Esther M. Sternberg

Enhanced susceptibility to inflammatory and autoimmune disease can be related to impairments in HPA axis activity and associated hypocortisolism, or to glucocorticoid resistance resulting from impairments in local factors affecting glucocorticoid availability and function, including the glucocorticoid receptor (GR). The enhanced inflammation and hypercortisolism that typically characterize stress‐related illnesses, such as depression, metabolic syndrome, cardiovascular disease, or osteoporosis, may also be related to increased glucocorticoid resistance. This review focuses on impaired GR function as a molecular mechanism of glucocorticoid resistance. Both genetic and environmental factors can contribute to impaired GR function. The evidence that glucocorticoid resistance can be environmentally induced has important implications for management of stress‐related inflammatory illnesses and underscores the importance of prevention and management of chronic stress. The simultaneous assessment of neural, endocrine, and immune biomarkers through various noninvasive methods will also be discussed.

A direct competitive immunoassay in an antibody microarray format was developed for the sensitive detection of neuropeptide Y (NPY) and employed in the analysis of NPY in human sweat samples. This is the first demonstration that antibody microarray, as a powerful multiplex analysis tool, can be used for the sensitive determination of NPY and potentially other neuropeptides. 400 pg/mL of dibiotinylated NPY and 0.1 mg/mL spotting capture antibody were found to offer the best performance, yielding a sensitivity of 50 pg/mL and a linear dynamic range of 0.1–100 ng/mL for NPY. Evaluation of matrix effects by using artificial sweat revealed that dialysis is necessary for analyzing NPY in human sweat samples with microarray immunoassay. In a preliminary application, 50–210 pg/mL of NPY was detected in sweat samples collected with Macroduct collectors. This study indicates that antibody microarrays can be used for NPY analysis and that human sweat could be a valuable sample source for biomarker and proteomics studies, especially when noninvasive human sample collection is preferable.

Aims In this study we investigated the effects of the physical work environment on two physiological measures of the stress response.Methods and results Circadian variations in vagally mediated hea...

The hypothalamic-pituitary-adrenal (HPA) axis activation and glucocorticoid responses are critical for survival from a number of bacterial, viral and toxic insults, demonstrated by the fact that removal of the HPA axis or GR blockade enhances mortality rates. Replacement with synthetic glucocorticoids reverses these effects by providing protection against lethal effects. Glucocorticoid resistance/insensitivity is a common problem in the treatment of many diseases. Much research has focused on the molecular mechanism behind this resistance, but an area that has been neglected is the role of infectious agents and toxins. We have recently shown that the anthrax lethal toxin is able to repress glucocorticoid receptor function. Data suggesting that the glucocorticoid receptor may be a target for a variety of toxins is reviewed here. These studies have important implications for glucocorticoid therapy.

Central fatigue, a persistent and subjective sense of tiredness, generally correlates poorly with traditional markers of disease. It is frequently associated with psychosocial factors, such as depression, sleep disorder, anxiety, and coping style, which suggest that dysregulation of the body's stress systems may serve as an underlying mechanism in the maintenance of chronic fatigue (CF). This article addresses the endocrine, neural, and immune factors that contribute to fatigue and describes research regarding the role of these factors in chronic fatigue syndrome as a model for addressing the biology of CF. In general, hypoactivity of the hypothalamic‐pituitary‐adrenal axis, autonomic nervous system alterations characterized by sympathetic overactivity and low vagal tone, as well as immune abnormalities, may contribute to the expression of CF. Noninvasive methods for evaluating endocrine, neural, and immune function are also discussed. Simultaneous evaluation of neuroendocrine and immune systems with noninvasive techniques will help elucidate the underlying interactions of these systems, their role in disease susceptibility, and progression of stress‐related disorders.

The two main arms of the stress system include the autonomic nervous system (ANS) and the hypothalamic-pituitary-adrenal (HPA) axis. These two neural stress systems coordinate the response of many other physiological systems to a stressor, including the immune and cardiovascular systems, bringing the body back to homeostasis. The nervous and immune systems communicate with each other in a bidirectional manner. In this review, we will discuss the use of noninvasive methods to evaluate the immune system, ANS and HPA axis. Collection of sweat and saliva, and measurement of heart rate variability are noninvasive methods that can be applied to evaluate neuroimmune interactions. Recently, we validated a new methodology to simultaneously evaluate a large array of neural and immune biomarkers in sweat, collected through cutaneous sweat patches and measured by recycling immunoaffinity chromatography. Noninvasive and ambulatory methodologies of biomarker collection can overcome several limitations intrinsic to invasive methods, such as reducing the stress triggered by collection itself and allowing a wider application to field and community-based settings. Ultimately, simultaneous evaluation of neural and immune systems with noninvasive techniques will help elucidate the underlying interactions of these systems and their role in disease susceptibility and progression of stress-related disorders.

Clinicians have long known that a substantial proportion of patients treated with high‐dose glucocorticoids experience a variety of serious side effects, including metabolic syndrome, bone loss, and mood shifts, such as depressive symptomatology, manic or hypomanic symptoms, and even suicide. The reason for individual variability in expression or severity of these side effects is not clear. However, recent emerging literature is beginning to shed light on possible mechanisms of these effects. As an introduction to this volume, this chapter will review the basic biology of glucocorticoid release and molecular mechanisms of glucocorticoid receptor function, and will discuss how dysregulation of glucocorticoid action at all levels could contribute to such side effects. At the molecular level, glucocorticoid receptor polymorphisms may be associated either with receptor hypofunction or hyperfunction and could thus contribute to differential individual sensitivity to the effects of glucocorticoid treatment. Numerous factors regulate hypothalamic‐pituitary‐adrenal (HPA) axis responsiveness, which could also contribute to individual differences in glucocorticoid side effects. One of these is sex hormone status and the influence of estrogen and progesterone on HPA axis function and mood. Another is immune system activity, in which immune molecules, such as interleukins and cytokines, activate the HPA axis and alter brain function, including memory, cognition, and mood. The effects of cytokines in inducing sickness behaviors, which overlap with depressive symptomatology, could also contribute to individual differences in such symptomatology. Taken together, this knowledge will have important relevance for identifying at‐risk patients to avoid or minimize such side effects when they are treated with glucocorticoids. A framework for assessment of patients is proposed that incorporates functional, physiological, and molecular biomarkers to identify subgroups of patients at risk for depressive symptomatology associated with glucocorticoid treatment, and for prevention of side effects, which in many cases can be life‐threatening.