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Cortisol: Physiology, Regulation and Health Implications : Physiology, Regulation and Health Implications, edited by Alonzo Esposito, and Vito
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HUMAN ANATOMY AND PHYSIOLOGY
CORTISOL
PHYSIOLOGY, REGULATION
AND HEALTH IMPLICATIONS
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CORTISOL
PHYSIOLOGY, REGULATION
AND HEALTH IMPLICATIONS
ALONZO ESPOSITO
AND
VITO BIANCHI
EDITORS
Nova Science Publishers, Inc.

New York
Copyright © 2012 by Nova Science Publishers, Inc.
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CONTENTS
Preface vii
Chapter 1 Cortisol Transport across Biological Barriers 1
Marta Gonzalez-Alvarez,
Victor Mangas-Sanjuán,
Carmen Navarro-Fontestad,
Isabel Gonzalez-Alvarez
and Marival Bermejo
Chapter 2 Cortisol: Physiology, Regulation
and Health Implications 27
Katarina Dedovic
and Annie Duchesne
Chapter 3 Heightened Endocrine Responses
to Daily Life Stressors in Healthy Women
at Familial Risk for Breast Cancer 49
Gary D. James and Dana H. Bovbjerg
Chapter 4 Biopsychosocial Correlates of Cortisol Activity

in Children Exposed to Natural Disasters 73
Jacob M. Vigil, Amber Dukes
and Patrick Coulombe
Chapter 5 Cortisol-Cortisone Shuttle: A Functional
Indicator of 11β-HSD Activity 91
Julie A. Ray and A. Wayne Meikle
Chapter 6 Cortisol and Fatigue 107
Urs M. Nater and Johanna M. Doerr
Chapter 7 Importance of Cortisol Regulation
during Pregnancy 119
Catherine Louise Michel
and Xavier Bonnet
vi Contents
Chapter 8 Cortisol and Physical Exercise 129

Rodrigo Gomes de Souza Vale,
Guilherme Rosa,
Rudy José Nodari Júnior
and Estélio Henrique Martin Dantas
Chapter 9 Cortisol and Physcal Exercise, its Effects
in Athletic Performance 139
Alfredo Córdova and Antoni Sureda
Index 149
PREFACE
Cortisol, the main stress hormone, is a marker of the body's adaptation to challenge.
Physiology and regulation of cortisol are intricately related to an individual's health, both
physical and psychological. In this new book, the authors present current research in the
physiology, regulation and health implications of cortisol. Topics include cortisol transport
across biological barriers; the biophysical correlates of cortisol activity in children exposed to
natural disasters; predictions of physiological disorders by accurate measurement of the
cortisol to cortisone ratios and the relationship of cortisol to physical exercise and athletic
performance.
Chapter 1- The hypothalamic-pituitary-adrenocortical (HPA) system controls reactions to
stress and it has pleiotropic effects in the body. Depending upon the circumstances, it can
promote life and successful adaptation to stress or can contribute to disease. HPA system
dysregulation plays an important role in the physiopathology of depression, anxiety disorders,
obesity and other pathologies. Most of these diseases are associated with a high level of
Cortisol in blood due to the overactivity of the hypothalamus-pituitary-adrenocortical (HPA)
axis. The main reason for increased corticotropin-releasing hormone (CRH) activity is
assumed to be a disturbance of the physiological negative feedback loop of the HPA axis, i.e.
the ability of Cortisol to suppress CRH and adrenocorticotropic hormone (ACTH) secretion.
There are several hypotheses to explain the down-regulation of the HPA axis such as deficit
of transport of Cortisol across the blood brain barrier or changes on glucocorticoid receptors.
The objectives of this review are to briefly explain the physiology and regulation of the
hypothalamic-pituitary adrenocortical system, to describe the transport of Cortisol across
biological barriers and to summarize the implications of Cortisol levels in plasma and brain
on human health.
Chapter 2- Cortisol, the main stress hormone, is a marker of the body‘s adaptation to
challenge. As such, physiology and regulation of cortisol are intricately related to an
individual‘s health, both physical and psychological. In the following chapter, the authors
first provide an overview of many effector pathways of cortisol, focusing on the impact of
cortisol on immune, metabolic, reproductive and cognitive functions, and examining the role
of two cortisol receptor types: mineralocorticoid and glucocorticoid receptors, in these
processes. Second, they focus on cortisol as a marker of stress response, elaborating on the
view of cortisol as an objective and a specific measure of stress response, which is sometimes
found to be at odds with an individual‘s subjective feeling of stress. Evidence from human
neuroimaging studies for the neural regulatory sites of cortisol will be presented. Third, they
viii Alonzo Esposito and Vito Bianchi
outline how dysregulation of cortisol secretion in times of stress can have important
implications for one‘s vulnerability to a host of illnesses. Moreover, the authors consider how
factors such as early life experiences, personality, and genes affect cortisol response to stress.
Finally, they suggest that in order to continue to further their understanding of the intricate
connection between cortisol dysregulation and various health outcomes, they need to consider
other markers of stress response in tandem with cortisol. This approach may prove to be more
effective in understanding individual vulnerabilities to stress-related illnesses.
Chapter 3- The authors have investigated the possibility that familial risk for breast
cancer may be associated with increased endocrinological reactivity to psychological stress.
Such effects could be the result of chronic stress associated with having a family history of
breast cancer in close relatives, a circumstance that increases a woman‘s lifetime risk of
developing the disease by up to four times, or due to genetic predisposition to stress
reactivity. In a series of studies using a natural experimental approach, the authors have
compared diurnal changes and variation in urinary cortisol and catecholamine excretion rates
between working women who are either at familial risk due to their family histories breast
cancer, or do not have family histories of cancer. The effects of work stress over time on the
daily variation of these hormones as well as possible psychological triggers such as breast
cancer specific intrusive thoughts have also been examined. The results of these studies show
that women at familial risk exhibit heightened cortisol and catecholamine responses to work
stress during the day, phenomena that are reproducible over a two-month time frame. In
addition, they have found that breast-cancer specific intrusions are associated with the
increased cortisol responses to work stress, even in women without family histories. These
results suggest that women with family histories of breast cancer have a pattern of increased
reactivity to daily stress. They also suggest that there is likely a psychological component to
the increase, but whether there are other underlying biological mechanisms has yet to be
determined. However, regardless of the initiating mechanisms, persistently heightened
cortisol and catecholamine responses to daily stress may have significant health
consequences.
Chapter 4- In all cultures in which they have been studied, exposure to and losses
resulting from natural disasters are associated with increased prevalence of severe
psychological distress, along with changes in activation of the limbic system (e.g., cortisol
regulation) and changes in activation of the sympathetic nervous system. These patterns of
psychological and physiological reactivity vary with the severity and duration of the attendant
losses, biological sex, and psychosocial factors such as the reliability and attentiveness of
available social partners. In this chapter, the authors review several biopsychosocial factors
that have been found to covary with psychological distress and physiological stress reactivity
in children and adolescents exposed to natural disasters. The authors then describe their own
work examining psychosocial and biological correlates in children and adolescents who were
displaced as a result of Hurricane Katrina (Vigil, Carle, Geary, Granger, Flinn, & Pendleton,
2009; Vigil & Geary, 2008; Vigil, Geary, Granger, & Flinn, 2010; Vigil & Brophy, in press).
These studies show that exposure to natural disasters is associated with unique patterns of
psychological functioning, social perceptions and behaviors, and physiological stress
regulation, and that the patterns vary by social environment and biological sex. The studies
also highlight the utility of assessing psychological and physiological stress responses outside
of laboratory conditions and in individuals who have experienced chronic and pervasive
stress.
Preface ix
Chapter 5- Levels of cortisol obey a strict circadian rhythm where they are highest in the
morning hours, declining during the day and lowest at 3-5 hours after the onset of sleep.
Temporary alteration of this rhythm is observed under unusual conditions such as a person
working on irregular shifts or suffering from jet lag. However complete loss of this episodic
secretion is observed when problems with the Hypothalamic-Pituitary-Adrenal (HPA) axis
are suspected such as those of Cushing‘s syndrome or Adrenal tumors producing cortisol.
Chronically high levels of glucocorticoids such as cortisol are known to be associated with
hypertension, immunosuppression, osteoporosis and depression. Cortisone is one of the
several end products of enzyme mediated steroidogenesis that begins with cholesterol.
Cortisol is converted to non active cortisone by the unidirectional action of the 11-beta
hydroxy steroid dehydrogenase type 2 (11β-HSD type 2) enzyme, which is highly expressed
in the kidney, colon, salivary glands and fetal tissues. This enzyme helps in maintaining
normal levels of cortisol in the body by protecting the non selective mineralocorticoid
receptor (MR) from glucocorticoid excess. Conversely, 11β-HSD type 1 enzyme which is
highly expressed in the key metabolic tissues such as the liver, adipose tissue and central
nervous system, controls the oxoreductase conversion of inactive cortisone to cortisol and
vice versa. Inactivation of 11-βHSD type 1 or 2 enzymes leads to elevated levels of cortisol
which activates the MR promoting mineralocorticoid excess conditions thereby elevating
levels of sodium and water. These conditions are exhibited as hypertension in the form of
apparent mineralocorticoid excess syndrome (AME). Evaluation of cortisol to cortisone ratios
(CCR) provides us with information about the HPA axis as well as the effective balance of
the 11β-HSD type 1 and 2 enzymatic activities. Even though the major site for the oxidation
of cortisol to cortisone is the kidney, CCR values obtained from serum/plasma or saliva or
urine are indicative of the tissue specific availability and activity of 11β-HSD type 1 and 2
enzymes. Precise measurement of CCR aids in understanding the cortisol-cortisone shuttle in
preterm infants, clinical outcomes of in vitro fertilization, chronic fatigue syndrome,
depressive illnesses and men with fatty liver apart from patients with Cushing‘s syndrome.
Reduced metabolites of cortisol and cortisone (5α and β tetrahydrocortisol, allo-
tetrahydrocortisol and tetrahydrocortisone) are also used to assess diseases based on their
ratios. This commentary focuses on significant predictions that have been made for
physiological disorders by accurate measurement of CCRs.
Chapter 6- In better understanding the debilitating nature of fatigue, the hypothalamic–
pituitary–adrenal (HPA) axis has been of primary interest, because hormones of the HPA axis
may contribute to the peripheral and central causes of fatigue. For example, glucocorticoid
deficiency is associated with fatigue and related symptoms, such as malaise, somnolence,
myalgia, and arthralgia. In general, dysregulation in basal HPA axis function is reflected in
changes of diurnal cortisol rhythm. In healthy individuals an increase after awakening and a
steady decrease of cortisol levels throughout the day is observed. Research has shown that
disturbances of this typical time curve may be associated with negative health outcomes. A
recent study found associations between an attenuation of cortisol concentrations in the
morning and fatigue as well as physical symptoms in a population-based sample of older
adults. A growing literature indicates that flattened diurnal cortisol curves are found in a
variety of different conditions, such as posttraumatic stress disorder (PTSD), depression,
chronic stress, and breast cancer. All of these disorders may present with fatigue. In chronic
fatigue syndrome (CFS), a disorder characterized by severe fatigue that is not medically
explained, a number of studies have examined circadian cortisol rhythms, with findings
x Alonzo Esposito and Vito Bianchi
pointing to lower cortisol decreases over the day and a flattened slope. Flattened salivary
cortisol slopes, as shown in one of their own studies, might contribute to symptom
manifestation. Cortisol exerts inhibitory effects on the secretion of cytokines, including IL-6,
and helps return these cytokines to baseline levels after stress. Studies have reported elevated
cytokine (IL-6 and TNF-alpha) levels in CFS. However, other authors found decreased IL-6
levels in CFS cases or no differences in comparison to healthy controls. Also, administration
of IL-6 during a hypocortisolemic state causes symptoms of CFS. Taken together, cortisol
seems to play a substantial role in the manifestation of fatigue, in a variety of conditions. In
this chapter, the authors will briefly review the current literature on cortisol abnormalities in
selected conditions (such as CFS) and provide a theoretical model of how cortisol alterations
may be associated with fatigue and related symptoms.
Chapter 7- Cortisol is one of the main effectors of the stress response in mammals,
therefore high plasma levels of this glucocorticoïd maintained over prolonged time periods
are usually perceived as negative in terms of human health. This notion applies with force
during reproduction. Many studies reported the negative effects of increasing circulating
cortisol on reproduction. Stress-induced increases of plasma cortisol which negatively impact
fertility, entail elevated abortion risks, can precipitate parturition and produce underweight
neonates. However, cortisol is also an essential hormone for various adequate physiological
performances, notably during gestation. For example, cortisol is a strong stimulus for the
mobilization of maternal reserves, an essential physiological task during gestation.
Throughout pregnancy, the HPA axis (Hypothalamic-pituitary-adrenal axis) is progressively
activated and basal cortisol plasma level raise in response to increasing nutritional demand of
the developing offspring. Interestingly, the fetus participates to the production of cortisol
(during late pregnancy fetal HPA-placenta axis is functional), and thus somehow manipulates
maternal metabolism and behavior. Empirical and experimental studies also demonstrated
that cortisol plays a key role in the development of different embryonic organs before birth.
Maternal hypo-cortisolemia (e.g. caused by adrenalectomy or Addison‘s disease) results in
fetal retardation, alteration of respiratory performances, and reduced body mass at birth for
instance. Overall, a precise cross regulation of both maternal and fetal HPA-axis activity is
essential to modulate circulating levels of cortisol during pregnancy. Insights from
evolutionary theory and from studies performed on various species, suggest that cortisol
occupies a central role for the regulation of gestation and the well-development of the
embryos. This steroid is notably involved in maternal/offspring conflict (trade-offs) were
adequate levels of cortisol are associated with the production of optimal offspring phenotypes
and optimal maternal reproductive investments.
Chapter 8- Glucocorticoids exert many beneficial effects in humans, increasing the
availability of metabolic substrates, while maintaining normal vascular integrity and
protecting the body from an exaggerated immune system response in the face of exercise-
induced muscle damage. The main glucocorticoid is cortisol, accounting for 90% of the total
activity of these substances. It is secreted by the adrenal cortex of the adrenal glands and
among other functions, plays important roles during and after exercise, including taking part
in gluconeogenesis and accelerating the mobilization and use of fats to produce energy.
Cortisol has important metabolic functions such as influencing the metabolism of glucose,
proteins and lipids. It raises blood glucose and increases fatty acid mobilization from fat
reserves to active tissues. On the other hand, it can inhibit protein synthesis and increase
muscle mass by its catabolic action. Cortisol levels are measured by saliva and blood
Preface xi
collection, and can be influenced by different factors, such as sleep deprivation, stress and
exercise, in addition to variations caused by circadian rhythm. Responses to exercise depend
on the characteristics of stimuli and can be classified as acute and chronic responses. This
chapter discusses the main biological functions of this hormone, factors that influence its
levels and response to various acute and chronic exercise protocols.
Chapter 9- Exercise is a stressful situation that has been shown to induce an inflammatory
status with changes in immune cells resembling the acute phase immune response to infection
and muscular damage. Corticosteroids are substances secreted from the adrenal cortex in
response to stress situations as exercise. The plasma concentrations of cortisol increase only
in relation to exercise of long duration or as result of accumulating stress. These facts indicate
that cortisol probably does not have a major role in the acute exercise-induced effects. The
physiological and pharmacological effects of cortisol are primarily anti-inflammatory and
immunosuppressive. The corticoids mechanism action are multifactorial. The inhibition of
NF-kB reduces the synthesis of pro-inflammatory cytokines and the expression of endothelial
adhesion molecules. Prolonged exercise results in glycogen depletion which induces hormone
secretion such as cortisol to ensure the maintenance of blood glucose level. During exercise
cortisol has also a direct and positive relation with lipid catabolism. In addition to endogenous
glucocorticoids there exist the synthetic corticosteroids, whose properties derive from the
hormone hydrocortisone. The glucococorticoids are used for the treatment of many
inflammatory and allergic diseases. Obviously, like any corticosteroids drugs are not absent
of side effects. However, when the prescription is correct and under medical supervision,
these are minimized. While it is true that steroids have been described as anti-inflammatory
and analgesic, these effects have been seen in patients at rest and there only few studies
concerning the behavior of steroids during exercise. The studies analyzing the effects of
steroids on athletic performance have not found any improvement. Therefore, and in light of
existing scientific literature, it can be said that steroids do not improve athletic performance.
In: Cortisol ISBN: 978-1-61942-458-6
Editors: A. Esposito and V. Bianchi © 2012 Nova Science Publishers, Inc
Chapter 1
CORTISOL TRANSPORT ACROSS BIOLOGICAL

BARRIERS
Marta Gonzalez-Alvarez1, Victor Mangas-Sanjuán1, Carmen

Navarro-Fontestad2, Isabel Gonzalez-Alvarez1
and Marival Bermejo1
1
Universidad Miguel Hernández, Spain
2
Universidad de Valencia, Spain
ABSTRACT
The hypothalamic-pituitary-adrenocortical (HPA) system controls reactions to stress
and it has pleiotropic effects in the body. Depending upon the circumstances, it can
promote life and successful adaptation to stress or can contribute to disease. HPA system
dysregulation plays an important role in the physiopathology of depression, anxiety
disorders, obesity and other pathologies. Most of these diseases are associated with a high
level of Cortisol in blood due to the overactivity of the hypothalamus-pituitary-
adrenocortical (HPA) axis. The main reason for increased corticotropin-releasing
hormone (CRH) activity is assumed to be a disturbance of the physiological negative
feedback loop of the HPA axis, i.e. the ability of Cortisol to suppress CRH and
adrenocorticotropic hormone (ACTH) secretion. There are several hypotheses to explain
the down-regulation of the HPA axis such as deficit of transport of Cortisol across the
blood brain barrier or changes on glucocorticoid receptors. The objectives of this review
are to briefly explain the physiology and regulation of the hypothalamic-pituitary
adrenocortical system, to describe the transport of Cortisol across biological barriers and
to summarize the implications of Cortisol levels in plasma and brain on human health.
Cortisol is a glucocorticoid hormone that is synthesized in the adrenal glands from

cholesterol of diet or endogenous synthesis. The secreted Cortisol circulating in the plasma
bound to proteins (transcortin and albumin). The unbound or free fraction (< 5%) is the
physiologically active one. Cortisol is eliminated mainly through hepatic metabolism and
only the free circulating fraction can be filtered in the glomeruli. The secretion of Cortisol
follows a pronounced circadian cycle, although different types of stimuli can increase the
2 M. Gonzalez-Alvarez, V. Mangas-Sanjuán, C. Navarro-Fontestad et al.
secretion that is regulated through the hypothalamic-pituitary-adrenocortical (HPA) axis

(Figure 1). The hypothalamus produces corticotrophin-releasing hormone (CRH) which acts
at the pituitary level causing the release of the adrenocorticotropic hormone (ACTH). Finally,
ACTH causes the secretion of Cortisol at the adrenal gland. The free-circulating Cortisol
regulates the production of CRH and ACTH by a negative feedback mechanism. So, an
increase in plasma of unbound Cortisol levels inhibits CRH release, ACTH secretion and
finally decreases Cortisol levels.
The kinetic parameters describing this negative feedback mechanism of Cortisol on the
HPA axis are being investigated (Navarro et al., 2011).
Endogenous glucocorticoids, especially Cortisol, contributes to the stabilization of
neuronal excitability (Joels and de Kloet, 1994; Magri et al., 2006; Prager et al., 2009),
maintenance of neuronal integrity (McEwen et al., 1993; Scheel et al.), suppression of
hypothalamic-pituitary-adrenal activity (Dallman et al., 1992; Lattova et al.; Wardenaar et al.)
and facilitation of behavioral adaptation (Oitzl et al., 1997; Putman and Roelofs).
Several diseases are associated with an impaired function of the negative feedback
mechanism of Cortisol on the HPA axis. In particular, one of the most consistent findings in
psychiatry is the HPA axis hyperactivity in patients with major depression (Holsboer, 2000;
2001; Holsboer and Ising, 2008; Ising and Holsboer, 2007; Schule et al., 2009). Specifically,
patients with major depression show elevated levels of Cortisol in plasma, urine and
cerebrospinal fluid, exaggerated Cortisol response to adrenocorticotropic hormone (ACTH)
and an enlargement of the pituitary and adrenal glands (Brown et al., 2004; Holsboer, 2000;
Muller et al., 2003). This hyperactivity is thought to be secondary to an increase in the
secretion of a corticotropin-releasing hormone (CRH), probably due to an inhibition of the
physiological process of the HPA axis negative feedback by endogenous glucocorticoids.
This hypothesis is based on numerous studies showing that in the depressed patients, the
administration of synthetic glucocorticoid dexamethasone does not suppress endogenous
Cortisol secretion. This lack of Cortisol response in depressed patients suggests that the
feedback process disturbances of the HPA axis are not only at the level of the pituitary, but
also in the brain (Juruena et al., 2004; Pariante et al., 2001; Pariante and Miller, 2001;
Pariante et al., 2004).
This hyperactivity of the HPA axis in depression is related to changes in the immune
response and inflammation (Licinio and Wong, 1999; Maes et al., 1995; Murck et al., 2004;
Ratnasinghe et al., 2001). Some of the changes characteristic of severe depression are an
increased secretion of prostaglandin E2 (PGE2) and hyperactivity of the enzyme cyclo-
oxygenase 2 (COX2). This immunoactivation is correlated (via PGE2 and COX2) with the
expression of P-glycoprotein (Ratnasinghe et al., 2001).
Glucocorticoids interact with their own receptors (GR) in different target tissues,
including the HPA axis. These receptors are predominantly in the cytoplasm in an inactive
form until they join their ligands glucocorticoids, leading to the activation of the receptor.
Numerous studies show that the role of GR is reduced in patients with depression, although
there is a decrease in expression of this receptor. This lack of sensitivity of the receptor
observed not only at the HPA axis, but also manifests itself in peripheral tissues through a
decrease in immune function or metabolism. It has also been observed that HPA axis
hyperactivity decreases in chronic antidepressant treatments in mice, but this reduction occurs
even without an increase in expression of GR (Mason and Pariante, 2006; Pariante et al.,
2004).
Cortisol Transport across Biological Barriers 3
Figure 1. Scheme of the negative feed-back regulation of HPA axis by Cortisol.
TRANSPORT OF CORTISOL ACROSS THE BLOOD-BRAIN BARRIER:

THE CONTROVERSY ABOUT P-GLYCOPROTEIN
Transport across the blood-brain barrier is a relevant factor in the pharmacological action
of many drugs and endogenous substances whose action site is located in brain. Some serious
medical and mental health diseases including depression are associated with the balance of
chemicals in the brain. Fundamental processes of the body are regulated by the hypothalamic-
pituitary-adrenal (HPA) axis and depression is associated with a high level of Cortisol in
blood due to the over activity of hypothalamus-pituitary-adrenocortical (HPA) axis (Juruena
et al., 2004; Pariante et al., 2001; Pariante and Miller, 2001; Pariante et al., 2004; Wolkowitz
et al., 2009)
The proper functioning of the HPA axis is dependent on the ability of glucocorticoids,
mainly Cortisol in humans to access brain targets such as the hypothalamus and regulate their
own secretion. Based on their high lipophilicity, glucocorticoids have been assumed to
passively diffuse through the cell membrane because they must reach their intracellular
receptors to exert their actions (Holsboer, 2000). This notion is also supported by the fact that
the lipophilicity of these molecules correlates with their cellular accumulation in artificial
phospholipids/cholesterol membranes. However, the ability of these glucocorticoids to access
the brain may be a more complicated process. The free movement of molecules into the
majority of brain regions is restricted by the presence of the blood-brain barrier and blood-
cerebrospinal fluid. Some researchers have found that changes in blood-brain barrier (BBB)
composition (for example, over-expression of transport proteins as P-glycoprotein) are
responsible for differences in brain penetration of Cortisol and/or antidepressant drugs

(Holsboer, 2000; Karssen et al., 2001; Mason and Pariante, 2006; Pariante et al., 2001;
Pariante and Miller, 2001; Pariante et al., 2004; Ueda et al., 1992; Uhr et al., 2003; Uhr et al.,
2000). The inhibition of Cortisol transport across BBB interfere with the HPA negative feed-
back mechanism (Pariante, 2006; Raison and Miller, 2003). Studies using mice deficient for
the different types of P-gps provide evidence that P-gp at BBB might exert an important
influence on HPA system activity (Fromm, 2004; Mason et al., 2008). An overactive P-gp has
been suggested to be of relevance for the resistance of the HPA system to be suppressed by
glucocorticoids, that is one of the best described biological abnormalities in certain types of
depression (Murck et al., 2004; Ratnasinghe et al., 2001; Uhr et al., 2003; Uhr et al., 2000).
Studies carried out by Schüle et al (Schule et al., 2009) underline the importance of HPA
dysregulation for treatment outcome in depression and determine that the best predictor for
response to an antidepressant seems to be the early responsiveness and downregulation of
HPA axis activity.
In order to clarify the questions around the access of Cortisol to the brain, it is necessary
understand the specific characteristics of the barriers that protect the brain. There are three
barriers that control the access of endogenous substances and xenobiotics to the central
nervous system. These physiological structures are the blood-brain barrier (BBB), the blood-
cerebrospinal fluid barrier (BCSFB) and the ependyma (the epithelial layer of cells covering
the brain). The BBB is found at the level of the capillary endothelial cells of cerebral
vasculature, whereas the BCSFB is found at the fluid-secreting epithelium of the choroid
plexus and at the arachnoid membrane. Figure 2 shows a scheme of the localization and
organization of these barriers (Pavan et al., 2008). The fenestrated capillaries of the vessels
that feed the choroid plexus allow for relatively free movement of molecules into choroid
plexus tissue and some of these molecules may be transported into CSF. The BBB represents
the main determinant of the effective delivery of drugs to the central nervous system (Abbott,
2000; Gaillard et al., 2003; Lo et al., 2001). The structure of the BBB is formed by
endothelial cells lining the cerebral micro vessels (Nicolazzo et al., 2006) characterized by its
tight junctions (Brightman and Reese, 1969) and lack of fenestrae. The tight junctions are
composed of transmembrane and associated cytoplasmic proteins (Hawkins and Davis, 2005).
The transmembrane proteins of the claudin family seal the intercellular region between
adjacent endothelial cells, whereas occluding, an important support molecule, increases
electrical resistance across the barrier and decreases paracellular permeability (Hawkins and
Davis, 2005). The associated cytoplasmic proteins ZO-1 and ZO-2 stabilize tight junctions by
connecting them to actin.
In addition, several transporter proteins are expressed at the luminal and/or abluminal
membranes of the brain endothelial cells. These influx and efflux transporter play a vital role
in the regulation of molecule transfer across the BBB (Pardridge, 2007). From a drug delivery
perspective, the expression of drug efflux transporter at the BBB can limit brain exposure to
substrate drugs (Urquhart and Kim, 2009). Therefore, the brain permeability of certain
compounds, which are subject to metabolism and/or drug efflux at the BBB, is much lower
than the expected based on physicochemical properties alone (Begley, 2004a; Cordon-Cardo
et al., 1989; Hermann and Bassetti, 2007)
There are two controlled pathways for molecules to cross the BBB, namely paracellular
(junctional) and transendothelial routes. In Figure 3, a scheme of all the permeation routes to
access the brain is showed.
Figure 2. Localization and structure of BBB and BCSF barriers. Adapted from Pavan et al, (Pavan et
al., 2008).
Figure 3. Permeation mechanisms through the endothelial cells. Paracellular diffusion is restricted.
Transcellular route includes passive diffusion, carrier mediated transport or endocytosis. The presence
of efflux transporters contributes to limit the access of xenobiotics to the CNS.
The paracellular pathway regulated by tight junctions is very restrictive and for this
reason, transport of hydrophilic and low molecular weight compounds for this route is
limited. The transendothelial pathway is also restricted to hydrophilic substances due to the
lipophilic nature of the membrane and a lower rate of pinocytosis than in the peripheral
endothelium. Passive diffusion depends on the lipophilicity and molecular weight. In general,
Lipinski‘s rule of five as well as Abraham‗s equation can be used to predict the passive
transport of a drug molecule across the BBB (Abraham, 2004). Other sets of rules that have
been proposed to predict BBB permeation are the rules of Norinder& Haeberlein (Norinder
and Haeberlein, 2002) and Clark (Clark, 2005).
Molecules that cannot cross the barrier via passive diffusion could enter in the CNS by
interaction with endogenous transport systems located within the brain capillary endothelium
or the neuroepithelial cells of the choroid plexus. The transport mechanisms are classified in
three groups (Pardridge, 2007):
(a) CMT (carrier mediated transport)q is the responsible to transport into the CNS low
molecular weight compounds (less than 600Da). There are active and facilitated
diffusion carriers (de Boer et al., 2003). Many nutrients such as glucose, amino acids
and purine bases use some CMT system to enter into the brain. At least eight
different nutrient transport systems have been identified. These systems are substrate
selective but could be used by drugs that closely mimic the endogenous carrier
substrates.
(b) RMT (receptor mediated transport), allow the entrance to a relatively large
compounds (peptide and proteins) via an endocytotic process. Classic examples of
receptors involved in receptor-mediated transcytosis are the insulin receptor, the
transferring receptor and the transporters for low density lipoprotein, leptin and
insulin-like growth factors. These systems are studied for targeted delivery to the
brain of drugs with high molecular weight (de Boer et al., 2003).
(c) AET (active efflux transport), responsible of the active secretion of a multiplicity of
drugs from the CNS to the bloodstream. As a consequence, AET substrates cannot
effectively penetrate into the brain. The best known AET system is P-glycoprotein
(P-gp) that limits the transport into the brain of a a wide range of cationic and
lipophilic compounds as cytotoxic anti-cancer drugs, antibiotics, hormones and HIV
protease inhibitors (Begley, 2004b; Loscher and Potschka, 2005). Other active efflux
transporters identified at the BBB are the MRP proteins. The development of co-
drugs that inhibit the AET systems can be a strategy for increasing brain penetration
of drugs (Pardridge, 2005).
Because of the physicochemical properties of glucocorticoids (small and lipophilic

molecules), it was suggested that they could quickly cross cellular membranes and it is
assumed that they would also easily enter the CNS by passive diffusion. It is known that
glucocorticoids also interact with glucose transporters in human cells (de Leon et al., 1997;
Horner et al., 1990; Lacko et al., 1975; Virgin et al., 1991) and also the ABCB1-type multi-
drug resistance efflux transporter P-glycoprotein (P-gp) has been hypothesized to regulate
hypothalamic-pituitary-adrenal axis activity by limiting the access of glucocorticoid to the
brain in murine cells and members of the organic anion transporter polypeptide (oatp) family
in rat cells (Beery et al., 2003; Bossuyt et al., 1996). These transporters have been identified
at the rodent and human BBB and choroid plexuses (Abe et al., 1998; Gao and Meier, 2001;
Ohtsuki et al., 2004; Rao et al., 1999; van Montfoort et al., 2002; Yousif et al., 2007). The
contribution of these transporters to glucocorticoids physiology is still unclear, partly because
of the different techniques used to examine this issue (Mason et al., 2008).
Figure 4. Cortisol permeability values obtained from apical to basal (PA–B) and from basal to apical
(PB–A) at different concentrations of Cortisol in MDCK and MDCK-MDR1 cell lines (Navarro et al.,
2011), Caco-2 (Navarro C. Unpublished results), LLC-GA5-COL300, LLC-PK1 (Ueda et al., 1992),
LLC-PK, LLC-PK-MDR1 (Yates et al., 2003).
Cortisol as a substrate of P-gp has been characterized in some in vivo models as well as
in vitro cell cultures: LLC-PK1 and LLC-GA5-COL300 by Ueda et al (Ueda et al., 1992) also
in LLC-PK1 by Yates et al. (Yates et al., 2003); in caco-2 cells by Farrell et al. (Farrell et al.,
2002) and Pariante et al. (Pariante et al., 2003) in DC-3F (transformed hamster lung cells) or
DC-3F/ADX derivative line and A2780 (human ovarian carcinoma cells and the drug-
resistant variant 2780AD) by van Kalken et al. (van Kalken et al., 1993) Figure 4 shows
Cortisol permeability values obtained from different in vitro systems by different research
groups. As it can be seen, there is a marked difference between the permeability in the
basolateral to apical direction compared with the apical to basolateral one, indicating the
potential contribution of a carrier protein.
In vivo experiments confirm the results obtained in vitro suggesting that P-gp present in
BBB hampers the penetration of Cortisol into the mouse brain (Karssen et al., 2001; Meijer et
al., 1998; Uhr et al., 2002). The first assays were carried out during the 1970‘s and the results
demonstrated a lower retention of Cortisol compared with corticosterone in rodent brain
(McEwen et al., 1975; Pardridge and Mietus, 1979). Later, more sophisticated experiments
were carried out by using whole body distribution methods after peripheral injection of
radioactive glucocorticoids in mice obtaining similar results (Karssen et al., 2001; Uhr et al.,
2002). Meijer (Meijer et al., 1998) and Karssen et al. (Karssen et al., 2001) used
adrenalectomized mdr1a null and wild-type mice injected with tracer dose of [3H]Cortisol or
[3H]corticosterone, which freely crosses the BBB. They found a higher brain-to-blood
concentration of [3H]dexamethasone and [3H]Cortisol, but not [3H]corticosterone in abcb1a-
deficient mice compared with wild-type controls. They concluded that abcb1a plays a role in
the access of dexamethasone and Cortisol, but not of corticosterone, to the brain. In contrast,
Uhr et al. (Uhr et al., 2002) found that abcb1a and 1b-deficient mice subcutaneously injected
with [3H]corticosterone had higher levels in their brains compared with wild-type controls,
thus implicating mdr1b in the removal of corticosterone from the brain.
However, in situ assays have presented different results. The examination of the role of
P-gp at the BBB without ensuring the physiological integrity of the barrier or confirming the
presence of intact, radio labeled drug, can create misleading data. To address these concerns,
Mason and co-workers (Mason et al., 2008) quantified the ability of [3H]dexamethasone,
[3H]Cortisol, and [3H]corticosterone to cross the BBB in P-gp-deficient [FVB-abcb1a/b (-/-)]
and wild-type [FVB-abcb1a/b (+/+] mice, with a sensitive brain perfusion technique linked
with capillary depletion analysis. The systemic administration of these radio-labeled
glucocorticoids was also examined in new experiments conducted similar to the work by
Meijer (Meijer et al., 1998), Karssen (Karssen et al., 2001), and Uhr (Uhr et al., 2002) but
confirming the integrity of all the radio-labeled drugs. Results show that P-gp restricts the
accumulation of [3H]Cortisol only in specific brain regions, such as hypothalamus but it does
not restrict the access of [3H]corticosterone(Mason et al., 2008). Indeed, after systemic
administration of these [3H]glucocorticoids, the presence of radio-labeled products in the
plasma was observed, which make the interpretation of these studies difficult (Mason et al.,
2008). Interestingly, Mason and co-workers found no difference between abcb1a/b (-/-) mice
and abcb1a/b (+/+) in the uptake of [3H]Cortisol in the hippocampus, contrary to the results
found by Karssen et al. (Karssen et al., 2001) using autoradiography after systemic
administration. Mason et al. (Mason et al., 2008) determined that P-gp can limit Cortisol
entry to the hypothalamus but this effect was not detected in any other brain regions. Because
the hypothalamus is highly vascularized, this may provide a greater density of P-gp
expression allowing this effect to be detected in this area. Table 1 summarized the results
found in respect to the implication of P-gp on brain access of Cortisol.
Mason et al (Mason et al.) also determined that although an influx mechanism is present,
it must have a relatively large Km (greater than the physiological concentrations of GCs),
because a quite large concentration of either Cortisol or corticosterone (>30 μM) is needed to
detect any transporter activity. Furthermore, it makes only a relatively small contribution to
the overall brain distribution of these glucocorticoids.
Our research team has also characterized Cortisol transport through the blood-brain
barrier using an in vitro model of MDCK or MDCK-MDR1 cell culture (Navarro et al.,
2011). Madin-Darby canine kidney cell culture (MDCK) and especially the transfected line
MDCK-MDR1, mimic certain properties of the blood-brain barrier (BBB). These cells
display morphological, enzymatic, and anti-genic cell markers, also found in cerebral
endothelial cells and have been reported as a suitable model for this barrier. The MDCK-
MDR1 cell line was identified as the most promising cell line among several cell lines, for
qualitative predictions of brain distribution, and to distinguish between compounds that pass
the blood–brain barrier by passive diffusion and those that are substrates for active efflux by
P-gp (Garberg et al., 2005; Veronesi, 1996; Wang et al., 2005). The MDR P-gp and other
membrane transporters belonging to the ATP-binding cassette family of transporters have
been extensively described to regulate intracellular concentrations of steroids. Moreover, the
MDR P-gp localized on the apical membrane of the endothelial cells of the blood-brain
barrier has been described to limit the access of dexamethasone and Cortisol (but not
corticosterone) to the human brain (Ueda et al., 1992). Our results in MDCK monolayers
were consistent with the presence of an influx and and efflux transporters (Navarro et al.,
2011). The permeability ratios (Permeability basal to apical chamber (Pba) over Permeability
apical to basolateral chamber (Pab) obtained from MDCK-MDR1 confirm that Cortisol is a
substrate of P-gp transporter. The mathematical modeling of the apical to basal and basal to
apical permeabilities versus concentration allowed to detect the presence of both an influx
and and efflux carrier. In summary, in our in vitro cell culture model, Cortisol transport is
concentration-dependent and it is affected by several transporters (absorption and secretion
carriers). Probably, the secretion process is mediated by P-gp as it is confirmed by the
observed differences between the MDCK and the MDCK-MDR1 cell lines. The absorption
process could be mediated by OCT2 also expressed in MDCK cells (Shu et al., 2001).
Respect to the transport of Cortisol at the BCSFB and in a non-barrier region, the
characteristics are different than across the BBB.
Findings of several research teams (Gazzin et al., 2008; Mason et al.) provide evidence
that the contribution of P-gp in the transport of Cortisol or corticosterone across the BCSFB is
negligible. Gazzin et al (Gazzin et al., 2008) reached this conclusion using immuno-
histochemical analysis with P-gp-specific antibody C219 and Mason et al (Mason et al.)
arrived to similar conclusions working with transporter-deficient mice. Moreover, assays
using 99mTc-sestamibi (a non-metabolized pharmaceutical that is known to be transported by
both human P-gp and multi-drug resistance associated protein 1 )(Rao et al., 1999) were
performed and the CSF-to-serum concentrations were not significantly different in
abcd1a/b(+/+) and abcd1a/b(−/−) mice (Rao et al., 1999).
Table 1. Summary of experimental techniques and results showing the implication of P-

gp in the access of Cortisol to brain
Implication of P-gp Reference

In vitro
LLC-PK1 and LLC-GA5- Positive (Ueda et al., 1992)
COL300
LLC-PK1 Positive (Yates et al., 2003)
Caco-2 Positive (Farrell et al., 2002)
DC-3F and DC-3F/ADX Positive (Pariante et al., 2003)

A2780 and A2780AD Positive (van Kalken et al., 1993)
MDCK and MDCK-MDR1 Positive (Navarro et al., 2011)
In vivo
Adrenalectomized- Positive (McEwen et al., 1993)
ovariectomized rats.
Rat Positive (Pardridge and Mietus,
1979)
Adrenalectomized mdr1a null Positive (Karssen et al., 2001)
and wild-type mice
Adrenalectomized mdr1a null Found (Meijer et al., 1998)
and wild-type mice
Wild, Abcb1a and abcb1b Found (Uhr et al., 2002)
deficient mice
In situ Brain perfusion technique Not found (Mason et al., 2008)
However, P-gp has been detected in porcine and rodent choroid plexuses previously
(Baehr et al., 2006; Rao et al., 1999), and evidence of P-gp activity at the choroid plexus has
been seen (Kassem et al., 2007). Together, these findings indicate that P-gp exerts a
negligible effect in the distribution of [3H]Cortisol and [3H]corticosterone at the BCSFB.

Because P-gp has also been detected in rat and human pituitary cells (Ritz et al., 1999;
Tachibana et al., 1994), it can be concluded that although P-gp is present and functioning in
the murine choroid plexus and in the pituitary gland, P-gp does not significantly affect the
accumulation of [3H]Cortisol or [3H]corticosterone in these regions.
On the other hand, a strong effect of an influx carrier of [3H]Cortisol and
3
[ H]corticosterone (Mason et al.) was seen in the choroid plexus, the site of the BCSFB, and
the pituitary gland, a CNS region that is not controlled by a blood-CNS barrier. This influx
mechanism can affect the accumulation of [3H]GCs in these areas, because the lipophilicity of
these molecules and the characteristics of the barrier in these structures (presence of fewer
tight junctions and fenestrated capillaries) would allow more free movement than in BBB-
regulated regions. The presence of an influx mechanism at the pituitary gland is particularly
interesting because it could indicate a small facilitative mechanism in HPA axis regulation.
This finding, coupled with the lack of an effect of P-gp detected in the pituitary gland, would
give support to the idea that the pituitary gland is an extremely important point of regulation
for the HPA axis (Mason et al.). Previous research has indicated interactions of steroid
hormones with oat/oatp transporters in rat and bovine cells (Asaba et al., 2000; Bossuyt et al.,
1996; Steffgen et al., 1999). Mason et al. (Mason et al.) found that the transporter oatp2
seems to have some role in the influx of [3H]Cortisol and [3H]corticosterone to the choroid
plexus, and the pituitary gland and other transporters, unlikely to be oatp2, may play a very
minor role in the access of [3H]Cortisol and [3H]corticosterone to the brain, through both the
BBB and BCSFB, as well as having a significant effect on [3H]GC accumulation in a non-
barrier region.
DEPRESSION: THERAPEUTIC STRATEGIES

RELATED TO CORTISOL
The pharmaceutical industry has developed antidepressants with different mechanisms of

action in order to regulate de HPA axis. The majority of these drugs act by enhancing central
monoaminergic neurotransmission, mostly by inhibiting presynaptic reuptake transporters
(Holsboer and Ising, 2008). Current antidepressant therapies have an unsatisfactory high
failure rate. Anxiolytic drugs, including benzodiazepines, are highly effective in ameliorating
acute anxiety in a quick and sustained manner but these drugs are not suitable for medium- or
long-term treatment owing to their high risk for dependence and the increasing likelihood of
severe withdrawal symptoms after discontinuation (O'Brien C, 2005; Stevens and Pollack,
2005). These limitations of current antidepressant and anxiolytic medications have fueled the
discovery of new drugs targets and treatment options in depression and anxiety disorders. A
number of compounds not primarily acting on monoamine neurotransmission are currently
under development, including substrates of P-gp, neurokinin I receptor agonists, N-methyl-D-
aspartate receptor agonists, vasopressin receptor antagonists, glucocorticoid receptor
antagonists and corticotrophin releasing hormone (CRH; or corticotropin-releasing factor,
CRF) antagonists. Regardless of class, antidepressants need to penetrate the BBB to reach
their site of action within the brain; therefore, it has been suggested that drug efflux by P-gp
at the BBB may be involved in treatment resistant depression. Indeed, many antidepressant
drugs interact with P-gp in vitro and in vivo, both substrates and inhibitors (O'Brien et al.).
The modulation of the activity of the membrane transporters can be a strategy to
normalize the activity of the HPA axis. Compounds that interact with P-gp can be classified
as substrates, modulators or inhibitors (Table 2). Substrates are subjected to active efflux by
P-gp and therefore have a reduced ability to penetrate P-gp expressing membranes.
Modulators reduce substrate binding via a negative allosteric interaction, thereby reducing P-
gp mediated substrate efflux whereas inhibitors reduce P-gp function by interfering with the
substrate or nucleotide binding steps (Colabufo et al.). Therefore, modulators and inhibitors
achieve the same pharmacological effect, albeit via different mechanisms. Some, but not all
P-gp substrates also reduce P-gp function and as such can be classed as both substrates and
inhibitors. Antidepressants that reduce or inhibit P-gp function at BBB increase the Cortisol
access to the brain (Pariante et al., 2003; Pariante et al., 2001; Pariante et al., 2004) and can
decrease the HPA axis activity. Moreover, is has been described that psychological stress as a
cause or consequence of depression could lead to a progressive increase in the expression of
P-glycoprotein increasing resistance to negative feedback process Cortisol-mediated HPA
axis (Murck et al., 2004). Chhristoph et al. (Thoeringer et al., 2007) examined how an acute
pharmacological inhibition of MDR1 P-gp at the BBB by tariquidar impacts the
neuroendocrine and behavioral processing stress in C57BL/6JIcoHim inbred mice. Their
findings indicate that tariquidar has an anxiolytic-like effect in mice that have been sensitized
by mild psychological stress. This behavioral effect is paralleled by a reduction of circulating
corticosterone, which confirms the modulation of HPA system activity. They suggest that the
inhibition of P-gp increases the corticosterone (equivalent to Cortisol in humans)
concentration in the brain, which, in turn, enhances the negative feedback control of the HPA
system and improves anxiety-related stress processing. Although numerous studies are
consistent with the hypothesis that depression is associated with over-expression of P-
glycoprotein which prevents the normal Cortisol negative feed-back mechanism on the HPA
axis activity, so far, in vivo studies in humans lead to inconsistent results, not confirming or
contradicting the relevance of P-glycoprotein in the pathophysiology of depression in humans

(Murck et al., 2004). Studies carried out by Gotlib (Gotlib et al., 2008) demonstrated that the
probability of depression depends on not only exposure to stress but genotype. There is now
growing literature demonstrating higher rates of depression among individuals with at least
one copy of the short allele of the 5-HTTLPR polymorphism with increasing exposure to
stressful life events that among individuals who are homozygous for the long allele. They
demonstrated that the exaggerate response of the HPA axis to stressing events is a plausible
mechanism underlying depression.
On the other hand, ample evidence has emerged that abnormalities of stress hormone
regulation observed in depression and anxiety are caused by elevated secretion of
hypothalamic CRH. This neuropeptide acts through CRH1 receptors to produce a number of
anxiety- and depression-like symptoms, which has resulted in extensive validation of CRH1
receptors as a potential drug target. Since 1991, a large number of small molecule CRH1
antagonists have been developed (Grosman and Jensen, 1984; McCarthy et al., 1999;
Saunders and Williams, 2003; Steckler and Dautzenberg, 2006; Valdez, 2006; Zorrilla and
Koob, 2004). The studies indicate that CRH1 antagonists have the potential as a new class of
drugs for the treatment of stress-related diseases (Holsboer and Ising, 2008). Many
pharmaceutical companies have initiated drug discovery and development programs aiming at
novel CRH1 antagonists.
Some research groups have recognized the relation between the serotonin system and
depression and serotonin system and stress. In fact, several lines of evidence now suggest that
serotonin system plays an important role in regulating HPA-axis activity. For example,
researchers have now documented the involvement of serotonin neurotransmission in both
activation and feedback control of the HPA axis (O'Hara et al., 2007). More specifically,
investigators have demonstrated in animals that serotonin activates the HPA axis by
stimulating CRF release, triggering ACTH release and stimulating Cortisol secretion (Fuller,
1996). Indeed, serotonin has been found to enhance the negative feedback control of Cortisol
(Porter et al., 2004). Moreover, as they noted earlier, mice with the serotonin transporter gene
knocked out have been found to exhibit increase HPA-axis response to acute stress (Li et al.,
1999). Finally, Barr et al (Barr et al., 2004) examined the interactive influence of variation in
the serotonin transporter gene promoter region and rearing condition on endocrine responses
to stress in infant rhesus macaques. These investigators found that serotonin transporter gene
variation affects HPA-axis activity. Later, Baldwin et al (Baldwin and Stabenfeldt, 1974)
determine that the 5-HTTLPR is associated with Cortisol responses to laboratory-based
psychosocial stressors in a healthy adult sample.
Table 2. List of selected P-gp substrates and inhibitors. Adapted from reference
(O'Brien et al.)
P-gp substrates
Drug class Selected examples
Anti-cancer agents Daunorubicin, doxorubicin, etoposide, imatinib, methotrexate,
mitoxantrone, paclitaxel, vinblastine, vincristine
Antidiarrheal agents Loperamide
Antidepressants Amitriptyline, citalopram, desipramine, doxepine, fluoxetine,
fluvoxamine, imipramine, nortryptyline, paroxetine,

trimipramine, venlafaxine
Antihistamines Cetrizine, desloratadine, fexofenadine
Anti-psychotics Risperidone
Anti-retroviral drugs Amprenavir, indinavir, lopinavir, nelfinavir, ritonavir,
saquinavir
Cardioactive drugs Amiodarone, digoxine, diltiazem, quinidine, verapamil
Antiemetics Domperidone, ondansetron
Β-blockers Talinolol
H2 receptor antagonists Cimetidine, ranitidine
P-gp inhibitors
First generation Amiodarone, ciclosporin, nifedipine, quinidine, verapamil
Second generation Dexverapamil, GF120918(elacridar), PSC-833 (valspodar),
VX-710= (bricodar)
Third generation LY-335979 (zosuquidar), LY475776, OC144-093, R-101933
(laniquidar), XR-9576 (tariquidar)
However, depression medication has various side effects such as sedation, headache, and
blurred vision. For this reason, some research groups are working on new methods and
strategies for the treatment of this pathology. In this sense, it has been found that the
concentration of the omega 3-fatty acids, especially EPA (eicosapentaenoate), is decreased in
the serum and red-cell membranes of patients with depression (Colin et al., 2003; Nemets et
al., 2002; Peet and Horrobin, 2002). The administration of E-EPA (ethyl-eicosapentaenoate) a
PUFA (polyunsaturated fatty acid) have shown clinical efficacy in these group of patients
(Colin et al., 2003; Nemets et al., 2002; Peet and Horrobin, 2002). Among the different
possible effects of EPA on the global process of depression, the inhibition of P-gp activity has
been hypothesized, as the increase in Cortisol transport through BBB which would normalize
the feedback control of the HPA axis (Murck et al., 2004). Our research group has found
carrying out in vitro experiments, a great decrease in the TEER measurement when
monolayers were preincubated in the presence of EPA, DPA (docosapentaenoic acid) or DHA
(docosahexaenoic acid ) acids indicating the opening of the tight junctions, leading to an
increase of the paracellular permeability (Navarro et al., 2011). This effect has been described
for other polyunsaturated acids like oleic acid which decreased TEER (Aspenstrom-Fagerlund
et al., 2007; Sawai et al., 2001) and increased mannitol flux in caco-2 cells (Deli, 2009). Oleic
acid can also induce a reversible opening of the BBB (Kim et al., 2005; Sztriha and Betz,
1991). The modulators of BBB absorption have a great clinical potential to be used in drug
delivery and it is expected that their number will greatly increase in the near future and
provide an unprecedented selectivity for various barriers, as well as better efficacy and safety.
Further in vivo studies will allow to determine if the BBB opening is transient (as oleic acid)
and to evaluate their potential use as pharmaceutical excipients to improve drug delivery into
brain.
EFFECT OF CORTISOL ON THE PERMABILITY

OF BIOLOGICAL MEMBRANES
Cortisol is a biologically active molecule. Some studies have shown that it has an effect
on the permeability of some biological membranes by acting over the tight junctions. The
tight junction or zonula occludens, a ―gas tet-like‖ structure, is a part of the junctional
complex and surrounds endothelial or epithelial cells in close proximity to the cell‘s apical
domain. Tight junctions are composed of a branching network of sealing strands, each strand
acting independently from the others. They help to maintain the polarity of cells by
preventing the lateral diffusion of integral membrane proteins between the apical and
lateral/basal surfaces, allowing the specialized functions of each surface (for example,
receptor-mediated endocytosis at the apical surface and exocytosis at the basolateral surface)
to be preserved. This aims to preserve the transcellular transport. Moreover, they prevent the
passage of molecules and ions through the space between cells. So, materials must actually
enter the cells (by diffusion or active transport) in order to pass through the tissue. Stelwagen
et al (Stelwagen et al., 1998), demonstrated by in vitro studies the importance of
glucocorticoids in the formation and maintenance of tight junctions in the lactating bovine
mammary epithelium. In the mammary gland, epithelial tight junctions, when ―t ight‖, form a
barrier between the blood and milk in the alveolar lumen, thus preventing serum components
from entering into milk and vice versa (Stelwagen et al., 1995). However, permeability of
tight junctions can increase during established lactation if milk is allowed to accumulate
(Stelwagen et al., 1997) producing a reduction in milk secretion (Neville and Peaker, 1981).
Experiments carried out in presence of dexamethasone indicated that glucocorticoids play an
important role in the maintenance and formation of mammary tight junctions. More specific
studies using and in vivo model to examine whether elevated levels of plasma Cortisol
decrease permeability of tight junctions in the lactating gland showed that the concentration
of lactose in plasma was significantly reduced in cows with elevated Cortisol levels. These
assays represent in vivo evidence that Cortisol can reduce tight junction permeability in the
lactating mammary gland (Stelwagen et al., 1998).
Besides the effect of Cortisol on mammary tight junctions, it also has an effect on BBB.
Breakdown of the BBB is a key feature of neuroinflammatory conditions, such as multiple
sclerosis, encephalitis, meningitis, brain tumors and cerebral ischemia (Hamann et al., 1995;
Rosenberg, 2002; Sellner and Leib, 2006). Therapeutic strategies for such diseases with
impaired BBB function include treatment with glucocorticoids (Engelhardt, 2000), although
the mechanism of glucocorticoid action is still not precisely determined. Some studies have
highlighted the importance of the brain endothelial cells in forming the morphological
correlative of the blood-brain barrier is this modular organization: the permeability properties
of the BBB reflect, to a major degree, the tightness of the intercellular junctions between
brain microvascular endothelial cells (Rubin et al., 1991). Barrier-tightening effects of
glucocorticoids treatment have been demonstrated for cerebral endothelial cells in vitro from
murine or rat (Forster et al., 2005; Hoheisel et al., 1998; Romero et al., 2003; Weksler and
Burt, 1998). Dexamethasone up-regulates occluding and ZO-1 in an immortalized endothelial
cell line (Romero et al., 2003) and hydrocortisone up-regulates occluding in immortalized
cerebral capillary endothelial cells (Forster et al., 2005). Matching data supporting an
important role for glucocorticoid-mediated tightening of the BBB by junctional protein
induction has been demonstrated in vivo in the mouse (Forster et al., 2006). Glucocorticoids
have further been shown to effectively restore the barrier in a rat model of multiple sclerosis
(Paul and Bolton, 1995; Schmidt et al., 2003). Moreover, using serial magnetic resonance
imaging (MRI) recordings, a reduction in the number of enhancing lesions has been observed
in patients suffering from optic neuritis and multiple sclerosis after high-dose glucocorticoids
treatment and in clinical studies (Grauer et al., 2001). The verification of identified molecular
glucocorticoid targets in human cells was carried out (Forster et al., 2008) and was discovered
and additional mode of glucocorticoids action on brain microvascular endothelium that
appears to consist of tightening of the barrier, which is likely to diminish leukocyte
recruitment across the BBB. Moreover, some studies demonstrated that maternal
glucocorticoids treatment reduces blood-brain permeability early, but not late in fetal
development and pre-treatment with glucocorticoids does not affect barrier permeability in
newborn lambs (Stonestreet et al., 1999; Stonestreet et al., 2000; Sysyn et al., 2001). In
addition, endogenous increases in plasma Cortisol levels are associated with decreases in
blood-brain barrier permeability during normal fetal development (Stonestreet et al., 2000).
Malaeb et al (Malaeb et al., 2007) findings suggests increases and decreases in certain key
proteins in the tight junctions complex in the fetal cerebral context after maternal treatment
with antenatal corticosteroids and ischemia-reperfusion injury. They found that maternal
corticosteroid treatment differentially regulates the expression of components proteins of the
tight junctions in the cerebral cortex of ovine fetuses exposed to the brain ischemia. Duncan
et al go deeper into the hypotheses that development as well as endogenous and exogenous
glucocorticoids alters the expression of tight junction proteins in the cerebral cortex of sheep
(Duncan et al., 2009). They conclude that claudin-1, claudin-5, ZO-1 and ZO-2 expression
exhibit differential development regulation. Exogenous glucocorticoids regulate claudin-5
and ZO-2 in vivo at some, but not all ages and increases in endogenous fetal glucocorticoids
are associated with increases in ZO-2 expression, but not with occluding claudin-1, claudin-5
or ZO-1 expression in ovine cerebral cortices.
Effects of glucocorticoids have also demonstrated on skin. Corticoids are well known as
effective anti-inflammatory agents that act by inhibition of the increase of vascular
permeability (Bauck, 1998). This activity has been widely used to treat skin inflammatory
processes. Glucocorticoids inhibit edema formation caused by serotonin and dextran
(Calignano et al., 1985) through the synthesis of vascular permeability inhibitory protein.
This glucocorticoid-induced protein is distinct from lipocortin and inhibits the increase of
vascular permeability. This action of glucocorticoids and the inhibition of mediator release
form basophiles and mast cells (Grosman and Jensen, 1984; Nagai et al., 1983) might
contribute simultaneously to their anti-allergic effects (Inagaki et al., 1988). Owing to their
potent anti-inflammatory activity, these agents have gained considerable attention as
therapeutic candidates in ophthalmology for vision-threatening retinal diseases such age-
related macular degeneration, proliferative vitreoretinopathy and macular edema. Treatment
of the posterior segment requires delivery of high corticosteroid doses intravitreally so, novel
nanoparticulate gel formulations are used (Boddu et al.).
Finally, a relation has been found between glucocorticoids and urea transport.
Glucocorticoids reduce urea permeability in the mammalian kidney by causing a
downregulation of the quantity of urea transporters mRNA and proteins. (Naruse et al., 1997;
Peng et al., 2002). Moreover, an interesting study of Rodela et al (Rodela et al., 2009)
demonstrated in vivo infusion of Cortisol caused a significant 4.3-fold reduction in
basolateral membrane vesicle urea transport capacity in lab-crowded fish, suggesting that
Cortisol inhibits the recruitment of urea transporters to the basolateral membrane, which may
ultimately affect the size of the urea pulse event in gulf toadfish. There is considerable
diversity of physiological roles of urea transporters characterized from fish, amphibians and
mammals; however, structural analysis of urea transporters demonstrated a high degree of
similarity (Bagnasco, 2005; McDonald et al., 2006). The mechanisms regulating the
expression of the non-mammalian urea transporters are not well characterized, however,
evidence from the gulf toadfish demonstrated that it is likely that the system may be similar to
the one described in mammals.
CONCLUSION
Depression is a serious medical and mental health diagnosis that is associated with many
factors including a high level of Cortisol in blood due to the over-activity of the
hypothalamus-pituitary-adrenocortical (HPA) axis. The studies of Cortisol transport through
the BBB to access the brain and regulate the HPA activity reveal that this transport is affected
by several transporters: influx transported and efflux transported, probably mediated by P-gp.
Compounds capable to modulate or inhibit the P-gp activity are excellent candidates for
depression therapy because they can increase the access of Cortisol to the brain and on the
other hand, they can also increase the access of other antidepressants employed in co-
administration to their site of action in the brain and enhance the probabilities of a successful
results. Levels of Cortisol must be controlled because this hormone is able to modify the
permeability of biological membranes producing, in consequence, side effects at different
levels.
ACKNOWLEDGMENTS
The authors acknowledge the funding support from the Spanish Ministry of Science and
Innovation: Consolider Ingenio 2010, CSD2007-00063(Fun-c-Food). Project UMH Bancaja
IPYD01 and EUAlpha iii Project: RedBiofarmaDCI/ALA/21526/245-297/
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In: Cortisol ISBN: 978-1-61942-458-6
Chapter 2
CORTISOL: PHYSIOLOGY, REGULATION AND

HEALTH IMPLICATIONS
Katarina Dedovic1 and Annie Duchesne2

1
Department of Psychology, University of California,
Los Angeles, US
2
Integrated Program in Neuroscience, Douglas Mental Health Institute,
McGill University, Canada
ABSTRACT
Cortisol, the main stress hormone, is a marker of the body‘s adaptation to challenge.
As such, physiology and regulation of cortisol are intricately related to an individual‘s
health, both physical and psychological. In the following chapter, we first provide an
overview of many effector pathways of cortisol, focusing on the impact of cortisol on

immune, metabolic, reproductive and cognitive functions, and examining the role of two
cortisol receptor types: mineralocorticoid and glucocorticoid receptors, in these
processes. Second, we focus on cortisol as a marker of stress response, elaborating on the
view of cortisol as an objective and a specific measure of stress response, which is
sometimes found to be at odds with an individual‘s subjective feeling of stress. Evidence
from human neuroimaging studies for the neural regulatory sites of cortisol will be
presented. Third, we outline how dysregulation of cortisol secretion in times of stress can
have important implications for one‘s vulnerability to a host of illnesses. Moreover, we
consider how factors such as early life experiences, personality, and genes affect cortisol
response to stress. Finally, we suggest that in order to continue to further our
understanding of the intricate connection between cortisol dysregulation and various
health outcomes, we need to consider other markers of stress response in tandem with
cortisol. This approach may prove to be more effective in understanding individual
vulnerabilities to stress-related illnesses.
28 Katarina Dedovic and Annie Duchesne
INTRODUCTION
What Is Cortisol?
Cortisol is a type of glucocorticoid, a steroid hormone produced by the adrenal cortex in

the human body[1]. Its synthetic pathway involves transformation starting from acetate to
cholesterol to pregnenolone to cortisol, although steroidogenic tissues can also directly
harvest low-density lipoprotein cholesterol from the plasma (~80%) or mobilize pools of
intracellular cholesteryl ester [2]. Cortisol is considered one of the main stress hormones, and
is released upon activation of the hypothalamic-pituitary-adrenal (HPA) axis, the main stress
axis, and the subsequent release of corticotropin releasing hormone (CRH) from the
hypothalamus, and adrenocorticotropic hormone (ACTH) from pituitary, culminating in the
stimulation of the adrenal cortex to release cortisol. Cortisol is essential for an organism‘s
survival as it plays a major role in maintenance of homeostasis; however, when in excess, it
can lead to a host of deleterious effects such as increased risk for cardiovascular, metabolic,
immune, cognitive, and emotional disorders.
What Is Stress?
Until 1936, the term ―s tress‖ was employed primarily in engineering circles to mean the
forces applied to exert a strain on any given object. In 1936, Dr. Hans Selye introduced
―s tress‖ within the realm of medicine to define a non-specific phenomenon representing a
collection of symptoms produced by the body in response to various noxious stimuli, or
―s tressors‖ [3]. For Selye, stress was a physiological response to a wide-variety of stimuli.
Since then, other definitions of stress have been proposed (reviewed in [4]. At present,
stress is most often conceptualized as a threat, real or implied, to homeostasis [5-7].
Homeostasis, a notion first introduced by Walter Cannon [8], represents a complex dynamic
equilibrium of an organism both with respect to physical and emotional realms. Therefore, the
words ―s tress‖ and ―stressor‖ refer to a situation which poses a real or implied threat to an
organism and leads to a set of physiological responses. The ―s tress response‖ refers to the
organism‘s response to a stressor, characterized by synchronized activation of the sympathetic
nervous system and the HPA axis. Contribution to the body‘s adaptation to challenge by each
of these systems depends greatly on the type of the stressor.
Selye posited that the determinants of stress response are non-specific [3]. However, he
primarily investigated the effects of physical stressors (such as pain, cold, immobilization) on
the HPA axis. Yet, it is psychological and experiential factors that are among the most
powerful of stressors and are the most potent activators of the HPA axis [6, 9, 10]. The
studies from this field revealed that there are specific characteristics of a given situation that
are the most likely to consistently elicit a strong HPA axis response: a motivated performance
task, with elements of uncontrollability, and especially, presence of social evaluation [10].
In the following chapter, we focus on the impact of psychosocial stressors on the HPA
axis, and in particular, the increased release of cortisol, as the main biological indicator of the
stress response.
Cortisol: Physiology, Regulation and Health Implications 29
HYPOTHALAMIC-PITUITARY-ADRENAL AXIS:
IN TIMES OF STRESS AND REST
HPA Axis in Times of Stress
In response to a perceived threat, the hypothalamic-pituitary-adrenal (HPA) axis is

activated. When the HPA axis is triggered, neurons from the paraventricular nucleus (PVN)
of the hypothalamus secrete corticotropin releasing hormone (CRH) in order to stimulate the
pituitary gland [11]. Specifically, parvicellular neurons of the hypothalamic PVN synthesize
CRH and arginine vasopressin. These neurons project to the median eminence of the
hypothalamus. From there, CRH enters hypopohyseal portal veins and stimulates corticotroph
cells of the anterior pituitary to release the adrenal corticotropic hormone (ACTH) [12].
Vasopressin, for its part, stimulates ACTH very weakly although it does potentiate the effect
of CRH [13]. The released ACTH travels through systemic circulation and binds to the
receptors on the adrenal gland. In response to ACTH, the adrenal cortex secretes cortisol. The
secreted hormones then enter the blood circulation. Peak in cortisol in saliva generally
appears between 10-30 minutes after the cessation of a psychological stressor [14].
HPA Axis in Times of Rest
At rest, the HPA axis shows pulsatile rhythmicity and is characterized by infradian and
ultradian cycles, with a most distinct circadian rhythm [15]. During basal condition, the CRH
is released approximately every 60min, leading the adrenals to produce hourly secretory
bursts of cortisol [16]. This oscillatory pattern of cortisol ultradian release has been proposed
to provide the basis for ―co ntinous dynamic equilibration‖, which may be the mechanisms
that allow for the self-regulatory process of homeostasis [17]. Furthermore, the pulsatile
activity of the HPA axis at rest is important for the maintenance of stress responsitivity,
allowing the organism to flexibly respond to and recover from stress [17]. For example,
animal studies have shown that the ACTH response to stress was greater when occurring at
the rise of the glucocortiocoid pulse than compared to the falling phase of the pulse [18, 19].
In addition, when adrenalectomized animals were given a constant infusion of glucocorticoids
rather than a pulsatile infusion, the ACTH response to stress was markedly reduced [19],
indicating the importance of having the pulsatile pattern at rest to appropriately react to
challenge of a stressor. Indeed, disruption of pulsatile cortisol secretion at rest has been
associated with several stress-related illnesses [17].
The amplitude of ultradian pulses varies across the 24 hrs and can distinguish between
different secretory episodes that then define the circadian profile of cortisol [20]. The 24 hour
cycle circadian oscillation of basal cortisol is characterized by the highest levels in the
morning after awakening, followed by a subsequent decline over the course of the day, and
the nadir achieved around midnight [21]. The range of free cortisol concentration in saliva is
3.5-27 nmol/l at 8am and less than 6 nmol/l at 10pm [22]. This pattern of daily plasma
glucocorticoid rhythm is fully established by the ages of two or three, and remains fairly
stable, sheltered from day-to-day changes in behavioral and environmental influences [23]. It
is however affected by illness: for example, individuals suffering from major depressive
disorder show higher evening and night cortisol levels compared to healthy controls [24].
A distinct phenomenon above that of the circadian oscillation, the cortisol awakening
response (CAR), is a sharp rise in cortisol following awakening and typically peaks at about
30min following the awakening [25, 26].
It has been hypothesized that this additional surge of cortisol following awakening may
be due to a reduced pre-awakening adrenal sensitivity to ACTH, followed by an increased
post-awakening adrenal sensitivity to ACTH [27]. Interaction between the regulatory
mechanisms controlling the HPA axis (for example, input from the hippocampus), as well as
extra-pituitary mechanism (e.g., input from the suprachiasmatic nucleus) may underlie this
process [27].
The CAR is thought to reflect the sensitivity of the HPA axis to a natural challenge (the
awakening) and can be differentially affected by stress and psychopathologies (reviewed in
[28, 29].
Most recently, it has been proposed that the CAR may play an important role in other
awakening-induced processes such as restoration of consciousness and full alertness, changes
in other hormones and the balance of the immune system, as well as mobilization of the
motor system [26-28].
When the released cortisol binds to its receptors, it has a widespread impact on several
systems of the body such as cardiovascular, metabolic, immune and reproductive systems, as
well as cognitive and emotional processes. In addition, cortisol regulates its own secretion
through negative feedback at the level of hypothalamus and pituitary, and also at regulatory
sites within the central nervous system (CNS), in particular, the hippocampus, amygdala and
prefrontal cortex [30].
GLUCOCORTICOID RECEPTOR TYPES

Effects of cortisol on target tissues are mediated by two types of nuclear receptors:
mineralocorticoid receptors (MR; Type I) and glucocorticoid receptors (GR; Type II) [31,
32].
These receptors are ligand-driven transcription factors that regulate gene transcription
[33, 34]. There have also been reports of membrane MR receptors [35], as well as GR-like
membrane receptors [36, 37], which would allow cortisol to exert fast, non-genomic actions
on its target cells.
Role of the Genomic MR and GR Receptors
The genomic MR controls basal HPA activity, exerts tonic inhibition in times of rest and
determine the sensitivity or threshold of the stress system, while genomic GR contributes to
adaptation to a stressor, contributes to the negative feedback loop, facilitates recovery from
stressor-induced disturbances, as well as exerts negative feedback during the peak circadian
activity [13]. The ratio of MR and GR occupancy has been suggested to contribute to
differences in cognitive function during the day and in times of stress [5]. The differential
involvement of these receptors in the actions of cortisol is due to their differential affinity to
cortisol and their distribution in the body and the brain. The MR has a very high affinity for
glucocorticoids, about 6-10 times higher than that of GR [38]. During low levels of
circulating cortisol more than 90% of MR is occupied, but only about 10% of GR. However,
at times of increased levels of cortisol (such as the circadian peak or in times of stress), MR is
completely saturated, and occupation of GR is at about 67-74% [5]. The MR is highest in
density in the hippocampus, lateral septum, dentate gyrus, brain stem, entorhinal, insular
cortices, amygdala and frontal cortices [12, 39]. However, the MR is absent from the
hypothalamus and pituitary gland, which have a high concentration of GR. The GR is also
localized in the hippocampus and the prefrontal cortex regions, and is distributed in every cell
type in the organism [38, 39]. Importantly, the promoter region of GR contains 15 binding
sites of different transcription factors [40], suggesting that although present in every cell type
in the organism, expression of GRs is subject to additional regulation mechanisms [41].
Role of the Non-Genomic MR and GR-Like Receptors
These membrane-embedded receptors seem to be of a similar type to the nuclear

receptors, except that, in the case of membrane MR, they seem to show lower affinity to
glucocorticoids [35]. The GR-like receptors in the cell membrane of the hypothalamus seem
to exert a similar role as the nuclear GR receptors (i.e. inhibit hypothalamic hormone
secretion) [36, 42]. However, membrane MR receptors show both similar and distinct
functions from nuclear MR receptors. Firstly, the low affinity of hippocampal membrane MR
suggests that, unlike its nuclear counterpart, membrane MR would be activated in times when
cortisol levels are increased, namely during stress and at the peak of ultradian pulse [34], or
the peak of circadian activity [43]. In addition, preliminary data also seem to suggest that
hippocampal membrane MR may first amplify enhanced excitability induced by stress
hormones and synergize with other mediators in the primary stress reaction, such as CRH,
(nor)adrenalin or vasopressin [34, 44]. However, activation of membrane MR was also shown
to lead to an enhanced glutamate release in the hippocampus. Given that the hippocampus
exerts its inhibitory control of the HPA axis by stimulating the inhibitory connections
surrounding the PVN, it may be possible that hippocampal membrane MR also contributes to
inhibitory tone exerted by the hippocampus on the HPA axis (a function that so far was
ascribed to nuclear MR) [34]. Importantly, the studies to date suggest that all non-genomic
effects of cortisol are permissive or conditional, facilitating or inhibiting signaling of ion
channels, receptors and neurotransmitters; the nature and the extent of these effects largely
vary across the HPA regulatory brain areas, namely the hypothalamus, hippocampus,
amygdala and prefrontal cortex (reviewed in [45]). The field is just beginning to understand
the functional implications of the non-genomic MR and GR receptors.
Importantly, proper functioning and balance between all of these receptor types are
essential for an adaptive and healthy profile of the HPA axis output both at times of rest and
of stress [34, 37, 38].
MODES OF CORTISOL ACTION

The principle role of the HPA axis and cortisol is to allow an organism and its many
systems to respond to life‘s many challenges in an adaptive manner. Specific modes of
cortisol action (permissive, suppressive and preparative) make this possible [13, 46].
It should be noted that it is assumed that only free, unbound cortisol is biologically active
and exerts its effects on the target cells [47]. The free cortisol constitutes between 5% and
10% of all cortisol, as the majority of the circulating cortisol in the blood is primarily bound
to corticosteroid binding globulin (CBG), and then to sex-hormone-binding globulin and
albumin [48]. The CBG is a plasma transport glycoprotein that has a high affinity for
glucocorticoids, binding 80-90% of cortisol [47, 49]. The CBG plays a role in both circadian
and stress-related cortisol pattern, as it shows a slight diurnal variation opposite to that of
plasma cortisol levels, and it can be released from liver in response to an acute stress [49].
Recently, it has been suggested that a fraction of bound cortisol may also have an impact on
target tissues [48], and thus may also contribute to the many modes of cortisol action.
Permissive cortisol actions are provided by basal levels of cortisol and serve to prime the
defensive mechanism prior to stress onset[1, 46, 50]. Some of the mechanisms include
enhancement by cortisol of receptors of various mediators of stress response [1, 46, 51].
These effects are seen on cardiovascular, immunological, metabolic and cognitive functions
and are present irrespective of stress-induced increases in cortisol, although their
consequences only become apparent during the initial stress response [46]. For example,
cortisol permissively mediates the metabolic stress response by contributing to stimulation of
lipolysis and to elevation of circulating glucose concentrations by stimulating glycogenolysis
and gluconeogenesis [46].
Suppressive actions of cortisol are observed an hour or more following the stressor and
function to restrain stress reaction from overshooting and becoming damaging to the
organism (for example, immune response to infection or neurochemical reaction to
psychosocial stressors are curtailed) [13]. Indeed, cortisol suppresses a host of cytokines and
inflammatory agents (for eg.[52]), hormones and neurotransmitters (for eg. [53]), and cell
adhesion molecules (for eg. [54]). For instance, onset of a stressor triggers inhibition of both
reproductive physiology and behavior by leading to a decline in portal concentrations of
gonadotropin-releasing hormone and pituitary release of gonadotropins within minutes [46].
Finally, preparatory action, as the name implies, prepares the organism‘s response to
subsequent stressors, with these effects observed in metabolic processes, appetite and
reproductive behavior and physiology, and cognitive processes (for example cortisol acts on
disposition of glycogen and facilitates storage of information) [13, 46].
EFFECTS OF CORTISOL ON THE BODY AND MIND

Immune System – Inflammatory Cytokines
The immune system is characterized by both natural and specific immunity (reviewed in
[55]). Natural immunity can be mounted within minutes to hours of a given challenge and
involves granulocytes and natural killer cells. In addition, proinflammatory cytokines,
communication molecules, are released and include interleukin (IL)-1, IL-6, and tumor
necrosis factor alpha (TNF ). The specific immunity takes a longer time to mount and it
involves several types of lymphocytes, and release of other cytokines, such as IL2, IL4, and
IL10.
Many studies investigating the complex effect of psychological stress on the immune
system have focused on the impact of stress on levels of cytokines, in particular IL-6, TNF,
and IL-1, as well as levels of C-reactive protein [56]. A recent meta-analysis has shown that
acute stress leads to a significant increase in circulating levels of IL6 and IL-1, with a
similar tendency for C-reactive protein, but no effect for the TNF levels [56].
Inflammatory cytokines also stimulate the stress system at the level of the central nervous
system and peripheral system [57]: cytokines act on the pituitary and hypothalamus to
promote release of CRH and ACTH [58] and also stimulate adrenal cortex to release cortisol
[59]. Cortisol, in turn, down-regulates the immune system by affecting trafficking and
function of leukocytes and other immune cells, and suppressing secretion of the inflammatory
cytokines (TNF, IL-1, IL6, IL-8, IL12) [57]
Cognition - Learning and Memory
Confronted with a stressful situation, the organism must acquire strategies to recognize
and cope with the current threat. Well-known effects of cortisol on cognition include its
impact on learning and memory processes. In particular, declarative memory (consisting of
long-term conscious memory) is greatly influenced by cortisol levels.
Memory is established through acquisition, consolidation and retrieval phases.
Acquisition or initial learning seems to be differently impacted by cortisol depending on the
time of day that a given challenge occurs: for example, cortisol administration in the morning
(when basal levels of cortisol are high) produces detrimental effects on memory acquisition,
while beneficial effects could be observed when cortisol is administered in the afternoon
(when resting levels of cortisol are low) [60]. This dynamic relationship demonstrates both
permissive and suppressive roles of cortisol over memory acquisition.
Animal studies have consistently demonstrated that stress induction or administration of
glucocorticoids can further enhance memory consolidation, but that it impairs memory
retrieval [61]. It is of note that these effects are only observed in animals naïve to the learning
paradigm, supporting that stress or corticosteroids administration is modulated by a novel
context and an arousal state [61]. Further examination of the mechanisms underlying the role
of corticosteroids in modulating memory consolidation demonstrated that corticosteroids
amplify the central noradrenergic response, which subsequently leads to a strengthening of
memory consolidation. In the absence of the initial noradrenergic response, the effects of
corticosteroids are absent [61].
Interestingly, a meta-analysis on human data assessing the effect of corticosterone
administration on declarative memory could not confirm the positive effect of cortisol on
memory consolidation due to inconsistencies in results, but it replicated animal findings of
increased levels of cortisol impairing memory retrieval [62]. As recently reviewed by
Schwabe and colleagues, several factors may contribute to diverse effects of cortisol on
memory consolidation: for example, variations in the emotional valence of the learned
material, the time intervals between the stressful episode and the learning experience, and the
time when the memory is tested [63]. In regard to the impairment of memory retrieval, it has
been suggested that initial cortisol administration or stress exposure may act to suppress
memory retrieval of previously learned material in favor of facilitating the subsequent new
learning processes [63].
The experience of stress does not only impact the degree to which a given material can be
remembered, but also it modulates the way new information is learned (for review [63]).
Stress and/or corticoid administration seems to favor selection of a stimulus response strategy
in spatial learning where animals focus specifically on the characteristics of the stimulus and
ignore the spatial cues in the environment; for instrumental learning (learning how to achieve
a desired state), stress leads to a switch from a goal oriented to habitual learning strategy [64,
65].
Emotion - Subjective Psychological Distress and Physiological Stress

Response
An underlying assumption with respect to the response to a psychological stressor is that

the level of subjective psychological distress that an individual perceives or feels in a given
situation is reflected in the individual‘s physiological response (HPA axis activation and
cortisol release) to that same situation. Overall evidence shows that the subjective
psychological distress and the physiological stress response do reflect the same construct,
however, the relationship between these two concepts is not a simple one [66].
Indeed, several studies investigating the association between subjective measures of
distress and cortisol levels in response to several challenges have reported inconsistent
findings (for example [67-69]. A recent study by Schlotz and colleagues revealed that there
seems to be a time component to the association between subjective measures and cortisol
measures that might explain the inconsistency in findings: the authors found that subjective
psychological responses preceded same-direction changes in the HPA axis activity with a
maximum lag between anxiety levels and cortisol to be around 17.5 minutes in response to a
psychological task [70].
It is important to note that psychological stressors involve higher order brain areas such
as the limbic system and the prefrontal cortex [30, 71]. Therefore, another source of
inconsistencies may be the intricate connections that exist between limbic system structures
and prefrontal brain areas and are involved in monitoring, evaluating and regulating internal
and external environmental and situational demands and regulating the HPA axis. These
connections may complicate the association between subjective and physiological measures
of stress response and could perhaps account for conservative associations between these two
variables reported thus far.
In addition, the limited association may also be due to the assessment methods of
perceived stress by self-report questionnaires [66]. For example, many of these investigations
have focused on measures of anxiety and tension as reflective of the experience of stress,
while recently it has been suggested that the key feeling of a stress response to a psychosocial
stressor may rather be a feeling of embarrassment and shame in the presence of a social
evaluative threat [10].
Another working hypothesis to explain the lack of consistent correspondence between

mood and stress-related cortisol levels has recently been proposed [72]. The authors suggest
that the role of stress-related cortisol release is a regulatory one, acting in the aftermath of
acute threat to rather facilitate a decrease in subjective stress instead of inducing the feeling of
stress [72]. This proposal is in line with the data showing temporal delay between an initial
subjective response to stress and subsequent cortisol increase, as previously mentioned, [70]
and is also supported by cumulative evidence from studies on the anxiolytic role of
glucocorticoids pretreatments prior to exposure to a stressor on subjective ratings of distress
right after the completion of the stressor [72].
Therefore, although the association between psychological distress and physiological
mediators of stress is a conservative one, these concepts are still thought to represent a similar
construct. Nevertheless, this relationship is clearly a complex one and additional research is
needed to fully understand the mechanisms underlying physiological stress response and
subjective feelings of distress.
Maladaptive Effects of Cortisol
From what has been outlined so far, it should be clear that the cortisol stress response is
meant to be an adaptive response of an organism to a threat. However, when this response is
inappropriate (either inadequate, excessive and/or prolonged), a strain is placed on a range of
central and peripheral systems thus increasing the likelihood of development of a host of
physical and/or psychological illnesses [6, 57].
Dysregulated basal and stress cortisol levels may contribute to onset of allergic episodes,
such as asthma or eczema, to manifestation of gastrointestinal symptoms such as pain,
diarrhea or constipation, to mental health issues such as anxiety, depression, and cognitive
dysfunction, to physical disorders such as hypertension, metabolic syndrome, neurovascular
degenerative disease and sleep disorders [57, 73-75].

It is these associations that have given cortisol and the stress response a negative
connotation in relation to physical and mental health. Most importantly these associations
bring to light the importance of continuing to assess the intricate mechanisms that underlie
proper regulation of the HPA axis and cortisol secretion in times of rest and stress.
REGULATORY MECHANISMS
Animal studies as well as pharmacobehavioral human studies have provided a body of
evidence outlining a central framework of HPA axis regulation (for example, [30, 76-79]). In
addition, recent advances in neuroimaging techniques now allow for noninvasive
investigations of changes that are taking place in the central nervous system in response to an
acute psychological stressor, allowing for examination of some of these regulatory
mechanisms directly in humans [80].
As previously mentioned, cortisol exerts negative feedback at the level of the pituitary
and the hypothalamus of the HPA axis, and it also affects other brain regions that form the
regulatory circuit of the HPA axis, most notably the hippocampus, amygdala and prefrontal
cortex [12].
Involvement of these areas in the regulation of the HPA axis seems to be influenced by
several factors, one of which is stressor type (reviewed in [81]). Findings from animal
literature suggest that reactive stressors - those that increase the demand on the system
through a real sensory stimulus (pain, bodily injury or an immune challenge) - would
implicate the brainstem and the bed nucleus of stria terminalis and specific hypothalamic
nuclei, both of which have direct connections to the PVN [76]. Anticipatory stressors, those
that tap into innate or memory programs (such as social challenges or unfamiliar situations)
seem to involve the limbic system areas and monosynaptic connections. The hippocampus
and prefrontal regions have primarily inhibitory connections with the PVN of the
hypothalamus, although specific components of the prefrontal cortex may play quite different
roles in the regulation of the cortisol secretion and these may be stressor specific [30, 76]. The
amygdala for its part seems to promote activation of the HPA axis. In animals it responds to
both physical and psychological stressors [30]. In humans, some have suggested that the
amygdala may underlie a response primarily to the physical threat [81, 82], while others have
proposed that the amygdala‘s role in stress processing may be similar to its role in general
emotion regulation in that it may underlie threat detection and vigilance regulation [83].
Limbic structures do not seem to innervate the hypothalamic PVN directly, but rather
influence the HPA axis through neurons located in the peri-PVN area [30, 84]. These neurons
are primarily GABAergic and therefore exhibit an inhibitory influence on the PVN [85].
Excitatory glutamate inputs from the hippocampus and specific prefrontal regions to the peri-
PVN contribute to the inhibition of the HPA axis, while the GABAergic connection from
amygdala nuclei to the peri-PVN promote HPA activation through disinhibition [30].
Human neuroimaging studies have also provided insight into the dynamic changes that
can be observed within the neural regulatory network of stress processing.
Hippocampus
The hippocampus is an important site for regulation of the HPA axis both at rest,
particularly with respect to CAR, and in times of stress. For example, studies investigating
patients with brain lesions in the temporal lobe [86], particularly the hippocampus [87], have
shown that damage to this area leads to altered basal cortisol release in terms of a clear
flattening of the normal rise in cortisol response to awakening (CAR). In healthy individuals,
a positive relationship has been observed between hippocampal volume and the CAR [88,
89], although some studies found no association between these two variables [90, 91].
Neuroimaging studies investigating the role of the hippocampus in the regulation of HPA
in response to stress have revealed that there is a decrease in activity in the limbic system,
particularly in HC, in response to stress [82], specifically in response to negative social
evaluation [92]. Moreover, studies have shown that there is a negative correlation between the
level of activity in the hippocampus and cortisol release [82, 93]. These findings suggest that
the hippocampus may exercise a tonic inhibition of the HPA axis, which is removed upon
stress perception allowing for the increase in cortisol secretion.
Studies employing the serial subtraction paradigm to elicit stress have also put forth
evidence for the role of hippocampus with respect to perceived stress measured. It has been
reported that in women, cerebral blood flow in the hippocampus was positively correlated
with perceived stress during the task, but negatively associated with perceived stress in men
[94].
Amygdala
Investigation of the role of the amygdala in acute stress response in humans is often
difficult as both spatial and temporal resolution of the fMRI is limited. For example, change
in activity in the head of the hippocampus may often ― spill-over‖ to encompass parts of the
amygdala, or the poor temporal resolution may not be adequate to assess transient change in
amygdala activity in response to stress [82]. Therefore, many studies investigating the role of
the amygdala in cortisol regulation have opted for an approach where cortisol rise is initiated
outside of the scanner, and then subjects are asked to perform a relevant neuroimaging task
inside the scanner that specifically probes involvement of the amygdala.
For example, one study investigated the association between psychological resources (i.e.
personal dispositions that may help people perceive potentially threatening events as less so
and allow them to manage their responses to events perceived to be threatening [95], cortisol
reactivity to a behavioral stress task outside of the scanner, and amygdala activity during non-
intentional threat regulation in response to fearful or angry faces inside the scanner [96]. It
was found that greater psychological resources were associated with lower cortisol stress
response, and less amygdala activity during a threat regulation task. These results show that
successful threat regulation in response to fearful or angry faces requires dampening of
amygdala activity. Further, the relation of greater psychological resources to lower cortisol
reactivity was mediated by lower amygdala activity during threat regulation [97].
Another study has shown that indeed under acute stress context, activity in the amygdala
seems to shift toward higher sensitivity, but lower specificity: the amygdala increased activity
to both threat related and positively valenced stimuli when in the stress context, thus
diminishing a threat-selective response pattern [98]. These findings are suggestive that
amygdala activity would need to be curtailed following a stressor in order to regulate the level
of this indiscriminate hypervigilence under stress. Cortisol contributes to this regulation.

As previously mentioned, while activity in the amygdala potentiates cortisol release in
response to stress, the released cortisol regulates activity in the amygdala through a negative
feedback loop. Indeed, a recent neuroimaging study has shown that cortisol downregulates
amygdala response to emotional stimuli in a time-sensitive and emotion-specific manner [99].
Nongenomic cortisol effects seem to work to rapidly desensitize amygdala response to
emotional stimuli, while slower genomic cortisol action has been shown to normalize
amygdala response to negative stimuli, while also continuing to keep amygdala response to
positive stimuli suppressed. This latter effect seems to be associated with the amygdala‘s
increased coupling with medial prefrontal cortex, and allows the amygdala to be selectively
vigilant for negative stimuli in the event that another threat is lurking in vicinity [99].
Prefrontal Cortex
Several human neuroimaging studies have implicated specific regions of the prefrontal
cortex, such as the medial orbitofrontal cortex, dorsal anterior cingulate cortex (ACC), and
VLPFC, in processing psychological stress and in regulation of the HPA axis and output of
cortisol. For example, a study showed that in those individuals who showed a significant
stress response, the responders, a decreased activity was observed in the medial orbitofrontal
cortex and the dorsal ACC. Interestingly, a specific comparison between the responders and
non-responders revealed that the brain areas that significantly differentiated between these
two groups of subjects were the right orbitofrontal/inferior frontal gyrus region and the left
ACC. Nevertheless, activity in these regions did not correlate with the secreted cortisol. It has
therefore been suggested that the role of these areas may be in the appraisal process and error
monitoring, detecting the social evaluative threat and the initial stress perception [82].
Another study also observed that increase in the right ventral PFC in response to
psychological stress was correlated with both cortisol output and subjective measures of
psychological stress, and that this association persisted after the stressor [100]. This may
suggest that the activation of the right ventral PFC could reflect a prolonged state of
heightened vigilance and arousal elicited by the stressor [100].
Interestingly, stress coping strategies, such as seeking social support in times of stress,
seem to interact with some of these HPA axis regulatory sites. For example, a study found
that greater social support and diminished cortisol responses to behavioral psychological
stress tasks were associated with diminished activity in the dorsal ACC in response to an
exclusion neuroimaging paradigm [101], suggesting a role of dorsal ACC in cortisol
regulation through possible interaction with social support.
Most recent studies have also attempted to investigate how the connectivity between key
brain regions may be associated with cortisol output in response to stress. For example, one
study investigated the association between functional connectivity of the salience network at
rest and stress related cortisol release in youth [102]. They observed that greater cortisol
levels in response to stress were positively correlated with higher functional connectivity
between the subgenual anterior cingulate cortex and the salience network (ACC and anterior
insula), suggesting that areas involved in arousal and subjective feeling states show altered
functional connectivity associated with stress responsivity early in life [102].
INDIVIDUAL DIFFERENCES
An important aspect of the cortisol stress response that needs to be addressed is the fact
that there are individual differences in the occurrence, frequency and magnitude of the
cortisol stress response to a given situation. For example, both behavioral and neuroimaging
human studies have shown that at least two patterns of the cortisol stress response could be
observed to a given challenge: a subgroup of participants typically shows a significant
increase in cortisol (―r esponders‖), while the other subgroup may show a flat or even
declining cortisol response (―non -responders‖), even though the group as a whole responds
with an overall increase in cortisol [82, 103].
In addition, studies employing repeated exposure to a stressor paradigm have also
revealed that there are individual differences in how the HPA axis responds to multiple bouts
of the same stressor over time: some individuals show a significant cortisol stress response
the first time they are exposed to a stressor, but then adapt to subsequent challenges; however,
there are also those who do not adapt and consistently show an increase in cortisol every time
they are faced with the same challenge [104-107].
Typically, these subgroups differ on levels of self-esteem, anxiety and depression, with
the non-adaptive response being associated with a vulnerable personality profile. Indeed,
psychological traits of an individual greatly affect how one judges whether a given situation is
a source of threat and thus whether HPA cascade should be triggered: typically, an
assessment of threat is made when one perceives the demand of the situation to outweigh
one‘s resources to deal with these demands [108]. Individuals who report low self-esteem
tend to show a heightened cortisol stress response and are not able to habituate over several
stress exposures [104, 105, 109].
Other factors that may underlie individual differences in stress response include one‘s
genetic make-up, early life experiences, and environmental factors. For example, several
genetic variations have been observed within the glucocorticoid receptors, with certain
polymorphisms being associated with increased glucocorticoid sensitivity (N363S and BclI)
and others with glucocorticoid resistance (E22/23EK and A3669G; for review [110]).
Furthermore, the polymorphisms N363S and BclI have been shown to significantly impact
the cortisol stress response [111].
Experience of early life trauma for its part has been associated with increased cortisol
stress reactivity [112, 113], although some have also reported attenuated cortisol response in
maltreated adolescents and adults [114, 115].
A recent study in healthy young adults suggested that the degree of early life adversity
might make a difference with respect to its impact on cortisol stress response [106]. In this
study, an inverted U function of cortisol response emerged between groups of low, medium
and high mother care groups, where low and high care groups showed a blunted stress
response (the former effect probably reflecting exhaustion of the HPA axis due to exposure to
high levels of early life stress [116], and the latter probably reflecting lack of perception of
threat [108]), while the medium care group showed an increased stress response [106].
While differences in genetic variants and early life environment have been identified as
main programming factors of the stress response and HPA axis activity, carrying their effects
over one‘s lifetime [117], factors such as personality traits and presence of social support
have been shown to punctually impact the stress response [118, 119].
Importantly, the effect of these factors is not always negative: for example, the presence
of positive social interactions and social support have been found to reduce cortisol stress
response [97].
CONCLUSION
As it has been briefly outlined in this chapter, cortisol, the main stress hormone, has a
widespread effect on an individual‘s mind and body. The main role of cortisol is to allow the
organism to successfully adapt to challenges from internal and external environments. When
the HPA axis function and cortisol levels are dysregulated, a person is at risk for developing a
variety of physical and mental illnesses. There are individual differences with respect to one‘s
vulnerability and resilience to these various illnesses, and factors such as early life adversity,
genetic make-up, and personality - just to name a few - all interact with environmental
demands to tip the scale in one or the other direction. Needless to say, it is essential to
continue to investigate the intricacies of the mechanisms underlying HPA axis regulation,
psychological stress processing, and individual differences in vulnerability and resilience to
stress-related disorders.
This task, however, is not a simple one, and future studies will need to find ways to move
past the assessment of cortisol dynamics in isolation and only at a systems level. Already,
researchers have developed measures that may reflect the contribution of other systems to
cortisol secretion. For example, several recent studies have begun to consider examining a
ratio of cortisol over dehydroepiandrosterone (DHEA) [120-122]. DHEA is also released by
adrenals following a stressor but its role is still not well understood [74]. It has been
suggested that DHEA may serve as a buffer against excessive cortisol activity. Therefore,
several studies have proposed that in order to assess a full effect of cortisol on an organism,
the opposing effect of DHEA should be accounted for [74].
Similarly, it has been proposed that a measure that may capture contribution of the
sympathetic nervous system along with the HPA axis activity may be a better predictor of
one‘s vulnerability to stress-related illnesses than either of the measures alone [123]. A
potential measure that may exemplify this concept is the ratio between levels of alpha
amylase (an indicator of sympathetic activity [124]) over cortisol levels released in response
to psychological stress [123].
Furthermore, advances in molecular biology and genetics also allow for the investigation
of processes involved in cortisol regulation and sensitivity at a more refined level. For
example, one‘s sensitivity to cortisol can be investigated at the cellular level [125] and at the
level of genes [126]. Work to date seems to indicate that an altered pattern of glucocorticoid
sensitivity in relevant target tissues may distinguish between two stress-related disorders:
depression and post-traumatic stress disorder. Namely, this approach shows that while both
psychiatric disorders show inefficient GC signaling, dysregulation seems to be occurring at
different levels of the cascade [127].
These are just a few examples of how this field is moving forward. With developments of
novel approaches to the assessment of the dynamics of HPA axis, cortisol release, and other
auxiliary systems involved in the processing of stress, as well as with steady improvements in
neuroimaging data acquisition and analyses, we will be able to gain greater knowledge
regarding mechanisms underlying cortisol physiology, regulation and health implications.
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In: Cortisol ISBN: 978-1-61942-458-6
Chapter 3
HEIGHTENED ENDOCRINE RESPONSES TO DAILY

LIFE STRESSORS IN HEALTHY WOMEN AT FAMILIAL
RISK FOR BREAST CANCER
Gary D. James1 and Dana H. Bovbjerg2

1
Decker School of Nursing and Department of Anthropology,
Binghamton University, Binghamton, NY, US
2
Biobehavioral Medicine in Oncology Program, University of Pittsburgh Cancer
Institute, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, US
ABSTRACT
We have investigated the possibility that familial risk for breast cancer may be
associated with increased endocrinological reactivity to psychological stress. Such effects

could be the result of chronic stress associated with having a family history of breast
cancer in close relatives, a circumstance that increases a woman‘s lifetime risk of
developing the disease by up to four times, or due to genetic predisposition to stress
reactivity. In a series of studies using a natural experimental approach, we have compared
diurnal changes and variation in urinary cortisol and catecholamine excretion rates
between working women who are either at familial risk due to their family histories
breast cancer, or do not have family histories of cancer. The effects of work stress over
time on the daily variation of these hormones as well as possible psychological triggers
such as breast cancer specific intrusive thoughts have also been examined. The results of
these studies show that women at familial risk exhibit heightened cortisol and
catecholamine responses to work stress during the day, phenomena that are reproducible
over a two-month time frame. In addition, we have found that breast-cancer specific
intrusions are associated with the increased cortisol responses to work stress, even in
women without family histories. These results suggest that women with family histories
of breast cancer have a pattern of increased reactivity to daily stress. They also suggest
that there is likely a psychological component to the increase, but whether there are other
underlying biological mechanisms has yet to be determined. However, regardless of the
initiating mechanisms, persistently heightened cortisol and catecholamine responses to
daily stress may have significant health consequences.
50 Gary D. James and Dana H. Bovbjerg
INTRODUCTION
In experimental studies of humans, subjects who experience chronic or ―backgr ound‖
stress have been reported to show increased stress hormone responses to acute stress [e.g.,
Gump and Mathews, 1999; Cacciopo et al., 2000, Gold et al., 2003]. In most studies, subjects
with chronic general life stress exhibit a heightened reactive rise in cortisol and/or
catecholamines (epinephrine and/or norepinephrine) but there are also studies where such
subjects show a decline in response or no difference in response, which may reflect the
complexity of chronic stress and its experience [Gump and Matthews, 1999; Chida and
Hamer, 2008]. Although women are known to have stronger stress hormone responses to
acute stress, possible synergistic effects with chronic stress have received little research
attention [Chida and Hamer, 2008; Kudielka et al., 2009]. Several lines of epidemiological,
psychological and physiological evidence have established that being at familial risk for
breast cancer is a potent chronic stressor for many women [Spittle and Morgan, 1999;
Bovbjerg and Valdimarsdottir, 2001; Gold et al., 2003; Henderson et al., 2008]. Both
retrospective and prospective sources of chronic stress have been identified for these women
[Erblich et al., 2000]. In addition to the psychological sequellae of experiencing the diagnosis,
treatment and possible death of a close relative to breast cancer, healthy women with family
histories of breast cancer are up to four times more likely to develop the disease themselves,
even if they test negative for the primary breast cancer susceptibility genes (BRCA1,
BRCA2) [Metcalfe et al., 2009].
It is also important to recognize that the mechanisms responsible for more than two thirds
of the genetic risk for breast cancer are not yet known, and are likely to include multiple
polygenic effects [Turnbull and Rahman, 2008]. In light of accumulating evidence that
differences in stress hormone reactivity to acute stress have a strong genetic basis [Redei,
2008; Kudielka et al., 2009] and increasing recognition of possible pathways by which stress
hormones may contribute to the etiology of breast cancer [Antonova et al., 2011], it is
tempting to speculate that an inherited tendency to an overly exuberant stress response could
contribute to the increased risk of breast cancer in women with family histories of the disease.
Over the past several years, we have investigated the possibility that women with family
histories of breast cancer in close relatives may have increased stress hormone reactivity to
psychosocial stress in everyday life. The purposes of this chapter are to summarize the results
of our investigations to date and to discuss their health implications.
NATURAL EXPERIMENTAL APPROACH TO

STUDYING STRESS IN EVERYDAY LIFE
One means of evaluating acute stress response differences in everyday life is to employ a
―natural experimental‖ approach which takes advantage of naturally occurring environmental
contrasts [Garruto et al., 1999; James and Ice, 2007]. This approach has its roots in laboratory
experiments of stress reactivity, where a baseline condition is established and then
participants are exposed to stressful stimuli. The difference between measurements taken at
baseline and during or after the stimuli defines the magnitude of the stress response [James,
2007a]. Moving this laboratory experimental paradigm to a ―nat ural experimental‖ setting
Heightened Endocrine Responses to Daily Life Stressors ... 51
requires some modification since no true baseline can be established in everyday life [James
and Ice, 2007].
Several researchers have shown that the urban environment is heterogeneous, with
several distinct microenvironments [Harrison and Jefferies, 1977; Harshfield et al., 1982;
James, 1991; Garruto et al., 1999]. There are clear transitions between these
microenvironments that define them as separate settings. A ―nat ural experiment‖ can be set
up by contrasting biological responses across the settings.
Work (place of employment) and home (place of residence) have been firmly established
as microenvironmental settings that are useful in studying reactive physiological or endocrine
changes in everyday life [e.g., Reynolds et al., 1981; Harshfield et al., 1982; Frankenhaeuser
et al., 1989; James et al., 1993; Leucken et al., 1997; Chandola et al., 2010]. The work
microenvironment is a natural setting where social interaction occurs with non-related
individuals, where a specific occupational hierarchy dictates social relationships and where
there is a general conformity of behavior [James, 1991; 2007b]. The parameters of this
microenvironment contrast sharply with the home microenvironment, where domestic tasks
and leisure activity occur in a social context where interactions are mostly with relatives and
neighbors [James, 1991; 2007b]. The changes in physiological or endocrine measures
associated with the work and home microenvironments can be evaluated as a ―nat ural
experiment‖ in which the response to the stresses associated with paid employment and
domestic life are compared. A microenvironment that is similar for all subjects (such as
overnight sleep, or more specifically, lying quietly in a dark room) can act as a pseudo-
baseline in this ―natural experiment.‖ Figure 1 shows the comparative elements of this natural
experimental design relative to the framework of a laboratory study.
Figure 1. Comparison of laboratory study design with natural experimental design for assessing
endocrine reactivity. (Modified from James, 2007a).
EXPERIMENTAL DESIGN FOR THIS STUDY

In developing our field study of endocrine reactivity in women at familial risk for breast
cancer, we took advantage of the naturally occurring and easily differentiable
microenvironmental variation inherent in cosmopolitan New York City and compared the
endocrine responses of employed women across their work, home and sleep
microenvironments within this urban setting. To add further control in the study, occupational
variation and location were also limited; thus only women working in technical and clerical
positions who were employed at three major medical centers in Manhattan were examined.
The women all worked a typical day shift (e.g., 9AM-5PM). Women were excluded from
study if: (1) they were not English speaking, (2) had a history of HIV, cancer or abnormal
breast exams (including abnormal breast biopsy or abnormal mammogram), (3) were on
medications other than birth control pills and (4) were participating in any other research trial
that could affect the study variables [James et al., 2004; Dettenborn et al, 2005]. Table 1
shows selected demographic characteristics of the women recruited for the study.
While the study design included assessment of endocrine variation at both work and
home, there was a particular emphasis on the responses to the work microenvironment. The
reason for this focus is that there is compelling evidence that the conditions at work are a
potent daily stressor that has been associated with significant increases in both cortisol and
catecholamine output in many other studies [e.g., Frankenhaeuser et al., 1989; Pollard et al.,
1996; James and Brown, 1997; Leucken et al., 1997; Ice and James, 2012]. Thus, the primary
hypothesis being tested was that women with family histories of breast cancer in close
relatives would show an accentuated response to the stressors at work relative to women
without family histories of breast cancer [James et al., 2004; Dettenborn et al, 2005].
A limitation of this research design is the fact that the ―bas eline‖ conditions uniformly
follow the experimental conditions, such that data were collected at work first, followed by
home and then sleep. Many studies have found that there can be carry-over effects of stress at
work that could elevate the subsequent endocrine measures at home and during sleep [e.g.,
James et al., 1989a; James et al., 2004]. This would suggest that examining the difference
between work and sleep as an indicator of reactivity would likely underestimate the true
reactivity to work stress. However, if the sleep ―bas eline‖ before the work condition was
used, the possible carry-over effects of work the previous day on that sleep measure would be
unknown and thus have an inestimable bias. Also, it is possible that women with family
histories of breast cancer could have a general elevation in their endocrine output under all
circumstances (a tonic increase related to their chronic stress), which might be missed if we
only examined the differences between the groups in the work microenvironment. Therefore,
a MANCOVA repeated measures analytic approach was employed to compare hormonal
output both across the microenvironments and between the groups so that reactive and tonic
variation between the groups could simultaneously be evaluated. Using this statistical
approach also limited type 1 error in our assessments.
Finally, in evaluating the differences in daily endocrine stress responses, we were also
interested in whether the responses persisted over time [Gastrich et al., 2007; James et al.,
2008] and whether psychological factors or perceptions related to familial breast cancer risk
may mediate the endocrine reactivity to work stressors [Dettenborn et al., 2006a; Dettenborn
et al., 2006b]. Studies examining these questions also employed repeated-measures statistical
analytic approaches in which endocrine differences across the daily microenvironments were
assessed.
Table 1. Socio-demographic Characteristics of the Overall Study Samplea
Socio-demographic Characteristics FH- FH+ Statistical test p-value

n=141b n=74 value
Mean Age 37.2 + 37.8 F(1,208)=0.231 p=0.65
9.2 +9.1
Ethnic Group 2=6.709, df=2 p=0.04*
-White 53.3% 64.8%
-Black 35.8% 18.8%
-Other 10.9% 17.4%
Marital Status 2=2.566, df=1 p=0.11
-Currently married 34.8% 45.9%
Education 2=2.230, df=2 p=0.28
-Some college or less 33.1% 22.5%
-College degree 33.1% 39.4%
-Graduate degree 33.8% 38.0%
Employment 2=0.528, df=1 p=0.47
-Full time 94.1% 91.4%
a
Mean + standard deviation or percent (%) of total. FH- Women without family histories of breast
cancer; FH+ Women at familial risk for breast cancer, with at least one first-degree relative with
breast cancer.
b
Number of subjects varies slightly in both groups across variables due to missing values for some
factors.
* Significant difference. (Modified from Dettenborn et al, 2005).
ENDOCRINE MEASURES AND DATA COLLECTION PROTOCOL

To be consistent with the research design, the endocrine measurements needed to be

integrated so that the assessment reflected the ―average‖ response over the time spent in each
microenvironment. Urinary measures provide such an assessment and were thus used in the
studies as both cortisol and the catecholamines (epinephrine and norepinephrine) can be
easily assayed in urine [Pollard and Ice, 2007; Brown, 2007].
Procedures
There was a significant logistical advantage in having the data collection centered at the
subject‘s place of employment (work microenvironment), as we could set up a centrally
located study room where subjects could be interviewed, medically assessed, have the
specifics of the daily study procedures explained, and to where the study urine samples could
be returned to the study staff. The general procedures for data collection were as follows: on
the study day, at the beginning of their workday (e.g., between 8:00-9:00 AM), study
participants came to the study room and completed informed consent and baseline
psychometric questionnaires. Anthropometric measurements, demographic data and medical
history were also collected at this time. All participants were then provided with a 3-liter
polyethylene bottle for the collection urine while at work and the procedures for collection
were explained. At the end of the timed work collection period, the women were contacted at
their workplace and the work specimens were retrieved. At this time, two bottles for timed
urine collections that night at home and upon awakening in the morning (overnight collection
corresponding to sleep) were provided. These specimens were returned the following
morning.
The specific urine collection protocol was based on that reported in James et al. [1993].
Briefly, approximately 1-2 hours after completion of the baseline questionnaires during a
workday (e.g., 11:00 AM), participants were asked to go to the bathroom and empty their
bladder. This urine specimen was not collected, but the time was noted and represented the
beginning of the work urine collection period for the study. The participants then collected all
their urine over a convenient block of time (e.g., four hours) in the provided 3-liter
polyethylene bottle with preservative (0.5 g of sodium metabisulphite). This preservative has
been widely used in field studies of urinary catecholamine variation [e.g., Reynolds et al.,
1981; James et al., 1985; Jenner et al., 1987; Brown and James, 2000] and has no known
effect on the cortisol assay we employed [Doering et al., 2000; Cohen et al., 2001; Glover and
Poland, 2002]. The time of the final work voiding was noted and represented the end of the
work collection period. Identical procedures were followed for the home and sleep sampling
periods. The three distinct daily microenvironments compared were thus defined as work
(approximately 11:00 AM – 3:00 PM), home (approximately 6:00 PM – 10:00 PM), and sleep
(approximately 10:00 PM – 6:00 AM). The length of time of the collection (to the nearest
minute) and total volume of each sample were recorded for each urine collection. A 5-ml
aliquot was taken from each sample and frozen at -60º C until subsequent batch assay.
Potential collection confounding was addressed by preliminary analyses comparing urinary
volumes between the two groups for each of the three time blocks, which revealed no
significant differences.
Concentrations of cortisol were determined using radioimmunoassay (Diagnostic
Products Corporation, Los Angeles, USA) with a sensitivity of 0.2 μg/dL and inter- and intra-
assay coefficients of variance below 7% for all analyses [Dettenborn et al., 2005].
Concentrations of epinephrine and norepinephrine were determined using HPLC with
electrochemical detection following the procedures noted in Brown and James [2000]. For the
purpose of analysis, cortisol and the catecholamines were expressed as rates of excretion
(µg/24 hrs for cortisol and ng/min for epinephrine and norepinephrine) over each sampling
period. These rates were calculated by multiplying the urine production rate by the measured
concentration. We chose not to assess hormonal excretion as a ratio with urinary creatinine
because a considerable literature indicates that urinary creatinine levels are highly variable
both within and between individuals, particularly over shorter time frames and thus cannot
provide a reliable indicator of the adequacy of urinary sampling, serve as a valid referent for
other urinary metabolites or act as an adjustment for body size [e.g., Vestergaard and
Leverett, 1958; James et al, 1988].
For the cortisol excretion rate comparisons, we determined the cortisol nadir for each
participant, the lowest level of the day (home or sleep period) and used it as the referent value
in the analysis. This adjustment was made due to the known distinct circadian rhythm of
cortisol in the preponderance of normal healthy people, where the highest levels occur usually
shortly after awakening, with sharp decreases during the first few hours in the morning, more
gradual decrease thereafter over the course of the day, and then a rapid rise prior to
awakening [Dettenborn et al., 2005]. Given the hormonal sampling strategy for the study, it is
likely that in the majority of subjects, the average rate of excretion during sleep might be
somewhat higher than that in the evening at home due to the fact that the rapid rise in cortisol
secretion prior to awakening is being averaged in with the generally low levels that occur
during the majority of sleep. We also computed the percent increase from this cortisol nadir to
work using the formula ((work-nadir)/nadir x 100) for further follow-up comparisons
[Dettenborn et al., 2005; 2006b].
Studies have also shown that body fat, fat distribution or body mass is positively
associated with urinary catecholamine excretion [Sowers et al., 1982; James et al., 1989b;
Leonetti et al., 1991]. Therefore, in the analyses of urinary epinephrine and norepinephrine
excretion, body mass index (BMI) was included as a covariate. As with cortisol, follow-up
comparisons of the percent increases in the rates of epinephrine and norepinephrine excretion
from sleep (baseline) to work (calculated as (work-sleep)/sleep x 100) were also done [James
et al, 2004].
Psychological Evaluation
As previously noted, subjects provided answers to several psychometric questionnaires

the morning of their study. These instruments were employed for the purpose of evaluating
potential psychological mediators of the endocrine responses; most specifically, we evaluated
the perception of individual breast cancer risk, intrusive thoughts about breast cancer and
avoidance behavior [Dettenborn et al., 2006a; 2006b]. Breast cancer risk perception was
assessed with one item (―H ow likely do you think it is that you will develop breast cancer in
your lifetime?‖). The response options to this question ranged from 0 (0%) to 100 (100%),
and were dichotomized for analysis at the median split. Intrusive thoughts about breast cancer
and avoidance were assessed using the Impact of Event Scale (IES) [Horowitz et al., 1979],
which is a 15-item self-report instrument measuring intrusive thoughts (7 items), avoidant

behaviors (7 items), and interference with daily activities (1 item) over the last 7 days in
relation to a specified stressful event, here breast cancer.
Consistent with previous IES analyses [Zakowski et al., 2001], participant responses were
dichotomized as having had intrusions about breast cancer during the past week or not having
had intrusions about breast cancer during the past week. Avoidance behavior was similarly
categorized.
REACTIVITY TO WORK STRESSORS: PRINCIPAL FINDINGS

Because of the different design elements that emerged as a consequence of the difference
in circadian rhythms between cortisol and the catecholamines, the comparisons of responses
to work stressors between women with family histories of breast cancer and women without
family histories were examined and reported separately in Dettenborn et al. [2005] and James
et al. [2004]. The results of these studies are summarized below.
Cortisol
In examining urinary cortisol excretion during the day, we found a significant main effect
of microenvironment on the excretion rates, with overall higher rates in the work as compared
to the home and sleep microenvironments [Dettenborn et al., 2005] (see Figure 2).
There was also a significant breast cancer risk group by microenvironment interaction
effect such that women with family histories of breast cancer had significantly higher cortisol
excretion during work than women without family histories (p<.05) (see Figure 2), while the
rates of cortisol excretion at home and during sleep did not differ between the groups.
Figure 2. Comparison of urinary cortisol (µg/24 hr) excretion rates across the three contrasting daily
microenvironments in women with familial risk (FH+) and women without familial histories (FH-) for
breast cancer. (Modified from Dettenborn et al., 2005).
Finally, consistent with increased responsivity to work stressors, the women with family
histories of breast cancer had a greater percentage increase from the cortisol nadir to work
compared to women without family histories (p=0.05) (see Figure 3).
Epinephrine and Norepinephrine
Our findings of the comparisons of diurnal urinary epinephrine and norepinephrine

excretion between the women with family histories of breast cancer and women without
family histories are shown in Table 2 [James et al., 2004]. As with cortisol excretion, women
with family histories of breast cancer had significantly higher epinephrine excretion at work,
while the rates of excretion at home and during sleep did not differ. However, unlike the
cortisol results, women with family histories also had higher epinephrine excretion overall
(the arithmetic average across the three different daily conditions) than women without family
histories, suggesting a tonic increase as well as a greater reactivity to work stressors.
To further evaluate differences in the effects of work stressors between the groups, the
percent increases in the rates of excretion from sleep (baseline) to work were examined.
Figures 4 and 5 show the comparisons of the percent increase from sleep to work in
epinephrine and norepinephrine excretion respectively between the breast cancer risk groups.
As indicated, women with family histories of breast cancer showed significantly (p<.05)
greater proportional increases from the sleep baseline in both epinephrine and norepinephrine
excretion than women without family histories.
Table 2. Comparison of Urinary Epinephrine (ng/min) and Norepinephrine (ng/min)

Excretion Rates Across the Three Contrasting Daily Microenvironments in Women at
Familial Risk (FH+) and Women without Familial Histories (FH-) of Breast Cancera
a
average values at a BMI of 24.8 Kg/M2.
** groups different at p<.01
*** groups different at p<.005
(Modified from James et al, 2004).
Finally, as indicated in Table 2 and both Figures 4 and 5, the results were presented at a
BMI of 24.8 (the average BMI of the women with family histories of breast cancer). The
reason for this designation is that in the analyses, BMI had a significant (p<.05) moderating
(interaction) effect on the group differences in the catecholamine excretion rates, particularly
epinephrine excretion. To better understand the nature of this moderating effect, the
relationships between BMI and epinephrine excretion at work were plotted separately for
each of the study groups (see Figure 6). As can be seen, among the women without family
histories, the rate of epinephrine excretion increased linearly with BMI consistent with most
studies of epinephrine variation and body size in healthy, normal subjects. However, women
with family histories of breast cancer had markedly elevated epinephrine excretion rates when
BMI was low, which remained at a similar to slightly lower level as BMI increased. These
data indicate that at low to moderate BMI, women with family histories of breast cancer have
a relatively elevated rate of epinephrine excretion compared to women without family
histories of breast cancer; but with increasing obesity, the differences in the rate of excretion
diminish so that in the heaviest women the difference disappeared.
Figure 3. Comparison of the percent increase in urinary cortisol excretion rates from the cortisol nadir
to work between women with familial risk (FH+) and women without familial histories (FH-) for breast
cancer. (Modified from Dettenborn et al., 2005).
Figure 4. Comparison of the percent difference in urinary epinephrine excretion from sleep to work
between women with familial risk (FH+) and without familial histories (FH-) for breast cancer (at
BMI=24.8 Kg/M2). (Modified from James et al., 2004).
Figure 5. Comparison of the percent difference in urinary norepinephrine excretion from sleep to work
between women with familial risk (FH+) and without familial histories (FH-) for breast cancer(at
BMI=24.8 Kg/M2). (Modified from James et al., 2004).
Figure 6. The moderating effect of body mass on the rate of urinary epinephrine excretion at work in
women with familial risk (FH+) and without familial histories (FH-) for breast cancer. (Modified from
James et al., 2004).
Table 3. Cortisol Excretion (µg/24 hr) by Microenvironment Over the Two Assessments
One Month Apart in Women with Familial Risk (FH+) and Without Family Histories
(FH-) of Breast Cancer (Mean ± Standard error)
* Assessment 2 and Total, FH+ > FH-, p<.05.(Modified from James et al., 2008).
REPRODUCIBILITY OF THE HEIGHTENED REACTIVITY RESPONSE

TO WORK STRESSORS
As with the initial comparisons, evaluation of the persistence of the cortisol [James et al,
2008] and catecholamine [Gastrich et al., 2007] responses to work stressors was examined
and reported separately. The primary findings of these studies are summarized below.
Cortisol
In evaluating the persistence of the risk group differences over two months, we found that
the pattern of cortisol excretion across the microenvironments was consistent over time, with
the highest rates of excretion occurring at work across both months [James et al., 2008]. In
addition, as with the initial cross-sectional study, there was also a significant breast cancer
group x microenvironment interaction effect, which indicated that cortisol excretion at work
was also persistently higher in women with family histories of breast cancer over the two
months (see Table 3).
A Bland-Altman plot of the difference in work excretion rates from the first to second
assessment Vs the average work excretions rates (Figure 7) showed that 94.1% of the
difference values fall within 2 standard deviations of the average difference (top and bottom
horizontal lines on the graph) consistent with good reproducibility, although the pattern of
differences relative to the mean showed a marked heteroscedasticity. Nonetheless, the results
suggested that on an individual basis, work cortisol levels were reproducible, regardless of
whether the women had family histories of breast cancer.
Copyright © 2012. Nova Science Publishers, Incorporated. All rights reserved. Heightened Endocrine Responses to Daily Life Stressors ... 61
Figure 7. Bland-Altman plot of the mean difference in work cortisol excretion rates from assessment 1
to assessment 2 and the mean rate of work cortisol excretion (µg/24 hr.).(Modified from James et al.,
2008).
Epinephrine and Norepinephrine
Our analysis of the reproducibility of the catecholamine differences between the breast
cancer risk groups indicated that women with family histories of breast cancer tended to
maintain heightened epinephrine excretion rates at work over the two month period, similar to
the effect seen with cortisol [Gastrich et al., 2007] (see Table 4). As with the initial
assessment, there were no statistically significant differences in the levels of norepinephrine
between the breast cancer risk groups.
A Bland-Altman plot of the difference in work epinephrine excretion rates showed that
97% of the difference values fell within 2 standard deviations of the average difference,
similar to the pattern seen with cortisol (see Figure 8). These findings suggested that the rate
of epinephrine excretion at work, like the rate of cortisol excretion at work, was individually
reproducible over two months.
Table 4. Epinephrine Excretion (ng/min) Comparisons by Microenvironment Over the

Two Assessments One Month Apart in Women with Familial Risk (FH+) and Without
Familial Histories (FH-) of Breast Cancer (Mean ± Standard Error)
______________________________________________________________________________
Work* Home Sleep
FH+ FH- FH+ FH- FH+ FH-

______________________________________________________________________________
Assessment 1 3.89±0.42 3.02±0.34 2.34±0.34 2.22±0.27 1.35±0.19 1.35±0.16
Assessment 2 4.07±0.45 3.10±0.36 3.35±0.41 2.67±0.33 1.23±0.23 1.01±0.19
Total 3.98±0.36 3.06±0.29 2.86±0.31 2.44±0.23 1.29±0.16 1.18±0.13
* Total FH+ > FH-, p<.05.

Figure 8. Bland-Altman plot of the mean difference in work epinephrine excretion rates from
assessment 1 to assessment 2 and the mean rate of work epinephrine excretion (ng./min.).
PSYCHOLOGICAL FACTORS, BREAST CANCER RISK

AND CORTISOL REACTIVITY
To explore a possible psychological basis of the breast cancer risk group differences in
work cortisol reactivity, we evaluated the effects of psychological factors that might relate to
women‘s fear of breast cancer, such as intrusive thoughts about breast cancer, avoidant
behaviors and breast cancer risk perceptions [Dettenborn et al., 2006a; Dettenborn et al.,
2006b]. We initially evaluated these effects in conjunction with the risk group differences
[Dettenborn et al., 2006a].
This analysis showed that having intrusive thoughts but not avoidance behaviors or
perceived increased breast cancer risk was associated with significantly higher work cortisol
levels, and that having intrusive thoughts appeared to partially mediate the effects of having a
family history of breast cancer in that when both factors were simultaneously included as
independent predictors of cortisol excretion, the importance of family history as a source of
cortisol variation was diminished (see Table 5).
In a subsequent analysis we also found that even among women without a family history
of breast cancer, having intrusive thoughts about breast cancer still increased cortisol levels at
work [Dettenborn et al., 2006b] (see Figure 9).
Figure 9. Urinary cortisol excretion rates (µg/24 hr.) at work, home, and sleep among women without
familial histories for breast cancer with and without intrusions relating to breast cancer. (Modified from
Dettenborn et al., 2006b).
Delta cortisol levels (sqrt) between women with and without breast
cancer-specific intrusions
1.8
Intru=0
1.6
Intru>0
1.4
1.2
0.8
0.6
0.4
0.2
Figure 10. Change in cortisol levels among women without familial histories for breast cancer with and
without intrusions for breast cancer. (Modified from Dettenborn et al., 2006b).
Table 5. Model with Familial Risk Groups (FH+/FH-) and Intrusions (Dichotomized) as
Fixed Independent Variables and Work Cortisol as Dependent Variable
Model F p-level Partial eta2

FH+/FH- 2.519 0.114 0.012
Intrusions (0 vs. >1) 5.309 0.022 0.024
In addition, this analysis revealed that women who reported having intrusive thoughts
also had significantly greater work related cortisol reactivity (work cortisol minus nadir
cortisol) (see Figure 10).
DISCUSSION
We have investigated cortisol and catecholamine reactivity to everyday work stressors in
healthy women who were either at familial risk (those with one or more first degree relatives
with breast cancer) or population risk (those with no family histories) for breast cancer,
finding significantly higher levels of urinary cortisol and epinephrine levels during a stressful
period of the day (work) in women at familial risk compared to women without family
histories. In addition, the percent increase from the cortisol nadir (lowest value on either
home or sleep) to work and the percent increase in epinephrine from sleep (baseline) to work
were both significantly higher in women at familial risk. These results are consistent with
previous laboratory experimental data indicating significantly elevated cortisol and

epinephrine responses to a standardized laboratory stressor in healthy women with family
histories of breast cancer [Gold et al., 2003]. These findings are also consistent with the idea
that women who experience the chronic stress of familial risk of breast cancer are more
reactive to acute stressors, or alternatively that these women may have inherited a genetic
propensity to overly-exuberant stress hormone responses. Our findings also support the view
that it is a joint effort of the HPA axis and the SAM that mediates the stress response, with
catecholamines acting in concert with cortisol [Sapolsky et al., 2000; Nicolaidis, 2002].
In evaluating the validity of the cortisol results, it is important to consider that the
literature on cortisol variation views reactive responses and the circadian rhythm as two
separate phenomena, each of which may be influenced by different physiologic, genetic and
psychological factors. Thus, it might be argued that evaluating cortisol reactivity in daily life
may not be practicable, because of a confounding of the actions of the underlying
mechanisms that regulate the separate responses. For example, physiologically, the circadian
rhythms of HPA activity appear to be regulated mainly by high affinity mineralocorticoid
receptors in the central nervous system, while acute stress responses appear to be regulated by
low affinity glucocorticoid receptors [Dallman et al., 2000; Lightman, 2008]. From a genetic
perspective, Wust et al. [2000] have reported that the cortisol waking response but not levels
over the remainder of the day are under some genetic control. They have also reported that
common polymorphisms in the glucocorticoid receptor gene may have modulating effects on
the relationship between psychosocial stress and cortisol, suggesting another and perhaps
synergistic mechanism for variation in cortisol reactivity [Wust et al., 2004; Kudielka et al.,
2009]. Psychological factors associated with chronic stressors and their relationships to
cortisol reactivity and diurnal variation also appear to show differing relationships. Thus,
while factors such as long-term unemployment and burnout have been shown to increase
acute cortisol reactivity in the laboratory [Ockenfels et al., 1995; Cacioppo et al., 2000; De
Vente et al., 2003], the effects on patterns of salivary cortisol concentrations measured over
the day have yielded inconsistent results with some studies supporting an influence on trough
cortisol levels [Linkowski et al., 1987; Cella et al., 1995; Van Cauter et al., 1996; Powell et
al., 2002] and others not [Ockenfels et al., 1995; Wust et al., 2000]. Inconsistencies in the
results of studies evaluating daily salivary cortisol levels, however, could stem from the wide
variation in the sources of chronic stress examined as well as with differing aspects of the
currency (ongoing vs. resolved) or duration of the stressors [Gump and Matthews, 1999;
Chida and Hamer, 2008]. It may also be that the salience of a stressor influences the timing of
the daily cortisol responses, which could explain reported contrasting results between
unemployment and divorce as chronic stressors, where unemployment affects the response
more during the day and divorce influences the response more later at home [Powell et al.,
2002]. How familial risk of breast cancer compares to other chronic stressors with regard to
effects on stress hormone reactivity in women, is not yet clear as these topics were not
explored in the recent meta-analysis [Chida and Hamer, 2008]. There can be no doubt that
acute events during the day do initiate responses from the HPA axis, and it should be possible
to detect differences in these responses despite the circadian rhythm of cortisol [Chandola et
al., 2010]. We believe that the natural experimental approach employed in our studies was
able to do this, because of the elements of the study design. Specifically, cortisol comparisons
during the stress period of interest (work) were restricted to a time frame (11AM-3PM) that
was further imbedded in a diurnal work routine (9AM-5PM) while the participants had
similar types of work (limited range of occupations) and work conditions (limited places of
employment). The cortisol levels obtained are highly likely to be from a similar point in the
circadian rhythms of the study subjects, so that if one group (familial risk women) had
elevated levels in response to their work conditions at that point in the circadian rhythm, it
would suggest an increased reactivity to those conditions. The fact that we also measured
activity of the SAMS and the comparisons of epinephrine showed a similar pattern of results
provides strong additional evidence that the rise in cortisol was in response to work stressors
and not a difference in circadian rhythm, which is in line with numerous earlier studies which
have demonstrated that a natural experimental approach like the one we have employed
captures endocrine variance related to the differing stressfulness of contrasting daily
microenvironments [Frankenhaeuser et al., 1989; James et al., 1993; Leucken et al., 1997; Ice
and James, 2012]. While we have found differences in the levels of cortisol and epinephrine
associated with work stressors between groups of women who differ with regard to the
chronic stress of familial risk of breast cancer, the magnitude of the increase and the levels of
hormone attained are not pathological, meaning that they fall within normal physiological
limits. This fact raises a simple question: if the heightened response of the hormones at work
among the women at familial risk for breast cancer is not pathological, how might the
increase affect their long-term health? Both endocrine measures are allostatic, meaning that
they have many stable states that are directly related to the many and ever changing internal
and external environmental conditions to which an individual must adapt [Sterling, 2004]. If
there is an inappropriate sustained allostatic response to environmental conditions, it could
lead to allostatic load following the logic of McEwen [2004], where the system that is
inappropriately stimulated fails, triggering cellular and metabolic dysregulation, ending in
chronic disease. Both cortisol and epinephrine have mediating and moderating effects in
regulating most of the body‘s metabolic systems and tissue functions, and initiate their effects
at the cellular level by binding to receptors in the cytoplasm and then entering the cell nucleus
as a receptor complex to activate or repress particular genes [Pollard and Ice, 2007; Brown,
2007]. Because we have found that the increase in these hormones persists over at least two
months among women at familial risk, one could speculate that even though the levels are not
pathological, their persistent increase might lead to allostatic load through the inappropriate
up- or downregulation of the genes they affect, potentiating a variety of negative health
consequences including the possible development of breast cancer [Kudielka and Wust, 2010;
Antonova et al., 2011]. Finally, we have also found that the experience of intrusive thoughts
regarding breast cancer is associated with increased cortisol levels during the work day, an
association that appears to contribute to the difference between women at familial and
population risk for breast cancer, but also apparent even among women with no familial
history of breast cancer. While these results suggest that psychological mechanisms play a
key role in cortisol reactivity, there is other compelling evidence that genetic factors may also
be important. As previously noted, Wust et al. [2004] have reported that common
polymorphisms in the glucocorticoid receptor gene may have modulating effects on the
relationship between psychosocial stress and cortisol reactivity. It is thus highly plausible that
particular allelic variants, which could be more prevalent in women at familial risk but also
present in the general population, potentiate the enhanced cortisol reactivity in women who
fear and/or worry about their risk for breast cancer. Further research is needed to elucidate the
precise mechanisms and roles of genetic and psychological factors that increase the daily
cortisol reactivity, which we have found in the studies described above.
CONCLUSION
Healthy women at familial risk for breast cancer have accentuated epinephrine and
cortisol responses to everyday acute stressors (specifically, those that occur at work)
compared to women without family histories of breaset cancer. The accentuated responses
appear to be relatively stable characteristics of these women, as the differences were found to
persist over two months of assessment. The chronic stress associated with breast cancer risk
may be mediated by intrusive thoughts about breast cancer, as these thoughts accentuate
cortisol responses to work stressors, even in women who have no family history.
Alternatively, inherited genetic influences may be involved. While the increased reactivity in
both cortisol and epinephrine is not outside the normal range, the up-regulation of these
hormones over the long term could contribute to allostatic load, leading to adverse health
outcomes. It remains to be determined whether the increase in these hormones is mostly
psychologically driven, facilitated by underlying genetic mechanisms or by a combination of
both.
ACKNOWLEDGMENTS
This research was supported by NIH grant CA72457; Department of Defense Breast
Cancer Research Program grants: DAMD17-99-1-9303 and DAMD 17-03-1-0346.
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In: Cortisol ISBN: 978-1-61942-458-6
Chapter 4
BIOPSYCHOSOCIAL CORRELATES OF CORTISOL

ACTIVITY IN CHILDREN EXPOSED
TO NATURAL DISASTERS
Jacob M. Vigil*, Amber Dukes and Patrick Coulombe

University of New Mexico, Albuquerque, NM, US
ABSTRACT
In all cultures in which they have been studied, exposure to and losses resulting from
natural disasters are associated with increased prevalence of severe psychological
distress, along with changes in activation of the limbic system (e.g., cortisol regulation)
and changes in activation of the sympathetic nervous system. These patterns of
psychological and physiological reactivity vary with the severity and duration of the
attendant losses, biological sex, and psychosocial factors such as the reliability and
attentiveness of available social partners. In this chapter, we review several
biopsychosocial factors that have been found to covary with psychological distress and
physiological stress reactivity in children and adolescents exposed to natural disasters.
We then describe our own work examining psychosocial and biological correlates in
children and adolescents who were displaced as a result of Hurricane Katrina (Vigil,
Carle, Geary, Granger, Flinn, & Pendleton, 2009; Vigil & Geary, 2008; Vigil, Geary,
Granger, & Flinn, 2010; Vigil & Brophy, in press). These studies show that exposure to
natural disasters is associated with unique patterns of psychological functioning, social
perceptions and behaviors, and physiological stress regulation, and that the patterns vary
by social environment and biological sex. The studies also highlight the utility of
assessing psychological and physiological stress responses outside of laboratory
conditions and in individuals who have experienced chronic and pervasive stress.
*
Address correspondence: Jacob M. Vigil. Department of Psychology. University of New Mexico. 1 University of
New Mexico, MSC03 2220; Albuquerque, NM, 87131-1161; Phone: 505-277-0374. Email: vigilj@unm.edu;
Web: http://www.unm.edu/~psych/faculty/sm_vigil.html.
74 Jacob M. Vigil, Amber Dukes and Patrick Coulombe
STRESS REACTIONS IN ADULTS

Natural disasters are a significant source of stress in adult victims, and responses to these
events include health problems (e.g., sleep disturbance, and substance abuse); psychological
disturbances (e.g., depression, anxiety, panic, and post-traumatic stress disorder);
interpersonal problems (e.g., conflicts with intimate and community partners); self-esteem
losses (e.g., decreased self-efficacy, social embeddedness, and sense of control); and non-
specific distress (e.g., low mood, perceived stress) (e.g. Freedy, Saladin, Kilpatrick, Resnick,
& Saunders, 1994; Norris, Friedman & Watson, 2002; Norris et al., 2002, Friedman, Watson,
Byrne, Diaz & Kaniasky 2002).
These negative consequences can be exacerbated by additional factors such as economic
disadvantage and post-disaster circumstances, including displacement and relocation from
one‘s existing community (Adams, Boscarino, & Galea, 2006; Cohen, Doyle, & Baum, 2006;
McFarlane, 1990; Najarian, Goenjian, Pelcovitz, Mandel, & Najarian, 2001; Perez-Sales,
Cervellon, Vazquez, Vidales, & Gaborit, 2005). Displacement may compound the likelihood
of experiencing prolonged difficulties in social and economic recovery and negative health
consequences that can accompany exposure to natural disasters (e.g., Osofsky, Osofsky, &
Harris, 2007).
Physiologically, responses to acute stressors include: (a) increased activation of the
hypothalamic–pituitary–adrenal (HPA) axis and release of the stress hormone cortisol; and
(b) increased activation of the sympathetic nervous system (SNS) and release of
catecholamines (e.g., norepinephrine) and associated biomarkers (e.g., alpha-amylase) into
the blood stream and oral fluids (Chrousos & Gold, 1992; Nater & Rohleder, 2009). Cortisol
levels and SNS activity vary diurnally, and according to the severity and duration of internal
and external stressors (e.g., de Weerth & Buitelaar, 2005; Flinn & England, 2003; Flinn,
Quinlan, Turner, Decker, & England, 1996; Miller, Chen, & Zhou, 2007). Repeated and
chronic stress exposure—for example, living under low-resource conditions—is instead
associated with low or blunted HPA activity (e.g., low cortisol levels or flat-shallow diurnal
pattern of cortisol production [e.g., Burke, Fernald, Gertler, & Adler, 2005; Flinn et al., 1996;
Miller et al., 2007]). This blunting of the response may reflect habituation or adaptation to
circumstances that are out of the individuals‘ ability to control, and an overall dampening of
HPA reactivity (e.g., Burke, et al., 2005; Flinn et al, 1996; Miller et al, 2007). Repeated
activation of HPA and SNS has been linked to physical health consequences, such as lower
immune functioning, increased susceptibility to viral infection, higher morbidity, and actual
onset of certain diseases (e.g., pulmonary constriction; Cohen et al.,, Frank, Doyle, Skoner, &
Rabin et al., 1998; Flinn & England, 2003; Kunz-Ebrecht, Mohamed-Ali, Feldman,
Kirschbaum, & Steptoe, 2003; Misra et al., 2004, Miller, Almazan, Ramaswamy, &
Lapcharoensap et al., 2004; Rotton & Dubitsky, 2002; Segerstrom & Miller, 2004; Uchino,
Cacioppo, & Kiecolt-Glaser, 1996).
STRESS REACTIONS IN CHILDREN

Some research suggests that exposure to natural disasters may be particularly stressful for
youth, due to losses in social resources (e.g., dispersion of friends and family) and to changes
Biopsychosocial Correlates of Cortisol Activity in Children ... 75
and uncertainty in the home environment (e.g., Aptekar & Boore, 1990; Freedy, Shaw, Jarrell,
& Masters, 1992; Lonigan, Shannon, Taylor, Finch, & Sallee, 1994). Children who
experience social and material losses evidence similar levels of PTSD symptoms and cortisol
activity as do children who experience more violent forms of trauma (e.g., abuse, witnessing
violence; Taylor, Weems, Costa, & Carrion, 2009). Thus, loss should be regarded as a
traumatic and stressful event for children, in and of itself, in addition to other circumstances
(e.g., uncertainty, fear of death) that contribute to the impact of natural disasters on children‘s
psychophysiological functioning (Taylor et al., 2009).
Repeated activation of the HPA and SNS in children is associated with impulsivity
(Spinrad et al., 2009, Eisenberg, Granger, Sallquist, Kupfer, Hofer, et al., 2009), aggression
(Gordis et al., 2006), insecure attachment (Hill-Soderlund, et al., 2008Mills-Koonce, Propper,
Calkins, & Grangeret al., 2008), general maladjustment (El-Sheikh, Erath, Buckhalt, Granger,
& Mize, 2008), unhealthy sleeping patterns (El-Sheikh, Buckhalt, Keller, & Granger, 2008),
and asthma (Wolf, Nicholls, & Chen, 2008). Other research shows that poor sleep quality is
also associated with blunted stress reactivity in children and adolescents (Capaldi,
Handwerger, Richardson, & Stroud, 2005).
Children may suffer permanent alterations in some aspects of stress regulation that
manifest in adulthood, such as atypical HPA activity and mood behaviors, though these
phenomena are not fully understood (Meaney, 2001; Vigil et al., 2009). Prospective
assessments reveal that HPA and SNS activity are predictive of prolonged (i.e., over two
years) psychological difficulties, such as externalizing symptoms in children (Keller & El-
Sheikh, 2008). Children‘s levels of cortisol are also predictive of future behavioral problems.
In one study of children at a summer camp, withdrawal behaviors were associated with higher
afternoon cortisol levels one year later, whereas more aggressive behaviors were associated
with lower morning cortisol levels one year later (Alink, Cicchetti, Kim, & Rogosch, 2011).
In another study among preschoolers, Gunnar and colleagues showed that inhibition is
associated with internalizing behaviors only in children with comparatively higher cortisol
levels; children with lower cortisol levels did not show this effect (Gunnar, Kryzer, Ryzin, &
Phillips, 2011), potentially reflecting an overall blunting of the affective system that may
correspond with repeated stress exposure.
As in adults, HPA and SNS biomarkers in children appear to interact in their association
with psychological and social functioning. In one study among toddlers, cortisol was more
predictive of low mood and withdrawal behaviors, whereas salivary alpha-amylase (sAA) was
more predictive of positive affect and approach behaviors (Fortunato, Dribin, Granger, &
Buss, 2008). These studies add to an emerging body of research that shows that sAA and
cortisol provide unique information in the prediction of individual differences in behavioral
adjustment of children to stress (e.g., El-Sheikh, Erath, et al., 2008; Gordis, Granger, Susman,
& Trickett, 2008; Nater et al., 2006La Marca, Florin, Moses, Langhans, Koller, et al., 2006;
Stroud, Salovey, & Epel, 2009). For example, El-Sheikh and colleagues recently showed that
higher basal cortisol levels were positively associated with higher internalizing and
externalizing problems among children with higher SNS activity, as measured by sAA (a
marker of SNS activity; Granger, Kivlighan, El-Sheikh, Gordis, & Stroud, 2007; Rohleder,
Nater, Wolf, Ehlert, & Kirschbaum, 2004) and skin conductance (El-Sheikh, Erath, et al.,
2008). Other researchers have observed that adolescents with low levels of both cortisol and
sAA activity exhibit the highest levels of aggression (Gordis et al., 2006).
DEVELOPMENTAL FACTORS
Children show age-related variation in psychophysiological stress reactions, which may
be attributable to developmental changes in major components of stress regulation such as
comprehensive and coping skills (Eth & Pynoos, 1985; Dogan-Ates, 2010). However, these
results are mixed: some research has found that disaster-exposed children younger than 8
years old were less distressed than children between the ages of 8 and 15 (Green et al., Korol,
Grace, Vary, Leonard, Gleser et al., 1991), while other research has found that children aged
9 to 12 were more distressed than children aged 13 to 16 (Lonigan et al., 1994; Shannon,
Lonigan, Finch, & Taylor, 1994). Unfortunately, due to the cross-sectional nature of these
studies, the corollary role of pubertal maturation on psychological functioning could not be
examined.
Despite these mixed results, it is generally established that younger and older children
experience related forms of distress as a result of exposure to disaster trauma. For example,
while preschool-age children typically suffer less post-disaster psychological distress than do
school-age children and adolescents, the younger children exhibit more dependency and
separation disturbances, behavioral problems, fears (general and trauma-specific), regressive
behaviors (e.g., thumb sucking), and reenactments of disaster in their play (Dogan-Ates,
2010). Interestingly, some research has shown that young children often anthropomorphize
their disaster event by personifying it as a bad person (e.g., Saylor, Swenson, & Powell,
1992), suggesting that at certain stages of development, children make obscure distinctions
between interpersonal and non-interpersonal forms of trauma. As described by Dogan-Ates
(2010), compared to younger children, pre-adolescents demonstrate a greater understanding
of disastrous events and their implications and tend to be more irritable and emotional, and to
demonstrate more performance problems in school following the disaster (e.g., attention and
attendance problems). Adolescents are also more likely to experience disruptions in
established social networks and material losses, which may result in adolescents experiencing
more trauma-specific and adult-like symptoms fromor the disaster such as hyperarousal and
avoidance behaviors, whereas younger children tend to express more general distress
symptoms (Dogan-Ates, 2010; Sugar, 1999).
SOCIAL FACTORS
Children‘s mental and physical (e.g., HPA) responses to traumatic experiences are also
influenced by genetic factors (Ouellet-Morin et al., Boivin, Lupien, Arsenault, & Barr, et al.
et al., 2008), as well as by the availability and extent of available emotional support and
family characteristics such as socioeconomic status (e.g., Uchino et al., 1996; Vernberg, La
Greca, Silverman, & Prinstein, 1996; Wickrama & Kaspar, 2007). Maternal cortisol reactivity
is associated with both pre- and post-natal cortisol levels of children, and it may play a
corollary role in fetal development, for instance affecting placental structure and fetal
hormones (Cheng & Pickler, 2010; Jensen, Wood, & Keller-Wood, 2002). In their research,
Cheng and Pickler (2010) found that perceived stress was negatively correlated with waking
cortisol levels in pregnant and postpartum mothers, which is consistent with the hypothesis
that chronic stress exposure may result in habituated or blunted cortisol reactivity.
Other studies have highlighted maternal depression as a potential predictor of children‘s

HPA regulation; however, the exact nature of this relation remains elusive. Some studies
found that maternal depression was related to higher cortisol levels in children (e.g., Lupien,
King, Meaney, & McEwen, 2000), but others suggested it was related to lower levels
(Fernald, Burke, & Gunnar, 2008). The latter findings were from low-income families and
thus they may confound maternal depression with broader socioeconomic factors. The
combination of maternal and economic factors in these families likely places children at risk
for repeated stress exposure that may in turn result in blunted HPA reactivity as found in
adults. Melancholic depression appears to be unique predictor of hypercortisolemia (Kupfer,
1991), and some research has found that mothers with melancholic depression are more likely
to have children with higher morning cortisol levels and lower positive emotions (Dougherty,
Klein, Olino, Dyson, & Rose, 2009). This same research showed that mothers with non-
melancholic depression were at no greater risk of having children with high morning cortisol
levels as compared to control mothers. It is important to note that these studies were
examining women with lifetime depression, and not people who recently experienced an
acute traumatic event, such as a natural disaster.
SEX DIFFERENCES
Differences in cortisol and stress reactivity between males and females are pervasive. In
laboratory settings, males produce greater HPA and SNS activity in anticipation of and
immediately following stressful stimuli, especially those involving social evaluation, as
compared to females (Kajantie & Philips, 2006; Kudielka et al., Hellhammer, Hellhammer,
Wolf, & Pirke et al. 1998; Uhart, Chong, Oswald, Lin, & Wand, 2006). This research
suggests that females may be more psychophysiologically sensitive to produce stress
responses as a result of (perceived risk of) social exclusion, whereas males may be more
sensitive to respond to social competitive situations (Salvador, 2005; Stroud et al., 2002).
Other research has found that the cortisol spikes that immediately follow a traumatic
experience (e.g., measurements taken at hospital admission centers) are more predictive of
boys‘ rather than girls‘ subsequent risk for developing PTSD (Delahanty, Nugent,
Christopher, & Walsh, 2005). Thus, males may be at greater risk for adjustment problems
following traumatic events that diminish the individual‘s relative social standing (Flinn, 2006;
Sapolsky, 2004), for instance, through significant material losses.
CASE STUDY: HURRICANE KATRINA

Hurricane Katrina struck the North-Central Gulf Coast (mostly Louisiana and
Mississippi, USA) on August 29, 2005. Structural devastation and displacement were
widespread; however, the region most heavily affected by the hurricane was New Orleans,
due in part to breaches in the levees that protected the city from surrounding nearby Lake
Pontchartrain (Travis, 2005). In addition to the direct loss of life, injury, and structural
devastation, hundreds of thousands of people were displaced to government and community
shelters across multiple locations throughout the United States. In the following section, we
describe findings from our research investigating biopsychosocial correlates of exposure to

Hurricane Katrina among displaced children and adolescents, and thus among some of the
most severely affected victims of this disaster.
The site chosen for data collection was located near Baton Rouge, Louisiana and was the
largest of the government-funded, semi-permanent relocation camps. Referred to by its
residents and the local community as ―Renai ssance Village,‖ the camp consisted of
approximately 500 travel trailers. Supplies, such as clothing, were dispersed from a central
tent and barracks area, which served as the local post office and cafeteria; the site also
included a basketball court and several small laundry houses. Each of the 500 trailers housed
an average of three people (not including infants and young children). At the time of data
collection the mood was generally observed to be low, despite frequent efforts, such as
seasonal festivities, taken to provide the residents with comfortable living conditions. such as
seasonal festivities. Data were collected between October 28, 2005 and November 2, 2005,
approximately two months after the hurricane and three weeks after the relocation camp
opened.
Researchers solicited participation from the Katrina victims by introducing themselves
(door-to-door) and targeting families living in the trailer units with children. Parents were
then asked if they wanted to participate in the study: ― Child and Family Wellness after a
Major Natural Disaster;‖ approximately sixty-five percent of families agreed to participate.
Upon debriefing, the participants were given a small monetary payment. All the camp
residents reported having been relocated from the New Orleans region. The Katrina victims
were compared to demographically (i.e. SES and ethnicity) matched controls. The control
sample consisted of families who were recruited from residential neighborhoods in mid-
Missouri, USA and selected based on characteristics (e.g., age, race, SES) matching the
Katrina participants, from August, 2006 through January, 2007.
Preliminary analyses showed that mothers in the Katrina and control groups had similar
demographic and socio-economic backgrounds: both groups were primarily African
American (both groups > 93%) and the mothers did not differ (ps > .10) for years of
education (average between 11 and 12 years), history of government assistance (e.g., welfare,
food stamps; > 67%), or for indicators of wealth. The average yearly income of both samples
was between $4,000 and $6,000, with current (post-hurricane) financial assets of less than
$200. The child and adolescent participants from the Katrina and control groups were also
similar (ps > .05) in age and proportion by sex (Vigil & Geary, 2008; Vigil et al., 2009, 2010;
Vigil & Brophy, in press).
Psychophysical Reactions
Consistent with research on children exposed to Hurricane Andrew (Vernberg et al.,

1996), adolescents displaced by Hurricane Katrina (12-19 years) reported lower self-esteem,
more internalizing behaviors, and greater symptoms of distress than the demographically
similar group of non-affected adolescents (Vigil & Geary, 2008; Vigil et al., 2010). The
average anxiety and depressive scores of the Katrina adolescents exceeded clinical cut-off
levels (Brooks & Kutcher, 2001, p. 365; Stallard, Velleman, Langsford, & Baldwin, 2001, p.
200). Katrina adolescents also showed moderately lower cortisol levels and slightly higher
sAA activity compared to matched controls; however, these differences were more
pronounced among females (Vigil et al., 2010).
These findings are consistent with the previously mentioned research showing that
chronic stress exposure is associated with blunted cortisol activity, potentially reflecting a
general habituation or desensitization to this stress exposure (Flinn et al., 1996; Miller et al.,
2007). Higher sAA activity is indicative of more acute stress reactivity that may be due to
daily stressors such as the lack of security in the displacement camp (Vigil et al., 2010).
Moreover, we found support for the hypothesis that sAA moderates the relation between
cortisol and internalizing behaviors. That is, lower cortisol was associated with lower self-
esteem, but only among adolescents with above-average sAA reactivity. This finding
complements recent laboratory studies (e.g., Fortunato et al., 2008), and suggests that
individual differences in HPA axis activity and psychological functioning may be associated
with differential sensitivity or functioning of the SNS.
Maternal Factors
In younger children displaced by Hurricane Katrina (6–10 years), no differences were

found for behavioral distress relative to control children, but there were substantive (> 1 SD)
differences in sAA and cortisol levels (Vigil et al., 2009). Specifically, Katrina children
showed higher sAA and lower cortisol levels, suggesting higher SNS reactivity and blunted
HPA reactivity in the displaced children. The pattern for these children is consistent with
studies of adolescents and adults who have been exposed to acute and chronic stressors, and
suggest that under extreme conditions, children may respond to psychosocial stressors with
similar neuro-endocrine regulation patterns to adults.
The mothers of these children reported poorer psychological well-being than control
mothers, including increased symptoms of depression and distress and higher sAA levels. The
Katrina mothers also reported lower anxiety than the control mothers, which is consistent
with the hypothesis that prolonged or recurrent stress exposure is associated with deactivation
(e.g., habituation) of certain elements of stress processing. Maternal symptoms of low mood
(e.g., low self-esteem) were positively associated with their children‘s cortisol activity. The
findings are therefore consistent with previous studies showing that maternal depression is
associated with blunted HPA activity in children of families living under low-resource
conditions (e.g., Fernald et al., 2008).
As suggested elsewhere (Vigil et al., 2009), the relationship between children‘s and
mothers‘ cortisol and emotional factors could be due to a number of influences such as: (a)
similar mechanisms for, and patterns of, regulating stress exposure and shared experiences
(e.g., hurricane exposure, financial hardship, and access to social support) in children and
adults; (b) hereditary factors that result in dyadic similarities in stress regulation; (c) basic
learning (e.g., via social modeling, operant/classical conditioning) of stress behaviors and
adrenocortical rhythms in children and their mothers; and (d) more direct causality between
maternal psychological functioning (e.g., low mood) and children‘s stress reactivity (e.g.,
Hibel, Granger, Blair, Cox, & The Family Life Project Key Investigators, 2009).
.
Sex Differences
Consistent with research among non-traumatized adolescents (e.g., Ge et al.,, Kim,

Brody, Conger, & Simons et al., 2003; Rushton, Forcier, & Schectman, 2002; see also Vigil,
2008), the female adolescents in our studies reported higher symptoms of depression than did
the male adolescents (Vigil et al., 2010). The pattern is consistent with a socio-relational
perspective of distress behaviors, and with the evolutionary hypothesis that people in general,
and especially females, may respond to negative life events with behaviors that exaggerate the
displays of vulnerability and trustworthiness to other people (Vigil, 2009). From this
perspective, certain types of behavioral distress such as worrying, crying, or feelings of
hopelessness may be functional for consolidating one‘s social network and for evoking
increased emotional support from intimate confidantes such as family members and close
friendships in times of greatest need (Vigil, 2009; see also Hagen, 2003).
Trait aAggression for the Katrina adolescent males was in the normative range but
substantially lower than that reported by the control males, or by females of either the Katrina
or the control group (Vigil et al., 2010). Although counterintuitive, this finding was predicted
based on higher normative (no- trauma) levels of aggressive behaviors in males in
stressfuldifficult circumstances, and based on the hypothesis that people respond to chronic,
non-interpersonal stressors (such as those experienced after the Katrina displacement) with
decreased dominance and increased submissive behaviors (Allen & Badcock, 2003; Fournier,
Moskowitz, & Zuroff, 2002; Sloman & Gilbert, 2000; Vigil, 2009). Similar patterns are found
in non-human male primates under chronic stress and following loss of status (Sapolsky,
2004, 2005). From a socio-relational perspective, aggressive behaviors may be a form of
social behavior that is more adaptive for males than females under normal conditions, but that
are associated with added costs when males experience events that decrease their social status
or their ability to protect themselves (Vigil, 2009).
Biological Ssex also moderated the relation between sAA and symptoms of depression,
such that higher sAA levels among the youth in both the Katrina and the control groups
wereas related to lower symptoms of depression (e.g., greater confidence and reported
elation) in males. This is consistent with a recent study that showed that sAA is associated
with positive affect and overall approach behaviors (Fortunato et al., 2008). However,
females in this sample with higher sAA exhibited slighltly higher depressive symptoms,
which is again supportive of research indicating normative sex differences in behavioral
reactivity that indicates differential responding to mild stressors with more externalizing in
males versusand with more internalizing behuaviors in females (Vigil, 2008).
Sex also moderated the relation between sAA and symptoms of depression, such that
higher sAA among the youth in both the Katrina and the control group was related to lower
symptoms of depression (e.g., greater confidence and reported elation) in males and to
slightly higher depressive symptoms among females. These findings are consistent with a
recent study that showed that sAA is distinctly associated with positive affect and overall
approach behaviors (Fortunato et al., 2008). These results are also supportive of research
indicating normative sex differences in behavioral reactivity that indicates differential
responding to mild stressors with more externalizing versus internalizing behaviors; Vigil,
2008).
Other Social Factors
Compared to the controls, the Katrina adolescents also reported lower externalizing
behaviors, greater desires for social comfort, and higher levels of trustworthiness perceptions
of other people (Vigil & Brophy, in press). That is, they exhibited a pattern of social
processing and externalizing behaviors that is opposite to the pattern of response exhibited by
victims of interpersonal assault, who instead show increased sensitivities to detect threat (e.g.,
in facial stimuli), decreased perceptions of the trustworthiness of other people, and increased
behavioral biases to display aggression toward others (e.g., Bennell, Alison, Stein, Alison, &
Canter, 2001; Connor, Steingard, Cunningham, Enderson & Melloni, 2004; Masten et al.,
2008; Guyer, Hodgdon, McClure, & Charney, et al., 2008; Pollak & Sinha, 2000; Vigil,
Brophy, Garrett, McMurry, & Garrett, & Dukes, 2011).
The data collected from adolescents also lent preliminary support for the suggestion that
trustworthiness perceptions may partially mediate the influence of the hurricane and
relocation experiences on psychological functioning, corroborating similar research on adults
(Vigil et al., 2011). For both the Katrina and control samples, adolescents with higher
perceptions of the trustworthiness of others reported lower self-esteem (Vigil & Brophy, in
press). These findings support the socio-relational hypothesis that humans are sensitive to
adjust the expression of distress behaviors in coordination with the risks and opportunities of
trusting other people, and in ways that may ultimately induce social affiliation or avoidance
from others (Vigil, 2009). Internalizing behaviors may be effective at consolidating one‘s
immediate social network, whereas externalizing behaviors may be more effective at averting
interactions with other people (Vigil, 2008; Vigil & Coulombe, 2011). Situational stressors,
unlike the trauma associated with assault, do not depreciate the perception of trustworthiness
of others, which may result in an overall shift from an externalizing to an internalizing
behavioral strategy, or in other words, from a dominant to a submissive behavioral strategy.
In this sense, internalizing behaviors in humans may have evolved, in part, to remedy the
deleterious consequences—such as social and material losses—of, such as social and material
losses, of situational forms of trauma such as natural disasters (Vigil, 2009).
IMPLICATIONS FOR FUTURE RESEARCH

The research discussed herein has clear and distinct implications for understanding and
treating traumatized children and adolescents who have been exposed to natural disasters. Our
observations of Hurricane Katrina victims suggest that children and adolescents may respond
to severe and repeated (situational) trauma with increased tendencies to demonstrate
submissive behavioral strategies (i.e., internalizing behaviors) and deactivation (e.g.,
habituation) of certain elements of physiological stress reactivity (e.g., Flinn et al., 1996;
Miller et al., 2007). Further, the established severity of the trauma (e.g., homelessness) that
was experienced by the hurricane survivors supports the possibility of eventual use of
practical, noninvasive salivary cortisol and sAA measurements to assess posttraumatic HPA
and SNS functioning (Vigil et al., 2009). Inclusion of information about the coordination
between HPA and SNS activity as well as the interaction of these systems between mothers
and children may be particularly important for biosocial models of risk and resilience in
young victims of natural disasters. Further investigations should focus on how early
childhood trauma affects ontological processes and discrete learning mechanisms (e.g., social
modeling, shared experiences) that contribute to intergenerational synchrony of stress
regulation in children and their parents. In addition, based on the current findings, treatment
programs that focus on strengthening the trustworthiness of adolescents‘ social networks (or
their perceptions thereof) may be particularly effective for healing remedying the deleterious
consequences ofprototypical disaster-related experiencesdistress reactions. Although this
suggestion is not entirely novel (e.g., see Wu, Chen, Weng & Wu, 2009; also see Amaya-
Jackson et al., 2009; Reynolds et al. xxxx, Murray, McCarthy, & Nelson et al.; Berger &
Geklopf, 2009 for the related efficacy of school-based treatments), few researchers
specifically recommend treatments that address social processing; and those who do, do not
usually emphasize that aspect.
CONCLUSION
For decades, the positive association between social support and general psychological
well-being has been investigated (e.g., Turner, 1981). Generally, high levels of social
capital—such as perceptions of attachment, sense of community, and received communal
support—predict lower levels of disaster-related problems and stronger community recovery
after a disaster (e.g., see Beaudoin, 2007; Doerfel, Lai & Chewning, 2010; Norris, Stevens,
Pfefferbaum, Wyche & Pfefferbaum, 2008). From an evolutionary perspective, normative
patterns of behavioral distress, such as sadness and worrying behaviors, have been described
as functional for soliciting increased remedial and social provisioning from others (e.g., Allen
& Badcock, 2003; Fournier et al., 2002; Keller & Nesse, 2005; Sloman & Gilbert, 2000).
From a socio-relational perspective, increased internalizing behaviors and decreased
externalizing behaviors, as as were found among the children in our study, evolved in part as
expressive behaviors that are specialized and functional for eliciting affiliation from intimate
confidantes (Vigil, 2009). From this perspective, distress behaviors may operate in part to
strengthen the reliability of one‘s intimate relationships, in order to gain the support needed
during adverse or traumatic life experiences (see also Hagen, 2003). Behavioral distress may
be expressed differently depending on the type of trauma experienced and in accordance with
individuals‘ current perception of the overall trustworthiness of the people within their
immediate social environment. Other factors, such as sex and age of the children and
characteristics of their caregivers, may also be associated with psychobiological stress
responses (e.g., Swain, 2009; Vigil, 2009). The potential confluence of learning mechanisms
and heredity makes it difficult to determine when children may begin to regulate psychosocial
stressors in a manner that is similar to adults. Further research is needed to accurately model
biological and psychological consequences of exposure to natural disasters during childhood
and adolescence.
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perspective study on earthquake-impacted adolescents in taiwan. Journal of Traumatic
Stress, 22, 451-459.
In: Cortisol ISBN: 978-1-61942-458-6
Chapter 5
CORTISOL-CORTISONE SHUTTLE:
A FUNCTIONAL INDICATOR OF
11Β-HSD ACTIVITY
Julie A. Ray1 and A. Wayne Meikle1,2,3

1
ARUP Institute for Clinical and Experimental Pathology,
Salt Lake City, UT, US
2
Department of Pathology, University of Utah, Salt Lake City, UT, US
3
Department of Medicine, University of Utah, Salt Lake City, UT, US
ABSTRACT
Levels of cortisol obey a strict circadian rhythm where they are highest in the
morning hours, declining during the day and lowest at 3-5 hours after the onset of sleep.
Temporary alteration of this rhythm is observed under unusual conditions such as a
person working on irregular shifts or suffering from jet lag. However complete loss of
this episodic secretion is observed when problems with the Hypothalamic-Pituitary-
Adrenal (HPA) axis are suspected such as those of Cushing‘s syndrome or Adrenal
tumors producing cortisol. Chronically high levels of glucocorticoids such as cortisol are
known to be associated with hypertension, immunosuppression, osteoporosis and
depression. Cortisone is one of the several end products of enzyme mediated
steroidogenesis that begins with cholesterol. Cortisol is converted to non active cortisone
by the unidirectional action of the 11-beta hydroxy steroid dehydrogenase type 2 (11β-
HSD type 2) enzyme, which is highly expressed in the kidney, colon, salivary glands and
fetal tissues. This enzyme helps in maintaining normal levels of cortisol in the body by
protecting the non selective mineralocorticoid receptor (MR) from glucocorticoid excess.
Conversely, 11β-HSD type 1 enzyme which is highly expressed in the key metabolic
tissues such as the liver, adipose tissue and central nervous system, controls the
oxoreductase conversion of inactive cortisone to cortisol and vice versa. Inactivation of
11-βHSD type 1 or 2 enzymes leads to elevated levels of cortisol which activates the MR
promoting mineralocorticoid excess conditions thereby elevating levels of sodium and
water. These conditions are exhibited as hypertension in the form of apparent
mineralocorticoid excess syndrome (AME). Evaluation of cortisol to cortisone ratios
(CCR) provides us with information about the HPA axis as well as the effective balance
92 Julie A. Ray and A. Wayne Meikle
of the 11β-HSD type 1 and 2 enzymatic activities. Even though the major site for the
oxidation of cortisol to cortisone is the kidney, CCR values obtained from serum/plasma
or saliva or urine are indicative of the tissue specific availability and activity of 11β-HSD
type 1 and 2 enzymes. Precise measurement of CCR aids in understanding the cortisol-
cortisone shuttle in preterm infants, clinical outcomes of in vitro fertilization, chronic
fatigue syndrome, depressive illnesses and men with fatty liver apart from patients with
Cushing‘s syndrome. Reduced metabolites of cortisol and cortisone (5α and β
tetrahydrocortisol, allo-tetrahydrocortisol and tetrahydrocortisone) are also used to assess
diseases based on their ratios. This commentary focuses on significant predictions that
have been made for physiological disorders by accurate measurement of CCRs.
INTRODUCTION
Cortisol, an important hormone secreted by the adrenal cortex, is involved in most
dynamic functions of the body starting with glucose metabolism [1] to immune response [2],
insulin regulation and heightened memory functions [3]. Secretion of cortisol is primarily
controlled by adrenocorticotrophic hormone (ACTH), an important peptide of the pituitary
gland. Under conditions of stress, the corticotrophin releasing hormone (CRH) discharged
from the hypothalamus directs the anterior pituitary gland to secrete ACTH. ACTH in turn
directs the adrenal cortex to secrete cortisol. In a negative feedback mechanism, once an
adequate quantity of cortisol has been produced, it affects any further release of CRH and
ACTH from the hypothalamus and pituitary respectively (Figure 1). Cortisol activates glucose
and fat metabolism to provide the body with quick energy during stress and helps in restoring
homeostasis after the stress causing factor is removed.
Levels of cortisol obey a strict circadian rhythm where they are highest in the morning
hours, declining during the day and lowest at 3-5 hours after the onset of sleep. Alteration in
this tempo is observed under unusual conditions such as a person working on irregular shifts
or suffering from jet lag. However complete loss of this rhythm is observed when problems
with the Hypothalamic-Pituitary-Adrenal (HPA) axis are suspected such as those of

Cushing‘s syndrome, Adrenal hyperplasia [4] or Addison‘s disease [5]. Chronically high
levels of glucocorticoids are also known to be associated with hypertension [6]
immunosuppression, osteoporosis [7] visceral obesity [8] and depression [9, 10].
Cortisone is one of the several end products of enzyme mediated stereogenesis that
begins with cholesterol. Cortisol is converted to less active cortisone by the action of the
enzyme 11-beta hydroxy steroid dehydrogenase type 2 (11β-HSD type 2) which is highly
expressed in the kidney, colon, salivary glands and fetal tissues (Figure 2). This enzyme helps
in maintaining normal levels of cortisol in the body by protecting the non selective
mineralocorticoid receptor (MR) from glucocorticoid excess. Conversely, 11β-HSD type 1
enzyme which is highly expressed in the key metabolic tissues such as the liver, adipose
tissue and central nervous system, controls the oxoreductase conversion of inactive cortisone
to cortisol [11]. While aldosterone, a mineralocorticoid, and cortisol have similar affinity for
MR, the concentrations of circulating glucocorticoids exceed that of mineralocorticoids by
over 100 times. Inactivation or problems with 11β-HSD type 1 or 2 enzymes lead to elevated
levels of cortisol which activates the mineralocorticoid receptors (MR) promoting elevated
levels of sodium and water in the blood. These conditions are exhibited as hypertension in the
form of apparent mineralocorticoid syndrome (AME) [12]. Hypertension due to licorice abuse
Cortisol-Cortisone Shuttle 93
[13] or use of carbenoxolone, a synthetic derivative of glycyrrhizic acid used to treat

gastroesophageal reflux disease [14] is also caused by blocked 11β-HSD activity [15].
Uncontrolled secretion of ACTH by a pituitary, adrenal or ectopic cortisol secreting
tumor can also elevate cortisol concentrations just as chronic pharmacological doses of
glucocorticoids.
Evaluation of Cortisol to Cortisone ratios (CCR) or the ratios of their metabolites
provides us with information about the HPA axis as well as the effective balance of the 11β-
HSD type 1 and 2 enzymatic activities. Even though the major site for the oxidation of
cortisol to cortisone is the kidney, CCR values obtained from serum/plasma or saliva are
individually indicative of the tissue specific availability and activity of 11β-HSD type 1 and 2
enzymes. Reduced metabolites of cortisol and cortisone (5α and β tetrahydro cortisol, allo-
tetrahydrocortisol and tetrahydrocortisone) are also used to assess diseases based on CCRs
[16, 17]. This commentary brings to light several significant diagnoses and predictions that
have been made for physiological disorders or conditions by accurately measuring CCRs.
Both cortisol and cortisone are measured with high sensitivity and specificity by
radioimmunoassay (RIA), gas chromatography mass spectrometry (GC-MS) and liquid
chromatography-tandem mass spectrometry (LC- MS/MS) techniques.
Figure 1. Cortisol feedback loop.
Figure 2. 11β-HSD isoforms catalyzing interconversion of cortisol to cortisone. Type 1: in vivo,

generating cortisol from inactive cortisone. Type 2: exclusively generating cortisone from cortisol.
1. CCR IN GLUCOCORTICOID THERAPY

Glucocorticoids are steroid hormones, those when administered at pharmacological doses
suppress an aggravated immune system and also reduce inflammation. They interact with the
glucocorticoid receptors at the nuclear level through trans-activation (up regulation of anti
inflammatory proteins) or trans-repression (down regulation of pro-inflammatory proteins).
Based on the severity of the disease condition and the effected organ, several approaches of
glucocorticoid therapies are employed. The benefits of this therapy are very often offset by
side effects such as hypertension, arthritis [18], musculoskeletal effects [19] and seizures [20-
22].
Urinary cortisol to cortisone metabolite ratios have been measured to evaluate the
incremental risk of hypertension after glucocorticoid therapy. Prednisone, a common oral
corticosteroid is metabolized in the liver to its active component prednisolone. It is roughly 4
times more potent than cortisone. Both prednisone and prednisolone impede the activity of
11β-HSD type 2 enzyme by lowering the conversion of cortisol to cortisone. 100
normotensive patients that underwent glucocorticoid therapy (7-8 mg/day of oral prednisone)
were compared for their ratio of tetrahydrocortisol (THF) and tetrahydrocortisone (THE) with
101 essential hypertensive (EH) participants and 141 EH Hypertensive participants. Results
indicated that one third of the patients on prednisone therapy had elevated THF/TFE (>1.5)
which was similar to 3% and 14% of EH and EH Hypertensive participants. This ratio was
established to be associated with almost 4 fold risk of hypertension after glucocorticoid
therapy. The results were regardless of the duration and dosage of prednisone thus presenting
a challenge for the pharmacological role of 11β-HSD type 2 enzyme [23].
12 adults with Cushing‘s syndrome, 12 adults with hypercortisolism and 20 healthy adult
controls were tested for plasma cortisol and cortisone concentrations before and after ACTH
test using RIA. CCR was found to be significantly higher in patients with Cushing's disease
(13.9 ± 1.1), adrenal cortisol secreting tumors (11.5 ± 2.3), and in healthy volunteers after
ACTH stimulation (14.1 ± 2.0) than untreated controls (6.0 ± 0.5) (P < 0.001, P < 0.05, and P
< 0.001, respectively). While cortisone concentrations did not differ among the groups, a
similar trend in difference was observed for active cortisol plasma concentrations. Results
collected by RIA after automated Sephadex LH 20 chromatography suggest that the excessive
mineralocorticoid effects in patients with high cortisol (possibly due to inadequate conversion
of cortisol to cortisone by 11β-HSD type 2) are caused by elevated CCR [24]. This may
provide a possible explanation for the occurrence of hypertension in such patients.
2. ELEVATED FETAL CCR

In normal adults, plasma cortisol is known to be almost 10 fold that of cortisone [25].
Most fetal tissues contain the 11β-HSD type 2 enzyme that converts cortisol to inactive
cortisone. This is a protective mechanism against elevated fetal cortisol levels. Pregnancy
involves changes in the maternal HPA axis and approximately 10-20% of maternal cortisol is
known to pass on to the fetus [26]. For a growing fetus, moderately high maternal cortisol
concentrations (which could be due to maternal stress) could have harmful effects such as
fetal heart enlargement.
Using quantitative real-time PCR, 11β-HSD type 2 expression has been shown to be
negatively correlated to left ventricular wall thickness in gestational ewes [27]. In instances
where the levels of maternal cortisol are normal, the concentration of cortisone in fetal tissues
is found to be 3 times higher than cortisol due to higher incidence of 11β-HSD type 2 which
converts cortisol to cortisone. Evaluation of CCR could give us indications about the
maintenance of cardiovascular homeostasis and fetal growth.
Interconversion of cortisol-cortisone has also been clarified in human tissues in the fetus,
neonate, child and adult. While cortisol to cortisone conversion increased in the tissues
obtained from placenta > fetal kidney and lung > adult testis and ovary > other fetal tissues,
the reverse conversion from cortisone to cortisol increased as adult liver > membranes > adult
ovary and testis > term uterus. Substantial decrease in both conversions was observed for both
mature and preterm infants. It has been concluded that while growth inhibiting effects of high
fetal cortisol are prevented by a low CCR, production of some cortisol from cortisone in the
membranes and uterine wall maintains the fetal allograft [28].
3. CCR IN ACUTE PHASE RESPONSE

C Reactive Protein (CRP) levels are known to be altered in response to inflammation
[29]. This protein is measured in some forms of arthritis [30], autoimmune [31] and pelvic
inflammatory diseases [32]. Abnormal CRP concentrations are also associated with acute-
phase response [33]. Using LC-MS/MS, a pilot study was carried out to investigate CCR
changes due to altered modulations of the 11β-HSD enzyme isoforms between hospitalized
patients with normal and abnormal CRP concentrations. Results showed that CRP
concentrations significantly correlated with elevated CCR (P <0.001; r=6.5, Spearman
correlation coefficient). The median ratio was 6.4 (interquartile range 5.5-7.4; n=30) in
patients with normal CRP concentrations (≤ 20mg/L) and 11.2 ((interquartile range 8.8-13.9;
n=60) in patients with abnormal CRP (> 20 mg/L) [34]. These results indicate that the normal
balance between cortisol and cortisone is disturbed during acute-phase response with a trend
towards active cortisol. This could be due to altered modulation of 11β-HSD isoenzymes
during acute illness.
Such elevated CCR were also noticed using liquid-chromatography tandem mass
spectrometry in post operative acute-phase response such as in 16 patients undergoing
aortocoronary bypass grafting. Results indicated that preoperatively, morning serum cortisol
concentrations were lower (245 nmol/L (IQR (interquartile range) 198-331)) than the 1st
POD (Post Operative Days), (532 nmol/L (interquartile rangeIQR 409-678)) and 4th POD,
373 nmol/L (interquartile rangeIQR 306-493); showing statistically significant trend for P
=0.019. In contrast, the CCR constantly increased (approximately twofold) on all POD
compared to preoperative sampling: preoperatively, 5.4 (IQR 5.0-7.2); 1st POD, 11.3 (IQR
9.2-13.6); 4th POD, 9.9 (IQR 7.7-11.0), with no significant trend towards normalization (IQR
=Interquartile Range). The increase in active cortisol could be related to an overall shift in
11β-HSD enzyme activity favoring cortisol formation while the high CCR could be related to
long term activation of the HPA axis by surgical stress and systemic inflammation [35].
In another set of experiments, samples of ICU patients were collected from University of
Utah hospital and analyzed for cortisol and cortisone by LC-MS/MS. CCRs from ICU patient
samples were found to be more than two times higher than CCRs from non-ICU patient
samples (Figure 3); the median cortisol: cortisone ratio for ICU patients was 16 as compared
to the median of outpatient samples which was found to be 7. These samples however
exhibited median cortisone concentrations that were in the normal range. Hypercortisolism
accompanied by normal cortisone concentrations could imply inactivity of 11β-HSD type 2
enzyme or tumors producing large amount of ACTH which could elevate cortisol
concentrations [36].
Figure 3. [36] Elevated CCR in samples from ICU in comparison with non ICU samples.
4. CCR IN ACUTE PULMONARY TUBERCULOSIS (PTB)

Endocrine disturbances are frequently observed in tuberculous patients [37]. Dysfunction
of the adrenal glands due to adrenal insufficiency also is manifested by weakness, low blood
pressure and muscular weakness, are common indications of tuberculosis. Adrenal therapy
has been efficacious against phthisis in many cases against phthisis. Although the exact
etiological relationships have not been established, some facts are suggestive.
A possible explanation for immunoparesis observed during progressive pulmonary
tuberculosis has been offered by measurement of CCR. The patient group comprised of 30
patients subjects with PTB (Pulmonary Tuberculosis), 14 with proven previous pulmonary
TB (who had completed treatment between 6 and 23 months before the study), 6 diagnosed
with acute pneumonia and 23 healthy adults with no clinical evidence of tuberculosis.
Activity of the HPA axis was reflected by measurement of cortisol, cortisol, metabolites of
cortisol and cortisone and their ratios through ACTH stimulation, dexamethasone suppression
test (DST) and cortisol releasing hormone (CRH) tests. CCRs obtained from bronchoalveolar
lavage fluid were found to be higher in patients with acute TB when compared with healthy
volunteers (7.73 ± 1.48 vs 4.05± 0.38 (P <0.05) while their plasma CCRs were found to be
similar. Since substantial expression of both 11β-HSD type 1 and 2 exist in the lung [38, 39]
it may point towards an altered intrapulmonary cortisol-cortisone shuttle [40].
5. CCR IN SMALL GESTATIONAL AGE CHILDREN (SGA)

Low birth weight is associated with risk for unusual rate of metabolic and cardiovascular
disorders. Poor equilibrium between cortisol and cortisone affected by alteration of 11β-HSD
enzyme activity are considered to be key mechanisms for these effects [41].
In a study carried out to observe the effect of adrenocortical function on intrauterine
growth (IUGR) using LC-MS/MS, it was found out that while the mean cortisol and cortisone
concentrations and CCR did not differ between SGA and the control group of children
between 0 and 12 years of age, the SGA children in the highest CCR category showed poorer
gain in height as compared to those with lower CCR in the same age group. High CCR has
been implied to be associated with decreased 11β-HSD type 2 activity and hence to IUGR, its
metabolic consequences and poor catch-up growth in a subset of SGA children [42].
6. CCR IN GROWTH HORMONE (GH)

REPLACEMENT THERAPY
Significantly low CCR values in hypo pituitary adults placed on GH replacement therapy
have been reported. The effect of GH on urinary cortisol, cortisonel and cortisol metabolites
has been measured using gas chromatography in hypopituitary patients receiving increasing
doses of cortisol before and during 2 months of GH replacement (0.25/kg/week) using gas
chromatography. Twice daily doses of cortisol (10/10, 20/10 and 40/20mg) each week were
administered to 7 adults (3 men and 4 women, age range 47-64 years) who had ACTH
deficiency and 3 whose ACTH reserves were intact. The urinary tetrahydrocortisol/
tetrahydrocortisone ratio was found to decrease with each dose of cortisol in both groups
(P=0.49; P=0.018; P=0.043). While free urinary cortisol/cortisone ratioCCRs did not show
any change in the group receiving GH therapy, the serum cortisol/cortisone ratiosCCRs fell
significantly at each cortisol dose. Decrease in urinary tetrahydrocortisol/ tetrahydrocortisone
ratio (which is also a measure of 11β-HSD activity) as well as serum cortisol/cortisone
ratioCCR points towards direct or indirect modulation of cortisol metabolism by growth
hormone and also suggests that this modulation occurs at hepatic or an alternative site of 11β-
HSD activity[43].
7. CCR FOR PREDICTING CLINICAL OUTCOME OF IVF-ET

(IN VITRO FERTILIZATION AND EMBRYO TRANSFER)
A significant rise in intrafollicular cortisol concentration occurring prior to ovulation
suggests that this glucocorticoid may have a physiological role in oocyte maturation and
ovulation. Higher CCRs associated with follicular fluids in pregnancy cycles of
gonadotrophin-stimulated IVF women as compared with non-pregnant women suggests the
role of cortisol and 11β-HSD type 1 in embryo implantation and development of the oocyte
[44, 45].
Intraovarian cortisol metabolism is known to be influenced by 11β-HSD activity [46]. It
has been used in the establishment of IVF-FT pregnancies [44]. Intrafollicular cortisol and
cortisone were measured by radioimmunoassay in random samples of ovarian fluid collected
from 23 women undergoing gonadotrophin-stimulated IVF-ET cycles. Concentrations of both
cortisol and cortisone were found to be significantly lower in the follicular fluid of 6 patients
that conceived than 17 that did not achieve pregnancy (P=0.041 for difference in cortisol and
P=0.0002 for difference in cortisone). In addition, intrafollicular CCRs were found to be
significantly higher in samples from conception cycles than those obtained from non
conception cycles (P=0.0060). While only 1 of the 13 patients with intrafollicular CCR <7.7
became pregnant, 5 out of 10 samples with mean intrafollicular CCR higher than 7.7 became
pregnant. Conception of gonadotrophin IVF-ET seems to be associated with low level
intraovarian oxidation of cortisol to cortisone by 11β-HSD type 2 enzyme.
8. CCR IN HUMAN HYPERTENSION

Urinary CCR is known to be elevated in patients with hypertension. This is caused by
prolonged half life of circulating cortisol. The 11β-HSD type 2 enzyme generating gene is
highly expressed in all sodium transporting epithelia. Mutations in this gene cause AME.
Compromised 11β-HSD type 11 BSHD 2 enzyme activity manifests as glucocorticoid excess
and overstimulation of the MR causing hypernatraemia, hypokalemia and salt dependent
hypertension[6, 47].
In a study conducted with two elderly patients with AME significant elevations were
observed in urinary CCRs clearly suggesting a clinical role of measuring CCRs in the
diagnosis of 11β-HSD type 2 impairment [48].
Licorice which has been used for its medicinal purposes for several thousands of years,
induces mineralocorticoid excess state by the action of its active components such as
glycyrrhizic and its hydrolytic product glycyrrhetinic acid by inhibiting the action of 11-
βHSD type 2 enzyme thereby decreasing the conversion of cortisol to cortisone [49]][50].
Elevated levels of urinary metabolites of cortisol and cortisone are also observed due to
licorice abuse.
In a 38 year old woman who was hospitalized, the intake of large amounts of licorice was
found to be the cause for hypertension. The excess cortisol produced in the body caused by
the inactivation of 11β-HSD type 2 enzyme, acts as a mineralocorticoid. This acts as a basis
for decrease in serum potassium levels and thereby an elevation in serum sodium levels
leading to water retention and hypertension [51].
Ectopic ACTH syndrome patients show high CCRs by virtue of saturation in levels of
cortisol rather than impaired 11β-HSD activity. Hypercortisolism arising out of ectopic
ACTH syndrome activates the MR leading to hypertension [52].
9. CCR AND OBESITY

Hypercortisolism (Cushing‘s syndrome) and obesity seem to have a direct relationship
[53]. These elevated levels of cortisol can be systemic or intracellular. The former reports
overall bodily excess of the steroid while the later shows intracellular excesses of cortisol
without affecting the bodily levels. While circulating cortisol levels are reported to be normal
in obese patients, studies show enhanced conversion of cortisone to cortisol through the
expression of 11β-HSD type 1 activity in cultured omental adipose stromal cells indicating a
major function played by cortisol in the pathogenesis of central obesity [54]. Urinary cortisol
measured by GC-MS in six males and six premenopausal females (age 23-44 yrs) in three
categories of BMI (Group A: 20-25 kg/m2m, Group B: 25-30 kg/m2 and Group C: greater
than 30 kg/m2) showed low CCR values for Group C vs Group A: 0.34 +/- 0.03 (C) vs 0.41
+/- 0.03, P < 0.05. These results point towards the primary role of 11β-HSD type 1 in body fat
distribution.
Another interesting hypercortisolism study reports a higher overall reductase activity of
11β-HSD type 1 found in men [55]. Non-obese and obese men and women (BMI> 25kg.m2)
were measured for cortisol conversion to cortisone by recording the amount of cortisone
produced due to a continuous infusion of labeled cortisol (8 am to 6pm). Labeled cortisone
produced by this method reflected the interconversion of cortisol and cortisone due to the
activity of 11β-HSD enzymes. The amount of labeled cortisone generated in men was found
to be higher than in women (P < 0.0001). Also this difference was higher in obese patients
(Pp=0.0062) indicating that this specificity is maintained in obesity.
10. CCR IN DEPRESSED PATIENTS

Major depression is frequently associated with elevated concentrations of cortisol and
ACTH [56-60].
Diurnal concentrations of cortisol and cortisone and CCRs were compared in 25 severely
depressed patients (14 male, 11 female subjects, between the ages of 22-77 yrs) and 30
control patients [61]. Both steroids were measured by RIA and found to be significantly
higher than the controls (cortisol, 251.7 ± 113.1 vs. 160 ± 96.6 nmol/L; cortisone, 32.8 ± 10.9
vs. 21.9 ± 10.9 nmol/L). Although CCRs of patients were found to be similar to the controls
this could suggest increased activity of both 11β-HSD type 1 and 2 during depression.
11. CCR IN CHRONIC RENAL FAILURE (CRF)

11β-HSD type 2 enzyme is known to be active in the kidney and placenta of normal
humans. CRF is usually associated with increased arterial blood pressure due to decreased
activity of this enzyme. A 2000 publication in the Journal of Endocrinological Investigation
showed a patient with AME who was cured after a kidney transplant [62]. Based on this
observation and to further prove the significance of 11β-HSD type 2 enzyme during CRF in
children, a study was conducted to investigate the conversion of cortisol to cortisone after
renal transplantation in children [63]. 15 children with CRF, 17 with steroid-free
immunosuppression after renal transplantations and 18 healthy controls were tested for
plasma CCRs using LC-MS/MS. Results indicated that CCRs of CRF and renal
transplantation children continued to be significantly higher than the controls (5.6 +/- 1.9/0.6,
7.12 +/- 3.1/0.9) vs (1.18 +/- 0.2/0.03, P < 0.0001) groups. This clearly demonstrated that
there was no normalization of CCRs or their metabolites after renal allograft transplantation.
It also suggested that 11β-HSD type 2 activity is not reinstated after renal transplantation.
These findings are in accordance with the direct relationship between CRF and 11β-HSD type
2 in adults [64, 65].
12. CCR AS CLINICAL MARKER FOR DIABETES AND

CARDIOVASCULAR DISEASES (CVD)
Early recognition of diabetes prevents cardiovascular complications such as strokes,
peripheral arterial diseases and possible cardiomyopathy [66]. 3 new markers were evaluated
for their use as possible predictors of diabetes and CVD. Among them determination of CCR
was found be a positive one [67]. Plasma asymmetric dimethylarginine (measured using high-
pressure liquid chromatography and fluorescence), C-peptide (using chemiluminiscent
immunoassay) and CCR (using LC-MS/MS) were analyzed in 850 subjects, namely those
with normal fasting glucose (<110 mg/dL), impaired fasting glucose (110-125 mg/dL) and
diabetic (≥126 mg/dL). Results indicated that among a high coronary risk case-control group
while CCR results (P=0.13) showed moderate association with glycemic categories, CCRs
from quartiles 2 to 4 were protective against incident death/myocardial infarction (adjusted
hazard ratio, 0.48; P < 0.001) evidencing its possible use as a new candidate for dysglycemia
and CVD prediction.
CONCLUSION
11β-HSD type and 2 enzymes play a key role in the regulating the metabolic functions of
the body. The extent of measuring cortisol to cortisone ratio for assessing the activity of the
11β-HSD isoforms is expanding. Apart from the diagnosis of Cushing‘s syndrome, primary
adrenal insufficiency and hypopituitarism, CCR is as an important marker for providing an
explanation for hypercortisolism induced hypertension, depression, predicting clinical
outcomes of IVF, growth hormone therapy and obesity. Elevated or reduced CCRs act as a
direct functional indicator of 11β-HSD activity in the body.
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In: Cortisol ISBN: 978-1-61942-458-6
Chapter 6
CORTISOL AND FATIGUE
Urs M. Nater* and Johanna M. Doerr

Clinical Biopsychology, University of Marburg, Germany
1. ABSTRACT
In better understanding the debilitating nature of fatigue, the hypothalamic–
pituitary–adrenal (HPA) axis has been of primary interest, because hormones of the HPA
axis may contribute to the peripheral and central causes of fatigue. For example,
glucocorticoid deficiency is associated with fatigue and related symptoms, such as
malaise, somnolence, myalgia, and arthralgia. In general, dysregulation in basal HPA axis
function is reflected in changes of diurnal cortisol rhythm. In healthy individuals an
increase after awakening and a steady decrease of cortisol levels throughout the day is
observed. Research has shown that disturbances of this typical time curve may be
associated with negative health outcomes. A recent study found associations between an
attenuation of cortisol concentrations in the morning and fatigue as well as physical
symptoms in a population-based sample of older adults. A growing literature indicates
that flattened diurnal cortisol curves are found in a variety of different conditions, such as
posttraumatic stress disorder (PTSD), depression, chronic stress, and breast cancer. All of
these disorders may present with fatigue. In chronic fatigue syndrome (CFS), a disorder
characterized by severe fatigue that is not medically explained, a number of studies have
examined circadian cortisol rhythms, with findings pointing to lower cortisol decreases
over the day and a flattened slope. Flattened salivary cortisol slopes, as shown in one of
our own studies, might contribute to symptom manifestation. Cortisol exerts inhibitory
effects on the secretion of cytokines, including IL-6, and helps return these cytokines to
baseline levels after stress. Studies have reported elevated cytokine (IL-6 and TNF-alpha)
levels in CFS. However, other authors found decreased IL-6 levels in CFS cases or no
differences in comparison to healthy controls. Also, administration of IL-6 during a
hypocortisolemic state causes symptoms of CFS. Taken together, cortisol seems to play a
substantial role in the manifestation of fatigue, in a variety of conditions. In this chapter,
we will briefly review the current literature on cortisol abnormalities in selected
conditions (such as CFS) and provide a theoretical model of how cortisol alterations may
be associated with fatigue and related symptoms.
* Correspondence should be addressed to Urs M. Nater, PhD, Clinical Biopsychology, University of Marburg,
Gutenbergstrasse 18, 35032 Marburg, Germany; E-mail nater@uni-marburg.de.
108 Urs M. Nater and Johanna M. Doerr
2. INTRODUCTION
In better understanding the debilitating nature of fatigue, the hypothalamic–pituitary–
adrenal (HPA) axis has been of primary interest, because hormones of the HPA axis may
contribute to the peripheral and central causes of fatigue. For example, glucocorticoid
deficiency is associated with fatigue and related symptoms, such as malaise, somnolence,
myalgia, and arthralgia (Clauw & Chrousos, 1997). In general, dysregulation in basal HPA
axis function is reflected in changes of diurnal rhythmicity of the glucocorticoid cortisol. In
healthy individuals an increase after awakening and a steady decrease of cortisol levels
throughout the day is observed (Stone et al., 2001). Research has shown that disturbances of
this typical time curve may be associated with negative health outcomes. A recent study
found associations between an attenuation of cortisol concentrations in the morning and
fatigue as well as physical symptoms in a population-based sample of older adults (Adam,
Hawkley, Kudielka, & Cacioppo, 2006). A growing literature indicates that flattened diurnal
cortisol curves are found in a variety of different conditions, such as posttraumatic stress
disorder (PTSD) (Yehuda, Teicher, Trestman, Levengood, & Siever, 1996), depression
(Deuschle et al., 1997), chronic stress (Miller, Cohen, & Ritchey, 2002), and breast cancer
(Bower et al., 2005; Sephton, Sapolsky, Kraemer, & Spiegel, 2000). All of these disorders
may present with fatigue. In chronic fatigue syndrome (CFS), a disorder characterized by
severe fatigue that is not medically explained, a number of studies have examined circadian
cortisol rhythms, with findings pointing to lower cortisol decreases over the day and a
flattened slope (reviewed in Cleare, 2003; Papadopoulos & Cleare, 2011). Flattened salivary
cortisol slopes, as shown in one of our own studies (Nater, Youngblood, et al., 2008), might
contribute to symptom manifestation. Cortisol exerts inhibitory effects on the secretion of
immune system markers, such as cytokines, and helps return those to baseline levels after
stress (Glaser & Kiecolt-Glaser, 1998). Studies have reported elevated cytokine (e.g.
interleukin-6, IL-6, and tumor necrosis factor-alpha, TNF-alpha) levels in CFS patients
(Patarca-Montero, Antoni, Fletcher, & Klimas, 2001; Patarca, 2001). However, other authors
found decreased IL-6 levels in CFS cases (Ter Wolbeek et al., 2007) or no differences
(Tomoda et al., 2005) in comparison to healthy controls. Also, administration of IL-6 during a
hypocortisolemic state has been shown to result in symptoms typical of CFS (Papanicolaou,
Tsigos, Oldfield, & Chrousos, 1996).
Taken together, cortisol seems to play a substantial role in the manifestation of fatigue in
a variety of conditions. In this chapter, we will briefly review the current literature on cortisol
abnormalities in CFS and provide a theoretical model of how cortisol alterations may be
associated with fatigue and related symptoms.
3. DEFINITION OF FATIGUE
Fatigue is a very common response to physical or mental exertion. The symptom may be
characterized by a feeling of exhaustion, tiredness, weakness, and lack of energy (Schwarz,
Krauss, & Hinz, 2003). In some chronic and severe diseases (such as cancer (e.g. Ashbury,
Findlay, Reynolds, & McKerracher, 1998; Barsevick, Frost, Zwinderman, Hall, & Halyard,
2010; Cella, Davis, Breitbart, & Curt, 2001), multiple sclerosis (Bethoux, 2006, for an
Cortisol and Fatigue 109
overview) or HIV (reviewed in Barroso, 1999)), fatigue is amongst the most impairing
symptoms. In these diseases, fatigue may also occur as a side effect of treatment. It is an
unspecific symptom, thus not allowing for a specific diagnosis but rather an endpoint of
various possible causes. Fatigue may, however, also occur as a medically unexplained
symptom, e.g. in the context of the above mentioned chronic fatigue syndrome.
As fatigue is a subjective condition, its assessment relies on self-report measures (Dittner,
Wessely, & Brown, 2004). There are two types of fatigue measures: unidimensional and
multidimensional scales. Unidimensional scales usually assess fatigue severity (Whitehead,
2009), whereas multidimensional scales rely on the assumptions a) that fatigue has different
qualities which each can be assessed individually and b) that each of those qualities has to be
assessed in order to get a comprehensive picture of the respective fatigue experience. Similar
to pain measurement, fatigue may be described on dimensions like intensity, duration, and
resulting distress (see Belza, Henke, Yelin, Epstein, & Gilliss, 1993). Fatigue intensity is
commonly measured on scales ranging from 0 to 10, with 10 indicating the worst possible
fatigue. Concerning duration, fatigue is labelled ― chronic‖ if it persists longer than 6 months,
otherwise it is referred to as ―s hort-term‖ fatigue. Another approach is to assess fatigue on
dimensions concerning different subjective experiences accompanying fatigue, e.g. lack of
energy, lack of motivation, or limited ability to concentrate. Consequently, a wide array of
measures have been developed and used in both research and clinical practice (Whitehead,
2009). In an attempt to unify various multidimensional approaches Hardy and Studenski
(2010) proposed a model with mental and physical fatigue as the most prominent dimensions.
Mental fatigue encompasses emotional qualities (such as a feeling of emptiness or boredom)
as well as cognitive qualities (such as difficulty concentrating or memory impairment). The
physical component on the other hand comprises qualities such as sleepiness, weakness, and
low energy. In summary, fatigue can be described as a debilitating experience that
encompasses mental as well as physical qualities.
Fatigue is a very common complaint in the general population. Depending on how it was
operationalized, prevalence rates range from 4.9% (for short-term fatigue) (van't Leven,
Zielhuis, van der Meer, Verbeek, & Bleijenberg, 2010) until up to 38% (without taking into
account duration) (Pawlikowska et al., 1994). In primary care patients, prevalence rates of up
to 24% are reported (Kroenke, Wood, Mangelsdorff, Meier, & Powell, 1988). It can be
assumed that prevalence of fatigue increases with increasing age: in older (≥ 65 years)
primary care patients, a prevalence of 70% was reported (Hardy & Studenski, 2010).
Apart from age, further important risk factors of fatigue have been reported to be female
sex (odds ratio of 1.9) and obesity (odds ratio of 4.1) (van't Leven, et al., 2010). In addition, a
number of psychosocial causes for fatigue have been described, such as work, lifestyle
factors, or anxiety and depression (Pawlikowska, et al., 1994).
On one end of a fatigue spectrum, one may place chronic fatigue syndrome (CFS) as the
most extreme form of fatigue manifestation. According to the CDC 1994 criteria CFS is
defined by: 1) clinically unexplained, persistent or relapsing fatigue of at least 6 months‘
duration that is not the result of ongoing exertion, is not substantially alleviated by rest, and
results in substantial reduction in previous levels of occupational, educational, social, or
personal activities, and 2) concurrent occurrence of at least 4 accompanying symptoms
(unusual post-exertional malaise, unrefreshing sleep, significant impairment in
memory/concentration, headache, muscle pain, joint pain, sore throat and tender lymph
nodes) (Fukuda et al., 1994). CFS affects about 0.1-2.5% of the general adult population
(Jason et al., 1999; Reeves et al., 2007) and those suffering the illness are profoundly
functionally impaired (Solomon, Nisenbaum, Reyes, Papanicolaou, & Reeves, 2003). As
there are no validated clinical biomarkers or laboratory abnormalities, CFS must be diagnosed
by self reported symptoms and by ruling-out medical and psychiatric conditions with similar
clinical presentations (Fukuda, et al., 1994). Because the pathophysiology remains inchoate
(Nater, Heim, & Raison, in press; Prins, van der Meer, & Bleijenberg, 2006), current
treatment modalities seek to alleviate symptoms. Various psychosocial and biological factors
are thought to be important in both the etiology and pathophysiology of CFS. Among these
are childhood trauma, coping styles, adult chronic stress, personality, as well as endocrine
markers, which have been associated with typical symptoms of CFS (Nater, Heim, & Reeves,
2010). In the following, we will focus on cortisol as the best examined endocrine marker in
both fatigue and CFS.
4. HYPOTHALAMIC-PITUITARY-ADRENAL AXIS
The hypothalamic-pituitary-adrenal (HPA) axis is a complex physiological system, which
is located in both the central nervous system (CNS) and the periphery of the body. The CNS
part involves brain areas located in the hypothalamus and the brainstem. In particular, it
involves inhibitory and excitatory limbic-sensitive structures. The central control of the HPA
axis is governed by the hypothalamic paraventricular nucleus (PVN). The purpose of these
circuits is to evaluate the importance of a stimulus to survival and to use the resulting
information to elicit an appropriate hormonal response (Herman et al., 2003). The assumed
purpose of these regulatory inputs in the PVN resembles the cognitive appraisal processes
involved in the subjective experience of stress (Gaab, Rohleder, Nater, & Ehlert, 2005). The
peripheral components include outflow from the HPA axis, the efferent sympathetic-
adrenomedullary (SAM) system, and components of the parasympathetic system (Campeau,
Day, Helmreich, Kollack-Walker, & Watson, 1998; Ehlert & Straub, 1998; Huether, 1996;
Pacak & Palkovits, 2001; Stratakis & Chrousos, 1995), with the latter two comprising the
autonomic nervous system (ANS). These systems closely interact with the immune system
(Sternberg, 2006).
A substantial body of research on potential alterations of the HPA axis in CFS has
focused on dysregulation of the secretion of cortisol. Cortisol has been of primary interest,
because this hormone may contribute to the peripheral and central causes of CFS symptoms,
such as pain and fatigue. Cortisol is pleiotropic and exerts its effects through ubiquitously
distributed intracellular receptors. It affects glucose production, fat metabolism, inflammatory
responses, cardiovascular responsiveness, and central nervous system and immune
functioning (Charmandari, Kino, Souvatzoglou, & Chrousos, 2003; de Kloet, 2003). As is
evident from numerous studies, the above mentioned symptoms also reflect alteration of the
immune system via inflammatory cytokines, such as interleukin (IL)-6 or interleukin 1 beta
(IL-1b) (Vollmer-Conna, Lloyd, Hickie, & Wakefield, 1998), which are thought to reflect
disease activity, and are potent stimulators of the endocrine stress axis (Chrousos, 1995). In
turn, the interaction between HPA axis and immune system is mediated by both the
sympathetic and the parasympathetic branches of the ANS.
5. CORTISOL AND FATIGUE

Only few studies have been conducted so far examining associations between cortisol and
fatigue in the general population (that is, not focusing on fatigue in the context of a severe
primary disease or CFS). Poteliakhoff (1981), assessing plasma morning cortisol of primary
care patients, found lower levels in persons who reported being mentally or physically
fatigued for longer than one month compared to healthy controls. Thinking the other way
around, Fibiger, Singer, Miller, Armstrong, and Datar (1984) could show a positive
relationship between mean urinary cortisol levels of healthy male graduate students and their
self-reported alertness. Several following studies assessed salivary cortisol levels and fatigue
levels at multiple time points. Adam et al. (2006) found that low morning cortisol was
associated with more fatigue during the day. Dahlgren, Kecklund, Theorell and Akerstedt
(2009), on the other hand, found high fatigue levels to be associated with low cortisol levels
at awakening the next day. In a longitudinal cross-sectional cohort study, Kumari et al. (2009)
found that low cortisol levels in the morning as well as a flat diurnal cortisol slope were each
associated with high fatigue levels 2.5 years later. However, they found no association
between high fatigue levels at the first time point and cortisol levels 2.5 years later. In
conclusion, current evidence points to an association between high fatigue levels and
attenuated cortisol levels in the morning as well as a flat slope of cortisol secretion throughout
the day. However, data are somewhat inconclusive concerning the direction of this
association. Ultimately, both directions are plausible. On one hand, it can be assumed that
psychosocial stressors lead to high levels of fatigue. In this scenario, a compensating lower
cortisol secretion might follow. On the other hand, it seems possible that e.g. an infection
repelled by the body‘s immune system might lead to lower levels of cortisol. Those, in turn,
may then lead to higher levels of fatigue.
However, there were some studies, which did not find an association between fatigue
levels and cortisol parameters (Burton, Hinton, Neilson, & Beastall, 1996; Ter Wolbeek, van
Doornen, Coffeng, Kavelaars, & Heijnen, 2007; van Zuiden et al., 2009). This might be
explained by methodological issues, e.g. timing of cortisol sampling (not enough time points)
or choice of sample (adolescent girls in the study of Ter Wolbeek, van Doornen, Coffeng et
al. (2007)). Nevertheless, more research is needed to assess influences on the association
between cortisol and fatigue.
Apart from the relationship between cortisol and ―non -pathological‖ fatigue, as
summarized in the previous section, a wealth of information has accumulated on both basal
and challenge outcomes of cortisol regulation in CFS (Cleare, 2003, 2004; Van Den Eede,
Moorkens, Van Houdenhove, Cosyns, & Claes, 2007). In a seminal study by Demitrack and
colleagues, low levels of cortisol in 24-hour urine of CFS patients were found in comparison
to healthy controls (Demitrack et al., 1991). These findings were among the first to suggest
hypoactivity of this axis in CFS. Subsequent studies of basal HPA axis found similar results.
Some studies reported on lower cortisol levels after awakening in comparison to healthy
controls (Jerjes, Cleare, Wessely, Wood, & Taylor, 2005; Nater, Maloney, et al., 2008;
Roberts, Wessely, Chalder, Papadopoulos, & Cleare, 2004; Strickland, Morriss, Wearden, &
Deakin, 1998), which is of particular interest considering the notion that altered awakening
cortisol levels are associated with increased stress levels (Pruessner, Hellhammer, &
Kirschbaum, 1999; Schlotz, Hellhammer, Schulz, & Stone, 2004; Steptoe, Cropley, Griffith,
& Kirschbaum, 2000). Furthermore, a generally reduced diurnal fluctuation of salivary
cortisol in CFS compared to healthy controls was observed (Jerjes, et al., 2005; Nater,
Youngblood, et al., 2008). However, other studies found no difference in salivary cortisol
concentrations between CFS and healthy controls (Gaab et al., 2002; Young et al., 1998).
Insight from pharmacological challenge studies testing specific levels of HPA axis regulation
indicates enhanced feedback sensitivity (Gaab, et al., 2002; Jerjes, Taylor, Wood, & Cleare,
2007; Papadopoulos et al., 2009; Segal, Hindmarsh, & Viner, 2005), increased adrenocortical
sensitivity to adrenocorticotropic hormone (ACTH), and a reduced maximal cortisol response
compared to normal subjects (Demitrack, et al., 1991; Scott, Medbak, & Dinan, 1998), with
non-significant findings being reported also (Gaab et al., 2003; Hudson & Cleare, 1999).
Clearly, findings point toward relative hypocortisolism in CFS. Recent findings from
psychotherapeutic trials have shown that hypocortisolism may be reversed after successful
implementation of cognitive-behavioral therapy (CBT) (Roberts, Papadopoulos, Wessely,
Chalder, & Cleare, 2009), and that it may be predictive of a poor response to CBT (Roberts et
al., 2010).
CONCLUSION
The overall picture of the findings discussed in this contribution may be summarized as a
relative hypoactivity of the HPA axis in fatigue and CFS. This is in accordance with a recent
meta-analysis in which the authors identified a ― statistical significant basal hypocortisolism in
CFS‖ (Tak et al., 2011). Hypocortisolism is a phenomenon that has been found in numerous
conditions that are known to be associated with stress (Ehlert, Gaab, & Heinrichs, 2001;
Heim, Ehlert, & Hellhammer, 2000; Heim & Nater, 2007). It might potentially be able to
explain at least some of CFS symptomatology: in CFS hypocortisolism leads to immune
activation, which in turn leads to fatigue (Clauw & Chrousos, 1997). Despite these potentially
explanatory relationships, directionality of the association between fatigue and cortisol still
needs to be determined. Research in this field is in dire need of longitudinal studies. Fatigue is
a common phenomenon fluctuating over time (on a day-to-day basis) in every person. It
might be worthwhile to follow-up on individuals at risk of experiencing fatigue over longer
periods of time. Another approach may be to follow-up on individuals identified with relative
HPA axis hypoactivity.
A logical conclusion from the summarized findings may be to treat relative
hypocortisolism by administering cortisol in the form of hydrocortisone or fludrocortisone
pharmacologically. Indeed, this approach has been attempted, with inconclusive success
(Rimes & Chalder, 2005). Interestingly, some studies indicated reduced fatigue in healthy
subjects at least on a momentary basis (Reuter, 2002; Tops, van Peer, Wijers, & Korf, 2006).
Apparently, more studies are needed to determine the fate of pharmacological treatment as a
feasible and effective intervention possibility. Recent years have shown empirical evidence
for successful treatment of chronic fatigue by cognitive-behavioral therapy (Malouff,
Thorsteinsson, Rooke, Bhullar, & Schutte, 2008; Price, Mitchell, Tidy, & Hunot, 2008). It is
of particular interest to our discussion of hypocortisolism that some of these studies have used
cortisol measurements as outcome variables. It was shown that hypocortisolism at the
beginning of the intervention was brought back to normal levels after successful therapy
(Roberts, et al., 2009). Also, low cortisol levels at the beginning of the intervention were
indicative of worse therapy outcome (Roberts, et al., 2010). Thus, psychotherapy seems to be
effective in addressing abnormal endocrine functioning and levels of fatigue. Whether
positive effects persist over time, however, needs to be determined in long-term intervention
studies.
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In: Cortisol ISBN: 978-1-61942-458-6
Chapter 7
IMPORTANCE OF CORTISOL REGULATION

DURING PREGNANCY
Catherine Louise Michel and Xavier Bonnet

Centre d‘Etudes Biologiques de Chize,
Centre National de la Recherche Scientifique,
Beauvoir sur Niort, France
ABSTRACT
Cortisol is one of the main effectors of the stress response in mammals, therefore
high plasma levels of this glucocorticoïd maintained over prolonged time periods are
usually perceived as negative in terms of human health. This notion applies with force
during reproduction. Many studies reported the negative effects of increasing circulating
cortisol on reproduction. Stress-induced increases of plasma cortisol which negatively

impact fertility, entail elevated abortion risks, can precipitate parturition and produce
underweight neonates. However, cortisol is also an essential hormone for various
adequate physiological performances, notably during gestation. For example, cortisol is a
strong stimulus for the mobilization of maternal reserves, an essential physiological task
during gestation. Throughout pregnancy, the HPA axis (Hypothalamic-pituitary-adrenal
axis) is progressively activated and basal cortisol plasma level raise in response to
increasing nutritional demand of the developing offspring. Interestingly, the fetus
participates to the production of cortisol (during late pregnancy fetal HPA-placenta axis
is functional), and thus somehow manipulates maternal metabolism and behavior.
Empirical and experimental studies also demonstrated that cortisol plays a key role in the
development of different embryonic organs before birth. Maternal hypo-cortisolemia (e.g.
caused by adrenalectomy or Addison‘s disease) results in fetal retardation, alteration of
respiratory performances, and reduced body mass at birth for instance. Overall, a precise
cross regulation of both maternal and fetal HPA-axis activity is essential to modulate
circulating levels of cortisol during pregnancy. Insights from evolutionary theory and
from studies performed on various species, suggest that cortisol occupies a central role
for the regulation of gestation and the well-development of the embryos. This steroid is
notably involved in maternal/offspring conflict (trade-offs) were adequate levels of

Email: catherine.louise.michel@gmail.com.
120 Catherine Louise Michel and Xavier Bonnet
cortisol are associated with the production of optimal offspring phenotypes and optimal
maternal reproductive investments.
INTRODUCTION
During pregnancy the developing fetus entails an increase of energy demands (Winick
1990). To respond to this metabolism change, mother should modify her behavior (increase in
food consumption) and morphology (increase in body mass). These variations are associated
to a chronic elevation of cortisol level (Michel et al. 2001). Increasing placental production of
estrogen stimulates hepatic production of corticosteroid-binding globulin (CBG), thus
stimulating cortisol production and increasing circulating levels of bound cortisol. Both
circulating and urinary free cortisol levels increase, excretion of free cortisol in urine is
elevated, values of up to 500 µg/24h being recorded in normal pregnant women (Gibson and
Tulchinsky 1980), this value is more than twice the upper limit of normal for non-pregnant
women. Indeed, glucocorticoids are involved in the mobilization and use of energy in various
physiological processes: maintaining blood pressure and cardiovascular function (Whitworth
et al. 2005), slowing the immune system‘s inflammatory response (McEwen et al. 1997),
balancing the effects of insulin in breaking down sugar for energy and regulating the
metabolism of proteins, carbohydrates and fats. Elevated concentration of cortisol during
pregnancy may promote the release of and thermogenic response to L-triiodothyronine-
mediated norepinephrine and epinephrine (Owen et al. 1986). Norepinephrine plays a role in
facultative energy expenditure associated with carbohydrate metabolism. It facilitates several
energy-requiring processes, including intracellular translocation, oxidation and storage of
glucose, lipogenesis and protein synthesis (Butte et al. 1999). Moreover, the elevation of
cortisol level and specific transport protein (CBG) during pregnancy positively influence
myometrial activity and uterine blood flow (Chang and Zhang 2008; Jensen et al. 2005).
Therefore, cortisol levels influence immunity and inflammation, metabolism, neurobiology
and reproductive physiology (Sapolsky et al. 2000).

A small amount of glucocorticoids in maternal plasma cross the placenta, both because
the reentry pathway dominates and because cortisol within the trophoblast is converted to
cortisone by 11beta-hydroxysteroid dehydrogenase type 2 (11β-HSD2; Brown et al. 1993,
O‘Donnel et al. 2009). Within the placenta, 11β-HSD2 is primarily expressed in the
syncytiotrophoblast (Sun et al. 1997), it acts to prevent the majority of maternal cortisol from
crossing the placenta, resulting in circulating cortisol levels in the fetus being approximately
13-fold lower than those in the mother (Gitau et al. 1998). Approximately 10% of maternal
cortisol does cross to the fetus (Zarrow 1970). However, an increase in maternal cortisol
levels could increases fetal cortisol level (Gitau et al. 1998). Some studies of preterm birth
and intrauterine growth restriction, reporting reduced placental 11β-HSD2 gene expression,
highlight the clinical relevance of cortisol metabolism in pregnancy (Causevic and Mohaupt
2007; Wächter et al. 2009). Moreover, a recent study shown that maternal stress during
pregnancy is associated with a downregulation of 11β-HSD2 gene expression (O‘Donnell et
al. 2011). Therefore, cortisol could cross the placenta and thus may affect the fetus and
disturb ongoing developmental processes. The short-term and long-term health of the fetus is
influenced by the environment in which it develops. This environment is created by its
mother and, once developed, by the placenta. The developmental origins hypothesis proposes
Importance of Cortisol Regulation during Pregnancy 121
that fetal programming resulting in an altered risk of disease in adult life (Gluckman et al.
2005).
Several phenomenons could change the standard level of cortisol of the mother during
pregnancy: disease (Cushing‘s syndrome, Addison‘s disease) or stress (death of a loved one,
financial problems, heavy work responsibility and workload, strained relationship, chronic
illnesses).
The overproduction of cortisol by the adrenal glands leads to Cushing‘syndrome. This
hypercortisolemia is usually due to a corticotrophin (ACTH)-producing pituitary tumor,
ectopic ACTH secretion by a nonpituitary tumor, or cortisol secretion by an adrenal adenoma
or carcinoma. Cushing‘s syndrome is associated with ovulatory disturbances induced by
cortisol excess (Aron et al. 1990), high glucocorticoids level entails in about 75% of woman
with Cushing‘s syndrome suppression of gonadotropin secretion and result in amenorrhea. As
a result, woman with untreated Cushing‘s syndrome rarely become pregnant (Buescher et al.
1992). Since 1953, 136 pregnancies have been reported (Lindsay and Nieman 2005). The
most common complications during pregnancy are hypertension and diabetes or impaired
glucose tolerance (Aron et al. 1990; Mellor et al. 1998; Guillaume et al. 1992). In the 136
pregnancies, there were 107 (79%) live births, 43% premature, 8 stillbirths, 6 intrauterine
deaths and 1 ectopic pregnancy (Lindsay and Nieman 2005).
A hypercortisolism could also be induced by a stress. Now, it is well establish in animals
models (see Weinstock 2001, 2005), and increasingly in humans, that stress experienced by
the mother during pregnancy is associated with increased risk for many adverse short-term
and long-term effects on the child (Talge et al 2007, O‘Donnel et al 2009). It has also been
shown that these effects are mediated by increased exposure to glucocorticoids (Seckl and
Holmes 2007). Glucocorticoids are released into the circulation after maternal exposure to
stressors, such as physical illness (Lou et al. 1994), separation from a partner (Rothberg et al.
1991), national event like war (van Os et al. 1998). Furthermore, it seems that physiological
and psychological stresses are associated with social disadvantage, and cause complication
during pregnancy and poor maternal and neonatal health. Epidemiological studies show a
strong relationship between social disadvantage and low birthweight (Kramer 1987; Wilkins
1991; Berkowitz 1993). Low birthweight, usually defined as weight less than 2500 grams, is a
major health problem. Many animal studies showed that glucocorticoïds administration
during gestation result in reduced fetal weight: ewes (Sloboda et al. 2000), mice (Reinisch et
al. 1978), rats (Benediktsson et al. 1993), rabbits (Barrada et al. 1980), rhesus monkeys
(Johnson et al. 1981), guinea pigs (Dean et al. 2001).
High glucocorticoïds level in the mother plasma impact also negatively the fetus with
elevated cortisol levels at birth (Economides et al. 1988) and elevated HPA activity in adult
life (Phillips et al. 2000, Reynolds et al. 2001). A study of van Os et al. (1998) shown that
pregnant women in their first trimester exposed to the stress of war gave birth to offspring
with an increased risk of developing schizophrenia. Stressful events during midgestation may
entail small head circumference (Lou et al. 1994), suggesting an effect on the brain.
Glucocorticoids administration could induce neurological damage too (Gumbinas et al. 1973,
Huang et al. 1999). Prenatal stress can induce mental retardation and sleep disturbance in the
infant (Scott 1973; Shell 1981). Chronic stress like war, could result to delayed language
development (Scott 1973) and lowered intellectual functioning (Brouwers et al. 2001).
However, glucocorticoids are crucial for the development and maturation of fetal organs.
In many viviparous species there is a rise in cortisol concentrations during late pregnancy that
parallels the increased maturity of fetal organs (Smith et al. 1974). Glucocorticoids affect
directly adrenal growth and lung development (Liggins 1968, Liggins 1969), and contribute
to maturation of other organs including the heart (Wintour 2006), thymus, gastrointestinal
tract (Liggins 1976, Liggins 1994), liver (Schwartz and Rall 1975), and kidney (Zanardo
1990).
Since many years women with risk of preterm delivery receive glucocorticoïds
administration in order to increase the maturation of the fetal lungs, this treatment lows the
proportion of neonatal respiratory distress syndrome and its associated mortality (Liggins and
Howie 1972). Concretely, glucocorticoïds increase surfactant synthesis (Spellacy et al. 1973,
Caspi et al. 1975). However, this administration of glucocorticoïds during gestation may have
adverse effects on the fetus, it could increase incidence of gastroesophageal reflux (Chin et al.
2003) and modify fetal heart rate (Rotmensh et al. 1999, Subtil et al. 2003). Moreover,
multiple doses of antenatal glucocorticoïds have been linked to reductions in fetal growth
compared with single doses (Banks et al. 1999).
On the other hand, when maternal cortisol levels fall to low plasma concentration (due to
hypocorticism) negative effects on the offspring are also observed. The first origin of
hypocorticism in pregnant women is the Addison‘s disease. Addison‘s disease is a chronic
adrenal failure of the adrenal gland, resulting in a deficiency of cortisol. This disease may be
caused by destruction of the adrenal glands by tuberculosis, metastatic carcinoma, fungal
infection or amyloidosis. This disease is also called chronic adrenal insufficiency or
hypocortisolism. Urinary and plasma cortisol and aldosterone levels are low or undetectable
(Symonds and Craven 1977). The low plasma cortisol concentration accentuates the
hypotension and reduction in glomerular filtration rate and, because of reduced
gluconeogenesis, it also predisposes to hypoglycemia (Van der Spuy et al. 1984).
Addison‘s disease during pregnancy has deleterious outcomes for both mother and fetus
(Drucker 1984; O‘Shaughnessey and Hackett. 1984; Seaward et al. 1989), although women
with diagnosed Addison‘s disease can be adequately managed with increase steroid treatment
(Albert et al. 1989). Since 1953, there were approximately 50 cases of Addison‘s disease
during pregnancy reported (Lindsay and Nieman 2005). Before 1950 and the availability of
cortisone, Addison‘s disease during pregnancy was associated to a high risk of maternal and
fetal mortality (O‘Sullivan 1954). Moreover, hypocortisolism during pregnancy entails an
intrauterine growth retardation and a low birth weight (Osler and Pedersen 1962).
However, during pregnancy a new endocrine organ develop, the fetoplacental unit,
producing several hormones such as estrogens, progesterone and cortisol. Moreover, the
adrenal glands of the human fetus at term are as large as those of adults (about 8-10g). These
fetal glands have a huge steroidogenesis capacity, the fetal adrenals secret 100-200 mg of the
steroid per day. The total daily steroid production by the adrenals in an unstressed adult is
approximately 35mg. There exists a transplacental passage of cortisol from the fetus to the
mother. Studies on primates showed that up to 60% of fetal cortisol is normally transmitted to
the mother, representing 6.6% of total maternal cortisol levels (Drucker et al. 1984). The
cortisol synthesis of the fetus is so extremely important, and can compensate the deficit of
mother cortisol.
CONCLUSION
Cortisol level plays an important physiological role in pregnancy. When maternal cortisol
levels exceed or fall below the physiological limits, such as during moments of
hypercorticism or hypocorticism, incidences of fetal growth, prematurity and death are
elevated. Although this opposite phenomenon may exert similar biological responses, notably
restricted growth rates, the mechanisms involved are dissimilar. It seems that during period of
low maternal cortisol, the resulting impaired placental perfusion mediates the restriction on
fetal growth. Alternatively, during periods of elevated cortisol level, growth restriction may
be caused by factors such as alterations in placental structure, change in fetal hormone levels,
or impaired growth factor function.
The impact of variation of cortisol level could be related to the timing of the pregnancy.
Glynn et al. (2001) reported that the gestational ages of the fetus whose mother were exposed
to an earthquake in their first trimester were shorter than those whose mothers were exposed
in their third trimester. Thus there may exist a critical period during prenatal development
when cortisol level could have more important effects on postnatal development.
Given the influence of maternal glucocorticoids on fetus development, the antenatal
glucocorticoïd treatment currently used at the end of pregnancy, for reducing the frequency of
respiratory distress syndrome and neonatal death (National Institutes of Health Consensus
Statement 1994) should be use with precaution. However, it seems that effects differ function
of the zone of administration: directly to the fetus or to the mother (Moss et al. 2003). If
cortisol is given to the fetus by ultrasound-guinded intramuscular injection, rather than to the
mother, the effects on lung maturation are similar, but growth is spared and blood pressure
after birth is unaltered (Newnham 2002).
A precise regulation of maternal and fetal HPA axis activity is necessary to maintain
cortisol level inside the limits values. This hormone plays a central role in the maternal trade-
offs of reproduction: synchronize optimal maternal reproductive investment and optimal
infant phenotypes. The fetal programming by prenatal stress may prepare the child for
survival in a dangerous environment (Glover 2011). Prenatal stress increase the risk for adult
psychopathology, it could be associated with increased vigilance, more perception of danger,
more exploration and aggression with the ability to fight intruders. However, maternal stress
could cause fetal malformation too. Some responses to environmental stress could be
adaptative and some could be non-adaptative, it might be difficult to decide if a response is
adaptative in particular cases. The phenotypic plasticity induced by the environmental
condition during fetus development may conferred survival advantage in the poorer
nutritional and high-energy expenditure environment of our ancestors. However, this
modification now appears to be increasingly inappropriate.
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In: Cortisol ISBN: 978-1-61942-458-6
Chapter 8
CORTISOL AND PHYSICAL EXERCISE
Rodrigo Gomes de Souza Vale1,2,, Guilherme Rosa2,

Rudy José Nodari Júnior3 and Estélio Henrique Martin Dantas2
1
Laboratory of Exercise Physiology (LAFIEX), Estácio de Sá University, Rod. Gen.
Alfredo B. Gomes Martins s/n, Braga, Cabo Frio, Rio de Janeiro, Brazil
2
Laboratory of Human Motricity Biosciences (LABIMH), Federal University of State
of Rio de Janeiro (UNIRIO), Urca, Rio de Janeiro, RJ, Brazil
3
Laboratory of Exercise Physiology and Evaluation Measures (LAFEMA),
University of Western of Santa Catarina (UNOESC), Joaçaba, Santa Catarina, Brazil
ABSTRACT
Glucocorticoids exert many beneficial effects in humans, increasing the availability
of metabolic substrates, while maintaining normal vascular integrity and protecting the
body from an exaggerated immune system response in the face of exercise-induced
muscle damage. The main glucocorticoid is cortisol, accounting for 90% of the total
activity of these substances. It is secreted by the adrenal cortex of the adrenal glands and
among other functions, plays important roles during and after exercise, including taking
part in gluconeogenesis and accelerating the mobilization and use of fats to produce
energy. Cortisol has important metabolic functions such as influencing the metabolism of
glucose, proteins and lipids. It raises blood glucose and increases fatty acid mobilization
from fat reserves to active tissues. On the other hand, it can inhibit protein synthesis and
increase muscle mass by its catabolic action. Cortisol levels are measured by saliva and
blood collection, and can be influenced by different factors, such as sleep deprivation,
stress and exercise, in addition to variations caused by circadian rhythm. Responses to
exercise depend on the characteristics of stimuli and can be classified as acute and
chronic responses. This chapter discusses the main biological functions of this hormone,
factors that influence its levels and response to various acute and chronic exercise
protocols.
Keywords: Hormones, stress and physical exercise, metabolism, acute and chronic responses

Corresponding author: At address: Rua Figueira de Mello, 415 - Condomínio São José D‘Aldeia - Bananeiras,
Araruama, RJ, Brazil. CEP: 28970-000. Phone: +(55-22) 26651595. E-mail: rodrigovale@globo.com.
130 Rodrigo G. de Souza Vale, Guilherme Rosa, Rudy J. N. Júnior et al.
CORTISOL
Glucocorticoids exert many beneficial effects in humans, increasing metabolic substrate
availability, maintaining normal vascular integrity and protecting the organism against
exaggerated response of the immunological system to exercise-induced muscle damage [1].
Cortisol is a glucocorticoid secreted by the adrenal cortex of the suprarenal glands [1, 2],
which, among other functions, plays important roles both during and after exercise [3], such
as helping gluconeogenesis. Cortisol stimulates protein fractionation for amino acid
components in all body cells. Amino acids released are transported to the liver, where they
participate in glucose synthesis via gluconeogenesis [4].
Among other functions of cortisol are accelerated mobilization and use of fats in order to
obtain energy. Adipocytes are specialized in synthesizing and storing triglycerides; their
molecules are cleaved in the hydrolysis process in glycerol and three fatty acid molecules.
After diffusion into the bloodstream, fatty acids are delivered to the active tissues, where they
are metabolized for energy production [5].
Further cortisol functions include: helping the body adapt to stress; maintaining adequate
glucose levels even during fasting; decreasing glucose capture and muscle glucose oxidation
to obtain energy, reserving it for the brain via an antagonic effect to that of insulin; blocking
lysosomal rupture, impeding additional tissue lysis, stimulating protein catabolism for the
release of amino acids used in tissue repair, synthesizing enzymes and producing energy in all
body cells, except in the liver; acting as an anti-inflammatory agent; reducing immunological
reactions to provoke a decrease in the number of lymphocytes; increasing epinephrine-
induced vasoconstriction; facilitating the action of other hormones, especially glucagon and
growth hormones (hGH), in the gluconeogenesis process [2, 5, 6].
Moreover, this hormone seems to be directly related to a number of cytokines secreted by
adipose tissue [7].
FORMS OF MEASUREMENT
The result of cortisol assessment is an important tool for understanding the actions of this
hormone in the human body. However, there are different collection and analysis
possibilities, each with its specific indications. Possible measurements are those based on data
obtained from saliva, urine and blood.
Saliva
Cortisol level measurement from saliva collection aims to assess individual stress levels.
This method involves a simple procedure that does not produce sufficient alterations to
interfere significantly in the results. Since it is a non-invasive technique, collection is not
stressful, in contrast to venipuncture, which many consider painful.
Cortisol and Physical Exercise 131
The simple collection method is widely used in research and individual assessments.
Samples are obtained without invasive procedures, which involve easy-to-calibrate
individuals in clinical analysis laboratories or academic investigations without requiring the
presence of a doctor or nurse. The material collected remains stable at ambient temperature
for up to one week without significant loss of information and can be sent through the post
without causing any alteration [8].
Saliva collection has additional advantages over the other techniques, since it is more
accurate and low cost, producing faster results than measuring urinary cortisol, for example.
Another advantage of this method is the increased possibility of collective collections at
different training or competition moments without the need for specific collection
environments, making it more dynamic [9-11].
This technique is readily accepted by children and adolescents. Moreover, it allows
cortisol investigators to study without undesirable and embarrassing reactions owing to
practical, ethical, cultural or religious reasons. These situations often occur in methods
involving blood or urine collection. However, it is important to remember that saliva-based
measurements have some limitations. Given their structure and composition, they may
interfere in the results of oral disorders, the presence of blood in saliva, the Sjögren
syndrome, use of oral hormone replacements and some types of birth control pills [9].
There are different ways to collect and analyze salivary cortisol. However, the most
common and most complex methods exhibit similar results. An example is a comparison
between the results obtained by Raff et al. [12] and those of Castro et al. [13], using different
methods. In the former, saliva samples were collected in plastic tubes by direct salivation for
15 minutes. The mouth was previously rinsed with distilled water, saliva samples were
centrifuged at 2000 rpm for 5 minutes and the supernatant separated and stored at -20°C for
subsequent determination of free cortisol by radioimmunoassay (RIA).
The other technique observed was the use of a collection device (Salivette). Salivette
cotton may retain some amount of cortisol, which could produce a lower result than would be
obtained if saliva were collected directly. However, cutoff points for salivary cortisol,
proposed for interpreting the dexamethasone suppression test, using the Salivette (103 ng/dl)
and direct collection (62-112 ng/dl), suggest that the collection technique is an important
factor. The most widely adopted reference values for measuring salivary cortisol in adults are
collection at 8:00 am (3.5 to 32.0 µmol/l) and at 11:00 pm ( < 3.6 µmol/l) [14].
Urine
Urine collection for cortisol determination is the second most frequently used method.
One of its advantages over other procedures is the collection of production accumulated over
24 hours, which solves the problem of understanding results in relation to secretion rate.
However, this method poses problems, given that collection is accumulative and depends on
transport and storage during the entire period. In this case, the following procedure should be
adopted: after collection flasks are removed from the laboratory, study subjects must totally
empty their bladders first thing in the morning and discard this urine, record the exact time,
and keep all subsequent urine (including nighttime urination) until the next morning at the
same time urine from the previous day was disposed of (this urine must also be collected and
kept). It is essential to send all collected urine to the laboratory to avoid measurement errors
[15].
Another technique is to collect urine discharge according to the time of day to be
investigated. With respect to studies on anxiety, urine seems to be a viable process when
collections are performed at night [16, 17].
The method has a number of limitations, such as falsely low values in individuals with
loss of kidney function [18] or those with chronic fatigue syndrome [19]. In the case of
individuals with above normal water intake, values may be falsely high during depression and
after physical exercise. There also seems to be a difference in urinary excretion of cortisol
between men and women, with men exhibiting slightly higher levels. Another significant
drawback is that measuring urinary cortisol is scarcely effective for studying acute stress.
Important rules that women must follow include not using creams/vaginal ovules in the
24 hours before collection and avoiding collection during menstrual periods [20].
High levels of urinary cortisol may also indicate secretory tumors of the
adrenocorticotropic hormone (ACTH), Cushing‘s syndrome and pituitary tumors. Reduced
levels of urinary cortisol may indicate Addison‘s disease, adrenal failure, hypopituitarism and
congenital adrenal hyperplasia. The most widely used reference values to measure urinary
cortisol are: Children 2.0 to 27.0 µg/24 hours; Adolescents 5.0 to 55.0 µg/24 hours and adults
10.0 to 90.0 µg/24 hours [14].
Blood
Assessment of blood cortisol levels is important for pathological or behavioral

observations. However, cortisol evaluation from blood collection seems to be the least
recommended by researchers when the aim is athletic assessment, with respect to pre-
competition stress. This is due to the negative reaction to venipuncture exhibited by most
individuals investigated.
Studies have been conducted on the use of this method in sport, demonstrating the
possibility of detecting this hormone in the blood in different volumes and at different phases
of competition [21]. Girardello [15] studied high-performance karate athletes, concluding
there was no significant correlation between blood cortisol levels and applied inventory of
stress symptoms [22] and the perceived stress scale [23]. In this case blood cortisol can be
considered a predictor of pre-competition stress. Furthermore, it is highly likely that this
alteration significantly influences athletic performance, since all subjects exhibited a
significant difference between basal and pre-competition cortisol. Athletes with less variation
finished in the top three places. Thus, the presence of this hormone in blood, in pre-
competition situations, may be an indicator of stress level, which could cause some type of
reaction (useful or not), in pre-competition athletes.
To understand adequate amounts of circulating cortisol, it is important to determine
reference values and be aware that they vary depending on collection time. In other words,
when collected at 8:00 am, the proposed value ranges between 5.0 and 25.0 µg/dl, at 4:00 pm
cortisol values should decline by more than 35% of the morning value, while at 6:00 pm the
drop should be greater than 50% [14].
INFLUENCING FACTORS
Circadian Rhythm
Levels of a number of hormones demonstrate circadian fluctuation and variation [24]. In

some cases, these variations are due to regulatory endocrine axis pulses [25]. In others, they
are related to humeral stimulus alterations caused by environmental or behavioral factors of
the individual [26]. Morning cortisol levels are generally twice as high as at the end of the day
[27].
Sleep and Stress
Sleep deprivation and stress are factors known to influence a number of hormones [24].
Emotionally disturbed individuals have high levels of cortisol [28]. Furthermore, hormones
that exhibit a circadian pattern, such as cortisol, may show alterations in this pattern in cases
of interrupted sleep cycles [29].
Physical Exercise
According to Lapin [30], physical exercise can become a stressor agent for the body,
resulting in an increase in cortisol concentrations. This may influence exercise results with
respect to weight loss, but, on the other hand, it may be an inhibitor of protein synthesis and
muscle growth by its catabolic action [4].
Canali [2] reports that both the type and intensity of exercise in relation to individual
training levels provoke alterations in hormone responses, making it somewhat difficult to
identify them.
Charmas [31] assessed the effects of a moderate aerobic exercise session accompanied by
music, on metabolic and hormonal responses in 11 women aged between 30 and 50 years.
Blood samples were collected at four different times: in the morning while fasting (measure
I), in the evening just before the exercise session (measure II), immediately after the 1-hour
exercise session (measure III), and in the morning of the day following the exercises after a
12-hour rest period (measure IV).
Cortisol results show high values in measure I and measure IV; however, there was no
significant difference between measures II and III. Therefore, a one-hour aerobics session
provoked no alterations in cortisol plasma levels.
Kraemer [32] examined the effects of amino acid supplementation on physiological
adaptations as a response to 12 weeks of strength training. To that end, hormonal and muscle
damage markers, including cortisol, were measured.
Seventeen healthy men were randomly allocated to experimental and placebo groups. The
experimental group received amino acid solution containing β-Hydroxy-β-Methylbutyrate,
whereas the placebo group was given only an isocaloric solution.
After 12 weeks of strength training for the primary muscle groups, ranging from 3-5
series of 8-14 repetitions, no alterations were observed in cortisol concentrations at rest.
However, the experimental group exhibited reduced levels immediately before exercise, when
compared to basal values.
In order to determine the effect of moderate-intensity aerobic training on muscle strength
in relation to hormonal alterations, Grandys [33] conducted a study with 15 physically active
male subjects. The research lasted five weeks and used stationary bicycle training. Tests were
carried out to obtain VO2max in individuals and 20 ml fasting blood samples were collected at
rest, before and after the training program.
Following the intervention period, a significant rise in VO2max was observed. Cortisol
plasma levels showed a tendency to increased concentrations. However, these alterations were
not statistically significant.
Izquierdo [34] examined the effects of two strength training methods on cytokines and
hormonal responses. The training program, involving 12 male volunteers, lasted seven weeks.
Acute cortisol responses were significantly lower in the group submitted to 5 series of 10
repetitions with the same absolute overload (Kg), compared to the group that performed 5
series of 10 repetitions with the same relative intensity [%].
In another study, which examined the chronic effects of aerobic and strength training
conducted separately over four months on hormonal concentrations, Izquierdo [35] found no
significant intergroup differences (aerobic training X strength training X control) for plasma
cortisol levels.
Hormonal responses induced by different strength training intensities were compared in
research conducted by Oliveira [36]. His results showed reduced cortisol levels in the acute
phase for the group that performed exercises at 50% 1RM and increased levels in the group
that exercised at 80% 1RM.
França [5] used 20 male athletes to analyze serum cortisol levels after a marathon race.
To that end, blood samples were collected at three different times: in the morning, 48h before
the marathon (control), immediately after the race (final) and on the following morning, 20 h
after the race (recovery). His results show a significant rise in cortisol levels at the end of the
race, with values returning to basal levels during recovery.
The study concluded that behavior exhibited by the variable confirmed marathon racing
causes intense physical stress, which can lead to hormonal imbalance.
Uchida [37] examined the influence of two training methods on hormonal responses.
Individuals were randomly divided into two groups, both of which were submitted to multiple
series and tri-set methods. The author reports that the group that underwent the tri-set method
showed a significant increase in cortisol levels as a response to acute and chronic stress levels
compared to the group submitted to the multiple series method.
Results obtained in this study suggest that the tri-test method imposes greater organic
stress and that the multiple series method promotes a more favorable environment to
anabolism after eight weeks of intervention.
Tremblay [38] sought to determine acute anabolic and catabolic hormonal responses to
strength and aerobic exercise of equal volume in subjects with different training levels.
Subjects engaged in strength training, aerobic training and sedentary individuals were
used. They completed one rest period, a 40-minute race at 50-55% VO2max, and one strength
training session. Blood samples were collected before the exercise session and 1, 2, 3 and 4
hours after onset of exercise.
Findings for this study demonstrated that cortisol concentrations exhibited a tendency to
decrease in the rest period. This behavior was attributed to the typical daytime cortisol
pattern. However, when groups were compared, cortisol concentrations were significantly
higher as a response to strength training than to rest or the race. Moreover, the race obtained
more elevated values than the rest period.
Vale et al. [39] investigated the effect of 12 weeks of different exercise protocols on the
cortisol levels of elderly subjects. The sample was divided into a strength training group,
aerobic training group and a control group. After the intervention there were no significant
alterations in intra and intergroup cortisol concentrations
The acute effect of physical exercise on serum cortisol levels was analyzed by Rosa et al.
[40]. A significant reduction was observed immediately after the concurrent training
protocols.
Rosa et al. [41] analyzed the behavior of cortisol levels as an acute response to physical
exercise. To that end, a concurrent training session composed of an indoor stationary bicycle
class followed by a weight training session was used as intervention protocol. Results showed
a significant reduction in cortisol concentrations after concurrent training.
Rosa et al. [42] analyzed the effect of different sequences of concurrent training on
cortisol concentrations. In one session aerobic exercise preceded strength training, while the
reverse occurred in another session. Data showed a significant reduction in cortisol levels,
irrespective of exercise sequence.
CONCLUSION
Cortisol is closely linked to individuals that engage in physical activities, especially the
high-intensity variety. It is catabolic, since it exerts an opposite effect to that of testosterone,
insulin and the growth hormone (hGH), decomposing muscle tissue, causing muscles to
suffer from sarcopenia. Cortisol, which is released when the body is in situations of high
physical and mental stress and high temperature, is the main catabolic hormone.
Considering the above, there is an increasing need for habitual activities practiced in
physical activity and sports sciences to be controlled by means of safe, reliable and viable
biochemical markers. These activities include: sport, physical activity for health and quality
of life, recreation, rehabilitation and physical exercise for individuals or groups with special
needs.
This study sought to demonstrate the potential of cortisol to act as a marker of both
physical and mental stress. The importance and complexity of the issue calls for new studies
to complement and extend the findings obtained in the present research.
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In: Cortisol ISBN: 978-1-61942-458-6
Chapter 9
CORTISOL AND PHYSCAL EXERCISE,

ITS EFFECTS IN ATHLETIC PERFORMANCE
Alfredo Córdova1, and Antoni Sureda2

1
Department of Physiology and Biochemistry, School of Physiotherapy, University of
Valladolid, Soria, Spain
2
Research Group on Community Nutrition and Oxidative Stress (IUNICS),
University of Balearic Islands, Illes Balears, Spain
ABSTRACT
Exercise is a stressful situation that has been shown to induce an inflammatory status
with changes in immune cells resembling the acute phase immune response to infection
and muscular damage. Corticosteroids are substances secreted from the adrenal cortex in
response to stress situations as exercise. The plasma concentrations of cortisol increase
only in relation to exercise of long duration or as result of accumulating stress. These
facts indicate that cortisol probably does not have a major role in the acute exercise-
induced effects. The physiological and pharmacological effects of cortisol are primarily
anti-inflammatory and immunosuppressive. The corticoids mechanism action are
multifactorial. The inhibition of NF-kB reduces the synthesis of pro-inflammatory
cytokines and the expression of endothelial adhesion molecules. Prolonged exercise
results in glycogen depletion which induces hormone secretion such as cortisol to ensure
the maintenance of blood glucose level. During exercise cortisol has also a direct and
positive relation with lipid catabolism. In addition to endogenous glucocorticoids there
exist the synthetic corticosteroids, whose properties derive from the hormone
hydrocortisone. The glucococorticoids are used for the treatment of many inflammatory
and allergic diseases. Obviously, like any corticosteroids drugs are not absent of side
effects. However, when the prescription is correct and under medical supervision, these
are minimized. While it is true that steroids have been described as anti-inflammatory and
analgesic, these effects have been seen in patients at rest and there only few studies
concerning the behavior of steroids during exercise. The studies analyzing the effects of

Address for correspondence Alfredo Córdova Martinez. Professor and Chair of Dpt. of Physiology. E.U.
Fisioterapia. University Campus of Soria. University of Valladolid. 42004 SORIA (SPAIN). Phone: 34 975
129187. Fax: 34 975 129102. E-mail: a.cordova@bio.uva.es.
140 Alfredo Córdova and Antoni Sureda
steroids on athletic performance have not found any improvement. Therefore, and in light
of existing scientific literature, it can be said that steroids do not improve athletic
performance.
Keywords: Corticosteroids, cortisol, inflammation, exercise, sport, cytokines
1. INTRODUCTION
Regular physical exercise has many health benefits including a reduction of risk factors
of cardiovascular disease, cancer, and diabetes [56]. However, intense and maintained
exercise in athletes induces fatigue, leading to a reduction in motor and cognitive
performance in players [11,15]. To counteract this stressful situation, there are a wide variety
of physiological responses and subsequent instrumental adaptations for increasing muscular
strength, power, hypertrophy, and endurance [31]. Neuroendocrine physiological response,
which is essential for acute resistance exercise performance and tissue remodelling, is the
most relevant response [27]. On the other hand, it has been documented that strenuous
exercise not only induces pyrogenesis but also elicits mobilization and functional
augmentation of neutrophils and monocytes whereas it suppresses cellular immunity leading
to increased susceptibility to infections [52]. Glucocorticoids have anti-inflammatory and
immunosuppressive properties. They inhibit the production of pro-inflammatory cytokines
and also inhibit their effects on target tissues [18,26].
It is also clear that contracting skeletal muscles generate reactive oxygen species (ROS)
which can result in oxidative damage to cellular components [35,42]. It was well established
that low/moderate and physiological levels of ROS are required for normal force production
in skeletal muscle, but high levels of ROS can induce contractile dysfunction resulting in
muscle weakness and fatigue and consequently a reduction in athletic performance [42,51]. In
fact, moderate levels of oxidants play important regulatory roles in cells such as the control of
gene expression and cell signaling pathways. Recent investigations have provided new
insights into specific mechanisms through which both satellite cells and muscle fibers can
regulate extravasation of inflammatory cells and modulate inflammatory cell contribution to
muscle injury or growth [42].
2. INFLAMMATION AND MUSCULAR DAMAGE

High-intensity and/or long duration exercise provoke skeletal muscle damage which is
characterised by loss of muscular strength, muscle soreness, and elevated blood
concentrations of muscle proteins such as creatine kinase (CK) [14,16,41]. Serum CK and
serum lactate dehydrogenase (LDH) are often analyzed to indirectly assess the degree of
muscle damage. High CK and LDH levels are associated with exercise-induced skeletal
muscle damage [16]. Activities that involve eccentric muscle actions appear to be particularly
disruptive to muscle structure. Evidence of myofibrillar disruption, inability to buffer calcium
and Z band streaming in sarcomere structure, occurs in both high-intensity eccentric and
concentric muscle actions; however, greater disruptions occur during eccentric muscle action
Cortisol and Physcal Exercise, its Effects in Athletic Performance 141
[14]. Primary skeletal muscle damage promotes infiltration by inflammatory cells [38-40] to
produce an array of cytokines to regulate the inflammatory process [17,52].
Therefore, strenuous exercise induces an increase in the pro-inflammatory cytokines
Tumor Necrosis Factor alpha (TNF-α) and interleukin 1 Beta (IL-1β) and a dramatic increase
in the inflammatory responsive cytokine interleukin 6 (IL-6). This is balanced by the release
of cytokine inhibitors interleukin 1 receptor alpha (IL-1ra) and the anti-inflammatory
cytokine interleukin 10 (IL-10) [36]. The highest concentration of IL-6 has been found
immediately after a marathon race, whereas IL-1ra peaks 1 h post-exercise. The plasma level
of IL-10 showed an increase immediately post-exercise. The plasma levels of IL-1β and TNF-
α peak in the first hour after the exercise. The pro- inflammatory cytokines including IL-1β
facilitate an influx of lymphocytes, neutrophils, monocytes, which participate in the healing
of tissue [36,50]. Moreover, the plasma level of C-reactive protein (CRP) increases and peaks
24 h after plyometric exercise or a marathon race compared to the pre-exercise value
[13,36,50]. However, inadequate or excessive inflammatory response may lead to improper
cellular repair, tissue damage and muscle dysfunction leading to loss in performance [30].
This immune response plays a beneficial role and may be involved in mediating exercise-
related metabolic changes and in muscle repair. In addition, achieving an appropriate balance
between training and competition stresses and recovery is important in maximizing the
performance of athletes [7].
3. GLUCOCORTICOSTEROIDS
Glucocorticosteroids (also called glucocorticoids or corticosteroids) are steroid hormones
secreted by the adrenocortical glands under hypothalamic and pituitary control, as defined by
the hypothalamic-pituitary-adrenal (HPA) axis. Glucocorticoids are secreted from the adrenal
cortex in response to stress situations that regulate the metabolism of protein, carbohydrate
and fat, and play an important role in almost all cells and organs [33,43]. Glucocorticoids also
stabilize cell membranes, which are important for treatment of allergic and inflammatory
reactions [26]. In addition to endogenous glucocorticoids, there are synthetic forms, whose
properties and hormonal activity are derived from hydrocortisone.
The physiological and pharmacological effects of efficacy and to their growth arrest and
death inducing activity [6,44]. The effects of glucocorticoids are mainly due to their
interaction with cytoplasm glucocorticoid receptors which modulate gene transcription by
direct DNA interaction or by independent mechanisms involving protein to protein
interactions [5,46]. Glucocorticoids may increase the transcription of genes coding for anti-
inflammatory proteins, including lipocortin-1, interleukin-10, interleukin-1 receptor
antagonist, and repress many pro-inflammatory genes that have been activated in
inflammation [6].
Glucocorticoids decrease the production of eicosanoids by inhibiting phospholipase and
consequently preventing the release of arachidonic acid from membranes and by reducing the
expression of the isoform of cyclooxygenase, COX II [10], inhibit the activation of the
transcription factor NF-kB by complexing with NF-kB subunits, or by increasing the rate of
IkB a protein synthesis, resulting in sequestration of activated NF-kB in inactive cytoplasmic
complexes [1]. The Inhibition of NF-kB results in decreased synthesis of proinflammatory
cytokines (Il-1 and IL-2) and decreased expression of endothelial and leukocyte adhesion
molecules [37]. Glucocorticoids also inhibit the function of leukocytes and tissue
macrophages, reducing the ability of these cells to respond to antigens and mitogens. It has
been reported that high doses of glucocorticoids decrease the concentration of proteolytic
enzymes at the site of inflammation [10,34].
Glucocorticoids are the most effective anti-inflammatory drugs available for the
treatment many chronic inflammatory and immune diseases, including asthma, rheumatoid
arthritis, inflammatory bowel disease and autoimmune diseases [5,18,26].
4. GLUCOCORTICOIDS IN EXERCISE
The activation of the HPA axis is a physiological response to the energetic, metabolic and
vascular needs of exercise. In sportsmen usually stress and fatigue generate an increase in
ACTH, cortisol [16,17], and decrease testosterone serum levels [25]. In fact,
testosterone/cortisol ratio is an indicator of anabolic/catabolic balance [20] and is usually
increased in chronic fatigue [53], thus being a good method in order to detect overtraining
and/or prevent excessive psychophysical activity, derived from competition.
The plasma concentrations of cortisol increase only in relation to exercise of long
duration [19,28,29]. Thus, short-term exercise does not increase the cortisol concentration in
plasma, and only minor changes in the concentrations of plasma cortisol were described in
relation to acute time-limited exercise stress of 1 h [20,29]. This suggests that cortisol
probably does not have a major role in the acute exercise-induced effects.
Glucocorticoids in exhaustive exercise increase the availability for energy in muscle –
accelerating the lipolysis and glycolisis induced by catecholamines and growth hormone- and
play a role in maintaining normal vascular integrity and responsiveness during exercise [24].
In addition, their anti-inflammatory and immunosuppressive effects prevent the immune
system from overreacting as a result of exercise-induced muscle damage [48].

The studies that have examined the effect of adrenocortical insufficiency or subjects
adrenalectomized during exercise have suggested a reduced work capacity, which is improved
by appropriate cortisol replacement [8]. It has been also evidenced that administration of an
adrenergic blocker resulted in a greater cortisol response to exercise than non-competitive
condition [55]. By this, the primary use of exogenous glucocorticoids in exercise is as anti-
inflammatory. Their administration is permitted in aerosol creams and through infiltration.
5. GLUCOCORTICOSTEROIDS AND
ATHLETIC PERFORMANCE
Although steroids are primarily anti-inflammatory, they also have been given other
effects such as analgesics, or metabolics [18,26]. These effects of glucocorticoids suggest that
they could improve the athletic performance: the anti-inflammatory and analgesic effects
could inhibit the sensation of muscle pain and fatigue during exercise. The metabolic effects
could accelerate the muscle fuel availability leading to more efficient use of energy sources
by muscles during exercise. However, these all effects have well been described in patients at
rest and no few studies are reported with exercise [34]. Rochcongar [31] indicated that there
are no clear evidences of steroid improvement effects on athletic performance. Moreover,
glucocorticoids have adverse effects when used at higher doses and for longer periods such as
osteoporosis, insulin resistance, hypertension and atherosclerosis [12]. The adverse effects
clearly limit their use to improve the athletic performance.
Marquet et al. [34], in a study conducted to determine the effect of dexamethasone on the
energy metabolism, cardiovascular adaptation, exercise capacity and hormonal systems that
regulate metabolism of water and electrolytes at rest and exercise, concluded that
dexamethasone did not cause any improvement in physical or psychological capacity. In the
study [34], the authors compared athletes with nonathletes (divided according to their
maximal oxygen uptake, VO2max), using different doses of dexamethasone (4.5 mg / day to
13.5 mg / day) for 4 days. Subjects underwent a graded exercise test to VO2 max. They found
no improvement in performance in those taking dexamethasone, even at higher doses
compared to placebo. They concluded that the VO2max, the ventilatory threshold, the blood
pressure and the lactate at rest and with exercise, were insensitive to treatment with
dexamethasone. Blood glucose at rest was increased, but the effort did not increase in treated
subjects compared to placebo.
In a double-blind long-term study to treat subjects at intervals of 3 weeks with
dexamethasone, there was no evident effect on fitness or objective parameters for assessing
the physical capacity (VO2max, maximum lactate, ventilatory threshold) during exercise
[32,34]. The only significant result from the cardiovascular point of view was that those
taking dexamethasone, presented slightly lower heart rate at rest and during exercise (3-5
beats per minute) but not related to the used dose. Viru and Smirnova investigated the
influence of glucocorticoid levels in trained and untrained subjects [41]. Dexamethasone was
administered for 3 days before the test. These authors found that neither exercise capacity nor
maximal oxygen consumption (VO2 max), and cadence were influenced by the glucocorticoid
administration (dexamethasone during 3 days prior to the test or by injecting 25 U of
corticotropin 30 min pre-exercise).
Many studies conducted to determine the ergogenic effects of glucocorticoids during a

prolonged exercise test to exhaustion at intensities from 70% to 85% VO2max or using short
series of high intensity to exhaustion such as sprint series demonstrated no significant effects
[2,3,9,49]. The main limitation of the studies is the dosage of glucocorticoids used, which
remained within the physiological ranges of plasma cortisol levels [24].
Moreover, the use of steroids in physiological doses does not cause impairment of the
hypothalamic-pituitary adrenal axis. Deuster et al., indicate that the population can be divided
into persons of low and high stress response [23]. These same authors found that in 30-50%
of healthy men and women the release of ACTH and cortisol stimulated by exercise is not
suppressed by previous administration of a 4-mg dose of dexamethasone [22].
6. ASSUMED APPLICABILITY OF CORTICOSTEROIDS

AS AN ERGOGENIC AID
Several authors suggest that corticosteroids (betamethasone, dexamethasone,

triamcinolone, and prednisolone) may help to improve performance. They indicate that this
benefit is because steroids suppress the pain intensity or repetitive muscle contraction,
thereby increasing exercise tolerance. Others say that the hyperglycemic effect allows the
availability of glucose or they may help your euphoric. However, these effects have been
reported only in people at rest. None of these effects has been demonstrated in relation to
physical performance and sportsmanship.
First, the most important indication of steroids is anti-inflammatory, whereas their
analgesic effects are well established. Flórez et al., as other authors in his treatise on
pharmacology specifically mentions that the actions of glucocorticoids are usually classified
into two types: liver glycogen storage capacity and anti-inflammatory activity [26]. From
these pharmacological actions it is well established that steroids cause hyperglycemia, but
also increase insulin resistance. Consequently, corticosteroids reduce the penetration of
glucose into the cells of tissues such as muscle, acting as diabetogenic agent [18,26].
The affirmation that corticosteroids are euphoric is another inaccuracy, although it is
described that steroids give the feeling of wellbeing and euphoria. These hormones often
improve mood, but may cause euphoria, insomnia, restlessness or motor hyper-reactivity, and
sometimes produce anxiety or depression [57]. That is, the intended effect reported as an
extraordinary contribution, it is better considered as a side effect rather than a global positive
action.
If things were as noted by those who suggest the use of corticosteroids for their analgesic,
and hyperglycemic effects and the induction of euphoria, it would make a powerful
combination with an analgesic such as metamizol in a concentrated glucose syrup and
caffeine, all substances permitted, to be gained and secure stronger effects than those
attributed to steroids.
In conclusion, in light of existing scientific literature, one can state that steroids do not
improve athletic performance. Moreover, according to the criteria issued by WADA (World
Anti-Doping Agency) to consider a doping substance: a) improve the physical, b) health
hazard, and c) violation of the spirit of sport, we believe that glucocorticoids do not meet any
of these three requirements, and that their only benefit is derived from the efficacy in the
treatment of inflammatory diseases to disappear, leading the athlete to the normal situation
and therefore can yield under normal conditions.
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INDEX
adverse effects, 122, 143, 147

A
aerobic exercise, 133, 134, 135
Abraham, 6, 16 affective disorder, 20, 23
abuse, 21, 75, 92, 99, 101 age, 15, 46, 70, 72, 76, 78, 82, 83, 97, 99, 109, 137
access, 3, 4, 5, 6, 7, 8, 9, 10, 11, 15, 19, 79 aggregation, 46
accounting, x, 129 aggression, 75, 81, 83, 84, 123
acid, x, 13, 16, 19, 21, 22, 24, 93, 99, 129, 130, 141 aggressive behavior, 42, 75, 80, 85
ACTH, vii, 1, 2, 12, 28, 29, 30, 33, 92, 93, 94, 96, AIDS, 113
97, 99, 100, 104, 112, 114, 117, 121, 132, 142, airways, 145
143, 145, 147 alanine, 126
active transport, 13 albumin, 1, 21, 32
acute stress, 12, 32, 33, 37, 47, 50, 65, 67, 69, 71, 74, aldosterone, 24, 92, 122, 127
79, 132 alertness, 30, 111
AD, 126 allele, 11
adaptation, vii, 1, 2, 27, 28, 30, 41, 42, 68, 71, 74, alters, 15
86, 115, 124, 136, 143, 146 AME, ix, 91, 92, 98, 100
adaptations, 133, 140 amenorrhea, 121
addisonian crisis, 124 American Psychological Association, 68

adenine, 104 amino, 6, 130, 133, 134
adenoma, 121 amino acid, 6, 130, 133, 134
adhesion, xi, 32, 43, 139, 142, 146 amino acids, 6, 130
adipose, ix, 91, 92, 99, 130 amnesia, 45
adipose tissue, ix, 91, 92, 130 amniotic fluid, 124, 127
adiposity, 104 amphibians, 15
adjustment, 44, 54, 55, 68, 75, 77, 84, 87 amplitude, 29
adolescents, viii, 39, 46, 47, 73, 75, 76, 78, 79, 80, amygdala, 30, 31, 36, 37, 43, 45
81, 84, 85, 89, 117, 131 amylase, 40, 47, 74, 75, 85, 86, 87, 88, 89
adrenal gland, x, 1, 2, 29, 43, 97, 121, 122, 129, 145 amyloidosis, 122
adrenal glands, x, 1, 2, 97, 121, 122, 129 anabolism, 134
adrenal insufficiency, 97, 101, 116, 122, 127 analgesic, xi, 139, 142, 144
adrenocorticotropic hormone, vii, 1, 2, 28, 46, 102, anaphylaxis, 19
112, 132 ancestors, 123
adrenocorticotropic hormone (ACTH), vii, 1, 2, 28, anger, 117
112, 132 anorexia, 86
adulthood, 45, 46, 75 anorexia XE "anorexia" nervosa, 86
adults, ix, 39, 46, 75, 77, 79, 81, 82, 84, 88, 94, 95, ANS, 110
97, 100, 103, 107, 108, 113, 114, 116, 122, 126, anterior cingulate cortex, 37, 38
131, 132 antibody, 9
anti-cancer, 6
150 Index
antidepressant, 2, 4, 10, 24, 71 biopsy, 52

antidepressants, 10, 16, 20, 21, 24 birth control, 52, 131
anti-inflammatory agents, 15 birth weight, 97, 103, 122, 125, 126
anti-inflammatory drugs, 142 births, 121
antioxidant, 147 birthweight, 121
anxiety, vii, 1, 10, 11, 19, 24, 25, 34, 35, 38, 74, 78, blood, vii, x, xi, 1, 3, 4, 7, 8, 10, 13, 14, 15, 16, 17,
79, 109, 124, 126, 132, 144 18, 19, 20, 21, 22, 23, 24, 25, 29, 32, 68, 69, 70,
anxiety disorder, vii, 1, 10 72, 74, 86, 92, 97, 100, 101, 120, 123, 125, 129,
apoptosis, 22 130, 131, 132, 134, 139, 140, 143
apparent mineralocorticoid excess syndrome, ix, 91 blood circulation, 29
appetite, 32 blood flow, 86, 120, 125
arginine, 29 blood pressure, 68, 69, 70, 72, 97, 100, 101, 120,
arithmetic, 57 123, 143
arousal, 33, 38 blood stream, 74
arterial hypertension, 104 blood-brain barrier, 3, 4, 8, 14, 16, 17, 18, 19, 20, 21,
arthralgia, ix, 107, 108 22, 23, 24, 25
arthritis, 94, 95 bloodstream, 6, 130
aspartate, 10 BMI, 55, 57, 58, 59, 99
assault, 81 body composition, 46, 136
assessment, 34, 39, 40, 41, 52, 53, 61, 62, 63, 67, body fat, 55, 71, 99
103, 109, 114, 125, 130, 132 body mass index, 55
assets, 78 body mass XE "mass" index XE "body mass index"
asthma, 35, 75, 89, 142 (BMI XE "BMI" ), 55
astrocytes, 24 body size, 54, 58
asymmetry, 85 body weight, 126
atherosclerosis, 143 bone, 86, 104
athletes, 132, 134, 140, 141, 143, 145, 146 boredom, 109
ATP, 8, 18 brain, vii, 1, 2, 3, 4, 6, 7, 8, 9, 10, 11, 13, 14, 15, 16,
attachment, 75, 82 17, 18, 19, 20, 21, 22, 23, 24, 25, 31, 34, 35, 36,
attitudes, 87 38, 40, 41, 42, 43, 44, 110, 114, 115, 121, 125,
autoimmune disease, 102, 142 127, 130
autoimmune diseases, 142 brain damage, 23
autonomic nervous system, 110 brain growth, 125

avoidance, 55, 62, 76, 81 brain stem, 31
avoidance behavior, 55, 62, 76 brain structure, 115
brain tumor, 14
brainstem, 36, 110
B
branching, 13
bargaining, 85 Brazil, 129
barriers, vii, 1, 4, 5, 13, 17, 18, 20 breast cancer, viii, ix, 49, 50, 51, 52, 53, 55, 56, 57,
basal lamina, 18 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70,
BBB, 3, 4, 5, 6, 7, 8, 9, 10, 11, 13, 14, 15 72, 107, 108, 113, 117
behavioral problems, 75, 76 burnout, 65, 68
behaviors, viii, 55, 62, 73, 75, 76, 78, 79, 80, 81, 82, bypass graft, 96
88
beneficial effect, x, 33, 129, 130 C
benefits, 94, 147
bias, 52 caffeine, 144
binding globulin, 32, 43, 120 calcium, 21, 140
biological barriers, vii, 1 cancer, viii, 12, 49, 50, 52, 53, 55, 56, 57, 58, 60, 61,
biological responses, 51, 123 62, 63, 64, 65, 66, 67, 68, 69, 71, 72, 108, 113,
biomarkers, 68, 74, 75, 110 140
biophysical correlates, vii Cancer-related fatigue, 113
Index 151
candidates, 15 circadian rhythmicity, 72

capillary, 4, 6, 8, 14, 21 circadian rhythms, 56, 65
carbohydrate, 120, 141 circulation, 29, 121
carbohydrate metabolism, 120 citalopram, 12
carbohydrates, 120 City, 45, 51, 91
carcinoma, 7, 121, 122 classical conditioning, 79
cardiomyopathy, 100, 105 clinical presentation, 110
cardiovascular disease, 140 clothing, 78
cardiovascular disorders, 97 CNS, 5, 6, 10, 20, 23, 24, 110
cardiovascular function, 120 coding, 42, 141
cardiovascular risk, 102, 105, 126 cognition, 33, 40, 46
cardiovascular system, 70 cognitive dysfunction, 35
caregivers, 82 cognitive function, vii, 27, 30, 32
catabolism, xi, 130, 139 cognitive performance, 140, 145
catecholamines, 50, 53, 54, 56, 65, 68, 69, 70, 71, cognitive process, 22, 32, 44, 72
74, 114, 142 cognitive processing, 22, 44, 72
causality, 79 cognitive-behavioral therapy, 112
CCR, ix, 91, 93, 94, 95, 96, 97, 98, 99, 100, 101 collagen, 23
CDC, 109 colon, ix, 91, 92
cell culture, 7, 8, 16, 19, 22, 23 communication, 33, 84
cell line, 7, 8, 14, 24 community, 47, 74, 78, 82, 83, 115, 117
cell lines, 7, 8 competition, 131, 132, 141, 142, 145
cell membranes, 13, 17, 141 competitive sport, 145
cell signaling, 140 complement, 135
cellular immunity, 140 complexity, 50, 135
central nervous system, ix, 4, 17, 19, 22, 30, 33, 35, complications, 100, 121
47, 65, 91, 92, 110 composition, 3, 131, 136
central nervous system XE "nervous system" (CNS), compounds, 4, 5, 6, 8, 10, 16
30, 110 conception, 98
central obesity, 99 conductance, 75
cerebral blood flow, 36, 46 conflict, x, 119
cerebral cortex, 14, 20 conformity, 51
cerebrospinal fluid, 2, 3, 4, 102 congenital adrenal hyperplasia, 132

challenges, 32, 34, 36, 38, 39, 85 connectivity, 38, 45, 46
chemical, 19, 20, 103 consciousness, 30
chemicals, 3 Consensus, 123, 126
chemoprevention, 22 conservation, 85
child maltreatment, 83 consolidation, 33
childhood, 45, 46, 47, 82, 110 constipation, 35
children, vii, viii, 71, 73, 75, 76, 77, 78, 79, 81, 82, consumption, 104, 120
83, 84, 86, 87, 88, 89, 97, 100, 101, 103, 131 contingency, 88
cholesterol, ix, 1, 3, 28, 68, 91, 92 control group, 78, 80, 97, 100, 135
choroid, 4, 6, 10, 18, 19 cooperation, 85
chromatography, 93, 95, 96, 97, 100, 103 coordination, 81
chronic fatigue, ix, 92, 107, 108, 109, 112, 113, 114, coping strategies, 38
115, 116, 117, 118, 132, 137, 142 correlation, 36, 96, 132
chronic fatigue syndrome, ix, 92, 107, 108, 109, 113, correlation coefficient, 96
114, 115, 116, 117, 118, 132, 137 correlations, 46, 47
chronic illness, 118, 121 cortex, x, xi, 15, 17, 28, 29, 33, 37, 92, 129, 130,
chronic renal failure, 104 139, 141
circadian cortisol rhythms, ix, 107, 108 corticosteroids, xi, 14, 20, 23, 33, 43, 45, 124, 125,
circadian rhythm, ix, xi, 29, 55, 56, 65, 72, 91, 92, 127, 139, 141, 143, 144, 145, 147
129, 136 corticotropin, vii, 1, 2, 10, 23, 28, 29, 143
152 Index
corticotropin-releasing hormone (CRH), vii, 1 diabetes, 100, 105, 121, 126, 140
cortisol activity, vii, 75 diagnostic criteria, 113
cortisol receptor types, vii, 27 diarrhea, 35
cost, 131 diet, 1
cotton, 131 diffusion, 5, 6, 8, 13, 130
covering, 4 directionality, 112
creatine, 140 disaster, 74, 76, 78, 82, 83, 84, 85, 86, 87, 88
creatinine, 54, 70, 72 disease activity, 110
CRF, 11, 12, 100 diseases, vii, ix, xi, 1, 2, 3, 12, 14, 20, 74, 92, 93,
critical period, 123 100, 108, 139, 142, 145
cross-sectional study, 60 disorder, ix, 21, 47, 83, 84, 107, 108, 114, 118
CRP, 95, 102, 141 dispersion, 74
CSF, 4, 9, 19 displacement, 74, 77, 79, 80
cues, 34 disposition, 32
culture, 8 distilled water, 131
currency, 66 distress, viii, 34, 35, 69, 73, 74, 76, 78, 79, 80, 81,
CVD, 100 82, 83, 109
cycles, 29, 98, 103, 117, 133 distribution, 7, 8, 10, 16, 17, 20, 21, 31, 55, 71, 99
cyclooxygenase, 141 diversity, 15, 42
cytokines, x, xi, 19, 32, 33, 86, 107, 108, 110, 115, DNA, 141, 146
130, 134, 139, 140, 141, 142 DNA damage, 146
cytoplasm, 2, 66, 141 docosahexaenoic acid, 13, 16
cytotoxicity, 43 domestic tasks, 51
dominance, 80
doping, 144, 146
D
dosage, 94, 143
danger, 123 down-regulation, vii, 1
data analysis, 70 drug delivery, 4, 13, 17, 21, 22
data collection, 53, 78 drug dependence, 23
database, 116 drug discovery, 12
deaths, 121 drug efflux, 4, 11, 20
declarative memory, 33 drug resistance, 6, 9, 18, 19, 22
deficiency, ix, 24, 97, 102, 107, 108, 116, 122 drugs, xi, 3, 4, 6, 8, 10, 12, 24, 139
deficit, vii, 1, 122
degradation, 23 E
demographic characteristics, 52
demographic data, 54 earthquakes, 87
Department of Defense, 67 economic disadvantage, 74
depression, vii, ix, 1, 2, 3, 4, 10, 11, 12, 13, 16, 17, ectopic pregnancy, 121
18, 19, 20, 22, 24, 35, 38, 40, 47, 74, 77, 79, 80, eczema, 35
83, 84, 85, 91, 92, 100, 101, 102, 104, 107, 108, edema, 15, 17
109, 114, 117, 132, 144 editors, 137
depressive symptomatology, 84 education, 78
depressive symptoms, 19, 80, 87, 117 efflux transporters, 5, 6, 8
deprivation, 133 El Salvador, 87
desensitization, 79 electrical resistance, 4
destruction, 122 e-mail, 107
detection, 36, 54, 125 emotion, 36, 37, 45, 87, 88
deterrence, 87 emotion regulation, 36
developmental change, 76 emotional disorder, 28
developmental process, 120 emotional processes, 30
dexamethasone suppression test, 97, 101, 114, 116, emotional stimuli, 37, 45
131 emotional valence, 33
Index 153
employment, 51, 53, 66 exertion, 108, 109, 145

encephalitis, 14 exocytosis, 13
encephalomyelitis, 22 experimental condition, 52
endocrine, 12, 43, 44, 51, 52, 53, 55, 66, 69, 79, 86, experimental design, 51
110, 113, 122, 125, 127, 133 exploitation, 83
endocrine disorders, 127 exposure, viii, 4, 11, 20, 34, 35, 38, 39, 73, 74, 75,
endocrinology, 124 76, 77, 78, 79, 82, 121, 124, 125, 126, 127, 128
endogenous synthesis, 1 expressivity, 72
endorphins, 102 external environment, 34, 39, 66
endothelial cells, 4, 5, 8, 14, 17, 21, 22 externalizing behavior, 81, 82
endothelium, 5, 6, 14 extravasation, 140
endurance, 137, 140, 144
energy, x, 92, 108, 109, 120, 123, 124, 129, 130,
F
142, 143
energy expenditure, 120, 123, 124 facial expression, 89
engineering, 28 families, 77, 78, 79, 83
England, 21, 74, 85 family characteristics, 76, 83
enlargement, 2, 95 family history, viii, 49, 62, 63, 67, 69, 71
environment, 34, 39, 51, 75, 120, 123, 134 family members, 80
environmental conditions, 66 fasting, 100, 130, 133, 134
environmental factors, 39, 71 fasting glucose, 100
environmental influences, 29 fat, x, 55, 92, 110, 129, 141
environmental stress, 70, 123 fatty acids, 13, 23, 130
environments, 69, 70, 131 fear, 62, 67, 75
enzyme, ix, 2, 91, 92, 94, 95, 96, 97, 98, 99, 100, 104 fears, 76, 88
enzymes, ix, 91, 92, 93, 99, 101, 102, 130 feelings, 35, 80
EPA, 13 fertility, x, 119
epidemiology, 68 fertilization, ix, 92, 103
epinephrine, 50, 53, 54, 55, 57, 58, 59, 60, 61, 62, fetal development, 14, 76, 102, 124, 125
63, 65, 66, 67, 69, 84, 120, 130 fetal growth, 86, 95, 122, 123, 125, 126
epithelia, 98 fetal growth retardation, 126
epithelial cells, 13, 18, 147 fetus, x, 20, 23, 95, 119, 120, 121, 122, 123, 125,
epithelium, 4, 13, 21, 23 126, 127

equilibrium, 28, 97 fibers, 140
erythrocytes, 19 fibromyalgia, 102
ester, 28 Filipino, 68
estrogen, 120, 127 filtration, 122, 128
ethnicity, 78 financial, 78, 79, 121
etiology, 50, 110, 114 first degree relative, 65
euphoria, 144 fish, 15
everyday life, 50, 51 fitness, 143
evidence, 4, 9, 10, 11, 12, 14, 15, 16, 19, 22, 34, 35, fluid, 4, 22, 97, 98
36, 44, 47, 50, 52, 66, 75, 97, 103, 111, 112, 124, fluorescence, 100
147 fluoxetine, 12, 21, 24
evolution, 20, 85, 124 fluvoxamine, 12
exaggerated immune system, x, 129 fMRI, 37, 43, 45
excitability, 2, 31 follicle, 103
exclusion, 38 follicular fluid, 98
excretion, viii, 49, 54, 55, 56, 57, 58, 59, 60, 61, 62, food, 78, 120
63, 64, 70, 71, 72, 120, 128, 132, 137 force, x, 119, 140, 146
exercise, x, xi, 36, 129, 130, 133, 134, 135, 136, 137, formation, 13, 15, 96
138, 139, 140, 141, 142, 143, 144, 145, 146, 147 formula, 55
exercise performance, 140 France, 119
154 Index
functional MRI, 46 growth hormone, 71, 98, 101, 103, 127, 130, 135,
funding, 16 136, 142
fungal infection, 122 growth rate, 123
Gulf Coast, 77
G
H
gastroesophageal reflux, 93, 122, 124
gastrointestinal tract, 122 habituation, 74, 79, 81
gel, 15, 17 harmful effects, 95
gene expression, 47, 86, 120, 140 HE, 126
gene promoter, 12 headache, 13, 109
gene regulation, 42 healing, 82, 141
generalized tonic-clonic seizure, 102 health, vii, viii, ix, 18, 27, 40, 41, 42, 49, 50, 66, 67,
genes, viii, 27, 40, 50, 66, 141 74, 83, 87, 88, 107, 108, 114, 117, 120, 121, 125,
genetic factors, 46, 67, 76 135, 140, 144, 146
genetic predisposition, viii, 49 health problems, 74
genetics, 40, 71, 147 heart rate, 68, 122, 126, 127, 143
genotype, 11 height, 97
Georgia, 116 heredity, 82
Germany, 47, 107 heritability, 87
gestation, x, 102, 119, 121, 122, 126 heteroscedasticity, 61
gestational age, 103, 123, 124, 127 high fat, 111
gill, 22 hip replacement, 69
gland, 2, 10, 13, 23, 92 hippocampus, 8, 30, 31, 36, 37, 45
glia, 19 histamine, 18
glucagon, 126, 130 history, 46, 52, 62, 67, 78, 84
glucocorticoid, vii, ix, x, 1, 2, 6, 10, 14, 15, 17, 18, HIV, 6, 52, 109, 113
19, 20, 21, 22, 24, 27, 28, 29, 30, 39, 40, 41, 42, HM, 41, 137
43, 46, 65, 68, 72, 85, 91, 92, 94, 98, 102, 107, homelessness, 81
108, 115, 116, 117, 129, 130, 141, 143, 145, 147 homeostasis, 28, 29, 84, 92, 95
glucocorticoid receptor, vii, 1, 10, 19, 21, 27, 30, 39, hopelessness, 80
42, 46, 65, 72, 94, 141, 147 hormone, vii, x, xi, 1, 2, 10, 11, 16, 19, 28, 29, 31,
glucocorticoids, ix, xi, 2, 3, 6, 7, 8, 13, 14, 15, 17, 32, 50, 65, 66, 74, 86, 92, 97, 103, 110, 119, 123,
18, 19, 20, 25, 29, 31, 32, 33, 35, 43, 71, 91, 92, 130, 131, 132, 133, 137, 139, 147
93, 120, 121, 123, 126, 127, 136, 139, 141, 142, hormone levels, 86, 123
143, 144, 145, 146, 147 hormones, viii, ix, 6, 10, 16, 21, 24, 28, 29, 30, 31,
gluconeogenesis, x, 32, 122, 129, 130 32, 40, 43, 49, 50, 66, 67, 68, 76, 84, 94, 107,
glucose, x, xi, 6, 17, 19, 24, 32, 92, 100, 110, 120, 108, 122, 124, 127, 130, 133, 137, 138, 141, 144,
121, 126, 129, 130, 139, 143, 144 146
glucose tolerance, 121 host, viii, 27, 28, 32, 35, 117
glutamate, 24, 31, 36, 42 HPA axis, vii, ix, x, 1, 2, 3, 10, 11, 12, 13, 18, 28,
glutamine, 145 29, 30, 31, 32, 34, 35, 36, 37, 38, 39, 40, 41, 42,
glycerol, 130 44, 45, 46, 65, 66, 79, 91, 93, 95, 96, 97, 107,
glycogen, xi, 32, 139, 144 108, 110, 111, 112, 114, 119, 123, 126, 142
glycoproteins, 20, 24 human, vii, x, 1, 6, 7, 8, 9, 10, 14, 16, 18, 19, 22, 24,
graduate students, 111 27, 28, 33, 35, 37, 38, 40, 43, 44, 45, 47, 68, 70,
grants, 67 80, 84, 85, 88, 95, 102, 103, 104, 113, 119, 122,
graph, 61 124, 125, 126, 127, 130, 136, 147
growth, 6, 71, 95, 97, 98, 101, 103, 120, 122, 123, human behavior, 45
126, 127, 130, 133, 135, 136, 140, 141, 142 human body, 28, 130
growth arrest, 141 human brain, 8, 19
growth factor, 6, 123 human chorionic gonadotropin, 24
human cognition, 40
Index 155
human development, 113 infants, 78, 86

human health, vii, x, 1, 119 infection, xi, 32, 111, 113, 139
Hurricane Andrew, 78, 88 inflammation, 2, 94, 95, 96, 102, 113, 120, 140, 141,
Hurricane Katrina, viii, 73, 77, 78, 79, 81, 88, 89 142, 145, 146
hydrocortisone, xi, 14, 18, 112, 139, 141 inflammatory bowel disease, 142, 144
hydrolysis, 130 inflammatory cells, 140, 141
hyperactivity, 2 inflammatory disease, 144
hyperarousal, 76 inflammatory mediators, 19
hyperglycemia, 144 inflammatory responses, 110, 146
hyperplasia, 92 informed consent, 54
hypertension, ix, 35, 91, 92, 94, 95, 98, 99, 101, 102, inhibition, xi, 2, 4, 11, 13, 15, 18, 24, 30, 32, 36, 42,
103, 104, 121, 124, 143 75, 85, 103, 139
hypertrophy, 140 inhibitor, 22, 23, 133
hypoglycemia, 122 injections, 126
hypokalemia, 98 injury, 36, 77, 140
hypotension, 122 innate immunity, 117
hypothalamic-pituitary-adrenocortical (HPA), vii, 1, insomnia, 144
2 insulin, 6, 71, 92, 103, 120, 126, 130, 135, 143, 144
hypothalamo-pituitary-adrenal axis, 17, 24 insulin resistance, 103, 143, 144
hypothalamus, vii, 1, 2, 3, 8, 15, 28, 29, 30, 31, 33, integration, 41, 43, 44, 115, 146
35, 36, 41, 42, 70, 92, 110, 114 integrity, x, 2, 8, 21, 129, 130, 142
hypothesis, 2, 11, 19, 35, 52, 77, 79, 80, 81, 83, 120 interaction effect, 56, 60
interference, 55
internalizing, 75, 78, 79, 80, 81, 82
I
intervention, 83, 112, 134, 135, 146
ID, 127 intramuscular injection, 123
IL-8, 33, 147 intrauterine growth retardation, 122, 124
immobilization, 28 intrusions, viii, 49, 55, 64, 68
immune activation, 112 investment, 123
immune function, 2, 74, 110, 125 investments, x, 120
immune modulation, 114 ion channels, 31
immune response, xi, 2, 32, 85, 92, 101, 139, 141, ion transport, 17
146 ionization, 103

immune system, x, 30, 32, 33, 43, 85, 88, 94, 108, ions, 13
110, 111, 120, 129, 142, 146 ischemia, 14, 18, 20
ISCHEMIA XE "ISCHEMIA" -REPERFUSION INJURY,
immunity, 32, 43, 120, 145
immunomodulator, 145 14
immunosuppression, ix, 91, 92, 100 isolation, 40
improvements, 40 issues, 35, 111
impulsivity, 75
in utero, 20, 124 J
in vitro, ix, 7, 8, 11, 13, 14, 18, 21, 92, 103, 147
in vivo, 7, 11, 13, 14, 15, 21, 94 job strain, 68
incidence, 95, 122 joint pain, 109
income, 77, 78, 83, 84, 127 Jordan, 115
Independence, 147
individual differences, 38, 39, 47, 75, 79, 86
K
individuals, viii, ix, 11, 30, 36, 37, 38, 51, 54, 68, 73,
74, 82, 107, 108, 112, 117, 131, 132, 133, 134, kidney, ix, 8, 15, 91, 92, 93, 95, 100, 103, 104, 122,
135 132
induction, 14, 22, 33, 144 kidney XE "kidney" transplantation, 104
industry, 10 kinetic parameters, 2
infant mortality, 127 kinetics, 147
156 Index
magnitude, 38, 50, 66

L
major depression, 2, 19, 21, 23, 47, 85, 101, 104,
laboratory studies, 79 118, 137
lactate dehydrogenase, 140 major depressive disorder, 30
lactation, 14, 124 majority, 3, 10, 32, 55, 120
lactose, 14 malaise, ix, 107, 108, 109
Lake Pontchartrain, 77 maltreatment, 46, 47, 83
language development, 121 mammals, x, 15, 119
LC-MS, 95, 96, 97, 100 mammogram, 52
LC-MS/MS, 95, 96, 97, 100 mammography, 69
lead, 11, 28, 31, 66, 92, 111, 134, 141 man, 41, 137
learning, 33, 34, 79, 82 management, 71, 87
learning process, 34 mannitol, 13
lecithin, 124, 127 marital status, 71
leisure, 51 mass, x, 55, 60, 93, 96, 103, 119, 120
leptin, 6, 136, 138 mass spectrometry, 93, 96, 103
lesions, 14, 36 mast cells, 15, 18
LEUKOCYTES, 33, 142
materials, 13
levees, 77 maternal care, 46
LFA, 43 measurement, vii, ix, 13, 83, 92, 97, 109, 118, 131,
life experiences, viii, 27, 39, 47, 82 132
lifetime, viii, 39, 49, 55, 77 measurements, 50, 53, 54, 77, 81, 112, 130, 131, 137
ligand, 30 median, 29, 55, 96
light, xi, 35, 50, 93, 140, 144 medical, xi, 3, 15, 17, 52, 54, 110, 137, 139
limbic system, viii, 34, 36, 44, 73 medical history, 54
lipids, x, 129 medication, 13, 21
lipolysis, 32, 142 medicine, 28, 137
liquid chromatography, 93, 100, 103 membranes, 3, 4, 6, 11, 13, 16, 95, 127, 141
liver, ix, 17, 32, 91, 92, 94, 95, 122, 126, 130, 144 memory, 21, 25, 33, 36, 43, 45, 92, 109
living conditions, 78 memory function, 92
local community, 78 memory performance, 45
localization, 4 memory processes, 33
locus, 45 memory retrieval, 33

longitudinal study, 70, 117 meningitis, 14, 23
lordosis, 20 mental arithmetic, 44
Louisiana, 77, 78 mental health, 3, 15, 35, 45, 87, 89, 127
low birthweight, 121 mental illness, 39
low-density lipoprotein, 28 mental retardation, 121
lumen, 13 meta-analysis, 33, 41, 42, 43, 66, 112, 115, 125
lying, 51 Metabolic, 68, 136, 146
lymph, 109 metabolic changes, 141
lymph node, 109 metabolic syndrome, 35
lymphocytes, 33, 130, 141 metabolism, x, 1, 2, 4, 17, 23, 86, 92, 98, 101, 104,
lysis, 130 110, 119, 120, 127, 129, 130, 141, 143, 144, 146,
147
metabolites, ix, 54, 92, 93, 97, 99, 100, 102
M metabolized, 9, 94, 130
metaphor, 87
machinery, 42 metastatic disease, 68
macrophages, 142 methodology, 70, 137
macular degeneration, 15 Mexico, 73
magnetic resonance, 14, 23, 44 mice, 2, 4, 7, 8, 9, 11, 12, 19, 20, 24, 121
magnetic resonance imaging, 14, 44 microenvironments, 51, 52, 54, 56, 60, 66
magnetic resonance spectroscopy, 23
Index 157
microRNA, 42 nervous system, 4, 20, 30, 42, 110

migration, 147 Netherlands, 127
mineralocorticoid, vii, ix, 21, 27, 30, 42, 65, 91, 92, neurasthenia, 118
95, 99, 101, 102, 103, 104 neurobiology, 40, 120
mineralocorticoid receptor, ix, 91, 92 neurodegenerative diseases, 17
Missouri, 78, 102 neuroimaging, vii, 27, 35, 36, 37, 38, 40, 44, 47
mitogens, 142 neuroinflammation, 22
MMP, 23 neurokinin, 10
MMP-9, 23 neurons, 19, 20, 29, 36
models, 7, 18, 45, 69, 70, 71, 81, 121 neuroprotection, 19
moderates, 79, 85, 86 neurotoxicity, 19, 24
modifications, 115 neurotransmission, 10, 12
molecular biology, 40, 68 neurotransmitters, 31, 32
molecular weight, 5, 6 neutrophils, 140, 141
molecules, xi, 3, 4, 6, 10, 13, 32, 33, 130, 139, 142 nicotinamide, 104
mood disorder, 88 norepinephrine, 50, 53, 54, 55, 57, 59, 62, 74, 120
Moon, 19, 124 North America, 124
morbidity, 74 nuclear receptors, 30, 31
morphology, 120, 127 nuclei, 36
mortality, 122 nucleus, 29, 36, 66, 110
Moses, 75, 87 null, 7, 9
motivation, 109 nurses, 68
motor system, 30 nutrient, 6
MR, ix, 30, 31, 42, 91, 92, 98, 99 nutrients, 6
MRI, 14
mRNA, 15, 102
O
multidimensional, 109, 118
multiple regression, 46 obesity, vii, 1, 58, 72, 92, 99, 101, 104, 109
multiple regression analysis, 46 oleic acid, 13
multiple sclerosis, 14, 18, 22, 23, 108, 113 omega-3, 21
muscle contraction, 144 oocyte, 98
muscle mass, x, 129, 137 opportunities, 81
muscle strength, 134, 137, 138 optic neuritis, 14, 18

muscles, 135, 142 organ, 94, 122
musculoskeletal, 94 organism, 28, 29, 31, 32, 33, 35, 39, 40, 130
music, 133 organs, x, 119, 121, 126, 141
mutation, 71, 104 oscillation, 29, 30
myalgia, ix, 107, 108 osteoporosis, ix, 91, 92, 101, 143
myocardial infarction, 100 outpatient, 96
ovarian cancer, 71
N overproduction, 121
overtraining, 142, 147
NAD, 124 ovulation, 98
National Academy of Sciences, 69 oxidation, ix, 92, 93, 98, 120, 130
National Institutes of Health, 123 oxidative damage, 140
natural disaster, vii, viii, 73, 74, 77, 81, 82, 85, 86, oxidative stress, 146, 147
87, 89 oxygen, 143
natural disasters, vii, viii, 73, 74, 81, 82, 85 oxygen consumption, 143
natural killer cell, 32
necrosis, 145
P
negative consequences, 74
negative effects, x, 119, 122 paclitaxel, 12
neonates, x, 119, 124 pain, 28, 35, 36, 109, 110, 113, 142, 144
158 Index
parenting, 88 polymorphisms, 39, 46, 65, 72

parents, 82 polypeptide, 6, 16, 21, 24
paroxetine, 12 polypeptides, 19
participants, 38, 50, 54, 66, 78, 94 polyunsaturated fat, 13, 21
parvicellular, 29 polyunsaturated fatty acids, 21
pathogenesis, 99, 101 pools, 28
pathogens, 117 population, ix, 65, 67, 70, 71, 107, 108, 109, 111,
pathology, 13 113, 115, 116, 117, 143
pathophysiological, 44 portal vein, 29
pathophysiology, 11, 21, 22, 72, 110, 114, 117, 127 positive emotions, 77
pathways, vii, 4, 27, 46, 50, 140 positive feedback, 42
PCR, 95 positive relationship, 36, 111
pelvic inflammatory disease, 95, 102 positron, 44
peptide, 6, 92, 100, 105 positron emission tomography, 44
perfusion, 8, 9, 25, 123 posttraumatic stress, ix, 47, 83, 107, 108, 114, 118
perinatal, 126 post-traumatic stress disorder, 40, 74, 86
peripheral blood, 117 posttraumatic stress disorder (PTSD), ix, 107, 108
peripheral blood mononuclear cell, 117 potassium, 99, 113
permeability, 4, 7, 8, 13, 14, 15, 16, 18, 19, 21, 22, prednisone, 94, 102, 126
23, 24 preeclampsia, 124
permeation, 4, 6, 16, 17 prefrontal cortex, 30, 31, 34, 36, 37
personality, viii, 27, 38, 39, 46, 110 pregnancy, x, 84, 98, 103, 119, 120, 121, 122, 123,
personality traits, 39, 46 124, 125, 126, 127
pharmaceutical, 9, 10, 12, 13, 17 premature infant, 125
pharmacological treatment, 112 prematurity, 123
pharmacology, 41, 144 preparation, 69
phenotypes, x, 120, 123, 136 preschool, 76
Philadelphia, 124 preschoolers, 75, 84, 88
phosphate, 127 preservative, 54
phospholipids, 3, 23 preterm delivery, 122
physical activity, 135, 147 preterm infants, ix, 92, 95
physical exercise, vii, 130, 132, 133, 135, 140, 145 prevention, 125
physical health, 74 primate, 87

physical stressors, 28 probability, 11, 137
physicochemical properties, 4, 6 processing biases, 88
Physiological, 34, 68, 71, 72, 84, 114, 137 progesterone, 16, 24, 122
physiology, vii, 1, 6, 20, 27, 32, 40, 43, 120 prognosis, 102, 125
physiopathology, vii, 1 programming, 39, 121, 123, 127
pigs, 121, 124, 125 pro-inflammatory, xi, 94, 115, 139, 140, 141
pilot study, 84, 89, 95 project, 29, 47
pituitary gland, 10, 24, 29, 31, 92 prolactin, 102
pituitary tumors, 132 promoter, 31
placebo, 134, 143 protease inhibitors, 6
placenta, x, 95, 100, 119, 120, 126, 127 protein synthesis, x, 120, 129, 133, 141
plasma levels, x, 119, 133, 134, 141 proteins, x, 1, 3, 4, 6, 13, 14, 15, 17, 18, 22, 42, 94,
plasticity, 20, 123 120, 129, 140, 141
plexus, 4, 6, 10, 16, 18, 19, 22 proteolytic enzyme, 142
PM, 46, 54, 126, 127, 145 psychiatric disorders, 40
pneumonia, 97 psychiatry, 2, 16, 17, 18, 21, 24
Poland, 46, 54, 69 psychological distress, viii, 34, 35, 73, 76, 85, 116
polarity, 13 psychological illnesses, 35
policy, 87 psychological resources, 37, 83
polymorphism, 11, 21
Index 159
psychological stress, viii, 11, 29, 33, 34, 35, 36, 37, resistance, 4, 11, 17, 20, 22, 24, 39, 115, 137, 140,
38, 39, 40, 41, 43, 45, 46, 49, 68, 69, 86, 114, 145
115, 121 resolution, 37
psychological stressors, 34, 36, 68, 114 resources, 37, 39, 45, 85
psychological well-being, 79, 82, 88, 89 respiratory distress syndrome, 122, 123, 125
psychology, 83 responsiveness, 4, 41, 44, 47, 110, 115, 142
psychopathology, 44, 123, 124 restoration, 30
psychosocial factors, viii, 42, 68, 73 retardation, x, 119
psychosocial stress, 12, 28, 32, 34, 41, 44, 46, 47, 50, retinal disease, 15
65, 72, 79, 82, 86, 111, 115 RH, 2
psychosomatic, 114 rheumatoid arthritis, 102, 113, 142, 145
psychotherapy, 113 rhythm, ix, 29, 41, 66, 71, 91, 92, 107, 113, 115, 117
PTSD, ix, 69, 75, 77, 84, 85, 89, 107, 108 rhythmicity, 29, 68, 108
purification, 124 risk, viii, 10, 28, 39, 44, 49, 50, 51, 52, 53, 55, 56,
57, 58, 59, 60, 61, 62, 65, 66, 67, 68, 69, 70, 77,
81, 83, 84, 89, 94, 97, 100, 109, 112, 121, 122,
Q
123, 140, 146
quality of life, 135 risk factors, 109, 140
risk perception, 55, 62
risks, x, 71, 81, 119
R roots, 50
routes, 4
race, 78, 134, 135, 141, 145 rules, 6, 132
racing, 134
radio, 8
RE, 41, 46 S
reactions, vii, 1, 82, 84, 130, 131, 141
reactive oxygen, 140 sadness, 82
reactivity, viii, 18, 37, 39, 45, 46, 49, 50, 51, 52, 57, safety, 13
62, 65, 67, 69, 70, 71, 73, 74, 75, 76, 77, 79, 80, saliva, ix, x, 29, 41, 92, 93, 113, 114, 129, 130, 131
81, 83, 84, 85, 86, 87, 88, 144 salivary gland, ix, 91, 92
receptors, 2, 3, 6, 11, 18, 19, 21, 29, 30, 31, 32, 42, salivary glands, ix, 91, 92
sarcopenia, 135, 136
65, 92, 110, 145

recognition, 50, 87, 100 saturation, 99
recommendations, 18 schizophrenia, 121, 127
recovery, 30, 69, 74, 82, 134, 141, 145 school, 76, 82, 83
recreation, 135 science, 137
regeneration, 146 sclerosis, 14
regression, 117 secrete, 29, 92
rehabilitation, 135 secretion, vii, viii, ix, x, xi, 1, 2, 3, 6, 9, 11, 12, 14,
rejection, 88 27, 29, 30, 31, 33, 35, 36, 40, 41, 47, 55, 91, 93,
relatives, viii, 49, 50, 51, 52 101, 107, 108, 110, 111, 115, 121, 126, 131, 136,
relevance, 4, 11, 19, 21, 40, 114, 120 137, 139, 147
reliability, viii, 73, 82 security, 79
repair, 130, 141, 146 selectivity, 13
repetitions, 134 self-efficacy, 74
replication, 117 self-esteem, 38, 46, 74, 78, 79, 81
repression, 94 sensation, 142
reproduction, x, 119, 123 sensitivity, 2, 30, 37, 39, 40, 47, 54, 79, 93, 112, 115,
requirements, 126, 144 136
researchers, 3, 12, 40, 51, 75, 82, 114, 132 septum, 31
reserves, x, 97, 119, 129 serotonin, 12, 15, 22
residential neighborhood, 78 serum, ix, 9, 13, 19, 20, 41, 92, 93, 96, 98, 99, 103,
resilience, 39, 81, 87 104, 134, 135, 137, 138, 140, 142, 145
160 Index
SES, 78 stimulation, 28, 32, 44, 95, 97, 145

sex, viii, 32, 69, 70, 73, 78, 80, 82, 88, 109 stimulus, x, 34, 36, 110, 119, 133
sex differences, 80, 88 storage, 32, 120, 132, 144
shame, 34 strength training, 133, 134, 135
sheep, 15, 125, 126 stress factors, 113
shelter, 87 stress reactions, 76
shock, 126 stress response, vii, viii, x, 27, 28, 32, 34, 35, 37, 38,
showing, 2, 9, 35, 79, 96 39, 41, 42, 43, 45, 46, 50, 52, 65, 68, 70, 71, 73,
side effects, xi, 13, 16, 94, 139 77, 82, 84, 85, 88, 114, 119, 125, 143, 147
simulation, 89 stressful life events, 11
sinus arrhythmia, 86 stressors, 28, 32, 36, 41, 44, 52, 56, 57, 58, 65, 67,
skeletal muscle, 140, 147 68, 69, 70, 74, 79, 80, 81, 84, 121, 125
skin, 15, 75 stromal cells, 99
sleep deprivation, xi, 129 structure, 4, 5, 13, 76, 123, 131, 140
sleep disorders, 19, 35 style, 68
sleep disturbance, 74, 102, 121 subgroups, 38
SNS, 74, 75, 77, 79, 81 subjective experience, 109, 110
social behavior, 80 subjective fatigue, 117
social capital, 82, 83, 84 substance abuse, 74
social context, 51 substrate, 4, 6, 7, 8, 11, 19, 124, 130
social environment, viii, 73, 82 substrates, x, 6, 8, 10, 11, 12, 129
social evaluation, 28, 36, 77 subtraction, 36
social exclusion, 77 suicide, 17
social hierarchy, 87 sulfate, 16
social interactions, 39 Sun, 71, 120, 127
social network, 76, 80, 81, 82 supervision, xi, 139
social perception, viii, 73 supplementation, 133, 145
social relations, 51, 83 suppression, 2, 121, 136
social relationships, 51 suprachiasmatic nucleus, 30
social resources, 74 surfactant, 122
social standing, 77 survival, 22, 28, 110, 117, 123
social status, 80 survivors, 69, 81, 87, 89, 113
social stress, 45 susceptibility, 42, 50, 74, 84, 140

social support, 38, 39, 46, 47, 79, 82, 87, 88 sympathetic nervous system, viii, 28, 40, 68, 72, 73,
socioeconomic status, 41, 76, 86 74, 84, 87
sodium, ix, 54, 91, 92, 98, 99, 113, 128 symptomology, 86
solution, 21, 134 symptoms, ix, 11, 28, 35, 75, 76, 78, 79, 80, 84, 85,
somnolence, ix, 107, 108 86, 88, 89, 107, 108, 109, 110, 132
Spain, 1, 139 synchronize, 123
spatial learning, 34 syndrome, ix, 40, 42, 91, 92, 94, 99, 101, 102, 104,
species, x, 119, 121, 140 115, 116, 118, 121, 123, 124, 125, 131, 132, 136
Spring, 104 synergistic effect, 50
Sri Lanka, 89 synthesis, xi, 15, 41, 68, 120, 122, 130, 139, 141
SS, 41, 147
stabilization, 2
T
stable states, 66
standard deviation, 53, 61, 62 T cell, 18
starvation, 101 T lymphocytes, 18, 147
state, x, 33, 34, 38, 45, 86, 87, 99, 107, 108, 144 target, 2, 11, 18, 30, 32, 40, 140
states, 38, 87 taxonomy, 71
status epilepticus, 102 teams, 9
steroids, xi, 8, 17, 19, 20, 23, 100, 127, 139, 142, techniques, 6, 9, 35, 93, 131
143, 144, 145 temperament, 84, 88
Index 161
temperature, 19, 125, 131, 135 triiodothyronine, 120

tempo, 92 trustworthiness, 80, 81, 82
temporal lobe, 36 tuberculosis, 97, 103, 122
tension, 34 tumor, 33, 93, 102, 108, 121
testing, 112 tumor necrosis factor, 33, 102, 108
testis, 95 tumors, ix, 91, 95, 96, 132
testosterone, 135, 137, 142 twins, 87
TFE, 94 type 2 diabetes, 105
therapeutics, 72
therapy, 16, 18, 19, 20, 22, 94, 97, 101, 102, 103,
U
113, 115, 116
thoughts, viii, 49, 55, 62, 63, 65, 67 ultrasound, 123
thrombosis, 102 underlying mechanisms, 65, 88
thymus, 122 UNESCO, 69
thyroid, 16, 101 United, 78, 113
time frame, viii, 49, 54, 66 United States, 78, 113
time periods, x, 119 urban, 45, 51, 52, 69, 70, 116, 127
TIMP, 23 urea, 15, 16, 20, 22
TIMP-1, 23 urine, ix, 2, 53, 54, 92, 111, 120, 130, 131, 132
tissue, ix, 4, 13, 16, 18, 66, 92, 93, 130, 135, 136, USA, 42, 46, 54, 69, 77, 78
140, 141, 142 uterus, 95
tissue remodelling, 140
TNF, x, 33, 107, 108, 141
TNF-alpha, x, 107, 108 V
TNF-α, 141
toddlers, 75, 85 Valencia, 1
tonic, 30, 36, 52, 57 validation, 11
toxicity, 145 variables, 34, 36, 52, 53, 112
trade, x, 119, 123 variations, xi, 33, 39, 120, 129, 133
trade-off, x, 119, 123 vasculature, 4
trafficking, 33 vasoconstriction, 130
training, 131, 133, 134, 135, 136, 137, 138, 141, 145, vasopressin, 10, 20, 29, 31
146 venipuncture, 131, 132

traits, 38 venlafaxine, 12
transcription, 22, 30, 31, 42, 141 vesicle, 15
transcription factors, 30, 31 vessels, 4
transformation, 28 victimization, 88
translocation, 23, 120 victims, 74, 78, 81, 84, 87
transmission, 42, 86 violence, 75, 83, 85, 86
transplant, 100 viral infection, 74, 114
transplantation, 100, 104 vision, 13, 15
transport, vii, 1, 3, 5, 6, 8, 9, 13, 15, 16, 18, 19, 20, voiding, 54
21, 22, 23, 24, 25, 32, 120, 132 vulnerability, viii, 27, 39, 40, 80
trauma, 39, 75, 76, 80, 81, 82, 84, 88, 110
traumatic events, 77 W
traumatic experiences, 76
treatment, xi, 4, 10, 12, 13, 14, 17, 19, 20, 21, 23, 44, waking, 65, 76, 84
50, 68, 71, 82, 83, 86, 97, 102, 109, 110, 112, war, 121
122, 123, 125, 126, 127, 139, 141, 142, 143, 144, Washington, 68, 84
145 water, ix, 24, 91, 92, 99, 132, 143
trial, 52, 83, 125, 126, 127 weakness, 97, 108, 109, 140
triggers, viii, 32, 49 wealth, 78, 111
triglycerides, 130 weight loss, 133
162 Index
welfare, 78
Y
white-collar workers, 69
withdrawal, 10, 75, 116 yield, 144
withdrawal symptoms, 10 young adults, 39
workers, 8 young women, 102
working memory, 101
working women, viii, 49, 68, 70
workload, 121 Z
workplace, 54, 68
World Anti-Doping Agency, 144 zinc, 138, 145
World Health Organization, 125
World Trade Center, 83
worry, 67

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Copyright © 2012. Nova Science Publishers, Incorporated. All rights reserved.

Additional books in this series can be found on Nova‘s website

Additional E-books in this series can be found on Nova‘s website

Nova Science Publishers, Inc.

NOTICE TO THE READER

DECLARATION OF PARTICIPANTS JOINTLY ADOPTED BY A COMMITTEE OF THE

LIBRARY OF CONGRESS CATALOGING-IN-PUBLICATION DATA

ISBN: 978-1-61942-465-4 (eBook)

Published by Nova Science Publishers, Inc. New York

Chapter 4 Biopsychosocial Correlates of Cortisol Activity

Chapter 8 Cortisol and Physical Exercise 129

CORTISOL TRANSPORT ACROSS BIOLOGICAL

Marta Gonzalez-Alvarez1, Victor Mangas-Sanjuán1, Carmen

Cortisol is a glucocorticoid hormone that is synthesized in the adrenal glands from

secretion that is regulated through the hypothalamic-pituitary-adrenocortical (HPA) axis

Figure 1. Scheme of the negative feed-back regulation of HPA axis by Cortisol.

TRANSPORT OF CORTISOL ACROSS THE BLOOD-BRAIN BARRIER:

responsible for differences in brain penetration of Cortisol and/or antidepressant drugs

Because of the physicochemical properties of glucocorticoids (small and lipophilic

Table 1. Summary of experimental techniques and results showing the implication of P-

Implication of P-gp Reference

DC-3F and DC-3F/ADX Positive (Pariante et al., 2003)

negligible effect in the distribution of [3H]Cortisol and [3H]corticosterone at the BCSFB.

DEPRESSION: THERAPEUTIC STRATEGIES

The pharmaceutical industry has developed antidepressants with different mechanisms of

contradicting the relevance of P-glycoprotein in the pathophysiology of depression in humans

fluvoxamine, imipramine, nortryptyline, paroxetine,

EFFECT OF CORTISOL ON THE PERMABILITY

dehydroepiandrosterone sulfate, via organic anion transporting polypeptide 2. J

transporters in the rat adrenal cortex with adrenocorticotropin-regulated zonal expression.

Ghersi-Egea, J.F., 2008. Differential expression of the multi-drug resistance-related

CORTISOL: PHYSIOLOGY, REGULATION AND

Katarina Dedovic1 and Annie Duchesne2

overview of many effector pathways of cortisol, focusing on the impact of cortisol on

Cortisol is a type of glucocorticoid, a steroid hormone produced by the adrenal cortex in

In response to a perceived threat, the hypothalamic-pituitary-adrenal (HPA) axis is

HPA Axis in Times of Rest

GLUCOCORTICOID RECEPTOR TYPES

Role of the Genomic MR and GR Receptors

Role of the Non-Genomic MR and GR-Like Receptors

These membrane-embedded receptors seem to be of a similar type to the nuclear

MODES OF CORTISOL ACTION

EFFECTS OF CORTISOL ON THE BODY AND MIND

Cognition - Learning and Memory

Emotion - Subjective Psychological Distress and Physiological Stress

An underlying assumption with respect to the response to a psychological stressor is that

Another working hypothesis to explain the lack of consistent correspondence between

Maladaptive Effects of Cortisol

degenerative disease and sleep disorders [57, 73-75].

of this indiscriminate hypervigilence under stress. Cortisol contributes to this regulation.

glucocorticoid signaling in rat brain. Endocrinology 2010, 151:1177-1186.

[27] Clow A, Hucklebridge F, Stalder T, Evans P, Thorn L: The cortisol awakening

in health and disease. Endocr. Rev. 1998, 19:269-301.

[58] Marshall GD: Cytokines. In Stress Science: Neuroendocrinology. Edited by Fink G.

affect neural social stress processing in humans. Nature 2011, 474:498-501.

N Y Acad. Sci. 2004, 1032:186-190.

HEIGHTENED ENDOCRINE RESPONSES TO DAILY

Gary D. James1 and Dana H. Bovbjerg2

associated with increased endocrinological reactivity to psychological stress. Such effects

NATURAL EXPERIMENTAL APPROACH TO