Re : Stress, Endocrine physiology and pathophysiology

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STRESS, ENDOCRINE PHYSIOLOGY AND PATHOPHYSIOLOGY Chapter 8 - Constantine Tsigos, Ioannis Kyrou, and George Chrousos,MD May 19, 2004 TO OBTAIN A DOWNLOAD OF THIS CHAPTER IN WORD OR PDF FORMAT, CLICK HERE

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STRESS, ENDOCRINE PHYSIOLOGY

Stress and Stress Syndrome ? Definitions and Phenomenology

Maintaining the body steady state, or homeostasis, is essential for life. This complex dynamic equilibrium is constantly challenged by intrinsic or extrinsic adverse, real or perceived forces, the stressors. Stress is, thus, defined as a state of threatened homeostasis or dysharmony and is counteracted by a complex repertoire of physiologic and behavioral responses that reestablish homeostasis (adaptive stress response). The stress response is subserved by a complex neuroendocrine, cellular and molecular infrastructure, the stress system, which is located in both the central nervous system and the periphery. The adaptive response of an individual to stress is determined by a multiplicity of genetic, environmental and developmental factors. Alterations of the ability to respond to stressors, as for example inadequate, excessive and/or prolonged reactions, may lead to disease. Moreover, excessive and/or chronically imposed stressors may have adverse impact on a variety of physiologic functions, such as growth, reproduction, metabolism and the immunocompetence, as well as on personality development and behavior. Prenatal life, infancy, childhood and adolescence are critical periods characterized by increased vulnerability to stressors.

The stress system receives and integrates a great diversity of neurosensory (visual, auditory, somatosensory, nociceptive, visceral), blood-borne and limbic signals, which arrive through distinct pathways. Acute activation of the stress system leads to a cluster of time-limited behavioral and physical changes that are remarkably consistent in their qualitative presentation and are collectively defined as the stress syndrome (Table 1). These changes are nor mally adaptive and improve the chances of the individual for survival (1). It should be noted that initially the stimulation of the components of the stress system follows a stressor-specific mode, but as the potency of the stressor increases the specificity of the adaptive response decreases to eventually present the relatively nonspecific stress syndrome phenomenology that follows the exposure to powerful or severe stressors.

Behavioral adaptation includes increased arousal, alertness, vigilance, and cognition, focused attention, and enhanced analgesia, with concurrent in hibition of vegetative functions, such as feeding and reproduction. Concomitantly, physical adaptation occurs principally to promote an adap tive redirection of energy. Thus, oxygen and nutrients are shunted to the central nervous system (CNS) and the stressed body site(s), where they are needed the most. Increases in cardiovascular tone, respiratory rate, and in termediate metabolism (gluconeogenesis, lipolysis) all work in concert to promote availability of vital substrates, while energy consuming functions such as digestion, reproduction, growth, and immunity are temporally suspended.

In parallel to the adaptive response, restraining forces are also activated during stress in order to prevent a potential excessive response of the components of the stress system. The ability of the indi vidual to timely and accurately develop the restraining forces that prevent such an overresponse is equally essential for a successful general adaptive response. If the counteracting forces of the body fail to control the elements of the stress response in a precise manner, the prolongation of the initial adaptive responses may turn mal adaptive and contribute to the development of disease.

The mobilization of the stress system is often of a magnitude and nature that allows the perception of control by the individual. Under these conditions, stress can be rewarding and pleasant, even exciting, providing positive stimuli to the individual for emotional and intellectual growth and development (2). Thus, it is not surprising that activation of the stress system during feeding and sexual activity, both sine qua non functions for survival, is primarily linked to pleasure.

Stress system - Physiology and Interactions

Neuroendocrine effectors of the stress response: “The Stress System”

Although the entire central nervous system is directly or indirectly involved in the maintenance of the internal homeostasis and participates in the organization of the stress response, specific areas of the brain have critical roles in these mechanisms. Thus, modulation of the activity of the stress system at the level of both the hypothalamic-pituitary-adrenal axis and the cen tral and peripheral components of the autonomic nervous system is critical for a successful adaptive response to stressors. The central compo nents of the stress system are located in the hypothalamus and the brainstem and include the parvocellular corticotropin-releasing hormone (CRH) and arginine-vasopressin (AVP) neurons of the paraventricular nu clei (PVN) of the hypothalamus, and the CRH neurons of the paragigantocellular and parabranchial nuclei of the medulla, as well as the locus ceruleus (LC) and other catecholaminergic cell groups of the medulla and pons (central sympathetic system) (3, 4). The peripheral limps of the hypothalamic-pituitary-adrenal (HPA) axis, together with the efferent sympathetic/adrenomedullary sys tem, represent the peripheral components of this complex system.

Corticotropin-Releasing Hormone, Arginine Vasopressin and Catecholaminergic Neurons

The central neurochemical circuitry responsible for the activation of the stress system forms a complex physiological system in the CNS, consisting of both stimulatory and inhibitory networks with multiple sites of interaction that modulate the adaptive response to the various stressors. Hypothalamic corticotropin-releasing hormone (CRH) and arginine-vasopressin (AVP), neurons in combination with central catecholaminergic (LC/NE) neurons, are the key components of these networks (Figure 1). The central stress system activation is based on reciprocal reverberatory neural con nections that exist between the PVN CRH and the catecholaminergic LC/NE neurons, with CRH and norepinephrine (NE) stimulating the secretion of each other, primarily through CRH-R1 and α1-noradrenergic receptors, respectively (5, 6, 7). Notably, autoregulatory ultrashort negative feedback loops exist in both the PVN CRH and the brainstem catecholaminergic neurons (8, 9), with collateral fibers inhibiting CRH and catecholamine secretion respectively, via inhibition of the corresponding presynaptic CRH and α2-noradrenergic receptors (10). In addition, multiple other regulatory central pathways exist since both the CRH and the catecholaminergic neurons receive stimulatory innervation from the serotoninergic and cholinergic systems (11, 12) and inhibitory input from the gamma-aminobutyric acid (GABA)/benzodiazepine (BZD) and the opioid neuronal systems of the brain (13, 14), as well as by the end-product of the HPA axis, glucocorticoids (15).

Figure 1. A simplified representation of the central and peripheral components of the stress system, their functional interrelations and their relationships to other central nervous system pathways involved in the stress response. CRH: corticotropin-releasing hormone, LC/NE sympathetic system: locus ceruleus/norepinephrine-sympathetic system, POMC: proopiomelanocortin, AVP: arginine vasopressin, GABA: γ-aminobutyric acid, BZD: benzodiazepine, ACTH: corticotrophin, NPY: neuropeptide Y, SP: substance P. Activation is represented by solid green lines and inhibition by dashed red lines.

CRH, a 41-amino acid peptide, was first isolated as the principal hypo thalamic stimulus to the pituitary-adrenal axis by Vale et al. (16) in 1981. The subsequent availability of synthetic CRH and of inhibitory analogues opened huge vistas for the investigation of stress. Thus, CRH and CRH re ceptors were found in many extrahypothalamic sites of the brain, includ ing parts of the limbic system, the basal forebrain, the anterior pituitary and the central arousal- sympathetic systems (LC-sympathetic systems) in the brainstem and spinal cord (17, 18). In addition, central administration of CRH was shown to set into motion a coordinated series of physiologic and behavioral responses, which included activation of the pituitary-adrenal axis and the sympathetic ner vous system, as well as characteristic stress-related behaviors (19, 20). CRH appears, therefore, to have a broader role in coordinating the stress response than had been suspected previously (3, 4). In fact, this neuropeptide seems to reproduce the phenomenology of the stress response as it is summarized in Table 1.

CRH binds to specific receptors that belong to the class II seven-transmembrane G-protein-coupled receptor superfamily of receptors (21). In addition to their wide expression‎ throughout the brain, CRH receptors are found in a variety of peripheral sites, such as the adrenal medulla, prostate, gut, spleen, liver, kidney, and testes. To date, two distinct CRH receptor subtypes have been identified in humans, designated CRH-R1 and CRH-R2, which are encoded by distinct genes on human chromosomes 17 and 7, respectively (Figure 2) (22, 23). The CRH-R subtypes share a 70% homology of their amino acid sequence, but exhibit unique pharmacologic profiles, are differentially expressed and appear to mediate selective actions of CRH at different tissues. The CRH-R1 subtype is widely distributed in the brain, mainly in the anterior pituitary, the neocortex and the cerebellum, as well as in the adrenal gland, skin, ovary and testis (24). CRH-R2 receptors are expressed mainly in the peripheral vasculature, the skeletal muscles, the gastrointestinal tract and the heart, but also exhibit a widespread distribution in subcortical structures of the brain, such as the lateral septum, amygdala, hypothalamus and brain stem (25). CRH-R1 is considered the only receptor type present in locus ceruleus, cerebellar cortex, thalamus and striatum, while exclusive CRH-R2 expression‎ has been reported in the bed nucleus of the stria terminalis (26, 27, 28). It is noteworthy that, both CRH receptor genes have the ability of variant splicing, thus, producing different isoforms for each subtype. The CRH-R1 gene appears to have several splice variants, termed R1b, R1c, R1d, R1e, R1f, R1g and R1h, which encode proteins with altered N-terminal (CRH-R1c, CRH-R1e, CRH-R1h), intracellular (CRH-R1b, CRH-R1f) and transmembrane (CRH-R1g, CRH-R1d) segments compared to the prototypic CRH-R1a, but their expression‎ in native tissues has not been determined yet and their ligand-binding affinity is low (29). Accordingly, the CRH-R2 gene has three splice variants, encoding the CRH-R2a, CRH-R2b, CRH-R2c isoforms, which differ only at the extracellular N-terminus and have unique tissue distributions. The CRH-R2a receptor is localized to subcortical regions, including the lateral septum, and the paraventricular and ventromedial nuclei of the hypothalamus. Conversely, the CRH-R2b receptor in rodents is primarily localized to the heart, gastrointestinal tract, skeletal muscles and in non-neural brain tissues, such as the cerebral arterioles and the choroid plexus, while the CRH-R2c receptor has recently been identified in human limbic regions (25). The diversity of CRH receptor subtype and isoform expression‎ is considered to play a key role in the modulation of the stress response by implicating locally the actions of different ligands (CRH and CRH-related peptides) and different intracellular second messengers.

Figure 2. Corticotropin-releasing hormone receptor subtypes, splice variants and tissue distribution. CRH-R: Corticotropin-releasing hormone receptor, TM: transmembrane. CRH is considered the specific endogenous ligand for CRH-R1, while Urocortin 2 and Urocortin 3 are considered the specific endogenous ligands of CRH-R2. Urocortin 1 is considered an endogenous ligand for both subtypes of the receptor. CRH binds to CRH-R2 with an affinity that is 100-fold lower compared to the binding affinity of the urocortines.

Arginine vasopressin (AVP) is a nonapeptide produced by parvocellular neurons of the PVN and by the magnocellular neurons of the neurohypophysis. While the AVP from the posterior pituitary is secreted into the circulation and modulates fluid and electrolyte homeostasis, AVP of PVN origin is secreted into the hypophyseal portal system, like CRH, and holds a key role in the response to stressors, being the second most important mod ulator of pituitary ACTH secretion (30). Whereas CRH appears to directly stimulate the ACTH secretion, AVP and other factors, such as angiotensin II, have primarily synergistic or additive effects (31, 32, 33). AVP exhibits synergy with CRH in vivo, when the peptides are co-administered in humans (34), acting on a V1-type receptor (V1β, also referred as V3) and exerting its effects through calcium/phospholipid-dependent mecha nisms (35). The synergistic effect of AVP on the pituitary ACTH secretion offers an alternate pathway to influence the subsequent HPA axis activation at the hypothalamic level, since the secretion of CRH and AVP is further regulated by a variety of different neuropeptides, such as catecholamines which stimulate CRH secretion and ghrelin, a novel GH secretagogue factor, which appears to stimulate predominantly AVP secretion (36, 37).

A subset of parvocellular neurons synthesize and secrete both CRH and AVP and interestingly the relative proportion of this subset is increased significantly by stress. The terminals of the parvocellular PVN CRH and AVP neurons project to different sites, including the noradrenergic neurons of the brainstem and the hypophysial portal system in the median eminence. PVN CRH and AVP neurons also send projections to and activate pro-opiomelanocortin (POMC)-containing neurons in the arcuate nucleus of the hypothalamus. In turn, these POMC-containing neurons project reciprocally to the PVN CRH and AVP neurons, innervate LC/NE-sympathetic neurons of the central stress system in the brainstem and terminate on pain control neurons of the hind brain and spinal cord. Thus, activation of the stress system, via CRH and catecholamines, stimulates the hypothalamic β-endorphin and other POMC-peptides secretion, which reciprocally inhibit the activity of the stress system, produce the "stress- induced" analgesia and may influence the emotional tone (Figure 1).

Among the multiple regulatory central pathways that influence the activity of the central stress system, it is noteworthy that neuropeptide Y (NPY) stimulates the CRH neu rons, whereas it inhibits the central sympathetic system (38, 39). This may be of particular relevance to changes in stress system activity in states of dysregulation of food intake and obesity. Interestingly, glucocorticoids, which stimulate appetite, stimulate hypothalamic NPY gene expression‎, while they inhibit both the PVN CRH and LC/NE-sympathetic systems (40). Substance P (SP), on the other hand, has reciprocal actions to those of NPY, since it inhibits the CRH neuron (41), whereas it activates the central catecholaminergic system (42). Presumably, sub stance P release is increased centrally by peripheral activation of somatic afferent fibers and may, thus, have relevance to changes in the stress system activity induced by chronic inflammatory or painful states (43).

Hypothalamic-Pituitary-Adrenal axis

The integrity of the Hypothalamic-Pituitary-Adrenal (HPA) axis and the precise regulation of its function are critical for the successful response to any stressor, since this axis is a vital component of both the central and the peripheral limb of the stress system. At the level of the hypothalamic-pituitary unit, CRH is released into the hypophyseal portal system and acts as the principal regula tor of the anterior pituitary ACTH secretion (4). The binding of CRH on the CRH-R1 receptors of the corticotrophs is permissive for the secretion of ACTH, while AVP acts as a potent synergistic factor of CRH with little ACTH secretagogue activity by itself (44, 45, 46). In nonstressful situations, both CRH and AVP are secreted in the portal system in a circadian and highly concordant pulsatile fashion (47, 48). The amplitude of the CRH and AVP pulses increases in the early morning hours, resulting eventually in increases of both the amplitude and frequency of ACTH and cortisol secretory bursts in the general circulation (49, 50).

The circadian release of CRH/AVP/ACTH/cortisol in their charac teristic pulsatile manner appears to be controlled by one or more pace makers (51), whose exact location in the brain is not known in humans. These diurnal variations are perturbed by changes in lighting, feeding schedules, and physical ac tivity, and are disrupted when a stressor is imposed. During acute stress, the amplitude and synchronization of the CRH and AVP pulsations increases, with additional recruitment of PVN CRH and AVP secretion. Especially in conditions of strong hypovolemic stress, such as created by marked hypotension or hemorrhage, additional AVP of magnocellular neuron origin is secreted into both the hypophyseal portal system, via collateral neuraxon terminals, and into the sys temic circulation. In addition, depending on the stressor, angiotensin II, as well as various cytokines and lipid mediators of inflam mation are secreted and act on hypothalamic, pituitary and/or adrenal components of the HPA axis, mostly to potentiate its activity.

The adrenal cortex is the principal target organ of the pituitary-derived circulating ACTH. The latter is the key regulator of glucocorticoid and adrenal androgen secretion by the zonae fasciculata and reticularis, re spectively, while it also participates in the control of aldosterone secretion by the zona glomerulosa (52). Moreover, there is evidence suggesting that the reg ulation of cortisol secretion is further influenced by other hormones and/or cytokines, originating from the adrenal medulla or coming from the systemic circulation, and/or by neuronal signals via the autonomic innervation of the adrenal cortex (Figure 1).

Glucocorticoids are the final effectors of the HPA axis. These hormones are pleiotropic and exert their effects through their ubiquitously distrib uted intracellular receptors (53). The n[안내]태그제한으로등록되지않습니다-[안내]태그제한으로등록되지않습니다-[안내]태그제한으로등록되지않습니다-onactivated glucocorticoid receptor re sides in the cytosol in the form of a hetero-oligomer with heat shock pro teins and immunophilin (54). Upon ligand binding, the glucocorticoid receptors dissociate from the rest of the hetero-oligomer, they homodimerize, and translocate into the nucleus, where they interact with specific glucocorticoid responsive elements (GREs) within the DNA to transactivate or transrepress appropriate hormone-responsive genes (55). In addition, the activated receptors in hibit, by protein-protein interactions, important transcriptional factors, such as the c-jun/c-fos heterodimer, which promotes the transcription of several genes involved in the activation of immune and other cells (56, 57), and the NF-κB (58) heterodimer, which is of particular importance in immune and inflammatory responses. Furthermore, the activation of the glucocorticoid receptors causes changes in the stability of mRNAs and, hence, the translation rates of several glucocorticoid-responsive proteins. Notably, glucocorticoids influence the secretion rates of specific proteins and alter the electrical potential of neuronal cells, through mechanisms that have not yet been precisely defined.

Glucocorticoids play a key regulatory role in the basal control of HPA axis activity and in the termination of the stress response, by acting at extrahypothalamic regulatory centers, the hypothalamus and the pituitary gland (59). The inhibitory glucocorticoid feedback on the ACTH secretory re sponse acts to limit the duration of the total tissue exposure to glucocorticoids, thus minimizing the catabolic, lipogenic, antireproductive, and immunosuppressive effects of these hormones. Interestingly, a dual receptor system exists for glucocorticoids in the CNS, including the glucocorticoid receptor type I, or mineralocorticoid receptor, which responds to low lev els of glucocorticoids and is primarily activational, and the classic glucocorticoid receptor (type II), which responds to higher levels of glucocorticoids, stress-related or not, and is dampening in some systems and activational in others. The negative feedback control of the CRH and ACTH secretion is mediated through type II glucocorticoid receptors.

Sympathetic/adrenomedullary and parasympathetic systems

The autonomic nervous system provides a rapidly responsive mechanism to control a wide range of functions. Cardiovascular, respiratory, gastrointestinal, renal, endocrine, and other systems are regulated by either the sympathetic nervous system or the parasympathetic system or both (60). The modulation of the autonomic nervous system activity is generally achieved through a dual reaction, since the parasympathetic system can equally assist or antagonize most of the sympathetic func tions by withdrawing or by increasing its activity, respectively.

Sympathetic innervation of peripheral organs is derived from the ef ferent preganglionic fibers whose cell bodies lie in the intermediolateral column of the spinal cord. These nerves synapse in the bilateral chain of sympathetic ganglia with postganglionic sympathetic neurons, which innervate widely the smooth muscle of the vasculature, the skeletal muscles, heart, kidney, gut, adipose tissue, and many other organs (61). The preganglionic neurons are primarily cholinergic, whereas the postganglionic neurons release mostly noradrenaline. The sympathetic system activity has an additional humoral con tribution that comes from the circulating epinephrine and, to a lesser extent, norepinephrine released by the adrenal medulla, which can be considered as a modified sympathetic ganglion.

It must be noted that the regulatory actions of the autonomic nervous system activity involve a broader spectrum of neurotransmitters that complement the actions of acetylcholine and norepinephrine. Both the sympathetic and the parasympathetic system contain several subpopulations of target-selective and neurochemically coded neurons that express a variety of neuropep tides and, in some cases, adenosine triphosphate (ATP), nitric oxide, or lipid mediators of inflammation (62). Interestingly, CRH, NPY, somatostatin, and galanin are colocalized in noradrenergic vasoconstrictive neurons, whereas vasoactive intestinal polypeptide (VIP) and, to a lesser extent, substance P (SP) and calcitonin gene-related peptide (CGRP) are colocalized in cholinergic neu rons. Additionally, the signal transmission in sympathetic ganglia is further modulated by neuropeptides released from preganglionic fibers and short interneurons (e.g. enkephalin, neurotensin), as well as by primary afferent (e.g. substance P, VIP) nerve collaterals (63). Thus, the particular combination of neurotransmitters in sympa thetic neurons is strongly influenced by central and local factors, which may trigger or suppress specific genes.

Stress system - Interactions with other CNS components

In addition to setting the level of arousal and influencing the vital signs, the stress system also interacts with other major CNS elements, primarily with the mesocorticolimbic dopaminergic system (“reward” system), the amygdala/hippocampus complex and the arcuate nucleus proopiomelanocortin (POMC) neuronal system (64, 65, 66). Conversely, these systems after their activation by a stressor act via specific neuronal pathways to modify the activity of the stress system forming a complex reciprocal mechanism that fine-tunes the adaptive response. It is of note that well established interactions exist between the stress system and centers of the CNS that are crucial for the survival of the individual, such as the thermoregulatory and the appetite-satiety centers.

Mesocorticolimbic dopaminergic system

The mesocortical and mesolimbic com ponents of the dopaminergic system are potently innervated by PNV CRH neurons and the LC/NE-sympathetic noradrenergic system. Both components are activated by catecholamines, CRH and glucocorticoids during stress. The mesocortical system contains dopaminergic neurons of the ventral tegmentum that send projections to the prefrontal cortex. The activation of these neurons is thought to centrally suppress the response of the stress system and is implicated in anticipatory phenomena and cognitive functions (65). The mesolimbic sys tem also consists of dopaminergic neurons of the ventral tegmentum. These neurons innervate the nucleus accumbens and are considered to play a pivotal role in motivational/reinforcement/reward phenomena and in the formation of the central dopaminergic “reward” system (67). Accordingly, euphoria and dysphoria is likely to be mediated by the mesocorticolimbic system, which is also considered the central target of several addictive substances, such as cocaine.

Amygdala/Hippocam pus

The amygdala/hippocampus complex is activated during stress pri marily by ascending catecholaminergic neurons originating in the brain stem or by inner emotional stressors, such as conditioned fear, possibly from cortical association areas (66). The amygdala nuclei are the principal brain locus for fear-related behaviors and their activation is important for retrieval‎ and emotional analysis of all the relevant stored information for any given stressor. In response to emotional stressors, the amygdala can directly stimulate both central components of the stress system, as well as the mesocorticolimbic dopaminergic system. Interestingly, there are CRH peptidergic neurons in the amygdala which respond positively to glucocorticoids and whose activation leads to stimulation of the stress system and anxiety. CRH neurons in the central nucleus of the amygdala send projections to the parvocellular regions of the PVN and the parabrachial nucleus of the brain stem, which are considered crucial for the CRH induced neuroendocrine, autonomic and behavioral effects. CRH fibers also interconnect the amygdala with the bed nucleus of the stria terminalis and the hypothalamus (68, 69). Conversely to the stimulatory influence of norepinephrine and CRH, the hippocampus exerts an important tonic and stimulated inhibitory influence on the activity of the amygdala, as well as of the PVN CRH and LC/NE-sympathetic systems.

Arcuate Nucleus Proopiomelanocortin (POMC) Neuronal System

Opioid peptide (POMC-producing) neurons by the arcuate nucleus of the hypothalamus innervate and is reciprocally innervated by both the LC/NE-noradrenergic and the CRH/AVP-producing neurons (5, 64). Activation of the stress system stimulates hypothalamic release of POMC-derived peptides, such as α-melanocyte-stimulating hormone (α-MSH) and β-endorphin, which reciprocally inhibit the activity of both central components of the stress system. Moreover, through projections of these neurons to the hind brain and the spinal cord, analgesia ("stress- induced" analgesia) is achieved by inhibition of the ascending pain pathways (Figure 1).

Thermoregulatory center - Temperature Regulation

It is well-established that the activation of the LC/NE-noradrenergic and PVN CRH systems by stressors elevates the body core temperature. Intracerebroventricular administration of both norepinephrine and CRH can cause temperature elevation, possibly through prostanoid-mediated actions on the septal and hypothalamic temperature-regulating center. CRH has also been shown to partly mediate the pyrogenic effects of the three major inflammatory cytokines, tumor necrosis factor-α (TNF-α), interleukin 1 (IL-1), and interleukin-6 (IL-6), when stimulated by lipopolysaccharide, a potent exogenous pyrogen (67).

Appetite-satiety centers - Appetite Regulation

Stress is implicated in the regulation of appetite by influencing the central appetite-satiety centers in the hypothalamus. Acutely, CRH causes anorexia, whereas NPY, which is orexiogenic, stimulates CRH secretion, via Y1 receptors, probably to counter-regulate its own actions. Interestingly, at the same time, NPY inhibits the LC/NE-sympathetic system and activates the parasympathetic system, actions that decrease thermogenesis and help with digestion and storage of nutrients (38, 39). On the other hand leptin, the adipose tissue-derived satiety-stimulating hormone, inhibits the secretion of hypothalamic NPY, while it stimulates arcuate nucleus POMC neurons that secrete α-MSH, a potent anorexiogen and thermogenic peptide, which exerts its effects through specific melanocortin receptors type 4 (MC4) (Figure 3).

Figure 3. Schematic representation of the interactions between the hypothalamic-pituitary-adrenal axis, the adipose tissue and the hypothalamic appetite-satiety centers. ARC: arcuate nucleus, PVN: paraventricular nucleus, LHA: lateral hypothalamic area, CRH: corticotropin-releasing hormone, ACTH: corticotrophin, POMC: proopiomelanocortin, NPY: neuropeptide Y AgRP: agouti related peptide, α-MSH: α-melanocyte-stimulating hormone, Y1: neuropeptide Y receptor type 1, MC4R: melanocortin receptor type 4, TRH: thyrotropin-releasing hormone, MCH: melanin concentrating hormone, OXY: oxytocin. Activation is represented by solid green lines and inhibition by dashed red lines.

Stress system - Endocrine axis interactions

Reproductive axis

The reproductive axis is inhibited at all levels by various components of the HPA axis (Figure 4). CRH suppresses the gonadotropin hormone-releasing hor mone (GnRH) neuron both directly and indirectly, via enhancing β-endorphin secretion by the arcuate POMC neurons. In addition glucocorticoids, exert inhibitory effects at the level of the GnRH neuron, the pituitary gonadotroph and the gonads themselves and additionally render target tissues of sex steroids resistant to these hormones (70, 71, 72). Thus, steroidogenesis is directly inhibited at both ovaries and testes, with concomitant inhibition of the pulsatile secretion of the gonadotropin-releasing hormone from the hypothalamus. The latter effect is exerted both directly and by activating hypothalamic neural circuits that contain CRH and POMC, as well as by peripheral elevations of glucocorticoids. It is of note that, cytokines also suppress reproductive function at sev eral levels (73).

Figure 4. Schematic representation of the interactions between the hypothalamic-pituitary-adrenal axis and the reproductive and growth axes. Chronic hyperactivation of the stress system may lead to osteoporosis and metabolic syndrome. CRH: corticotropin-releasing hormone, GnRH: gonadotropin-releasing hormone, ACTH: adrenocorticotropic hormone, LH: luteinizing hormone, FSH: follicle-stimulating hormone, GHRH: growth hormone releasing hormone, STS: somatostatin, GH: growth hormone, SmC: somatomedin C. Activation is represented by solid green lines and inhibition by dashed red lines.

The interaction between CRH and the gonadal axis appears to be bidirectional. The presence of estrogen response elements in the promoter area of the CRH gene and direct stimulatory estrogen effects on CRH gene expression‎ have been shown (74). This finding implicates the CRH gene and, therefore, the HPA axis as a potentially important target of ovarian steroids and a potential mediator of gender-related differences in the stress response/HPA axis activity (75). On the other hand, the activated estrogen re ceptor interacts with and, on occasion, potentiates the c-jun/c-fos heterodimer, which mediates several cytokine effects. In addition, estrogen appears to stimulate adhesion molecules and their receptors in immune and immune accessory cells, thus offering a possible explanation as to why autoimmune diseases afflict frequently females than males.

Growth axis

The growth axis is also inhibited at many levels during stress (Figure 4). Prolonged activation of the HPA axis leads to suppression of growth hor mone secretion and inhibition of somatomedin C (SmC) and other growth fac tor effects on their target tissues by glucocorticoids (76, 77, 78), presum ably via inhibition of the c-jun/c-fos heterodimer. However, acute transient elevations of growth hormone concentrations in plasma may occur at the onset of the stress response in man, as well as after acute administration of glucocorticoids, presumably through GRE-stimulated growth hormone expression‎ (79). In addition to the direct ef fects of glucocorticoids, which are pivotal in the suppression of growth observed in prolonged stress, increases in somatostatin secretion caused by CRH, with resultant inhibition of growth hormone secretion, have also been implicated as a potential mechanism of stress-related suppression of growth hormone secretion (80). The redirection of nutrients and vital substrates to the brain and other areas where they are needed most during stress is the apparent teleology for the adverse effects of chronic stress on growth.

Thyroid axis

A corollary phenomenon to growth axis suppression is the stress-related inhibition of thyroid axis function (Figure 5). Activation of the HPA axis is associated with decreased production of thyroid stimulating hormone (TSH) and inhibition of conversion of the relatively inactive thyroxine to the more biologically active triiodothyronine in peripheral tissues (the "euthyroid sick" syndrome) (81, 82). Although the exact mechanism(s) for these phenomena is not known, both phenomena maybe caused by the increased levels of glucocorticoids and theoretically serve a desired energy conservation during stress. Inhibition of TSH secretion by CRH-induced increases in somatostatin might also participate in the central component of thyroid axis suppres sion during stress. In the case of inflammatory stress, inhibition of TSH secretion and enhancement of somatostatin production may be in part through the action of cytokines on the hypothalamus and/or the pituitary (83, 84).

Figure 5. Schematic representation of the interactions between the hypothalamic-pituitary-adrenal axis and the thyroid and immune function. CRH: corticotropin-releasing hormone, STS: somatostatin, TRH: thyrotropin releasing hormone, TSH: thyroid stimulating hormone, T4: thyroxine, T3: triiodothyronine, TNF-α: tumor necrosis factor-α, IL-1: interleukin-1, IL-6: interleukin-6. Activation is represented by solid green lines and inhibition by dashed red lines.

Stress system - Metabolism

Glucocorticoids, the hormonal end-product of the HPA axis, exert primarily catabolic effects as part of a generalized effort to utilize every available energy resource against the challenge posed by intrinsic or extrinsic stressors. Thus, glucocorticoids increase hepatic gluconeogenesis and plasma glucose concentration, induce lipolysis (although they favor abdominal and dorsocervical fat accumulation) and cause protein degradation at multiple tissues (e.g. muscle, bone, skin) to provide amino acids that would be used as an additional substrate for oxidative pathways. In addition to their direct catabolic actions, glucocorticoids also antagonize the beneficial anabolic actions of GH, insulin and sex steroids on their target tissues (85). This shift of the metabolism toward a catabolic state by the activated HPA axis normally reverses upon retraction of the enforced stressor. Chronic activation of HPA axis, however, would be damaging as it is expected to increase visceral adiposity, decrease lean body (muscle and bone) mass, suppress osteoblastic activity and cause insulin resistance (Figure 6). Interestingly, the phenotype of Cushing’s syndrome, characterized by abdominal and trunk fat accumulation and decreased lean body mass, in combination with manifestations of the metabolic syndrome (visceral adiposity, insulin resistance, dyslipidemia, hypercoagulability, hypercytokinemia, hypertension), is present in a variety of pathophysiologic conditions, collectively described as pseudo-Cushing’s states. This phenotype could be are presumably attributed to HPA-induced mild hypercortisolism or to peripheral tissue hypersensitivity to glucocorticoids (85, 86, 87).

Figure 6. Schematic representation of the detrimental effects of chronic stress on adipose tissue, bone and muscle metabolism. GH: growth hormone. Stimulation is represented by solid green lines and inhibition by dashed red lines.

The integrity of metabolic homeostasis is also centrally affected by the neuroendocrine integration of the HPA axis and the central stress pathways to the CNS centers that control appetite/satiety and energy expenditure (Figure 3) (88). It is a common observation that stressful situations are associated with anorexia and profound suppression of food intake. Indeed, CRH stimulates the POMC neurons of the arcuate nucleus which, via α-MSH release, elicit antiorexigenic signals and increase thermogenesis (89). Suppression of the orexiogenic neuropeptide Y secretion is also likely to be involved in stress-induced anorexia. However, it should also be noted, that glucocorticoids enhance the intake of carbohydrates and fat and inhibit energy expenditure by stimulating the secretion of NPY at the hypothalamus, which additionally inhibits the locus ceruleus-norepinephrine system and activates the parasympathetic system, thus, facilitating digestion and storage of nutrients (90, 91, 92).

Stress system - Gastrointestinal function

An increasing body of evidence suggests that CRH is involved in the cen tral mechanisms by which stress influences the gastrointestinal function. During acute stress, PVN CRH, independently of the associated stimulation of the HPA axis, induces both inhibition of gastric emptying and stimulation of colonic motor function by alterations in the autonomic nervous system activity (Figure 7). It is considered that inhibition of the vagus nerve activity at the dorsal vagal complex results in selective inhibition of gastric motility, while stimulation of the sacral parasympathetic system activity, possibly through CRH projections of the Barrington nucleus (which is part of the locus ceruleus complex) (93) results in selective stimulation of colonic motility (94). It is believed that, inhibition of gastric emptying involves the central medullary CRH-R2 receptors and possibly the peripheral CRH-R2 receptors at the gastrointestinal track, while the CRH-R1 subtype appears to mediate the colonic motor responses. Thus, CRH may be implicated in the gastric stasis that is associated with the stress of surgery or with high levels of central interleukin-1 (95), as well as in the stress-induced colonic hypermotility of the irritable bowel syndrome. Interestingly, the colonic contraction in pa tients with irritable bowel syndrome may activate the LC/sympathetic neurons, thus, forming a vicious cycle, which may help explain the chronicity of the condition. In addition to altering the motility pattern, stressors exert profound influences in several other aspects of the gastrointestinal function, as it has been found that the stress-induced activation of central and peripheral CRH receptors causes dysfunction of the intestinal barrier, increases gastrointestinal permeability and may enhance relapses of inflammatory bowel disease (96, 97, 98).

Figure 7. Schematic representation of the effects of stress on gastrointestinal function. CRH: corticotropin-releasing hormone, ACTH: corticotrophin, PVN: paraventricular nucleus, LC: locus ceruleus. Stimulation is represented by solid green lines and inhibition by dashed red lines.

Stress system - Immune system interactions

Effects of the immune system on the stress system

The immune system exerts its surveillance-defense function constantly and mostly unconsciously for the individual. It has been known for several decades that immune/inflammatory insults in the form of an infectious disease, an active autoimmune inflammatory process, or an accidental or operative trauma, are associated with concurrent activation of the HPA axis. More, recently it also became apparent that immune cytokines and other humoral mediators of inflammation are potent activators of central stress-responsive neurotransmitter systems, constituting the afferent limb of the feedback loop though which the immune/inflammatory system and the CNS communicate (Figure 5). Through this pathway, the peripheral immunologic apparatus signals the brain to participate in maintaining immunological and behavioral homeostasis (99, 100).

The three main “inflammatory” cytokines, tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1) and interleukin-6 (IL-6), are produced at in flammatory sites and elsewhere in a cascade-like fashion, with TNF-α appearing first followed by IL-1 and IL-6 in tandem, and can cause stim ulation of the HPA axis in vivo, alone or in synergy with each other (101, 102). This can be blocked significantly with CRH-neutralizing antibodies, prostanoid synthesis inhibitors and glucocorticoids. In addition, all three cytokines directly stimulate hypothalamic CRH secretion in vitro, an action also suppressed by glucocorticoids and prostanoid synthesis in hibitors (103, 104, 105).

There is evidence to suggest that IL-6, the main endocrine cytokine, plays the primary role in the immune stimulation of the human HPA axis, especially in the long term. Thus, in humans, IL-6 is an extremely potent activator of the axis, importantly without the vascular leak-promoting and hypotensive side-effects of the other two inflammatory cytokines (83, 106). The elevations of ACTH and cortisol attained by IL-6 are well above those observed with maximal stimulatory doses of CRH, suggest ing that parvocellular AVP and other ACTH secretagogues are additionally stimulated by this cytokine. At high doses, IL-6 also stimulates peripheral elevations of AVP, presumably as a result of a stimulatory effect on magnocellular AVP-secreting neurons (107). This suggests that IL-6 may be involved in the genesis of the syndrome of inappropriate antidiuretic hor mone secretion (SIADH), which is observed during the course of infectious/inflammatory disease or during trauma.

Some of the activating effects of inflammation on the HPA axis may be exerted indirectly, via stimulation of the central catecholaminergic path ways by the inflammatory cytokines and other humoral mediators of in flammation. Also, activation of peripheral nociceptive, somatosensory, and visceral afferent fibers would lead to stimulation of both the catecholaminergic and CRH neuronal systems via ascending spinal pathways. Interestingly, in chronic inflammatory states, where chronic central eleva tions of substance P may take place, an impairment of HPA axis respon siveness to stimuli or stress is observed, probably because of the suppres sive effect of substance P on the CRH neuron (41). Such an impairment has been observed in African trypanosomiasis and extensive burns in humans and in animal models of chronic inflammation (108).

Other inflammatory mediators may also participate in the activation of the HPA axis, in addition to the three inflammatory cytokines. Thus, sev eral eicosanoids, platelet activating factor (PAF) and serotonin, show potent CRH-releasing properties (109, 110). It is not clear, however, which of the above effects are endocrine and which are paracrine. Direct effects, albeit delayed, of most of the above cytokines and mediators of inflammation on pituitary ACTH secretion, on the other hand, have also been shown (83, 111, 112), and direct effects of these substances on adrenal glucocorticoid secretion appear also to be present (113).

An interesting aspect of the immune response is that CRH is also secreted peripherally at inflammatory sites (peripheral or immune CRH) by postganglionic sympathetic neurons and by cells of the immune system (e.g. macrophages, tissue fibroblasts) (114). The secretion of immune CRH has been examined both in experimental animal models of inflammation (114), as well as in patients with rheumatoid arthritis (115), Hashimoto thyroiditis and other inflammatory illnesses (116). Immune CRH secretion is suppressed by glucocorticoids and somatostatin (114). Mast cells are considered as the primary target of immune CRH where, along with substance P, it acts via CRH-R1 receptors causing degranulation. Subsequently, histamine is released causing vasodilation, increased vascular permeability and other manifestations of local inflammation. Thus, locally secreted CRH triggers a peripheral CRH-mast cell-histamine axis, which has potent pro-inflammatory properties, whereas central CRH alleviates the immune response (99, 117).

Effects of the stress system on the immune/inflammatory reaction

Activation of the HPA axis has profound inhibitory effects on the inflammatory/immune response, because virtually all the components of the immune response are inhibited by cortisol (Figure 8). At the cellu lar level, alterations of leukocyte traffic and function, decreases in pro duction of cytokines and mediators of inflammation and inhibition of their effects on target tissues are among the main anti-inflammatory effects of glucocorticoids (53). These effects are exerted at both the resting, basal state and during inflammatory stress, when the circulating concentrations of glucocorticoids are elevated. Thus, a circadian activity of several immune functions has been demonstrated in re verse-phase synchrony with that of plasma glucocorticoid levels.

Figure 8. Schematic representation of the interactions between the stress and the immune system. LC/NE: locus ceruleus/norepinephrine-sympathetic system, SPGN: sympathetic postgaglionic neurons, CRH: corticotropin-releasing hormone, AVP: arginine vasopressin, ACTH: corticotrophin, PAF: platelet activating factor, NE/E: norepinephrine/epinephrine,: Th1: T-helper lymphocyte 1, Th2: T-helper lymphocyte 2. Stimulation is represented by solid green lines and inhibition by dashed red lines.

A large infrastructure of anatomical, chemical, and molecular connec tions allows communication not only within, but also, between the neuroendocrine and the immune system. The efferent sympathetic/adrenomedullary system apparently participates in a major fashion in the interactions of the HPA axis and the immune/inflammatory stress by being reciprocally connected with the CRH system, by receiving and transmitting humoral and nervous immune signals from the periphery, by densely innervating both primary and secondary lymphoid organs, and by reaching all sites of inflammation via the postganglionic sympathetic neurons (118, 119). Thus, leukocytes and macrophages contain specific receptors for neurotransmitters, neuropeptides and neurohormones, that influence their functions, while the immune cells themselves are also capa ble of producing many of these substances. When activated during stress, the autonomic system exerts its own di rect effects on immune organs, which can be immunosuppressive (e.g. inhibition of natural killer cell activity) or both immunopotentiating and immunosuppressive by inducing secretion of IL-6 in the systemic circulation (120).

It should be underlined that the effects of stress on the immune system are better characterized as immunomodulating, rather than immunosuppressing. Both glucocorticoids and catecholamines directly inhibit the production of type 1 cytokines, such as IL-12, IL-2, TNF-α and INF-γ, that enhance cellular immunity and T-helper 1 (Th1) formation and conversely favor the production of type 2 cytokines, such as IL-10, IL-4, IL-13, that induce humoral immunity and T-helper 2 (Th2) formation (121). Thus, during an immune challenge, stress causes an adaptive Th1 to Th2 shift in order to protect the tissues from the potentially destructive actions of the pro-inflammatory type 1 cytokines and other products of activated macrophages. The homeostatic role of stress-induced Th2 shift against overshooting of cellular immunity often complicates pathologic conditions where, either cellular immunity is beneficial (e.g. carcinogenesis, infections) or humoral immunity is deleterious (e.g. allergy, autoimmune diseases).

STRESS, ENDOCRINE PATHOPHYSIOLOGY

According to the general principles of homeostasis that apply to physiologic systems, the mobilization of the different components of the stress system, manifested as the stress response, must be of intensity that correlates to the presented threat by the posed stressor and of duration that permits a timely return to the initial resting state. In this context, a successful stress response should be of a magnitude to overpower the stressor without overshooting and of time-limited duration that would render its accompanying catabolic, antireproductive, antigrowth and immunosuppressive effects temporarily beneficial and of no adverse consequences. The dose-response relationship between the responsiveness of the stress system and the potency of a stressor can be graphically represented by a sigmoidal curve that starts from basal stress system activity levels at rest and plateaus at a maximum level, when all available forces have been utilized. This sigmoidal curve varies according to the individual, yet there is a relatively narrow limited range between basal and maximum activity that characterizes the normal reactive individuals. Thus, dose-response curves located outside the two extremes of this range denote pathologic stress responses, with higher and lower-shifted curves denoting excessive and defective reactions, respectively (Figure 9A). Similarly, the dose-response relationship between the sense of well-being or performance ability of an individual and the activity of the stress system is represented by an inverted U-shaped curve that covers the normal range of the stress system activity. Shifts to either the left or the right of this range would result in hypoarousal or hyperarousal (anxiety) states, respectively, and a suboptimal sense of well-being or diminished performance (Figure 9B) (1).

Figure 9. A. The dose-response curve between the potency of a posed stressor and the activity of the components of the stress system that respond to this specific stressor. Curve 1 (green) : the normal dose-response curve, Curve 2 (red) : the dose-response curve that defines the upper physiologic level of stress system activity, Curve 3 (purple): the dose-response curve that defines the lower physiologic level of stress system activity. Any curve higher than 2 represents stress system hyperactivity and any curve lower than 3 represents stress system hypoactivity. B. The inverted U-shaped dose-response curve between the sense of well-being or performance ability and the activity of the stress system. Curve 1 (green) : optimal activity curve, Curve 2 (red) : excessive stress system activity curve, Curve 3 (purple): defective stress system activity curve. Curves 2 and 3 curtail the top of the optimal curve and represent shifts to the left (hypoarousal) and to the right (hyperarousal-anxiety) and both are associated with suboptimal sense of well-being or diminished performance (Figure 9B). (Adapted from Chrousos G.P. and Gold P.W., JAMA, 267,1244,1992.)

Several of the multiple factors that determine the stress responses of individuals are inherited, as indicated by quantitative genetics of human complex behaviors (1, 122, 123). It has been estimated that approximately two thirds of reliable variance in measured personality traits are due to genetic influences. Thus, the observed variability in the activity of the stress system is expected to reflect genetic polymorphisms and clinically significant alterations of the expression‎ of genes involved in the regulation of the stress system, such as those of CRH, AVP, their receptors and their regulators. However, a significant variance of the stress responses of individuals is due to environmental influences. The intrauterine period, infancy, childhood, and adolescence are periods of increased plasticity for the stress system. Excessive or sustained activation due to environmental factors during these critical periods may have profound effects on its later function, especially as it relates to pathophysiology (1, 4, 124-126).

Chronic Hyperactivation of the Stress System - Pathophysiology

The chronic hyperactivation of the stress system leads to the syndromal state that Selye first described in 1936 (1). Since CRH coordinates behavioral, neuroendocrine, autonomic, and immunologic adaptation during stressful situations, increased and prolonged production of CRH is regarded to play a pivotal role in the pathogenesis and the manifestations of the chronic stress syndrome, including its circulatory, endocrine, psychiatric, metabolic, and immune components.

The syndrome of adult melancholic depression represents a prototypical example of dysregulation of the generalized stress response, leading to dysphoric hyperarousal, chronic activation of the HPA axis and the SNS, and relative immunosuppression (127, 128). Indeed, these patients exhibit increased cortisol excretion, decreased plasma ACTH response to exogenous CRH and elevated cerebrospinal fluid (CSF) levels of CRH (129, 130). These findings suggest that melancholic depression correlates with distinct hypersecretion of CRH, which may participate in the initiation and/or perpetuation of a vicious pathophysiologic cycle. Indeed, depressed patients were found on autopsy to have markedly increased numbers of PVN CRH neurons (131), while imaging studies have also documented marked hippocampal atrophy and a small and hypofunctioning section of the medial frontal lobe (Figure 10) (132, 133). Whether this pathology is genetically determined, environmentally induced, or both is unclear at the present time.

Figure 10. Schematic representation of the central neurocircuitry and its altered activity in acute stress and melancholic depression (chronic hyperactivation of the stress system). Hyperfunctioning amygdala, hypofunctioning hippocampus and/or hypofunctioning mesocorticolimbic system (MCLS) could be associated with chronic hyperactivation of the PVN CRH-AVP system and predispose to melancholic depression. PVN: paraventricular nucleus, CRH: corticotropin-releasing hormone, AVP: arginine vasopressin. Stimulation is represented by solid lines and inhibition by dashed lines. Stimulation is represented by solid green lines and inhibition by dashed red lines.

In addition to melancholic depression, a broad spectrum of other conditions may be associated with increased and prolonged activation of the HPA axis (Table 2). These include anorexia nervosa and malnutrition (134, 135, 136), obsessive-compulsive disorder (137), panic anxiety (138), excessive exercise, chronic active alcoholism (139), alcohol and narcotic withdrawal (140, 141), diabetes mellitus types, especially when complicated by diabetic neuropathy (142, 143), central (visceral) obesity (85, 87, 144), childhood sexual abuse (145) and, perhaps, hyperthyroidism (146).

It is of interest that anorexia nervosa and malnutrition are characterized by increased levels of NPY in the CSF, which together with the markedly decreased leptin levels, could provide an explanation as to why the HPA axis in these subjects is activated while the LC/NE-sympathetic system shows clear evidence of profound hypoactivity (38, 39). Glucocorticoids, on the other hand, by stimulating NPY and by inhibiting the PVN CRH and the LC/NE-sympathetic systems, would produce the hyperphagia and obesity observed in Cushing’s syndrome and many rodent models of obesity, such as the Zucker rat. The association between chronic, experimentally induced psychosocial stress and a hypercortisolism or metabolic syndrome-like state, with increased incidence of atherosclerosis, has been reported in cynomolgus monkeys. In these animals, chronic, stress-induced activation of the HPA axis, and therefore hypercortisolism, apparently leads to visceral obesity, insulin resistance, and suppression of GH secretion, all converging to the development of varying degrees of the physical and biochemical phenotype of the metabolic syndrome (85, 87).

Increasing evidence from recent studies indicate a strong correlation between states of chronic stress hyperactivity and gastrointestinal (GI) illness (96, 97, 98). In a study of selectively referred patients with chronic GI pain, a high incidence of physically and sexually abused women was reported. Sexually abused girls suffer chronic activation of the HPA axis, as do patients with melancholic depression. Thus, CRH hypersecretion could be the hidden link between the symptoms of chronic GI pain and a history of abuse. Additionally, chronic activation of the HPA axis and/or of the LC/NE-sympathetic system may promote depletion or tachyphylaxis of the opioid-peptide system responsible for stress-induced analgesia, which might explain the observed lower pain thresholds for visceral sensation in patients with functional GI disorders.

Psychosocial dwarfism is a term describing severe childhood or adolescent growth arrest, delayed puberty, or both due to emotional deprivation or psychologic harassment. Decreased GH secretion that is reversible after separation of the child from the responsible environment is a characteristic finding in this condition, which is also associated with a variety of behavioral abnormalities, such as depression and disturbed eating behaviors. Psychosocial dwarfism was first studied in infants housed in foundling homes or orphanages, who had decreased growth and high mortality rates. It was hypothesized that this failure to thrive resulted from lack of attention and positive stimulation, deficient nutrition, or both. Later, it was shown in these infants that weight gain was independent of food intake, whereas a caring and attentive environment, was able to improve their growth rate and the psychological profile. Interestingly, although very little is known about the activity of the HPA axis in children with this condition, it is very likely that the HPA axis is chronically activated, which would explain the other endocrine abnormalities observed in these children.

Infantile malnutrition is characterized by hypercortisolism, decreased responsiveness to CRH, incomplete dexamethasone suppression, and thyroid function test changes reminiscent of the euthyroid sick syndrome, abnormalities that are restored after nutritional rehabilitation (1, 136). Premature infants are especially at risk for delayed growth, development, or both, especially after a prolonged hospitalization in the intensive care nursery. The condition is similar to psychosocial dwarfism, but known as reactive attachment disorder of infancy. Interestingly, activation of the fetal HPA axis is also associated with fetal growth retardation. The master influence of infant care on growth and development was recently shown in a species of nonhuman primates that are socially organized in extended families (147).

Pregnancy in the third trimester is another condition characterized by hypercortisolism of a degree similar to that observed in severe depression, anorexia nervosa, and mild Cushing’s syndrome and is the only known physiological state in humans in which CRH circulates in plasma at levels high enough to cause activation of the HPA axis (148, 149, 150). Although circulating CRH, which is placental in origin, is bound with high affinity to CRH-binding protein (151, 152, 153) it appears that the circulating free fraction is sufficient to explain the observed escalating hypercortisolism when the plasma concentrations of CRH-binding protein starts to gradually decrease in plasma after the 35th week of pregnancy.

Finally, hyperactivation of the HPA axis is associated with increased susceptibility of the individual to a host of infectious agents and tumors. An excessive response of the HPA axis and a prolonged Th2 shift has been associated with relapse of mycobacterial infections, progression of HIV infection and infections that follow major traumatic injuries or burns. In addition, several studies report a higher incidence of tumor growth and metastases in correlation to stress, highlighting the role of cellular immunity in surveillance and eradication of tumor cells (154).

Chronic Hypoactivation of the Stress System - Pathophysiology

Hypoactivation of the stress system, in which chronically reduced secretion of CRH may result in pathologic hypoarousal, characterizes another group of pathophysiologic states (Table 2). Patients with atypical and seasonal depression and the chronic fatigue syndrome belong to in this category (155, 156). In the depressive (winter) state of the former and in the period of fatigue in the latter, there is chronically decreased activity of the HPA axis. Similarly, patients with fibromyalgia have decreased urinary free cortisol excretion and frequently complain of fatigue(157). Hypothyroid patients also have clear evidence of CRH hyposecretion and it is interesting that one of the major manifestations of hypothyroidism is depression of the “atypical” type. Additionally, withdrawal from smoking has been documented as a state associated with decreased cortisol and catecholamine secretion (158, 159). Decreased CRH secretion in the early period of nicotine abstinence could explain the hyperphagia, hypometabolism, and weight gain frequently observed in these patients. It should be noted that in Cushing’s syndrome, the clinical picture of atypical depression, hyperphagia, weight gain, fatigue, and anergia is consistent with the suppression of the CRH neuron by the associated hypercortisolism. The period after cure of hypercortisolism, the postpartum period, and periods after cessation of chronic stress are also associated with suppressed PVN CRH secretion and decreased HPA axis activity (1-4, 148, 160, 161).

A defective HPA axis response to inflammatory stimuli would reproduce the glucocorticoid-deficient state and would lead to relative resistance to infections and neoplastic disease, but increased susceptibility to autoimmune/inflammatory disease (99, 154, 162, 163). Indeed, such properties were unraveled in an interesting pair of near-histocompatible, highly inbred rat strains, the Fischer and Lewis rats, both of which were genetically selected out of Sprague-Dawley rats, for their resistance or susceptibility, respectively, to inflammatory disease (164, 165, 166). Setting off from the findings in this animal model, there is an increasing body of evidence that patients with rheumatoid arthritis have mild form of central hypocortisolism, as they have reduced 24-h cortisol excretion, less pronounced diurnal rhythm of cortisol secretion, and blunted adrenal responses to surgical stress (166, 167). Thus, dysfunction of the HPA axis may actually play a role in the development and/or perpetua tion of autoimmune disease, rather than being an epiphenomenon. The same rationale may explain the high incidence of autoimmune disease in the period after cure of hypercortisolism and the postpartum period, as well as in the untreated or under-replaced adrenal insufficiency (154).

Potential role of CRH antagonists in clinical practice

The association of a wide spectrum of disease with dysregulation of the stress system response suggests that small molecular weight CRH-R1 and CRH-R2 antagonists, which could be absorbed orally and cross the blood brain barrier, might have a potential role in the treatment of disorders characterized by pathogenetic disturbances of the CRH pathways (29).

Antalarmin, is a non-peptidic prototype CRH antagonist (Figure 11), which binds with high affinity to the CRH-R1. This small lipophilic pyrrolopyrimidine compound decreases the activity of the HPA axis and the LC/NE-sympathetic system, blocks a variety of manifestations associated with anxiety, as well as, the development and expression‎ of conditioned fear (168). In addition, antalarmin suppresses stress-induced peptic ulcer and colonic hyperfunction, neurogenic inflammation and blocks CRH-induced skin mast cell degranulation (29, 169-173). Importantly, the chronic administration of antalarmin is not associated with glucocorticoid or catecholamine deficiency and permits adequate HPA axis and LC/NE responses to severe stress (174). The data from several studies that tested the efficacy of such CRH-R1 antagonists indicate a potential therapeutic role in human pathologic states, such as melancholic depression, chronic anxiety, narcotic withdrawal, irritable bowel syndrome, allergic reactions, and autoimmune inflammatory disorders.

Figure 11. Non-peptidic CRH receptor 1 antagonists.

Experimental data from the use of selective CRH-R2 antagonists are limited (29). The identification of the specific CRH-R2 neuronal pathways that are implicated in pathologic conditions in humans and a better understanding of the physiologic role of CRH-related peptides, such as urocortin (Ucn) I, UcnII, UcnIII and urotensin I, will clarify the therapeutic potential of these agents. CRH-R2 antagonists are expected to be useful in the treatment of atypical depression, chronic fatigue syndrome, fibromyalgia and stress-induced anorexia (29, 175, 176, 177).

Conclusion

Despite the many difficulties in studying the stress system and defining the conditions related to the different degrees of its activity, stress and its disturbances provide a challenging and important area of medical research. The proposed existence of stressor-specific pathways and neurochemical networks is definitely a step forward in the study of the pathogenesis of stress-related disorders. Through the integration and organization of these networks, mutually interdependent linkages emerge between neurobehavioral psychoemotional states and “classic” disease states of malignancy, autoimmunity, inflammation, reproductive disturbances, and disturbances in growth. Although the views presented now initially largely inferential, are increasingly supported by solid experimental and epidemiologic evidence. Establishing an even more solid scientific basis for the views presented in this chapter and further exploring the pathogenesis of stress-related disorders is an ongoing challenge.