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Adrenocorticotropin (ACTH)- and Non-ACTH-Mediated Regulation of the Adrenal Cortex: Neural and Immune Inputs

Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Stefan R. Bornstein, M.D., National Institute of Child Health and Human Development, National Institutes of Health, Building 10, Room 10N242, 10 Center Drive, Bethesda, Maryland 20892.

	Introduction

Top Introduction Innervation of the adrenal... Interactions between the adrenal... How do adrenomedullary secretory... Immune-adrenal interactions An adrenal view of... Does non-ACTH-mediated... Does non-ACTH-mediated... Does the extrapituitary... Can we distinguish the... Perspectives References

 
The maintenance of life depends on the capacity of the body to sustain its steady state or homeostasis; hence, the survival of the organism relies on its ability to react and adapt to the constant bombardment by physical and emotional threats or stressors (1, 2). To accomplish this, all living beings have developed an efficient but complex adaptive response system that allows the integration of the necessary defense mechanisms directed against both external and internal stressors. This coordinated response, the stress response, involves the nervous, endocrine, and immune systems. A qualitatively and quantitatively appropriate and time-limited stress response is a prerequisite for a healthy life. Inappropriate or inappropriately excessive and chronic hyperactivation of the stress system may lead to disease and, eventually, premature death.

The two major peripheral limbs of the stress system are the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (1, 2). Their central components are, respectively, located in the hypothalamus and the brain stem. Stress-induced activation of the HPA axis is associated with release of hypothalamic CRH and vasopressin (AVP), the principal regulators of anterior pituitary corticotropin (ACTH) secretion, into the hypophyseal portal system. These hormones synergistically stimulate systemic ACTH secretion, which, in turn, stimulates the adrenal cortexes to secrete glucocorticoids. Central activation of the sympathetic neurons leads to activation of both the systemic sympathetic nervous system and, through the splanchnic nerves, the adrenal medullae (3). As the proper functioning of both the HPA axis and the sympathetic nervous system is crucial for survival and maintenance of health, it is not surprising that their regulation is developmentally plastic and complex, multilevel, and redundant. The regulation and central interaction of the HPA axis and the sympathetic nervous system and the immune system have been extensively studied and summarized in recent review articles (1, 3, 4, 5). The purpose of this brief review is to outline and discuss recent advances in the interactions and regulation of the adjacent peripheral limbs of the stress system, particularly the adrenal cortex and medulla, and to point out their implications for clinical endocrinology (Fig. 1).

View larger version (33K): [in this window] [in a new window]   Figure 1. ACTH- and non-ACTH-mediated regulation of the adrenal cortex: neural and immune inputs.

The adrenal gland, as the end organ of the human stress system, reacts with the above changes in many clinical situations that involve severe or chronic stress. Subacute or chronic stress, for example major surgery, or lingering affective disorders, chronic infections, and chronic autoimmune diseases are frequently associated with adrenal alterations (16). Only recently it became evident that in these states, dissociation between central activation of the HPA axis and the adrenal cortex may occur (7, 17). Thus, frequently, ACTH levels do not correspond to the chronically elevated concentrations of glucocorticoids and the hypertrophy/hyperplasia of the adrenal gland. This dissociation cannot be explained by the different half-lives of the pituitary and adrenal hormones and suggests a reset of the HPA axis and/or the presence of extrapituitary mechanisms of adrenal regulation.

Mounting evidence in recent years suggests that the interaction of the two ontogenetically different parts of the adrenal gland, the cortex and the medulla, is not a one-way street but, rather, a bidirectional phenomenon that also receives input from the nervous and immune systems (Fig. 1) (17, 18). The influence of the adrenal cortex on the adrenal medulla and on the expression of catecholamine biosynthetic enzymes and synthesis has been well characterized in vitro (19) and in vivo (20). On the other hand, the influence of the sympatho-adrenomedullary system on adrenocortical functions includes the diurnal variation of adrenal steroidogenesis, which depends on the integrity of sympathetic innervation (for review, see Refs. 21, 22). Also, neural inputs seem to mediate compensatory growth in the remaining adrenal after unilateral adrenalectomy (23). The sympatho-adrenomedullary system produces these effects on the adrenal cortex in part by increasing sensitivity to ACTH. Indeed, splanchnic nerve stimulation enhanced the production of glucocorticoids in response to ACTH, whereas sectioning of both splanchnic nerves in calves decreased adrenocortical sensitivity to ACTH (24). In recent experiments in isolated perfused pig adrenal glands with intact splanchnic innervation, steroidogenesis was stimulated independently of ACTH through electrical activation of the sphlanic nerves and, hence, the sympathoadrenomedullary system (25, 26, 27, 28). Therefore, this ganglion turned gland in the middle of the steroid-producing endocrine gland appears to be intimately involved in the regulation of adrenocortical function in mammals.

	Innervation of the adrenal cortex

Top Introduction Innervation of the adrenal... Interactions between the adrenal... How do adrenomedullary secretory... Immune-adrenal interactions An adrenal view of... Does non-ACTH-mediated... Does non-ACTH-mediated... Does the extrapituitary... Can we distinguish the... Perspectives References

 
Neuroendocrine regulation of the adrenal zona fasciculata may depend on neurotransmitters released from nerve endings that originate from two different sources but terminate in the adrenal cortex (22, 29). Some of these nerves have their cell bodies outside the adrenal gland and reach the cortex with the blood vessels; these are quite independent from the splanchnic nerves. Other neurons originate in cell bodies from within the adrenal medulla and may be regulated by splanchnic nerve activity. These adrenal nerves are mainly catecholaminergic and peptidergic, storing the catecholamines dopamine, epinephrine, and norepinephrine and a wide variety of neuropeptides, including opioid peptides, calcitonin gene-related peptide, neuropeptide Y, vasoactive intestinal polypeptide (VIP), CRH, and substance P (6, 17). These neurotransmitters and neuropeptides have been shown to modulate adrenocortical function (Table 1).

	Interactions between the adrenal medulla and cortex

Top Introduction Innervation of the adrenal... Interactions between the adrenal... How do adrenomedullary secretory... Immune-adrenal interactions An adrenal view of... Does non-ACTH-mediated... Does non-ACTH-mediated... Does the extrapituitary... Can we distinguish the... Perspectives References

As mentioned above, adrenomedullary chromaffin cells also produce, store, and secrete a whole host of neuropeptides, including CRH, enkephalins, calcitonin gene-related peptide, neuropeptide Y, neurotensin, galanin, substance P, AVP, oxytocin, VIP, somatostatin, PACAP, and POMC-derived peptides (for review, see Ref. 17). In the normal human adrenal, catecholamines have no major effect on adrenal steroidogenesis, whereas several neuropeptides produced in the adrenal medulla, such as VIP, PACAP, ANP, and vasopressin regulate adrenocortical steroid production. Finally, the adrenal medulla and intraadrenal immune cells are a source of extrahypothalamic CRH and extrapituitary ACTH (17). ACTH immunoreactivity was demonstrated in extracts of human adrenals and in the adrenal venous effluent of hypophysectomized calves in response to splanchnic stimulation (31). Therefore, local ACTH, possibly in response to local CRH, may stimulate adrenal cortisol production in the absence of pituitary ACTH. Nevertheless, local ACTH plays only a minor role in the up-regulation of basal cortisol release in bovine cortico-chromaffin cell cocultures (32).

Coculture systems of bovine adrenomedullary chromaffin with adrenocortical cells have now supplied direct evidence for the paracrine influence of chromaffin cells on adrenocortical cells. In these systems, medullary and adrenocortical cells are separated by semipermeable membranes. We demonstrated that secretory products released from chromaffin cells under basal conditions were potent stimulators of adrenocortical steroidogenesis; this stimulatory effect was independent of a direct cell-cell contact (32).

	How do adrenomedullary secretory products reach the adrenal cortex?

Top Introduction Innervation of the adrenal... Interactions between the adrenal... How do adrenomedullary secretory... Immune-adrenal interactions An adrenal view of... Does non-ACTH-mediated... Does non-ACTH-mediated... Does the extrapituitary... Can we distinguish the... Perspectives References

 
The accepted textbook view holds that the two different components of the adrenal gland are clearly separated in an outer steroid-producing cortex and a central medulla with blood circulation directed centripetally (33). However, this concept is not supported by the morphological characteristics of this organ. In fact, the adrenal medulla and cortex are significantly interwoven in many mammals, including humans. Indeed, adrenomedullary chromaffin cells can be found in all zones of the adult adrenal cortex. Some form ray-like structures stretching from the adrenal medulla through the entire cortex (14, 34, 35). Others form small islets or are simply dispersed in the zona fasciculata and reticularis, fully surrounded by steroid-producing cells. In the zona glomerulosa, chromaffin cells spread frequently into the capsular region, forming subcapsular nests of cells (34, 35, 36).

The presence of adrenomedullary chromaffin cells in the adrenal cortex may be explained on the basis of the embryologic development of the adrenal gland. In humans, chromaffin precursor cells start to invade the adrenal primordium from the outside at the sixth week of embryonic life (37); thus, chromaffin cells located in the cortex probably discontinued their migration toward the future medulla before they reached the center of the gland. On the other hand, some adrenocortical cells are located within the adrenal medulla, suggesting that they extended their migration from the subcapsular region inward. Besides a small number of adrenocortical cells surrounding the greater vessels, isolated accumulations of such cells are found within the adrenomedullary chromaffin tissue, whereas other accumulations are connected to the adrenal cortex; in some cases, the human adrenal medulla appears to be peppered with cortical cells (38); interestingly, in the human adrenal, these adrenocortical islets are composed of cells from all three cortical zones (39). Ultrastuctural analyses of the contact areas in all three zones of the adrenal cortex revealed that adrenocortical and adrenomedullary chromaffin cells were posed next to each other without separation by connective tissue or an interstitial membrane (36, 38, 40, 41); this intimate intermingling of the two cell types allows extensive contact for paracrine and juxtacrine interactions (18).

In addition to a direct paracrine action, some adrenomedullary secretory products may reach the adrenal cortex via interstitial fluid and lymphatics, as has been shown in the cat adrenal. Small molecules, such as catecholamines, appear to enter the blood vessels directly and therefore can only influence adrenocortical cells that are in direct contact with the producing chromaffin cell. Larger molecules, such as neuropeptides and proteins, may cross into and from the lymph, reaching adrenocortical cells (42).

	Immune-adrenal interactions

Top Introduction Innervation of the adrenal... Interactions between the adrenal... How do adrenomedullary secretory... Immune-adrenal interactions An adrenal view of... Does non-ACTH-mediated... Does non-ACTH-mediated... Does the extrapituitary... Can we distinguish the... Perspectives References

 
Immune cells, including macrophages, monocytes, dendritic cells, mast cells, and lymphocytes, are located within the adrenal cortex of rodents and humans. Resident macrophages are mostly located in the inner adrenocortical zone and express tumor necrosis factor- (TNF) (43), interleukin-1 (IL-1) (44), IL-6 (45), and transforming growth factor-ß (46) when activated. These cytokines may differently influence adrenal function by exerting stimulatory and/or inhibitory effects (47, 48). Similarly, circulating leukocytes and lipopolysaccharide-stimulated macrophages respectively stimulate or inhibit glucocorticoid biosynthesis by human or rabbit adrenocortical cells and may participate in a local immune-adrenal regulation. Lymphocytes may also be found in the inner cortical layers in a focal manner; these foci are observed in childhood (49), and their number increases with age (50). They mostly belong to the compartment of CD4-positive cells and express IL-2 receptors. As cells of this phenotype produce a variety of cytokines, it is likely that these cells are also an important source of cytokines in the adrenal gland. Finally, lymphocytic infiltration of adrenal tissue has been noted in histological sections of the adrenals of some patients with adrenal Cushing’s syndrome (51, 52).

Adrenocortical cells themselves are able to synthesize several cytokines. Similarly to macrophages within the adrenal, they contain TNF (43), IL-1 (44), and IL-6 messenger ribonucleic acid (53). The distribution of this expression varies in a species-specific manner; in rats, high amounts of cytokines have been detected in the zona glomerulosa (47), whereas in humans, the main site of cytokine production is the inner zona reticularis (43, 44, 53). Studies in mice and rats indicated that potent activators of hormone synthesis in the adrenal cortex, such as angiotensin II (47) and ACTH (47), induce IL-6 secretion in the adrenal cortex, whereas TNF release is inhibited by ACTH (47). The recent discovery of migration inhibitory factor expression in the rat adrenal may provide an explanation for the ability of adrenal lymphocytes and steroid-secreting cells to synthesize and secrete these inflammatory cytokines in the presence of high local production of glucocorticoids (54). Migration inhibitory factor, a natural counterregulatory hormone for glucocorticoid action, could override the immunosuppressive effects of steroids on cytokine production and cellular activation.

Most of the cytokines shown to be produced in the adrenal cortex are able to exert direct effects on adrenocortical cells (47, 48) (Table 1). These include effects on growth and differentiation of the adrenocortical cells and changes in adrenocortical steroidogenesis. Particularly, the inflammatory cytokines TNF, IL-1, and IL-6 all seem to play a role in local immune-adrenal regulation. IL-1 induced corticosteroid biosynthesis in vivo independently from ACTH and caused glucocorticoid secretion in hypophysectomized rats (55), perfused rat adrenals (56), and dispersed human adrenal cells (57). IL-6 stimulated corticosterone release from rat adrenocortical cells alone and in synergy with ACTH, an effect probably mediated and amplified by PGs (58). Recombinant human IL-6 also increased the secretion of cortisol and adrenal androgens in humans both via ACTH and directly. Expression of the IL-6 receptor on steroid-producing cells was demonstrated (45).

TNF inhibited the secretion of aldosterone from rat adrenal cells (59), whereas in human fetal adrenal cells, it decreased both basal and ACTH-stimulated cortisol production. In the latter cell system, it caused a shift toward androgen synthesis (60). TNF- and interferon- both inhibited the expression of insulin-like growth factor I, a factor that potentiates steroidosynthesis in human fetal adrenals (61).

	An adrenal view of stress regulation

Top Introduction Innervation of the adrenal... Interactions between the adrenal... How do adrenomedullary secretory... Immune-adrenal interactions An adrenal view of... Does non-ACTH-mediated... Does non-ACTH-mediated... Does the extrapituitary... Can we distinguish the... Perspectives References

 
Although the differential regulation between the systemic sympathetic and adrenomedullary components of the sympathetic nervous system has been well recognized (3, 62), the differential regulation of the adrenal cortex by ACTH- or non-ACTH-mediated mechanisms has yet to be defined. The following questions have been raised regarding this theme. 1) As hypophysectomy leads to adrenal atrophy and ACTH to restoration of adrenal glucocorticoid secretion, does non-ACTH-mediated regulation of the adrenal cortex have any biological relevance? 2) Does non-ACTH-mediated regulation occur in physiological situations, or is it only a mechanism activated in certain severe or chronic states or diseases? 3) Is non-ACTH-mediated regulation an exclusive or additive pathway of adrenal regulation? 4) Finally, can we distinguish between the different components of this regulation of the HPA axis by specific tests, and would such tests be useful in the understanding, diagnosis, and treatment of human disease?

	Does non-ACTH-mediated regulation of the adrenal cortex have physiological relevance?

Top Introduction Innervation of the adrenal... Interactions between the adrenal... How do adrenomedullary secretory... Immune-adrenal interactions An adrenal view of... Does non-ACTH-mediated... Does non-ACTH-mediated... Does the extrapituitary... Can we distinguish the... Perspectives References

 
Pituitary ACTH is the primary regulator of glucocorticoid secretion by fetal and adult adrenal glands. However, there is compelling evidence for non-ACTH factors playing a significant role in adrenal responses to stressful stimuli in fetal and early life (21). In prolonged hypoxemia in the fetal sheep, the elevated cortisol concentrations were independent from ACTH and dependent on the splanchnic innervation of the gland (21). Similarly, carotid sinus nerve dissection delayed the rise in plasma cortisol in response to acute hypoxemia without affecting the ACTH response (63). Hypothalamic-pituitary disconnection of the late gestation ovine fetus resulted in profound changes in cortisol secretion, which were not reflected in commensurate changes in ACTH secretion (64). When pituitary POMC cells were eliminated by ablation in transgenic mice, thus removing circulating ACTH during the first 3 weeks of postnatal life, there was no discernible difference in adrenocortical morphology between the mice that had no pituitary POMC cells and the controls (65). These results suggested that during this period, the trophic and regulatory stimuli contributing to normal adrenal function were largely independent from pituitary ACTH. In fact, the so-called adrenal-hyporesponsive period in postnatal life (65, 66, 67, 68, 69, 70) is most likely an ACTH-hyporesponsive period.

The cellular mechanisms involved in the neural to ACTH regulation switch that occurs early in life are unclear at this point. If these animal data have any relevance to humans, the answer to the first question is in support of a general physiological relevance for non-ACTH-mediated regulation of the adrenal cortex, especially during early life, under both physiological and pathological conditions. It will be intriguing to redefine the role of ACTH during the early phases of life in human fetuses and young infants. Recent findings obtained in healthy adults may suggest a dissociation of ACTH and cortisol secretion during certain sleep stages (70A ).

	Does non-ACTH-mediated regulation of the adrenal cortex play a role in clinical situations?

Top Introduction Innervation of the adrenal... Interactions between the adrenal... How do adrenomedullary secretory... Immune-adrenal interactions An adrenal view of... Does non-ACTH-mediated... Does non-ACTH-mediated... Does the extrapituitary... Can we distinguish the... Perspectives References

 
In many clinical situations, there is a dissociation between plasma ACTH concentrations and cortisol secretion in humans (17) that cannot be explained by the different metabolic kinetics of these hormones (Table 2). To begin with, suppression of ACTH secretion with dexamethasone did not prevent a rise in plasma cortisol in response to surgical stress, whereas it did in the stress of exercise (17, 71). Furthermore, in postoperative patients and in patients with bacterial sepsis and in the chronic severe illness of late stage human immunodeficiency virus disease, persistently elevated cortisol levels were accompanied by low or normal plasma ACTH values (17, 72, 73, 74, 75). The same phenomenon was observed in cancer patients who received up to seven daily injections of human recombinant IL-6 (76, 77). Similarly, in depressed patients with enlarged adrenals and cortisol hypersecretion, the ACTH levels are normal, and their response to exogenous CRH blunted (78, 79). In atypical depression, frequent sampling of ACTH and cortisol revealed a dissociation of the hormone profiles that occurred periodically within days (80). A dissociation also occurred in patients with diabetes mellitus; mild chronic hypercortisolism in diabetic patients was accompanied by a diminished ACTH response to metyrapone (81).

In this context, it is intriguing that various forms of stress that activate the adrenomedullary system, such as hypoxemia (62), chronic inflammatory or metabolic stress, and affective disorders (3), are also implicated in non-ACTH-mediated increases in adrenocortical function.

	Does the extrapituitary-adrenocortical stress response constitute an exclusive or additive pathway?

Top Introduction Innervation of the adrenal... Interactions between the adrenal... How do adrenomedullary secretory... Immune-adrenal interactions An adrenal view of... Does non-ACTH-mediated... Does non-ACTH-mediated... Does the extrapituitary... Can we distinguish the... Perspectives References

 
In nonmammalian species, such as birds and amphibians, ACTH does not play a crucial role in maintaining adrenocortical function and local paracrine mechanisms can fully replace ACTH regulation of adrenocortical steroidogenesis. In rodents, non-ACTH mediated mechanisms can preserve adrenal function in fetal and early postnatal life to a certain extent (65). However, in adult mammalian organisms, loss of ACTH clearly leads to adrenal atrophy, and the presence of ACTH is required for maintenance of normal adrenocortical function.

Extrapituitary regulation of adrenocortical function, however, may be responsible for maintaining a basal small reserve of cortisol production in adults, as frequently observed in hypophysectomized patients. Also, based on a substantial body of experimental data in various animal models, the innervation of the adrenal is important for maintaining a normal circadian rhythm, adrenal zonation, fine tuning of glandular secretion, and compensatory adrenal growth after unilateral adrenalectomy (17, 18, 23). The latter is particularly striking, because, contrary to what is generally believed, ACTH blocks adrenocortical cell division and reduces cell size when applied to isolated adrenal cells (85). Interestingly, it was recently recognized that corticosterone secretion had a peak preceding the elevation of ACTH induced by immobilization stress (86). As the sympathetic nervous system responds earlier than the HPA axis to stressors, it is possible that the phase advance of the corticosterone response over that of ACTH is explained by an earlier splanchnic nerve stimulation of the adrenal cortex.

In acute stress situations, the body activates all three levels of the HPA axis, and an acute increase of ACTH is followed and accompanied by an increase in cortisol. In severe forms of stress, such as major trauma, extensive surgery, acute sepsis, or hemorrhage, the human body can increase its ACTH-mediated adrenal cortisol production 5- to 10-fold (2). This increase is crucial for coping with these severe forms of stress, because we know that such situations are life-threatening for inadequately replaced experimental animals or patients with adrenocortical insufficiency.

Very importantly, the extrapituitary regulation of adrenocortical function comes into major play in chronic forms of stress. Thus, if increased cortisol production needs to be maintained over a prolonged period, ACTH levels return to the normal or low normal range, whereas cortisol levels remain elevated (74, 75, 76, 79). This suggests that extrapituitary mechanisms may assist in the maintenance of high cortisol levels in chronic forms of stress.

This adaptation of the adrenal cortex to chronic stress is reflected by an increase in adrenal size, hypervascularization, and augmentation of the intracellular apparatus necessary for steroidogenesis, i.e. the mitochondria and the smooth endoplasmic reticulum (13). The increase in steroidogenesis after ACTH stimulation is fueled by the use of cholesterol stored in liposomes within the adrenocortical cells, by uptake of cholesterol from the circulation, and by de novo synthesis of cholesterol (14).

Although ACTH stimulates adrenal androgen production, it is well known that ACTH alone is unable to maintain a normal cortisol to androgen ratio (87). In fact, there are many physiological and pathological conditions in which there is a dissociation of adrenal androgen and cortisol production. This has been documented during fetal development, the neonatal period, and aging. Dissociation between plasma adrenal androgens and cortisol has been reported in Cushing’s disease (88), in patients receiving steroid replacement (89), in poorly controlled insulin-dependent diabetes mellitus (90), in critical illness, and even in psychological stress (91). In times of chronic or severe illness, steroid synthesis may be diverted from adrenal androgens to glucocorticoids to allow maintenance of high glucocorticoid levels, which are crucial for coping with the illness. The precise mechanisms involved in this dissociation of adrenal androgen and cortisol production have not been identified, and both extraadrenal and intraadrenal factors have been implicated. Extraadrenal non-ACTH factors, such as other pituitary POMC-derived peptides, PRL, and GH, as well as growth factors and cytokines produced locally within the adrenal can regulate adrenal androgen production. A differential regulation of 17,20-desmolase expression, which governs the biosynthesis of ⁵-adrenal androgens through a specific factor has, however, not been convincingly demonstrated as yet.

On the other hand, adrenal androgen-producing cells express major histocompatibility complex class II molecules and Fas receptor (49). It is, therefore, conceivable that in critical illness due to inflammation or infections or in autoimmune disease, activated lymphocytes may trigger a major histocompatibility complex class II/CD95-mediated cell death in the inner zone of the adrenal cortex, which could contribute to the observed reduction of adrenal androgen secretion (for review, see Ref. 16).

Circulating or locally produced IL-6 has the capacity to increase adrenal steroid production chronically but not acutely (45, 92). This cytokine is markedly elevated in situations characterized by chronic inflammatory stress, such as in critically ill patients (93, 94). Although in severe stress of limited duration, for example septic patients, the maintenance of high glucocorticoid production is beneficial and desirable, chronic activation of the extrapituitary-adrenocortical stress system may have devastating side-effects due to chronically elevated glucocorticoid levels. Also, chronic hyperstimulation of the adrenal cortex in conjunction with overexpression of receptors for neuropeptides (95, 96), neurotransmitters (97), or cytokines (51) may lead to adrenal tumor formation and possibly non-ACTH-mediated Cushing’s syndrome in humans.

Thus, it appears that the extrapituitary-adrenocortical stress response was not designed by nature to be an exclusive pathway, but, rather, to be an ancillary regulatory mechanism that participates in the chronic regulation of the adrenal gland.

	Can we distinguish the non-ACTH-mediated response from the ACTH-mediated one by specific clinical testing?

Top Introduction Innervation of the adrenal... Interactions between the adrenal... How do adrenomedullary secretory... Immune-adrenal interactions An adrenal view of... Does non-ACTH-mediated... Does non-ACTH-mediated... Does the extrapituitary... Can we distinguish the... Perspectives References

 
To analyze the role of the extrapituitary-adrenocortical stress response in patients, selective clinical tests should be developed. This is not an easy task, because an in vivo dissection of these highly intertwined systems would be expected to be inherently complex (18). Frequent serial sampling for simultaneous measurement of both plasma ACTH and cortisol levels may reveal dissociation of the two hormones, a phenomenon that we observed in humans using this technique during the postoperative period (73).

A more specific set of tests would be desirable. For this purpose, existing tests could be adapted or combined. Thus, the combination of the insulin-induced hypoglycemia test with dexamethasone suppression may be suited to test the role of the sympathoadrenal regulation of adrenocortical function. Dexamethasone suppression is expected to block pituitary ACTH release induced by CRH and AVP, whereas activation of the adrenal medulla will most likely not be affected as much. A physiological or pathological action of the sympathetic nervous system on adrenocortical cortisol secretion mediated by several medullary products could be studied using such a test. In this context, it is of interest that in transgenic CRH knockout mice, the ACTH release after insulin hypoglycemia was completely blunted, whereas there was still a measurable increase in adrenal corticosterone secretion (98).

Another promising approach would be to employ a combination of CRH receptor type 1 and AVP receptor type 3 antagonists (99). These antagonists should have a greater inhibitory effect on the ACTH- than on the non-ACTH-mediated pathways of adrenocortical regulation.

	Perspectives

Top Introduction Innervation of the adrenal... Interactions between the adrenal... How do adrenomedullary secretory... Immune-adrenal interactions An adrenal view of... Does non-ACTH-mediated... Does non-ACTH-mediated... Does the extrapituitary... Can we distinguish the... Perspectives References

 
Integration of the molecular and physiological data from isolated cell systems of the stress axis has taught us that there is a close link and important interaction among all major components of the stress system, including the endocrine, nervous, and immune systems. An adrenocortical cell deprived of its tissue integrity, of input from the nervous system, and of its intercellular communication with chromaffin, vascular, and immune cells loses its normal capacity to produce glucocorticoids and to adequately respond to the homeostatic challenges of stress (18).

Highlighting the importance of the extrapituitary mechanisms of adrenocortical regulation may be a worthwhile starting point for a more complete analysis of the human stress system in vivo. It is also a call to look at the systems in parallel not only in endocrine disorders, but in all diseases related to stress (1). This should allow us to develop more specific and more efficient diagnostic and therapeutic strategies for such diseases.

Received August 12, 1998.

Revised December 11, 1998.

Accepted December 17, 1998.

	References

Top Introduction Innervation of the adrenal... Interactions between the adrenal... How do adrenomedullary secretory... Immune-adrenal interactions An adrenal view of... Does non-ACTH-mediated... Does non-ACTH-mediated... Does the extrapituitary... Can we distinguish the... Perspectives References

 

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