Acute and Prolonged Critical Illness as Different Neuroendocrine Paradigms1
Greet Van den Berghe2,
Francis de Zegher and
Roger Bouillon
Departments of Intensive Care Medicine (G.V.d.B.), Pediatrics
(F.d.Z.), and Medicine, Division of Endocrinology (R.B.), University
Hospital Gasthuisberg, University of Leuven, B-3000 Leuven,
Belgium
Address all correspondence and requests for reprints to: Greet Van den Berghe, M.D., Ph.D., Department of Intensive Care Medicine, University Hospital Gasthuisberg, University of Leuven, B-3000 Leuven, Belgium. E-mail: greta.vandenberghe{at}uz.kuleuven.ac.be
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Introduction
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THROUGHOUT evolution, the human species has
been selected to survive disease and trauma. Accordingly, the body has
developed natural defense mechanisms to face a great diversity of
insults, most of which are accompanied by temporary starvation, without
having to rely upon external support. Consequently, the initial
response to acute insults, such as illness or trauma, results in an
increased availability of glucose, amino acids and free fatty acids.
Utilization of these substrates is reduced and preferentially directed
toward vital organs, such as the brain and the immune system (1, 2, 3).
This acute metabolic response, which occurs even if food intake is
maintained, is thought to be at least partly evoked by endocrine
changes, including an activated hypothalamic-pituitary-adrenocortical
axis, hypersecretion of PRL and GH in the presence of low circulating
insulin-like growth factor I (IGF-I), and a low activity state of the
thyroid and gonadal axis (4, 5, 6, 7, 8, 9). These changes have consistently been
viewed as adaptive or beneficial, as they may reduce and redirect
energy consumption, postpone anabolism and, at the same time, activate
the immune response while protecting the host against deleterious
biological effects of the latter (4, 8, 10, 11). It is still unclear to
which extent some of these defense mechanisms may hyperrespond and, as
a consequence, be harmful. However, as they have been continuously
selected by the challenges of nature and time, there is at present
little argument for medical interference with these adaptive changes
during the first hours or days of illness or after trauma.
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Metabolic response to protracted critical illness in the intensive
care setting
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The development of intensive care medicine over the past 3 decades
has enabled humans to survive conditions such as septic or
cardiogenic shock, fecal peritonitis, multiple trauma, or extensive
burns. The latter insults are examples of a magnitude and duration
requiring nutritional and vital organ function support that are beyond
the capacity of the natural defense systems. Patients previously died
from these challenges, and it is therefore unlikely that nature has
been able to select coping mechanisms for the chronic phase of these
disorders or for the intensive care conditions in which survival is
nowadays possible. Indeed, it has now become clear that survival
mediated by intensive care also has a reverse side. The highly
technological intervention in the natural course of the dying process
has unmasked previously unknown conditions, including a nonspecific
wasting syndrome: despite feeding, protein continues to be lost from
vital organs and tissues due to both activated degradation and
suppressed synthesis, whereas reesterification (instead of oxidation)
of free fatty acids allows fat stores to build up (12, 13). Moreover,
the wasting is accompanied by hyperglycemia and insulin resistance,
hypoproteinemia, hypercalcemia, intracellular water and potassium
depletion, and hypertriglyceridemia, which often prompt
symptomatic treatment.
Protein hypercatabolism becomes functionally important when the
critical condition is protracted for several weeks. An impaired
capacity to synthesize protein underlies the inability to restore
normal protein content and hereby hampers recovery of the
dysfunctioning systems (13). Muscle atrophy and weakness are some of
the most overt functional consequences of protein wasting and provoke,
among other problems, failure of the muscular ventilatory system, thus
perpetuating the need for mechanical support. Atrophy of the intestinal
mucosa and disturbed motility of the gastrointestinal tract prolong the
need for parenteral feeding. In addition, delayed tissue repair and
immune dysfunction jeopardize the healing process. Hence, dependency on
intensive care support is further prolonged (14, 15).
The development of the wasting syndrome and ensuing intensive care
dependency does not appear to be related to the initial disease or
trauma, but, rather, to the duration of the critical condition (13). In
clinical practice, a limited number of patients, who survived an acute
life-threatening insult, continue to occupy high dependency beds for a
long time (weeks, often months) because of their catabolic state and
require a considerable fraction of the resources for intensive care
(14, 15). Many of these "long stay" patients ultimately die from
(infectious) complications, for which they are increasingly vulnerable
(14, 15).
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Neuroendocrinology of protracted critical illness
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It has long been known that the anterior pituitary gland plays a
crucial role in normal metabolic and immunological homeostasis.
However, until recently, data on the neuroendocrinology of prolonged
critical illness within an intensive care setting were scarce, and data
from models of acute catabolic state (such as healthy starved
volunteers, the perioperative phase of elective surgery, the admission
phase of trauma, or acute infection) were extrapolated, without
validation, to this type of protracted catabolic state. Other
confounding factors have been concomitant malnutrition, the
heterogeneity of the studied populations, and the use of intensive care
drugs with neuroendocrine side-effects, such as dopamine (6, 7, 16).
Human data on the neuroendocrine characteristics of prolonged critical
illness (defined as dependent on intensive care support for at least 10
days) are now becoming available, and they appear to be quite different
from those observed in the first few hours or days after the onset of a
life-threatening disease or trauma (17, 18, 19, 20). Whether they also
represent a beneficial adaptation or, instead, a neuroendocrine
dysfunction or exhaustion has not been established. The latter
hypothesis, which implies major therapeutic consequences, is being
actively explored and appears to gain plausibility.
This review provides a synopsis of the endocrine changes observed in
the initial phase and in the prolonged intensive care-dependent phase
of critical illness, focusing on the hypothalamic-pituitary-dependent
axes. It will appear that the acute phase is mainly characterized by an
actively secreting anterior pituitary gland and a peripheral
inactivation or inactivity of anabolic hormones, whereas prolonged
critical illness is hallmarked by reduced neuroendocrine stimulation
(Fig. 1
). Thus, acute and prolonged
critical illness may be different neuroendocrine paradigms, and this
concept clarifies many of the currently apparent paradoxes.

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Figure 1. Simplified concept of the
pituitary-dependent changes during the course of critical illness. In
the acute phase of illness (first hours to a few days after onset), the
secretory activity of the anterior pituitary is essentially maintained
or amplified, whereas anabolic target organ hormones are inactivated.
Cortisol levels are elevated in concert with ACTH. In the chronic phase
of protracted critical illness (intensive care dependent for weeks),
the secretory activity of the anterior pituitary appears uniformly
suppressed in relation to reduced circulating levels of target organ
hormones. Impaired anterior pituitary hormone secretion allows the
respective target organ hormones to decrease proportionately over time,
with cortisol being a notable exception, the circulating levels of
which remain elevated through a peripheral drive, a mechanism that
ultimately may also fail. The onset of recovery is characterized by
restored sensitivity of the anterior pituitary to reduced feedback
control.
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Adrenocortical function
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The activity of the hypothalamic-pituitary-adrenocortical axis
displays a biphasic pattern during the course of critical illness (20).
By 1856, Brown-Séquard had noted that immediate postoperative
survival depends on adrenal function (21). It is now known that the
high serum cortisol concentrations present during the initial phase
after surgery, trauma, or sepsis are associated with augmented ACTH
release, which, in turn, is presumably driven by CRH, cytokines, and
the noradrenergic system (4, 22, 23, 24). Concomitantly, circulating
aldosterone rises markedly, most likely under the control of an
activated renin-angiotensin system (25).
Hypercortisolism acutely shifts carbohydrate, fat, and protein
metabolism, so that energy is instantly and selectively available to
vital organs such as the brain, that overall utilization of substrates
is reduced, and anabolism is postponed. Intravascular fluid retention
and the enhanced inotropic and vasopressor response to respectively
catecholamines and angiotensin II offer hemodynamic advantages in the
fight and flight reflex. In addition, as virtually all components of
the immune response are inhibited by cortisol, the hypercortisolism
elicited by acute disease or trauma can be interpreted as an attempt of
the organism to mute its own inflammatory cascade, thus protecting
itself against overresponses (26). Thus, available evidence is still
compatible with the time-honored view that the hyperactive state of the
adrenocorticotropic axis in the initial phase of severe illness or
posttrauma is part of the "wisdom of the body" (27, 28).
In prolonged critical illness, serum ACTH levels are low whereas
cortisol concentrations usually remain elevated, indicating that
cortisol release may in this phase be driven through an alternative
pathway, possibly involving endothelin (20). Why ACTH levels are low in
prolonged critical illness is unclear; a role for atrial natriuretic
peptide (20) or substance P (23) has been suggested. In contrast to
serum cortisol, circulating levels of adrenal androgens such as
dehydroepiandrosterone sulfate (DHEAS), which has immunostimulatory
properties on Th1 helper cells, are low during prolonged critical
illness (29, 30, 31). Moreover, despite increased PRA, paradoxically
decreased concentrations of aldosterone are found in protracted
critical illness (32). This constellation suggests a shift of
pregnenolone metabolism away from both mineralocorticoid and adrenal
androgen pathways toward the glucocorticoid pathway, orchestrated by a
peripheral drive. Ultimately, the latter mechanism may also fail, as
indicated by a substantially higher incidence of adrenal insufficiency
in prolonged critical illness (33).
Hypercortisolism in the chronic phase of critical illness probably
continues to exert its beneficial hemodynamic effects. However, the
benefit for the host defense of a sustained hypercortisolism in the
presence of low levels of DHEAS is questionable, as prolonged imbalance
between immunosuppressive and immunostimulatory hormones of
adrenocortical origin may participate in the increased susceptibility
for infectious complications. Other conceivable, although yet unproven,
drawbacks of prolonged hypercortisolism include impaired wound healing
and myopathy, complications that are often observed during protracted
critical illness.
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Somatotropic axis
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The acute phase response of the somatotropic axis, as evoked by
trauma, surgery, or acute infectious disease, has a characteristic
presentation. Firstly, circulating levels of GH are elevated (5) (Fig. 2
). Normally, the serum profile of GH
consists of peaks alternating with virtually undetectable troughs. In
acute illness, the total amount of GH released from the somatotropes
appears to be increased, and interpulse concentrations of GH are
relatively high (6, 7).

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Figure 2. Nocturnal serum concentration profiles of
GH, TSH, and PRL illustrating the differences between the initial phase
(thin black line) and the chronic phase (thick
black line) of critical illness within an intensive care
setting. The gray lines illustrate normal patterns.
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Secondly, serum concentrations of IGF-I are low (6, 34, 35). The
concurrence of elevated GH and low IGF-I levels has been interpreted as
resistance to GH, which may be related to decreased GH receptor
expression (35).
Thirdly, there are changes in the circulating IGF-binding proteins
(IGFBPs), which regulate IGF-I plasma half-life and bioavailability
(36). The low serum concentrations of IGF-I are associated with low
levels of IGFBP-3 and acid-labile subunit (11, 34, 37); the synthesis
of these three polypeptides is normally up-regulated by GH, and
together, they form a 150-kDa ternary complex in the circulation (34).
In acute illness, there is increased presence of IGFBP-3 protease
activity in plasma, resulting in increased dissociation of IGF-I from
the ternary complex and a shortening of IGF-I plasma half-life (11, 34). IGFBP-1, which normally binds only a small amount of IGF-I
compared to IGFBP-3, remains in the circulation in normal or slightly
elevated concentrations (37, 38).
As serum concentrations of free fatty acids and glucose are elevated by
the acute stress response, and as nonfasting insulin levels are also
increased, it is possible that the abundantly released GH still exerts
direct lipolytic and insulin-antagonizing actions, whereas its indirect
somatotropic effects are attenuated.
Inflammatory cytokines may be among the mediators of the aforementioned
changes. Alternatively, nutritional factors may be involved, as most
conditions of acute stress are accompanied by starvation or at least a
degree of protein malnutrition (35, 39, 40, 41).
The constellation of changes observed within the somatotropic axis
during acute stress, in balance with the response of the adrenocortical
axis, has been interpreted as an attempt to provide essential
substrates for survival while anabolism is postponed. In the human,
this defense mechanism appears to be fundamental, as it can be
activated before birth (42).
Therefore, in the acute phase of life-threatening disease or trauma,
there is at present still no solid pathophysiological basis for
endocrine intervention. Accordingly, it is anticipated that ongoing
trials with exogenous GH may be unable to demonstrate major benefit in
the acute phase of illness.
Prolonged critical illness, supported with intensive care for weeks, is
characterized by a different set of changes in the somatotropic axis.
Firstly, the pattern of GH secretion has been characterized as having a
reduced pulsatile fraction (Figs. 2
and 3
), whereas the nonpulsatile or tonic
fraction is (still) somewhat elevated, and the number of pulses is high
(17). This pattern results in mean serum GH concentrations that are low
normal (17) (Fig. 2
). Moreover, GH appears to be released in an erratic
fashion, as indicated by a high calculated approximate entropy (17, 43).

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Figure 3. Upper part, Nocturnal serum
GH profiles in the prolonged phase of illness illustrating the effects
of continuous infusion of placebo, GHRH (1 µg/kg·h), GHRP-2 (1
µg/kg·h), or GHRH plus GHRP-2 (1 + 1 µg/kg·h). The age range of
the patients was 6285 yr; the duration of illness was between 1348
days; infusions were started 12 h before the onset of the
respective profiles. Adapted from Refs. 17 and 19. Lower
part, Exponential regression lines have been reported between
pulsatile GH secretion and the changes in circulating IGF-I,
acid-labile subunit, and IGFBP-3 obtained with 45-h infusion of either
placebo, GHRP-2 or GHRH plus GHRP-2. They indicate that the parameters
of GH responsiveness increase in proportion to GH secretion up to a
certain point, beyond which a further increase in GH secretion has
apparently little or no additional effect. It is noteworthy that the
latter point corresponds to a pulsatile GH secretion of approximately
200 µg/Lv over 9 h or less, a value that can be evoked by the
infusion of GHRP-2 alone. In the chronic, nonthriving phase of critical
illness, GH sensitivity is clearly present, in contrast to the acute
phase of illness, which is thought to be primarily a condition of GH
resistance. Adapted from Ref. 19.
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Secondly, the reduced amount of GH that is released in pulses appears
to correlate positively to the low circulating levels of IGF-I,
IGFBP-3, and acid-labile subunit (17, 19). Indeed, it has been shown
that when pulsatile GH secretion falls below a critical threshold
during the chronic phase of illness, circulating IGF-I and acid-labile
subunit progressively decrease over time (19). As low serum IGF-I
levels and, even more so, low levels of acid-labile subunit are markers
of protein wasting in this condition (11, 44), these findings suggest
that the neuroendocrine component of the somatotropic axis participates
in the pathogenesis of the wasting syndrome in prolonged critical
illness. This hypothesis has been corroborated by studying the effects
of GH secretagogue administration (17, 19); the whole somatotropic axis
was found to be readily responsive to GH secretagogues in the chronic
phase of critical illness, as evidenced by pulsatile GH secretion
followed by substantial increases in the circulating levels of IGF-I,
IGFBP-3, and the acid-labile subunit (Fig. 3
). The presence of
considerable responsiveness to restored endogenous GH secretion further
delineates the distinct pathophysiological paradigm of the chronic
phase of critical illness, as opposed to the acute phase, which is
thought to be primarily a condition of GH resistance.
The pathogenesis of the secretory pattern of GH in prolonged critical
illness is probably complex. One of the possibilities is a deficiency
of the endogenous GH-releasing peptide (GHRP)-like ligand together
with a reduced somatostatin tone and maintenance of some GHRH effect;
this hypothetical combination would explain both reduced spontaneous GH
secretion and pronounced responsiveness to GH secretagogues (17, 19, 45).
From a therapeutic perspective, the aforementioned data provide a sound
pathophysiological basis to explore the safety and efficacy of GH
secretagogue administration as a strategy to counter the wasting
syndrome and, consequently, to actually accelerate the process of
recovery from prolonged critical illness. As the administration of a
hypothalamic releasing factor implies respect for pituitary feedback
inhibition loops and allows for peripheral adjustment of metabolic
pathways according to the needs determined by the disease, it is
expected that the infusion of GH secretagogues will be a safer strategy
than the administration of (high doses) GH and/or IGF-I in the chronic,
GH-responsive, phase of critical illness, particularly in vulnerable
elderly subjects (46).
In summary, the acute stress-regulated changes within the somatotropic
axis appear to consist primarily of activated GH secretion and a
peripheral shift toward its direct effects, whereas the chronic phase
is mainly characterized by relative hyposomatotropism of essentially
hypothalamic origin and preserved peripheral GH responsiveness. When a
renewed acute phase, such as an intercurrent infection or surgical
intervention, complicates the chronic phase, protease activity
reappears in serum, and circulating levels of IGFBP-3 and IGF-I drop
(34). In other words, repetitive episodes of GH resistance may appear
on a background of relative hyposomatotropism, thus forming mixed
conditions that may be difficult to interpret and may explain some of
the apparent paradoxes in the literature.
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Thyroid axis
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Critical illness is characterized by multiple and complex
alterations in the thyroid axis with, again, a dual presentation (9, 47). During the initial phase of severe illness and/or starvation,
there appear to be mainly changes in peripheral metabolism, binding,
and receptor occupancy of thyroid hormones, whereas a low activity
state of primarily neuroendocrine origin predominates in prolonged
critical illness within intensive care conditions (Figs. 1
and 2
).
Mixed forms are again possible and may further complicate the difficult
interpretation of thyroid function tests in this setting.
Acute illness or trauma induces alterations in thyroid hormone
equilibrium within hours. Although serum TSH usually remains normal,
circulating T3 rapidly drops partly due to decreased
conversion of T4 to T3 (48) and/or
increased turnover of thyroid hormones (49). The magnitude of the
T3 drop within 24 h reflects the severity of
illness (50, 51). Serum rT3 levels increase
partly due to reduced rT3 degradation (48). In
animal models, hepatic nuclear T3 receptors
appear to decrease in number and in occupancy (52, 53). The absence of
a TSH elevation in the face of low circulating T3
levels suggests that there is also an altered feedback setting at the
hypothalamic-pituitary level (54, 55). Experimental data indicate that
reduced TRH gene expression as well as enhanced nuclear
T3 receptor occupancy within the thyrotropes may
be involved (55, 56).
The cytokines TNF-
, interleukin-1 (IL-1), and IL-6 have been
investigated as putative mediators of the acute low
T3 syndrome (55, 57, 58, 59). Although these
cytokines are capable of mimicking the acute stress-induced alterations
in thyroid status, cytokine antagonism in sick mice failed to restore
normal thyroid function (60). Endogenous thyroid hormone analogs
resulting from alternative deamination and decarboxylation, such as
tri- and tetraiodothyroacetic acid, may also participate in the
pathogenesis of the low T3 syndrome by blunting
the TSH response to low thyroid hormone feedback and by competing with
active thyroid hormone for binding to transport proteins (61, 62).
Finally, low concentrations of binding proteins and inhibition of
hormone binding, transport, and metabolism by elevated levels of free
fatty acids and bilirubin have been proposed as factors contributing to
the low T3 syndrome at tissue level (63).
Teleologically, the acute changes in the thyroid axis occurring during
starvation have been interpreted as an attempt to reduce energy
expenditure (64) and, thus, as an appropriate response that does not
warrant intervention. Whether this is also applicable to other acute
stress conditions, such as the initial phase of critical illness, is
still a matter of controversy.
Alterations in the thyroid axis during the prolonged phase of critical
illness appear to be different. Essentially, pulsatile TSH secretion is
diminished and positively related to the low serum levels of
T3 (18, 19). These findings indicate that the
reduced production of thyroid hormones in the prolonged phase of
critical illness may have a neuroendocrine origin. In line with this
concept are the findings that hypothalamic TRH gene expression is
positively related to serum T3 in this condition
(65) and that an increase in serum TSH is a marker of the onset of
recovery from severe illness (54).
The neuroendocrine pathogenesis of the low T3
syndrome of prolonged critical illness is unknown. As circulating
cytokine levels are usually low (66), other mechanisms operational
within the central nervous system are presumably involved. Endogenous
dopamine and prolonged hypercortisolism may each play a role (16, 67);
exogenous dopamine is known to provoke or aggravate central
hypothyroidism in critical illness (68, 69).
As normal levels of T3 are required for protein
synthesis, lipolysis, fuel utilization by muscle, and GH secretion and
responsiveness, central hypothyroidism has been hypothesized to
contribute to the feeding-resistant catabolic state of prolonged
critical illness. It remains speculative whether the low serum and
tissue (70) concentrations of T3 are also
involved in several problems distinctively associated with prolonged
critical illness, such as diminished cognitive status with lethargy
(71), somnolence, or depression; ileus and gallbladder dysfunction;
pleural and pericardial effusions; glucose intolerance and insulin
resistance; hyponatremia; normocytic normochromic anemia; and deficient
clearance of triglycerides.
The concept of a low T3 syndrome of
neuroendocrine origin has been corroborated by investigating the effect
of TRH administration (19): the thyroid axis of patients with prolonged
critical illness can be reactivated by TRH infusion, from TSH secretion
to increases in circulating T4 and T3
(Fig. 4
). Interestingly, coinfusion of
TRH and GH secretagogues appears necessary to increase the pulsatile
fraction of TSH release and to avoid a rise in circulating reverse
T3 (Fig. 4
). During TRH infusion in prolonged
critical illness, the negative feedback exerted by thyroid hormones on
the thyrotropes was maintained, thus precluding overstimulation of the
thyroid axis (19). Moreover, TRH infusion allows for peripheral shifts
in thyroid hormone metabolism during intercurrent events and,
accordingly, permits the body to elaborate appropriate concentrations
of thyroid hormones in circulation and at the tissue level, thus
setting the scene for a safer treatment than the administration of
T3.

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Figure 4. Upper part, Nocturnal serum
TSH profiles in the prolonged phase of illness (duration of illness,
1518 days; patients age, 6980 yr), illustrating the effects of
continuous infusion of placebo, TRH (1 µg/kg·h), and TRH plus
GHRP-2 (1 µg/kg·h). Although TRH elevated TSH secretion, addition
of GHRP-2 to the TRH infusion appeared necessary to increase its
pulsatile fraction. Adapted from Ref. 19. Lower part,
Continuous administration of TRH (1 µg/kg·h), infused alone or
together with GHRP-2 (1 + 1 µg/kg·h), induces a significant rise in
serum T4 and T3 within 24 h.
rT3 is increased after the infusion of TRH alone, but not
if TRH is coinfused with GHRP-2. The patients studied were ill for
1259 days; the age range was 3287 yr. *, P <
0.05; **, P < 0.001; ***, P <
0.0001. Adapted from Ref. 19.
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The pioneering studies with T4 or
T3 administration have failed to demonstrate
clinical benefit in the intensive care setting (72, 73). The clinical
significance of combined TRH- and GH secretagogue-induced stimulation
of the thyroid axis in prolonged critical illness remains to be
delineated.
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Gonadal axis
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A variety of catabolic states are associated with low serum
testosterone levels in men. These conditions include starvation (74, 75), the postoperative phase (8), myocardial infarction (76), burn
injury (77, 78), psychological and physical stress (79, 80), and
prolonged critical illness (81).
It appears that acute injury primarily leads to an immediate and direct
Leydig cell suppression. Indeed, low serum testosterone concentrations
despite elevated LH levels have been documented during the acute stress
of surgery or myocardial infarction, whereas FSH and inhibin levels
remain normal (8, 76, 82). The mechanisms underlying the immediately
decreased secretory Leydig cell responsiveness in humans remain largely
unknown. A role for inflammatory cytokines (IL-1 and IL-2) is possible,
as suggested by experimental studies (83, 84).
It may again be considered appropriate that the secretion of anabolic
androgens be switched off in circumstances of acute stress to reduce
the consumption of energy and substrates. When a severe stress
condition becomes prolonged, hypogonadotropism ensues (77, 85). A
progressive decrease in serum gonadotropin levels has been documented
within 1 or 2 days, albeit lagging behind the rapid decline in serum
testosterone (76, 82, 86). In prolonged critically ill men within
intensive care conditions, mainly the pulsatile fraction of LH release
was attenuated (81). In critically ill women, a reversible reduction of
LH and FSH secretion, and of serum estradiol concentrations, has been
observed and correlated with outcome (85, 86, 87). Endogenous dopamine or
opiates may be involved in the pathogenesis of hypogonadotropic
hypogonadism, as iatrogenic factors such as exogenous dopamine and
opioids may further diminish blunted LH secretion (81, 88). Animal data
suggest that prolonged exposure of the brain to IL-1 may also play a
role through the suppression of LHRH synthesis (83).
The pioneering studies evaluating androgen treatment in prolonged
critical illness failed to demonstrate conclusive clinical benefit
(89). In view of the secretory characteristics of the other anterior
pituitary hormones, the therapeutic potential of androgens should
perhaps be reappraised in a combined treatment. The effect of pulsatile
GnRH administration remains to be explored.
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PRL
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PRL was among the first hormones known to have increased serum
concentrations in response to acute physical or psychological stress
(5), a rise that may be mediated by vasoactive intestinal peptide,
oxytocin, dopaminergic pathways, and/or other still uncharacterized
factors (90, 91). Cytokines may again play a signaling role. Although
PRL appears to have immunostimulatory properties in animal models as
well as in humans (91, 92, 93), it remains unclear whether the relative
hyperprolactinemia during the initial phase of critical illness or
posttrauma contributes to the initial activation of the inflammatory
cascade.
In prolonged critical illness, serum PRL appears to be no longer
elevated, and the secretory pattern is characterized by a reduction in
the pulsatile fraction (18, 19) (Fig. 2
). It is unknown whether the
blunted PRL secretion plays a role in the anergic immune dysfunction or
in the increased susceptibility for infections characterizing the
chronically ill (15, 94). However, dopamine, which is often infused as
an inotropic and vasoactive supportive agent in intensive
care-dependent patients, has been shown to further suppress PRL (and
DHEAS) secretion without altering elevated serum cortisol levels, and
was found to aggravate concomitantly both T lymphocyte dysfunction and
impaired neutrophil chemotaxis (31, 68, 93).
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Conclusion
|
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Acute and prolonged critical illness seem to result in different
neuroendocrine paradigms and should perhaps be approached with
different therapeutic strategies.
The initial endocrine response evoked by severe illness or trauma and
by starvation consists primarily of a peripheral inactivation of
anabolic pathways (low IGF-I, T3, and testosterone levels),
whereas pituitary activity is essentially maintained or amplified:
substrates for survival are provided, anabolism is postponed, and the
immune response is activated while the host is protected against
deleterious systemic effects of the latter. At present, there still is
no solid pathophysiological basis for hormonal intervention in this
acute phase.
The development of intensive care has led to survival in previously
lethal conditions, thus unmasking newly recognized disorders such as
the wasting syndrome of protracted intensive care dependency. In the
chronic phase of critical illness, reduced pulsatile secretion of
anterior pituitary hormones correlates positively with reduced activity
of target tissues; cortisol secretion is a notable exception, being
maintained through a peripheral drive.
An acute event complicating the chronic phase of illness, such as an
intercurrent infection or surgical intervention in a "long stay"
intensive care unit patient, may be accompanied by mixed
acute/prolonged endocrine patterns, which are difficult to interpret
and may account for some of the apparently conflicting data in the
literature.
It is unlikely that the reduced neuroendocrine drive, distinctively
present in the chronic phase of illness within an intensive care
setting, has been selected by evolution and should accordingly be
considered as time-honored and appropriate. The hypothesis of
inappropriate neuroendocrine function can be validated by studying the
effects of either combined peripheral hormonal substitution or
hypophysiotropic releasing peptide administration. The latter
demonstrated that selected pituitary-dependent axes can readily be
reactivated in the chronic phase of critical illness, with preserved
peripheral responsiveness. Intervening at the hypothalamic-pituitary
level appears a safer strategy than the administration of peripherally
active hormones, as the presence of feedback inhibition protects from
dose-related side-effects. It remains to be determined whether
endocrine interventions in prolonged critical illness will result in
beneficial metabolic effects and will, ultimately, accelerate the
recovery of those patients who need it most.
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Acknowledgments
|
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The authors thank the medical and nursing staff of the Intensive
Care Unit of the University Hospital of Leuven and the technical staff
of the Laboratories Legendo and Hormonology for their appreciated
contribution to the original studies.
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Footnotes
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1 This work was supported by research grants from the Fund for
Scientific Research Flanders, Belgium (G.0162.96), and the Research
Council of the University of Leuven (OT 95/24). 
2 Clinical Research Investigator (G.3c05.95N) with the Fund for
Scientific Research (Flanders, Belgium) and The Belgian Endocrine
Society Award Lecture (1998). 
Received October 17, 1997.
Revised January 12, 1998.
Accepted January 16, 1998.
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