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Indication of attenuated DHEA-s response during acute psychosocial stress in patients with clinical burnout
Journal of Psychosomatic Research 79 (2015) 107–111
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Journal of Psychosomatic Research
Indication of attenuated DHEA-s response during acute psychosocial stress in patients with clinical burnout Anna-Karin Lennartsson ⁎, Anna Sjörs, Ingibjörg H. Jonsdottir The Institute of Stress Medicine, Göteborg, Sweden
a r t i c l e
i n f o
Article history: Received 28 January 2015 Received in revised form 25 April 2015 Accepted 13 May 2015 Keywords: Clinical burnout Trier Social Stress Test Acute stress response Dehydroepiandrosterone sulphate
a b s t r a c t Objective: Dehydroepiandrosterone sulphate (DHEA-s) is an anabolic protective hormone. We have previously reported that DHEA-s production capacity is attenuated in stressed individuals. The aim of the present study was to investigate the DHEA-s response during acute psychosocial stress in patients with clinical burnout. Methods: Seventeen patients with clinical burnout were compared to 13 non-chronically stressed healthy controls, aged 31–50 years (mean age 41 years, SD 6 years), as they underwent the Trier Social Stress Test (TSST). All patients fulfilled diagnostic criteria for stress-related exhaustion disorder, which is a criteria-based diagnosis that has been used in Sweden since 2005 to define patients seeking health-care for clinical burnout. Blood samples were collected before, directly after the stress test, and after 30 min of recovery. DHEA-s levels were measured and delta values (peak levels minus baseline levels) plus area under the curve with respect to increase (AUCI) were calculated. Results: The patients had 43% smaller AUCI DHEA-s (p = 0.041) during the stress test. The delta DHEA-s was 34% lower in the patients, however, this difference was not statistically significant (p = 0.054). Conclusion: The study indicates that DHEA-s production capacity during acute stress may be attenuated in patients with clinical burnout. Reduced DHEA-s production may constitute one of the links between stress, burnout and the associated adverse health. © 2015 Elsevier Inc. All rights reserved.
Introduction Burnout could be defined as a negative affective state consisting of emotional exhaustion, cognitive weariness and physical fatigue caused by chronic psychosocial stress [1]. Burnout has also been associated with increased risk for developing physical adverse health [1–6]. Most research on hormonal levels and hormonal responses in burnout subjects has focused on cortisol [7–12], a hormone produced and released by the adrenal cortex in response to adrenocorticotropic hormone (ACTH). Another hormone produced by the adrenal cortex in response ACTH is dehydroepiandrosterone sulphate (DHEA-s). In addition to being a precursor to androgens and estrogens, DHEA-s is an active hormone with effects on its own [13]. DHEA-s has regenerative and protective roles important for maintenance and restoration of health [13,14]. Production of DHEA-s peaks in young adulthood, thereafter the levels decline progressively [15,16]. Levels of DHEA-s are known to temporarily increase during acute psychosocial stress [17,18] and the acute stress-induced DHEA-s release has been suggested to play a protective role, as an antagonist to the consequences of cortisol [18]. Besides the effects of ageing, different types of prolonged stress are reported to be negatively associated with DHEA-s production, both in samples taken ⁎ Corresponding author at: Carl Skottsbergs gata 22 B, 413 19 Göteborg, Sweden. E-mail address: [email protected] (A-K. Lennartsson).
http://dx.doi.org/10.1016/j.jpsychores.2015.05.011 0022-3999/© 2015 Elsevier Inc. All rights reserved.
during resting conditions [19,20] and during an acute stress situation [21]. We have previously reported that individuals who perceive prolonged stress (perceived stress at work) exhibit attenuated DHEA-s response to acute stress (approximately 50% lower) compared to nonstressed individuals [21]. Since burnout is a potential consequence of long-term stress, it could be speculated that patients with burnout may also have lower DHEA-s production capacity during acute stress. The aim of the present study is to investigate whether this is the case. Since ACTH regulates the DHEA-s production, ACTH was also investigated during the experiment. Method Participants 17 patients with clinical burnout (10 men and 7 women) and 13 healthy controls without chronic stress (9 men and 4 women), aged 31–50 years (mean age 41 years, SD 6 years), were included in the study. The patients were recruited from a specialist clinic, which exclusively treats patients with stress-related mental disorders, in the region of Västra Götaland, Sweden. The patients were originally referred to the stress clinic from primary health care centres or occupational health service centres. They were ambulatory at the time of the study, and none had received in-patient care due to their illness. All the patients fulfilled
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the diagnostic criteria for stress-related exhaustion disorder (ED) as previously described by Jonsdottir and co-workers [22]. Stress-related exhaustion disorder is a criteria-based diagnosis that has been used in Sweden since 2005 to define patients seeking health-care for clinical burnout. Table 1 shows the diagnostic criteria. Five of the patients had co-morbid depression and anxiety. One of the patients had co-morbid depression only and 6 patients had co-morbid anxiety only. The controls were recruited from a cohort study, surveying psychosocial work environment and health, and through advertising in a local daily newspaper. For this particular study, out of 36 control subjects, those who scored low stress at work (lower tertile) on the Stress-Energy (SE) Questionnaire [23] were included as controls. For both patients and controls, to be included in the study, subjects had to be between 30 and 50 years of age, having a normal body weight and being without known psychiatric or somatic disorder (except clinical burnout in the patient group). Subjects who were taking any medication that may affect the HPA axis function, such as for example antidepressant or oestrogens were not included. The study was approved by the Regional Ethical Review Board in Göteborg, Sweden, and was conducted according to the Helsinki Declaration. Scoring of mental health Symptoms of burnout were measured, mostly to ensure that the controls were not suffering from burnout. The Shirom–Melamed Burnout Questionnaire (SMBQ) [1] was used to measure burnout. SMBQ contains 22 items (graded 1–7) measuring the different aspects of burnout; emotional and physical exhaustion, tension, listlessness and cognitive weariness. A mean burnout index was calculated for each participant. The index can range from 1 to 7. The SMBQ correlates strongly with the Maslach Burnout Inventory [24], the most widely used instrument for measurement of burnout. However, clinical burnout in this study is set by using the diagnostic criteria of ED. Study procedure The participants underwent the TSST, a well-known standardized laboratory stress test described in detail elsewhere [25]. At arrival, an intravenous catheter was inserted in an antecubital vein (− 30 time point). At the start of the TSST, the participants are introduced to the tasks and asked to prepare for a simulated job interview (10 min). After this, the participants participated in a simulated job interview
Table 1 Diagnostic criteria for stress-related exhaustion disorder as proposed by the Swedish National Board of Health and Welfare. A
B C
D E
F
Physical and mental symptoms of exhaustion with duration of at least 2 weeks. The symptoms have developed in response to one or more identifiable stressors, which have been present for at least six months Markedly reduced mental energy, which is manifested by reduced initiative, lack of endurance or increase in time needed for recovery after mental efforts At least four of the following symptoms have been present most of the day, nearly every day, during the same 2-week period: 1. Persistent complaints of impaired memory 2. Markedly reduced capacity to tolerate demands or to work under time pressure 3. Emotionally instability or irritability 4. Insomnia or hypersomnia 5. Persistent complaints of physical weakness or fatigue 6. Physical symptoms such as muscular pain, chest pain, palpitations, gastrointestinal problems, vertigo or increased sensitivity to sounds The symptoms cause clinically significant distress or impairment in social, occupational or other important areas of functioning The symptoms are not due to direct physiological effects of substance (such as drug of abuse or medication) or general medical condition (such as hypothyroidism, diabetes and inflectional disease) If criteria for major depressive disorder, dysthymic disorder or generalized anxiety disorder are met, exhaustion disorder is set as a comorbid condition
(5 min) and thereafter performed a mental arithmetic task (5 min). Blood samples were drawn before the test (− 10 time point and 0 time point) and directly after the test (the +20 time point). Thereafter, participants rested (recovery period of total 30 min), and at 10 and 20 min into the recovery period, the fourth and fifth blood samples were drawn (+ 30 and + 40 time points). A final blood sample was drawn at the end of the recovery period (+50 time point). The test procedure was conducted between 1300 h and 1700 h. Hormone assays A total of 122 ml blood was collected from the participants during the TSST. Blood samples were collected at six time points (− 10, 0, +20, +30, +40, and +50; 7 ml at each time point) for measurements of plasma ACTH (and other hormones that were included in the original study plan). Additional blood samples were collected at four of the six time points (−10, 0, +20, +50; 20 ml at each time point). These samples were available for measurement of DHEA-s. The samples were collected in two different tubes; pre-chilled tubes containing EDTA and serum separator tubes. After the tubes had been centrifuged, plasma and serum were stored at − 80 °C until assayed. Serum concentration of DHEA-s was measured the by radioimmunoassay (RIA) (limit of detection, 0.14 μmol/l, Diagnostic Products Corporation, Los Angeles, CA). Plasma concentrations of ACTH were measured by immunoradiometric assay (limit of detection, 0.4 pmol/L) (CIS bio International, Gif-surYvette Cedex, France). Interassay coefficient of variation was below 12% for DHEA-s and below 10% for ACTH. Data handling Baseline values for ACTH and DHEA-s were calculated as means of the values determined at the − 10 and the 0 time points. Delta ACTH and delta DHEA-s were calculated (baseline levels subtracted from the peak levels). Area under the curve with respect to increase (AUCI) was calculated based on the baseline level, the levels at the + 20 time point and the + 50 time point [26]. Variables that showed a nonnormal distribution (tested by Kolmogorov –Smirnov test) were converted by logarithmic transformation. Statistical analysis Using t-test, the patient group was compared to the control group regarding age, BMI, and DHEA-s at baseline. Since ACTH stimulates the production of DHEA-s, ACTH response (log delta ACTH) was compared between patients and controls using t-test. Even though basal DHEA-s levels are higher in men than in women [15], the magnitude of DHEAs response does not differ between the sexes [17]. Men and women were therefore analysed together. This was confirmed in the present study by comparing log DHEA-s and log AUCI DHEA-s between the men and women by performing t-tests. To compare DHEA-s responses between patients and controls, t-tests were performed on log AUCI DHEA-s and log delta DHEA-s. Homogeneity of variance was checked for all performed t-test. Figures were created reporting delta DHEA-s and AUCI DHEA-s in men and women separately. Furthermore, mixed between–within ANCOVA (time x group) controlling for baseline DHEA-s (log DHEA-s at baseline) was conducted. Log transformed Table 2 Characteristic of the burnout patient group (n = 17) and the control group (n = 13).
Number of men/women Age BMI Baseline DHEA-s, μmol/L Burnout score
Patients
Controls
p value
10/9 42 (34–50) 24.8 (19.2–30) 4.69 (2.6–9.15) 4.33 (1.95–6.00)
9/4 39 (31–50) 24.1 (20.5–30.1) 5.05 (2.70–9.10) 1.98 (1.18–4.59)
0.471 0.208 0.496 0.582 na
Mean (range) if nothing indicated. na = not applicable.
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Fig. 1. Geometric mean ACTH levels during the TSST in burnout patients (n = 17) and controls (n = 13).
Fig. 2. Geometric mean DHEA-s levels during the TSST in burnout patients (n = 17) and controls (n = 13).
values of the concentrations of DHEA-s at the 0 time point, the +20, and the +50 time points were used in the analysis. The level of significance was set at p ≤ 0.050. Analyses were conducted with IBM Statistics 20 (SPSS Inc., Chicago, IL, USA).
Mixed between–within ANCOVA (time-group) controlling for baseline DHEA-s showed a main effect for time (F [2,26] = 4.47, p b 0.022, partial eta-squared = 0.256), indicating a change in DHEA-s concentration during the experiment. Between baseline and the +20 time point, the DHEA-s concentration increased on average by 17% in the patient group (ranging from 5% to 31%). In the control group, the DHEA-s concentration increased in average by 23% (ranging from 9% to 47%). There was no interaction effect between group and time (F [2,26] = 0.937, p = 0.405, partial eta-squared = 0.067), indicating that patients and controls show similar response patterns of DHEA-s during psychosocial stress (as seen in Fig. 2). There was a significant effect of group (F [1,27] = 5.77, p = 0.023, partial eta-squared = 0.176), indicating that patients and controls differ in DHEA-s levels during the stress test.
Results Table 2 reports characteristics of the burnout patient group and the controls. The patients were not significantly different from controls regarding age, BMI, DHEA-s at baseline or in proportions of men and women.
Discussion
ACTH response Since ACTH stimulates the production of DHEA-s, ACTH response was first evaluated. Fig. 1 shows the ACTH levels during the stress test in patients and controls. Table 3 also reports the corresponding 95% CI. Delta ACTH (baseline levels subtracted from the peak levels) and AUCI ACTH (based on baseline and all the time points during and after the stress test), did not differ between patients and controls (11.1 and 14.2 pmol/l, respectively; p = 0.458 and 358 and 379, respectively; p = 0.781). DHEA-s response DHEA-s levels in patients and controls during the acute stress test are reported in Fig. 2. Table 3 also reports the corresponding 95% CI. In parallel with our previous observations [21], acute stress-induced DHEA-s increase did not differ significantly between men and women (DHEA-s AUCI: 21 and 21, respectively, p = 0.994; delta DHEA-s: 0.76 μmol/l and 0.86 μmol/L, respectively, p = 0.601). The AUCI DHEA-s, which take into account the concentration at baseline the +20 time point and the +50 time point, was 43% smaller in the patients than the controls (AUCI = 16 and 28, respectively, p = 0.041). AUCI DHEA-s values in patients and controls are reported, separately in men and women in Fig. 3. The delta DHEA-s was 34% lower in the patients (0.67 μmol/l) compared to the controls (1.00 μmol/l), however this difference was not significantly different (p = 0.054). Delta DHEA-s values in patients and controls are reported, separately in men and women in Fig. 4.
This study investigated DHEA-s production capacity during acute psychosocial stress in patients with clinical burnout. The results indicate that patients with burnout have lower DHEA-s response than nonchronically stressed healthy controls. One of the two measures of DHEA-s response (AUCI) was on average 43% lower in the patients and the other one (delta values) was on average 34% lower in the patients. However the difference between patients and controls did not reach significance for the latter one. The lower DHEA-s production during acute stress shown in the patients with clinical burnout seems to be similar to our findings in a stressed non-clinical sample [21]. In that study, delta DHEA-s was compared between 10 non-chronically stressed controls, and two groups of individuals who reported prolonged stress (medium and high stress, 13 individuals in each group). The groups who reported prolonged stress exhibited on average 50% lower DHEA-s response. These findings suggest that attenuated DHEA-s production during acute stress seems to occur as a consequence of chronic stress but it is not unique for a clinical population as this is also seen in a stressed non-clinical population.
Table 3 Geometric mean and (95% CI) ACTH and DHEA-s in the burnout patients (n = 17) and controls (n = 13) during the acute stress test. ACTH (pmol/L)
Time (min) −10 0 20 30 40 50
DHEA-S (μmol/L)
Controls
Patients
Controls
Patients
7.06 (5.60–8.89) 7.47 (5.33–10.5) 19.65 (13.30–29.0) 12.70 (8.90–18.1) 9.99 (7.34–13.6) 8.48 (6.25 11.5)
4.64 (3.60–5.97) 5.04 (3.78–6.71) 13.93 (8.60–22.6) 9.81 (6.33–15.2) 7.14 (4.77–10.7) 5.98 (4.30–8.32)
4.75 (3.87–5.83) 4.85 (3.97–5.92) 5.88 (4.69–7.37)
4.43 (3.71–5.30) 4.39 (3.65–5.29) 5.13 (4.35–6.04)
5.13 (4.24–6.22)
4.52 (3.76–5.44)
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Fig. 3. Median (range) AUCI DHEA-s in burnout patients (men: n = 10; women: n = 7) and controls (men: n = 9 and women: n = 4).
may lead to higher risk for adverse effects on psychological and physiological health. The number of participants in this study is small and the results should be confirmed by larger studies. It can be noted that some patients report rather low burnout scores although they do indeed fulfil diagnostic criteria for exhaustion disorder. In most cases, the agreement between self-rating and clinical diagnose is good but there are always exceptions. Furthermore, one of the controls scored rather high on the burnout scale. However, none of the controls fulfilled criteria for exhaustion disorder or any other condition. In conclusion, this study indicates that patients with clinical burnout may exhibit attenuated DHEA-s production capacity during acute stress, compared to healthy controls who are not reporting chronic stress. Reduced DHEA-s production may constitute one of the links between stress, burnout and the associated adverse health. Conflict of interest
Most research on hormonal levels and hormonal responses in burnout subject focus on cortisol [7–12]. It has been suggested that burnout could be associated with hypocortisolism, thus, inability to produce sufficient amounts of cortisol (9), however it is not yet clear whether this is the case. Cortisol and ACTH in these particular patients included in the present study have also been published, which indicates that only severe cases of burnout exhibit hypocortisolism [7]. Cortisol and DHEA-s are both produced from the adrenal cortex in response to ACTH, but from different zones. There are few publications on DHEA-s in burnout. To our knowledge, this is the first publication on DHEA-s production capacity during acute stress in burnout subjects. Four publications were found which included a comparison of baseline DHEA-s between burnout subjects and healthy controls. One of these reported higher DHEA-s levels in the burnout subjects [27], and three of them reported no differences in baseline DHEA-s levels between burnout subjects and controls [24,28,29]. Production capacity might however more likely be reflected when investigating the response to a challenge, as in the present study. Long-term changes of DHEA-s production capacity levels are modulated by the number of zona reticularis cells and levels of certain enzymes within the cells (3β-HSD, CYP17A1, CYB5, and SULT2A1). It might be that changes occur in the zona reticularis after long-term stress comparable to the changes that occur during ageing, namely reduced number of zona reticularis cells that produce DHEA-s [16] as well as shifted enzymatic activity within the zona reticularis leading to a reduced capacity to produce DHEA-s [30]. In prolonged stress, steroid biosynthesis may be shifted from biosynthesis of adrenal androgens to corticosteroid pathways ensuring maintained production of cortisol, which is essential during exposure to stressors. Given the protective functions of DHEA-s, attenuated DHEA-s production during acute stress
Fig. 4. Median (range) delta DHEA-s in burnout patients (men: n = 10; women: n = 7) and controls (men: n = 9 and women: n = 4).
There are no conflicts of interest for any of the authors. Acknowledgement The research nurses Karin Nygren and Anna Palmgren performed stress test and blood sampling. References [1] Melamed S, Kushnir T, Shirom A. Burnout and risk factors for cardiovascular diseases. Behav Med 1992;18:53–60. http://dx.doi.org/10.1080/08964289.1992. 9935172 [published Online First: Epub Date]. [2] Honkonen T, Ahola K, Pertovaara M, Isometsa E, Kalimo R, Nykyri E, et al. The association between burnout and physical illness in the general population—results from the Finnish Health 2000 Study. J Psychosom Res 2006;61:59–66. http://dx.doi.org/ 10.1016/j.jpsychores.2005.10.002 [published Online First: Epub Date]. [3] Melamed S, Shirom A, Toker S, Berliner S, Shapira I. Burnout and risk of cardiovascular disease: evidence, possible causal paths, and promising research directions. Psychol Bull 2006;132:327–53. http://dx.doi.org/10.1037/0033-2909.132.3.327 [published Online First: Epub Date]. [4] Melamed S, Shirom A, Toker S, Shapira I. Burnout and risk of type 2 diabetes: a prospective study of apparently healthy employed persons. Psychosom Med 2006;68: 863–9. http://dx.doi.org/10.1097/01.psy.0000242860.24009.f0 [published Online First: Epub Date]. [5] Toker S, Shirom A, Shapira I, Berliner S, Melamed S. The association between burnout, depression, anxiety, and inflammation biomarkers: C-reactive protein and fibrinogen in men and women. J Occup Health Psychol 2005;10:344–62. http://dx. doi.org/10.1037/1076-8998.10.4.344 [published Online First: Epub Date]. [6] Sheiner EK, Sheiner E, Carel R, Potashnik G, Shoham-Vardi I. Potential association between male infertility and occupational psychological stress. J Occup Environ Med/ Am Coll Occup Environ Med 2002;44:1093–9. [7] Lennartsson AK, Sjors A, Wahrborg P, Ljung T, Jonsdottir IH. Burnout and hypocortisolism — a matter of severity? A study on ACTH and cortisol responses to acute psychosocial stress. Front Psychiatry 2015;6. http://dx.doi.org/10.3389/ fpsyt.2015.00008 [published Online First: Epub Date]. [8] Danhof-Pont MB, van Veen T, Zitman FG. Biomarkers in burnout: a systematic review. J Psychosom Res 2011;70:505–24. http://dx.doi.org/10.1016/j.jpsychores. 2010.10.012 [published Online First: Epub Date]. [9] Pruessner JC, Hellhammer DH, Kirschbaum C. Burnout, perceived stress, and cortisol responses to awakening. Psychosom Med 1999;61:197–204. [10] Kudielka BM, Bellingrath S, Hellhammer DH. Cortisol in burnout and vital exhaustion: an overview. G Ital Med Lav Ergon 2006;28:34–42. [11] Bellingrath S, Weigl T, Kudielka BM. Cortisol dysregulation in school teachers in relation to burnout, vital exhaustion, and effort–reward-imbalance. Biol Psychol 2008;78: 104–13. http://dx.doi.org/10.1016/j.biopsycho.2008.01.006 [published Online First: Epub Date]. [12] De Vente W, Olff M, Van Amsterdam JG, Kamphuis JH, Emmelkamp PM. Physiological differences between burnout patients and healthy controls: blood pressure, heart rate, and cortisol responses. Occup Environ Med 2003;60:i54–61. [13] Traish AM, Kang HP, Saad F, Guay AT. Dehydroepiandrosterone (DHEA)—a precursor steroid or an active hormone in human physiology. J Sex Med 2011;8:2960–82. http://dx.doi.org/10.1111/j.1743-6109.2011.02523.x [quiz 83 [published Online First: Epub Date]]. [14] Theorell T. Anabolism and catabolism. In: Sonnentag S, Perrewé PL, Ganster DC, editors. Research in occupational stress and wellbeing. Current perspectives on jobstress recovery; 2009. p. 249–76. [15] Orentreich N, Brind JL, Rizer RL, Vogelman JH. Age changes and sex differences in serum dehydroepiandrosterone sulfate concentrations throughout adulthood. J Clin Endocrinol Metab 1984;59:551–5.
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Journal of Psychosomatic Research
Indication of attenuated DHEA-s response during acute psychosocial stress in patients with clinical burnout Anna-Karin Lennartsson ⁎, Anna Sjörs, Ingibjörg H. Jonsdottir The Institute of Stress Medicine, Göteborg, Sweden
a r t i c l e
i n f o
Article history: Received 28 January 2015 Received in revised form 25 April 2015 Accepted 13 May 2015 Keywords: Clinical burnout Trier Social Stress Test Acute stress response Dehydroepiandrosterone sulphate
a b s t r a c t Objective: Dehydroepiandrosterone sulphate (DHEA-s) is an anabolic protective hormone. We have previously reported that DHEA-s production capacity is attenuated in stressed individuals. The aim of the present study was to investigate the DHEA-s response during acute psychosocial stress in patients with clinical burnout. Methods: Seventeen patients with clinical burnout were compared to 13 non-chronically stressed healthy controls, aged 31–50 years (mean age 41 years, SD 6 years), as they underwent the Trier Social Stress Test (TSST). All patients fulfilled diagnostic criteria for stress-related exhaustion disorder, which is a criteria-based diagnosis that has been used in Sweden since 2005 to define patients seeking health-care for clinical burnout. Blood samples were collected before, directly after the stress test, and after 30 min of recovery. DHEA-s levels were measured and delta values (peak levels minus baseline levels) plus area under the curve with respect to increase (AUCI) were calculated. Results: The patients had 43% smaller AUCI DHEA-s (p = 0.041) during the stress test. The delta DHEA-s was 34% lower in the patients, however, this difference was not statistically significant (p = 0.054). Conclusion: The study indicates that DHEA-s production capacity during acute stress may be attenuated in patients with clinical burnout. Reduced DHEA-s production may constitute one of the links between stress, burnout and the associated adverse health. © 2015 Elsevier Inc. All rights reserved.
Introduction Burnout could be defined as a negative affective state consisting of emotional exhaustion, cognitive weariness and physical fatigue caused by chronic psychosocial stress [1]. Burnout has also been associated with increased risk for developing physical adverse health [1–6]. Most research on hormonal levels and hormonal responses in burnout subjects has focused on cortisol [7–12], a hormone produced and released by the adrenal cortex in response to adrenocorticotropic hormone (ACTH). Another hormone produced by the adrenal cortex in response ACTH is dehydroepiandrosterone sulphate (DHEA-s). In addition to being a precursor to androgens and estrogens, DHEA-s is an active hormone with effects on its own [13]. DHEA-s has regenerative and protective roles important for maintenance and restoration of health [13,14]. Production of DHEA-s peaks in young adulthood, thereafter the levels decline progressively [15,16]. Levels of DHEA-s are known to temporarily increase during acute psychosocial stress [17,18] and the acute stress-induced DHEA-s release has been suggested to play a protective role, as an antagonist to the consequences of cortisol [18]. Besides the effects of ageing, different types of prolonged stress are reported to be negatively associated with DHEA-s production, both in samples taken ⁎ Corresponding author at: Carl Skottsbergs gata 22 B, 413 19 Göteborg, Sweden. E-mail address: [email protected] (A-K. Lennartsson).
http://dx.doi.org/10.1016/j.jpsychores.2015.05.011 0022-3999/© 2015 Elsevier Inc. All rights reserved.
during resting conditions [19,20] and during an acute stress situation [21]. We have previously reported that individuals who perceive prolonged stress (perceived stress at work) exhibit attenuated DHEA-s response to acute stress (approximately 50% lower) compared to nonstressed individuals [21]. Since burnout is a potential consequence of long-term stress, it could be speculated that patients with burnout may also have lower DHEA-s production capacity during acute stress. The aim of the present study is to investigate whether this is the case. Since ACTH regulates the DHEA-s production, ACTH was also investigated during the experiment. Method Participants 17 patients with clinical burnout (10 men and 7 women) and 13 healthy controls without chronic stress (9 men and 4 women), aged 31–50 years (mean age 41 years, SD 6 years), were included in the study. The patients were recruited from a specialist clinic, which exclusively treats patients with stress-related mental disorders, in the region of Västra Götaland, Sweden. The patients were originally referred to the stress clinic from primary health care centres or occupational health service centres. They were ambulatory at the time of the study, and none had received in-patient care due to their illness. All the patients fulfilled
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the diagnostic criteria for stress-related exhaustion disorder (ED) as previously described by Jonsdottir and co-workers [22]. Stress-related exhaustion disorder is a criteria-based diagnosis that has been used in Sweden since 2005 to define patients seeking health-care for clinical burnout. Table 1 shows the diagnostic criteria. Five of the patients had co-morbid depression and anxiety. One of the patients had co-morbid depression only and 6 patients had co-morbid anxiety only. The controls were recruited from a cohort study, surveying psychosocial work environment and health, and through advertising in a local daily newspaper. For this particular study, out of 36 control subjects, those who scored low stress at work (lower tertile) on the Stress-Energy (SE) Questionnaire [23] were included as controls. For both patients and controls, to be included in the study, subjects had to be between 30 and 50 years of age, having a normal body weight and being without known psychiatric or somatic disorder (except clinical burnout in the patient group). Subjects who were taking any medication that may affect the HPA axis function, such as for example antidepressant or oestrogens were not included. The study was approved by the Regional Ethical Review Board in Göteborg, Sweden, and was conducted according to the Helsinki Declaration. Scoring of mental health Symptoms of burnout were measured, mostly to ensure that the controls were not suffering from burnout. The Shirom–Melamed Burnout Questionnaire (SMBQ) [1] was used to measure burnout. SMBQ contains 22 items (graded 1–7) measuring the different aspects of burnout; emotional and physical exhaustion, tension, listlessness and cognitive weariness. A mean burnout index was calculated for each participant. The index can range from 1 to 7. The SMBQ correlates strongly with the Maslach Burnout Inventory [24], the most widely used instrument for measurement of burnout. However, clinical burnout in this study is set by using the diagnostic criteria of ED. Study procedure The participants underwent the TSST, a well-known standardized laboratory stress test described in detail elsewhere [25]. At arrival, an intravenous catheter was inserted in an antecubital vein (− 30 time point). At the start of the TSST, the participants are introduced to the tasks and asked to prepare for a simulated job interview (10 min). After this, the participants participated in a simulated job interview
Table 1 Diagnostic criteria for stress-related exhaustion disorder as proposed by the Swedish National Board of Health and Welfare. A
B C
D E
F
Physical and mental symptoms of exhaustion with duration of at least 2 weeks. The symptoms have developed in response to one or more identifiable stressors, which have been present for at least six months Markedly reduced mental energy, which is manifested by reduced initiative, lack of endurance or increase in time needed for recovery after mental efforts At least four of the following symptoms have been present most of the day, nearly every day, during the same 2-week period: 1. Persistent complaints of impaired memory 2. Markedly reduced capacity to tolerate demands or to work under time pressure 3. Emotionally instability or irritability 4. Insomnia or hypersomnia 5. Persistent complaints of physical weakness or fatigue 6. Physical symptoms such as muscular pain, chest pain, palpitations, gastrointestinal problems, vertigo or increased sensitivity to sounds The symptoms cause clinically significant distress or impairment in social, occupational or other important areas of functioning The symptoms are not due to direct physiological effects of substance (such as drug of abuse or medication) or general medical condition (such as hypothyroidism, diabetes and inflectional disease) If criteria for major depressive disorder, dysthymic disorder or generalized anxiety disorder are met, exhaustion disorder is set as a comorbid condition
(5 min) and thereafter performed a mental arithmetic task (5 min). Blood samples were drawn before the test (− 10 time point and 0 time point) and directly after the test (the +20 time point). Thereafter, participants rested (recovery period of total 30 min), and at 10 and 20 min into the recovery period, the fourth and fifth blood samples were drawn (+ 30 and + 40 time points). A final blood sample was drawn at the end of the recovery period (+50 time point). The test procedure was conducted between 1300 h and 1700 h. Hormone assays A total of 122 ml blood was collected from the participants during the TSST. Blood samples were collected at six time points (− 10, 0, +20, +30, +40, and +50; 7 ml at each time point) for measurements of plasma ACTH (and other hormones that were included in the original study plan). Additional blood samples were collected at four of the six time points (−10, 0, +20, +50; 20 ml at each time point). These samples were available for measurement of DHEA-s. The samples were collected in two different tubes; pre-chilled tubes containing EDTA and serum separator tubes. After the tubes had been centrifuged, plasma and serum were stored at − 80 °C until assayed. Serum concentration of DHEA-s was measured the by radioimmunoassay (RIA) (limit of detection, 0.14 μmol/l, Diagnostic Products Corporation, Los Angeles, CA). Plasma concentrations of ACTH were measured by immunoradiometric assay (limit of detection, 0.4 pmol/L) (CIS bio International, Gif-surYvette Cedex, France). Interassay coefficient of variation was below 12% for DHEA-s and below 10% for ACTH. Data handling Baseline values for ACTH and DHEA-s were calculated as means of the values determined at the − 10 and the 0 time points. Delta ACTH and delta DHEA-s were calculated (baseline levels subtracted from the peak levels). Area under the curve with respect to increase (AUCI) was calculated based on the baseline level, the levels at the + 20 time point and the + 50 time point [26]. Variables that showed a nonnormal distribution (tested by Kolmogorov –Smirnov test) were converted by logarithmic transformation. Statistical analysis Using t-test, the patient group was compared to the control group regarding age, BMI, and DHEA-s at baseline. Since ACTH stimulates the production of DHEA-s, ACTH response (log delta ACTH) was compared between patients and controls using t-test. Even though basal DHEA-s levels are higher in men than in women [15], the magnitude of DHEAs response does not differ between the sexes [17]. Men and women were therefore analysed together. This was confirmed in the present study by comparing log DHEA-s and log AUCI DHEA-s between the men and women by performing t-tests. To compare DHEA-s responses between patients and controls, t-tests were performed on log AUCI DHEA-s and log delta DHEA-s. Homogeneity of variance was checked for all performed t-test. Figures were created reporting delta DHEA-s and AUCI DHEA-s in men and women separately. Furthermore, mixed between–within ANCOVA (time x group) controlling for baseline DHEA-s (log DHEA-s at baseline) was conducted. Log transformed Table 2 Characteristic of the burnout patient group (n = 17) and the control group (n = 13).
Number of men/women Age BMI Baseline DHEA-s, μmol/L Burnout score
Patients
Controls
p value
10/9 42 (34–50) 24.8 (19.2–30) 4.69 (2.6–9.15) 4.33 (1.95–6.00)
9/4 39 (31–50) 24.1 (20.5–30.1) 5.05 (2.70–9.10) 1.98 (1.18–4.59)
0.471 0.208 0.496 0.582 na
Mean (range) if nothing indicated. na = not applicable.
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Fig. 1. Geometric mean ACTH levels during the TSST in burnout patients (n = 17) and controls (n = 13).
Fig. 2. Geometric mean DHEA-s levels during the TSST in burnout patients (n = 17) and controls (n = 13).
values of the concentrations of DHEA-s at the 0 time point, the +20, and the +50 time points were used in the analysis. The level of significance was set at p ≤ 0.050. Analyses were conducted with IBM Statistics 20 (SPSS Inc., Chicago, IL, USA).
Mixed between–within ANCOVA (time-group) controlling for baseline DHEA-s showed a main effect for time (F [2,26] = 4.47, p b 0.022, partial eta-squared = 0.256), indicating a change in DHEA-s concentration during the experiment. Between baseline and the +20 time point, the DHEA-s concentration increased on average by 17% in the patient group (ranging from 5% to 31%). In the control group, the DHEA-s concentration increased in average by 23% (ranging from 9% to 47%). There was no interaction effect between group and time (F [2,26] = 0.937, p = 0.405, partial eta-squared = 0.067), indicating that patients and controls show similar response patterns of DHEA-s during psychosocial stress (as seen in Fig. 2). There was a significant effect of group (F [1,27] = 5.77, p = 0.023, partial eta-squared = 0.176), indicating that patients and controls differ in DHEA-s levels during the stress test.
Results Table 2 reports characteristics of the burnout patient group and the controls. The patients were not significantly different from controls regarding age, BMI, DHEA-s at baseline or in proportions of men and women.
Discussion
ACTH response Since ACTH stimulates the production of DHEA-s, ACTH response was first evaluated. Fig. 1 shows the ACTH levels during the stress test in patients and controls. Table 3 also reports the corresponding 95% CI. Delta ACTH (baseline levels subtracted from the peak levels) and AUCI ACTH (based on baseline and all the time points during and after the stress test), did not differ between patients and controls (11.1 and 14.2 pmol/l, respectively; p = 0.458 and 358 and 379, respectively; p = 0.781). DHEA-s response DHEA-s levels in patients and controls during the acute stress test are reported in Fig. 2. Table 3 also reports the corresponding 95% CI. In parallel with our previous observations [21], acute stress-induced DHEA-s increase did not differ significantly between men and women (DHEA-s AUCI: 21 and 21, respectively, p = 0.994; delta DHEA-s: 0.76 μmol/l and 0.86 μmol/L, respectively, p = 0.601). The AUCI DHEA-s, which take into account the concentration at baseline the +20 time point and the +50 time point, was 43% smaller in the patients than the controls (AUCI = 16 and 28, respectively, p = 0.041). AUCI DHEA-s values in patients and controls are reported, separately in men and women in Fig. 3. The delta DHEA-s was 34% lower in the patients (0.67 μmol/l) compared to the controls (1.00 μmol/l), however this difference was not significantly different (p = 0.054). Delta DHEA-s values in patients and controls are reported, separately in men and women in Fig. 4.
This study investigated DHEA-s production capacity during acute psychosocial stress in patients with clinical burnout. The results indicate that patients with burnout have lower DHEA-s response than nonchronically stressed healthy controls. One of the two measures of DHEA-s response (AUCI) was on average 43% lower in the patients and the other one (delta values) was on average 34% lower in the patients. However the difference between patients and controls did not reach significance for the latter one. The lower DHEA-s production during acute stress shown in the patients with clinical burnout seems to be similar to our findings in a stressed non-clinical sample [21]. In that study, delta DHEA-s was compared between 10 non-chronically stressed controls, and two groups of individuals who reported prolonged stress (medium and high stress, 13 individuals in each group). The groups who reported prolonged stress exhibited on average 50% lower DHEA-s response. These findings suggest that attenuated DHEA-s production during acute stress seems to occur as a consequence of chronic stress but it is not unique for a clinical population as this is also seen in a stressed non-clinical population.
Table 3 Geometric mean and (95% CI) ACTH and DHEA-s in the burnout patients (n = 17) and controls (n = 13) during the acute stress test. ACTH (pmol/L)
Time (min) −10 0 20 30 40 50
DHEA-S (μmol/L)
Controls
Patients
Controls
Patients
7.06 (5.60–8.89) 7.47 (5.33–10.5) 19.65 (13.30–29.0) 12.70 (8.90–18.1) 9.99 (7.34–13.6) 8.48 (6.25 11.5)
4.64 (3.60–5.97) 5.04 (3.78–6.71) 13.93 (8.60–22.6) 9.81 (6.33–15.2) 7.14 (4.77–10.7) 5.98 (4.30–8.32)
4.75 (3.87–5.83) 4.85 (3.97–5.92) 5.88 (4.69–7.37)
4.43 (3.71–5.30) 4.39 (3.65–5.29) 5.13 (4.35–6.04)
5.13 (4.24–6.22)
4.52 (3.76–5.44)
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Fig. 3. Median (range) AUCI DHEA-s in burnout patients (men: n = 10; women: n = 7) and controls (men: n = 9 and women: n = 4).
may lead to higher risk for adverse effects on psychological and physiological health. The number of participants in this study is small and the results should be confirmed by larger studies. It can be noted that some patients report rather low burnout scores although they do indeed fulfil diagnostic criteria for exhaustion disorder. In most cases, the agreement between self-rating and clinical diagnose is good but there are always exceptions. Furthermore, one of the controls scored rather high on the burnout scale. However, none of the controls fulfilled criteria for exhaustion disorder or any other condition. In conclusion, this study indicates that patients with clinical burnout may exhibit attenuated DHEA-s production capacity during acute stress, compared to healthy controls who are not reporting chronic stress. Reduced DHEA-s production may constitute one of the links between stress, burnout and the associated adverse health. Conflict of interest
Most research on hormonal levels and hormonal responses in burnout subject focus on cortisol [7–12]. It has been suggested that burnout could be associated with hypocortisolism, thus, inability to produce sufficient amounts of cortisol (9), however it is not yet clear whether this is the case. Cortisol and ACTH in these particular patients included in the present study have also been published, which indicates that only severe cases of burnout exhibit hypocortisolism [7]. Cortisol and DHEA-s are both produced from the adrenal cortex in response to ACTH, but from different zones. There are few publications on DHEA-s in burnout. To our knowledge, this is the first publication on DHEA-s production capacity during acute stress in burnout subjects. Four publications were found which included a comparison of baseline DHEA-s between burnout subjects and healthy controls. One of these reported higher DHEA-s levels in the burnout subjects [27], and three of them reported no differences in baseline DHEA-s levels between burnout subjects and controls [24,28,29]. Production capacity might however more likely be reflected when investigating the response to a challenge, as in the present study. Long-term changes of DHEA-s production capacity levels are modulated by the number of zona reticularis cells and levels of certain enzymes within the cells (3β-HSD, CYP17A1, CYB5, and SULT2A1). It might be that changes occur in the zona reticularis after long-term stress comparable to the changes that occur during ageing, namely reduced number of zona reticularis cells that produce DHEA-s [16] as well as shifted enzymatic activity within the zona reticularis leading to a reduced capacity to produce DHEA-s [30]. In prolonged stress, steroid biosynthesis may be shifted from biosynthesis of adrenal androgens to corticosteroid pathways ensuring maintained production of cortisol, which is essential during exposure to stressors. Given the protective functions of DHEA-s, attenuated DHEA-s production during acute stress
Fig. 4. Median (range) delta DHEA-s in burnout patients (men: n = 10; women: n = 7) and controls (men: n = 9 and women: n = 4).
There are no conflicts of interest for any of the authors. Acknowledgement The research nurses Karin Nygren and Anna Palmgren performed stress test and blood sampling. References [1] Melamed S, Kushnir T, Shirom A. Burnout and risk factors for cardiovascular diseases. Behav Med 1992;18:53–60. http://dx.doi.org/10.1080/08964289.1992. 9935172 [published Online First: Epub Date]. [2] Honkonen T, Ahola K, Pertovaara M, Isometsa E, Kalimo R, Nykyri E, et al. The association between burnout and physical illness in the general population—results from the Finnish Health 2000 Study. J Psychosom Res 2006;61:59–66. http://dx.doi.org/ 10.1016/j.jpsychores.2005.10.002 [published Online First: Epub Date]. [3] Melamed S, Shirom A, Toker S, Berliner S, Shapira I. Burnout and risk of cardiovascular disease: evidence, possible causal paths, and promising research directions. Psychol Bull 2006;132:327–53. http://dx.doi.org/10.1037/0033-2909.132.3.327 [published Online First: Epub Date]. [4] Melamed S, Shirom A, Toker S, Shapira I. Burnout and risk of type 2 diabetes: a prospective study of apparently healthy employed persons. Psychosom Med 2006;68: 863–9. http://dx.doi.org/10.1097/01.psy.0000242860.24009.f0 [published Online First: Epub Date]. [5] Toker S, Shirom A, Shapira I, Berliner S, Melamed S. The association between burnout, depression, anxiety, and inflammation biomarkers: C-reactive protein and fibrinogen in men and women. J Occup Health Psychol 2005;10:344–62. http://dx. doi.org/10.1037/1076-8998.10.4.344 [published Online First: Epub Date]. [6] Sheiner EK, Sheiner E, Carel R, Potashnik G, Shoham-Vardi I. Potential association between male infertility and occupational psychological stress. J Occup Environ Med/ Am Coll Occup Environ Med 2002;44:1093–9. [7] Lennartsson AK, Sjors A, Wahrborg P, Ljung T, Jonsdottir IH. Burnout and hypocortisolism — a matter of severity? A study on ACTH and cortisol responses to acute psychosocial stress. Front Psychiatry 2015;6. http://dx.doi.org/10.3389/ fpsyt.2015.00008 [published Online First: Epub Date]. [8] Danhof-Pont MB, van Veen T, Zitman FG. Biomarkers in burnout: a systematic review. J Psychosom Res 2011;70:505–24. http://dx.doi.org/10.1016/j.jpsychores. 2010.10.012 [published Online First: Epub Date]. [9] Pruessner JC, Hellhammer DH, Kirschbaum C. Burnout, perceived stress, and cortisol responses to awakening. Psychosom Med 1999;61:197–204. [10] Kudielka BM, Bellingrath S, Hellhammer DH. Cortisol in burnout and vital exhaustion: an overview. G Ital Med Lav Ergon 2006;28:34–42. [11] Bellingrath S, Weigl T, Kudielka BM. Cortisol dysregulation in school teachers in relation to burnout, vital exhaustion, and effort–reward-imbalance. Biol Psychol 2008;78: 104–13. http://dx.doi.org/10.1016/j.biopsycho.2008.01.006 [published Online First: Epub Date]. [12] De Vente W, Olff M, Van Amsterdam JG, Kamphuis JH, Emmelkamp PM. Physiological differences between burnout patients and healthy controls: blood pressure, heart rate, and cortisol responses. Occup Environ Med 2003;60:i54–61. [13] Traish AM, Kang HP, Saad F, Guay AT. Dehydroepiandrosterone (DHEA)—a precursor steroid or an active hormone in human physiology. J Sex Med 2011;8:2960–82. http://dx.doi.org/10.1111/j.1743-6109.2011.02523.x [quiz 83 [published Online First: Epub Date]]. [14] Theorell T. Anabolism and catabolism. In: Sonnentag S, Perrewé PL, Ganster DC, editors. Research in occupational stress and wellbeing. Current perspectives on jobstress recovery; 2009. p. 249–76. [15] Orentreich N, Brind JL, Rizer RL, Vogelman JH. Age changes and sex differences in serum dehydroepiandrosterone sulfate concentrations throughout adulthood. J Clin Endocrinol Metab 1984;59:551–5.
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