Ulrike Ehlert

The potential role of hypocortisolism in the pathophysiology of stress-related bodily disorders

Representing a challenge for current concepts of stress research, a number of studies have now provided convincing evidence that the adrenal gland is hypoactive in some stress-related states. The phenomenon of hypocortisolism has mainly been described for patients, who experienced a traumatic event and subsequently developed post-traumatic stress disorder (PTSD). However, as presented in this review, hypocortisolism does not merely represent a specific correlate of PTSD, since similar findings have been reported for healthy individuals living under conditions of chronic stress as well as for patients with several bodily disorders. These include chronic fatigue syndrome, fibromyalgia, other somatoform disorders, rheumatoid arthritis, and asthma, and many of these disorders have been related to stress. Although hypocortisolism appears to be a frequent and widespread phenomenon, the nature of the underlying mechanisms and the homology of these mechanisms within and across clinical groups remain speculative. Potential mechanisms include dysregulations on several levels of the hypothalamic-pituitary adrenal axis. In addition, factors such as genetic vulnerability, previous stress experience, coping and personality styles may determine the manifestation of this neuroendocrine abnormality. Several authors proposed theoretical concepts on the development or physiological meaning of hypocortisolism. Based on the reviewed findings, we propose that a persistent lack of cortisol availability in traumatized or chronically stressed individuals may promote an increased vulnerability for the development of stress-related bodily disorders. This pathophysiological model may have important implications for the prevention, diagnosis and treatment of the classical psychosomatic disorders.

Social support and oxytocin interact to suppress cortisol and subjective responses to psychosocial stress

BACKGROUND The presence of social support has been associated with decreased stress responsiveness. Recent animal studies suggest that the neuropeptide oxytocin is implicated both in prosocial behavior and in the central nervous control of neuroendocrine responses to stress. This study was designed to determine the effects of social support and oxytocin on cortisol, mood, and anxiety responses to psychosocial stress in humans. METHODS In a placebo-controlled, double-blind study, 37 healthy men were exposed to the Trier Social Stress Test. All participants were randomly assigned to receive intranasal oxytocin (24 IU) or placebo 50 min before stress, and either social support from their best friend during the preparation period or no social support. RESULTS Salivary free cortisol levels were suppressed by social support in response to stress. Comparisons of pre- and poststress anxiety levels revealed an anxiolytic effect of oxytocin. More importantly, the combination of oxytocin and social support exhibited the lowest cortisol concentrations as well as increased calmness and decreased anxiety during stress. CONCLUSIONS Oxytocin seems to enhance the buffering effect of social support on stress responsiveness. These results concur with data from animal research suggesting an important role of oxytocin as an underlying biological mechanism for stress-protective effects of positive social interactions.

Intranasal Oxytocin Increases Positive Communication and Reduces Cortisol Levels During Couple Conflict

BACKGROUND In nonhuman mammals, the neuropeptide oxytocin has repeatedly been shown to increase social approach behavior and pair bonding. In particular, central nervous oxytocin reduces behavioral and neuroendocrine responses to social stress and is suggested to mediate the rewarding aspects of attachment in highly social species. However, to date there have been no studies investigating the effects of central oxytocin mechanisms on behavior and physiology in human couple interaction. METHODS In a double-blind placebo-controlled design, 47 heterosexual couples (total n = 94) received oxytocin or placebo intranasally before a standard instructed couple conflict discussion in the laboratory. The conflict session was videotaped and coded for verbal and nonverbal interaction behavior (e.g., eye contact, nonverbal positive behavior, and self-disclosure). Salivary cortisol was repeatedly measured during the experiment. RESULTS Oxytocin significantly increased positive communication behavior in relation to negative behavior during the couple conflict discussion (F = 4.18, p = .047) and significantly reduced salivary cortisol levels after the conflict compared with placebo (F = 7.14, p = .011). CONCLUSIONS These results are in line with animal studies indicating that central oxytocin facilitates approach and pair bonding behavior. Our findings imply an involvement of oxytocin in couple interaction and close relationships in humans.

Stress-induced changes in human salivary alpha-amylase activity—associations with adrenergic activity

The salivary enzyme alpha-amylase has been proposed to indicate stress-reactive bodily changes. A previous study by the authors revealed marked increases in salivary alpha-amylase following psychosocial stress, indicating a stress-dependent activation of salivary alpha-amylase. Salivary alpha-amylase has been suggested to reflect catecholaminergic reactivity. Our aim was to assess/evaluate a possible relationship between salivary alpha-amylase and adrenergic parameters, i.e. catecholamines, as well as other stress markers. Using an intra-individual repeated measures design, 30 healthy young men underwent the Trier Social Stress Test (TSST), which consists of a mental arithmetic task and free speech in front of an audience and a control condition in randomized order. Salivary alpha-amylase and salivary cortisol as well as plasma catecholamines and cardiovascular activity were repeatedly measured before, during, and after both conditions. Significant differences were found between the stress and the rest condition in salivary alpha-amylase, salivary cortisol, plasma catecholamines, and cardiovascular parameters (heart rate, LF, HF, LF/HF). However, general alpha-amylase responses (area under the curve) were not associated with general responses in catecholamines and cortisol in the stress condition (r smaller than 0.25 for all analyses). Analysis of cardiovascular parameters indicates a positive relationship between amylase and sympathetic tone (LF/HF) during stress. Salivary alpha-amylase is sensitive to psychosocial stress. Since it does not seem to be closely related to other biological stress markers such as catecholamines and cortisol, salivary alpha-amylase may be a useful additional parameter for the measurement of stress.

Psychoneuroendocrinological contributions to the etiology of depression, posttraumatic stress disorder, and stress-related bodily disorders: the role of the hypothalamus-pituitary-adrenal axis

Following the assumption that stressors play an important part in the etiology and maintenance of psychiatric disorders, it is necessary to evaluate parameters reflecting stress-related physiological reactions. Results from these examinations may help to deepen the insight into the etiology of psychiatric disorders and to elucidate diagnostic uncertainties. One of the best-known stress-related endocrine reactions is the hormonal release of the hypothalamic-pituitary-adrenal (HPA) axis. Dysregulations of this axis are associated with several psychiatric disorders. Profound hyperactivity of the HPA-axis has been found in melancholic depression, alcoholism, and eating disorders. In contrast, posttraumatic stress disorder, stress-related bodily disorders like idiopathic pain syndromes, and chronic fatigue syndrome seem to be associated with diminished HPA activity (lowered activity of the adrenal gland). Hypotheses referring to (a) the psychophysiological meaning and (b) the development of these alterations are discussed.

Psychosocial stress-induced activation of salivary alpha-amylase: an indicator of sympathetic activity?

Abstract: Assessment of sympathoadrenal medullary system (SAM) activity is only possible to date via measurement of catecholamines in blood plasma or via electrophysiological methods. Both ways of measurement are restricted to endocrinological or psychophysiological laboratories, as both require either immediate freezing of blood samples or complex recording devices. Efforts have therefore been undertaken to find a method comparable to salivary cortisol measurements, in which noninvasive samples can be taken at any place and stored at room temperature for sufficient time before later analysis in the laboratory. Salivary alpha‐amylase (sAA) is a candidate that may prove useful in this context. We show here that sAA activity is increased by acute psychosocial stress (Trier Social Stress Test) and that increases in sAA correlate with increases in norepinephrine. We further report that sAA exhibits a stable circadian pattern that mirrors that of salivary cortisol. In conclusion, the current data show that salivary alpha‐amylase may serve as an easy‐to‐use index for SAM activity. However, some questions remain to be answered; for example, what impact does salivary flow rate exert on stress‐induced sAA activity?

Determinants of the diurnal course of salivary alpha-amylase.

OBJECTIVE Previous data from our group and others have shown that salivary alpha-amylase activity increases in response to stress. It has been suggested that salivary alpha-amylase may be a marker for adrenergic activity. Less is known about other determinants of salivary alpha-amylase activation. The objective of the current study was to describe the diurnal pattern of salivary amylase and its determinants. METHODS Saliva samples were collected immediately after waking-up, 30 and 60 min later, and each full hour between 0900 and 2000 h by 76 healthy volunteers (44 women, 32 men). Compliance was controlled by electronic monitors. In order to control factors which might influence the diurnal profile of salivary alpha-amylase (such as momentary stress, mood, food, or body activity), at each sampling time point the subjects filled out a diary examining the activities they had carried out during the previous hour. RESULTS Salivary alpha-amylase activity shows a distinct diurnal profile pattern with a pronounced decrease within 60 min after awakening and a steady increase of activity during the course of the day. Mixed models showed a relative independence of diurnal salivary alpha-amylase from momentary stress and other factors, but significant associations with chronic stress and mood. CONCLUSIONS Our results suggest that diurnal profiles of salivary alpha-amylase are relatively robust against momentary influences and therefore may prove useful in the assessment of sympathetic nervous system activity. The findings underscore the need to control for time of day in studies using salivary alpha-amylase as a dependent variable.

Psychological determinants of the cortisol stress response: the role of anticipatory cognitive appraisal

Psychosocial stress is a potent activator of the hypothalamus-pituitary-adrenal (HPA) axis. While the physiological mechanisms of HPA axis responses to stress as well as its short and long-term consequences have been extensively examined, less is known why someone elicits an acute neuroendocrine stress response, i.e. what are the psychological processes involved and how are they related to the acute neuroendocrine stress response. To examine this question, a questionnaire to assess anticipatory cognitive appraisal processes was developed and administered to 81 male healthy subjects in a standardized psychosocial stress situation (Trier social stress test). Cortisol stress responses were assessed with repeated measurement of salivary free cortisol. Hierarchical regression analyses show that anticipatory cognitive appraisal, in contrast to general personality factors and retrospective stress appraisal is an important determinant of the cortisol stress response, explaining up to 35% of the variance of the salivary cortisol response. The reported results emphasize the importance of psychological stress processing for the understanding of psychobiological stress responses. Since stress and its biological consequences have been shown to be associated with the onset and the maintenance of somatic illnesses and psychiatric disorders, psychological processes are prime targets for prevention and intervention.

Abuse-Related Posttraumatic Stress Disorder and Alterations of the Hypothalamic-Pituitary-Adrenal Axis in Women With Chronic Pelvic Pain

Objective Although numerous organic conditions may cause chronic pelvic pain (CPP), diagnostic laparoscopy reveals a normal pelvis in many patients with CPP. However, psychological studies yield a high frequency of psychopathology and increased prevalences of chronic stress and traumatic life events, ie, sexual and physical abuse, in women with CPP, suggesting a relationship between posttraumatic stress disorder (PTSD) and CPP. As chronic stress and PTSD have been associated with specific alterations of the hypothalamic-pituitary-adrenal (HPA) axis, we explored stress history, psychopathology and HPA axis alterations in women with CPP. Method We recruited 16 patients with CPP and 14 painfree, infertile controls from a general hospital where diagnostic laparoscopy was performed. Psychological assessment included standardized interviews on clinical symptoms, abuse experiences and major life events as well as psychometric testing for PTSD-like symptoms and depression. Endocrinological evaluation involved determinations of diurnal salivary cortisol levels and hormonal responses to a corticotropin-releasing factor (CRF) stimulation test (100 [micro sign]g human CRF) and a low-dose dexamethasone suppression test (0.5 mg). Results We observed increased prevalences of abuse experiences and PTSD in women with CPP as well as a higher total number of major life events, whereas the mean extent of depression was within the normal range. With respect to endocrine measures, women with CPP demonstrated normal to low diurnal salivary cortisol levels, normal plasma-adrenocorticotropin (ACTH), but reduced salivary cortisol levels in the CRF stimulation test, and an enhanced suppression of salivary cortisol by dexamethasone. Conclusion Women with CPP demonstrate HPA axis alterations, that partly parallel and partly contrast neuroendocrine correlates of PTSD, but show marked similarity to findings in patients with other stress-related bodily disorders. These findings suggest that a lack of protective properties of cortisol may be of relevance for the development of bodily disorders in chronically stressed or traumatized individuals.

Effects of different kinds of couple interaction on cortisol and heart rate responses to stress in women

In animal studies, positive social interaction and physical contact play a preeminent role in the control of behavioral and neuroendocrine responses to stress. The aim of this study was to determine whether specific kinds of couple interaction reduce hypothalamic-pituitary-adrenal (HPA) and autonomic responses to psychosocial stress in women. Sixty-seven women, aged 20-37 years, who had been married or cohabiting with a male partner for at least 12 months at the time of the study, were exposed to a standardized psychosocial laboratory stressor (Trier Social Stress Test). Participants were randomly assigned to three study groups differing in the type of a 10-min period of social interaction with their partner prior to stress: n=25 with no partner interaction, n=22 with verbal social support, and n=20 with physical contact (standardized neck and shoulder massage). Salivary free cortisol levels, plasma levels of oxytocin, heart rate, and psychological responses to stress were compared among the three study groups. Women with positive physical partner contact before stress exhibited significantly lower cortisol and heart rate responses to stress but no different plasma oxytocin levels compared to women who received social support or no social interaction. Verbal social support alone was not associated with reduced stress responsiveness. Our results are in line with previous human studies indicating reduced responsiveness to verbal social support by a spouse in women. More importantly, these findings imply a direct protective effect of touch on stress-related neurobiological systems as a possible underlying mechanism of health beneficial effects of positive couple interaction.