Adrenocorticotropin (ACTH)- and Non-ACTH-Mediated Regulation of the Adrenal Cortex: Neural and Immune Inputs
S. R. Bornstein and
G. P. Chrousos
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.
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Introduction
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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
).
The adrenal gland has an astonishing capacity to adapt to various forms
of acute and chronic stress (6, 7, 8). After central activation of the HPA
axis, ACTH triggers a physiologic, molecular, and morphological
response of the adrenal cortex. This leads not only to glucocorticoid
release, but also to up-regulation of steroidogenic cytochrome
P450 messenger ribonucleic acids (9, 10) and to conspicuous
structural changes in the adrenal gland characterized by both
hypervascularization and cellular hypertrophy and hyperplasia (11, 12).
These morphological changes are mirrored on the ultrastructural level;
adrenocortical cells increase the number of their mitochondria, whereas
their inner membranes form a dense vesicular pattern (13, 14). In
addition, there is an increase in smooth endoplasmic reticulum and
filopodia and a decrease in liposomes known to store cholesterol, the
substrate for glucocorticoid biosynthesis (13, 14, 15).
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.
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Innervation of the adrenal cortex
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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
).
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Interactions between the adrenal medulla and cortex
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The main adrenomedullary secretory products, epinephrine and
norepinephrine, stimulate mammalian adrenocortical function in
situ in perfused adrenals (25, 27) and in vitro in
adrenocortical cells in primary culture (for review, see Ref. 17) by
enhancing the transcriptional activity of several steroidogenic factors
and enzymes (10, 30). Thus, it appears that catecholamines and costored
neuropeptides released from adrenomedullary chromaffin cells in large
amounts stimulate adrenocortical steroidogenesis in a direct fashion
and are probably responsible for most of the observed activation of the
mammalian adrenal cortex by the splanchnic nerve.
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).
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How do adrenomedullary secretory products reach the adrenal
cortex?
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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).
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Immune-adrenal interactions
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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
Cushings 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).
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An adrenal view of stress regulation
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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?
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Does non-ACTH-mediated regulation of the adrenal cortex have
physiological relevance?
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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 ).
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Does non-ACTH-mediated regulation of the adrenal cortex play a role
in clinical situations?
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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).
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Table 2. Examples of life periods and clinical states
suggesting involvement of non-ACTH-mediated regulation of
adrenocortical function
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Several studies have supported a close link between the HPA axis and
adrenomedullary responses during stress (3). Thus, public speaking
markedly increased plasma levels and urinary excretion of cortisol and
epinephrine, with only small changes in norepinephrine levels (82).
Also, in humans playing a video game, responses of arterial ACTH levels
correlated positively with responses of epinephrine, but not
norepinephrine (3). In rats, electroconvulsive shock increased jugular
venous plasma concentrations of ACTH, ß-endorphin, and epinephrine,
whereas plasma concentrations of norepinephrine remained unchanged
(83); passive avoidance elicited large plasma epinephrine and
corticosterone responses, but small plasma norepinephrine responses
(84).
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.
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Does the extrapituitary-adrenocortical stress response constitute
an exclusive or additive pathway?
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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 Cushings 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 Cushings 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.
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Can we distinguish the non-ACTH-mediated response from the
ACTH-mediated one by specific clinical testing?
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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.
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Perspectives
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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.
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