Neuroendocrine Responses to Stress

GR Sridhar, Endocrine and Diabetes Centre, Visakhapatnam-530002

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'The ass endures the load, but not the overload' (Cervantes)
'There are indeed specific human virtues, but they are those necessary to existence, like patience and courage. Supported on these indispensable habits, mankind always carries an indefinite load of misery and vice' (George Santayana)

Stress has been defined as 'distress caused by demand on physical or mental energy'. In other words it is a specific response of the body to all non -specific demands, and is described as occuring when problems presented by life exceed ones resources for coping with them. Although stress is generally associated with negative connotations, it is a double edged phenomenon. The body would not be able to survive without the acute stress response, as in the 'fight or flight' phenomenon, and acute blood loss. However it is chronic persisting stress, rather than acute stress, that it is believed to be harmful (1). A variety of neurohormonal alterations mediate the effects of chronic stress, and form the subject of this presentation. Medical doctors are exposed to stress, which affects their personal health and indirectly, jeopardises that of their patients (2,3,4). Both junior doctors and consultants are stressed, which may be relieved by improving their job satisfaction (4).

Hormonal responses to acute stress

The hormonal responses to acute stress are well recognised (5). They modulate fuel use and in the initial phase of the critical illness, which is a catabolic phase, counterregulatory hormones such as glucagon, growth hormone, corticosteroids and catecholamines suppress insulin secretion. Peripheral insulin resistance assures glucose availability for insulin-insensitive tissues, and simultaneously promotes protein degradation; gluconeogenic amino acids are thus made available. The counteregulatory hormones sustain hepatic glucose production (5).

Hormonal responses to chronic stress: an overview

In addition to increased secretion of cortisol from the adrenal cortex, catecholamines from the adrenal medulla, and the anterior pituitary products growth hormone and prolactin (6), persons with Type A personality were shown to have an inverse relation with the adrenal secretion of dehydroandrosterone sulfate.

Elevated cortisol levels in association with chronic stress could lead to adverse cardiovascular events (1). Maladjustment to chronic stress may be associated with neuroendocrine dysfunction and upper body obesity, which is a risk factor for coronary artery disease (7). Similarly, response to stress may be related to reproductive hormones in women (8).

Good stress and bad stress

In short, the response to acute stress is good, often life-saving. However, lingering stress response to unremitting silent stress is bad and leads to chronic diseases alluded to earlier.

Stress activates the autonomic nervous system: the sympathetic nerves regulate the fight-or-flight response. The cerebral cortex activates the sympathetic nervous system, preparing the body for immediate action. Simultaneously, the adrenal medulla secretes the stress hormones, epinephrine and norepinephrine, all of which together, increase the blood presssure, the heart rate and divert the blood away from the gastrointestinal tract to the skeletal muscles. The metabolic rate increases along with oxygen consumption. Meanwhile, the adrenal cortical hormone cortisone levels rise, leading to high blood glucose, as part of the fight-or-flight response (9).

This response gears one up for action. It gives concentrated energy either to run away from danger, or to stand the ground and fend off danger. It was certainly useful, indeed life-saving when such reactions were an integral part of life, many thousands of years ago. The stress hormones saved the life, and were consumed in the process.

However, the kind of stress we face now is of a totally different kind. Such physical responses are rarely needed, yet the brain perceives stress as such and prepares the body for fight-or-flight. Only, the stress hormones are not dissipated and they stay in the bodies, leading to bodily damage.

Stress response at the hypothalamus

The exact central pathways of stress activation are not clearly known. Multiple ACTH secretagogues are released from the hypothalamus, the most important ones among them being corticotropin releasing hormone (CRH) and arginine vasopressin (AVP) (10). Endogenous depression is associated with elevated levels of cortisol.

Corticotropin releasing hormone (CRH) in stress

CRH, though the major regulator of pituitary ACTH secretion, shares the role with arginine vasopressin, catecholamines, angiotensin II and oxytocin. Other CRH secretagogues include serotonin, acetylcholine, and neuropeptide Y; inhibitory systems are the GABA/ benzodiazepine (11). The components of the stress system are central--hypothalamic CRH neuron in the paraventricular nucleus, and peripheral--locus coeruleus (LC), sympathetic system in the brainstem (12). The two are connected anatomically and functionally. CRH stimulates the locus coeruleus, which in turn is stimulated by brainstem norepinephrine (NE).

CRH and NE are both inhibitory to their own secretion. The CRH neuron and the LC receive stimulatory cholinergic and serotonergic innervation as well as inhibitory opioid peptiergic and gabaergic influences. Most opioid peptides inhibiting CRH originate from arcuate nucleons neurons. Glucocorticoids inhibit the activity of the CRH neuron and the sympathetic system centre. Vasopressin, a peptide of passive coping, that synergizes with CRH (13) is an important component of this system, interacts centrally through adrenergic receptor activation in the peripheral and visceral afferents to the brain (14). In addition, it also modulates synaptic transmission and thereby modulates various brain functions such as in ethanol addiction (15).

Glucocorticoids and stress

Glucocorticoids are the distal arm of the hypothalamic-pituitary-adrenal axis, and are essential, along with adrenal medullary catecholamines in responding to stress (16). As mentioned earlier, they increase glucose production, increase hepatic glycogen deposition, promote lipolysis and promote protein metabolism. In addition they also suppress the immune and inflammatory response.

Interactions of HPA axis and other neuroendocrine systems

Activation of the stress system inhibits the reproductive axis by inhibition of the LHRH neuron by CRH, beta endorphin and glucocorticoids. Glucocorticoids inhibit pituitary gonadotropin secretion and cause resistance of target tissues to sex steroids. Besides, the system suppresses the growth axis, mainly by suppressing growth hormone secretion and resistance of target tissues to somatomedins. Similarly, the thyroid axis function is also inhibited by activation of the stress system (11).

Role of CRH- glucocorticoids in stress-a consolidated hypothesis

CRH appears to be a CNS 'stimulant' involved in activation of stress response systems. Glucocorticoids appear to have a much more complex role, modulating the responsiveness, effectiveness and termination of these systems (11).

Two types of glucocorticoid receptors occur in the CNS: type I or mineralocorticoid receptor, which responds to low levels of glucocorticoids and is primarily activational. The type II or the classic glucocorticoid receptor responds to higher levels of glucocorticoids and is dampening in some and activational in others.

The distribution of the two receptor types is distinct, allowing a biphasic response. Thus low CRH and glucocorticoid might increase responsiveness, such as the hippocampus/amygdala complex, to a proper stimulus, such as norepinephrine, and at the same time decrease responsiveness of other systems, such as mesocorticolimbic system, to its major stimulus, dopamine.

Excess and prolonged activation of the stress system, involving increased secretion of CRH and glucocorticoid would stimulate the arousal system and cause tachyphylaxis of the mesocorticolimbic system (11).

Experimental models for chronic stress in humans

What constitutes stress ?

The above examples appear to be stressors, by intution. However, intution can often be just that -- intution, and not the truth is often proved by rigorous studies. Academic stress before the examination appears to be an undoubted chronic stressful condition. But, a prospective study of three to four weeks before a major academic examination, in 37 medical students, did not show alterations of serum growth and prolactin levels, as surrogates for stress (23). Thus, stressors may affect different hormonal systems variably, and proper selection criteria of what to study is necessary.

the hypothalamic-pituitary-adrenal cortical axis in mental disorders

Enormous data is being generated on endocrine correlates of mental illness. The field of psychoneuroendocrinology reminds us that control of endocrine glands rests not just on hormones, but also on other brain regions (24).

Major affective disorders such as major depression, anorexia nervosa and panic and obsessive-compulsive disorders, are associated with aberrations in the hypothalamic centers that control appetite, libido, and the synthesis and release of hypothalmic hormones (22).

Affective illness may be associated with diminished cerebrospinal fluid concentrations of somatostatin and arginine vasopressin, blunted secretion of growth hormone and reduced responses of TSH to TRH.

The most well documented abnormality is in patients with major depression, many of whom show hyperactivity of the hypothalamic-pituitary-adrenal axis. The propable reason is an abnormality of the central nervous system leading to hypersecretion of hypothalamic CRH. CRH evidently plays a major role in coordinating the endocrine, autonomic, behavioral and immune responses to stress through actions in the brain and in the periphery (22).

Morphological studies in patients with major depression showed the size of the pituitary was greater than in matched controls, suggesting there could be a structural neuroendocrine alteration, responsible for the pituitary-adrenal cortical hyperactivity. (25).

Integrated neuroendocrinal reaction to stress--the Bjorntorp's hypothesis

Bjorntorp hypothesised that both sympathetic nervous system overactivity and the cluster of steroid hormone abnormalities are responses to stress. The arousal along both axes are elicited at the hypothalmus. Different reactions to stress are well established in animal research, viz the defence reaction, in which sympathetic nervous system attempts to regain control by increasing the readiness of circulatory system and mobilising substrate to meet the challenge. The defeat reaction results when the individual loses control and ends in a submissive mode, which is associated with activation of CRF-ACTH-cortisol axis and low gonadal hormone levels. Both these reactions were shown to be associated with central deposition of adipose tissue in animals, and with metabolic aberrations including insulin resistance (26). Such reactions have not been unequivocally shown in humans, but indirect evidence suggests they could occur, and be responsible for the metabolic alterations associated with exposure to chronic stress.

Fat deposition around the abdomen, or trunkal obesity is a risk factor for many of modern day ills, including hypertension, diabetes mellitus, coronary artery disease, and carcinoma of breast and endometrium (the last in women) (27).

Earlier, it was shown that women with excess abdominal fat excreted excessive amounts of cortisol in the urine, and had greater serum cortisol response to ACTH administration. In addition, cortisol response to stress was correlated with sagital abdominal diameter (28). As an extension to this work, women with abdominal obesity were reported to have hyperactivity of the hypothalamic -pituitary-adrenal axis, either centrally or due to functional cortisol resistance (29). It is evident that stress responses of the hypothalamic pitutary adrenal axis are controlled independently of the mechanisms that control the normal circadian rhythm of the system (27). Excessive stress responses may result from persistent environmental or psychogenic stimulation (30), without impairing normal feedback control.

Melatonin, the mother of all stress hormones ?

Melatonin is the principal secretory hormone of the pineal, a small gland situated between the two cerebral hemispheres, just above the 3rd ventricle. The two established roles of melatonin are in setting the biological clock and in reproduction, the latter especially in animals (28). There has been an explosion of information about the role of melatonin as a modulator of aging (Ann New York Acad Sci vol 719, 1994; 'The aging clock', eds Pierpaoli W, Regelson W, Fabris N), followed by publications in the lay press (The Melatonin Miracle, Pocket Books, 1995, by the same editors). However, as of now, there is no unequivocal evidence that melatonin has significantly advantageous role, except in circadian rhythm and reproduction in animals (29)

In conclusion

Stress is ubiquitous, and response to stress is life-saving in acute situations. There is a complex interplay of higher neural centres, the endocrine system, and the immune system in responding to stressful conditions. The important aspect about stress is the emotional style with which one perceives it and copes with it. There is perhaps a biological basis in the adage 'what cannot be cured must be endured.' It is the quality of endurance that determines whether ones health is made or broken (1).


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