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The stress response is subserved by the stress system, which is located both in the central nervous system and the periphery. The principal effectors of the stress system include corticotropin-releasing hormone (CRH); arginine vasopressin; the proopiomelanocortin-derived peptides alpha-melanocyte-stimulating hormone and beta-endorphin, the glucocorticoids; and the catecholamines norepinephrine and epinephrine. Appropriate responsiveness of the stress system to stressors is a crucial prerequisite for a sense of well-being, adequate performance of tasks, and positive social interactions. By contrast, inappropriate responsiveness of the stress system may impair growth and development and may account for a number of endocrine, metabolic, autoimmune, and psychiatric disorders. The development and severity of these conditions primarily depend on the genetic vulnerability of the individual, the exposure to adverse environmental factors, and the timing of the stressful events, given that prenatal life, infancy, childhood, and adolescence are critical periods characterized by increased vulnerability to stressors.
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Annu. Rev. Physiol. 2005. 67:259–84
doi: 10.1146/annurev.physiol.67.040403.120816
2005 by Annual Reviews. All rights reserved
Evangelia Charmandari, Constantine Tsigos,
and George Chrousos
Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health
and Human Development, National Institutes of Health, Bethesda, Maryland 20892,
and Hellenic National Diabetes Center, Athens, 10675, Greece;
stress system, endocrinology of stress, stress-related disorders
Abstract The stress response is subserved by the stress system, which is lo-
cated both in the central nervous system and the periphery. The principal effectors
of the stress system include corticotropin-releasing hormone (CRH); arginine va-
sopressin; the proopiomelanocortin-derived peptides α-melanocyte-stimulating hor-
mone and β-endorphin, the glucocorticoids; and the catecholamines norepinephrine
and epinephrine. Appropriate responsiveness of the stress system to stressors is a cru-
cial prerequisite for a sense of well-being, adequate performance of tasks, and positive
social interactions. By contrast, inappropriate responsiveness of the stress system may
impair growth and development and may account for a number of endocrine, metabolic,
autoimmune, and psychiatric disorders. The development and severity of these con-
ditions primarily depend on the genetic vulnerability of the individual, the exposure
to adverse environmental factors, and the timing of the stressful events, given that
prenatal life, infancy, childhood, and adolescence are critical periods characterized by
increased vulnerability to stressors.
Life exists through maintenance of a complex dynamic equilibrium, termed home-
ostasis, that is constantly challenged by intrinsic or extrinsic, real or perceived,
adverse forces, the stressors (1, 2). Stress is defined as a state of threatened or per-
ceived as threatened homeostasis. The human body and mind react to stress by ac-
tivating a complex repertoire of physiologic and behavioral central nervous system
and peripheral adaptive responses, which, if inadequate or excessive and/or pro-
longed, may affect personality development and behavior, and may have adverse
consequences on physiologic functions, such as growth, metabolism, circulation,
reproduction, and the inflammatory/immune response (1, 2). The state of chronic
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dyshomeostasis due to inadequate or excessive/prolonged adaptive responses, in
which the individual survives but suffers adverse consequences, has been called
The present review focuses on the neuroendocrinology of the stress response
and the effects of stress on the major endocrine axes. It also provides a brief
overview of the altered regulation of the adaptive response in various physiologic
and pathologic states that may influence the growth and development of an in-
dividual and may define vulnerability of the individual to endocrine, psychiatric,
cardiovascular, neoplastic, or immunologic disorders.
Neuroendocrine Effectors of the Stress Response
The stress response is subserved by the stress system, which has both central ner-
vous system (CNS) and peripheral components (1–3). The central components of
the stress system are located in the hypothalamus and the brainstem, and include
(a) the parvocellular neurons of corticotropin-releasing hormone (CRH); (b) the
arginine vasopressin (AVP) neurons of the paraventricular nuclei (PVN) of the
hypothalamus; (c) the CRH neurons of the paragigantocellular and parabranchial
nuclei of the medulla and the locus ceruleus (LC); and (d) other mostly noradren-
ergic (NE) cell groups in the medulla and pons (LC/NE system). The peripheral
components of the stress system include (a) the peripheral limbs of the hypotha-
lamic-pituitary-adrenal (HPA) axis; (b) the efferent sympathetic-adrenome-
dullary system; and (c) components of the parasympathetic system (1–3)
(Figure 1).
The central neurochemical circuitry responsible for activation of the stress sys-
tem has been studied extensively. There are multiple sites of interaction among
the various components of the stress system. Reciprocal reverberatory neural con-
nections exist between the CRH and noradrenergic neurons of the central stress
system, with CRH and norepinephrine stimulating each other primarily through
CRH type 1 and α
-noradrenergic receptors, respectively (4–6). Autoregulatory
negative feedback loops are also present in both the PVN CRH and brainstem nora-
drenergic neurons (7, 8), with collateral fibers inhibiting CRH and catecholamine
secretion via presynaptic CRH and α
-noradrenergic receptors, respectively (7–9).
Both the CRH and the noradrenergic neurons also receive stimulatory innervation
from the serotoninergic and cholinergic systems (10, 11), and inhibitory input
from the γ -aminobutyric acid (GABA)-benzodiazepine (BZD) and opioid peptide
neuronal systems of the brain (7, 12, 13), as well as from the end-product of the
HPA axis, the glucocorticoids (7, 14).
Corticotropin-Releasing Hormone, Arginine Vasopressin,
and Catecholaminergic Neurons
CRH, a 41-amino acid peptide, is the principal hypothalamic regulator of the
pituitary-adrenal axis. CRH and CRH receptors have been detected in many
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TABLE 1 Behavioral and physical adaptation during acute stress
Behavioral adaptation: Physical adaptation:
adaptive redirection of behavior adaptive redirection of energy
Increased arousal and alertness Oxygen and nutrients directed to the CNS and
stressed body site(s)
Increased cognition, vigilance, and
focused attention
Altered cardiovascular tone, increased blood
pressure and heart rate
Euphoria (or dysphoria) Increased respiratory rate
Heightened analgesia Increased gluconeogenesis and lipolysis
Increased temperature Detoxification from toxic products
Suppression of appetite and feeding
Inhibition of growth and reproduction
Suppression of reproductive axis Inhibition of digestion-stimulation of colonic
Containment of the stress response Containment of the inflammatory/immune response
Adapted from Chrousos & Gold (2).
extrahypothalamic sites of the brain, including parts of the limbic system, the
basal forebrain, and the LC-NE sympathetic system in the brainstem and spinal
cord. Intracerebroventricular administration of CRH results in a series of behav-
ioral and peripheral responses, as well as activation of the pituitary-adrenal axis and
the sympathetic nervous system (SNS), indicating that CRH has a much broader
role in coordinating the stress response than initially recognized (1–3) (Table 1).
Since CRH was first characterized, a growing family of ligands and receptors has
evolved. The mammalian family members include CRH, urocortinI (UcnI), UcnII,
and UcnIII, along with two receptors, CRHR1 and CRHR2, and a CRH-binding
protein. These family members differ in their tissue distribution and pharmacol-
ogy and play an important role in the regulation of the endocrine and behavioral
responses to stress. Although CRH appears to play a stimulatory role in stress
responsivity through activation of CRHR1, specific actions of UcnII and UcnIII
on CRHR2 may be important for dampening stress sensitivity. UcnI is the only
ligand with high affinity for both receptors and its role may be promiscuous (15).
CRH receptors belong to the class B subtype of G protein–coupled receptors
(GPCR). CRHR1 and CRHR2 are produced from distinct genes and have several
splice variants expressed in various central and peripheral tissues (15). The CRH-
R1 subtype is widely distributed in the brain, mainly in the anterior pituitary, the
neocortex, and the cerebellum, as well as in the adrenal gland, skin, ovary, and
testis. CRH-R2 receptors are expressed mostly in the peripheral vasculature, the
skeletal muscles, the gastrointestinal tract, and the heart, but also in subcortical
structures of the brain, such as the lateral septum, amygdala, hypothalamus, and
brain stem. The diversity in CRH receptor subtype and isoform expression is
thought to play a key role in modifying the stress response by implicating locally
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the actions of different ligands (CRH and CRH-related peptides) and different
intracellular second messengers (15).
CRH is a major anorexiogenic peptide, whose secretion is stimulated by neu-
ropeptide Y (NPY). NPY is the most potent known orexiogenic factor, which
inhibits the LC-NE sympathetic system simultaneously (16–18). The latter may
be of particular relevance to alterations in the activity of the stress system in states
of dysregulation of food intake, such as malnutrition, anorexia nervosa, and obe-
sity. Glucocorticoids enhance the expression of hypothalamic NPY, whereas they
directly inhibit both the PVN CRH and LC-NE sympathetic systems. Substance
P (SP) has actions reciprocal to those of NPY, given that it inhibits the PVN CRH
neuron while it activates the LC-NE sympathetic system. SP release is likely to
be increased centrally secondary to peripheral activation of somatic afferent fibers
and may, therefore, have relevance to changes in the stress system activity induced
by chronic inflammatory or painful states (19).
A subset of PVN parvocellular neurons synthesize and secrete both CRH and
AV P, while another subset secretes AVP only (2, 20, 21). During stress, the relative
proportion of the subset of neurons that secrete both CRH and AVP increases sig-
nificantly. The terminals of the parvocellular PVN CRH and AVP neurons project
to different sites, including the noradrenergic neurons of the brainstem and the
hypophyseal portal system in the median eminence. PVN CRH and AVP neurons
also send projections to and activate proopiomelanocortin (POMC)-containing
neurons in the arcuate nucleus of the hypothalamus, which in turn project to the
PVN CRH and AVP neurons, innervate LC-NE sympathetic neurons of the cen-
tral stress system in the brainstem, and terminate on pain control neurons of the
hind brain and spinal cord (2, 20, 21). Thus, activation of the stress system via
CRH and catecholamines stimulates the secretion of hypothalamic β-endorphin
and other POMC-derived peptides, which reciprocally inhibit the activity of the
stress system and result in stress- induced analgesia.
The Hypothalamic-Pituitary-Adrenal Axis
CRH is the principal hypothalamic regulator of the pituitary-adrenal axis, which
stimulates the secretion of adrenocorticotropin hormone (ACTH) from the anterior
pituitary. AVP, although a potent synergistic factor of CRH, has very little ACTH
secretagogue activity on its own (22, 23). A positive reciprocal interaction between
CRH and AVP also exists at the level of hypothalamus, with each neuropeptide
stimulating the secretion of the other. In nonstressful situations, both CRH and AVP
are secreted in the portal system in a circadian, pulsatile, and highly concordant
fashion (24–27). The amplitude of the CRH and AVP pulses increases early in the
morning, resulting in increases primarily in the amplitude of the pulsatile ACTH
and cortisol secretion. Diurnal variations in the pulsatile secretion of ACTH and
cortisol are often perturbed by changes in lighting, feeding schedules, and activity,
as well as following stress.
During acute stress, there is an increase in the amplitude and synchronization of
the PVN CRH and AVP pulsatile release into the hypophyseal portal system. AVP
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of magnocellular neuron origin is also secreted into the hypophyseal portal system
via collateral fibers and the systemic circulation via the posterior pituitary (27,
28). In addition, depending on the stressor, other factors, such as angiotensin II,
various cytokines, and lipid mediators of inflammation are secreted and act on the
hypothalamic, pituitary, and/or adrenal components of the HPA axis and potentiate
its activity.
The adrenal cortex is the main target of ACTH, which regulates glucocorticoid
and adrenal androgen secretion by the zona fasciculata and reticularis, respectively,
and participates in the control of aldosterone secretion by the zona glomerulosa.
Other hormones, cytokines, and neuronal information from the autonomic nerves
of the adrenal cortex may also participate in the regulation of cortisol secretion
(27, 29–31).
Glucocorticoids are the final effectors of the HPA axis. These hormones are
pleiotropic, and exert their effects through their ubiquitously distributed intracel-
lular receptors (32–34). In the absence of ligand, the nonactivated glucocorticoid
receptor (GR) resides primarily in the cytoplasm of cells as part of a large multipro-
tein complex consisting of the receptor polypeptide, two molecules of hsp90, and
several other proteins (34). Upon hormone binding, the receptor dissociates from
hsp90 and other proteins and translocates into the nucleus, where it binds as homod-
imer to glucocorticoid-response elements (GREs) located in the promoter region
of target genes, and regulates the expression of glucocorticoid-responsive genes
positively or negatively, depending on the GRE sequence and promoter context.
The receptor can also modulate gene expression independently of GRE-binding, by
physically interacting with other transcription factors, such as activating protein-1
(AP-1) and nuclear factor-κB (NF-κB) (34).
Glucocorticoids play an important role in the regulation of basal activity of
the HPA axis, as well as in the termination of the stress response by acting at ex-
trahypothalamic centers, the hypothalamus, and the pituitary gland. The negative
feedback of glucocorticoids on the secretion of CRH and ACTH serves to limit the
duration of the total tissue exposure of the organism to glucocorticoids, thus mini-
mizing the catabolic, lipogenic, antireproductive, and immunosuppressive effects
of these hormones. A dual-receptor system exists for glucocorticoids in the CNS,
which includes the glucocorticoid receptor type I or mineralocorticoid receptor
that responds to low concentrations of glucocorticoids, and the classic glucocor-
ticoid receptor type II that responds to both basal and stress concentrations of
glucocorticoids. The negative feedback control of the CRH and ACTH secretion
is mediated through type II glucocorticoid receptors (1–3).
The LC-NE, Sympathetic, Adrenomedullary,
and Parasympathetic Systems
The autonomic nervous system (ANS) responds rapidly to stressors and controls
a wide range of functions. Cardiovascular, respiratory, gastrointestinal, renal, en-
docrine, and other systems are regulated by the SNS and/or the parasympathetic
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system. In general, the parasympathetic system can both assist and antagonize
sympathetic functions by withdrawing or increasing its activity, respectively (3).
Sympathetic innervation of peripheral organs is derived from the efferent pre-
ganglionic fibers, whose cell bodies lie in the intermediolateral column of the
spinal cord. These nerves synapse in the bilateral chain of sympathetic ganglia
with postganglionic sympathetic neurons, which innervate widely the smooth
muscle of the vasculature, the heart, skeletal muscles, kidney, gut, fat, and many
other organs. The preganglionic neurons are primarily cholinergic, whereas the
postganglionic neurons are mostly noradrenergic. The sympathetic system of the
adrenal medulla also provides all of circulating epinephrine and some of the nore-
In addition to the classic neurotransmitters acetylcholine and norepinephrine,
both sympathetic and parasympathetic subdivisions of the autonomic nervous sys-
tem include several subpopulations of target-selective and neurochemically coded
neurons that express a variety of neuropeptides and, in some cases, adenosine
triphosphate (ATP), nitric oxide, or lipid mediators of inflammation (3). Thus
CRH, NPY, somatostatin, and galanin are found in postganglionic noradrenergic
vasoconstrictive neurons, whereas vasoactive intestinal peptide (VIP), SP, and cal-
citonin gene-related peptide are found in cholinergic neurons. Transmission in
sympathetic ganglia is also modulated by neuropeptides released from pregan-
glionic fibers and short interneurons, and by primary afferent nerve collaterals.
Adaptive Responses to Stress
The stress system receives and integrates a diversity of cognitive, emotional, neu-
rosensory, and peripheral somatic signals that arrive through distinct pathways.
Activation of the stress system leads to behavioral and physical changes that are
remarkably consistent in their qualitative presentation and are collectively defined
as the stress syndrome (Table 1). These changes are normally adaptive and time
limited and improve the chances of the individual for survival.
Behavioral adaptation includes increased arousal, alertness, and vigilance; im-
proved cognition; focused attention; euphoria; enhanced analgesia; elevations in
core temperature; and inhibition of vegetative functions, such as appetite, feed-
ing, and reproduction. A concomitant physical adaptation also occurs mainly to
promote an adaptive redirection of energy. Oxygen and nutrients are shunted to
the CNS and the stressed body sites, where they are most needed. Increases in
cardiovascular tone, respiratory rate, and intermediate metabolism (gluconeogen-
esis, lipolysis) work in concert with the above alterations to promote availability
of vital substrates. Detoxification functions are activated to rid the organism of
unnecessary metabolic products from the stress-related changes in metabolism,
whereas digestive function, growth, reproduction, and immunity are inhibited
(3, 35).
During stress, the organism also activates restraining forces that prevent an over-
response from both the central and peripheral components of the stress system.
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These forces are essential for successful adaptation. If they are excessive or fail
to contain the various elements of the stress response in a timely manner, the
adaptive changes may become chronically deficient or excessive, respectively, and
may contribute to the development of pathology. Thus the restraining forces may
participate in the development of allostasis. Stress is often of a magnitude and
nature that allow the subjective perception of control by the individual. In such
cases, stress can be pleasant and rewarding, or at least not damaging. On the
other hand, stress of a nature, magnitude, or duration that is beyond the adaptive
resources of an individual may be associated with a perception of loss of control,
dysphoria, and chronic adverse behavioral and physical consequences (1, 3, 35).
Frequently allostasis and sense of loss of control go hand-in-hand, with the latter
serving as a useful index of the former.
Stress System Interactions with Other CNS Components
In addition to setting the level of arousal and influencing the vital signs, the stress
system interacts with three other major CNS components: the mesocorticolimbic
dopaminergic or reward system, the amygdala-hippocampus complex, and the
hypothalamic arcuate nucleus POMC neuronal system. All three CNS components
are activated during stress and, in turn, influence the activity of the stress system.
In addition, the stress system interacts with thermoregulatory and appetite-satiety
centers of the CNS, as well as the growth, thyroid, and reproductive axes and the
immune system (1, 3).
MESOCORTICOLIMBIC SYSTEM Both the mesocortical and mesolimbic components
of the dopaminergic system are innervated by PVN CRH neurons and the LC-NE
system and are activated during stress (36, 37). The mesocortical system con-
sists of dopaminergic neurons of the ventral tegmentum, which send projections
to the prefrontal cortex, and is involved in anticipatory phenomena and cognitive
functions. The mesolimbic system also consists of dopaminergic neurons of the
ventral tegmentum, which innervate the nucleus accumbens, and plays a principal
role in motivational/reinforcement/reward phenomena and in the formation of the
central dopaminergic reward system. Therefore, euphoria or dysphoria is likely to
be mediated by the mesocorticolimbic system, which is also considered to be the
target of several substances of abuse, such as cocaine. Interestingly, activation of
the prefrontal cortex, which is part of the mesocortical dopaminergic system, is
associated with inhibition of the stress system (38).
AMYGDALA-HIPPOCAMPUS COMPLEX The amygdala-hippocampus complex is ac-
tivated during stress primarily by ascending catecholaminergic neurons originating
in the brainstem, and by the end-product of the HPA axis, glucocorticoids, but also
by inner emotional stressors, such as fear, which is generated in the amygdala
(39). Activation of the amygdala is important for retrieval and emotional anal-
ysis of relevant information for any given stressor. The amygdala can directly
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stimulate both central components of the stress system and the mesocorticolimbic
dopaminergic system in response to emotional stressors. The hippocampus exerts
tonic and stimulated inhibitory effects on the activity of the amygdala, PVN CRH,
and LC-NE-sympathetic system.
LC-NE-noradrenergic and the CRH/AVP-producing
neurons reciprocally innervate and are innervated by opioid peptide (POMC)-
producing neurons of the arcuate nucleus of the hypothalamus (7, 40). Activation
of the stress system stimulates hypothalamic POMC-derived peptides, such as α-
melanocyte-stimulating hormone (α-MSH) and β-endorphin, which reciprocally
inhibit the activity of both of the central components of the stress system, produce
analgesia through projections to the hind brain and spinal cord, where they inhibit
ascending pain stimuli.
Activation of the LC-NE and PVN/CRH systems
increases the core temperature. Intracerebroventricular administration of nore-
pinephrine and CRH results in elevations in core temperature, probably through
prostanoid-mediated actions on the septal and hypothalamic temperature-
regulating centers (41, 42). CRH has also been shown to partly mediate the py-
rogenic effects of the inflammatory cytokines, tumor necrosis factor-α (TNF-α),
interleukin (IL)-1, and IL-6 (3).
APPETITE REGULATION Stress is also involved in the regulation of appetite by in-
fluencing the appetite-satiety centers in the hypothalamus. Acute elevations in CRH
concentrations cause anorexia. On the other hand, fasting-stimulated increases in
NPY enhance CRH secretion (43), while they concomitantly inhibit the LC-NE-
sympathetic system and activate the parasympathetic system, thereby facilitating
digestion and storage of nutrients (44). Leptin, a satiety-stimulating polypeptide
secreted by the white adipose tissue, is a potent inhibitor of hypothalamic NPY
and a stimulant of a subset of arcuate nucleus POMC neurons that secrete α-
MSH, another potent anorexiogen that exerts its effects primarily through specific
melanocortin receptors type 4 (45, 46).
In general, the stress response is meant to be of short or limited duration. The time-
limited nature of this process renders its accompanying antigrowth, antireproduc-
tive, catabolic, and immunosuppressive effects temporarily beneficial and/or of no
adverse consequences to the individual. However, chronic activation of the stress
system may lead to a number of disorders that are the result of increased and/or
prolonged secretion of CRH and/or glucocorticoids (Table 2).
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TABLE 2 States associated with altered hypothalamic-pituitary-adrenal (HPA) axis activity
and altered regulation or dysregulation of behavioral and/or peripheral adaptation
Increased HPA axis activity Decreased HPA axis activity
Chronic stress Adrenal insufficiency
Melancholic depression Atypical/seasonal depression
Anorexia nervosa Chronic fatigue syndrome
Malnutrition Fibromyalgia
Obsessive-compulsive disorder Hypothyroidism
Panic disorder Nicotine withdrawal
Excessive exercise (obligate athleticism) Discontinuation of glucocorticoid therapy
Chronic active alcoholism After Cushing syndrome cure
Alcohol and narcotic withdrawal Premenstrual tension syndrome
Diabetes mellitus Postpartum period
Truncal obesity (Metabolic syndrome X) After chronic stress
Childhood sexual abuse Rheumatoid arthritis
Psychosocial short stature Menopause
Attachment disorder of infancy
‘Functional’ gastrointestinal disease
Cushing syndrome
Pregnancy (last trimester)
Adapted from Chrousos & Gold (2).
Growth and Development
During stress, the growth axis is inhibited at many levels (Figure 2a). Prolonged
activation of the HPA axis leads to suppression of growth hormone (GH) secretion
and glucocorticoid-induced inhibition of the effects of insulin-like growth factor
I (IGF-I) and other growth factors on target tissues (47–49). Children with Cush-
ing’s syndrome have delayed or arrested growth and achieve a final adult height
that is on average 7.5–8.0 cm below their predicted height (49). The molecular
mechanisms by which glucocorticoids suppress growth are complex and involve
both transcriptional and translational mechanisms that ultimately influence GH
action (50, 51).
In addition to the direct effects of glucocorticoids, CRH-induced increases
in somatostatin secretion, and therefore inhibition of GH secretion, have been
implicated as a potential mechanism of chronic stress-related suppression of GH
secretion. However, acute elevations of serum GH concentrations may occur at the
onset of the stress response or following acute administration of glucocorticoids,
most likely due to stimulation of the GH gene by glucocorticoids through GREs
in the promoter region of the gene (52).
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Figure 2 Schematic representation of the interactions between the stress system
and (a) the GH/IGF-I axis, (b) the thyroid axis, (c) the hypothalamic-pituitary-
gonadal axis, and (d) metabolic functions. Adapted from Chrousos & Gold (2).
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In several stress-related mood disorders with a hyperactive HPA axis, such as
anxiety or melancholic depression, GH and/or IGF-I concentrations are signifi-
cantly decreased, and the GH response to intravenously administered glucocor-
ticoids is blunted. Compared with healthy control subjects, patients with panic
disorder have diminished GH response to intravenously administered clonidine,
whereas children with anxiety disorders may have short stature (53, 54). Fur-
thermore, nervous pointer dogs, an animal model of anxiety with both panic and
phobic components, have low IGF-I concentrations and deceleration in growth
velocity compared with normal animals. The tissue resistance to GH and/or IGF-
Iofchronically stressed animals can be restored following hypophysectomy or
adrenalectomy, a fact that further underlines the importance of glucocorticoids in
chronic stress-induced growth suppression (55).
Psychosocial short stature is characterized by severely compromised height in
children owing to emotional deprivation and/or physical/psychologic abuse and
represents another example of the detrimental effects of a chronically hyperactive
stress system on growth. These children display a significant decrease in GH
secretion, which is fully restored within a few days following separation of the
child from the adverse environment (56, 57). In addition to low GH secretion, they
have impaired thyroid function, biochemical findings reminiscent of those of the
euthyroid sick syndrome, and a variety of emotional, behavioral and/or psychiatric
The inhibited child syndrome usually involves a hyperactive or hyperreactive
amygdala, which generates excessive and prolonged fear and anxiety, an activated
stress system, which results in the corresponding peripheral physiologic responses,
a tachyphylactic or labile mesocorticolimbic dopaminergic system, which gener-
ates dysphoria, and/or a hypoactive hippocampus unable to inhibit/limit the activity
of the stress system and amygdala (58) (Figure 3). These alterations in the interrela-
tion of the above systems increase the vulnerability of the individual to conditions
characterized by a chronically hyperactive or hyperreactive stress, such as chronic
anxiety, melancholic depression, eating disorders, substance and alcohol abuse,
personality and conduct disorders, as well as psychosomatic conditions, such as
chronic fatigue syndrome. Other consequences of hyperactive stress system in-
clude delayed growth and puberty, manifestations of the metabolic syndrome, such
as visceral obesity, insulin resistance, hypertension, dyslipidemia, cardiovascular
disease, and osteoporosis.
Thyroid Function
Thyroid function is also inhibited during stress (Figure 2b). Activation of the
HPA axis is associated with decreased production of thyroid-stimulating hormone
(TSH), as well as inhibition of peripheral conversion of the relatively inactive thy-
roxine to the biologically active triiodothyronine (59). These alterations may be due
to the increased concentrations of CRH-induced somatostatin and glucocorticoids.
Somatostatin suppresses both TRH and TSH, whereas glucocorticoids inhibit the
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Figure 3 Central neurocircuitry in the stress-hyperresponsive/inhibited child leading
to a hyperactive stress system compared with the central neurocircuitry of the nor-
mal stress response. The hyperfunctioning amygdala, hypofunctioning hippocampus,
and/or hypofunctioning mesocorticolimbic dopaminergic system could predispose an
individual to anxiety, melancholic depression, and their somatic consequences. Solid
lines represent activation; dashed lines indicate inhibition. Adapted from Chrousos &
Gold (58).
activity of the enzyme 5-deiodinase, which converts thyroxine to triiodothyronine.
During inflammatory stress, the inflammatory cytokines, such as TNF-α, IL-1, and
IL-6, also activate CRH secretion and inhibit 5-deiodinase activity (3, 35).
The reproductive axis is inhibited at all levels by various components of the HPA
axis (Figure 2c). CRH suppresses the secretion of gonadotropin-releasing hormone
(GnRH) either directly or indirectly, by stimulating the arcuate POMC peptide-
secreting neurons (60, 61). Glucocorticoids also exert an inhibitory effect on the
GnRH neuron, the pituitary gonadotroph, and the gonads, and render target tis-
sues of gonadal steroids resistant to these hormones (60–63). During inflamma-
tory stress, the elevated concentrations of cytokines also result in suppression of
reproductive function via inhibition of both GnRH pulsatile secretion from the hy-
pothalamus and ovarian/testicular steroidogenesis. These effects are exerted both
directly and indirectly, by activating hypothalamic neural circuits that secrete CRH
and POMC-derived peptides and by increasing the circulating concentrations of
glucocorticoids (64).
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Suppression of gonadal function secondary to chronic activation of the HPA
axis has been demonstrated in highly trained runners of both sexes and ballet
dancers (65, 66). These subjects display elevated concentrations of serum cortisol
and plasma ACTH in the evening, increased 24-hour urinary-free cortisol excre-
tion, and diminished ACTH responses to exogenous CRH administration. Males
have low LH and testosterone concentrations and females have amenorrhea. In-
terestingly, obligate athletes develop withdrawal symptoms and signs following
discontinuation of their exercise routine, which may reflect withdrawal from the
daily exercise-induced elevation of opioid peptides and stimulation of the meso-
corticolimbic system.
The interaction between CRH and the hypothalamic-pituitary-gonadal axis is
bidirectional, given that estrogen increases CRH gene expression via estrogen-
response elements in the promoter region of the CRH gene (67). Therefore, the
CRH gene is an important target of gonadal steroids and a potential mediator of
sex-related differences in the stress-response and the activity of the HPA axis.
In addition to their direct catabolic effects, glucocorticoids also antagonize the
actions of GH and sex steroids on fat tissue catabolism (lipolysis) and muscle
and bone anabolism (Figure 2d) (3). Chronic activation of the stress system is
associated with increased visceral adiposity, decreased lean body (bone and mus-
cle) mass, and suppressed osteoblastic activity, a phenotype observed in patients
with Cushing’s syndrome, some patients with melancholic depression, and patients
with the metabolic syndrome (visceral obesity, insulin resistance, dyslipidemia,
hypertension, hypercoagulation, atherosclerotic cardiovascular disease, sleep ap-
nea), many of whom display increased HPA axis activity and demonstrate similar
clinical and biochemical manifestations (68–72). The association between chronic
stress, hypercortisolism and metabolic syndrome-related manifestations has also
been reported in cynomolgus monkeys (70, 71).
Because increased gluconeogenesis is a cardinal feature of the stress response
and glucocorticoids induce insulin resistance, activation of the HPA axis may
also contribute to the poor control of diabetic patients with emotional stress or
concurrent inflammatory or other diseases. Mild, chronic activation of the HPA axis
has been demonstrated in type I diabetic patients under moderate or poor glycemic
control, and in type II diabetic patients who had developed diabetic neuropathy
(71, 73). Over time, progressive glucocorticoid-induced visceral adiposity causes
further insulin resistance and deterioration of the glycemic control. Therefore,
chronic activation of the stress system in patients with diabetes mellitus may result
in a vicious cycle of hyperglycemia, hyperlipidemia, and progressively increasing
insulin resistance and insulin requirements.
Low turnover osteoporosis is almost invariably seen in association with hy-
percortisolism and GH deficiency, and represents another example of the adverse
effects of elevated cortisol concentrations and decreased GH/IGF-I concentrations
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on osteoblastic activity. The stress-induced hypogonadism and the reduced concen-
trations of sex steroids may further contribute to the development of osteoporosis.
Increased prevalence of osteoporosis has been demonstrated in young women with
depression or a previous history of depression (74).
Gastrointestinal Function
PVN CRH induces inhibition of gastric acid secretion and emptying, whereas it
stimulates colonic motor function (75, 76). These effects are mediated by inhibition
of the vagus nerve, which leads to selective inhibition of gastric motility, and by
stimulation of the LC-NE-regulated sacral parasympathetic system, which results
in selective stimulation of colonic motility. Therefore, CRH may be implicated in
mediating the gastric stasis observed following surgery or during an inflammatory
process, when central IL-1 concentrations are elevated (77). CRH may also play a
role in the stress-induced colonic hypermotility of patients with the irritable bowel
syndrome. Colonic contraction and pain in these patients may activate LC-NE-
sympathetic neurons, forming a vicious cycle that may account for the chronicity
of the condition.
CRH hypersecretion may also be a link between chronic gastrointestinal pain
and a history of abuse. A high incidence of physically and sexually abused women
has been reported in patients with chronic gastrointestinal pain. Sexually abused
women may suffer from chronic activation of the HPA axis (78), and increased CRH
secretion may produce colonic pain via activation of the sacral parasympathetic
system (79).
Immune Function
Activation of the HPA axis has profound inhibitory effects on the immune/
inflammatory response, given that virtually all the components of the immune
response are inhibited by glucocorticoids (80, 81). At the cellular level, the main
anti-inflammatory and immunosuppressive effects of glucocorticoids include al-
terations in leukocyte traffic and function, decreases in production of cytokines
and mediators of inflammation, and inhibition of their action on target tissues
by the latter. These effects are exerted both at the resting, basal state and during
inflammatory stress, when the circulating concentrations of glucocorticoids are el-
evated. A circadian activity of several immune factors has been demonstrated
in reverse-phase synchrony with that of plasma glucocorticoid concentrations
During stress, the activated ANS also exerts systemic effects on immune organs
by inducing the secretion of IL-6 in the systemic circulation (83). Despite its
inherent inflammatory activity, IL-6 plays a major role in the overall control of
inflammation by stimulating glucocorticoid secretion (84, 85) and by suppressing
the secretion of TNF-α and IL-1. Furthermore, catecholamines inhibit IL-12 and
stimulate IL-10 secretion via β-adrenergic receptors, thereby causing suppression
of innate and cellular immunity, and stimulation of humoral immunity (86).
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The combined effects of glucocorticoids and catecholamines on the monocyte/
macrophage and dendritic cells are to inhibit innate immunity and T helper-1-
related cytokines, such as interferon-γ and IL-12, and to stimulate T helper-2-
related cytokines, such as IL-10 (87). This suggests that stress-related immuno-
suppression refers mostly to innate and cellular immunity, facilitating diseases
related to deficiency of these immune responses, such as common cold, tubercu-
losis, and certain tumors (87).
Psychiatric Disorders
The syndrome of adult melancholic depression represents a typical example of
dysregulation of the generalized stress response, leading to chronic dysphoric
hyperarousal, activation of the HPA axis and the LC-NE/SNS, and relative im-
munosuppression (88, 89). Patients suffering from the condition have hypersecre-
tion of CRH, as evidenced by the elevated 24-hour urinary cortisol excretion, the
decreased ACTH responses to exogenous CRH administration, and the elevated
concentrations of CRH in the cerebrospinal fluid (CSF). They also have elevated
concentrations of norepinephrine in the CSF, which remain elevated even during
sleep (90), and a marked increase in the number of PVN CRH neurons on autopsy.
Childhood sexual abuse is associated with an increased incidence of adult psy-
chopathology, as well as abnormalities in the HPA function. Sexually abused girls
have a greater incidence of suicidal ideation, suicide attempts, and dysthymia com-
pared with controls (91). In addition, they excrete significantly higher amounts of
catecholamines and their metabolites, and display lower basal and CRH-stimulated
ACTH concentrations compared with controls. However, the total and free basal
and CRH-stimulated serum cortisol concentrations and 24-h urinary-free cortisol
concentrations in these subjects are similar to those in controls. These findings
reflect pituitary hyporesponsiveness to CRH, which may be corrected for by the
presence of intact glucocorticoid feedback regulatory mechanisms (91, 92).
A spectrum of other conditions may also be associated with increased and
prolonged activation of the HPA axis. These include anorexia nervosa (93), mal-
nutrition (94), obsessive-compulsive disorder, panic anxiety (95), excessive ex-
ercise (65, 66), chronic active alcoholism (96), alcohol and narcotic withdrawal
(97), diabetes mellitus types I and II (71, 73), visceral obesity (70), and perhaps,
Both anorexia nervosa and malnutrition are characterized by a marked decrease
in circulating leptin concentration and an increase in CSF NPY concentration,
which could provide an explanation as to why the HPA axis in these subjects is
activated in the presence of a profoundly hypoactive LC-NE-sympathetic system
(43–46). Glucocorticoids, on the other hand, may produce the hyperphagia and
obesity observed in patients with Cushing’s syndrome and many rodent models of
obesity, such as the Zucker rat, by stimulating NPY and by inhibiting the PVN CRH
and the LC-NE sympathetic systems. Glucocorticoids have also been associated
with leptin resistance (98). Zucker rats are leptin receptor–deficient with concurrent
hypercorticosteronism and decreased LC-NE-sympathetic system activity (99).
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Hypoactivation of the stress system is characterized by chronically reduced secre-
tion of CRH and norepinephrine, and may result in hypoarousal states (Table 2).
Forexample, patients with atypical or seasonal depression and the chronic fa-
tigue syndrome demonstrate chronic hypoactivity of the HPA axis in the depres-
sive (winter) state of the former, and in the period of fatigue of the latter (100).
Similarly, patients with fibromyalgia often complain about fatigue and have been
shown to have decreased 24-h urinary-free cortisol excretion (101). Hypothyroid
patients have clear evidence of CRH hyposecretion, and they often present with
depression of the atypical type. Withdrawal from smoking has also been associ-
ated with time-limited decreased cortisol and catecholamine secretion, which is
associated with fatigue, irritability, and weight gain (102). Decreased CRH se-
cretion in the early period of nicotine abstinence could explain the hyperphagia,
decreased metabolic rate, and weight gain frequently observed in these patients.
In Cushing’s syndrome, the clinical manifestations of atypical depression, hy-
perphagia, weight gain, fatigue, and anergia are consistent with the suppression
of CRH by the elevated cortisol concentrations. The period after cure of hyper-
cortisolism, the postpartum period, and periods after cessation of chronic stress
are also associated with suppressed PVN CRH secretion and decreased HPA axis
activity (1–3, 62, 103). Chronic hypoactivation of the HPA axis and/or the LC-
NE-sympathetic system owing to decreases in the activity of the opioid-peptide
system responsible for stress-induced analgesia may also account for the lower pain
threshold for visceral sensation reported in patients with functional gastrointestinal
Hyper- or Hypoactivation of the Stress System
and Immune Function
In theory, an exaggerated HPA axis response to inflammatory stimuli would be
expected to mimic the stress or hypercortisolemic state and lead to increased
susceptibility of the individual to certain infectious agents or tumors but en-
hanced resistance to autoimmune inflammatory disease. By contrast, a subopti-
mal HPA axis response to inflammatory stimuli would be expected to reproduce
the glucocorticoid-deficient state and lead to relative resistance to infections and
neoplastic diseases but increased susceptibility to autoimmune inflammatory dis-
ease (80, 87). These findings have been observed in an interesting pair of near-
histocompatible, highly inbred rat strains, the Fischer and Lewis rats, both of
which were genetically selected out of Sprague-Dawley rats, for their resistance
or susceptibility, respectively, to inflammatory disease (104).
Patients with depression or anxiety have been shown to be more vulnerable to
tuberculosis, both in terms of prevalence and severity of the disease (105). Simi-
larly, stress has been associated with increased vulnerability to the common cold
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virus. A compromised innate and T helper-1 driven immunity may predispose an
individual to these conditions. Furthermore, patients with rheumatoid arthritis, a
T-helper-1 driven inflammatory disease, have a mild form of central hypocorti-
solism, as indicated by the normal 24-h cortisol excretion despite the major in-
flammatory stress, and diminished HPA axis responses to surgical stress (106).
Therefore, dysregulation of the HPA axis may play a critical role in the de-
velopment and/or perpetuation of T helper-1-type of autoimmune disease. The
same theoretical concept may explain the high incidence of T helper-1 autoim-
mune diseases, such as rheumatoid arthritis and multiple sclerosis, observed fol-
lowing cure of hypercortisolism, in the postpartum period and in patients with
adrenal insufficiency, who do not receive adequate replacement therapy (87, 107,
Appropriate responsiveness of the stress system to stressors is a crucial prerequi-
site for a sense of well-being, adequate performance of tasks, and positive social
interactions. Improper responsiveness has been associated with inadequacies in
these functions and increased vulnerability to one or more of the stress-related
states. Vulnerability may be the result of genetic, developmental, and environ-
mental factors, and may be considered as the endpoint of converging influences.
Depending on the genetic background of the individual and his/her exposure to
adverse stimuli in prenatal and/or postnatal life (developmental influences), one
might fail to cope with life stressors and may develop any of the above-described
states in any combination and any degree of severity (58).
The stress response of an individual is determined by multiple factors, many
of which are inherited (1, 3, 109, 110). Genetic polymorphisms, such as those of
CRH, AVP, and their receptors and/or regulators, are expected to account for the
observed variability in the function of the stress system. This genetic vulnerability
is polygenic and allows expression of the clinical phenotype in the presence of
environmental triggers. There is a complex genetic background continuum in our
population that ranges from extreme resilience to extreme vulnerability to these
stress-related comorbid states. Stressors of gradually decreasing intensity may
be sufficient to result in the development of these conditions in an individual,
whose genetic vulnerability places him on the vulnerable side of the continuum
(Figure 4a).
The dose-response relation between the potency of a stressor and the responsive-
ness of the stress system is represented by a sigmoidal curve, which is expected to
differ from individual to individual. One individual’s dose-response curve might
be shifted to the left of that of an average reactive individual, whereas another
individual’s dose-response curve might be shifted to the right. The former de-
notes an excessive reaction, whereas the latter a defective one. Similarly, the dose-
response relation between an individual’s sense of well-being or performance
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Figure 4 (a) Schematic representation of the genetic continuum that defines an in-
dividual’s genetically determined vulnerability/resilience to stressors. The vertical ar-
rows indicate the magnitude of environmental stressors necessary to result in disease.
(b) Early environmental stressors may have a permanent effect on the ability of the
individual to respond to stress effectively, thus altering the constitutional vulnerabil-
ity/resilience of an individual to stressors. Adapted from Chrousos (58a).
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ability and the activity of the stress system is represented by an inverted U-shaped
curve that covers the range of the activity of the latter. Shifts to either the left or
the right of this range would result in hypoarousal or hyperarousal, respectively,
and a suboptimal sense of well-being or diminished performance (58). Develop-
mental influences, when propitious, may shift an individual toward a more re-
silient response to stress, whereas, when negative, may have the opposite effect
(Figure 4b). Therefore, a supportive or an adverse environment may alter the course
of one or more of the above stress-related states, indicating that genetics and devel-
opment define vulnerability, whereas environment may determine the triggering
and/or severity of a disease.
The prenatal life, infancy, childhood, and adolescence are periods of increased
plasticity for the stress system and, therefore, are particularly sensitive to stressors.
Excessive or sustained activation of the stress system during these critical periods
may have profound effects on its function (1, 3, 111, 112). These environmental
triggers or stressors may have not a transient, but rather a permanent effect on the
organism, reminiscent of the organizational effects of several hormones exerted
on certain target tissues, which last long after cessation of the exposure to these
hormones. Also, sufficiently strong or prolonged stressors may have permanent
effects on the organism even if they occur later in life, such as in the adult post-
traumatic stress disorders.
These effects of early environment on the development of the HPA axis re-
sponses to stress reflect a naturally occurring plasticity whereby factors such as
maternal care are able to program rudimentary, biologic responses to threaten-
ing stimuli. Developmental programming of CNS responses to stress in early life
is likely to be of adaptive value to the adult. Such programming would afford
an appropriate HPA response and would minimize the need for a long period of
adaptation in adult life.
The stress system coordinates the adaptive response of the organism to stressors
and plays an important role in maintenance of basal and stress-related homeosta-
sis. Activation of the stress system leads to behavioral and peripheral changes that
improve the ability of the organism to adapt and increase its chances for survival.
Inadequate and/or prolonged response to stressors may impair growth and devel-
opment and may result in a variety of endocrine, metabolic, autoimmune, and
psychiatric disorders. The development and severity of these conditions primarily
depend on genetic, developmental, and environmental factors. CRH antagonists
may be useful in states characterized by chronic hyperactivity of the stress system,
such as melancholic depression and chronic anxiety, whereas CRH agonists may
be useful in conditions characterized by chronic hypoactivity of the stress system,
such as atypical depression, postpartum depression, and the fibromyalgia/chronic
fatigue syndromes (113–116).
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Figure 1 Schematic representation of the central and peripheral components of the
stress system, their functional interrelations, and their relation to other central nervous
system components involved in the stress response. Adapted from Chrousos (80).
HI-RES-PH67-10-Charmandari.qxd 1/25/05 2:10 PM Page 1
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Annual Review of Physiology
Volume 67, 2005
Frontispiece—Michael J. Berridge xiv
PERSPECTIVES, Joseph F. Hoffman, Editor
Unlocking the Secrets of Cell Signaling, Michael J. Berridge 1
Peter Hochachka: Adventures in Biochemical Adaptation,
George N. Somero and Raul K. Suarez 25
CARDIOVASCULAR PHYSIOLOGY, Jeffrey Robbins, Section Editor
Calcium, Thin Filaments, and Integrative Biology of Cardiac Contractility,
Tomoyoshi Kobayashi and R. John Solaro 39
Intracellular Calcium Release and Cardiac Disease, Xander H.T. Wehrens,
Stephan E. Lehnart and Andrew R. Marks 69
CELL PHYSIOLOGY, David L. Garbers, Section Editor
Chemical Physiology of Blood Flow Regulation by Red Blood Cells:
The Role of Nitric Oxide and S-Nitrosohemoglobin, David J. Singel
and Jonathan S. Stamler 99
RNAi as an Experimental and Therapeutic Tool to Study and Regulate
Physiological and Disease Processes, Christopher P. Dillon,
Peter Sandy, Alessio Nencioni, Stephan Kissler, Douglas A. Rubinson,
and Luk Van Parijs 147
Martin E. Feder, Section Editor
Introduction, Martin E. Feder 175
Biophysics, Physiological Ecology, and Climate Change: Does Mechanism
Matter? Brian Helmuth, Joel G. Kingsolver, and Emily Carrington 177
Comparative Developmental Physiology: An Interdisciplinary
Convergence, Warren Burggren and Stephen Warburton 203
Molecular and Evolutionary Basis of the Cellular Stress Response,
Dietmar K
ultz 225
ENDOCRINOLOGY, Bert O’Malley, Section Editor
Endocrinology of the Stress Response, Evangelia Charmandari,
Constantine Tsigos, and George Chrousos 259
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Lessons in Estrogen Biology from Knockout and Transgenic Animals,
Sylvia C. Hewitt, Joshua C. Harrell, and Kenneth S. Korach 285
Ligand Control of Coregulator Recruitment to Nuclear Receptors,
Kendall W. Nettles and Geoffrey L. Greene 309
Regulation of Signal Transduction Pathways by Estrogen
and Progesterone, Dean P. Edwards 335
Mechanisms of Bicarbonate Secretion in the Pancreatic Duct,
Martin C. Steward, Hiroshi Ishiguro, and R. Maynard Case 377
Molecular Physiology of Intestinal Na
Nicholas C. Zachos, Ming Tse, and Mark Donowitz 411
Regulation of Fluid and Electrolyte Secretion in Salivary Gland
Acinar Cells, James E. Melvin, David Yule, Trevor Shuttleworth,
and Ted Begenisich 445
Secretion and Absorption by Colonic Crypts, John P. Geibel 471
NEUROPHYSIOLOGY, Richard Aldrich, Section Editor
Retinal Processing Near Absolute Threshold: From Behavior
to Mechanism, Greg D. Field, Alapakkam P. Sampath, and Fred Rieke 491
RENAL AND ELECTROLYTE PHYSIOLOGY, Gerhard H. Giebisch, Section Editor
APhysiological View of the Primary Cilium, Helle A. Praetorius
and Kenneth R. Spring 515
Cell Survival in the Hostile Environment of the Renal Medulla,
Wolfgang Neuhofer and Franz-X. Beck 531
Novel Renal Amino Acid Transporters, Francois Verrey, Zorica Ristic,
Elisa Romeo, Tamara Ramadam, Victoria Makrides, Mital H. Dave,
Carsten A. Wagner, and Simone M.R. Camargo 557
Renal Tubule Albumin Transport, Michael Gekle 573
RESPIRATORY PHYSIOLOGY, Carole R. Mendelson, Section Editor
Exocytosis of Lung Surfactant: From the Secretory Vesicle to the
Air-Liquid Interface, Paul Dietl and Thomas Haller 595
Lung Vascular Development: Implications for the Pathogenesis of
Bronchopulmonary Dysplasia, Kurt R. Stenmark and Steven H. Abman 623
Surfactant Protein C Biosynthesis and Its Emerging Role in
Conformational Lung Disease, Michael F. Beers and Surafel Mulugeta 663
SPECIAL TOPIC,CHLORIDE CHANNELS, Michael Pusch, Special Topic Editor
Channels: A Journey for Ca
Sensors to ATPases and Secondary
Active Ion Transporters, Michael Pusch 697
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Assembly of Functional CFTR Chloride Channels, John R. Riordan 701
Calcium-Activated Chloride Channels, Criss Hartzell, Ilva Putzier,
and Jorge Arreola 719
Function of Chloride Channels in the Kidney, Shinichi Uchida
and Sei Sasaki 759
Physiological Functions of CLC Cl
Channels Gleaned from Human
Genetic Disease and Mouse Models, Thomas J. Jentsch,
Mallorie Po
et, Jens C. Fuhrmann, and Anselm A. Zdebik 779
Structure and Function of CLC Channels, Tsung-Yu Chen 809
Subject Index 841
Cumulative Index of Contributing Authors, Volumes 63–67 881
Cumulative Index of Chapter Titles, Volumes 63–67 884
An online log of corrections to Annual Review of Physiology chapters
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... [6,8] Reciprocal neural connections exist between the CRF neurons of the PVH and NE neurons of the LC, suggesting that these two sites are major central coordinators of the stress system. [6,9] Evidence suggests that stress-induced activation of neurons at these two sites is under opioidergic modulation. [10,11] Notably, many animal studies have reported that the response to stress is dysregulated in adult rats subsequent to prenatal opioid exposure. ...
... [4][5][6][12][13][14][15][16][17][18][19][20] Given that the ability to activate the stress response system is a normative response serving as an adaptive function, the disrupted stress response suggests damaged adaptive capability and vulnerability to mood or behavioral disorders in offspring. [5,6,9] Accordingly, prenatal opioid exposure may impede the development of adaptive responses to environmental stimuli by altering the stress-sensitive brain circuitry or HPA axis. [4,6,15] Methadone (Meth) and buprenorphine (Bu) are two major types of synthetic opioid agonists for the first-line medication-assisted treatment of opioid use disorder in pregnant women. ...
... [31] There are reciprocal neural connections existing between the CRF neurons of the PVH and NE neurons of the LC and this suggests that these two sites are major central coordinators of the stress system. [6,9] CRF released from neurons in the PVH has emerged as a key molecule to initiate and integrate the stress response. No study has investigated the detrimental effects of perinatal opioid exposure on the central stress system. ...
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Prenatal opioid exposure may impede the development of adaptive responses to environmental stimuli by altering the stress-sensitive brain circuitry located at the paraventricular nucleus of the hypothalamus (PVH) and locus coeruleus (LC). Corticotropin-releasing factor (CRF) released from neurons in the PVH has emerged as a key molecule to initiate and integrate the stress response. Methadone (Meth) and buprenorphine (Bu) are two major types of synthetic opioid agonists for first-line medication-assisted treatment of opioid (e.g., morphine, Mor) use disorder in pregnant women. No studies have compared the detrimental effects of prenatal exposure to Meth versus Bu on the stress response of their offspring upon reaching adulthood. In this study, we aimed to compare stress-related neuronal activation in the PVH and LC induced by restraint (RST) stress in adult male rat offspring with prenatal exposure to the vehicle (Veh), Bu, Meth, or Mor. CFos-immunoreactive cells were used as an indicator for neuronal activation. We found that RST induced less neuronal activation in the Meth or Mor exposure groups compared with that in the Bu or Veh groups; no significant difference was detected between the Bu and Veh exposure groups. RST-induced neuronal activation was completely prevented by central administration of a CRF receptor antagonist (α-helical CRF9-41, 10 μg/3 μL) in all exposure groups, suggesting the crucial role of CRF in this stress response. In offspring without RST, central administration of CRF (0.5 μg/3 μL)-induced neuronal activation in the PVH and LC. CRF-induced neuronal activation was lessened in the Meth or Mor exposure groups compared with that in the Bu or Veh groups; no significant difference was detected between the Bu and Veh exposure groups. Moreover, RST- or CRF-induced neuronal activation in the Meth exposure group was comparable with that in the Mor exposure group. Further immunohistochemical analysis revealed that the Meth and Mor exposure groups displayed less CRF neurons in the PVH of offspring with or without RST compared with the Bu or Veh groups. Thus, stress-induced neuronal activation in the PVH and LC was well preserved in adult male rat offspring with prenatal exposure to Bu, but it was substantially lessened in those with prenatal exposure to Meth or Mor. Lowered neuronal activation found in the Meth or Mor exposure groups may be, at least in part, due to the reduction in the density of CRF neurons in the PVH.
... The recent incorporation of DHEA(S) therefore has been promising in evaluating HPA axis activity in response to social behavior and reproductive conditions. During acute stress or the normal reactive scope, GC and DHEA(S) levels temporarily elevate due to the activation of the HPA axis (Charmandari et al., 2005;Maninger et al., 2010;Reeder & Kramer, 2005;Seeley et al., 2022;Tsigos & Chrousos, 2002;Whitham et al., 2020). However, chronic stress attenuates the DHEAS response (Lennartsson et al., 2013). ...
... Based on evidence from experimental models, DHEAS is a GC antagonist (Goncharova et al., 2012;Hu et al., 2000;Lennartsson et al., 2013;Maninger et al., 2010;Prall et al., 2017) and increases in response to stress and elevated glucocorticoid levels (Charmandari et al., 2005;Goncharova & Lapin, 2000;Leowattana, 2004;Maninger et al., 2010;Reeder & Kramer, 2005;Takeshita et al., 2019;Tsigos & Chrousos, 2002;Whitham et al., 2020). For instance, a study in free-ranging captive seals reported that individuals with diseases had a higher serum GC:DHEAS ratio than healthy animals but found no differences in GC levels (Gundlach et al., 2018). ...
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The relationship between stress and behavior can help us to understand how physiological adaptations shape primate societies. Most studies have focused on glucocorticoids (GC) as stress biomarkers, but other extrinsic and intrinsic factors can influence GC levels and confound the results. To overcome this issue, including analyses of dehydroepiandrosterone-sulfate (DHEAS), a GC antagonist, can be useful in evaluating overall adrenal function in response to biological, social, and environmental factors. Our goal was to evaluate the effect of reproductive state, social behavior, ambient temperature, and season (mating and non-mating) on DHEAS levels and the ratio between GC metabolites and DHEAS (GCM:DHEAS) in 11 free-ranging, female, Japanese macaques (Macaca fuscata) (7 pregnant/lactating, 4 nonpregnant/nonlactating) from Jigokudani Monkey Park (Japan). We validated and measured fecal DHEAS levels in 354 samples by enzyme immunoassay and calculated GCM:DHEAS by using previously reported data for GC metabolites. We tested the effects of reproductive state, dominance rank, social behavior, season, and ambient temperature on adrenal steroids using Generalized Linear Mixed-Effect Models. We found that pregnant and lactating females had higher DHEAS levels than nonpregnant/nonlactating females and that DHEAS levels were higher during the mating season. Temperature was positively correlated with GCM:DHEAS. Dominant females had higher DHEAS levels and lower GCM:DHEAS than subordinate females. We suggest that the high DHEAS to GC ratio in high-ranking females explains why they have better body condition than low-ranking females despite high GCM levels. This study confirms that including DHEAS provides valuable information for evaluating the stress response in primates.
... Corticosteroids (CS) are vital hormones for mammals, which are involved in many physiological functions such as ion regulation, fluid constants, energy metabolism, respiration, and immune responses [1,2]. However, ray-finned fish lack the aldosterone synthase to produce a specific mineralocorticoid [3,4]. ...
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Cortisol is the predominant corticosteroid in ray-finned fish since it does not possess the aldosterone synthase necessary to produce specific mineralocorticoids. Cortisol is traditionally believed to function as a fish mineralocorticoid. However, the effects of cortisol are mediated through corticosteroid receptors in other vertebrates, and there is an ongoing debate about whether cortisol acts through the glucocorticoid receptor (GR) or the mineralocorticoid receptor (MR) in teleosts. To investigate this issue, we conducted a study using euryhaline Mozambique tilapia (Oreochromis mossambicus) as the experimental species. The experiment was designed to investigate the effect of cortisol on ionocyte development at both the cellular and gene expression levels in tilapia. We administered exogenous cortisol and receptor antagonists, used immunohistochemistry to quantify ionocyte numbers, and performed real-time PCR to assess the expression of the differentiation factor tumor protein 63 (P63) mRNA, an epidermal stem cell marker. We observed that cortisol increased the number of Na+-K+-ATPase (NKA)-immunoactive ionocytes (increased by 1.6-fold) and promoted the gene expression of P63 mRNA (increased by 1.4-fold). Furthermore, we found that the addition of the mineralocorticoid receptor antagonist Spironolactone inhibited the increase in the number of ionocytes (decreased to the level of the control group) and suppressed the gene expression of P63 (similarly decreased to the level of the control group). We also provided evidence for gr, mr, and p63 localization in epidermal cells. At the transcript level, mr mRNA is ubiquitously expressed in gill sections and present in epidermal stem cells (cells labeled with p63), supporting the antagonism and functional assay results in larvae. Our results confirmed that cortisol stimulates ionocyte differentiation in tilapia through the MR, rather than the GR. Therefore, we provide a new direction for investigating the dual action of osmotic regulation and skin/gill epithelial development in tilapia, which could help resolve previously inconsistent and conflicting findings.
... Mammals mainly secrete corticosteroids from the adrenal cortex, while teleost fish secrete them from interrenal tissue [6]. Corticosteroids play vital roles in many physiological functions, including ion regulation, fluid balance, energy metabolism, respiration, and the immune response [7,8]. However, fish lack aldosterone synthase, which is required to produce a specific mineralocorticoid; therefore, cortisol is considered the major corticosteroid in fish [9,10]. ...
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In this study, we investigated the effects of cortisol on the regulation of the glycogen metabolism biomarkers glycogen synthase (GS) and glycogen phosphorylase (GP) in the glycogen-rich cells of the gills of tilapia (Oreochromis mossambicus). In the gills of tilapia, GP, GS, and glycogen were immunocytochemically colocalized in a specific group of glycogen-rich cells adjacent to the gills’ main ionocytes and mitochondria-rich cells. Cortisol plays a vital role in the regulation of physiological functions in animals, including energy metabolism, respiration, immune response, and ion regulation. However, no studies have elucidated the mechanisms regulating cortisol and glycogen-rich cells in the gills. Therefore, we treated tilapia larvae with exogenous cortisol and a glucocorticoid receptor (GR) antagonist to investigate the regulatory mechanisms between cortisol and glycogen-rich cells in the gills. Our results showed that cortisol promoted the expression of gill glycogen phosphorylase isoform (GPGG) mRNA via GR, whereas the GS gene expression remained unaffected. We also found that GR mRNA was colocalized with some glycogen-rich cells in the gills, further confirming our hypothesis that cortisol directly acts on glycogen-rich cells in the gills of tilapia and regulates glycogen metabolism by promoting GPGG mRNA expression.
... The release of cortisol facilitates a coordinated and effective bio-behavioral response to immediate threat but becomes neurotoxic and debilitating when present for protracted periods of time (Charmandari et al., 2005), potentially impeding sensitive parenting behaviors. Thus, it is possible that one pathway through which ACEs may lead to disrupted parenting behaviors is through the cortisol stress response, which impedes the physiological down-regulation necessary to sensitively care for young children. ...
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Purpose Social support buffers the impact of stress on multiple psychosocial domains and may buffer the impact of parental Adverse Childhood Experiences (ACEs) on parenting. However, little is understood about the biological pathways through which social support buffering occurs and research has rarely examined social support among fathers. This study examined the effects of ACEs and social support on the physiological stress response (cortisol levels) of expectant fathers. Method Data were analyzed from a larger study of the influence of bio-psycho-social factors on early parenting processes in expectant mothers and fathers. Exposure to ACEs and social support were assessed, and salivary cortisol was collected from 38 expectant fathers, the majority of whom were African American, exposed to contextual risk. Multilevel random effects models tested associations between ACEs, social support and cortisol while controlling for sociodemographic covariates. Results There was a significant interaction between the higher ACEs category (three or more) and the level of social support so that increased social support moderated the effect of exposure to a higher number of ACEs on baseline cortisol levels (p < 0.05). Differences in cortisol between high and low ACEs groups decreased as social support increased until there was no difference between the high and low ACEs groups at an MSPSS score of 64 (p = 0.056). Conclusions The apparent dosing effect of social support on the ACEs-cortisol relationship has important implications for parenting, as the buffering effect of social support may reduce the potential for harsh or insensitive parenting among fathers with high ACEs.
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Rocking can make us feel relaxed and reduce anxiety. Now it has been proved that uniform rocking exercise can promote sleep in rodents, but there are less studies on whether it affects anxiety. The objective of this experiment is to explain the effect of uniform rocking exercise on anxiety level in rats under acute stress, using plantar electrical stimulation can induce acute stress model, which was verified by the open field test and elevated plus-mest. In addition, the levels of anxiety-related hormones adrenocorticotropic hormone (ACTH) and corticosterone (CORT) were examined by serum Enzyme-Linked Immuno Sorbent Assay (ELISA), and it was found that the anxiety level of rats, as well as the levels of ACTH and CORT, were significantly reduced after 1 hour of rocking. In addition, we examined the anxiety-related nuclei by C-fos and found that uniform rocking motion decreased neural activity in the hippocampus (HIP) and amygdala (AMY) and increased neural activity in the vestibular nucleus in rats under acute stress. In addition, we examined the expression of Iba1, a marker of microglia. We found that uniform rocking exercise alleviated anxiety levels in acutely stressed rats, which may be related to the activation of microglia in the hippocampus, medial prefrontal cortex, and vestibular nucleus. Our study reveals a significant correlation between the ability of rocking to alleviate anxiety, activation of neural nuclei, and microglia in acutely stressed rats.
When exposed to actual or threatened death or serious injury in austere settings, expedition members are at risk of acute stress reactions, as are search and rescue members involved with extricating the patient. Acute stress reactions are a normal response to significant trauma and commonly resolve on their own. If they do not, they can lead to post-traumatic stress disorder (PTSD), a set of persistent symptoms that cause significant effects on the person's life. Medication has a limited preventive role in the field for treatment of stress partly because so few are trained to administer it. Contrastingly, psychological first aid can be performed by lay team members with minimal training. Psychological first aid consists of interventions attempting to encourage feelings of safety, calm, self-efficacy, connection, and hope. These are interventions that provide guidance to not make the situation emotionally worse and might have a preventive effect on later development of PTSD. They are valuable in the field not only for the patient but also for affected team members as well as for search and rescue team members who may be indirectly affected by the trauma and experience repercussions later.
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Effects of different levels of 0.0 and 100 mg Coenzyme Q10/kg diet (CoQ10), 0.00 and 3 gm. WGO /kg (WGO) on a number of oxidation parameters, sex hormones, and histological structure of the testis in local rabbits buck were investigated under oxidative stress condition. A total 54 rabbits aged 4-5 months, randomly assigned to six treatments. Nine / treatment and three replicates per each. The results showed a significant decrease in GOT and GPT enzymes for T3 and T4 compared with the T1 and T2. With a significant decrease in cortisol levels. Treatments 3 and 4 showed a significant improvement in the GSH and MDA concentrations of normal and stressed rabbits compared with the control and the second. Treatment with H2O2 recorded decrease in hormones FSH, LH and testosterone compared to others. Whereas, treatments with CoQ10 and WGO, recorded an improvement in the concentration of FSH and LH hormones compared with others. The addition of Coenzyme Q10 and wheat germ oil improved histological structure of the testicle. We can conclude treatment with CoQ10 and WGO improved parameters of oxidation and the level of sex hormones, and histological structure of the testis.
The molecular mechanisms underlying the stress response are poorly described in crustaceans. This includes the snow crab (Chionoecetes opilio), a commercially important stenotherm species distributed throughout the northern hemisphere. A better understanding of the stress response in C. opilio is desperately needed for commercial and conservation purposes. The purpose of this study was to investigate the transcriptional and metabolomic response of C. opilio exposed to stressors. Crabs were randomly assigned to 24 or 72 h treatment groups where they were exposed to conditions simulating live transport (handling and air exposure). A control group was kept in cold (2 °C) and well‑oxygenated saltwater. The hepatopancreas of the crabs was sampled to perform RNA-sequencing and high-performance chemical isotope labeling metabolomics. Differential gene expression analyses showed that classic crustaceans' stress markers, such as crustacean hyperglycemic hormones and heat shock proteins, were overexpressed in response to stressors. Tyrosine decarboxylase was also up-regulated in stressed crabs, suggesting an implication of the catecholamines tyramine and octopamine in the stress response. Deregulated metabolites revealed that low oxygen was an important trigger in the stress response as intermediate metabolites of the tricarboxylic acid cycle (TCA) accumulated. Lactate, which accumulated unevenly between crabs could potentially be used to predict mortality. This study provides new information on how stressors affect crustaceans and provides a basis for the development of stress markers in C. opilio.
Background: Alterations in morning serum cortisol (MSC) have been associated with higher cardiometabolic risk. This finding has been documented primarily in populations with overweight or obesity; however, it has not been clearly established if obesity plays a requisite role in this relationship. This study seeks to extend earlier findings by examining whether body composition measures alter the relationship between MSC with glucose and insulin markers, blood pressure, and lipid parameters in Latino youth in middle adolescence. Methods: This cross-sectional study included 196 healthy adolescents (130F/66M; mean age: 16.4 ± 0.6 years; 95% Latino; mean body mass index, BMI: 24.3 ± 5.7) from Los Angeles, California. Morning cortisol, glucose, insulin, glycated hemoglobin, and lipids (triglycerides and high-density lipoprotein cholesterol) were assessed from a fasting blood sample. Sitting systolic and diastolic blood pressure was averaged from duplicate measures. Body composition measures included BMI and waist circumference, which were used as proxies for total body and abdominal adiposity, respectively. Triplicate measurements of weight and height were averaged for calculation of BMI; age- and sex-specific BMI z-score was used to classify into normal BMI or overweight/obese BMI status. Waist circumference was measured in duplicate and the average was used to classify participants into two strata: normal/healthy waist circumference (<90th percentile for age, sex, and ethnicity) and high waist circumference (≥90th percentile). Results: The primary findings were that higher MSC was associated with higher fasting glucose and systolic blood pressure after adjusting for age, sex, and BMI z-score (and/or waist circumference). BMI status or waist circumference status did not alter these relationships. Main Conclusion: Our results suggest that the relationships between hypothalamic-pituitary-adrenal axis function and certain cardiometabolic risk factors may be independent of adiposity. Future research is warranted to discover the contributors and underlying mechanisms of these relationships in adolescent populations. identifier: NCT02088294.
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The third trimester of human pregnancy is characterized by a hyperactive hypothalamic-pituitary-adrenal axis, possibly driven by progressively increasing circulating levels of placental CRH and gradually decreasing levels of CRH-binding protein. The postpartum period, on the other hand, is characterized by an increased vulnerability to psychiatric manifestations (postpartum "blues," depression, and psychosis), a phenomenon compatible with suppressed hypothalamic CRH secretion. To investigate the hypothesis that the postpartum period is associated with suppression of hypothalamic CRH secretion, we studied prospectively 17 healthy euthymic women (mean +/- SE age, 32.0 +/- 1.1 yr) with no prior history of depression, starting at the 20th week of gestation. Psychometric testing was performed monthly during pregnancy and postpartum on day 2 and weeks 2, 3, 6, 8, 12, 16, and 20, whereas serial ovine (o) CRH tests were performed postpartum at 3, 6, and 12 weeks. While pregnant, all 17 subjects remained euthymic; in the postpartum period, 7 women developed the "blues," and 1 developed depression. Overall, the mean plasma ACTH response to an iv bolus of 1 microgram/kg oCRH was markedly blunted at 3 and 6 weeks, but normal at 12 weeks postpartum, whereas the mean plasma cortisol response was at the upper limit of normal at all 3 times. These data are compatible with a suppressed hypothalamic CRH neuron that gradually returns to normal while hypertropic adrenal cortexes are progressively down-sizing. When the postpartum ACTH responses to oCRH were analyzed separately for the euthymic women and the women who had the "blues" or depression, the blunting of ACTH was significantly more severe and long lasting in the latter group; this was observed at all 3 times of testing. We conclude that there is central suppression of hypothalamic CRH secretion in the postpartum, which might explain the increased vulnerability to the affective disorders observed during this period. The suppressed ACTH response to oCRH might serve as a biochemical marker of the postpartum "blues" or depression.
Growth retardation to complete growth arrest is the hallmark of Cushing’s syndrome in children. The major mechanism for this has been considered the glucocorticoid-induced resistance of target tissues to insulin-like growth factor-I (IGF-I) and other growth factors. The purpose of this study was to examine the GH secretory dynamics of patients with Cushing’s disease before and up to 12 months after their cure by transsphenoidal adenomectomy. In 14 patients, blood sampling every 20 min over 24 h for determination of plasma GH was performed before and 10-11 days and 3, 6, and 12 months after therapy. These patients also underwent arginine infusion and L-dopa stimulation tests and had measurements of morning baseline GH-binding protein (GHBP), IGF-I, and IGF-binding protein-3 (IGFBP-3) plasma concentrations. Fourteen sex- and pubertal stage-matched normal volunteers were used as controls. Before therapy, the patient group had an increased body mass index (31.5 ± 5 kg/m²) and markedly decreased plasma mean 24-h GH concentration, mean peak height, and peak area values, with pulse frequency (mean number of peaks) similar to that in the controls. GH values after arginine and L-dopa stimulation were also subnormal in many of these patients, with 2 of 8 and 8 of 10 failing to show GH responses greater than 7 ng/mL in the respective test. In spite of these findings, plasma concentrations of IGF-I, IGFBP-3, and GHBP were within the normal range in these patients. Surprisingly, a pattern of GH suppression similar to that observed in patients with active disease was also seen in patients who were studied 10-11 days and 3, 6, and 12 months after their cure, when their body mass indexes were progressively normalizing, being relatively stable at 10 days, 26.9 ± 3.8 kg/m² at 3 months, and 24.8 ± 3.3 kg/m² at 12 months. In these patients, plasma IGF-I and GHBP remained normal, whereas IGFBP-3 decreased significantly, albeit within the normal range. The growth rate of 4 patients who were Tanner stage III or below and had not completed their growth at the time of the study increased the year after surgical cure. These findings suggest that patients with Cushing’s disease have marked GH suppression during their illness, which, however, does not appear to be a major contributor to the growth suppression observed in this condition. GH hyposecretion continues for at least a year during convalescence, in spite of significant increases in the growth rate in all growing patients.
CRF dose-dependently enhanced corticosterone (B) secretion by rat adrenal slices including both cortex and medulla. Conversely, CRF did not exert any B response by fragments of adrenocortical autotransplants, which are completely deprived of chromaffin tissue. However, autotransplant quarters exhibited a dose-dependent response to ACTH qualitatively similar to that of adrenal slices, although markedly less intense. The maximal B response of adrenal slices to CRF (10(-8) M) was completely annulled by corticotropin-inhibiting peptide (10(-6) M), a competitive inhibitor of ACTH, which totally blocked the secretory response to ACTH (10(-8) M) of both kinds of preparations. ACTH immunoreactivity was present in the adrenal gland of control rats, but was undetectable in autotransplanted adrenocortical nodules. Moreover, adrenal fragments mainly composed of chromaffin tissue released detectable amounts of ACTH in response to high concentrations of CRF (10(-8)/10(-6) M). These findings suggest that chromaffin medullary cells play a pivotal role in the direct adrenocortical secretagogue effect of CRF, probably by releasing ACTH, which, in turn, may evoke, in a paracrine manner, the glucocorticoid response.
Patients cured from endogenous Cushing syndrome usually develop postoperative adrenal suppression in the year ensuing surgery. To define whether the pituitary corticotroph is the rate limiting step in the postoperative recovery of this secondary/tertiary form of adrenal insufficiency, we examined surgically cured patients with Cushing syndrome 10 days, 3 months, and 6-12 months after surgery, by administering ovine CRH (oCRH) iv at the dose of 1 microgram/kg.h over 24 h. The pituitary corticotroph of these patients responded vigorously to oCRH, with ACTH concentrations reaching above the normal range at all three times of testing. Parallel measurements of cortisol in nonadrenalectomized patients demonstrated subnormal adrenal responsiveness at 10 days and 3 months and normalization at 6-12 months after surgery. The circadian rhythm of ACTH was maintained postoperatively at 10 days and 6-12 months, and the circadian rhythm of cortisol was also present at 6-12 months after surgery, in spite of the constant ...
Corticotropin-releasing hormone (CRH) secreted from the hypothalamus is the major regulator of pituitary ACTH release and consequent glucocorticoid secretion. CRH secreted in the periphery also acts as a proinflammatory modulator. CRH receptors (CRH-R1, R2alpha, R2beta) exhibit a specific tissue distribution. Antalarmin, a novel pyrrolopyrimidine compound, displaced 12SI-oCRH binding in rat pituitary, frontal cortex and cerebellum, but not heart, consistent with antagonism at the CRHR1 receptor. In vivo antalarmnin (20 mg/kg body wt.) significantly inhibited CRH-stimulated ACTH release and carageenin-induced subcutaneous inflammation in rats. Antalarmin, or its analogs, hold therapeutic promise in disorders with putative CRH hypersecretion, such as melancholic depression and inflammatory disorders.
CRH, the principal regulator of the hypothalamic-pituitary-adrenal axis and modulator of autonomic nervous system activity, also participates in the regulation of appetite and energy expenditure. Antalarmin, a pyrrolopyrimidine compound, antagonizes CRH type 1 receptor-mediated effects of CRH, including pituitary ACTH release, stress behaviors, and acute inflammation. We administered antalarmin chronically to evaluate its effects on hypothalamic-pituitary-adrenal axis function and metabolic status. Adult male rats were treated twice daily with 20 mg/kg of ip antalarmin or placebo over 11 days. The animals were weighed; plasma ACTH, corticosterone, leptin, and blood glucose levels were determined; and morphometric analyses were performed to determine adrenal size and structure, including sizing, histochemistry, immunohistochemistry, and electron microscopy. Leptin messenger RNA expression in peripheral fat was analyzed by Northern blot. Antalarmin decreased plasma ACTH (mean ± sd, 2.62 ± 0.063 pg/ml) and corticosterone concentrations (10.21 ± 1.80 μg/dl) compared with those in vehicle-treated rats [respectively, 5.3 ± 2.0 (P < 0.05) and 57.02 ± 8.86 (P < 0.01)]. Antalarmin had no significant effect on body weight, plasma leptin, or blood glucose concentrations or fat cell leptin messenger RNA levels. The width of the adrenal cortex of animals treated with antalarmin was reduced by 31% compared with that in controls without atrophy of the gland. On the ultrastructural level, adrenocortical cells were in a hypofunctional state characterized by reduced vascularization, increased content of lipid droplets, and tubulovesicular mitochondria with fewer inner membranes. The apoptotic rate was increased in the outer zona fasciculata of animals treated with the antagonist (26.6 ± 3.58%) compared with that in placebo-treated controls (6.8 ± 0.91%). We conclude that chronic administration of antalarmin does not affect body weight, carbohydrate metabolism, or leptin expression, whereas it reduces adrenocortical function mildly, without anatomical, clinical, or biochemical evidence of causing adrenal atrophy. These results are promising for future uses of such an antagonist in the clinic.