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The Endocrine Response to Stress - A Comparative View

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The Endocrine Response to Stress -
A Comparative View
Lluis Tort and Mariana Teles
Dpt. of Cell Biology, Physiology and Immunology
Universitat Autonoma de Barcelona
Spain
1. Introduction
1.1 The stress concept
The word stress is used extensively to name a situation of tension that can be applied to
living organisms such as animals or plants but also to ecosystems or in geological
phenomena. Nevertheless, the concept of biological stress is closely connected to the historic
development of the meaning of this word by Hans Selye after his short paper in Nature
(Selye, 1936), following a first approach by Walter Cannon who restricted the physiological
changes of stress and injuries to the effects of catecholamines and the adrenal medulla.
Other key contributions of Selye to the stress associated concepts were the word stressor,
meaning the agent causing stress effects and the non-specificity of the neuroendocrine
response, even after positive or negative stressors (Szabo, 1998). Being such a general and
widely used concept, the term stress has received many definitions, some of them trying to
characterize the phenomenon, others focusing the elicited response and others even
including the types of stressors, i.e. symbolic or real (physical, chemical, pathogenic).
Nevertheless, in all of them some key elements are included: A source or stressor, the non-
specific reaction and the neuroendocrine response.
As a relevant physiological mechanism, the stress response by itself is not inherently bad.
For example, glucocorticoids are released in animals in response to situations that are not
normally regarded as stressful, including courtship, copulation and hunting. In addition,
hormones which increase during stress periods, are also part of the reproductive process
and induce hormonal cascades causing parturition in some species (Möestl and Palme,
2002). As an example, brine shrimp Artemia exposed under gnotobiotic conditions to a non-
lethal heat shock increases the expression of Heat Shock Protein-70 (HSP-70), thus inducing
a non-specific molecular stress response. When Artemia was challenged with pathogenic
bacteria, Vibrio campbellii and Vibrio proteolyticus, a cross-protection against pathogens was
observed if an appropriate combination of heat application and recovery treatment was
applied (Sung et al., 2007).
1.2 Stress, a general phenomenon in living organisms
The overall stress response, meaning the array of reactions generated in most body
compartments as a result of the threat of the stressor, is common to all organisms. The fight-
or-fight response and the fear reactions can be seen as a common behavior from
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invertebrates to man and the necessary energetic supply and coordination of neural circuits
for these reactions are also common patterns among animals along the phylogenetic tree.
Nonetheless, evolutive ancient organisms are also sharing some of the basic responses that
are seen in lower vertebrates and mammals, for instance, heat shock protein expression or
the increase of antioxidant enzymes.
Stress responses have been also described in microorganisms. It has been shown that mitogen-
activated protein kinase (MAPK) cascades play an important role in transducing
environmental threats to transcriptional machinery by means of phosphorilation and
regulation of several key transcription factors (Karin, 1998). Although it is well known that
these cascades are activated by hormones or cytokines in vertebrates, stressors such as anoxia,
osmotic shock or radiation may also induce this activation. In bacteria such responses have
been detected as well as the heat shock response. Thus, in Escherichia coli it has been shown
that transcription factors recognize specific heat-shock promoters, and that in most bacteria the
control of major Heat-Shock genes is highly regulated (Segal and Ron, 1998). In fungi, it has
been observed that stress originated from nutrient deprivation causes debilitation of fungal
propagules, autolysis, inhibition of spores and loss of pathogenic aggressiveness (Hyakumachi
and Arora 1998). This is another common aspect of the stress reaction response, i.e. the
consequences derived from energy depletion that can be mirrored with the higher vertebrate
stress responses. Thus, all these changes are related to a reorganization of metabolic and
energetic pathways to face the effects of the stressor, a mechanism that is essentially the same
type of stress response in higher vertebrates and mammals.
The stress concept has also been applied to plants when facing unfavorable environment or
constriction of nutrients, water or inadequate soil conditions and a significant amount of
scientific literature is available concerning plant stress, mostly related to unfavorable or
changing environmental conditions. In plants, a multitude of stressors with different modes
of action elicit very similar non-specific responses, besides those specific ones related to the
particular stressor. Larcher (1987) defined the stress response in plants as the state in which
increasing demands made upon a plant lead to an initial destabilization of functions
followed by normalization and improved resistance. Lichtenthaler (1984) extended the stress
concept in plants by including regeneration and differentiating between eustress (activating
and stimulating positive elements for plant development) and distress (severe stress that
affects negatively the plant, causing damage), concepts that have been used also in animals.
Plants have a centralized system of stress response that enables to develop physiological
responses and this has been shown to work under low-resource environments such as
deserts, shaded understory or infertile soils. This response includes slow growth, low
synthetic rate (photosynthesis) and low nutrient uptake. As in animals, these responses are
driven by hormones and include changes in their balance, for instance producing more
abscisic acid and often cytokinins. Thus, there is now strong evidence that the plant
hormone abscisic acid (ABA) plays an important role in the regulation of drought stress,
since a plant can use the ABA signalling mechanism and other chemical signals to adjust the
amount of water loss in response to changes in both the rhizospheric and the aerial
environment. This hormone will work as an equivalent of renal hormones of animals after
environmental stress. Another example is the biotic stress that induces changes in hormone
synthesis and hormonal signalling cascades in the auxin, gibberellin, ABA, ethylene and
jasmonate pathways, and in addition modifying plant defense mechanisms, some of them
associated to the ubiquitin/proteasome system, a similar pathway that is found in
vertebrates (Wilkinson and Davies, 2002).
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2. The stress response
The stress response in vertebrates has been defined following the model proposed in
mammals by Selye. Together with the conserved cellular response, some other common
elements such as the non-specific neuroendocrine activation and the interaction between
regulatory systems, are also observed in non-mammalian vertebrates.
2.1 Molecular and cellular responses
Cells encounter a range of physiological and environmental stresses that require adaptive
changes in gene expression. Stress conditions include ultraviolet (UV) irradiation,
temperature changes, nutrient limitation, oxidative stress, hypoxia and exposure to various
drugs or toxins. Exposure of cells to stress elicits adaptive responses that require the
coordinated expression of stress-response genes, which affect cell survival, apoptosis, cell-
cycle progression and differentiation (Holcik and Sonenberg 2005). The cell stress response
assesses and counteracts stress-induced damage, temporarily increases tolerance to such
damage, and/or removes terminally damaged cells by programmed cell death (apoptosis).
The capacity of the response depends on the proteome expressed in a cell at a particular
time and is therefore species- and cell type-dependent (Kultz, 2005).
One of the major cell stressors is the oxygen radical. Although the concept of endogenous
oxidants was at first controversial, the identification of superoxide dismutase (SOD), an
enzyme whose main function is the removal of superoxide anions, involved that oxygen
radicals are main stressors for the cells and that removal mechanisms are stimulated to
reduce adverse effects. In terms of aging it was also proposed that higher metabolism and
elevated use of oxygen involve protein and cell damage and overall life reduction at longer
term. Given that mitochondria produce most of the energy in the cell, and correspondingly
consume the bulk of intracellular oxygen, the free-radical theory of ageing supports the
hypothesis that the higher the metabolic rate of an organism, the greater the production of
reactive oxygen species (ROS) and hence the shorter the life span. In this way, studies on
reactive oxygen species related to aging have determined a number of key molecules that
are regulating common mechanisms in organisms, from invertebrates to humans. For
instance, work done in a model organism, the worm Caenorhabditis elegans has determined
that the forkhead transcription factor, DAF-16, seems to be in a central position to integrate
a variety of signals induced by stress and the nutritional status, such as MAPK pathways
(through JNK-1), insulin (through DAF-2) and steroid hormone signalling through DAF-12
(Dawson & Dawson 2003). Moreover, insulin and insulin/IGF signalling may not only be
involved in the regulation of oxidative stress response and longevity, but also it is quite
likely that they may have a role in other degenerative disease mechanisms involving cellular
stress. (Baumeister et al., 2006).
However, in some species the strict correlation between metabolic rate and life span is not
maintained and this would depend on the production rate of reactive oxygen species
combined with the prevention mechanisms that avoid this production. This is particularly
true for birds and primates, who tend to live longer than would be predicted by their
metabolic rates. Careful analysis of oxidative production rates demonstrated that at a given
metabolic rate, mitochondria from these species tend to produce fewer ROS. (Finkel and
Holbrooke, 2000). This indicates that ROS production rather than metabolic rate provides
the strongest correlation with overall longevity. Another consequence, in terms of stress
regulation in cells, is that under situations of metabolic stress, mitochondrial oxidant
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products seem to function as signalling molecules (Finkel and Holbrooke, 2000). Therefore,
stress episodes involving a rise in intracellular oxidant levels have three important effects:
damage to various cell components, triggering of the activation of specific signalling
pathways and development of mechanisms reducing ROS production.
Another of the cell responses to stress is selective translation as it has been shown that this
event commonly occurs during cellular stress and during apoptosis. Moreover, global
translation is reduced in response to most types of cellular stress. This results in savings of
cellular energy, which is mainly consumed in the process of translation, estimated as an
average of about 50% of the cellular energetic resources. Remarkably, the stress-induced
attenuation of global translation is often accompanied by a switch towards the upregulation
of the selective translation of proteins that are required for cell survival under stress (Holcik
and Sonenberg 2005).
Another key aspect of the cell response is the modulation of major pathways of energy
metabolism, closely linked to the oxidative burst in stressed cells. Selected enzymes related
to energetic pathways contribute strongly to the control of key pathways such as glycolysis,
pentose phosphate pathway, and the citrate cycle. Induction of these enzymes during stress
may be necessary for generating reducing equivalents (NADH, NADPH) that are needed for
cellular antioxidant systems. In this way, a number of key enzymes such as the enzyme
Enolase have been shown to be highly induced under different types of potential stressors.
Thus, in vertebrates Enolase is expressed in most tissues as a response to either physical or
chemical stressors, pathogens or immune stimuli and even under pathogenic states such as
cancer. As it is a key enzyme of the glycolytic pathway, the role of this enzyme appears to be
relevant in switching the energetic flows under any type of stress source (Ribas et al.,2004).
Regarding cellular responses to stressors, heat shock proteins (Hsp) are considered one of the
main cell mechanisms responding against stressors. Stressors disturb cellular homeostasis and
induce a corresponding homeostatic response of these proteins that in most cases have the
characteristic of being permanent until environmental conditions change again, and that are
triggered by stressor-specific sensors that monitor specific environmental variables. Hsp are a
defined set of proteins that are conserved along evolution and perform protective cellular
functions such as cell cycle control, protein chaperoning and repair, DNA and chromatin
stabilization and repair, or removal of damaged proteins. Thus, from a number of 300 common
proteins that have been identified in many organisms from human to yeast or bacteria, about
40 of them are involved in the cell response to stress. This response can occur via stressor-
specific interactions, post-translational modifications, and fragmentation of stress proteins
resulting in an induction of a common set of stress proteins triggered by molecular damage or
oxidative accumulation (Kültz, 2005). In combination with the DNA repair machinery,
molecular chaperones are required to recognize unfolded proteins and either target them for
removal, stop their aggregation, or assist in their refolding into the native, functional state.
These proteins are extensively utilized as bioindicators of environmental stress in many
different types of organisms.
2.2 The integrated physiological response.
The stress response system in vertebrates has both central nervous system (CNS) and
peripheral components. The central tissue components of the stress system in mammals are
located in the hypothalamus and the Locus ceruleus in the brainstem, and include a number
of endocrine messengers with a principal role in mediating the neuroendocrine stress
response, being the CRH (Corticotrophin Releasing Hormone) the key peptide in this
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267
activation. The roles of the related peptides, the urocortins, in stress responses are beginning
to be understood in mammals, but very little is known about their expression and function
in non mammalian species. Also, CRH and urocortins are expressed throughout the body
where they may play diverse, but as yet poorly characterized, roles in tissue development
and homeostasis (Denver, 2009). Another hypothalamic peptide, TRH (Thyrotropin
Releasing Hormone) also has such activation properties in fish. These hypothalamic factors
stimulate the release of the Adrenocorticotropic Hormone (ACTH) from the pituitary which
in turn induces production and release of the major stress steroid, cortisol, by interrenal cells
located within the head kidney (Tort, 2010).
The components of the stress system include the peripheral limbs of the hypothalamic-
pituitary-adrenal (HPA) axis; the efferent sympathetic-adrenomedullary system; and
components of the parasympathetic system. Given the potential for the convergence of these
mechanisms, specifically in the nervous system, it may be suggested that interactions
between the two systems would be produced already at the initial stages of corticosteroid
signalling (Riedemann et al., 2010). In emergency situations, the hypothalamus is activated
and stimulates the sympathetic nervous system and the adrenal medulla which releases
adrenaline and noradrenalin, and the adrenal cortex which releases GCs. The effects
are global, and the nerves as well as hormones stimulate the systems needed for fight-or-
flight (it is usually a short duration stress response). These peripheral components may be
limited to these former elements, or one could include other hormonal axes and structures
that are stimulated by the neuroendocrine agents and that exert important actions on the
whole metabolism and the overall energetics. These other peripheral components are
considered below.
3. Comparative endocrine response to stress
Endocrine changes after stress are clearly observed in vertebrates where a common
endocrine pattern can be recognized (see table 1). Nevertheless, invertebrates also
experience changes in hormones after stressors. For instance, in crustaceans, the
hyperglycemic hormone (CHH) from the lobster, Homarus americanus increases in
hemolymph following emersion. Significant levels of hemolymph CHH have been also
measured in lobsters that had been eyestalk-ablated and it has been observed that these
animals continued to produce CHH, even though the main source of CHH had been
removed, probably produced in other portions of the central nervous system (Chang et al.,
1999). As another example, in arthropods, proteins of the hemocyanin gene family are
involved in major physiological processes, including aerobic respiration, the innate immune
response, and molting. Members of this hemocyanin family, cryptocyanin, and
phenoloxidase, are multi-subunit molecules that assemble into hexamers and higher
aggregates. The hemocyanin hexamer heterogeneity is maintained as a mechanism of
selection for functional diversity under environmental stress when changing developmental
and environmental conditions (Terwilliger et al., 2006), a similar response that can be
observed in vertebrates related to specific endocrine or immune molecules.
3.1 Mammals
The stress response in the brain starts in the parvocellular neurons of corticotropin-releasing
hormone (CRH); the arginine vasopressin (AVP) neurons of the paraventricular nuclei (PVN)
of the hypothalamus; the CRH neurons of the paragigantocellular and parabranchial
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Fish Amphibians Reptiles Birds Mammals
Pituitary
anatomy
Bigger pars
intermedia
Smaller
median
eminence
Bigger pars
intermedia
Smaller ventral
lobe
Longer pars
nervosa
Bigger pars
itermedia
Bigger ventral
lobe
Bigger median
eminence
Smaller pars
intermedia
Bigger ventral
lobe
Adrenal
anatomy
Cells
scattered in
the head
part of the
kidney
Cells inside the
kidney in islets
(urodele) or
strands (anuran)
Cells in lobular
structures close
to the gonads
Cells in lobular
structures at
top of the
kidneys
Cells in lobular
or irregular
structures at top
of the kidneys
Catecholamine Adrenaline Adrenaline Adrenaline Adrenaline and
Noradrenalin Adrenaline
Corticosteroid Cortisol Corticosterone Corticosterone Corticosterone Cortisol or
Corticosterone
Table 1. Details of the pituitary and adrenal anatomy and the main secretion,
catecholamines and corticosteroids in vertebrates
nuclei of the medulla and the Locus ceruleus (LC); and other mostly noradrenergic (NE) cell
groups in the medulla and pons (LC/NE system). The principal effectors include CRH,
AVP, the proopiomelanocortin-derived peptides (POMC) α-melanocyte-stimulating
hormone (MSH) and β-endorphin, the glucocorticoids (GC) and the catecholamines
noradrenalin and adrenaline. Signalling by CRH-like peptides is mediated by at least two
distinct G protein-coupled receptors and modulated by a secreted binding protein. These
neuropeptides function as hypophysiotropins and as neurotransmitters/ neuromodulators,
influencing stress-related behaviors, such as anxiety and fear. In addition to modulating
HPA activity and behavioral stress responses, CRH-like peptides are implicated in timing
key life history transitions, such as metamorphosis in amphibians and birth in mammals.
CRH-like peptides and signalling components are also expressed outside of the central
nervous system where they have diverse physiological functions (Denver, 2009).
In mammals, the adrenal gland, also known as the suprarenal gland, is a two-paired gland,
yellow- or orange-colored, triangle-shaped, located over the superior part of the kidney, one
on each side. The adrenals are mainly responsible for regulating the response to stress
through the synthesis of catecholamines and corticosteroid hormones. In other vertebrates,
this gland is also associated with kidneys but its anatomical arrangement is different, as it
will be described latter on this chapter. In mammals, the adrenals have a distinct outer-
cortex and inner-medulla arrangement, which is characteristic of this group of vertebrates.
The adrenal medulla occupies the central part of each adrenal gland and accounts for 22% of
the gland weight; the remaining 78% of the weight corresponds to the adrenal cortex and
adrenal capsule that surrounds the gland. Both the adrenal medulla and cortex receive
regulatory input from the nervous system (Binkley, 1995).
The central region (medulla) of the adrenal gland, have specific cells called chromaffin cells,
which are considered modified postganglionic cells of the sympathetic nervous system.
These chromaffin cells secrete catecholamines, adrenaline (or epinephrine), noradrenalin (or
norepinephrine) and to a lesser extent, dopamine. The mammalian adrenal cortex can be
divided into three layers: zona glomerulosa, zona fasciculata and zona reticularis; all three
layers produce corticosterone, but otherwise, the layers are specialized as regards their main
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hormone products. Briefly, the zona glomerulosa, which represent about 15% of the adrenal
weight, is the outer layer and is specialized in production of aldosterone. The zona
fasciculata is the central and widest layer of the adrenal cortex (around 50% of adrenal
weight) and secretes cortisol and androgens. Finally, the zona reticularis, represents 10% of
the adrenal weight, secrete cortisol and androgens. These two last zones respond to ACTH
stimulation.
In an initial alarm phase, catecholamines are released into the circulatory system, where
they circulate in a free form or conjugated to blood proteins; in blood, catecholamines have a
short half-life of about 3 to 4 minutes. Its biosynthetic pathway of synthesis is highly
conserved throughout the animal kingdom with the rate-limiting step controlled by the
enzyme tyrosine hydroxylase (Perry and Capaldo, 2010). Both catecholamines have a large
number of actions, most of which contribute to the sympathetic fight-or-flight response. The
best well known functions of adrenaline and noradrenalin are their actions in the
cardiovascular system, the stimulation of glycogenolysis in skeletal and cardiac muscle,
mobilizing glucose in those tissues, which aimed at reducing the detrimental effects of
stressors on physiological function or optimizing physiological processes during periods of
increased energetic demand. In the more highly evolved vertebrates, such as mammals and
birds, the acute humoral adrenergic stress response effectively complements the neuronal
regulation of physiological systems via the sympathetic division of the autonomic nervous
system (Perry and Capaldo, 2010).
Cells of adrenal cortex respond to the HPA axis and mediate the stress response through
production of steroid hormones, namely mineralocorticoids and GCs. The HPA axis
involves the release of corticotropin releasing hormone (CRH) and Vasopressin from
hypothalamic PVN, and CRH is the main responsible for stimulating adrenocorticotropic
hormone (ACTH) release from the anterior pituitary gland. ACTH arrives at the target cells
in the adrenal cortex where it stimulates the synthesis of GCs. In humans, monkeys, sheep
and cats cortisol is predominantly secreted; whereas rodents mainly secrete corticosterone.
Some other mammals, such as dogs, secrete a mixture of cortisol and corticosterone in a
similar ratio (Boonstra, 2004). GCs act at multiple sites within the body in an attempt to
maintain homeostasis, but because of the potential damaging effects of chronic exposure to
GCs, the HPA axis is tightly regulated through classic negative feedback loops.
Thus, cortisol feeds back on hypothalamus and pituitary to cause rapid inhibition of CRH
release. Under acute stress conditions, feedback mechanisms are efficient and the system
returns to normal, resulting in short-term effects on body processes. Under conditions of
chronic stress, feedback signals are weak and the system remains activated for longer
periods, resulting in effects on body processes that can be long term and detrimental
(Boonstra et al., 2004).
After short-term stressors, cortisol affects the intermediary metabolism by stimulating
gluconeogenesis in liver, increasing glycogen formation and increasing the availability of
substrates derived from proteins and fats. All these actions tend to produce hyperglycemia,
increasing the availability of quick energy to muscle and nervous tissue. Chronic or
repeated exposure to a stressor, characterized by lower but prolonged endocrine secretions,
often involve longer recovery periods and much higher energetic and performance costs,
due to both stressor persistence and the derived effects of the stress response effectors, i.e.,
GCs. These negative effects include alterations at several physiological levels, from impaired
growth and reproductive capacity to immune suppression (Tort, 2010).
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3.2 Birds
In birds adrenal glands may be a single median structure or two separate organs, in close
contact with each other, lying just cranial to the kidneys and gonads on either side of the
aorta and caudal vena cava. The adrenals are small, ovoid in form, with a yellow or orange
color, and are surrounded by a loose connective capsule. In contrast to mammals, the cortex
is not well differentiated from the medulla. Clusters of chromaffin cells are mixed with
blood vessels and the interrenal steroidogenic cells are radially arranged in the subcapsular
zone and in the inner part of the gland (reviewed by Ghosh et al., 2001).
Adrenaline and noradrenalin are secreted by the medullary part of the gland and unlike in
mammals, the enzyme PNMT exists in all adrenomedullary chromaffin cells, so it cannot be
considered a marker in differentiating adrenaline from noradrenalin cells. PNMT exists in
its active form only in the adrenaline-storing cells (Ghosh et al., 2001). The chromaffin cells
are usually mixed and arranged without any preferential location, but unlike most other
vertebrate groups, there is strong inter-specific variation in the noradrenalin/adrenaline cell
ratio (Varano, 1980). This ratio seems to bear a distinct relation to avian phylogeny; thus,
less evolved birds have more noradrenalin, while recently evolved birds have more
adrenaline. In these terms, birds occupy an intermediate evolutionary position having
noradrenalin/adrenaline ratios around 1/1 (Ghosh, 1977; Varano, 1980).
The most important glucocorticoid in birds is corticosterone, which is secreted by the
cortical part of the gland and has both glucocorticoid and mineralocorticoid activity, having
a more important role than aldosterone in electrolyte balance. In general, birds have low
basal circulating corticosteroids levels, but these levels increase during stress-related
responses as occurs in mammals (Boonstra et al., 2004). The acute short action stress
response (fight or flight) is activated within seconds by the sympathetic nervous system
which induces release of catecholamines from chromaffin cells of the adrenal medulla into
the general circulation and release of CRH primarily from the hypothalamus, which induces
ACTH secretion from the anterior pituitary and, in response to ACTH, release of
corticosterone into the general circulation within minutes.
Ghosh and collaborators (2001) demonstrated that catecholamines cause hepatic and muscle
glycogenolysis which can lead to hyperglycemia, as it occurs in mammals. The avian
adrenal chromaffin tissue is influenced by the steroidogenic cells; GCs increase noradrenalin
content in the chick and adrenaline content in the pigeon adrenal glands, with a synergistic
action requiring activity of the splanchnic nerve (Ghosh et al., 2001). Compared to
mammals, less is known about the effects of catecholamines on bird metabolism. Starvation
experiments on birds of different food habits demonstrated a simultaneous depletion and
release of catecholamines and glycogen.
3.3 Reptiles
In reptiles, the adrenal glands are discrete bodies; yellow/red in color, separated from the
kidneys, and in close relationship with the gonads, lying in its dorsal part. The only
exception to this pattern is in the chelonians where the adrenal gland is in close contact with
the ventral surface of the kidney, as in anuran amphibians. Chelonians have dorsoventrally
glands which lie against the kidney. Ventrally, they are covered by peritoneum that extends
forward to form the mesorchium or mesovarium of the adjacent gonads. Snakes and lizards
have adrenal glands incorporated into the mesorchium or mesovarium, close to their
respective gonads. They are elongated in snakes and usually globular in lizards. The right
gland is attached to the caudal vena cava (reviewed by Perry and Capaldo, 2010).
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271
The chromaffin and the steroidogenic tissues are associated, but there is a substantial variation
in the degree of mixing that depends on the considered group. Thus, in Crocodilians and
Chelonians, chromaffin and steroidogenic tissues are largely intermingled. In Rincocephalian
lizards, most of the chromaffin tissue forms a dorsal mass that send extensions between the
interrenal cells; moreover, many clusters of chromaffin cells are present within the
steroidogenic parenchyma, and some clusters of chromaffin cells are present on the ventral
surface of the gland. Most Squamata lizards or iguanas show a similar distribution, with the
exception of the ventral chromaffin tissue, usually absent in these reptiles (reviewed by Perry
and Capaldo, 2010). Moreover, the distribution of the two tissues presents a great variability,
which is correlated to the phylogeny of the species. Generally, a high degree of separation
between the two tissues is typical of ancient species, whereas a trend toward the close
association between them is typical of more recent species (Laforgia et al., 1991).
The distribution of noradrenalin and adrenaline cells is different among groups of reptiles.
Usually, the islets intermingled in the steroidogenic parenchyma are occupied only by
adrenaline cells, whereas noradrenalin and adrenaline cells are present in the chromaffin
superficial tissue. In reptiles, the ratio between noradrenalin/adrenaline reflects the degree of
separation between steroidogenic and chromaffin tissues. Thus, high values of this ratio, and
therefore a high number of noradrenalin cells, correspond to a high degree of separation of the
two tissues whereas low values of this ratio, correspond to a high degree of mixing between
them. The reason for this correspondence, as it has been clarified by Perry and Capaldo (2010),
is that in reptiles and mammals, the enzyme PNMT, that catalyses the methylation of
noradrenalin into adrenaline, is activated by GCs. Therefore, when the two tissues are spatially
separated, GC delivery to the chromaffin cells is likely to be impeded, whereas, when the
degree of integration is high, GC delivery to the chromaffin cells is likely to be facilitated.
In response to stress, reptiles produce different patterns of catecholamine release, which can
increase or decrease according to the type of stressor. For example, restraint stress in
alligators causes a decrease in plasma adrenaline and noradrenalin levels at 24 h, and an
increase in noradrenalin levels by 48 h. The role of catecholamines in regulating reptilian
metabolism is poorly studied although it is clear that adrenaline causes hyperglycemia and
promotes glycogenolysis in liver and glycogen deposition (Norris, 2007).
Corticosterone is the major adrenal corticosteroid secreted by reptiles (see Tyrrel and Cree,
1998) but the patterns of basal corticosterone secretion vary considerably among them.
However, almost all studies concerning the HPA modulation by stressors show that reptiles
respond to stressors by increasing plasma levels of corticosterone (Tyrrel and Cree, 1998;
Moore and Jessop, 2003). Nonetheless, it is evident a variation in the rate, duration and
magnitude of the adrenocortical response to the same type of stressor, reflecting a change in
the sensitivity of the HPA axis to stressors (Wingfield and Romero, 2001). A number of
studies have demonstrated that differences in physiological state among individuals, such
as body condition, reproductive state, disease status, age, sex, genotypic variation, and
social status can result in adrenocortical modulation (Dunlap and Schall, 1995). In addition,
differences in external environment such as variation in rainfall, temperature, food
availability, and humidity or general habitat quality can result in individual adrenocortical
modulation between populations (Moore et al., 2001).
3.4 Amphibians
The adrenal glands of amphibians are found in close association with the kidneys, although
their exact location varies with the species. Like reptiles and birds, the adrenal gland
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appears homogenous on cut surface, and histologically it is comprised of intermingled
cortical and medullary elements, rather than having the clear delineation between cortex
and medulla seen in mammalian species. Thus, in amphibians the chromaffin cells are
closely associated with the steroidogenic cells; additionally, chromaffin cells can be found
in the extra-adrenal chromaffin tissue, within the paravertebral sympathetic ganglia and
in the abdominal para-aortic region, but their precise role at these sites is not well
understood. The arrangement of adrenal chromaffin cells is markedly different in anurans
and urodeles (Accordi, 1991; Chimenti and Accordi, 2008). In urodeles, the steroidogenic
tissue forms numerous small bodies, partially embedded in the ventral surface of the
kidney with groups of chromaffin cells interspersed (reviewed by Perry and Capaldo,
2010). In anurans, noradrenalin and adrenaline cells are usually intermingled, with no
preferential distribution. The adrenal gland produces both catecholamines and
corticosteroids (Wright 2001).
Amphibian chromaffin cells generally receive a scarce nerve supply and because of the
tight intermingling between steroidogenic and chromaffin tissues, regulation of the
chromaffin cell activity is likely achieved by paracrine interactions between the two tissues
(Capaldo et al., 2008a, b). Amphibian chromaffin cells are regulated by multiple factors,
including humoral agents carried from the blood stream, neurotransmitters and
neuropeptides.
It is known that ACTH is one of the main regulators of steroidogenic tissue activity in
amphibians (Norris, 2007; Sicard and Vaudry, 2000) and that corticosterone, the main
corticosteroid secreted by amphibians, generally increase as a response to stress (reviewed
by Moore et al., 2003). However despite the existence of adrenocortical modulation, there is
little understanding of what physiological mechanisms operate within the HPA axis to
enable modulation of corticosterone release during stress both in amphibians and in reptiles
(Moore et al., 2001). A limited number of studies have documented the effects of stressors on
the catecholamine release in amphibians. But, in general, stress situations such as hypoxia
and forced exercise (Romero et al., 2004) elicit an increase in plasma catecholamines.
Elevated catecholamine concentrations cause hyperglycemia via its stimulatory action on
glycogenolysis in both liver and muscle (Norris, 2007).
Adaptation to an unfavorable environment can take place under very difficult conditions, as
demonstrated in desert amphibians: tadpoles of these species can accelerate metamorphosis as
their pond dries, with earlier birth of a more mature product, as long as an unfavorable larval
environment is not experienced too early or too severely. Significant changes in the hormonal
patterns are found under these circumstances. Similar adaptive phenomena are observed in
humans involving elevation of corticosteroid secretion when fetal adverse circumstances are
too severe. However, there is very likely a price to pay for this immediate beneficial effect on
survival. Hippocampal damage could explain the high rate of learning disabilities and a
number of diseases in adulthood (Amiel-Tison et al., 2004).
3.5 Fish
Although few studies have been undertaken in fish regarding the mechanisms and the
neurophysiology of stress detection by the central nervous system (CNS) and sensory
organs, the scheme of stress induced neuroactivation is similar than in other vertebrates.
Stressors are detected and first processed in the CNS and then through neuroendocrine axis.
In most species the Corticotropin Releasing Hormone or CRH-like activity has been found
in the preoptic nucleus of the hypothalamus. The CRH travels to the pituitary where it
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273
stimulates the corticotrope cells to release ACTH but in fish, it also stimulates the
melanotropic cells to release α-Melanocyte-stimulating-hormone (α-MSH) and β-endorphin.
Similarly, other peptides as TRH activates ACTH release and the HPI cascade. In the
interrenal tissue of fish, ACTH is the main responsible for the cortisol release but other
agents, like Angiotensin, Urotensin and Atrial Natriuretic Factor (ANF), may interact with
ACTH in the cortisol secretion. It has also been shown that melanotroph products (α-MSH
and β-Endorphin) may be important regulators of the corticosteroidogenesis and cortisol
secretion.
In fish there is close association between adrenocortical and chromaffin tissue except in
elasmobranch fishes where the tissues are completely separated and the adrenocortical
tissue comprise a discrete gland which lies dorsally between the two posterior lobes of the
kidney. The arrangement of chromaffin cells varies among the various groups of fishes
along an evolutionary timeline. For example, in hagfish (Myxine) and lampreys (Lampetra),
chromaffin cells are located within the heart (reviewed by Perry and Capaldo, 2010), as well
as in the great veins returning blood to the heart (Gallo and Civinini, 2003). In teleost fish,
the chromaffin cells are located within the walls of the posterior cardinal vein and in close
association with the lymphoid tissue of the kidney. In general, chromaffin cells are often
observed either singly or clustered into groups of several cells. The association of chromaffin
cells with the steroidogenic interrenal cells may vary amongst different teleost species (Perry
and Capaldo, 2010). Noradrenalin and adrenaline are the main catecholamines produced by
fish chromaffin cells as it occurs in the other vertebrate groups. Noradrenalin and
adrenaline producing cells can be distinguished on the basis of morphological
characteristics. In teleost fish as in the other groups of fishes, the aminergic chromaffin and
interrenal steroidogenic tissues form a diffuse organ at the anterior part of the kidney (called
the head kidney), which is situated around the posterior cardinal vein and their branches
(Gallo and Civini, 2004). Thus, the head kidney is the homolog to the adrenal gland, and is
an organ of particular importance due to its cellular diversity and multiple functions
associated (e.g. phagocytosis, hematopoiesis, catecholamine secretion by chromaffin cells,
and cortisol secretion by interrenal cells).
Catecholamines, predominantly adrenaline, are released from chromaffin cells (Reid et al.,
1998), immediately after stress. Once in the circulation, these hormones diminish the
detrimental consequences frequently associated with stressful situations as in the other
groups of vertebrates. Similarly, one of the primary roles of catecholamines is to modulate
cardiovascular and respiratory function in order to maintain adequate levels of oxygen in
the blood and, therefore, sufficient supply to the tissues mobilizing energy stores for the
increased energy demands that often accompany stress (Perry and Wood, 1989; Randall and
Perry, 1992 in Reid et al., 1998).
Activation of the hypothalamo-pituitary axis and release of ACTH into the circulation by the
pituitary is also an integral part of the primary stress response of fish. ACTH stimulates the
interrenal cells embedded in the kidney to synthesize and release cortisol into circulation for
distribution to target tissues (Barton, 2002; Tort, 2010). The release of cortisol in teleostean
and other bony fishes is delayed relative to catecholamine release. In fish, high plasma
cortisol levels have a wide range of metabolic effects including, the modulation of
carbohydrate metabolism through gluconeogenesis, increases in protein turnover,
regulation of amino acid metabolism, ammonia output, glutamine synthetase and
aminotransferase activity, and increased lipolysis (reviewed in Mommsen et al., 1999).
Cortisol modulates the inflammatory response (Mackenzie et al., 2006; Aluru and Vijayan,
Basic and Clinical Endocrinology Up-to-Date
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2009) and a range of other immune system responses (Maule and VanDerKooi, 1999), and
appears to attenuate the cellular heat shock protein response to thermal insult (Ackerman et
al., 2000; Basu et al., 2001 in Pankhurst 2010). Corticosteroid hormones also play a key role
in osmoregulation (reviewed in McCormick, 1995), and are critical for controlling
metabolism, hydromineral balance, and the overall stress response. Among corticosteroid
hormones that have been well characterized in most vertebrate groups, the identity of one of
the earliest vertebrate corticosteroid hormones, 11-deoxycortisol has been recently found in
lampreys, a member of the agnathans that evolved more than 500 million years ago. This
corticosteroid is regulated by the hypothalamus–pituitary axis and responds to acute stress
(Close et al., 2010). This indicates that a complex and highly specific corticosteroid signalling
pathway evolved at least 500 million years ago with the arrival of the earliest vertebrate,
although it is assumed that this molecule may be derived also from an early ancestral
corticosteroid receptor molecule (Thornton and Carroll, 2011).
Regarding the nuclear glucocorticoid receptor (GR), found in all vertebrates, it is known that
in fish regulates cell growth, bone density, metabolism and modulates the cardiovascular
system. Besides cortisol, also significant levels of 11-deoxycortisol and 11-
deoxycorticosterone occur and these ligands bind to GRs and Mineralocorticoid receptors
(MRs). It has been shown in fish that teleosts may have one or two different GR genes
(Acerete et al., 2007; Bury et al. 2003). This discrepancy likely results from the fish specific
genome duplication event. One of these two GR genes has two different transcripts that are
generated by alternative splicing (Bury et al. 2003; Greenwood et al. 2003). Most
interestingly, the three different GR forms in fish are differentially expressed in vivo and
show different transactivational capacities, but only slightly different affinity for their
ligand. As both genes and different splice variants are transcriptionally active, it is
suggested that they both play an important and probably different role in the fish
physiology (Bury et al. 2003, Greenwood et al. 2003). This multiple corticoid receptors in fish
and a more complex signalling mechanism by related steroids provides an interesting model
for comparative GR function (Stolte et al., 2006).
4. Consequences of the neuroendocrine activation
Response involving the sympatico-chromaffin axis, involves the activation of chromaffin
tissue by specific neurons, resulting in the release of catecholamines, adrenalin and
noradrenalin, which in turn induce the generation of large amounts of energy to meet the
energetic needs of this active reaction. This is a very rapid response among all vertebrates
and mainly involves the cardiovascular system. Regarding the HPA axis, a longer time is
needed, since an endocrine cascade is activated and therefore the effects will be produced
when the final hormone in the cascade, a corticosteroid has been released. Looking at the
knowledge on comparative animal physiology, it can be sustained that the proteins, gene
structures, and signalling pathways of the HPA axis are present in the earliest vertebrates
and have been maintained by natural selection because of their critical adaptive roles. In all
vertebrates so far studied, the HPA axis is activated as a response to stressors and is
controlled centrally by peptides of the CRH family. It can be assumed that, irrespective of
the behavioral or physiological outcomes, acute and chronic elevations of corticosteroid
secretion initiate metabolic alterations and biochemical processes. Because of the dichotomy
in the effects of acute and chronic GC responses, studies generally focus on either acute or
chronic elevations of GCs (elevated basal values). When basal GC concentrations are
The Endocrine Response to Stress - A Comparative View
275
elevated, a common consequence is a weakening of the further acute GC response, probably
through negative feedback mechanisms in the hypothalamic–pituitary-adrenal axis. This is
an endocrine vicious circle: a chronically high baseline can provoke pathologies, and a weak
acute response is ineffective at handling short-term stressors (Creel, 2001).
Since the energetic cost of the stress situation is high, it is clear that other hormone axes,
mostly devoted to the metabolic support will have an influence on the immune function.
Thus, the growth hormone and the somatotropic axis have also been shown to affect
immune processes, and opioids and thyroid hormones have also been shown to modulate
immune responses. The activation of catecholamines and corticosteroids induce a wide
number of changes, in particular because these molecules have receptors in most tissues.
Therefore, many if not all of the hormones involved in stress responses possess, in addition
to their direct effects, induce pleiotropic or collateral consequences that may or may not
reinforce direct or primary effect. These other effects can mediate the mechanisms that
might affect other unrelated adaptive needs, as for example to modulate the responses of the
cardiovascular system, osmotic equilibrium, disease resistance mechanisms and
immunocompetence, energetic metabolism and reproduction (see Figure 1).
Hypothalamus
ACTH
GC
Target tissues. Receptors
STS GHRH
GH
IGF1
Locus
Ceruleus
CRH NA
Hypothalamus
ACTH
GC
Target tissues. Receptors
STS TRH
TSH
T4-T3
Locus
Ceruleus
CRH NA
Hypothalamus
ACTH
GC
Target tissues. Receptors
GnRH
LH-FSH
E
2
-T
Locus
Ceruleus
CRH NA
β-endorphin
Hypothalamus
ACTH
GC
Target tissues. Receptors
Bone, Muscle, Adipose
GHRH
CRH
GH
GnRH
Sex
steroids
Stress a xis &
growthaxis
Stress axis &
energeticsaxis
Stress a xis &
reproductive axis
Stress a xis &
meta bolic axis
Fig. 1. Schematic diagrams of the endocrine interactions between the stress axis and growth,
reproduction, energetics and metabolism
In terms of energetics and growth effects, stress generally shows depressive effects,
inhibiting feeding behavior in all vertebrates. The effects of CRH on food intake are
evolutionarily ancient, as this peptide inhibits feeding already in fishes, and the same effect
is observed in birds and mammals. The effects of melanocortins on food intake have not
been as extensively studied, but available evidence suggests that the anorexic role of
neuronal melanocortins has been conserved. Data from mammals suggest an important role
for hypothalamic neuropeptides, in particular the melanocortins and CRH-like peptides, in
mediating stress-induced inhibition of feeding. Although there is evidence that CRH and the
melanocortins influence hypothalamic circuitry controlling food intake, these peptides may
have a more primitive role in modulating visuomotor pathways involved in the recognition
Basic and Clinical Endocrinology Up-to-Date
276
and acquisition of food. (Carr, 2002). Stress rapidly reduces visually guided prey-catching
behavior in toads, an effect that can be mimicked by administration of CRH, while
corticosterone and isoproterenol are without effect. Melanocortins also reduce prey
oriented turning movements in amphibians and, in addition, facilitate the acquisition of
habituation to a moving prey. The effects of these neuropeptides are rapid, occurring
within 30 min after administration. By modulating visual and motor processing circuits
these neuropeptides may help animals make appropriate behavioral decisions during
stress episodes.
Many studies in the last decade have shown that stress can affect immune system both in
mammals and lower vertebrates (Verburg-Van Kemenade et al., 2009; Dhabhar et al., 2009),
although most of the reports are related to the effects of corticosteroids, and describe
generally suppressive effects. Studies with human, murine and rat immune cells showed the
immunosuppressive effects of elevated GC levels following stressful circumstances. GCs
suppress Th1 cellular immunity and mediate a Th2 shift by suppressing production of T
helper cells type 1/(Th1; tumor necrosis factor-a, interferon-g, interleukin-2 and interleukin
-12 cytokines and inducing production of T helper cells type 1 (Elenkov 2004). Suppressive
effects have been shown also in fish, where administration of cortisol induce a reduction of
cytokine expression in cultured macrophages (Mackenzie et al., 2006; Castillo et al, 2009).
Husbandry stressors applied to different species of fish result in a reduction of
immunocompetence, showing decreased activity of immune response mechanisms
(Montero et al., 1999), and reduction in efficiency after a combination of stress and pathogen
treatment (Mauri et al., 2011).
Nevertheless, there are also episodes in which enhancement of immune function is
observed, for instance during the immediate reaction, and this may depend on several
considerations. One is the time-course, since acute or short-term stress often enhances innate
and adaptive immune responses whereas chronic or long-term stress normally suppress or
dysregulate immune function (Dhabhar et al., 2009; Tort, 2011). Another is the body
compartment at which we are looking. Thus, skin is enriched with immune cells during
acute stress, showing immuno-enhancement, while circulating blood may show depletion
of leukocytes. A third factor may be the energetic situation of the animal since the demand
of resources after stress are increased and they may be insufficient for other needs than
facing the coping with stress itself. Whether there is an excess of demands and a shortage of
energy resources, the immune system can be suppressed. Nevertheless, these arguments
based on conservation of energy have been invoked to explain potential adaptive benefits of
stress-induced immuno-suppression, but in one hand, some mechanisms for immuno-
suppression expend, rather than conserve, energy. On the other hand, it can be also
observed that while some immune responses are depressed or delayed, others are present
without any decrease in efficiency, for instance, reducing the number of lymphocytes but
increasing granulocytes . Therefore, the hypothesis is rather a temporal reorganization of
immune resources than a pure suppression response. Maladaptive implications are present
when stress becomes chronic; a situation that is unusual in nature and that evolution has yet
to resolve (Dhabhar et al., 2009).
Stressors have been shown to reduce reproductive performance and, in lower vertebrates,
even impair completely the reproductive process (Pottinger, 1999; Pankhurst 2009; Tort,
2011). In fact, the Hypothalamic-Pituitary-Gonadal axis and the Hypothalamic-Pituitary-
Adrenal/Interrenal axis share a number of mediators, mainly steroid hormones. Therefore,
stress and the activation of HPA axis affects the production of steroids. Interestingly, the
The Endocrine Response to Stress - A Comparative View
277
reproductive system can become resistant to inhibition by GCs in some reproductive
contexts. For example, if GCs allocate resources away from reproduction, and thereby
reduce individual fitness by impairing successful production of offspring, the benefit of the
reproductive system ignoring the GC signal may outweigh the cost of not responding to the
stressor. In salmon species and several marsupials, death occurs shortly after breeding. The
proximate cause of death is the extremely high levels of GCs that catabolize essential
proteins (Wingfield & Romero, 2001). Reproduction in these animals clearly continues
despite elevated GCs. Furthermore, GCs do not inhibit reproduction in many short-lived
species and in older individuals, and in dominant individuals in some species where the
dominant individual has a limited period with access to mates (Wingfield & Sapolsky, 2003).
Consequently, susceptibility to GC-induced inhibition of reproduction is highly specific
depending on the importance of continuing reproduction in the presence of stress, which
may vary depending upon age, sex or stage of the breeding cycle and of course, the species
(Romero and Butler, 2007).
In the regulation of the stress response by steroid hormones it has been assumed that the
production and regulation of steroid hormones has been viewed as a multi-organ process
involving glucocorticoids and sex steroids. However, active steroids can also be synthesized
locally in target tissues, either from circulating inactive precursors or de novo from
cholesterol. This may be the case in the brain for neurosteroids and in the immune system.
Furthermore, recent evidence suggests that other steroid hormones LH, GnRH, ACTH and
CRH are expressed locally in target tissues, potentially providing a mechanism for local
regulation of neurosteroid and immunosteroid synthesis. The balance between systemic and
local steroid signals depends critically on life history stage, species adaptations, and the
costs of systemic signals. Thus, individual tissues and organs may become capable of
autonomously synthesizing and modulating local steroid signals, perhaps interacting with
the HPG and HPA axes and the overall response to stress (Schmidt et al., 2008).
5. Integration and regulation
The stress response is characterized by the interplaying of several centers, mechanisms and
systems, in order to reestablish the homeostatic conditions. Although it has been known for
long time that the stress response is initiated by the activation of the Sympathetic-
Chromaffin (SC) and the hypothalamus-pituitary-interrenal (HPI) axes, it was also known
from the beginning that other regulatory systems are involved from the initial stages in the
building of the stress response. Thus, it was already described by Selye that some
pathological components were usually included in the events related to the General
Adaptation Syndrome, such as gastrointestinal ulcers and thymolymphatic atrophy, clear
signs of immunosuppressed status. Later on, an increasing number of evidences obtained
during the last decades, both in lower and higher vertebrates, indicate that the stress
response includes also the immune system. Even at the early life stages, the
neuroimmunoendocrine interaction is active under stress. Hence, an important number of
interconnections are established after stress, not only between the nervous and the
endocrine system, but also between the endocrine and immune system, thus constituting a
complex network of transmitters between the three regulatory systems. Although this aspect
has not been extensively studied in all vertebrates (Verburg-Van Kemenade et al., 2009), it
seems apparent that in all of them the nervous, endocrine and immune systems do not
operate independently but rather they are part of the repertoire of the physiological
Basic and Clinical Endocrinology Up-to-Date
278
responses available to react in front of particular circumstances out of the normal
physiological range, i.e.: disease, exercise, extreme environmental changes. Communication
between these three physiological systems has had less attention in lower vertebrates
compared to mammals, mainly because the amount of effort dedicated to such species is less
and because of the lack of specific biochemical tools. However, such functional connections
are present in all vertebrates and therefore this interconnection network may be an early
mechanism in the evolution (see figure 2).
Hypothalamus
ACTH
Adrenal
GC
Locus
ceruleus
CRH
AVP
NA
Pituitary
Immune
effector cells
IL1 IL6
TNFα
citoquines
CRH
GH
TSH
FSH
ACTH
PRL
α-MSH
β-End
Fig. 2. Stress axis and main neuroimmunoendocrine interactions
These interactions start already at the central levels and there are multiple sites of
interaction among the various components of the stress system. Neural control of stress is a
complex process that requires the integration of information regarding both actual and
potential outcomes. The organization of stress pathways further suggests that inputs on the
physiological status of the animal can contribute to the eventual endocrine or autonomic
response to the stressor. The majority of the pathways initiating physiological stress
responses seem to be made at the level of limbic structures, which communicate information
to subcortical sites positioned to interface with ongoing homeostatic feedback (Ulrich-Lai
and Herman, 2009). The physical separation of autonomic and HPA stress effector circuits
promotes some degree of independence of the two stress-modulatory cascades, allowing for
appropriate tuning of neural and hormonal responses to specific demand characteristics of
the actual or anticipated event. However, these two physiological systems also work
together, both in terms of overlap in their underlying neural circuitry and in terms of their
physiological functions. Charmandari et al., (2005) reviewed some of these connections.
Reciprocal neural connections exist between the CRH and noradrenergic neurons of the
cytokines
The Endocrine Response to Stress - A Comparative View
279
central stress system, with CRH and noradrenalin stimulating each other primarily through
CRH type 1 and α1-noradrenergic receptors, respectively. Autoregulatory negative feedback
loops are also present in both the PVN, CRH and brainstem noradrenergic neurons, with
collateral fibers inhibiting CRH and catecholamine secretion via presynaptic CRH and α2-
noradrenergic receptors, respectively. Both the CRH and the noradrenergic neurons also
receive stimulatory innervations from the serotoninergic and cholinergic systems, and
inhibitory input from the γ-aminobutyric acid (GABA)-benzodiazepine (BZD) and opioid
peptide neuronal systems of the brain, as well as from the end-product of the HPA axis, the
GCs (Charmandari et al., 2005). It is likely that dysfunctions of information processing
across these circuits, resulting from environmental adversity and/or genetic factors,
generate alterations that can culminate in maladaption.
In terms of the bidirectional relationships between endocrine and immune systems many of
the hormones assessed so far can have an influence on immune agents or mechanisms, and
even more some of them play significant roles in the regulation of the immune response.
This is the case of the hypothalamic CRH and the adrenal hormone cortisol. The other axis
related to stress, the sympathetico-chromaffin axis also influences immune response
through catecholamines. In the reverse direction, the majority of evidence indicates that
either direct or indirect stimulation of hypothalamic CRH secretion is the primary means by
which cytokines (IL-1, IL-6, and TNF-α) activate the HPA axis. Thus, the neural pathways
which IL-1 have been proposed to influence the neuroendocrine hypothalamus in mammals
are numerous and diverse, including the inhibitory effects of either inhibitors of
prostaglandin synthesis or disruption of catecholaminergic input into the hypothalamus
(Turnbull and Rivier, 1999)
Moreover, a reduced number of family molecules appear consistently in the interconnection
pathways in all vertebrates. For example, immunocytes can release Proopiomelanocortin
(POMC)-derived peptides which have been shown to be involved in the regulation of the
immune system. The Growth Hormone can stimulate the activity of the immune system.
Sympathetic neurotransmitters can modulate the respiratory burst activity of trout
phagocytes. Melanotropins, Melanocyte Stimulating Hormone (MSH), and Melanocyte
Concentrating Hormone, (MCH) exert relevant stimulatory effects of the immune system. In
mammalian species POMC is produced not only by neuroendocrine tissues, but also in
lymphoid cells, which reinforces the neuroimmunoendocrine connection. More work has to
be done to ascertain the regulatory mechanisms, and in particular, the role of the receptors
and the role of putative paracrine mechanisms that may explain at some extent the
interconnection mechanisms between regulatory systems.
This may be the case of organs such the head kidney in fish, as it concentrates several
secretory cells belonging to either immune or endocrine systems. It should be emphasized
that in fish the head kidney or pronephros is an important centre of the endocrine response.
In fact this organ becomes key player in the organization of the integrated response to
stressors. Head kidney plays a substantial endocrine role in the secretion of the two main
hormones of the hormonal axes, cortisol from interrenal cells, the major fish glucocorticoid
and mineralocorticoid, and catecholamines, released by chromaffin cells which are
components of the sympathetic nervous system releasing, and receiving specific connections
from the central nervous system [30]. Moreover, not only the neural and the endocrine
system meet in this organ, but also the immune and hematopoietic systems are found in the
pronephros. Thus, this organ is the homologous to the bone marrow of higher vertebrates
which involves that the production of lymphocytes, monocytes and neutrophils is localized
Basic and Clinical Endocrinology Up-to-Date
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in this organ. It is concluded, then, that the head kidney deals with a number of key
physiological responses in fish species. Therefore, fish represent an interesting comparative
model for the study of the stress effects on the nervous, endocrine and immune systems, due
to the structure and composition of the head kidney (Tort, 2010). In summary, the concept of
neuroimmunoendocrine connection identifying specific tissues with specific systems
(lymphoid tissue/ immune system, gland/ hormones or neurones/ nervous system)
appears to be no longer appropriate or complete as well in lower vertebrates [28]. Clearly in
this case, the head kidney in fish represents a tissue in which all three regulatory systems
are integrally connected forming a centralized network to coordinate endocrine, neural, and
immune, responses after stress.
6. Stress and adaptation in vertebrates
The adaptive value of responsiveness to stressors in animals in nature may provide
invaluable information regarding the dynamics and flexibility of neuroendocrine responses.
Absolute levels of transmitters or hormones may not matter in the induction of responses
and survival. Relative elevation or inhibition related to previous experience may adjust
specific neural centers to produce relevant output specifically related to the appropriate
environmental context. The neural mechanisms for transduction of relevant information are
necessarily very plastic, with many transmitters, neuromodulators and peripheral hormone
systems interacting between them. These systems influence behavioral and physiological
stress responses, but are also influenced by that output (Greenberg and Summers, 2002).
Taking the whole amount of data on the research in stress, it can be said that it generally
focuses on the use of negative stimuli. However, positive stimuli such as immediate reaction
or novel rewards can cause comparable physiological stress responses (Ulrich-Lai and
Herman, 2009). It has been proposed that acute rises in corticosteroids following
perturbations of the environment may actually avoid chronic stress as they may work
primarily as ‘‘anti-stress’’ hormones. Free-living populations may have elevated circulating
levels of corticosteroids under emergency stages. However, this situation may not always be
advantageous and there is accumulating evidence from birds that the adrenocortical
responses to perturbating factors are modulated both on seasonal and individual bases.
These data suggest that corticosteroid secretions allow flexibility so that the response is
integrated in relation to time of year, time of the day, as well as for individual differences
owing to body condition, disease and social status (Wingfield and Kitaysky 2002).
Although GC responses are viewed as a major evolutionary mechanism to maximize fitness
through stress management, phenotypic variability exists within animal populations, and it
remains unclear whether inter-individual differences in stress physiology can explain
variance in unequivocal components of fitness. For instance, it has been shown that the
magnitude of the adrenocortical response to a standardized perturbation during
development is negatively related to survival and recruitment in a wild population of birds,
providing empirical evidence for a link between stress response, not exposure to stressors,
and fitness in a vertebrate under natural conditions. Recent studies suggest that variability
in the adrenocortical response to stress may be maintained if high and low responders
represent alternative coping strategies, with differential adaptive value depending on
environmental conditions (Blas et al., 2007). In fish it has been shown that such a coping
strategy is an important determinant of the physiological response, either in behavior,
physiology and even gene expression, and therefore much of the phenotypic expression
The Endocrine Response to Stress - A Comparative View
281
may be significantly conditioned by the coping strategy, not only in one species but
specifically in groups of individuals (Mackenzie et al., 2009).
7. Conclusion
All living organisms have developed responses to face stress situations, and some at cellular
level such as heat shock protein activation, have been well conserved along evolution. In
vertebrates the physiological stress response is driven by the neuroendocrine axes which in
turn affect many other physiological compartments until the homeostasis is regained. In this
chapter, after revisiting the stress concept, we have reviewed the general character of the
stress phenomenon and the cellular responses, and afterwards we summarize the
physiological stress response in vertebrates: mammals, birds, reptiles, amphibians and fish.
Finally, the consequences of the endocrine activation and the neuroimmunoendocrine
integrated response to stressors have been reviewed in relation to the adaptive value of the
stress reaction.
8. Acknowledgements
The authors want to thank the support of the Spanish Ministry of Science and Innovation
(BFU2009-07354) and Generalitat de Catalunya (SGR2009-0554). LT and MT are members of
the Xarxa de Referencia en Aquicultura de Catalunya.
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... El organismo de los carneros estresados por calor presenta una serie de cambios para evitar hipertermia (1,(6)(7)(8) . Así, la capacidad reproductiva de los carneros disminuye mientras hacen esfuerzos fisiológicos, metabólicos y endocrinológicos para mantenerse en normotermia (3,7,(9)(10)(11) . El EC puede afectar negativamente la reproducción del carnero por diferentes mecanismos, siendo los principales: 1) disminución en las concentraciones de testosterona, y 2) daño directo en la morfometría y contenido de material genético del espermatozoide (12,13) . ...
... Los carneros, en repuesta a las condiciones de EC, activan el sistema simpático adrenomedular (SAM) y el eje hipotálamo-hipófisis-adrenal (HHA) (12) . El SAM estimula la liberación de catecolaminas (adrenalina y noradrenalina) en la médula de las glándulas adrenales (9) , las cuales inducen una vasodilatación periférica e incrementan la disponibilidad de energía por medio de la gluconeogénesis y lipólisis (1,13) . Por su parte, el eje HHA comienza su activación con la secreción hipotalámica de las hormonas liberadoras de corticotropinas (CRH), quienes a su vez estimulan la secreción de la hormona adrenocorticotrópica (ACTH) en la adenohipófisis (12,13,17) . ...
... La ACTH vía endocrina estimula la síntesis de glucocorticoides (cortisol y corticosterona) y mineralocorticoide (aldosterona) en la corteza adrenal a partir del colesterol (13,17,32) . La liberación de cortisol es el principal mecanismo a través del cual el eje HHA inhibe el funcionamiento del eje hipotálamo-hipófisis-gonadal (HHG) (9,11) , y consecuentemente, el grado de actividad reproductiva en los carneros expuestos a EC (34) . ...
Article
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Las temperaturas elevadas registradas durante la época de verano en las regiones cálidas comprometen la capacidad reproductiva de los animales domésticos. En carneros, el estrés por calor (EC) causa en el organismo una serie de ajustes fisiológicos, metabólicos, endocrinos y moleculares con el objeto de mantener normotermia y sobrevivir; sin embargo, varios de estos cambios se asocian negativamente con su fertilidad, principalmente los endocrinos. El EC en carneros provoca una disminución en las concentraciones sanguíneas de testosterona a través de diferentes mecanismos, y esto se refleja negativamente en el proceso de espermatogénesis y en la conducta sexual. En consecuencia, los carneros estresados por calor presentan baja calidad seminal y apetito sexual; a nivel de espermatozoides se ha observado daño estructural y en el ADN. Dada esta situación, se recomienda el uso de estrategias de mitigación del EC durante el verano en las explotaciones ovinas de regiones cálidas, tales como el uso de sombras en corrales, la administración de antioxidantes o modificaciones en la alimentación. Por lo tanto, el objetivo de este documento es revisar el conocimiento actual en relación al efecto del EC sobre la capacidad de termorregulación y reproductiva de los carneros, así como la aplicación de estrategias para su mitigación.
... This mechanism has been described to a greater or lesser extent for all extant vertebrate groups and demonstrates functional similarity despite structural differences (Denver, 2009;Romero and Gormally, 2019;Trudeau and Somoza, 2020). Tetrapods and ray-finned fishes are the most well-studied jawed vertebrates (i.e., gnathostomes) showing conserved features of their respective HPA/I systems (Wendelaar Bonga, 1997;Tort and Teles, 2011). However, considerably less is known about HPA/I systems in more phylogenetically ancient gnathostomes and jawless vertebrates. ...
... The hypothalamus-pituitary-adrenal (HPA) axis in mammals is incredibly well studied (Denver, 2009;Deussing and Chen, 2018;Herman et al., 2016;Norris and Carr, 2020;Romero and Butler, 2007;Smith and Vale, 2006;Tort and Teles, 2011). Upon perception of a stressor, neurosecretory parvocellular neurons within the paraventricular nucleus (PVN) of the hypothalamus secrete corticotropin-releasing factor (CRF; Yao and Denver, 2007). ...
... The site of steroidogenesis, the adrenal cortex, is subdivided into three layers: the zona glomerulosa, zona fasciculata, and zona reticularis. Synthesis of B occurs in all layers, while F is only synthesized in the latter two (Tort and Teles, 2011). In the steroidogenic pathway of F and B, biosynthesis from precursors 11-deoxycortisol (S) and 11-deoxycorticosterone (DOC), respectively, is mediated by the enzyme CYP11B1 (Baker et al., 2015;Bureik et al., 2002). ...
Article
The neuroendocrine mechanism underlying stress responses in vertebrates is hypothesized to be highly conserved and evolutionarily ancient. Indeed, elements of this mechanism, from the brain to steroidogenic tissue, are present in all vertebrate groups; yet, evidence of the function and even identity of some elements of the hypothalamus-pituitary-adrenal/interrenal (HPA/I) axis is equivocal among the most basal vertebrates. The purpose of this review is to discuss the functional evolution of the HPA/I axis in vertebrates with a focus on our understanding of this neuroendocrine mechanism in the most ancient vertebrates: the agnathan (i.e., hagfish and lamprey) and chondrichthyan fishes (i.e., sharks, rays, and chimaeras). A review of the current literature presents evidence of a conserved HPA/I axis in jawed vertebrates (i.e., gnathostomes); yet, available data in jawless (i.e., agnathan) and chondrichthyan fishes are limited. Neuroendocrine regulation of corticosteroidogenesis in agnathans and chondrichthyans appears to function through similar pathways as in bony fishes and tetrapods; however, key elements have yet to be identified and the involvement of melanotropins and gonadotropin-releasing hormone in the stress axis in these ancient fishes warrants further investigation. Further, the identities of physiological glucocorticoids are uncertain in hagfishes, chondrichthyans, and even coelacanths. Resolving these and other knowledge gaps in the stress response of ancient fishes will be significant for advancing knowledge of the evolutionary origins of the vertebrate stress response.
... Such responses are thought to play an important role in the persistence and stability of social groups, yet the proximate mechanisms regulating these responses are not well understood. Because glucocorticoids help to coordinate behavioural and physiological responses during periods of stress (Creel et al., 2013;Raulo and Dantzer, 2018;Tort and Teles, 2011), these hormones have been hypothesized to be involved in the regulation of prosocial behaviours during periods of instability. ...
... Glucocorticoid synthesis increases when individuals encounter physical or psychological challenges in their surrounding environment (i.e. a stressor) and elevated glucocorticoid levels help individuals overcome challenges primarily through their effects on metabolism, osmoregulation, and immune function (Mommsen et al., 1999;Sapolsky et al., 2000;Tort and Teles, 2011). Production of glucocorticoids is regulated by the hypothalamic-pituitary-adrenal (HPA) axis in mammals and birds, or by the hypothalamic-pituitary-interrenal (HPI) axis in other vertebrates (Dallman et al., 1994;José et al., 2011;Wendelaar Bonga, 1997). ...
... These differences may have ultimately resulted in glucocorticoids fulfilling different behavioural functions in fishes compared to other vertebrates. The potential role of elevated glucocorticoids as mediators of behavioural responses to social disturbances has received considerable attention (e.g., Dantzer et al., 2017;Santema et al., 2013;Soares et al., 2014;Voellmy et al., 2014); however, many hormones mediate stress responses (Tort and Teles, 2011). It is therefore unlikely that the behavioural responses to stress are mediated by changes in glucocorticoid production alone and responses are more likely the result of Table 2 Comparison of pre-treatment performance of social behaviours (over 10 min) by focal subordinate N. pulcher that were eventually injected with saline (n = 15) or cortisol (n = 14). ...
Article
Individuals often respond to social disturbances by increasing prosociality, which can strengthen social bonds, buffer against stress, and promote overall group cohesion. Given their importance in mediating stress responses, glucocorticoids have received considerable attention as potential proximate regulators of prosocial behaviour during disturbances. However, previous investigations have largely focused on mammals and our understanding of the potential prosocial effects of glucocorticoids across vertebrates more broadly is still lacking. Here, we assessed whether experimentally elevated glucocorticoid levels (simulating endogenous cortisol responses mounted following disturbances) promote prosocial behaviours in wild groups of the cichlid fish, Neolamprologus pulcher. Using SCUBA in Lake Tanganyika, we observed how subordinate group members adjusted affiliation, helping, and submission (all forms of prosocial behaviour) following underwater injections of either cortisol or saline. Cortisol treatment reduced affiliative behaviours-but only in females-suggesting that glucocorticoids may reduce overall prosociality. Fish with elevated glucocorticoid levels did not increase performance of submission or helping behaviours. Taken together, our results do not support a role for glucocorticoids in promoting prosocial behaviour in this species and emphasize the complexity of the proximate mechanisms that underlie prosociality.
... Stress is defined as a state of real or perceived challenge for homeostasis that induces a response consisting in an array of biological reactions to compensate for the consequences of the threat created by the stressor (Tort and Teles, 2011;Schreck and Tort, 2016). After the stressor is perceived, the neuroendocrine cells of the ventral parvocellular section of the nucleus preopticus, secrete different neuroendocrine players: Corticotropin Releasing Hormone (CRH), CRH Binding Peptide (CRHBP), Arginin Vasotoccin (AVT) and Thyroid Releasing Hormone (TRH) that control the production of adrenocorticotropic hormone (ACTH) in corticotropic cells of the anterior pituitary gland . ...
... In addition, our recent data in skin mucus showed both an increment of cortisol induced by V. anguillarum vaccine and also a significant rise of hsp70 (Khansari et al., 2018). During stress, global RNA translation is supposed to be reduced to save energy, while a selective translation is up-regulated, which facilitates coping with challenges (Holcik and Sonenberg, 2005;Tort and Teles, 2011). Thus, after vaccination, a decreased expression of some stress genes together with the enhancement of other key response genes might be associated to energy savings, and thus protective immunity responses could be maintained (Pulendran and Ahmed, 2011). ...
... The significant raise of pro-inflammatory signaling genes observed in brain and pituitary suggests that vaccines induced inflammation in these two tissues. It can also be speculated that stimulation of cortisol by the vaccine may be associated with an interaction of il1β expression at the pituitary, as previously proposed (see Tort and Teles, 2011). Moreover, the increased expression of c3, responsible for the complement protein C3, and even more the dramatic raise of lys, responsible for the bacteriolytic protein lysozyme (Sunyer et al., 1997;Hernández and Tort, 2003;Saurabh and Sahoo, 2008), indicates an effective activation of innate immune responses in the central neuroendocrine tissues after the intraperitoneal vaccination. ...
... Stress is defined as a state of real or perceived challenge for homeostasis that induces a response consisting in an array of biological reactions to compensate for the consequences of the threat created by the stressor (Tort and Teles, 2011;Schreck and Tort, 2016). After the stressor is perceived, the neuroendocrine cells of the ventral parvocellular section of the nucleus preopticus, secrete different neuroendocrine players: Corticotropin Releasing Hormone (CRH), CRH Binding Peptide (CRHBP), Arginin Vasotoccin (AVT) and Thyroid Releasing Hormone (TRH) that control the production of adrenocorticotropic hormone (ACTH) in corticotropic cells of the anterior pituitary gland . ...
... In addition, our recent data in skin mucus showed both an increment of cortisol induced by V. anguillarum vaccine and also a significant rise of hsp70 (Khansari et al., 2018). During stress, global RNA translation is supposed to be reduced to save energy, while a selective translation is up-regulated, which facilitates coping with challenges (Holcik and Sonenberg, 2005;Tort and Teles, 2011). Thus, after vaccination, a decreased expression of some stress genes together with the enhancement of other key response genes might be associated to energy savings, and thus protective immunity responses could be maintained (Pulendran and Ahmed, 2011). ...
... The significant raise of pro-inflammatory signaling genes observed in brain and pituitary suggests that vaccines induced inflammation in these two tissues. It can also be speculated that stimulation of cortisol by the vaccine may be associated with an interaction of il1β expression at the pituitary, as previously proposed (see Tort and Teles, 2011). Moreover, the increased expression of c3, responsible for the complement protein C3, and even more the dramatic raise of lys, responsible for the bacteriolytic protein lysozyme (Sunyer et al., 1997;Hernández and Tort, 2003;Saurabh and Sahoo, 2008), indicates an effective activation of innate immune responses in the central neuroendocrine tissues after the intraperitoneal vaccination. ...
Article
Full-text available
Vaccination is a widely used therapeutical strategy in aquaculture, but whether vaccination elicits stress responses in the central neuroendocrine system and enhances the crosstalk between the immune and endocrine systems in the brain or pituitary after vaccination is unclear. To answer this question two experiments using two different vaccine exposure routes, i.e., bath or intraperitoneal (i.p.) injection, were carried out on gilthead seabream (Sparus aurata L.). In the first one, the stress responses of fish subjected to waterborne Vibrio anguillarum bacterin were compared with responses after air exposure or their combination. In the second experiment, fish were subjected to an intraperitoneal injection of Lactococcus garvieae bacterin and we assessed the central stress response and also whether or not a significant immune response was induced in brain and pituitary. In both experiments, blood, brain and pituitary tissues were collected at 1, 6, and 24 h post stress for plasma hormone determination and gene expression analysis, respectively. Results indicated that bath vaccination induced a decreased central stress response compared to air exposure which stimulated both brain and pituitary stress genes. In the second experiment, injection vaccination kept unchanged plasma stress hormones except cortisol that raised at 6 and 24 h. In agreement, non-significant or slight changes on the transcription of stress-related genes were recorded, including the hormone genes of the hypothalamic pituitary interrenal (HPI) axis and other stress markers such as hsp70, hsp90, and mt genes in either brain or pituitary. Significant changes were observed, however, in crhbp and gr. In this second experiment the immune genes il1β, cox2, and lys, showed a strong expression in both brain and pituitary after vaccination, notably il1β which showed more than 10 fold raise. Overall, vaccination procedures, although showing a cortisol response, did not induce other major stress response in brain or pituitary, regardless the administration route. Other than main changes, the alteration of crhbp and gr suggests that these genes could play a relevant role in the feedback regulation of HPI axis after vaccination. In addition, from the results obtained in this work, it is also demonstrated that the immune system maintains a high activity in both brain and pituitary after vaccine injection.
... The stress response is found across all vertebrate groups (Tort and Teles, 2011) and is mediated by glucocorticoids acting on glucocorticoid receptors and ultimately causing changes in the expression of stress-response genes. The ability to perceive and respond to stressful situations is considered an adaptive response (Wendelaar Bonga, 1997;Barton, 2002), and it helps the organism cope with stressors by increasing the amount of available energy. ...
... The vertebrate stress response has been well studied (for reviews see Wendelaar Bonga, 1997;Mommsen et al., 1999) and involves the activation of the sympathetic-chromaffin axis and the hypothalamic-pituitary-adrenal/interrenal (HPA/I) axis. Activation of the HPA/I axis triggers a release of corticotropin-releasing hormone (CRH), a neuropeptide released from the hypothalamic paraventricular nucleus or preoptic nucleus, in mammals and fish, respectively (Tort and Teles, 2011). CRH binds to corticotrophinreleasing hormone receptors on corticotrophs located in the pars distalis of the anterior pituitary, and triggers the release of adrenocorticotropic hormone (ACTH). ...
... CRH binds to corticotrophinreleasing hormone receptors on corticotrophs located in the pars distalis of the anterior pituitary, and triggers the release of adrenocorticotropic hormone (ACTH). ACTH then stimulates the synthesis and release of glucocorticoids from the adrenal gland in tetrapods and the interrenal tissue in fish (Wendelaar Bonga, 1997;Tort and Teles, 2011 Abbreviations: HPA, hypothalamic-pituitary-adrenal; HPI, hypothalamic-pituitary-interrenal; ACTH, adrenocorticotropic hormone; CRH, corticotropin releasing hormone; MRM, multiple reaction monitoring; TIC, total ion current; UHPLC, ultra high performance liquid chromatography; UHPLC/MS/MS, ultra high performance liquid chromatography-tandem mass spectrometry. ...
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