 h within 24 h after acute hip fracture and without signs of concomitant infection or sepsis.

Study protocols for all cohorts had been approved by the local research ethics committee. Healthy controls and patients with acute hip fracture had given written informed consent before study participation, whereas in patients with septic shock, written informed consent had been obtained from either the patients themselves or their relatives.

Serum hormone measurements

All serum samples had been stored at –20 C before analysis by RIA. Serum steroid hormone concentrations were determined by duplicate measurements using established specific RIAs: DHEA (Diagnostic Systems Laboratories, Inc., Sinsheim, Germany) (cross-reactivity to DHEAS, 0.04%); DHEAS (DPC Biermann, Bad Nauheim, Germany) (cross-reactivity to DHEA, 0.08%); and cortisol (DPC Biermann). All samples from an individual were measured within one assay. Intra- and interassay coefficients of variation were less than 8 and 12%, respectively.

Statistical analysis

We used the SPSS statistical software package version 13.0 (SPSS Inc., Chicago, IL). All data are reported as median with intraquartile range (IQR). The normal distribution of results was ascertained by using the Kolmogorov-Smirnov-Liliefors test, after log transformation of results. Comparisons between two groups were performed with t test for unpaired samples. Significance was defined as P < 0.05. Differences among three groups were tested using one-way ANOVA followed by LSD post hoc test for statistical significance. Statistical comparisons analyzing the influence of severity of disease were performed after subtraction of subscores for age from the total SAPS II score, thus using age-corrected SAPS II scores. Statistical comparisons after stratification for survival status were carried out for only that part of the septic shock cohort that did not receive hydrocortisone after baseline assessment (n = 88; 40 survivors, 48 nonsurvivors).


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Baseline serum cortisol in septic shock was significantly higher than in healthy controls, whereas serum DHEAS was lower (all P < 0.001) (Fig. 1Go, A and B). However, by contrast, DHEA was significantly increased in septic shock (P < 0.001) (Fig. 1CGo). This striking discordance between serum DHEA and DHEAS in septic shock resulted in a significantly increased DHEA to DHEAS ratio (P < 0.001) (Fig. 1DGo). The septic shock-associated increase in cortisol exceeded the increase in DHEA, leading to a significantly increased cortisol to DHEA ratio in septic shock patients, compared with healthy controls [21.1 (9.2, 47.3) vs.10.2 (6.5, 16.4), P < 0.001].


Figure 1
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  		FIG. 1. Circulating cortisol, DHEAS, and DHEA in patients with septic shock (n = 181) and healthy controls (n = 60) before and 60 min after stimulation with ACTH. Panel D represents the baseline DHEA/DHEAS ratio calculated for both cohorts. The box plots represent the median and IQR (25th to 75th percentile) and the whiskers represent the fifth and 95th percentile, respectively.

 
ACTH stimulation in healthy controls led to a brisk increase in both cortisol and DHEA to levels slightly below (cortisol) or above (DHEA) those observed in patients with septic shock at baseline (Fig. 1Go, A and C). Conversely, ACTH stimulation in the septic shock cohort did not elicit a further increase in either steroid (Fig. 1Go, A and C).

Sex-specific analysis of the control cohort showed that neither basal nor stimulated cortisol and DHEA levels differed between sexes (Table 1Go). Subsequently there was no difference in cortisol to DHEA ratios between healthy men and women (Table 1Go). By contrast, serum DHEAS was significantly lower in women than men (P < 0.001), which resulted in a significantly higher DHEA to DHEAS ratio in women than men (P = 0.006). This difference was not preserved in the septic shock cohort (Table 1Go).


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  		TABLE 1. Sex-specific analysis of serum cortisol, DHEA, and DHEAS in septic shock (n = 181) and in healthy controls (n = 60)

 
We also analyzed the cohort with regard to the influence of previous drug treatment. Thirty-two of 181 patients had received a single dose of etomidate before baseline endocrine assessment; however, cortisol, DHEA, DHEAS, or their respective ratios or the cortisol and DHEA response to ACTH did not differ between this subcohort and the remaining patients (data not shown).

To examine a potential influence of the underlying illness, we also measured serum cortisol, DHEA, and DHEAS in patients with acute hip fracture, i.e. severe stress of noninflammatory origin. Serum cortisol in this trauma cohort was significantly higher than healthy controls (P < 0.001) but still lower than septic shock (P < 0.001) (Fig. 2AGo). Serum DHEAS in the trauma cohort was significantly lower than in healthy controls (P < 0.001) (Fig. 2BGo), with significantly older age in the hip fracture cohort certainly contributing here. However, in contrast to the septic shock cohort, DHEA in acute trauma patients was not up-regulated but significantly decreased, compared with healthy controls (P = 0.015) (Fig. 2CGo). Thus, in the trauma cohort, circulating DHEA was concordant with circulating DHEAS, contrasting with the striking discordance of DHEA and DHEAS in septic shock.


Figure 2
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  		FIG. 2. Baseline cortisol, DHEAS, and DHEA in healthy controls, patients with acute trauma, and patients in septic shock. Healthy controls (n = 60) vs. patients with acute hip fracture (n = 31) vs. septic shock patients (n = 181). The box plots represent the median and IQR (25th to 75th percentile) and the whiskers represent the fifth and 95th percentile, respectively.

 
Further analysis was performed to investigate potential effects of severity of disease, as assessed by the SAPS II score in the septic shock cohort. At baseline, the most severely ill patients [SAPS II scores within quartile 4 (q4)] tended to have higher serum cortisol (P = 0.069) and lower DHEA (P = 0.076) than patients with SAPS II scores within quartile 1 (q1) (Fig. 3Go, A and B). However, importantly, only the cortisol to DHEA ratio differentiated with statistical significance between most severely ill and least ill patients (P = 0.004) (Fig. 3CGo).


Figure 3
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  		FIG. 3. Baseline cortisol, DHEAS, DHEA, and cortisol/DHEA to DHEAS ratio in healthy controls and patients with septic shock stratified by severity of illness as assessed by the SAPS II. Healthy controls (n = 60) vs. least ill patients (SAPS II q1, n = 45) vs. most severely ill patients (SAPS II q4, n = 45). The box plots represent the median and IQR (25th to 75th percentile) and the whiskers represent the fifth and the 95th percentile, respectively.

 
Accordingly, nonsurvivors of septic shock, as defined by 28-d mortality, had a significantly higher cortisol to DHEA ratio than survivors (P = 0.026), whereas survivors and healthy controls did not differ (P = 0.322) (Table 2Go). Baseline and stimulated cortisol was significantly higher in nonsurvivors than survivors, whereas differences in serum DHEA failed to achieve statistical significance (Table 2Go). Age did not differ between the cohorts stratified for severity of disease (SAPS II, q1 median age 60, range 46–69 yr vs. q4 61, 51–70 yr, n.s.) and survival (survivors 55, 43–69 yr vs. nonsurvivors 63, 46–74 yr, n.s.).


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  		TABLE 2. Serum cortisol, DHEAS, and DHEA in healthy controls (n = 60) and patients with septic shock (n = 88) stratified according to survival status 28 d after admission to the intensive care unit

 

   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
In accordance with previous reports (10, 11, 12), we found significantly lower serum DHEAS in both our septic shock and trauma cohorts than in healthy controls. This may represent a stress-induced down-regulation of adrenal DHEAS output. Older age in our patients with septic shock and acute hip fracture certainly represents an important contributing factor. The lower DHEAS levels may also be partially explained by the higher median age in the septic shock cohort. However, one would have expected DHEA and DHEAS levels to be concordant, i.e. to observe similarly decreased DHEA levels in septic shock. However, we found that despite low circulating DHEAS, the levels of DHEA were actually significantly increased in the septic patients, a finding that detracts from the previous concept of DHEA deficiency in septic shock.

Both cortisol and DHEA appeared to be maximally stimulated in septic shock, with no significant further increase elicited by exogenous ACTH stimulation. By contrast, despite significantly increased circulating cortisol in the acute trauma cohort, circulating DHEA was significantly lower than in healthy controls. This suggests that up-regulation of DHEA may be a sepsis-specific phenomenon, possibly representing a previously unrecognized, counterregulatory mechanism in the endocrine response to inflammatory stress. However, to further confirm this, a comparison of septic shock patients to similarly stressed patients suffering from an underlying illness of noninflammatory nature would be required. The patients with acute hip trauma, however, had lower cortisol levels than the septic patients, indicating a milder degree of acute stress.

An up-regulation of DHEA in septic shock may aim at maintaining the balance between glucocorticoid- and DHEA-mediated effects on the immune and vascular system. Importantly, DHEA has been shown to modulate the human innate immune response including natural killer cell activity (32) and enhances IL-2 secretion by T lymphocytes (33). DHEA administration in systemic lupus erythematosus has significantly reduced disease activity and glucocorticoid dose requirements (34, 35, 36). Of note, in rodent models of experimental sepsis, DHEA has consistently exerted beneficial effects (15, 16, 17, 18, 19, 20, 21). However, these results need to be interpreted with caution because the rodent does not produce DHEA from the adrenal; circulating concentrations of DHEA and DHEAS are of gonadal origin and are very low. Further studies on the immune effects of DHEA in human-derived cell systems are therefore urgently needed.

In addition to immune effects, DHEA may also have beneficial effects on vascular function in sepsis. DHEA, but not DHEAS, enhances endothelial nitric oxide synthase expression and activity in human vascular endothelial cells (37, 38, 39) and increases flow-mediated vasodilation in vivo (40). Sepsis is associated with down-regulation of endothelial nitric oxide synthase and up-regulation of inducible nitric oxide synthase (41, 42), a disequilibrium that may contribute to sepsis-associated microvascular damage (43, 44).

With regard to the mechanism underlying the observed up-regulation of DHEA, but not DHEAS, in septic shock, we would propose that this may be caused by a sepsis-associated down-regulation of SULT2A1 that converts DHEA to DHEAS. In septic shock patients, DHEA to DHEAS ratios were approximately five times higher than in healthy controls. These data are in keeping with previously reported findings of SULT2A1 down-regulation in lipopolysaccharide-induced sepsis in mice (27). Furthermore, these findings support the concept that SULT2A1 activity, i.e. the conversion of DHEA to DHEAS, is the pivotal regulator of the DHEA-DHEAS equilibrium in humans. Circulating DHEAS levels may not appropriately reflect the biologically active, circulating DHEA pool and thus may not be a reliable marker of adrenal androgen output (26).

Importantly, steroid action during the inflammatory response to septic shock is reflected by not only circulating hormone levels but also tissue-specific regulatory mechanisms at the prereceptor level. Proinflammatory cytokines up-regulate 11ß-hydroxysteroid dehydrogenase type 1 that converts inactive cortisone to active cortisol (45, 46), a mechanism implicated in the endocrine response to critical illness (2). Similarly, we have recently shown that prereceptor metabolism of steroids including DHEA occurs within immune cells and varies as a function of age (47), another putative mechanism regulating corticosteroid action in critical illness. Down-regulation of SULT2A1 would represent another prereceptor mechanism impacting on the endocrine response to inflammatory stress, leading to up-regulation of DHEA by inhibiting its inactivation of DHEAS. Further studies are required to investigate whether this mechanism is indeed responsible for the dissociation of DHEA and DHEAS in humans with septic shock.

The documented up-regulation of DHEA in septic shock leads to a maintenance of the physiological cortisol to DHEA ratio and thereby stabilizes the balance between glucocorticoid- and DHEA-mediated effects. However, importantly, as observed in the most severely ill patients and the nonsurvivors, this counterregulatory mechanism can be exhausted. Increased disease severity and nonsurvival were not associated with a significant change in cortisol or DHEA but with an increased cortisol to DHEA ratio. This may represent a novel prognostic marker in septic shock, requiring further confirmation in a large prospectively studied cohort. An increase in the cortisol to DHEA ratio would inevitably result in a shift toward glucocorticoid-mediated action, and we suggest that this may be unfavorable for an effective endocrine response to septic shock. There are no obvious explanations for this decline in DHEA levels with increasing severity of disease. A partial inhibition of steroidogenic pathways involved in DHEA synthesis has been suggested as the cause of low DHEAS levels (14), but confirmatory evidence and elucidation of underlying regulatory mechanisms is still lacking.

Hydrocortisone treatment in septic shock is associated with significant survival benefits (1). These are modest but considerable when faced with a very high mortality. However, in the light of our preliminary findings, one could speculate that this therapeutic approach might be incomplete. Importantly, administration of hydrocortisone will increase the cortisol to DHEA ratio, first by increasing circulating cortisol and second by potentially suppressing the residual adrenal DHEA production via feedback inhibition. Future studies are required to determine the longitudinal course of circulating adrenal steroid concentrations during critical illness and confirm the prognostic value of the cortisol to DHEA ratio, set against the limited availability of DHEA assays. However, if results of future studies support the cortisol to DHEA ratio as a prognostic marker, it would be conceivable that a combined treatment with hydrocortisone and DHEA may be more beneficial than hydrocortisone monotherapy in septic shock.


   Acknowledgments
 
We thank Diana Filko (University of Würzburg, Würzburg, Germany) for skillful help with RIAs.


   Footnotes
 
This work was supported by grants from the Medical Research Council United Kingdom (Senior Clinical Fellowship G116/172 to W.A.), the Biotechnology and Biological Sciences Research Council (Project Grant 6/ERA16062 to J.M.L.), and the Wellcome Trust (Programe Grant 066357 to P.M.S.).

First Published Online April 11, 2006

Abbreviations: DHEA, Dehydroepiandrosterone; DHEAS, DHEA sulfate; IQR, intraquartile range; q1, quartile 1; q4, quartile 4; SAPS II, Simplified Acute Physiology Score II; SULT2A1, DHEA sulfotransferase.

Received October 12, 2005.

Accepted April 4, 2006.


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 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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