Juliane Hellhammer

A new view on hypocortisolism

Low cortisol levels have been observed in patients with different stress-related disorders such as chronic fatigue syndrome, fibromyalgia, and post-traumatic stress disorder. Data suggest that these disorders are characterized by a symptom triad of enhanced stress sensitivity, pain, and fatigue. This overview will present data on the development, mechanisms and consequences of hypocortisolism on different bodily systems. We propose that the phenomenon of hypocortisolism may occur after a prolonged period of hyperactivity of the hypothalamic-pituitary-adrenal axis due to chronic stress as illustrated in an animal model. Further evidence suggests that despite symptoms such as pain, fatigue and high stress sensitivity, hypocortisolism may also have beneficial effects on the organism. This assumption will be underlined by some studies suggesting protective effects of hypocortisolism for the individual.

Several daily measurements are necessary to reliably assess the cortisol rise after awakening: State- and trait components

The cortisol rise after awakening (CAR) is a frequently applied measure of pituitary-adrenal activity. This measure seems to reflect the acrophase of the diurnal cycle and can easily be assessed in saliva samples, collected by the proband or patient under real life conditions. Since different state and trait factors affect the CAR, we here address the questions (a) to which extent state and trait factors affect the CAR, and (b) how often cortisol measures after awakening have to be taken to obtain reliable results. In this study, we assessed the CAR on 6 consecutive days. After applying structural equation models and correlation analyses, we conclude that (a) the CAR of a single day is determined to a great extent by situational factors and only for a small proportion by trait factors and (b) from two (AUC(t)) to six (AUC(i)) days are necessary to achieve reliable trait measures, since state factors bias data from a single day.

Perceived work overload and chronic worrying predict weekend-weekday differences in the cortisol awakening response

Objective The cortisol increase after awakening has been shown to be associated with work-related stress. Several studies demonstrated a moderate stability of cortisol awakening responses on subsequent days, suggesting situation-dependent variance. This study tests whether cortisol awakening responses are different on weekdays compared with weekend days and whether such differences may be explained by chronic work overload and worrying. Methods Two hundred nineteen participants took saliva samples immediately after awakening and 30, 45, and 60 minutes later on 6 consecutive days starting on Saturday. Perceived chronic work overload and worrying were assessed by a standardized questionnaire. Results There is a clear weekend–weekday difference in the cortisol response to awakening. This difference is associated with chronic work overload and worry. Independent of sex and weekend–weekday differences in time of awakening and sleep duration, participants who report higher levels of chronic work overload and worrying show a stronger increase and higher mean levels of cortisol after awakening on weekdays, but not on weekend days. Conclusions The weekend–weekday differences in the cortisol awakening response and their association with chronic stress clearly demonstrate that the day of cortisol assessment is crucial in psychoendocrinological stress studies.

The physiological response to Trier Social Stress Test relates to subjective measures of stress during but not before or after the test.

The Trier Social Stress Test (TSST) is an effective psychosocial laboratory protocol for inducing stress in humans and has been used in numerous research studies. The stressor leads to a physiological response of the hypothalamus-pituitary-adrenal axis (HPAA) and the autonomous nervous system (ANS). Common biomarkers are cortisol levels and heart rate. In addition to the physiological stress response, the TSST also triggers a psychological response such as an increase in perceived stress, anxiety and emotional insecurity. Whereas HPA and ANS measures can easily be obtained for the TSST period itself, psychological measures are usually determined prior to (baseline) and after the TSST. This may exclude information of the stressful event itself. In the present study, we assessed perceived stress, anxiety and emotional insecurity before, during and after the TSST using visual analogue scales. In addition, cortisol levels and heart rates were assessed. Data of 260 healthy non-smoking males aged 16-60 yrs were used for analyses. Our results show that stress perception, anxiety and emotional insecurity were significantly higher during the TSST as compared to post-TSST ratings. Furthermore, our results suggest a covariance of the psychological stress response during the TSST and the physiological stress responses (cortisol and heart rate) for stress perception though the explained variance was small. This observation was not found for pre- and post-TSST ratings suggesting that assessing psychological stress measures during the stressor itself present a more informative measure of the stress response.

Opposing effects of DHEA replacement in elderly subjects on declarative memory and attention after exposure to a laboratory stressor.

Aging is accompanied by a continuous decline of the adrenal steroid hormone DHEA and its ester DHEAS. Results from studies in rodents have demonstrated that DHEA(S) administration can enhance memory in several test paradigms. However studies from this laboratory did not find positive effects of DHEA treatment on cognitive performance in young and elderly humans. With respect to a possible mechanism of DHEA activity, effects on several neurotransmitter receptors as well as a possible antiglucocorticoid action are discussed. For high levels of glucocorticoids, a disruptive effect on hippocampal mediated memory is documented in rodents and humans. Therefore it was speculated that, if an antiglucocorticoid action of DHEA would underlie the observed beneficial effects of DHEA on memory, these effects might only be detectable if subjects are stressed (and therefore have high cortisol levels). To test this hypothesis 75 elderly women and men participated in a placebo controlled experiment. Subjects took DHEA (50 mg/day) or placebo for 2 weeks (double blind). Thereafter they participated in a standardized psychosocial laboratory stressor (Trier Social Stress Test; TSST). Before and after stress exposure subjects completed two declarative memory tests (visual-verbal and spatial) as well as one attention test. In addition recall of visual material learned before stress was assessed after stress. Baseline DHEAS levels were significantly lower compared with young adults. DHEA replacement increased DHEAS levels into ranges found in young subjects. DHEA-substituted subjects showed a trend towards a larger cortisol stress response. In the visual memory test subjects under DHEA recalled less items after stress which they had learned before stress. In the attention test however subjects under DHEA performed better than subjects from the placebo group after stress. No interaction between stress and DHEA was found for the spatial memory task. The effects of DHEA substitution on memory and attention after stress exposure seem to be heterogenous. While recall of previously learned material seems to be impaired, attention is enhanced. These results do not support the idea of a direct antiglucocorticoid or anti-stress effect of DHEA on hippocampal mediated memory functions.

Trait anxiety moderates the impact of performance pressure on salivary cortisol in everyday life.

Stress and negative affective states are associated with cortisol in everyday life. However, it remains unclear what types of stressors and which affective states yield these associations, and the effect of trait anxiety is unknown. This study investigates the associations of specific task-related stressors and negative affective states in everyday life with salivary cortisol, and explores the mediating and moderating role of state negative affect and trait anxiety, respectively. Salivary cortisol, subjective stress, and state negative affect were measured three times a day on 2 days in 71 participants in everyday life, using a handheld computer to collect self-reports and time stamps and an electronic device to monitor saliva sampling compliance. Stress measures comprised the experience of performance pressure and failure during daily tasks; measures of negative affect comprised worn-out, tense, unhappy, and angry. Effects were tested using multilevel fixed-occasion models. Momentary performance under pressure was related to higher momentary cortisol measures, while mean task failure was related to lower daily cortisol concentrations. The association of performance pressure with cortisol varied between subjects, and this variation was explained by trait anxiety, yielding stronger associations in participants scoring high on trait anxiety. No evidence was found for a mediating role of state negative affect. These results describe the well-documented associations of everyday stressors and affect with salivary cortisol more precisely, suggesting that performance pressure is a significant condition related to short-term changes in cortisol. Subjects scoring high on trait anxiety seem to process stress-relevant information in a way that amplifies the association of performance pressure with reactions of the hypothalamus-pituitary-adrenal axis.

Omega-3 fatty acids administered in phosphatidylserine improved certain aspects of high chronic stress in men

Nutrients such as omega-3 oils and phosphatidylserine have been considered to exert stress-buffering effects. In this randomized, double-blind, placebo-controlled trial, we investigated effects of omega-3 phosphatidylserine (PS) on perceived chronic stress, assessed by the Trier Inventory for Chronic Stress (Schulz P, Schlotz W, Becker P. TICS: Trierer Inventar zum chronischen Stress. Göttingen, Germany: Hogrefe, 2004.), and on psychobiological stress responses to an acute laboratory stress protocol, the Trier Social Stress Test (Neuropsychobiology.1993;28:76-81), at baseline and after the treatment period. We hypothesized that omega-3 PS supplementation lowers chronic and acute stress. Sixty healthy nonsmoking men aged 30 to 60 years either received omega-3 PS or a matching placebo for 12 weeks. Results revealed no significant main effect of omega-3 PS supplementation on stress measures. However, by accounting for chronic stress level of study participants, stress-reducing effects of omega-3 PS were found exclusively for high chronically stressed subjects. As expected, these individuals also showed a blunted cortisol response to the Trier Social Stress Test. Treatment with omega-3 PS seemed to restore the cortisol response in this particular subgroup of low responders. These results are in line with previous findings. We conclude that subgroups characterized by high chronic stress and/or a dysfunctional response of the hypothalamus-pituitary-adrenal axis may profit from omega-3 PS supplementation.

Effects of a Homeopathic Combination Remedy on the Acute Stress Response, Well-Being, and Sleep: A Double-Blind, Randomized Clinical Trial

OBJECTIVES Stress impacts on health, causing stress-related illness. The aim of this study was to investigate stress dampening effects of the homeopathic combination remedy dysto-loges(®) S on physiological and psychological measures during acute stress. Additionally, effects of the substance on sleep and life quality were investigated. DESIGN This randomized, double-blind, placebo-controlled single center study had a total duration of 15 days for each participant. SETTING/LOCATION The study was performed by Daacro, Trier, Germany. SUBJECTS We included 40 women aged 30-50 years that regularly experienced impaired well-being when feeling stressed. INTERVENTION Participants took three tablets daily for 14 days. On the final study day, participants took three pills in the morning and upon arrival at the study site. Thereafter, the Trier Social Stress Test (TSST) was performed. OUTCOME MEASURES Primary endpoints were saliva cortisol responses to the stress test. Secondary biological endpoints were plasma cortisol, adrenocorticotrophic hormone, epinephrine, and norepinephrine (NE) and heart rates. Psychological secondary endpoints were well-being, anxiety, stress, and insecurity during the stress test as well as sleep and quality of life. RESULTS Stress-induced cortisol levels did not differ between groups, but verum-treated participants were characterized by lower NE levels. Two weeks of treatment with the homeopathic substance resulted in a better sleep quality. Sleep improvement was associated with a higher hormonal response to the TSST in both groups. In addition, individuals with impaired sleep in the placebo group had higher unstimulated NE levels. CONCLUSIONS This study provides preliminary evidence for beneficial effects of dysto-loges S on sleep quality. Improvement of sleep quality was positively associated with a normalized neuroendocrine stress response during acute stress, whereas an altered hormonal response was observed in participants with impaired sleep. We hypothesize that the test product may possibly reduce NE release.

Arbeitsstress, sozialer Stress und Schlafqualität:

Cross-sectional analyses of data from 309 subjects test two hypotheses: (1) Sleep disorders are related to social stress, not work stress, and (2) the personality trait “worry disposition” reveals a direct as well as an indirect, i.e. stress-mediated, effect on sleep disorders. A negative association of sleep quality to social stress, but not work stress is found after controlling for effects of worry, age, and illness frequency. This finding is confirmed by the findings of a subsequent path analysis. A subsequent longitudinal study tests hypothesis (3): Social stress causes impairments in sleep quality. Seventy-six subjects received handheld-computers to measure sleep quality and stress in different domains on two subsequent days. A cross-lagged panel analysis reveals associations of social stress at the first day to sleep quality at the second day, but no reversed relation. Findings point to the relevance of worry disposition and social stress in explaining sleep disorders. An 309 Probanden werden in einer Querschnittsuntersuchung zwei Hypothesen uberpruft: (1) Schlafstorungen hangen mit sozialem Stress zusammen, nicht mit Arbeitsstress und (2) das Personmerkmal Besorgnisneigung hat sowohl einen direkten als auch einen indirekten, uber Stress vermittelten, Effekt auf Schlafstorungen. Nach statistischer Kontrolle der Variablen Besorgnisneigung, Alter und Krankheitshaufigkeit findet sich neben anderen Ergebnissen ein negativer Zusammenhang von Schlafqualitat mit sozialem Stress, nicht aber mit Arbeitsstress. Dieser Befund kann in einer anschliesenden Pfadanalyse bestatigt werden. In einer Langsschnittuntersuchung wird dann Hypothese (3) uberpruft: Sozialer Stress verursacht Beeintrachtigungen der Schlafzufriedenheit. 76 Versuchsteilnehmern wurden Handheld-Computer ausgehandigt, die an zwei aufeinanderfolgenden Tagen Schlafzufriedenheit und verschiedene Arten der Beanspruchung erfassten. Eine crossed-lagged Panel Analyse zeigt einen Zusammenhang von sozialem Stress am ersten Tag mit Schlafzufriedenheit am zweiten Tag, aber keinen umgekehrten Zusammenhang. Die Ergebnisse weisen auf die Bedeutung von Besorgnisneigung und sozialem Stress fur die Erklarung von Schlafstorungen hin.

Zur Bestimmung von Alters- effekten bei der subjektiven Beurteilung des Schlafes

Self-report data on sleep in elderly persons are influenced by age-dependent, age-associated, and age-independent factors. This study seeks to test the effects of the age-independent factors chronic stress, personality, and health behavior on subjective measures of sleep. A first analysis tests age effects on sleep quality and feeling recreated after sleep in four samples (N = 958) and reveals lower sleep quality in the elderly, although they feel more recreated after sleep. A second analysis on a subsample of 277 subjects identifies and selects age-independent variables that have to be controlled for, if age-effects on sleep shall be assessed precisely: Perceived stress, personality factors, and health status variables. Finally, a third analysis on the same subsample tests the influence of these variables on age-sleep associations by successively partialling out their variance from the simple correlation between age and sleep parameters. Controlling these variables results in stronger associations of age with sleep quality and weaker associations of age with sleep-related recreation. The discussion clarifies the reasons why elderly persons feel more recreated in the morning even though they report lower sleep quality. Zusammenfassung: Selbstauskunftsdaten zum Schlaf alterer Menschen werden von altersabhangigen, altersassoziierten und altersunabhangigen Faktoren beeinflusst. Diese Faktoren werden einleitend hinsichtlich ihrer Relevanz zur Bestimmung von Alterseffekten auf den Schlaf diskutiert. Ziel der vorliegenden Arbeit ist es, die Effekte der altersunabhangigen Faktoren chronischer Stress, Personlichkeit und Gesundheitsverhalten auf den Zusammenhang zwischen Alter und subjektiver Beurteilung des Schlafes, d.h. Schlafqualitat (SQ) und Gefuhl des Erholtseins durch den Schlaf (GES), zu prufen. In einer ersten Analyse wird fur vier Stichproben (N = 958) gepruft, wie stark SQ und GES zusammenhangen und ob die Alterseffekte bei der SQ bzw. dem GES unterschiedlich ausfallen. Es zeigt sich, dass die berichtete SQ bei alteren Menschen zwar niedriger ist, sie sich dennoch am Morgen erholter fuhlen. In einer zweiten Analyse (N = 277) werden Variablen identifiziert und ausgewahlt, die zur Bestimmung von Alterseffekten auf die SQ kontrolliert werden sollten. In einer dritten Analyse wird abschliesend die Beziehung zwischen Alter und Schlafparametern unter Kontrolle dieser Faktoren gepruft. Ohne Berucksichtigung konfundierender Faktoren wird der Alterseffekt auf die SQ stichprobenbedingt erheblich unterschatzt und auf das GES uberschatzt. Die positive Korrelation zwischen Alter und GES nimmt bei Kontrolle konfundierender Variablen stark ab. Die Ergebnisse dieser Analysen werden ausfuhrlich diskutiert.