Physiology of the Hypothalamic–Pituitary–Adrenocortical Axis

The Hypothalamus–Pituitary–Adrenal Axis Edited by A. del Rey, G. P. Chrousos and H. O. Besedovsky

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Physiology of the Hypothalamic–Pituitary–Adrenocortical Axis HELMUT VEDDER Department of Psychiatry and Psychotherapy, Philipps-University of Marburg, Marburg, Germany

ABSTRACT The hypothalamic–pituitary–adrenocortical (HPA) axis represents one of the adaptational systems of the body with the function of adjusting the organism to challenges of homeostasis, the so-called stress response. Besides circadian and ultradian fluctuations in the activity of the HPA axis, also stressors can induce activation of this system. These stressors may include physical external or internal threats such as immune activation, pain, and exposure to heat and cold. The most potent stressors are, however, those psychological situations, either real or imagined, in which the HPA axis is activated, which subsequently may facilitate adaptation to the stressor. The HPA axis consists of both static (cell and tissues) and dynamic secretable (hormones and other modulators) elements which are components of the stress reaction. They react in a uniform manner under conditions of activation, although with marked quantitative differences. Following an increased secretion of corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) within the brain, the activation of the pituitary gland leads to the secretion of adrenocorticotropic hormone (ACTH), which in turn induces the release of corticosteroid hormones from the adrenal cortex. Multiple mediators also affect the HPA axis at all levels of biological organization, leading to distinct reactions of the key elements, to adequately respond to the type of stressor. The overall biological and psychological response of the organism under conditions of stress was termed “general adaptation syndrome.” If these responses persist or are inadequate, physiological immune, metabolic, and cardiovascular functions may be compromised. As a consequence, the individual may become more vulnerable to stress-related somatic and also neuropsychiatric disorders. Moreover, pathological reactions within the HPA system such as neuroendocrine disturbances and regulatory dysfunctions with a disinhibition and dysregulation of HPA axis functions may lead to inherent disease symptoms within the HPA system. ABBREVIATIONS ACTH AVP BNST CNS CRF CRH GR

adrenocorticotropic hormone arginine vasopressin bed nucleus of the stria terminalis central nervous system corticotropin-releasing factor corticotropin-releasing hormone glucocorticoid receptor

18 HPA IL-1b IL-6 LPS MR NE PVN SCN

Helmut Vedder

hypothalamic–pituitary–adrenocortical axis Interleukin-1b Interleukin-6 lipopolysaccharide mineralocorticoid receptor norepinephrine paraventricular nucleus suprachiasmatic nucleus

1.

INTRODUCTION

1.1.

The HPA axis represents one of the mediators of the stress reaction

Living organisms are continuously in dynamic contact with their environment. Because biological organisms are dynamic systems with regard to their basic structures and functions, they have the ability to alter their metabolism and behavior in order to react and to adapt to a changing environment – although within limits. In response to external and internal stimuli, termed “stressors,” the organism is (1) able to react and to adapt to a given stimulus via an alteration of inherent biological and/or behavioral responses; (2) able to evade the stimulus via a flight reaction, seek confrontation by fighting or use freezing as a survival strategy [1,2]; or (3) unable to survive the stimulus and die. The latter condition denotes the failure of the homeostatic mechanisms, whereas the former conditions induce altered patterns of homeostasis in the organism. In more complex biological systems, including man, a multiorgan system reacts and adapts to a variety of stimuli/stressors in order to maintain homeostasis. Every cell and tissue is functionally flexible with regard to its functions for the final goal of surviving and adapting to gain a better use of the environmental resources for the organism. This process continuously follows the rules of evolution. Multiorgan systems have developed coordinating systems to orchestrate the homeostatic reactions of the diverse tissues when a stress response is initiated. This process includes the hypothalamic–pituitary–adrenocortical (HPA) system, the so-called stress axis, and the accompanying reactions of the sympatho-adrenomedullary system and other tissues and body systems as the main players in this reaction [3]. Hans Selye defined “stress” as the “unspecific response of the body to every demand” and uncovered the important function of the corticosteroid hormones and the coordinated set of reactions during the stress response. He called this reaction the “general adaptation syndrome” [2,4]. In contrast to the “general adaptation syndrome,” a more localized stress reaction has been termed “local adaptation syndrome.” The type of stress that evokes a successful or even beneficial adaptation has been described as “eustress,” whereas stress resulting in an unsuccessful adaptation reaction was termed “disstress” by Hans Selye [2] (Fig. 1). The basic concepts of this syndromic reaction are still valid, although they have been enriched by a large amount of additional data during the last century [2,4–6]. These data show that every player within the HPA axis is involved in multiple aspects and reactions to optimally adapt the organism to its physical, biological, and psychosocial environment. Moreover, the HPA axis and its components not only facilitate adaptation of the organism as a whole to the challenges of daily life, but also specifically affect single responses of the body, with regard to either local reactions in separate tissues and organs, metabolic pathways in cells and tissues, or more complex systems such as immune reactions and complex brain functions such as cognition, emotion, and behavior.

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Figure 1. Reaction pathways to a stressor, leading either to “eustress” or to “disstress” of the biological unit and denoting the consequences. (The inset shows Hans Selye holding a rat, who described the different types of stress responses in tissues and organisms.)

2.

STATIC AND DYNAMIC COMPONENTS OF THE HPA AXIS

On a simplified structural basis, the HPA axis (“stress axis”) is formed by static and dynamic components (“static” denotes a localized position in the body on a complex cellular basis in contrast to “dynamic” elements, which are soluble compounds acting at multiple sites of the organism). Static components consist of different cellular body systems and tissues and are in constant interaction with dynamic elements like hormones and other dynamic components inside and outside the HPA axis (Fig. 2). The structural description of only a few key elements in the central nervous system (CNS) affecting the HPA axis represents a very limited approach to the complex functions of the “information collecting and integrating” brain. For example, the gathering and processing of information, including the function of association, constitutes one of the most refined senses of higher organisms, reaching levels beyond the physical environment. Different perceptions from the past and the present are integrated by the organism via mnemonic and cognitive processes to a model that finally influences the coordinated action of the HPA system under normal and pathological conditions. Quantitatively, it may be assumed that low-level stressors only affect integrated

Figure 2. Components of the hypothalamic–pituitary–adrenocortical axis. Boxes denote static components, text within the arrows shows soluble molecules/dynamic compounds.

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circadian functions of the HPA without pronounced alterations in the activity of the HPA. If the “stress level” due to internal or external factors rises, a more powerful and distinct reaction of the HPA axis is induced. This may represent the result of a cognitive or brain-related stimulus, but may also occur as the result of an immune reaction or a disturbance in other body functions including malfunctions of the HPA system itself. Up to now, the hippocampal formation is regarded as the first and most complex integrating part of the body influencing the activation of more downstream components of the axis [7,8]. Other brain areas that contribute to this process include the amygdala, the brainstem, the prefrontal cortex, and the bed nucleus of the stria terminalis (BNST) [9–14]. Following activation of the hippocampal formation, a specific reaction is evoked in distinct locations of the hypothalamus. One of the key players in this reaction is the corticotropin-releasing hormone (CRH; or corticotropin-releasing factor, CRF) system with its dynamic players CRH, the urocortins I, II, and III [15,16], and the corresponding receptor proteins. Interestingly, these substances are not only mediators of the neuroendocrine system, but are also involved in arousal, emotionality, aversive processes, anxiety, and also anxiolysis [15,16] leading to an integrative modulation of psychophysical responses of the organism. Under normal conditions, the hippocampal formation exerts a blocking/inhibiting action on the HPA system via the hypothalamic centers of the axis [8,9,17,18]. If this functional inhibition of the hippocampal formation disappears, a consecutive activation of the HPA axis occurs, leading to a regulatory dysfunction with increased secretion of the different dynamic elements, including corticosteroid hormones, and to enhanced and often also continuous effects of these players in the organism, with the possibility of detrimental effects. At the hypothalamic level, the medial parvocellular and magnocellular divisions of the lateral paraventricular nucleus (PVN) of the hypothalamus are critically involved in the activity of the HPA system. Neurons of this nucleus synthesize CRH and arginine vasopressin (AVP) and project to the median eminence [10,19]. The activity of the PVN can be directly inhibited by gamma amino butyric acid (GABA)-ergic neurons of the bed nucleus of the stria terminalis (BNST), the preoptic area, and the hypothalamus. In contrast, glutamate is able to activate the neuroendocrine cells via hypothalamic and brainstem projections to the PVN [10]. Additionally, these neurons interact with norepinephrine (NE)-containing neurons in the brainstem, resulting in reciprocal interactions between the central NE and CRH systems, probably even in the manner of a “feed-forward” loop [20]. Furthermore, serotonin and acetylcholine are also involved in the regulation of the HPA axis on different levels including the hypothalamus [9,13] and also with direct and indirect effects such as the different types of actions of serotonin on corticosteroid receptors. In addition to its neuroendocrine functions, AVP is also involved in specific social behavior functions [21] and other functions such as the water balance of the body [22], suggesting pleiotropic effects of this peptide similar to CRH and the urocortins. Moreover, CRH and AVP are not only acting as neurotransmitters in a direct synaptic action in the hypothalamus, but are also secreted in a circadian and pulsatile manner into a specific part of the blood system, the so-called hypophyseal portal circulatory system [23]. Thus, these peptides are secreted into blood vessels, outside the blood–brain barrier, and gain access to the pituitary and the periphery via this pathway. In the pituitary, they mainly act on a specific cell population, the corticotrophic cells of the anterior pituitary. These cells release adrenocorticotropic hormone (ACTH) in a highly complex process and specific pulsatile manner [24] and represent the anatomical end-point of the brain-related part of the HPA axis. Functionally, all central – and also a number of peripheral – influences, such as immune factors and the feedback actions of the corticosteroids, are integrated by corticotrophic cells, rendering them

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Figure 3. The pituitary, “bottleneck” of the hypothalamic–pituitary–adrenocortical axis, and the central role of adrenocorticotrophic hormone (ACTH) as the mediator between the brain/CRH and AVP and the periphery/the corticosteroid hormones.

the “functional bottle-neck” of this important pathway from the CNS to the adrenocortex and the tissues of the body [25] (Fig. 3). The HPA “pathway” from the hippocampus to the hypothalamus and to the pituitary is not a simple structural and uniform line of functioning in one direction, but consists of a variety of elements feeding into the “hormonal effector system of the brain,” the pituitary gland. Numerous other neuropeptides, immune mediators, cellular components, and also the biochemical and genetic setting within the factor-producing cells influence the secretion of the dynamic key components of the HPA system, such as CRH, ACTH, and AVP. Only during the last decade, an important function of immune mediators such as interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-a has emerged. These factors affect the HPA axis at both cellular and systemic levels [26–28]. This leads to a functional connection between the main mediators of both systems, the corticosteroids and the cytokines, termed the “cytokine-HPA axis feedback circuit” [29]. Thus, the corticotroph cells of the pituitary are one of the most highly integrating parts of the axis, powerfully affecting the activity of the adrenocortex, the next structural downstream element of the system. The adrenal cortex is a part of the peripheral body and is also affected by numerous other factors, including cytokines and other hormones. Thus, the release of the dynamic components cortisol or corticosterone (and of other steroids and compounds) from the adrenal and adrenocortical cells is not only regulated by ACTH. For example, in humans, IL-6 and other immune factors affect and regulate the release of cortisol from adrenocortical cells [30–32]. These data again underscore the pleiotropic nature of the inputs into the HPA axis, even at this most downstream localized level of the system. Corticosteroid hormones are able to affect nearly every tissue and cell of the body. Remarkably, the blood–brain barrier does not represent a major obstacle for these lipophilic hormones, which are even efficiently concentrated and taken up by highly specific binding sites, the mineralocorticoid receptors (MRs) [33,34] in the hippocampus, the “first structural key element of the HPA axis” (see above). Additionally, binding sites with lower affinity for cortisol/corticosterone, the glucocorticoid receptors (GRs), are found in nearly all brain areas including the hippocampus and also in most cells of the body [33,35]. Moreover, a variety of other interacting mechanisms act on the GR- and MR-mediated regulation of cellular and tissue events, leading to a complex network of effects of corticosteroids on body functions [35]. Thus, even at intracellular levels, these systems allow a tight adaptation of the evoked cell and tissue functions and the necessary biological, behavioral, cognitive, and psychosocial reactions of the adapting organism. This is supported by data on the behavioral effects of cortisol in humans, affecting numerous emotional and cognitive processes including attention, perception, and memory [36,37].

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Overall, these actions and also the neuroendocrine feedback effects of corticosteroids on the elements of the HPA axis show that the system is not only acting unidirectionally, but is also retrogradely influenced by the evoked reactions, tightly modulated, although adapting in a more or less open circuit, and affected by numerous external and internal influences. On the other side, the dynamic key elements ACTH, AVP, CRH, and cortisol form part of a more closed feedback circuit, setting the internal framework and most likely also some set-points for the evoked reactions [35]. An even more complex view of the HPA axis has developed in the last decades: It has been shown that other biological mechanisms such as immune reactions and functions of the autonomic nervous system interact in a closely integrated manner with this system, giving rise to a most complex network, which finally integrates all reactions of the body, although with an ever-changing hierarchy of the reactions due to the varying daily and situational demands.

3.

CIRCADIAN RHYTHMICITY OF THE HPA AXIS

Under physiological conditions, the activity of the HPA axis, as reflected by cortisol secretion, shows a circadian pattern with large interindividual differences (e.g., see Ref. [38]). A refined stochastic model on diurnal cortisol patterns indicated distinct aspects of diurnal cortisol secretion: In the early morning, before wakening, cortisol levels begin to rise from very low levels and show a distinct peak around wakening time. Levels then decrease and show another– albeit smaller– maximum after noon, dropping during the afternoon and the first part of the night to very low levels in the early morning hours [38]. Thus, the circadian pattern is related to the rest–activity cycle of the organism. This is also observed in the rat, in which peak levels are detected in the late evening, when the activity of the animal increases, and a nadir is detected during the start of the resting phase in the early morning. The circadian pattern of cortisol secretion develops in humans within the first months of life and is initiated in close relationship with the circadian sleep–wake rhythm [39]. In the brain, CRH shows a corticosteroid-independent pattern of daily fluctuations [40], representing probably one of the initiating pathways of the circadian rhythmicity of the HPA axis. Additional data indicate that other inputs are mediated, for example, by the effect of light on the eyes via the suprachiasmatic nucleus (SCN). The increased activity in the SCN leads to an enhanced secretion of CRH, which subsequently activates the HPA axis [41]. Besides the HPA activity, numerous other body functions and hormones show circadian fluctuations [42], embedding the HPA system into a complex network of daily oscillations within the organism, even on an ultradian level. Interestingly, also the stress response differs depending on the activity of the HPA axis and, indirectly, on the time of the day. This is most likely due to a differential occupation of the corticosteroid receptors, for example the MRs and GRs. Under conditions of low circulating corticosteroids, MRs, the high-affinity-type receptors, are occupied by the ligand and subsequently affect cellular functions. MRs are predominantly localized in the hippocampal formation of the brain, and MR functions influence the basal and low activity of the HPA during the afternoon, the evening, and the first part of the night [35,43]. Under conditions of increased corticosteroid secretion and an increased activity of the HPA axis, the GRs throughout the body are occupied, leading to a different pattern of cellular activation/ inactivation and subsequently also to specifically altered tissue responses of the organism [35]. As mentioned before, the components of the HPA system may be differentially activated by other systems, such as the immune system, in relation to the circadian activity levels, resulting in a coordinated interaction between the various systems [44].

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The extent of an acute stress response may be dampened during periods when the occupation/ activation of cellular systems via the GRs is increased. For example, during the morning hours, a decreased response to an activation of the HPA might occur due to the already occupied GRs and consecutive ceiling effects [35,43]. During periods of lower occupation of GRs in the evening hours and during the night, a more pronounced influence of external stressors on body functions is possible. Physiologically, this diurnal pattern corresponds to the resting phases of the organism in the afternoon and during the night, when circumstances with a low likelihood of occurring stressors are established by the organism via its self-initiated influences on the surrounding conditions and the environment (resting and sleeping conditions). This pattern corresponds to a primary and “dailyevoked mild endogenous and physiological stress reaction” from the morning hours to the early afternoon, when the body system works in an activating tone, including an activation of the HPA axis. If an increased “load with external and internal stressors” occurs during this part of the day, a dampening of the extent of the HPA activation due to ceiling effects should be detectable, whereas an increased reactivity to external stressors should be evident in the afternoon and the night due to the low HPA activity during this time period. This reaction pattern has been demonstrated during mild chronic stress [45] and also following a standardized immune stimulation of the HPA axis by bacterial lipopolysaccharide (LPS; endotoxin) in the morning and in the evening hours [46]. Subsequently, stressors induce increased hormonal responses at times when the internal activity of the stress axis is low [46], thus disturbing more profoundly the circadian rhythmicity of the HPA system. At present, there are only few data on the “reserve potential” of the HPA axis relating the coordinated regulation of circadian rhythmicity and the extent of an additional activation by an increased stressor load. For example, during normal aging, the inhibiting tone of the hippocampal system may gradually diminish due to a morphological decrease in the static components, such as the neuronal cells of the hippocampal formation. This leads to an altered circadian rhythmicity, for example a flattening of the diurnal amplitude [47], and most likely to a decreased response to external and internal stressors due to an already increased tone of the HPA system [48]. This may result from structural and functional changes of the HPA axis with aging, leading to a prolongation of the cortisol secretion and an insufficient feedback regulation, most likely within the hippocampal formation [48–51]. These alterations and subsequent dysfunctions may then contribute to neuroendocrine disturbances in a number of disorders and diseases such as cardiovascular diseases, diabetes, hypertension, and major depression [52,53].

4.

PARADIGMATIC ACTIVATION OF THE HPA AXIS

4.1.

Psychological activation of the HPA axis

It is well known that psychological stressors may induce an activation of the HPA axis as indicated by an increased secretion of cortisol [54–56]. Several studies have shown that novelty, predictability, anticipation of negative consequences, controllability, and ego involvement are critical factors that mediate the extent of the activation of the HPA axis. These data have been replicated in animals with regard to novelty effects [57,58] and in man [59,60] as well as in other species and for other variables under different conditions. Besides these stressor-related factors, individual variables, such as a chronic type of the stressor or emotional reactions, are relevant for the HPA activation. Other studies have also introduced and connected more specific personality-related factors, such as the ability to cope with a stressful situation, with the extent of the neuroendocrine reaction, and the secretion of cortisol [61,62].

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In addition to corticosteroid secretion, effects of stress on different brain systems and especially on the CRH system have been examined, suggesting that chronic psychological influences may lead to a specific activation of the CRH system itself, even in a perpetuating manner [63]. A large number of other psychological paradigms have been used to induce the activation of the HPA axis including social separation [57], psychosocial stress [64], and high and low emotional events [65]. Even more sophisticated stressors such as CO2 inhalation, which subsequently induce anxiety and increase emotional pressure [66,67], have been employed. 4.2.

Neuroendocrine activation of the HPA axis

Neuroendocrine activation of the HPA axis by external application of AVP, ACTH, and CRH or analog substances represents endocrine challenges for the diagnosis of endocrine malfunctions (e.g., see Refs [68–71]). More refined applications to test feedback mechanisms of the HPA axis use the combined application of dexamethasone, a synthetic glucocorticoid, and CRH (e.g., see Ref. [72]). Due to the relevance of stressors for the clinical incidence of affective disorders, these tests have been widely used for the detection of neuroendocrine disturbances in psychiatric disorders (e.g., see Refs [73–76]). The time frame of ACTH and cortisol secretion is well coordinated. After stimulation with human CRH, there is a nearly instant release of both, ACTH and cortisol (e.g., see Ref. [77]), clearly supporting an almost instantaneous reaction which affects nearly all body systems. 4.3.

Immune activation of the HPA axis

Bacterial LPS has also been used to activate the HPA axis in humans (for example and review, see Ref. [78]). Comparison of a neuroendocrine (CRH) and an immune (LPS) activation showed that the neuroendocrine response occurs about 2 h later and with a somewhat different time frame after LPS application, indicating that secondarily induced factors mediate the neuroendocrine activation and the subsequent hormonal response [77]. Further detailed studies underscored this finding showing that the complex network of reactions is also influenced by other factors, for example the effects of the cytokines interleukin-6 (IL-6) and interleukin-1b (IL-1b) at virtually all levels of the HPA axis [32,78–80]. Thus, the effects of different psychosocial stressors, of hormones such as CRH and AVP, as well as of other stressors such as an immune stimulation may induce a clearly detectable activation of the HPA axis, although with different characteristics and time kinetics.

5.

INTERACTION OF THE HPA AXIS WITH OTHER SYSTEMS OF THE BODY

It is well known that an increased stress response including the activation of the HPA axis leads to alterations in basal body functions such as cardiovascular adaptation, changes in metabolic and immune functions as well as cognitive and behavioral alterations like changes in sleep and activity patterns (Fig. 4). For example, the basal relationship between the resting/activity cycle and the circadian HPA activity underscores this interaction already under physiological conditions. Infused glucocorticoids raise blood pressure and increase the reactivity of tissues to NE directly affecting the blood pressure and also glucose tolerance. Moreover, glucocorticoids or an activation of the HPA axis may be involved in the development of obesity [81–84]. Recently, these data led to the hypothesis that stress-induced disturbances of the HPA axis also contribute to the incidence of type 2 diabetes [85–87].

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Figure 4. Central role of the hypothalamic–pituitary–adrenocortical axis (HPA axis) in the coordination of the homeostatic systems of the body.

Numerous other reports have shown that stress experience alters the sleep–wake cycle [88–90], pointing to a tight relationship between HPA axis activity and the sleep–wakefulness cycle [88,91]. In this regard, sleep seems to represent a major pacemaker for the initiation of diurnal processes including the secretion of several hormones [42]. Remarkably, not only sleep in general depends on HPA activity but different sleep elements are selectively influenced by HPA components such as ACTH and cortisol. ACTH increases slow-wave sleep and paradoxical sleep [92] Cortisol and other synthetic glucocorticoids also alter slow-wave sleep and therefore critically affect sleep architecture [93]. Recently, the neuroendocrine–immune network has been extended to sleep regulation (e.g., see Refs [94,95]), linking the networks and mediators to specific alterations in sleep parameters. With focus on behavioral aspects, it has been shown that cortisol affects cognitive processing and specific emotions such as fear and anxiety [96,97]. Additionally, it has been demonstrated that CRH induces specific alterations in anxiety-related behavior, other behavioral responses, and cognitive deficits [98]. Thus, these data show that activation of the HPA system leads to alterations in a large number of body functions including metabolic, cardiovascular, and behavioral aspects as well as specific brain functions such as cognition and memory.

6.

REGULATION AND CHRONIC ACTIVATION OF THE HPA AXIS

As described above, the activation and adaptation of the HPA axis is tightly regulated at different levels by several feedback circuits [18,99] (Fig. 5). These circuits consist of timerelated reactions such as a fast feedback response via circulating glucocorticoids on the secretion of CRH and ACTH [18,99] probably even on the biosynthesis and secretion of the glucocorticoids in the adrenocortical tissue itself [100]. GRs and MRs have been implicated in different types of responses with the GR mediating a fast response at different levels of the HPA axis via a negative influence on the HPA activity [101]. MRs have been implicated in the regulation of the set-point of the axis within a longer time frame (days and weeks), setting the basal activity and subsequently also the reactivity pattern of the axis (see page 22) [43,102]. Therefore, mechanisms such as fast cellular responses are influenced via the fast effects of glucocorticoids on energy metabolism [103], calcium metabolism, and protein processing [104] and protein secretion. Moreover, they are accompanied by responses occurring within longer

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Figure 5. Modulatory factors of the activity of the hypothalamic–pituitary–adrenocortical axis (HPA axis) from the cellular level (1) up to sociocultural factors (6).

time periods such as genomic responses, affecting the protein equipment of a cell and other cellular processes within the relevant tissues and feedback loops. Longer feedback loops consist of adaptational effects within the HPA itself such as the influences of immune mediators and neurotransmitters on the activity of the HPA axis, also most likely including effects on the activity of the MR system within the HPA axis [43,102]. Further loops are represented by the adaptation of behavior such as the stress-coping strategies or memory storage [105], the fight or flight reaction itself, and the alteration in the environment of the individual with regard to physical or psychosocial stressors, leading to very long-loop feedback reactions to the responses of the HPA axis. If an adequate termination of the reactions of the HPA axis fails, a prolonged secretion of mediators impairs cellular adaptational events. This may result in cell and tissue damage, including alterations of elements of the HPA system such as the hippocampus [104]. A disinhibition of the activity of the HPA system may occur under certain conditions of aging [51,534], demonstrating that a prolonged, not an increased, activation of the HPA system with a consecutively altered secretion of cortisol as well as other dynamic components of the axis represents the common neuroendocrine alteration. In summary, the activity of the HPA axis is regulated by numerous and different types of feedback mechanisms that either inhibit or enforce the secretory drive of the neuroendocrine mediators or affect the basal activity of the cellular networks, constantly challenging the adaptational processes of the organism and improving homeostasis in a permanently changing environment. 7.

COMPREHENSIVE ASPECTS

Organisms are complex biological systems based on static, dynamic, and homeostatic conditions. All principles work together to ensure the survival of biological components from the cellular level to the whole organism and even further to the optimization of psychosocial, cultural, and environmental structures. Stress continuously influences and modulates these systems by initiating adaptational responses, either at a general or at a local level. The HPA axis represents one of the major components of these adaptation mechanisms integrating both psychosocial and physical influences on the organism, and contributing to improve the adaptation to the environment, to a more effective use of the resources, and to optimize survival. When a successful adaptation to given conditions cannot be achieved, even under conditions of

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recruitment of compensating systems such as the components of the HPA axis, disorders and diseases occur and symptoms of partial failure are observed. Death is the consequence of a total failure of adaptation, if the biological unit, which may be a cell, a tissue, an organism, or even a whole species, has no adequate resources to withstand the intensity and the type of the stressor. ACKNOWLEDGMENTS I thank J.-C. Krieg for a number of helpful comments as well as for his continuous support. The editorial help of Mrs A. Tittmar and Mrs B. Schmalz is gratefully acknowledged. Special thanks are given to E.R. deKloet for his valuable comments and additional substantial input to the contribution. REFERENCES 1. 2. 3. 4. 5. 6. 7. 8.

9. 10. 11. 12.

13. 14.

15. 16. 17.

Cannon WB. The wisdom of the body. New York: Norton 1932. Selye H. Confusion and controversy in the stress field. J Human. Stress 1975;1(2):37–44. deKloet ER. Hormones and the stressed brain. Ann N Y Acad Sci 2004;1018:1–15. Selye H. Forty years of stress research: principal remaining problems and misconceptions. Can Med Assoc J 1976 3;115(1):53–6. Chrousos GP. Stressors, stress, and neuroendocrine integration of the adaptive response. The 1997 Hans Selye Memorial Lecture. Ann N Y Acad Sci 1998;851:311–35. Charmandari E, Tsigos C, Chrousos G. Endocrinology of the stress response (1). Annu Rev Physiol 2005 17;67:259–84. Jacobson L, Sapolsky R. The role of the hippocampus in feedback regulation of the hypothalamicpituitary-adrenocortical axis. Endocr Rev 1991;12(2):118–34. Herman JP, Cullinan WE, Young EA, Akil H, Watson SJ. Selective forebrain fiber tract lesions implicate ventral hippocampal structures in tonic regulation of paraventricular nucleus corticotropinreleasing hormone (CRH) and arginine vasopressin (AVP) mRNA expression. Brain Res 1992 2;592(1–2):228–38. Herman JP, Prewitt CM, Cullinan WE. Neuronal circuit regulation of the hypothalamo-pituitaryadrenocortical stress axis. Crit Rev Neurobiol 1996;10(3–4):371–94. Herman JP, Mueller NK, Figueiredo H. Role of GABA and glutamate circuitry in hypothalamopituitary-adrenocortical stress integration. Ann N Y Acad Sci 2004;1018:35–45. de Kloet ER, Vreugdenhil E, Oitzl MS, Joels M. Brain corticosteroid receptor balance in health and disease. Endocr Rev 1998;19(3):269–301. Herman JP, Ostrander MM, Mueller NK, Figueiredo H. Limbic system mechanism of stress regulation: hypothalamo-pituitary-adrenocortical axis Prog Neuropsychopharmacol. Biol Psychiatry 2005;29(8):1201–13. Lowry C. Functional subsets of serotonergic neurones: implications for control of the hypothalamicpituitary-adrenal axis. J Neuroendocrinol 2002;14(11):911–23. Forray MI, Gysling K. Role of noradrenergic projections to the bed nucleus of the stria terminalis in the regulation of the hypothalamic-pituitary-adrenal axis. Brain Res Brain Res Rev 2004; 47(1–3):145–60. Suda T, Kageyama K, Sakihara S, Nigawara T. Physiological roles of urocortins, human homologues of fish urotensin I, and their receptors. Peptides 2004;25(10):1689–701. Heinrichs SC, Koob GF. Corticotropin-releasing factor in brain: a role in activation, arousal, and affect regulation. J Pharmacol Exp Ther 2004;311(2):427–40. Epub 2004 Aug 05. Calogero AE, Galluci WT, Gold PW, Chrousos GP. Multiple feedback regulatory loops upon rat hypothalamic corticotrophin-releasing hormone secretion. J Clin Invest 1988;88:767–74.

28

Helmut Vedder

18. Keller-Wood ME, Dallman MF. Corticosteroid inhibition of ACTH secretion. Endocr Rev 1984;5(1):1–24. 19. Engelmann M, Landgraf R, Wotjak CT. The hypothalamic-neurohypophysial system regulates the hypothalamic-pituitary-adrenal axis under stress: an old concept revisited. Front Neuroendocrinol 2004;25(3–4):132–49. 20. Dunn AJ, Swiergiel AH, Palamarchouk V. Brain circuits involved in corticotropin-releasing factornorepinephrine interactions during stress. Ann N Y Acad Sci 2004;1018:25–34. 21. Goodson JL, Bass AH. Social behavior functions and related anatomical characteristics of vasotocin/ vasopressin systems in vertebrates. Brain Res Brain Res Rev 2001;35(3):246–65. 22. Hertz L, Chen Y, Spatz M. Involvement of non-neuronal brain cells in AVP-mediated regulation of water space at the cellular, organ, and whole-body level. J Neurosci Res 2000;62(4):480–90. 23. Koenig JI. Pituitary gland: neuropeptides, neurotransmitters and growth factors. Toxicol Pathol 1989;17(2):256–65. 24. Gudmundsson A, Carnes M. Pulsatile adrenocorticotropic hormone: an overview. Biol Psychiatry 1997 1;41(3):342–65. 25. Dallman MF, Akana SF, Cascio CS, Darlington DN, Jacobson L, Levin N. Regulation of ACTH secretion: variations on a theme of B. Recent Prog Horm Res 1987;43:113–73. 26. Turnbull AV, Rivier CL. Regulation of the hypothalamic-pituitary-adrenal axis by cytokines: actions and mechanisms of action. Physiol Rev 1999;79(1):1–71. 27. Scho¨bitz B, Sutanto W, Carey MP, Holsboer F, de Kloet ER. Endotoxin and interleukin 1 decrease the affinity of hippocampal mineralocorticoid (type I) receptor in parallel to activation of the hypothalamic-pituitary-adrenal axis. Neuroendocrinology 1994;60(2):124–33. 28. Dunn AJ. Cytokine activation of the HPA axis. Ann N Y Acad Sci 2000;917:608–17. 29. Besedovsky HO, del Rey A. The cytokine-HPA axis feed-back circuit. Z Rheumatol 2000;59 (Suppl 2:II):26–30. 30. Marx C, Ehrhart-Bornstein M, Scherbaum WA, Bornstein SR. Regulation of adrenocortical function by cytokines – relevance for immune-endocrine interaction. Horm Metab Res 1998;30(6–7):416–20. 31. Mastorakos G, Chrousos GP, Weber JS. Recombinant interleukin-6 activates the hypothalamicpituitary-adrenal axis in humans. J Clin Endocrinol Metab 1993;77(6):1690–4. 32. Pa¨th G, Scherbaum WA, Bornstein SR. The role of interleukin-6 in the human adrenal gland. Eur J Clin Invest 2000;30(Suppl 3):91–5. 33. de Kloet ER, Reul JM, Sutanto W. Corticosteroids and the brain. J Steroid Biochem Mol Biol 1990 20;37(3):387–94. 34. de Kloet ER, Sutanto W, Rots N, van Haarst A, van den Berg D, Oitzl M, van Eekelen A, Voorhuis D. Plasticity and function of brain corticosteroid receptors during aging. 1. Acta Endocrinol (Copenh) 1991;125(Suppl 1):65–72. 35. de Kloet ER, Derijk R. Signaling pathways in brain involved in predisposition and pathogenesis of stress-related disease: genetic and kinetic factors affecting the MR/GR balance. Ann N Y Acad Sci 2004;1032:14–34. 36. Erickson K, Drevets W, Schulkin J. Glucocorticoid regulation of diverse cognitive functions in normal and pathological emotional states. Neurosci Biobehav Rev 2003;27(3):233–46. 37. Bemelmans KJ, Goekoop JG, de Rijk R, van Kempen GM. Recall performance, plasma cortisol and plasma norepinephrine in normal human subjects. Biol Psychol 2003;62(1):1–15. 38. Brown EN, Meehan PM, Dempster AP. A stochastic differential equation model of diurnal cortisol patterns. Am J Physiol Endocrinol Metab 2001 Mar;280(3):E450–61. 39. de Weerth C, Zijl RH, Buitelaar JK. Development of cortisol circadian rhythm in infancy. Early Hum Dev 2003;73(1–2):39–52. 40. Kwak SP, Morano MI, Young EA, Watson SJ, Akil H. Diurnal CRH mRNA rhythm in the hypothalamus: decreased expression in the evening is not dependent on endogenous glucocorticoids. Neuroendocrinology 1993;57(1):96–105. 41. Daikoku S, Yokote R, Aizawa T, Kawano H. Light stimulation of the hypothalamic neuroendocrine system. Arch Histol Cytol 1992;55(1):67–76.

Physiology of the HPA Axis

29

42. Czeisler CA, Klerman EB. Circadian and sleep-dependent regulation of hormone release in humans. Recent Prog Horm Res 1999;54:97–130; discussion 130–2. 43. Deuschle M, Weber B, Colla M, Muller M, Kniest A, Heuser I. Mineralocorticoid receptor also modulates basal activity of hypothalamus-pituitary-adrenocortical system in humans. Neuroendocrinology 1998;68(5):355–60. 44. de Kloet ER, Oitzl MS, Scho¨bitz B. Cytokines and the brain corticosteroid receptor balance: relevance to pathophysiology of neuroendocrine-immune communication. Psychoneuroendocrinology 1994;19(2):121–34. 45. Dallman MF, Akana SF, Bhatnagar S, Bell ME, Strack AM. Bottomed out: metabolic significance of the circadian trough in glucocorticoid concentrations. Int J Obes Relat Metab Disord 2000; 24(Suppl 2):S40–6. 46. Pollma¨cher T, Mullington J, Korth C, Schreiber W, Hermann D, Orth A, Galanos C, Holsboer F. Diurnal variations in the human host response to endotoxin. J Infect Dis 1996; 174(5):1040–5. 47. Deuschle M, Gotthardt U, Schweiger U, Weber B, Ko¨rner A, Schmider J, Standhardt H, Lammers CH, Heuser I. With aging in humans the activity of the hypothalamus-pituitary-adrenal system increases and its diurnal amplitude flattens. Life Sci 1997;61(22):2239–46. 48. de Kloet ER, Sutanto W, Rots N, van Haarst A, van den Berg D, Oitzl M, van Eekelen. Plasticity and function of brain corticosteroid receptors during aging. 1. Acta Endocrinol (Copenh) 1991;125 (Suppl 1):65–72. 49. Bjo¨rntorp P. Alterations in the ageing corticotropic stress-response axis. Novartis Found Symp 2002;242:46–58; discussion 58–65. 50. Sapolsky R, Armanini M, Packan D, Tombaugh G. Stress and glucocorticoids in. Endocrinol Metab Clin North Am 1987;16(4):965–80. 51. Miller DB, O’Callaghan JP. Effects of aging and stress on hippocampal structure and function. Metabolism 2003;52(10 Suppl 2):17–21. 52. McEwen BS. Sex, stress and the hippocampus: allostasis, allostatic load and the aging process. Neurobiol Aging 2002;23(5):921–39. 53. Traustadottir T, Bosch PR, Matt KS. Gender differences in cardiovascular and hypothalamicpituitary-adrenal axis responses to psychological stress in healthy older adult men and women. Stress 2003;6(2):133–40. 54. Kirschbaum C, Hellhammer DH. Salivary cortisol in psychobiological research: an overview. Neuropsychobiology 1989a;22:150–69. 55. Biondi M, Picardi A. Psychological stress and neuroendocrine function in humans: the last two decades of research. Psychotherapy and. Psychosomatics 1999;68:114–50. 56. Mason JW. A review of psychoendocrine research on the pituitary-adrenal cortical system. Psychosom Med 1968;30(Suppl):576–607. 57. Hennessy MB. Hypothalamic-pituitary-adrenal responses to brief social separation. Neurosci Biobehav Rev 1997;21(1):11–29. 58. Weinberg J, Wong R. Adrenocortical responsiveness to novelty in the hamster. Physiol Behav 1986;37(5):669–72. 59. Gunnar MR, Connors J, Isensee J. Lack of stability in neonatal adrenocortical reactivity because of rapid habituation of the adrenocortical response. Dev Psychobiol 1989;22:221–3. 60. Gunnar MR, Hertsgaard L, Larson M, Rigatusco J. Cortisol and behavioural responses to repeated stressors in the human newborn. Dev Psychobiol 1991;24:487–505. 61. Kirschbaum C, Bartussek D, Strasburger CJ. Cortisol responses to psychological stress and correlations with personality traits. Pers Individ Dif 1992;13(12):1353–7. 62. van Eck M, Berkhof H, Nicolson N, Sulon J. The effects of perceived stress, traits, mood states, and stressful daily events on salivary cortisol. Psychosom Med 1996;58:432–46. 63. Makino S, Hashimoto K, Gold PW. Multiple feedback mechanisms activating corticotropin-releasing hormone system in the brain during stress. Pharmacol Biochem Behav 2002;73(1): 147–58.

30

Helmut Vedder

64. Kudielka BM, Schommer NC, Hellhammer DH, Kirschbaum C. Acute HPA axis responses, heart rate, and mood changes to psychosocial stress (TSST) in humans at different times of day. Psychoneuroendocrinology 2004;29(8):983–92. 65. Miller DB, O’Callaghan JP. Neuroendocrine aspects of the response to stress. Metabolism 2002;51(6 Suppl 1):5–10. 66. Argyropoulos SV, Bailey JE, Hood SD, Kendrick AH, Rich AS, Laszlo G, Nash JR, Lightman SL, Nutt DJ. Inhalation of 35% CO2 results in activation of the HPA axis in healthy volunteers. Psychoneuroendocrinology 2002;27(6):715–29. 67. Kaye J, Buchanan F, Kendrick A, Johnson P, Lowry C, Bailey J, Nutt D, Lightman S. Acute carbon dioxide exposure in healthy adults: evaluation of a novel means of investigating the stress response. J Neuroendocrinol 2004;16(3):256–64. 68. Nye EJ, Grice JE, Hockings GI, Strakosch CR, Crosbie GV, Walters MM, Jackson RV. Comparison of adrenocorticotropin (ACTH) stimulation tests and insulin hypoglycemia in normal humans: low dose, standard high dose, and 8-hour ACTH-(1-24) infusion tests. J Clin Endocrinol Metab 1999;84(10):3648–55. 69. Clark PM, Neylon I, Raggatt PR, Sheppard MC, Stewart PM. Defining the normal cortisol response to the short Synacthen test: implications for the investigation of hypothalamic-pituitary disorders. Clin Endocrinol (Oxf) 1998;49(3):287–92. 70. Dullaart RP, Pasterkamp SH, Beentjes JA, Sluiter WJ. Evaluation of adrenal function in patients with hypothalamic and pituitary disorders: comparison of serum cortisol, urinary free cortisol and the human-corticotrophin releasing hormone test with the insulin tolerance test. Clin Endocrinol (Oxf) 1999 Apr;50(4):465–71. 71. Loriaux DL, Nieman L. Corticotropin-releasing hormone testing in pituitary disease. Endocrinol Metab Clin North Am 1991;20(2):363–9. 72. Reimondo G, Paccotti P, Minetto M, Termine A, Stura G, Bergui M, Angeli A, Terzolo M. The corticotrophin-releasing hormone test is the most reliable noninvasive method to differentiate pituitary from ectopic ACTH secretion in Cushing’s syndrome. Clin Endocrinol (Oxf) 2003;58(6):718–24. 73. Gold PW, Kling MA, Khan I, Calabrese JR, Kalogeras K, Post RM, Avgerinos PC, Loriaux DL, Chrousos GP. Corticotropin releasing hormone: relevance to normal physiology and to the pathophysiology and differential diagnosis of hypercortisolism and adrenal insufficiency. Adv Biochem Psychopharmacol 1987;43:183–200. 74. Holsboer F. Psychiatric implications of altered limbic-hypothalamic-pituitary-adrenocortical activity. Eur Arch Psychiatry Neurol Sci 1989;238(5–6):302–22. 75. Stratakis CA, Chrousos GP. Neuroendocrinology and pathophysiology of the stress system. Ann N Y Acad Sci 1995 Dec 29;771:1–18. 76. Claes SJ. Corticotropin-releasing hormone (CRH) in psychiatry: from stress to psychopathology. Ann Med 2004;36(1):50–61. 77. Schreiber W, Pollma¨cher T, Fassbender K, Gudewill S, Vedder H, Wiedemann K, Galanos C, Holsboer F. Endotoxin– and corticotropin-releasing hormone-induced release of ACTH and cortisol. A comparative study in men. Neuroendocrinology 1993;58(1):123–8. 78. Beishuizen A, Thijs LG. Endotoxin and the hypothalamo-pituitary-adrenal (HPA) axis. J Endotoxin Res 2003;9(1):3–24. 79. Del Rey A, Besedovsky HO. Metabolic and neuroendocrine effects of pro-inflammatory cytokines. Eur J Clin Invest 1992;22(Suppl 1):10–15. 80. Vedder H, Schreiber W, Yassouridis A, Gudewill S, Galanos C, Pollma¨cher T. Dose-dependence of bacterial lipopolysaccharide (LPS) effects on peak response and time course of the immuneendocrine host response in humans. Inflamm Res 1999;48(2):67–74. 81. Chalew S, Nagel H, Shore S. The hypothalamic-pituitary-adrenal axis in obesity. Obes Res 1995;3(4):371–82. 82. Pasquali R, Vicennati V. Activity of the hypothalamic-pituitary-adrenal axis in different obesity phenotypes. Int J Obes Relat Metab Disord 2000;24(Suppl 2):S47–9.

Physiology of the HPA Axis

31

83. Bjo¨rntorp P, Rosmond R. Neuroendocrine abnormalities in visceral obesity. Int J Obes Relat Metab Disord 2000;24(Suppl 2):S80–5. 84. Mastorakos G, Zapanti E. The hypothalamic-pituitary-adrenal axis in the neuroendocrine regulation of food intake and obesity: the role of corticotropin releasing hormone. Nutr Neurosci 2004; 7(5–6):271–80. 85. Chan O, Inouye K, Riddell MC, Vranic M, Matthews SG. Diabetes and the hypothalamo-pituitaryadrenal (HPA) axis. Minerva Endocrinol 2003;28(2):87–102. 86. Prestele S, Aldenhoff J, Reiff J. The HPA-axis as a possible link between depression, diabetes mellitus and cognitive dysfunction. Fortschr Neurol Psychiatr 2003;71(1):24–36. 87. Rosmond R. Stress induced disturbances of the HPA axis: a pathway to Type 2 diabetes. Med Sci Monit 2003;9(2):RA35–9. 88. Born J, Fehm HL. Hypothalamus-pituitary-adrenal activity during human sleep: a coordinating role for the limbic hippocampal system. Exp Clin Endocrinol Diabetes 1998;106(3):153–63. 89. Cespuglio R, Marinesco S, Baubet G, Bonnet C, el Kafi B. Evidence for a sleep-promoting influence of stress. Adv Neuroimmunol 1995;5:145–54. 90. Opp MR. Corticotropin-releasing hormone involvement in stressor-induced alterations in sleep and in the regulation of waking. Adv Neuroimmunol 1995;5:127–43. 91. Steiger A. Sleep and the hypothalamo-pituitary-adrenocortical system. Sleep Med Rev 2002;6(2):125–38. 92. Chastrette N, Cespuglio R, Jouvet M. Proopiomelanocortin POMC-derived peptides and sleep in the rat: Part 1. Hypnogenic properties of ACTH derivatives. Neuropeptides 1990;15:61–74. 93. Young AH, Sharpley AL, Campling GM, Hockney RA, Cowen PJ. Effects of hydrocortisone on brain 5-HT function and sleep. J Affect Disord 1994;32(2):139–46. 94. Marshall L, Born J. Brain-immune interactions in sleep. Int Rev Neurobiol 2002;52:93–131. 95. Schuld A, Haack M, Hinze-Selch D, Mullington J, Pollma¨cher T. Experimental studies on the interaction between sleep and the immune system in humans. Psychother Psychosom Med Psychol 2005;55(1):29–35. 96. Ohl F, Michaelis T,Vollmann-Honsdorf GK, Kirschbaum C, Fuchs E. Effect of chronic psychosocial stress and long-term cortisol treatment on hippocampus-mediated memory and hippocampal volume: a pilot-study in tree shrews. Psychoneuroendocrinology 2000;25(4):357–63. 97. Mu¨ller MB, Landgraf R, Keck ME. Vasopressin, major depression, and hypothalamic-pituitaryadrenocortical desensitization. Biol Psychiatry 2000 15;48(4):330–3. 98. Steckler T, Holsboer F. Corticotropin-releasing hormone receptor subtypes and emotion. Biol Psychiatry 1999 1;46(11):1480–508. 99. Calogero AE, Gallucci WT, Chrousos GP, Gold PW. Interaction between GABAergic neurotransmission and rat hypothalamic corticotropin-releasing hormone secretion in vitro. Brain Res 1988 25;463(1):28–36. 100. Brentano ST, Picado-Leonard J, Mellon SH, Moore CCD, Miller WL. Tissue-specific, cAMPinduced, and phorbolester repressed expression from the human P450c17 promoter in mouse cells. Mol Endocrinol 1990;4:1972–9. 101. de Kloet ER, Oitzl MS, Joels M. Functional implications of brain corticosteroid receptor diversity. Cell Mol Neurobiol 1993;13(4):433–55. 102. Oitzl MS, van Haarst AD, de Kloet ER. Behavioral and neuroendocrine responses controlled by the concerted action of central mineralocorticoid (MRS) and glucocorticoid receptors (GRS). Psychoneuroendocrinology 1997;22(Suppl 1):S87–93. 103. Martens ME, Peterson PL, Lee CP. In vitro effects of glucocorticoid on mitochondrial energy metabolism. Biochim Biophys Acta 1991 17;1058(2):152–60. 104. Sapolsky RM. Potential behavioral modification of glucocorticoid damage to the hippocampus. Behav Brain Res 1993 30;57(2):175–82. 105. de Kloet ER, Sutanto W, Rots N, van Haarst A, van den Berg D, Oitzl M, van Eekelen A, Voorhuis D. Plasticity and function of brain corticosteroid receptors during aging. Acta Endocrinol (Copenh) 1991;125(Suppl 1):65–72.