Review

Dissociation of ACTH and glucocorticoids

Stefan R. Bornstein1, William C. Engeland2, Monika Ehrhart-Bornstein1 and James P. Herman3
1 2

Medical Faculty Carl-Gustav-Carus of the Technical University Dresden, Fetscherstr 74, 01307 Dresden, Germany Department of Neuroscience, Graduate Program in Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA 3 Departments of Psychiatry and Cell Biology, Neurobiology and Anatomy, University of Cincinnati, Reading, OH 45237, USA

It is increasingly clear that signicant differential regulation of pituitary and adrenal gland activation exists, leading to a dissociation of plasma adrenocorticotropic hormone and corticosteroid secretion during fetal, postnatal and adult life. An increasing number of preclinical and clinical studies report dissociation of adrenocorticotropic hormone and cortisol levels in critical illness, inammation and mental disorders. Mechanisms involve an altered adrenal sensitivity, aberrant receptor expression or modulation of adrenal function by cytokines, vasoactive factors or neuropeptides. The degree of dissociation has been associated with the level of complications of sepsis, surgery, malignant disease and depression. The separation of adrenocorticotropic hormone and corticosteroid secretion is of clinical relevance and should be incorporated into our view on endocrine stress regulation. Introduction Adrenal glucocorticoid synthesis and release is regulated by the hypothalamicpituitaryadrenal (HPA) axis (see Glossary). Hypothalamic lesions and the absence of pituitary adrenocorticotropic hormone (ACTH) both lead to adrenal atrophy and adrenocortical insufciency. Based on these clear-cut anatomical, physiological and clinical observations, it has become generally accepted that adrenocortical glucocorticoid secretion is exclusively linked to pituitary ACTH release. However, nature tends to incorporate some redundancy into vitally important systems, and in recent years the picture has become more complex. There are alternative pathways for adrenal glucocorticoid regulation, and relevant physiological and clinical paradigms exist that demonstrate a dissociation between ACTH and glucocorticoid levels. Although the presence of pituitary ACTH is clearly essential for adrenocortical function, ACTH-independent mechanisms seem to have an important role in ne-tuning and modulating the highly sensitive adrenal stress system to adapt its response appropriately to physiological needs. Based on the notion of complete dependence of adrenal cortisol secretion on ACTH, these ACTH-independent mechanisms have not received adequate attention by the endocrine community. There are many potential reasons for a discordance between measured plasma ACTH and cortisol levels at
Corresponding author: Bornstein, S.R. (Stefan.Bornstein@uniklinikum-dresden.de).

any given time point. Biological factors inherent in the functioning of the HPA axis dictate that a dissociation between plasma ACTH and corticosteroids will occur under many physiological and pathophysiological conditions. First, there is a well-characterized temporal lag between stimulus-induced changes in ACTH and in corticosteroid levels [1]. Second, in all species studied, both ACTH and corticosteroids are secreted in a pulsatile or episodic fashion under basal [2,3] and stress conditions [4,5], and this might well occur in nonoverlapping pulses. Additionally, volume of distribution, metabolism and, in the case of corticosteroids, binding to plasma proteins, and also changes in intra-adrenal steroid metabolism and steroidogenic synthetic capacity [6], can affect hormone kinetics differentially [79]. Therefore, even under conditions in which adrenal corticosteroid responses might be governed completely by ACTH stimulation, the timing and frequency of sampling will inuence the apparent delity of the ACTHcorticosteroid relationship. Most studies are not designed to control or account for possible changes in each of these variables. When ACTHcorticosteroid mismatches occur, it is possible that one or more of these biological elements are responsible and that ACTH is the primary driving force for adrenal secretion. However, Glossary
Adrenal gland: this consists of the mesodermally-derived steroid-producing cortex which surrounds the catecholamine-producing medulla, and is derived from the embryonic neural crest. The medulla is innervated by the preganglionic sympathetic splanchnic nerves. This innervation is relevant not only for the regulation of medullary, but also for cortical function. Bed nucleus of the stria terminalis (BST): this stimulates HPA axis responses to acute stress. The BST receives limbic input from the amygdala, hippocampus and prefrontal cortex and has abundant projections to the paraventricular nucleus. It participates in anxiety and stress responses. Hypothalamic paraventricular nucleus: this contains neuroendocrine neurons that synthesize and secrete vasopressin and CRH. These two peptides regulate the anterior lobe of the pituitary gland by stimulating the secretion of ACTH. ACTH: this hormone stimulates glucocorticoid production and secretion (mainly cortisol in humans) from the adrenal cortex. Glucocorticoids feed back on the hypothalamus and pituitary gland to suppress CRH and ACTH secretion. In all species studied, both ACTH and glucocorticoids are secreted in a pulsatile fashion. Hypothalamicpituitaryadrenal (HPA) axis: this is a complex set of direct influences and feedback interactions between the hypothalamus, the pituitary gland and the adrenal gland. The key elements of the HPA axis are the hypothalamic paraventricular nucleus, the anterior lobe of the pituitary gland and the adrenal cortex. Hypothalamic suprachiasmatic nucleus (SCN): this controls endogenous circadian rhythms. The SCN is situated immediately above the optic chiasm on either side of the third ventricle.

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studies in humans that have used deconvolution analysis to account for time lags, pulsatility and hormone kinetics show signicant asynchrony in ACTH and cortisol responses [10], supporting the contention that signals in addition to ACTH have a signicant inuence on cortisol secretion. In recent years, numerous studies have been published, indicating that a large number of neuropeptides, neurotransmitters, opioids, growth factors, cytokines, adipokines and even bacterial ligands are capable of modulating adrenal glucocorticoid release independently of pituitary ACTH [1116] (Figure 1). Adrenocortical cells express a great variety of receptors for these factors, thus enabling potential direct actions on cortisol release. Recent studies have identied additional factors of adipose and endothelial origin that promote the ACTH-independent drive of corticosteroid synthesis [17,18]. Furthermore, adrenocortical cells are in close contact with chromafn cells, nerve endings, and also endothelial and immune cells that synthesize and release factors which can control steroidogenesis. Therefore, ample evidence exists for an extensive intra-adrenal paracrine regulation of adrenocortical release of corticosteroids. These data have been well documented in a series of comprehensive reviews in the past few years [11,19,20]. However, in these reviews the physiological and, to an even lesser extent, the clinical signicance of these ndings, has received little attention. Therefore, here we summarize the current evidence for a dissociation of ACTH and corticosteroid response, the mechanisms involved and their potential clinical relevance.

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Dissociation of ACTH and cortisol under physiological conditions A dual control of the adrenal cortex by pituitary ACTH and by adrenal neural circuitry has been demonstrated by several studies using intact isolated, perfused adrenals or in vivo models [21,22]. It is well known that adrenal innervation is involved in adrenocortical growth [23] and function [24,25] and that splanchnic nerve activation leads to a prompt and prominent release of corticosteroids that synergizes with ACTH to control glucocorticoid release [21,24,26]. In mammalian species, dissociation of ACTH and cortisol levels has been observed during late fetal and early postnatal life, corresponding to the so-called stress hyporesponsive period. Thus, when exposed to repeated hypoxia, seven-day-old rat pups exhibit an ACTHindependent increase in corticosterone that is attenuated by chemical sympathectomy [27]. This ACTH-independent increase in adrenal glucocorticoid levels might enable the neonate to augment circulating corticosterone levels, required for perinatal survival, while bypassing the hyporesponsiveness of the neonatal HPA axis. Furthermore, diurnal variations in resting levels of corticosterone are mediated by variations in adrenal responsiveness to ACTH [28,29] that require splanchnic nerve integrity [3032]. Consequently, a dual control of the adrenal cortex has been implicated in the prominent circadian rhythm of cortisol, a classical hallmark of endocrine regulation [22]. Using transneuronal labeling, the existence of a polysynaptic connection between the hypothalamic suprachiasmatic nucleus (SCN), the site of the master

Figure 1. Possible pathways contributing to dissociation of ACTH and glucocorticoid levels. Adrenal secretion of glucocorticoids is dependent on pituitary ACTH release, which itself is triggered by hypothalamic CRH release. However, in some cases, adrenal glucocorticoid production is dissociated from ACTH levels. This dissociation in ACTH and glucocorticoid levels can be due to an altered sensitivity of the adrenal cortex to ACTH, functioning through the ACTH receptor. In addition, ACTH-independent stimuli influence adrenal glucocorticoid synthesis and release. These include the innervation of the gland and neuropeptides released from neurons and adrenomedullary cells, the interaction with the immune system through the release of cytokines, release of paracrine factors from endothelial cells, in addition to adipocyte-derived adipokines and/or fatty acids. In addition to these mechanisms, that influence adrenal function, glucocorticoid levels are regulated by glucocorticoid metabolism, for example in the liver.

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clock for circadian rhythms, and the adrenal gland has been conrmed [33]. More recently, it has become evident that light, a powerful synchronizer of the circadian rhythm, induces clock gene expression in the adrenal gland [34]. The activity of adrenal clock genes might be responsible for the capacity of cultured adrenals to show circadian patterns of corticosteroid secretion in vitro [35,36]. The light-induced adrenal response in vivo results in a light dose-dependent surge of plasma corticosterone without an accompanying increase in pituitary ACTH, probably through sympathetic preganglionic neurons. In contrast to light-induced increases in corticosteroids, the timing of the end of nocturnal sleep in humans has been associated with an early surge in ACTH levels which is not accompanied by a rise in cortisol levels [37]. The adrenal mechanisms underlying these apparent dissociations are currently unknown. Mismatches between ACTH and corticosterone determinations are frequently observed in studies of HPA axis regulation following stress. Lesions of upstream stress regulatory pathways in the brain lead to dissociation between ACTH and corticosterone, suggesting that central nervous system (CNS) pathways are capable of regulating HPA axis function at both the pituitary and adrenal level. For example, lesions of the anterior bed nucleus of the stria terminalis are able to attenuate corticosterone secretion without an attendant change in circulating ACTH [38], suggesting a stimulatory involvement of this region on the adrenal gland but perhaps not the pituitary. In addition, in rats, sucrose or saccharine consumption causes a decrease in corticosterone secretion without an accompanying alteration in ACTH, indicating that adrenal secretion can be decreased directly by central activation of reward pathways in the brain [39]. There is also evidence that adrenal sensitivity to ACTH is regulated by gonadal steroids. Gonadal steroids alter corticosteroid clearance and production in female primates [40] and in rats [41,42], affording a mechanism for altering the circulating level of steroid without affecting ACTH release. In female rats, estrogens promote the stressinduced release of corticosterone while actually decreasing release of ACTH, consistent with direct or indirect actions on the adrenal gland. The facilitatory effects of estrogens on adrenal function are mediated, at least in part, by enhancement of adrenal sensitivity to ACTH [43]. Adrenal responsiveness to ACTH is also altered under conditions of chronic stress, long-term voluntary exercise or aging. Plasma ACTH and corticosterone are frequently dissociated after chronic stress, with the discordant relationship varying across strains of inbred rats [44] and outbred SpragueDawley rats [45]. Exposure to prolonged intermittent stress results in both adrenal hypertrophy and hyperplasia, which contribute to an enhanced maximal response to ACTH without affecting adrenal sensitivity [46]. As a result, chronically stressed animals release signicantly more corticosterone in response to a given level of ACTH stimulation. Long-term voluntary exercise in mice [47,48] and rats [49] also causes increased adrenal mass, and changes the corticosterone responses to subsequent stressors independently of ACTH. Interestingly, the corticosteroid response in exercising rodents is

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stress specic; physically demanding, life-threatening stressors result in an augmented adrenal response, whereas psychological, anxiety-producing stressors result in a diminished response. These ndings suggest that an extra-ACTH mechanism shapes the adrenal response in exercising animals, providing elevated corticosteroid when needed to withstand physical insults but reduced corticosteroid when exercise alone is sufcient to offset psychological challenges. Finally, aged rats exhibit decreased ACTH responses to stressors in the presence of normal or exaggerated corticosterone surges, again consistent with an enhancement in adrenal responsiveness to ACTH [50]. Altogether, neural and hormonal factors are sufcient to tune the relative activity of the adrenal cortex under certain physiological conditions, bypassing or complementing hypothalamicpituitary drive [51]. The nature and extent of independent regulation of the pituitary and adrenal glands during stress is currently unresolved. Alterations in adrenal sensitivity might be related to modulation of adrenal function by blood-borne hormones (e.g. estrogens) or vasoactive factors (e.g. catecholamines), local release of adrenomedullary hormones or centrally regulated neural activation of adrenocortical cells. Dissociation of ACTH and cortisol in disease An increasing number of preclinical and clinical studies have reported a dissociation of ACTH and cortisol levels in a great variety of disease states (Table 1), including critical illness such as adult respiratory stress syndrome, other forms of septicemia, inammation and psychiatric disorders. During critical illness, there is an intra-adrenal shift towards increased glucocorticoid production and away from mineralocorticoid and androgen production. Particularly during the chronic or prolonged phase of critical illness, plasma ACTH and total cortisol levels are dissociated, with low ACTH and elevated cortisol, suggesting non-ACTH-mediated mechanisms for the maintenance of high glucocorticoid levels [52]. In models of inammatory bowel disease and viral infection, interleukin-6 and ACTH-independent immune adrenal pathways have been identied to account for this dissociation [53,54]. Thus, corticotropin-releasing hormone (CRH)-knockout mice exhibited robust corticosterone responses to murine cytomegalovirus (MCMV), despite reduced baseline and MCMV-induced ACTH, compared with wild-type (WT) mice. This increase in corticosterone clearly correlates with serum interleukin-6 levels, suggesting that a direct immuneadrenal pathway can become a major driving force for glucocorticoid induction [53,54]. Recently, a large European multicenter study on 477 patients with severe sepsis and septic shock who had undergone an ACTH stimulation test on the day of onset of severe sepsis (the Corticus cohort study) was completed. This study revealed that patients who did not survive this severe critical illness had higher baseline glucocorticoid levels but a blunted response to ACTH compared with survivors [55]. In addition to a dissociation of ACTH and cortisol in sepsis [56], there is also a dissociation between adrenal androgens such as serum dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS). Most severe disease
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Table 1. Studies reporting a dissociation of ACTH and cortisol
Studies I. Physiological situation Fetal and early postnatal life Circadian rhythm Central regulation Aging and stress Refs [27] [10,22,28,29,36] [3843] [38,4350]

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II. Disease related [5256] Inammation and sepsis Mental disorders, including depression and anxiety [58,59,61] [50] Alzheimers disease [74] Chronic pulmonary disease [6365] Surgery and stress [67] Bone fracture [66] Alcoholism [73] Metabolic disease

and mortality has been associated with an increased cortisol-to-DHEA ratio, which might provide a novel prognostic marker in septic shock [57]. Therefore, exploring the clinical signicance of non-ACTH-driven glucocorticoid levels during critical illness should be of great interest. Hypercortisolism is a frequent feature of affective disorders [58]. However, the mechanisms mediating hypercortisolism in depression or other neuropsychiatric disorders remain controversial. Recent studies have attempted to elucidate the pathophysiology of hypercortisolism, clearly delineating a dissociation of central ACTH regulation and peripheral adrenal glucocorticoid regulators. Employing deconvolution analysis of 24-hour pulsatile secretion and quantization of forward and reverse ACTHcortisol synchrony, it has been convincingly demonstrated that hypercortisolemia in depressed patients results from an additional change in the adrenal cortex that causes ACTH-independent, disorderly basal cortisol release [59]. Similarly, a recent study analyzing adrenocortical responses to low- and high-dose ACTH in patients with major depression suggested that in spite of reduced pituitary ACTH secretion, there is an increase in adrenal gland size and cortisol secretion [60]. This phenomenon was not due to an increase in the sensitivity of the adrenal gland to ACTH, indicating that neurochemical and/or neurohormonal and neural stimulatory factors other than ACTH might be responsible for adrenal hyperactivity in this illness. Similarly, patients with posttraumatic stress disorder exhibit both altered and dissociated HPA function and signicant changes in autonomic nervous system and catecholamine activity [61]. Increased HPA axis responsiveness to the cold pressor test in Alzheimers disease patients has been demonstrated to occur at the level of the adrenal gland. Plasma ACTH levels did not differ between groups but there was an increased cortisol response in the Alzheimers disease patients, mediated by basal sympathoneural activity [62]. However, dissociation of ACTH and cortisol levels is not limited to inammatory or mental disorders. Differential ACTH and cortisol responses have been reported in many other clinical situations, ranging from chronic pulmonary disease to acute surgical stress (e.g. coronary artery bypass grafting surgery) [63,64]. For example, 30% of patients in the early postoperative period after gastrectomy exhibited a sustained elevation of serum cortisol level on the rst or second day following surgery, despite the return of plasma
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ACTH to preoperative levels [65]. Dissociation of ACTH and cortisol levels in these patients was associated with more advanced cancers and more postoperative complications. In men with a high-risk family history of alcoholism, there is a dysfunction in the HPA axis and a dissociation between plasma ACTH and cortisol levels [66]. Similarly, the cortisolACTH ratio is disrupted in elderly women with hip fracture, in whom plasma cortisol is elevated without concomitant changes in plasma ACTH [67]. CRH stimulation of HPA axis function in these patients two weeks after the injury revealed that the slope of the ACTHcortisol doseresponse relationship was not changed; these ndings suggest involvement of an ACTHindependent stimulus of the adrenals but not an increased sensitivity to ACTH [67]. In metabolic diseases such as diabetes and obesity, there is increasing evidence of a differential regulation of the HPA axis and glucocorticoid metabolism at both the central (CNS) and peripheral (adrenal gland) levels [58,68,69]. Thus, in patients with the metabolic syndrome, there is a change in the levels of several neuropeptides and fat cell-derived factors that function directly on the adrenal gland [70,71]. Cortisol secretion from the adrenal gland is increased in obesity [72], although its plasma levels and its main urinary metabolites are normal or even low. This has been explained by an increased metabolic clearance rate of cortisol [73] and a reduced hepatic conversion of cortisone to cortisol [74]. Furthermore, human adipose tissue expresses receptors for CRH [75] and enzymes, such as 11-b-hydroxysteroid dehydrogenase, that modify glucocorticoid metabolism [68]. Finally, hyperinsulinemia caused a differential activation of HPA axis activity in healthy men. In this study, the cortisolACTH ratio was increased in high versus low insulin conditions [76]. However, dissociation of ACTH and cortisol levels does not occur only in one direction, with high cortisol and low ACTH levels, but might also occur in the opposite direction. Thus, it has been shown by analyzing circadian hormonal ux by means of a mathematical model such as cosinor modeling and calculation of the area under the 24-hour curve that patients with nocturnal asthma present with markedly increased ACTH levels that are not accompanied by commensurate increases in cortisol levels [77]. Summary Given the evidence presented, there can be little doubt that dissociation of ACTH and cortisol levels is a frequently observed phenomenon. Less clear, however, are the mechanisms involved and the physiological and pathological signicance of this observation. The absence of a close link between ACTH and cortisol at a given time point does not mean that ACTH is not relevant in this particular physiological setting. Similarly, the fact that ACTH is indispensable for baseline maintenance of adrenal glucocorticoid production does not argue against a physiological and pathophysiological role for ACTH-independent stimuli in the maintenance, regulation and ne-tuning of the adrenal gland. Moreover, the mere nding and the degree of dissociation seems to correlate with the course and prognosis of some diseases and might therefore be of clinical signicance.

Review
Constitutive activation of ACTH receptor or signaling molecules, ACTH receptor polymorphism or involvement of intra-adrenal ACTH are rare and remote possibilities that are unlikely to account for all of these frequently observed changes [78,79]. It is conceivable that ectopic or aberrant expression of hormone receptors for neuropeptides, neurotransmitters, cytokines and adipokines on adrenal cells might lead to adrenal cortisol secretion which is not under the control of the regular negative feedback of the HPA axis [8083]. In addition, a shift in ACTH sensitivity might occur in several diseases associated with a clear-cut dissociation in the measurement of ACTH and cortisol levels. Considerable data from animal studies and clinical trials provide evidence for the involvement of neural, neuroendocrine or immuneadrenal stimuli in mediating these effects. Without doubt, these ancillary pathways of adrenal glucocorticoid regulation are important, even though baseline permissive levels of ACTH are absolutely required for the proper functioning of the gland. Finally, the most challenging question to answer concerns the biological and clinical signicance of these ndings. Is the dissociation of ACTH and glucocorticoid levels a consistent and distinct form of stress regulation? Is there a diagnostic and predictive value in determining this dissociation? Will this be useful for directing patient management issues? Designing experimental and clinical protocols addressing these questions will be an exciting area of research for basic and clinical endocrinologists.
Acknowledgements
Supported by grants NSF IOB-0548584 (W.C.E.), MH049698 (J.P.H.), MH069725 (J.P.H.), MH069680 (J.P.H.), AG12962 (J.P.H.), DFG Collaborative Research Centre Dresden (SFB 655-A6; M.E.B. and S.R.B.). Figure 1 was produced using SERVIER Medical Art.

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