Dirk H. Hellhammer

Two formulas for computation of the area under the curve represent measures of total hormone concentration versus time-dependent change

Study protocols in endocrinological research and the neurosciences often employ repeated measurements over time to record changes in physiological or endocrinological variables. While it is desirable to acquire repeated measurements for finding individual and group differences with regard to response time and duration, the amount of data gathered often represents a problem for the statistical analysis. When trying to detect possible associations between repeated measures and other variables, the area under the curve (AUC) is routinely used to incorporate multiple time points. However, formulas for computation of the AUC are not standardized across laboratories, and existing differences are usually not presented when discussing results, thus causing possible variability, or incompatibility of findings between research groups. In this paper, two formulas for calculation of the area under the curve are presented, which are derived from the trapezoid formula. These formulas are termed Area under the curve with respect to increase (AUCI) and Area under the curve with respect to ground (AUCG). The different information that can be derived from repeated measurements with these two formulas is exemplified using artificial and real data from recent studies of the authors. It is shown that depending on which formula is used, different associations with other variables may emerge. Consequently, it is recommended to employ both formulas when analyzing data sets with repeated measures.

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.

Dissociation between reactivity of the hypothalamus-pituitary-adrenal axis and the sympathetic-adrenal medullary system to repeated psychosocial stress

Objective This study investigated endocrine and autonomic stress responses after repeated psychosocial stress. A first goal of the study was to investigate whether peripheral catecholamines and cardiovascular parameters would show similar or different habituation patterns after repeated stress. The second aim was to detect possible subgroups with regard to individual habituation patterns in the hypothalamus-pituitary-adrenal (HPA) axis and monitor their respective sympathetic stress responses. Methods Sixty-five healthy subjects (19–45 years), 38 men and 27 women, were exposed to the Trier Social Stress Test (TSST) three times with a 4-week interval between stress sessions. Adrenocorticotropic hormone (ACTH), plasma cortisol, salivary cortisol, epinephrine, norepinephrine, and heart rates were measures repeatedly before and after each stress exposure. Results All endocrine measures as well as heart rates increased significantly after each of the three stress sessions (F values >16.00, all p values < .01). Although salivary free cortisol, total plasma cortisol, ACTH, and heart rate stress responses showed a significant decrease across the three stress sessions (all F values > 5.8, p < .01), no such decrease could be observed for the levels of norepinephrine and epinephrine. A cluster analysis performed on the salivary free cortisol responses to all three stress sessions revealed two response groups consisting of 30 so-called “high responders” and 35 “low responders.” The high responders also showed larger ACTH and total plasma cortisol responses compared with the low responders (all F values > 10.00, p < .01). No such differences between high and low responders could be observed with regard to catecholamine and heart rate responses. Conclusions From these data we conclude that habituation to psychosocial stress seems to be specific for a given response system. Although HPA responses quickly habituate, the sympathetic nervous system shows rather uniform activation patterns with repeated exposure to psychosocial challenge.

Self-reported depressive symptoms and stress levels in healthy young men: associations with the cortisol response to awakening.

Objective There is evidence that clinical depression and negative mood are associated with elevated basal cortisol levels. Recently, measuring the cortisol response during the first hour in the morning with strict reference to the time of awakening was established as a reliable marker of individual adrenocortical activity. In studies using this marker, a relationship with self-reported stress levels and psychosomatic symptoms has been found. The goal of the present study was to investigate the association of self-reported depressive symptomatology with early morning free cortisol levels and their relationship to measures of stress. Methods We assessed the severity of depressive symptoms using the Hamilton Depression Inventory and chronic and acute stress perception in 40 healthy young men. Once a week, for 4 consecutive weeks, subjects provided saliva samples collected at 0, 30, and 60 minutes after awakening. Results Higher levels of depressive symptomatology were associated with a greater cortisol response after awakening. This association seemed to be stronger when only subjects in the nonclinical range of depression were included. Furthermore, cortisol levels and depressive symptomatology were significantly positively correlated with measures of chronic and acute stress perception. Conclusions The present study extends earlier findings of hypothalamus-pituitary-adrenal axis hyperactivity in clinical depression to healthy young men with mild levels of depressive symptomatology. Measuring the cortisol response to awakening is proposed as an economical alternative to traditional approaches for determining basal hypothalamus-pituitary-adrenal axis activity. Associations between depressive symptomatology and chronic stress, as well as implications for future studies, are discussed.

Birth weight is associated with salivary cortisol responses to psychosocial stress in adult life

Fetal programming of the hypothalamus-pituitary-adrenal (HPA) axis was proposed as one mechanism underlying the link between prenatal stress, adverse birth outcomes (particularly low birth weight) and an enhanced vulnerability for several diseases later in life. In recent studies, birth weight was significantly related to basal cortisol levels as well as to cortisol responses to pharmacological stimulation. In order to investigate the association between cortisol responses to psychological challenge, birth weight and length of gestation, 106 young healthy males were exposed to the Trier Social Stress Test. Salivary cortisol responses to the stress exposure were significantly and inversely related to the subjects birth weight, while the analysis of the impact of gestational age yielded inconsistent results. This finding is consistent with the concept of fetal programming of the HPA axis and provides the first preliminary evidence for an association between birth weight and adrenocortical responses to psychosocial stress. As the investigated subjects were twins, possible implications of this sample characteristic for the present findings are discussed.

Basal and stimulated hypothalamic-pituitary-adrenal axis activity in patients with functional gastrointestinal disorders and healthy controls

Objective: The aim of this study was to investigate alterations of pituitary-adrenal activity under both stimulated and unstimulated conditions in patients with functional gastrointestinal disorders. Methods: Thirty subjects who fulfilled the Rome Diagnostic Criteria for either irritable bowel syndrome or nonulcer dyspepsia and 24 healthy controls took part in the study. Free salivary morning cortisol and diurnal cortisol profiles were obtained for all subjects. On a second day, a low-dose dexamethasone suppression test was applied. Additionally, in all subjects a corticotropin-releasing hormone (CRH) challenge test was performed. Results: The results show attenuated unstimulated cortisol levels in patients compared with controls. After CRH challenge, blunted adrenocorticotropic hormone and cortisol responses were observed. These findings suggest lower pituitary and adrenocortical activity in patients with functional gastrointestinal disorders. Conclusion: The observed pituitary-adrenal reactivity in these patients is discussed as a possible consequence of lower adrenocortical activity, possibly resulting in a disinhibition of CRH in the brain. CRH = corticotropin-releasing hormone; NUD = nonulcer dyspepsia; IBS = irritable bowel syndrome; ACTH = adrenocorticotropic hormone; HPA = hypothalamic-pituitary-adrenal; ANOVA = analysis of variance; AUCtot = area under the curve total.

Habituation of cortisol responses to repeated psychosocial stress—further characterization and impact of genetic factors

Although a rapid response habituation to repeated stress exposure is a key characteristic of the hypothalamus-pituitary-adrenal (HPA) axis, several studies document a substantial inter-individual variability of such HPA response patterns. In order to further investigate the individual differences in the habituation of this important neuroendocrine system to psychosocial stress, 54 male twin pairs were exposed to moderate psychosocial stress on three occasions, each exposure separated by a 1-week interval. Additionally, an ACTH(1-24) stimulation test (1 microg) and a dexamethasone suppression test (0.5mg) were performed. Although on average the expected decrease of mean cortisol and ACTH responses across stress exposures was observed, only 52% of the subjects showed this well-documented general decline and almost 16% of the participants even showed a response sensitization across sessions. Furthermore, a weak habituation was related to low cortisol responses to both the first stress exposure as well as the ACTH challenge. Moreover, genetic analyses did not reveal any evidence for a substantial heritability of the individual cortisol response habituation or an association between this habituation and two common polymorphisms in the glucocorticoid receptor gene.

Endocrine and Immune Responses to Stress in Chronic Inflammatory Skin Disorders

Abstract: Atopy is a genetically and environmentally determined condition predisposing to different forms such as atopic dermatitis (AD) or allergic asthma (AA). Both AD and AA are considered to be multifactorial diseases; however, distinct immunologic abnormalities have been described that play a crucial role. There is growing evidence that immunoglobulin‐E hypersecretion and activation of the predominantly T‐helper‐2 (TH2)‐like T cell subset trigger allergic inflammatory processes and cause the disease to become chronic. In the present paper, data suggesting reduced hypothalamic‐pituitary‐adrenal (HPA) axis responsiveness in patients with AD and AA are summarized, and the potential etiologic significance of a hyporeactive HPA axis is discussed. We propose that because of defective HPA axis, immunoregulation under stressful conditions is ineffective in patients with atopic conditions, leading to aberrant immune responses and subsequent exacerbation of the disease. Further research into the role of the HPA axis in atopy may elucidate the cause of stress‐induced exacerbation of atopic symptoms and may be of clinical relevance.