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Endocrine aspects of acute and prolonged

critical illness
Ilse Vanhorebeek, Lies Langouche and Greet Van den Berghe*

S U M M A RY INTRODUCTION
Major developments in intensive-care medicine,
Critical illness is characterized by striking alterations in the
such as the introduction of mechanical ventila-
hypothalamic–anterior-pituitary–peripheral-hormone axes, the severity
tion, a wide array of drugs, and high-technology
of which is associated with a high risk of morbidity and mortality. Most
monitoring systems, have fostered a tremendous
attempts to correct hormone balance have been shown ineffective or
even harmful because of a lack of pathophysiologic insight. There is a
increase in the immediate, short-term survival of
biphasic (neuro)endocrine response to critical illness. The acute phase is patients suffering from acute, previously lethal,
characterized by an actively secreting pituitary, but the concentrations insults. Since recovery is often not achieved
of most peripheral effector hormones are low, partly due to the within a few days, patients frequently enter a
development of target-organ resistance. In contrast, in prolonged critical chronic phase of critical illness during which they
illness, uniform (predominantly hypothalamic) suppression of the remain dependent on vital-organ support. Those
(neuro)endocrine axes contributes to the low serum levels of the respective patients who are critically ill for more than a few
target-organ hormones. The adaptations in the acute phase are considered days have a high risk of death, with on average 1
to be beneficial for short-term survival. In the chronic phase, however, in 5 not surviving the intensive-care phase, and
the observed (neuro)endocrine alterations appear to contribute to the an even higher risk of not leaving the hospital
general wasting syndrome. With the exception of intensive insulin therapy, alive. This high mortality is usually ascribed to
and perhaps hydrocortisone administration for a subgroup of patients, nonresolving failure of multiple organ systems
no hormonal intervention has proven to beneficially affect outcome. and vulnerability to infectious complications,
The combined administration of hypothalamic releasing factors does, rather than to the type or severity of the initial
however, hold promise as a safe therapy to reverse the (neuro)endocrine disease for which they were admitted to the inten-
and metabolic abnormalities of prolonged critical illness by concomitant sive care unit. Prolonged critical illness is further
reactivation of the different anterior-pituitary axes. characterized by ongoing hypercatabolism,
KEYWORDS critical illness, endocrine changes, therapeutic implications
despite artificial feeding, which results in a
profound decrease in lean body mass in the pres-
REVIEW CRITERIA ence of relative preservation of adipose tissue.
Publications discussed in this review were identified by searching the PubMed This induces weakness and prolongs convales-
database. Different combinations of the following search keywords, and variants cence. Patients become susceptible to infectious
thereof, were used: “critical illness”, “endocrinology”, “hypothalamic–pituitary complications, because of acquired impairment
axis”, “hormone”, “growth hormone”, “thyroid”, “gonadal axis”, “testosterone”,
“prolactin”, “cortisol”, “vasopressin”, “catecholamine” and “insulin”. A manual of INNATE IMMUNITY, and at the same time,
search of some references cited in these papers was also performed. All selected although it is at first sight paradoxical, they are
papers were English-language full-text articles. A number of references originally at risk of developing excessive systemic inflam-
cited were deleted because of space restrictions. mation and coagulation disorders, all increasing
morbidity and risk of death.
The hypothalamic–anterior-pituitary axes play
a central role in the endocrine regulation of meta-
bolic and immunologic homeostasis. Critical
illness is characterized by alterations within this
G Van den Berghe is a Professor of Medicine, and I Vanhorebeek and system that have long been known to contribute
L Langouche are Postdoctoral Fellows, at the University of Leuven, Belgium. to the high risk of morbidity and mortality.
Correspondence
Before one can consider such an association to
*Department of Intensive Care Medicine, Catholic University of Leuven, B-3000 Leuven, Belgium be a solid basis for exploring new therapeutic
greta.vandenberghe@med.kuleuven.be strategies, thorough understanding of the patho-
physiology underlying these (neuro)endocrine
Received 20 June 2005 Accepted 31 October 2005
www.nature.com/clinicalpractice
changes is vital. Indeed, erroneously extrapolating
doi:10.1038/ncpendmet0071 the changes observed in the acute-disease state

20 NATURE CLINICAL PRACTICE ENDOCRINOLOGY & METABOLISM JANUARY 2006 VOL 2 NO 1

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to the chronic phase of critical illness has misled
investigators to use certain endocrine treat-
ments that unexpectedly increased rather than
decreased mortality.1,2 One of the reasons for this
misjudgment was that results from early studies
on this topic were confounded by side-effects of
drugs, such as dopamine among others, which
profoundly affect the circulating concentrations
of most anterior-pituitary-dependent hormones.3
It is now clear that the (neuro)endocrine
responses to acute and prolonged critical illness
are substantially different.4,5
In this review we discuss the updated knowl-
edge on the biphasic alterations occurring
within the (neuro)endocrine system observed
during the two phases of critical illness and
summarize the therapeutic implications of these
novel insights.
THE SOMATOTROPIC AXIS
The regulation of the physiologic pulsatile release
of growth hormone (GH) by the somatotrope
cells in the anterior pituitary is highly complex.
Hypothalamic GH-releasing hormone (GHRH)
stimulates, and somatostatin inhibits, the secre-
tion of GH. Several synthetic GH-releasing
peptides (GHRPs) and nonpeptide analogues
with potent GH-releasing activity have been
developed.6 These GHRPs act via a G-protein-
coupled receptor located in the hypothalamus
and the pituitary.7 Ghrelin is a highly conserved
endogenous ligand for this receptor, and appears
to be a third key factor in the physiologic control
of GH release.8
GH exerts direct and indirect effects, the latter
being mediated by insulin-like growth factor I
(IGF-I), of which the bioactivity in turn is regu-
lated by several IGF-binding proteins (IGFBPs).
The pulsatile nature of GH secretion, consisting
of peak serum GH levels alternating with virtu-
ally undetectable troughs, is important for its
metabolic effects.9
The somatotropic axis in the acute phase
of critical illness
During the first hours to days after an acute
insult, the GH profile changes dramati-
cally (Figure 1). The amount of circulating
GH rises, with high peaks and interpulse
concentrations as well as an increased pulse
frequency.4,10 Concomitantly, a state of periph-
eral GH resistance develops,10,11 in part trig-
gered by CYTOKINES, such as tumor necrosis
factor α and interleukin-6. Indeed, despite the
JANUARY 2006 VOL 2 NO 1 VANHOREBEEK ET AL.
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Health Acute phase Chronic phase
14 14 14
GH (μg/l)
7 7 7
0 0 0
21:00 06:00 21:00 06:00 21:00 06:00
Time Time Time
Figure 1 Response of the somatotropic axis to critical illness. The nocturnal
growth-hormone serum concentration profile over time (X axis) is dramatically
altered in response to critical illness, with marked differences between the
acute and chronic phase of the disease. Reproduced with permission from
reference 4 © (1998) The Endocrine Society.
clearly enhanced GH secretion, levels of IGF-I, GLOSSARY
GH-dependent IGFBP-3 and the acid- INNATE IMMUNITY
First line of defense
labile subunit (ALS) of the ternary complex against infection, in
decrease.10,12 An enhanced clearance of IGF-I, in which phagocytic cells
use primitive nonspecific
part related to changes in IGFBPs, also contrib- recognition systems to kill
utes to its low serum levels. These events are microorganisms
preceded by a drop in circulating GH-binding CYTOKINES
protein, which presumably reflects the functional Intercellular soluble
proteins that activate and
GH receptor status.12 regulate inflammatory and
Reduced expression of the GH receptor,12,13 immune responses through
and therefore low circulating IGF-I, has been interactions with specific
receptors
suggested to be the primary event driving the
abundant release of GH in the acute phase of
stress as the result of reduced negative-feedback
inhibition. Theoretically, this constellation
could enhance the direct lipolytic and insulin-
antagonizing effects of GH, resulting in elevated
fatty-acid and glucose levels in the circulation,
whereas the indirect, IGF-I-mediated somato-
tropic effects of GH are attenuated. As a result,
costly anabolism, largely mediated by IGF-I and
considered less vital at this time, could be post-
poned. Hence, from a teleologic point of view,
this response to acute injury within the GH axis
seems appropriate in the struggle for survival.
The somatotropic axis in the prolonged
phase of critical illness
In contrast with the observations during the
acute phase of critical illness, the pulsatile
release of GH is suppressed in patients who are
critically ill for a prolonged time, whereas the
nonpulsatile fraction of GH release remains
somewhat elevated (Figure 1).14–16 Unlike the
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A 50 Placebo 50 GHRH 50 GHRP-2 50 GHRH + GHRP-2

40 40 40 40

GH (μg/l)
30 30 30 30
20 20 20 20
10 10 10 10
0 0 0 0

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21:00 06:00 21:00 06:00 21:00 06:00 21:00 06:00
Time Time Time Time

B 150
IGF-1 R2 = 0.67

concentration (%)
100 ALS R2 = 0.76

Change in
IGFBP-3 R2 = 0.57
50

–50
0 100 200 300 400 500 600
Pulsatile GH
(μg/lv over 9 h)
Figure 2 Effects of a growth-hormone secretagogue on the somatotropic axis in prolonged critical
illness. (A) Nocturnal serum growth hormone profiles with continuous infusion of placebo, growth-
hormone-releasing hormone (1 μg/kg/h), growth-hormone-releasing peptide 2 (1 μg/kg/h) or growth-
hormone-releasing hormone + growth-hormone-releasing peptide 2 (1 + 1 μg/kg/h) starting from 12 h before
onset of the respective profiles. The age range of the patients was 62–85 years and duration of illness was
between 13 and 48 days. (B) Exponential regression lines have been reported between pulsatile growth-
hormone secretion and the changes in circulating insulin-like growth factor I, acid-labile subunit and
IGF-binding protein 3 (for a detailed description, see reference 15). They indicate that the parameters
of growth-hormone responsiveness increase in proportion to growth-hormone secretion up to a point,
beyond which a further increase in growth-hormone secretion has apparently little or no additional effect.
It is noteworthy that the latter point corresponds to a pulsatile growth-hormone secretion of approximately
200 μg/lv over 9 h or less, a value that can be evoked by the infusion of growth-hormone-releasing peptide
2 alone. In the chronic, nonthriving phase of critical illness, growth-hormone sensitivity is clearly present, in
contrast to the acute phase of illness, in which a lack of sensitivity is thought to be primarily a condition of
growth-hormone resistance. Modified with permission from reference 4 © (1998) The Endocrine Society.
ALS, acid-labile subunit; GH, growth hormone; GHRH, GH-releasing hormone; GHRP-2, GH-releasing
peptide 2; IGF-I, insulin-like growth factor I; IGFBP-3, IGF-binding protein 3.

previous assumption that GH resistance persists
throughout critical illness, it has now become
clear that GH responsiveness at least partially
recovers in the chronic phase of critical illness.
A strong positive correlation has been found
between the pulsatile fraction of GH release and
circulating IGF-I, IGFBP-3 and ALS levels,14–16
which suggests that the loss of pulsatile GH
release contributes to the low levels of IGF-I,
IGFBP-3 and ALS in prolonged critical illness.
The administration of GH secretagogues (GHSs)
has, furthermore, been shown to increase IGF-I
and GH-dependent IGFBP levels.14,15 Since
the robust release of GH in response to GHSs
(Figure 2) excludes a possible inability of the
somatotropes to synthesize GH, the origin of the
relative hyposomatotropism is probably situated
within the hypothalamus. In addition, since
the release of GH in response to GHRH injec-
tion is less pronounced than that to a GHRP-2
injection in prolonged critical illness,9 a hypo-
thalamic deficiency or inactivity of endogenous
GHRP-like GHSs is a more plausible cause of the
hyposomatotropism than is GHRH deficiency.
On the other hand, the profound release of GH
in response to GHS could also be explained by a
reduced somatostatin tone. This interpretation
cannot, however, be reconciled with the spon-
taneous dynamics of low-amplitude GH bursts
and is thus less likely.

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The above-described ‘relative hypo- A Health Acute phase Chronic phase

somatotropism’, due to lack of pulsatile GH 7 7 7
secretion, is thought to contribute to the patho-

TSH (mlU/l)
genesis of the ‘wasting syndrome’ that character-
izes prolonged critical illness. This is suggested
from the tight relation between biochemical
markers of impaired anabolism, such as low
serum osteocalcin and leptin concentra-
0 0 0
tions and the low serum levels of IGF-I and
21:00 06:00 21:00 06:00 21:00 06:00
ternary-complex-binding proteins.16 Time Time Time

THE THYROID AXIS B Acute phase Chronic phase

Thyrotropin-releasing hormone (TRH), secreted changes in peripheral + neuroendocrine component
by the hypothalamus, stimulates the pituitary matabolism and binding
thyrotropes to produce TSH (thyrotropin) which,
in turn, regulates the synthesis and secretion of TRH TRH

thyroid hormones in the thyroid gland. Although

the thyroid gland predominantly produces T4,
the biologic activity of thyroid hormones is
largely exerted by T3.17 Different types of deio-
dinase are responsible for the peripheral activa-
tion of T4 to T3 or alternative conversion to the
biologically inactive reverse T3 (rT3),18 processes
that inherently require the presence of specific
thyroid-hormone transporters.19 The thyroid
hormones in their turn exert feedback control
on both TRH and TSH secretion.
The thyroid axis in the acute phase
of critical illness
The early response of the thyroid axis to a severe
physical stress consists of a rapid decline in the
circulating levels of T3 and a rise in rT3 levels,
predominantly as a consequence of altered
peripheral conversion of T4.20 TSH and T4
levels are elevated very briefly and subsequently
return to ‘normal’, although in the more severe
illness, T4 levels can also decrease (Figure 3).21
The low T3 levels persist beyond TSH
normalization, a condition referred to as ‘the
low T3 syndrome’. Although serum TSH levels
measured in a single daytime sample are normal
in acute critical illness, the TSH profile is already
affected as the normal nocturnal TSH surge is
absent.22 The severity of illness is reflected in
the degree of the fall in serum T3 during the first
24 h after the insult. Furthermore, an inverse
correlation between T3 levels and mortality has
been demonstrated.
Cytokines have been proposed as key factors
contributing to the low T3 syndrome, but cyto-
kine antagonists fail to restore normal thyroid
function after endotoxemic challenge.23 Other
factors possibly involved as triggers for the low-T3
TSH ( )= TSH
T4 ( )= T4
D2, D1 D3, D1 D2, D1 D3, D1
T3 rT3 T3 rT3 ( )=
D3, D1 D1, D2 D3, D1 D1, D2
T2 T2
Figure 3 Response of the thyroid axis to critical illness. (A) The nocturnal
serum concentration profiles of TSH in critical illness are abnormal and differ
markedly between the acute and chronic phase of the disease. Modified, with
permission, from reference 4 © (1998) The Endocrine Society. (B) Simplified
overview of the major changes occurring within the thyroid axis during the
acute and the chronic phase of critical illness. The normal regulation of the
thyroid axis is shown in black, whereas the alterations induced by critical illness
are indicated in gray. As indicated in the main text for the acute phase of critical
illness, TSH and T4 levels are elevated very briefly and subsequently return to
normal [represented by ( ) = in the figure]. Reproduced with permission from
reference 21 (2000) Society of the European Journal of Endocrinology.
D, iodothyronine deiodinase; T2, di-iodothyronine; TRH, thyrotropin-releasing
hormone; rT3, reverse T3.
syndrome at the tissue level include low concentra-
tions of thyroid-hormone-binding proteins
and inhibition of hormone binding, transport
and metabolism by elevated levels of free fatty
acids and bilirubin.24
During starvation, the immediate fall in circu-
lating T3 has been regarded as an appropriate
response in an attempt to reduce energy expen-
diture, and thus as an occurrence that warrants
no intervention.25 Reduced thyroid hormone

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A Placebo TRH TRH + GHRP-2 action in the acute phase of critical illness could
7 7 7 therefore be interpreted as beneficial when
6 6 6
exogenous provision of substrates is reduced. The
TSH (mlU/l)

5 5 5
4 4 4
validity of extrapolating this interpretation from
3 3 3 simple starvation to the acute phase of critical
2 2 2 illness, which is also accompanied by temporary
1 1 1 starvation, is still a matter of controversy.26
0 0 0
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21:00 06:00 21:00 06:00 21:00 06:00 The thyroid axis in the prolonged phase
Time Time Time of critical illness
B 80 P <0.0001 80 P <0.001
In prolonged critical illness, pulsatile TSH
Change in T4/24 h (%)

secretion is dramatically reduced (Figure 3).

Furthermore, serum levels of both T4 and T3
are low and the decline in T3 in particular corre-
lates positively with the diminished pulsatile
release of TSH.27 An alteration in the set-point
0 0 for feedback inhibition, impaired capacity of
–20 –20 the thyrotropes to synthesize TSH, inadequate
TRH-induced stimulation of TSH and elevated
140 P <0.0001 140 P <0.001
somatostatin tone could explain these findings.
Change in T3 /24 h (%)

Reduced TRH gene expression in the hypo-

thalamus has been described in specimens from
chronically ill patients who died,28 which is in
0 0 line with a predominantly central origin of the
suppressed thyroid axis, similar to lack of GHS
–80 –80 activity explaining the alterations within the
somatotropic axis. In addition, the rise in TSH
70 P <0.05 70 secretion and in peripheral thyroid-hormone
Change in T3 /24 h (%)

levels with an intravenous infusion of TRH in

0 0
–20 –20
Placebo TRH
Figure 4 Effects of thyrotropin-releasing hormone and a growth-hormone
secretagogue on the thyroid axis in prolonged critical illness. (A) Nocturnal
serum TSH profiles with continuous infusion of placebo, of thyrotropin-
releasing hormone (1 μg/kg/h) or of thyrotropin-releasing hormone + growth-
hormone-releasing peptide 2 (1 + 1μg/kg/h). The age range of the patients was
69–80 years and duration of illness was between 15 and 18 days. Although
thyrotropin-releasing hormone elevated the TSH secretion, addition of growth-
hormone-releasing peptide to the thyrotropin-releasing-hormone infusion
appeared necessary to increase its pulsatile fraction. Reproduced with
permission from reference 4 © (1998) The Endocrine Society. (B) Continuous
administration of thyrotropin-releasing hormone (1 μg/kg/h), infused alone or
together with growth-hormone-releasing peptide 2 (1 + 1μg/kg/h), induces a
significant rise in serum T4 and T3 within 24 h. Here, reverse T3 is increased
after the infusion of thyrotropin-releasing hormone alone, but not if thyrotropin-
releasing hormone is co-infused with growth-hormone-releasing peptide 2.
The patients studied were ill for 12–59 days; the age range was 32–87 years.
Modified with permission from reference 4 © (1998) The Endocrine Society.
GHRP-2, growth-hormone-releasing peptide 2; GHS, growth-hormone
secretagogue; rT3, reverse T3; TRH, thyrotropin-releasing hormone.
prolonged critically ill patients15,16 is consis-
tent with such an interpretation (Figure 4).
Furthermore, reduced GHS action might also be
involved, as the pulsatility of the TSH secretory
pattern is only improved when TRH is infused
together with a GHRP.15 Since circulating cyto-
GHRP-2 TRH
+ kine levels are usually much lower than in the
GHRP-2 acute phase, other factors such as endogenous
dopamine and prolonged hypercortisolism
might be important.29,30
A disturbed peripheral metabolism of thyroid
hormone is another factor contributing to the
low-T3 syndrome in the chronic phase of crit-
ical illness (Figure 3). This is illustrated by a
reduced activity of type 1 deiodinase (D1), the
enzyme mediating peripheral conversion of T4
to T3, and the induction of type 3 deiodinase
(D3) activity, responsible for conversion of T4
to inactive rT3 in liver, muscle or both.31 Serum
levels of rT3 and the ratio of T3 to rT3 were also
demonstrated to correlate with post-mortem
tissue deiodinase activity.32 Interestingly,
combined infusion of TRH and GHRP-2 not
only increased TSH, T4 and T3 levels but also
prevented the rise in rT3 seen with infusion of

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TRH alone (Figure 4). This suggests that deio-
dinase activity might be affected by GHRP-2,
either directly or indirectly, through its effect
on the somatotropic axis. Combined administra-
tion of TRH and GHRP-2 to a rabbit model of
prolonged critical illness indeed augmented
D1 and decreased D3 activity.33 A recent study
showed that D1 suppression in critical illness
is related to alterations within the thyroid axis,
whereas D3 is increased under joint control of the
somatotropic and thyroid axes.34 Importantly,
regulation of thyroid-hormone action at the level
of the thyroid-hormone receptor also appears
to be altered by critical illness, so that thyroid-
hormone sensitivity might be upregulated in
response to low T3 levels (Timmer et al., personal
communication). The prognostic value of the
disturbed thyroid axis with regard to mortality
is illustrated by the lower TSH, T4 and T3 and
higher rT3 levels in patients who ultimately die
as compared with those surviving prolonged
critical illness.32
THE GONADAL AXIS
Gonadotropin-releasing hormone (GnRH),
secreted in a pulsatile pattern by the hypo-
thalamus, stimulates the release of luteinizing
hormone (LH) and follicle-stimulating hormone
(FSH) from the gonadotropes in the pituitary.35
In men, LH stimulates the production of andro-
gens (testosterone and androstenedione) by the
Leydig cells in the testes, whereas the combined
action of FSH and testosterone on Sertoli cells
supports spermatogenesis. In women, LH also
mediates androgen production by the ovary,
whereas FSH drives the aromatization of andro-
gens to estrogens in the ovary. Sex steroids exert
a negative feedback on GnRH and gonadotropin
secretion. Several other hormones and cytokines
are also involved in the complex regulation of
the gonadal axis.35 Clinical data on the changes
within the gonadal axis are scarce in critically ill
women, as most patients are of high age and thus
in the menopausal state. Therefore, we focus on
the changes documented in critically ill men.
The gonadal axis in the acute phase
of critical illness
Conditions of acute stress, such as surgery or
myocardial infarction, bring along an imme-
diate fall in the serum levels of testosterone,36–38
even though LH levels are elevated. The exact
cause remains obscure but involvement of
cytokines is again possible, as put forward by
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experimental studies.39,40 Switching off the
secretion of anabolic androgens can be viewed,
at least in the short term, as an attempt to reduce
energy consumption and conserve substrates for
more-vital functions.
The gonadal axis in the prolonged phase
of critical illness
With prolongation of the disease, more dramatic
changes develop within the male gonadal axis,
and hypogonadotropism ensues.41,42 The circu-
lating levels of testosterone become extremely
low and are often even undetectable, yet the mean
LH concentrations and pulsatile LH release are
suppressed.43,44 Total estradiol levels are also
relatively low. The level of bioavailable estradiol
is, however, probably maintained in view of the
simultaneous decrease in sex-hormone-binding
globulin.44 On the other hand, a remarkable
rise in estrogen levels has been observed in other
studies.35 Together, these data point to increased
aromatization of androgens. Multiple mechanisms
can be invoked to explain the profound hypo-
androgenism.35 Since exogenous GnRH is only
partially and transiently effective in correcting
these abnormalities, they must result from
combined central and peripheral defects within
the male gonadal axis.44 Endogenous dopamine,
opiates and particularly the maintained bioactive
estradiol level all could be involved,43–45 as well
as prolonged exposure of the brain to increased
local levels of cytokines.39 The abnormalities in
the gonadal axis could be important with regard to
the catabolic state of critical illness as testosterone
is the most potent endogenous anabolic steroid.
PROLACTIN
Prolactin is a well-known stress hormone,
which is physiologically secreted in a pulsatile
and diurnal pattern,46 and is presumed to have
immune-enhancing properties.
Prolactin in the acute phase of critical
illness
Prolactin levels rise in response to acute phys-
ical or psychological stress.4,47 Factors possibly
involved are vasoactive intestinal peptide,
oxytocin and dopaminergic pathways, but again
cytokines or as-yet uncharacterized factors
might also play a role. The elevated serum
prolactin concentrations following acute stress
are thought to contribute to the vital activa-
tion of the immune system early in the disease
process, but this remains speculative.
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GLOSSARY
T LYMPHOCYTE
A type of leukocyte that
is central to all adaptive
immune responses,
characterized by high
specificity for a particular
pathogen
26 NATURE CLINICAL PRACTICE ENDOCRINOLOGY & METABOLISM
Prolactin in the prolonged phase of critical
illness
The pulsatile fraction of prolactin release
becomes suppressed in patients with prolonga-
tion of a life-threatening disease.4,27 The impair-
ment of prolactin secretion during chronic illness
has recently been confirmed in an animal model
of prolonged critical illness.5 Endogenous dopa-
mine might, again hypothetically, play a role.29 It
is unclear whether the blunted prolactin secre-
tion contributes to the immune suppression or
increased susceptibility to infection associated
with prolonged critical illness.48 This remains
a tempting speculation since exogenous dopa-
mine, a frequently used inotropic drug, further
suppresses prolactin secretion and concomitantly
aggravates T-LYMPHOCYTE dysfunction and
disturbed neutrophil chemotaxis.29,49
THE ADRENAL AXIS
In a stress-free healthy human, cortisol is secreted
from the adrenal cortex according to a diurnal
pattern. Cortisol release is controlled by adreno-
corticotropic hormone (ACTH, also known as
corticotropin) produced by the pituitary, in turn
under the influence of the hypothalamic cortico-
tropin-releasing hormone (CRH).50 Cortisol
itself exerts negative-feedback control on both
hormones. More than 90% of circulating cortisol
is bound to binding proteins, predominantly
corticosteroid-binding globulin (CBG) but also
albumin. Only the free hormone, however, is
biologically active.
The adrenal axis in the acute phase
of critical illness
Cortisol levels usually rise in the early phase of
critical illness, in response to an increased release
of CRH and ACTH, either directly or via resis-
tance to or inhibition of the negative-feedback
mechanism exerted by cortisol.50,51 Several of
the elevated cytokines have also been shown to
modulate cortisol production, as well as gluco-
corticoid receptor number or affinity, or both.52
CBG levels are, moreover, substantially decreased,
in part due to elastase-induced cleavage,53,54
resulting in proportionally much higher increases
in the free hormone.55,56 The diurnal variation in
cortisol secretion is lost in response to any type of
acute illness or trauma.50
An appropriate activation of the hypo-
thalamic–pituitary–adrenal axis and cortisol
response to critical illness is essential for survival,
since both very high and low cortisol levels have
©2006 Nature Publishing Group
been associated with increased mortality.57–62
High cortisol levels reflect more-severe stress,
whereas low levels point to an inability to
sufficiently respond to stress, labeled ‘relative
adrenal insufficiency’. The vital stress-induced
hypercortisolism in critically ill patients fosters
the acute provision of energy by altering carbo-
hydrate, fat and protein metabolism, protects
against excessive inflammation by suppression
of the inflammatory response and improves
hemodynamic status by induction of fluid
retention and sensitization of the vasopressor
response to catecholamines.4,52
The adrenal axis in the prolonged phase
of critical illness
Hypercortisolism is usually sustained in the
chronic phase of critical illness, but appears to
be driven by non-ACTH-mediated pathways
since ACTH levels are low.63,64 Cortisol levels
only slowly decrease, reaching normal levels in
the recovery phase.4 CBG levels recover in the
chronic phase of illness.55
Whether the persisting elevation in cortisol
is exclusively beneficial in prolonged critical
illness remains uncertain. Theoretically, it
could contribute to the increased susceptibility
to infectious complications. Alternatively, the
risk of ‘relative adrenal failure’ might increase in
the chronic phase of critical illness65 and could
predispose to adverse outcome.
VASOPRESSIN AND CATECHOLAMINES
Vasopressin (also known as antidiuretic
hormone) is synthesized as a large prohormone
in the hypothalamus.66 The prohormone
complex is transported to the posterior pitu-
itary, where it is stored in granules. Vasopressin is
released mainly in response to hyperosmolality,
hypotension and hypovolemia and has vaso-
pressor and antidiuretic effects. Vasopressin
levels increase rapidly in the early phase of
certain stressful situations such as hemorrhagic
and septic shock.66 With persistence of the septic
shock state, however, vasopressin levels fall
to very low levels compared with other causes
of hypotension.
Such a biphasic response could also be present
for catecholamines, other hormones with vaso-
pressor or inotropic activity, all derived from
tyrosine. An elevated release of norepinephrine
and epinephrine has been demonstrated for a
variety of acute clinical conditions, including
major surgery, trauma, hemorrhage and severe
VANHOREBEEK ET AL. JANUARY 2006 VOL 2 NO 1

sepsis.67 With prolongation of the illness, levels
of norepinephrine and epinephrine decrease.67
In severe sepsis, catecholamines must be
administered exogenously when the disease
has proceeded to the state of prolonged hypo-
tension. Scarce data on serum levels of dopa-
mine during critical illness in humans showed
increased levels in patients with chronic heart
failure or pulmonary tuberculosis.68
THERAPEUTIC IMPLICATIONS
Differentiation between beneficial and harmful
(neuro)endocrine responses to critical illness
is difficult, but extremely important before
considering therapeutic intervention. The endo-
crine adaptations in the acute phase are probably
directed towards reduced energy and substrate
consumption, drive the release of substrates for
vital tissues, postpone costly anabolism and
modulate the immune responses in order to
improve chances for survival. Thus, the hyper-
catabolic reaction is probably beneficial and, at
present, there is no evidence that supports inter-
vention. In the chronic phase of critical illness,
however, sustained hypercatabolism despite
feeding results in substantial loss of lean body
mass and often concomitant fatty infiltration
of vital organs, which can compromise vital
functions, cause weakness and delay or hamper
recovery. A strategy of therapeutic intervention
to correct these abnormalities could theoretically
improve survival. Several hormonal therapies
have been proposed with varying success (see
Box 1). 69–74
In view of the uniform hypoactivity of most
hypothalamic–pituitary axes during prolonged
critical illness, treatment with hypothalamic
releasing factors to reactivate the pituitary could
be more effective and safer than administration
of pituitary or peripheral hormones. Indeed,
infusions of GHS, TRH or GnRH reactivate
the corresponding pituitary axes, resulting in
elevated levels of the corresponding periph-
eral effector hormones (as described above).
Concomitant infusion of GHRP-2 and TRH
furthermore reactivates both the somatotropic
and thyrotropic axes, but prevents the rise of
inactive rT3 levels seen with infusion of TRH
alone.15 This intervention was shown to be
associated with a reduction in hypercatabolism
and stimulation of anabolism.16 Additional
coactivation of the gonadal axis by adminis-
tering GnRH together with GHRP-2 and TRH
in men with prolonged critical illness at least
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©2006 Nature Publishing Group
REVIEW
www.nature.com/clinicalpractice/endmet
Box 1 Proposed therapeutic strategies to correct the (neuro)endocrine
abnormalities in prolonged critical illness.
Administration of supraphysiologic doses of growth hormone (GH), inspired by
the assumption of sustained GH resistance in the prolonged phase of critical
illness, unexpectedly reveals a significant increase in morbidity and mortality.1 It
is now clear, however, that peripheral GH sensitivity at least partially recovers in
the chronic phase of critical illness. Hence, the administration of such high doses
(up to 20 times the substitution dose) could expose patients to toxic side effects.
Alternatively, infusion of insulin-like growth factor I inhibits protein breakdown,
stimulates protein synthesis69 and reduces postoperative catabolism. The efficacy
of the intervention is, however, reduced with prolonged administration. Initial trials
studying administration of high doses of glucocorticoids have clearly shown that
this strategy is ineffective and perhaps even harmful.2,70 In contrast, studies using
much lower doses—which, although the doses used were still high (200–300 mg
hydrocortisone per day), had been labeled ‘low-dose’ glucocorticoid-replacement
therapy for relative adrenal insufficiency—reported beneficial effects, at least in
patients with septic shock.61,70 It remains controversial whether administration of
thyroid hormone to critically ill patients is beneficial or harmful71 and no conclusive
clinical benefit has been demonstrated for androgen treatment in prolonged
critical illness.72,73 Broad clinical use of vasopressin should await the results of
randomized controlled trials for the assessment of safety and efficacy to improve
outcome, now in progress for patients with vasodilatory shock.66,74 The use of
catecholamines is often required, but whether either norepinephrine or epinephrine
is superior to the other for hemodynamic stabilization in septic shock needs to
be delineated by large clinical trials.74 On the other hand, it is now clear that low-
dose dopamine has many side effects, including suppression of anterior-pituitary
hormones, and is not successful in organ protection.3
Box 2 Hyperglycemia and insulin resistance.
Critically ill patients usually develop hyperglycemia, known as ‘stress diabetes’ or
‘diabetes of injury’. In the acute phase of critical illness, hepatic glucose production is
accelerated by upregulation of gluconeogenesis and glycogenolysis. After a transient
fall in insulin levels hyperinsulinemia develops. Such high insulin levels normally
suppress both pathways but in critical illness are unable to maintain normoglycemia.
Increased levels of glucagon, growth hormone, cortisol, catecholamines and
cytokines all play a role. How the hyperglycemic response is maintained during
prolonged critical illness remains relatively unclear. In comparison with the acute
phase, growth-hormone, cortisol, catecholamine and cytokine levels are usually
decreased in the chronic phase of critical illness, whereas glucagon levels are not
well documented. Glucose uptake mechanisms are affected by critical illness, which
also contributes to the hyperglycemia. Exercise-stimulated glucose uptake in skeletal
muscle almost totally disappears as the patient is immobilized. Insulin-stimulated
glucose uptake by glucose transporter 4 is compromised. Total body glucose uptake
is, however, increased, accounted for by tissues that are not dependent on insulin for
glucose uptake. The higher levels of insulin, the elevated hepatic glucose production
and impaired peripheral glucose uptake reflect the development of peripheral insulin
resistance during critical illness.
partially restores the three pituitary axes and
appears to induce an even more pronounced
anabolic effect.75 These data underline the
interaction among the different endocrine axes
NATURE CLINICAL PRACTICE ENDOCRINOLOGY & METABOLISM 27
REVIEW
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Box 3 Eye to the future.
The ultimate goal of intensive-care medicine is
to improve survival and to enhance rehabilitation
of critically ill patients. On the basis of the
new insights into the endocrine alterations
associated with critical illness, the involvement
of these alterations in the risk of morbidity and
mortality and the interaction among different
endocrine systems, suggestions for several first-
priority clinical trials emerge. The concomitant
administration of thyrotropin-releasing hormone
and growth-hormone-releasing peptide 2—
superimposed on strict glycemic control with
intensive insulin therapy—holds promise for the
future, but needs to be tested in a large-scale
clinical outcome study, which awaits the availability
of these hormone-releasing factors. Furthermore,
in view of the glucose-counter-regulatory effects
of growth hormone and glucocorticoids and the
benefits of preventing hyperglycemia with insulin,
one could also hypothesize that when growth-
hormone or glucocorticoid therapy is combined
with tight blood glucose control, the negative
outcome with these interventions could be in
part prevented.
Serum concentration or secretion
and the superiority of jointly correcting all hypo-
thalamic–pituitary defects instead of applying a
single hormone treatment. Importantly, over-
stimulation of the respective axes, and thus
toxic side effects of high peripheral hormone
levels, are avoided, since endogenous negative-
feedback mechanisms and the ability to adap-
tively change peripheral hormonal metabolism
remain intact during critical illness.15,16,75
It is crucial to take into account certain side
effects of single-hormone treatments when inter-
preting results of available clinical studies. Since
high doses of GH and of glucocorticoids exert
unexpected negative effects, perhaps a mutual
side effect is the missing link. Indeed, high
doses of either GH or glucocorticoids aggravate
the insulin resistance and hyperglycemia that
usually develop during critical illness (Box 2).76
Hence, the toxic side effects of glucose counter-
regulation might have surpassed any possible
benefits of these therapies.1,2,70 Indeed, although
it had long been commonly accepted that stress-
induced hyperglycemia is beneficial to organs
that largely rely on glucose for energy supply but
do not require insulin for glucose uptake, recent

Cortisol

Normal
level

Anterior pituitary hormones

Target-organ hormones

Acute Chronic Recovery

phase phase phase

Figure 5 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 (green) are inactivated.
Cortisol levels (blue) are elevated in concert with adrenocorticotropic hormone. 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
hormone secretion from the anterior pituitary (red) allows the respective target-organ hormones to decrease
proportionally over time, with cortisol being a notable exception; the circulating levels of cortisol remain
elevated through a peripheral drive, a mechanism that ultimately might also fail. The onset of recovery is
characterized by restored sensitivity of the anterior pituitary to reduced feedback control. Shaded areas
represent the range within which the hormonal changes occur. Reproduced with permission from
reference 4 © (1998) The Endocrine Society.

28 NATURE CLINICAL PRACTICE ENDOCRINOLOGY & METABOLISM VANHOREBEEK ET AL. JANUARY 2006 VOL 2 NO 1

©2006 Nature Publishing Group


data on strict blood glucose control with inten-
sive insulin therapy clearly proved otherwise. In
a large group of surgical-intensive-care patients,
this intervention strikingly lowered mortality
in patients who had prolonged critical illness
and largely prevented several complications
associated with critical-illness.77 The patients
less frequently developed critical-illness poly-
neuropathy, bloodstream infections, acute renal
failure and anemia and were less dependent on
prolonged mechanical ventilation and inten-
sive care. In addition, a protective effect on the
peripheral nervous system, and in brain-injured
patients also on the central nervous system, has
been demonstrated.78 Even moderate hyper-
glycemia appeared, moreover, to be detrimental
to the patients.78,79 Both avoiding glucose
toxicity and nonglycemic effects of insulin
are important in order to bring about clinical
benefits.80 Several other large clinical trials on
intensive insulin therapy are ongoing. Safety and
efficacy of other hormonal interventions might
also improve when they are combined with this
therapy (Box 3).
CONCLUSIONS
The anterior pituitary responds biphasically to
the severe stress of illness and trauma (Figure 5).
In the acute phase of critical illness the pituitary
is actively secreting, but target organs become
resistant and concentrations of most peripheral
effector hormones are low. These acute adapta-
tions are probably beneficial in the struggle
for short-term survival, refuting the need for
intervention. In contrast, prolonged, intensive-
care-dependent critical illness is hallmarked
by a uniform (predominantly hypothalamic)
suppression of the (neuro)endocrine axes,
which contributes to the low serum levels of the
respective target-organ hormones. These chronic
alterations might no longer be beneficial, espe-
cially in view of their participation in the general
wasting syndrome of prolonged critical illness.
Attempts to reverse these abnormalities with
hormonal therapies have demonstrated that the
choice of hormone and corresponding dosage
are of crucial importance and lack of patho-
physiologic insight holds danger. The only inter-
ventions that have so far proven to beneficially
affect outcome of critical illness are intensive
insulin therapy and, perhaps in some patients,
hydrocortisone therapy. On the other hand,
concomitant reactivation of the somatotropic,
thyrotropic and gonadal axes with hypothalamic
JANUARY 2006 VOL 2 NO 1 VANHOREBEEK ET AL.
©2006 Nature Publishing Group
REVIEW
www.nature.com/clinicalpractice/endmet
releasing factors holds promise as a safe therapy
to reverse the (neuro)endocrine and metabolic
abnormalities of prolonged critical illness.
KEY POINTS
■ The (neuro)endocrine responses to acute and
prolonged critical illness are substantially different;
in the acute phase, the adaptations are probably
beneficial in the struggle for short-term survival,
whereas the chronic alterations participate in the
wasting syndrome of prolonged critical illness and
can be maladaptive
■ Thorough understanding of the
pathophysiology underlying endocrine
disturbances in critical illness is of vital importance
when considering new therapeutic strategies to
correct these abnormalities; indeed, the choice
of hormone and corresponding dosage are
crucial and lack of insight has been shown to
be dangerous.
■ In contrast to the classic dogma that stress-
induced hyperglycemia is beneficial to organs that
largely rely on glucose for energy supply but do
not require insulin for glucose uptake, it is now
clear that the development of hyperglycemia is
an important risk factor in terms of mortality and
morbidity of critically ill patients; importantly, strict
blood glucose control with intensive insulin therapy
improves survival and largely prevents several
critical-illness-induced complications
■ A remarkable interaction has been
demonstrated among the different (neuro)endocrine
axes; the concomitant administration of several
hypothalamic releasing factors holds promise as
an effective and safe intervention to jointly restore
the corresponding axes and to counteract the
hypercatabolic state of prolonged critical illness
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