3. ENDOCRINAL RESPONSE TO STRESS By D. AMIRA AHMED Ghiaty Endocrinology and Geriatric Unit Zagazig Faculty Of Medicine

4. Human respond to stress by activating a wide array of behavioral and physiological responses that are collectively referred to as the stress response. Corticotropin-releasing factor (CRF) plays a central role in the stress response by regulating the hypothalamic-pituitary-adrenal (HPA) axis.

5. The stress response is subserved by: a complex neuroendocrine, cellular and molecular infrastructure, which is located in both the central nervous system and the periphery.

10. Concomitantly, physicaladaptation occurs principally to promote an adaptive 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 intermediate 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.

11. In parallel to the adaptive response, restrainingforces are also activated during stress in order to prevent a potential excessive response of the components of the stress system. The ability of the individual to timely and accurately develop the restraining forces that prevent such an overresponse is equally essential for a successful general adaptive response.

12. 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 maladaptive and contribute to the development of disease.

13. Components of the stress system

14. The central components of the stress system: are located in the hypothalamus and the brainstem and include the parvocellularcorticotropin-releasing hormone (CRH) and arginine-vasopressin (AVP) neurons of the paraventricular nuclei (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) .

15. The peripheral components of this complex system. The peripheral limps of the hypothalamic-pituitary-adrenal (HPA) axis, together with the efferent sympathetic/adrenomedullary system .

17. The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress.

18. HPA axis PVN -ve CRF Cortisol Anterior Pituitary -ve ACTH Adrenal Gland

19. CRF Regulates basal and stress-induced release of pituitary ACTH Detected in cerebral cortex, hypothalamus, anterior pituitary, adrenal glands, testis, ovary, gut, heart, and lungs Three homologus neuropeptides – Urcortin I, Urcortin II, and Urcortin III CRF gene expression can be altered (catecholamines, serotonin, cytokines, glucocorticoids)

20. 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. Crit Care. 2004;8(1) © 2004 BioMed Central, Ltd.

21. 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.

22. CRF-continued CRF R1 Corticotrophs of the anterior pituitary Mediates actions of the HPA axis and anxiety-related behavior CRF R2 Brain and periphery Regulation of feeding behavior and cardiovascular function

24. Hypothalamic-Pituitary-Adrenal axis 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 regulator of the anterior pituitary ACTH secretion . 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.

25. In nonstressful situations, both CRH and AVP are secreted in the portal system in a circadian and highly concordant pulsatile fashion. 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 cortisolsecretory bursts in the general circulation. The circadian release of CRH/AVP/ACTH/cortisol in their characteristic pulsatile manner appears to be controlled by one or more pace makers, whose exact location in the brain is not known in humans. These diurnal variations are perturbed by changes in lighting, feeding schedules, and physical activity, and are disrupted when a stressor is imposed.

26. 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 hypophysealportalsystem, via collateral neuraxon terminals, and into the systemic circulation. In addition, depending on the stressor, angiotensinII, as well as various cytokines and lipidmediatorsofinflammation are secreted and act on hypothalamic, pituitary and/or adrenal components of the HPA axis, mostly to potentiate its activity.

27. The adrenalcortexis the principal target organ of the pituitary-derived circulating ACTH. The latter is the key regulator of glucocorticoid and adrenal androgen secretion by the zonaefasciculata and reticularis, respectively, while it also participates in the control of aldosterone secretion by the zonaglomerulosa. Moreover, there is evidence suggesting that the regulation 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

28. 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. The inhibitory glucocorticoid feedback on the ACTH secretory response acts to limit the duration of the total tissue exposure to ………glucocorticoids, thus minimizing the………… catabolic…………… lipogenic, antireproductive, …………..and immunosuppressive effects of these hormones.

29. Glucocorticoids Reseptors

30. Actions of glucocorticoids Two receptors Mineralocorticoid receptors Hippocampus and sensory and motor nuclei outside the hypothalamus Regulation of basal expression of ACTH, CRF and AVP Glucocorticoid receptors Hypothamic PVN, brainstem catecholaminergic cell groups, amygdala, hippocampus, pituitary Termination of the HPA axis response to stress

31. Actions of glucocorticoids Fetal organ maturation (esp. lungs) Metabolism (stimulates gluconeogenesis) Immune system (anti-inflammatory, immunosuppression) Maintain vascular tone

32. Arginine vasopressin (AVP) 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 modulator of pituitary ACTH secretion. Whereas CRH appears to directly stimulate the ACTH secretion, AVP and other factors, such as angiotensin II, have primarily synergistic or additive effects.

33. 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.

34. POMC Proopiomelanocortin (POMC) Binding of CRF with CRF R1 on corticotrophs Simulation of POMC mRNA synthesis ACTH release

35. 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.

36. 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

37. 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. 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 functions by withdrawing or by increasing its activity, respectively.

38. Sympathetic innervation of peripheral organs is derived from the efferent 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. The preganglionic neurons are primarily cholinergic, whereas the postganglionic neurons release mostly noradrenaline. The sympathetic system activity has an additional humoral contribution 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.

39. 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 neuropeptides and, in some cases, adenosine triphosphate (ATP), nitric oxide, or lipid mediators of inflammation.

40. 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 neurons. 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. Thus, the particular combination of neurotransmitters in sympathetic neurons is strongly influenced by central and local factors, which may trigger or suppress specific genes.

41. Mediators of Homeostasis and Stress Stress mediators, which include the classic neuroendocrine hormones of the stress system, but also several other neurotransmitters, cytokines and growth factors, regulate both basal and threatened homeostasis and might mediate the pathogenesis of dyshomeostasis-related diseases. Pivotal to our understanding of these mediators and their effects on the human organism in health and disease has been the above-mentioned concept of hypothalamic hypophysiotropic factors.

42. Central and Peripheral Effectors The principal, greatly interconnected CNS effectors of the stress system, include the hypothalamic hormones arginine vasopressin (AVP), corticotropin-releasing hormone (CRH), the pro-opiomelanocortin-derived peptides α-melanocyte-stimulating hormone and β-endorphin, and norepinephrine produced in the A1/A2 centers of the brainstem's locus ceruleus and in the central, autonomic nervous system.

43. other ascending aminergic pathways, such as the serotonergic pathways that originate from the midbrain (nuclei raphe) and the posterior hypothalamic histaminergic systems, accompany the locus ceruleus-derived norepinephrine central stress response through secretion of 5-hydroxytryptamine and histamine, respectively.

44. The principal peripheral effectors are glucocorticoids, which are regulated by the hypothalamic–pituitary–adrenal axis, and the catecholaminesnorepinephrine and epinephrine, which are regulated by the systemic and adrenomedullary sympathetic nervous systems. Interestingly, postganglionic sympathetic nerve fibers also secrete CRH, among other substances, whereas both catecholamines

45. stimulate interleukin (IL-) 6 release by immune cells and other peripheral cells via β-adrenergic receptors.Thetargets of all these stress mediators include the executive and/or cognitive, the fear/anger and reward systems, the wake–sleep centers of the brain, the growth, reproductive and thyroid-hormone axes, as well as the gastrointestinal, cardiorespiratory, metabolic, and immune systems.

46. Arousal and Sleep Activation of the stress system stimulates arousal and suppresses sleep;conversely, loss of sleep is associated with inhibition of the stress system. Interestingly, sleep loss is also associated with elevated level of circulating IL-6 in spite of the reduced stimulatory effect of catecholamines on IL-6 secretion; this change possibly results from the concurrently decreased cortisol-mediated inhibition

47. Thermoregulatory center - Temperature Regulation

48. It is well-established that the activation of the LC/NE-noradrenergic and PVN CRH systems by stressors elevates the body core temperature.

49. 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

50. 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 .

51. 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)

52. Growth, Reproduction and Thyroid Function The growth, reproductive and thyroid-hormone axes are inhibited at several levels by stress mediators, whereas estradiol and thyroid hormones stimulate the stress system

53. Reproductive axis The reproductive axis is inhibited at all levels by various components of the HPA axis. CRH suppresses the gonadotropin hormone-releasing hormone (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.

54. 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 several levels

55. 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. 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.

56. On the other hand, the activated estrogen receptor interacts with and, on occasion, potentiates the c-jun/c-fosheterodimer, 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

58. Growth axis The growth axis is also inhibited at many levels during stress . Prolonged activation of the HPA axis leads to suppression of growth hormone secretion and inhibition of somatomedin C (SmC) and other growth factor effects on their target tissues by glucocorticoids , presumably via inhibition of the c-jun/c-fosheterodimer.

59. 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 . In addition to the direct effects of glucocorticoids, which are pivotal in the suppression of growth observed in prolonged stress, increases in somatostatin secretion caused by CRH

60. , with resultant inhibition of growth hormone secretion, have also been implicated as a potential mechanism of stress-related suppression of growth hormone secretion . 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.

61. 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) .

62. 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 suppression 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

64. Metabolism During acute stress, the heart rate and arterial blood pressure are increased, while gluconeogenesis, glycogenolysis, lipolysis and hepatic glucose secretion are stimulated, owing to elevated levels of catecholamines and cortisol

65. 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.

66. In addition to their direct catabolic actions, glucocorticoids also antagonize the beneficial anabolic actions of GH, insulin and sex steroids on their target tissues . 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

67. 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 .

68. 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

70. Gastrointestinal Function During stress, the gastrointestinal system is inhibited at the level of the stomach via the vagus nerve, while being stimulated at the level of the large bowel via the sacral parasympathetic system, which is activated by brainstem-derived norepinephrine

71. 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 . 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) results in selective stimulation of colonic motility

72. . 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 as well as in the stress-induced colonic hypermotility of the irritable bowel syndrome.

73. Interestingly, the colonic contraction in patients 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

75. The Immune System Stress has complex effects on the immune system and influences both innate and acquired immunity. Glucocorticoids and catecholamines influence trafficking and/or function of leukocytes and accessory immune cells and suppress the secretion of proinflammatory cytokines (tumor necrosis factor [TNF], IL-1, IL-6, IL-8 and IL-12), whereas both hormone families induce a systemic switch from a TH1 response (that is, cellular immunity) to a TH2 response (humoral immunity).

76. Conversely, proinflammatory cytokines stimulate the stress system, also at multiple levels, in both the CNS and peripheral nervous system, including the hypothalamus, central noradrenergic system, pituitary and adrenal glands, which increases glucocorticoid levels and consequently suppresses the inflammatory reaction. These actions form another important negative-feedback loop that protects the organism from overshoot of the inflammatory response.

77. Peripheral secretion of 'authentic' CRH (originally described as 'immune' CRH because of its inflammatory actions) by postganglionic sympathetic neurons and norepinephrine-activated release of IL-6 by peripheral immune cells and other cells, respectively, lead to degranulation of mast cells (that is, the release of inflammatory and vasoactive molecules from their secretory vesicles) in several tissues and activates the sickness syndrome

78. The former action represents an important component of the neurogenic inflammatory response, whereas the sickness syndrome results from innate processes of the organism that are triggered and sustained by a systemic, inflammatory reaction. The syndrome includes somnolence, fatigue, nausea and depressive mood; these symptoms occur concurrently with activation of the acute-phase reaction by the liver and stimulation of the sensory-afferent nervous system, which manifests as hyperalgesia and fatigue.

80. The hypothalamic-pituitary-adrenal (HPA) axis is the major endocrine stress axis of the human organism. Cortisol, the final hormone of this axis, affects metabolic, cardiovascular and central nervous systems both acutely and chronically.

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