Allostatic Load and Allostasis
Summary prepared by Bruce McEwen and Teresa Seeman in
collaboration with the Allostatic Load Working Group. Last revised August, 1999.
.
Chapter Contents:
a. Introduction
b. Where Stress Fits In
c. Allostasis and Allostatic Load
d. Allostatic Load Requires Understanding of Physiological
Mechanisms
e. Validation of Allostatic Load
f. Further Refinement of Allostatic Load
g. References
Introduction 
There are gradients of health when groups of people are classified according to their
socioeconomic status, which reflect both income and level of education. The poor suffer
earlier mortality and worse health, on the average, than the middle class, which, in turn,
is not as healthy as those who are wealthier and/or better educated. Attempts to explain
these gradients on the basis of access to health care or such behaviors as smoking have
failed to explain the gradient (1;2). Instead there is a need to understand more
comprehensively how various aspects of life impact collectively on health, involving such
factors as living environment, work, relationships, community, knowledge and practice of
health promoting or health damaging behaviors including diet and exercise. In order to do
this we must move from groups to individuals and understand how behavior and biology
interact.
Often, we use the word "stress" to refer to these
biological factors, but this is an oversimplification because they are more that
"stress" and include many aspects of lifestyle and daily experience and
behavior, including the adjustments to the circadian light-dark cycle. Moreover, the
widespread use of the term "stress" in popular culture has made this word a very
ambiguous term to describe the ways in which the body copes with psychosocial,
environmental and physical challenges. Thus we have been in search of a more comprehensive
term for the role of biological mediators in adaptation and maladaptation of the
individual to the circumstances of life.
Where Stress Fits In
The body responds to the external and internal environment by
producing hormonal and neurotransmitter mediators that set in motion physiological
responses of cells and tissues throughout the body, leading to a coordination of
physiological responses to the current circumstances. The measurement of the physiological
responses of the body to environmental challenges constitutes the primary means of
connecting experience with resilience or the risk for disease. Because the subjective
experience of stress does not always correlate with the output of physiological mediators
of stress(13), the measurement of the physiological responses of the body to environmental
challenges constitutes the primary means of connecting experience with resilience or the
risk for disease. The so-called "stress mediators", hormones such as cortisol
and catecholamines, also vary in their basal secretion according to a diurnal rhythm that
is coordinated by the light-dark cycle and sleep-waking patterns, a fact that reinforces
the inadequacy of the popular use of the term "stress" as a useful descriptor of
the source of all biological dysregulations. For example, the internal biological clock of
the hypothalamic suprachiasmatic nucleus regulates cyclicity of sleep and waking and the
production of adrenocortical hormones that are entrained by the light-dark cycle; shifting
the light-dark cycle, as by trans-Atlantic jet airplane travel, results in disregulation
of adrenocortical hormone and contributes to disruption of sleep, activity, appetite and
cognitive function.
With regard to stress, the sudden occurrence of danger, as for a gazelle being chased by a
lion or a person confronted by a threat to physical safety, calls forth release of both
adrenalin and adrenocoritcal hormones ("fight of flight" response) that help the
body survive the immediate crisis. Indeed, new research has reinforced the fact that the
so-called "stress mediators" have protective and adaptive as well as damaging
effects, and the search for biological mechanisms that determine protective versus
damaging effects of these mediators is a theme in biobehavioral research (22). This search
has also led to a new formulation of the relationship between environmental challenge and
biological responses.
Allostasis and Allostatic Load
Rather than referring to everything dealing with responses to environmental and
psychosocial situations as "stress", we have provided a new formulation using
two new terms, "allostasis" and "allostatic load". Allostasis, meaning
literally "maintaining stability (or homeostasis) through change" was introduced
by Sterling and Eyer (33) to describe how the cardiovascular system adjusts to resting and
active states of the body. This notion can be applied to other physiological mediators,
such as the secretion of cortisol as well as catecholamines, and the concept of
"allostatic load" was proposed to refer to the wear and tear that the body
experiences due to repeated cycles of allostasis as well as the inefficient turning-on or
shutting off of these responses (22;26). As an example of allostatic load, the persistent
activation of blood pressure in dominant male cynomologus monkeys vying for position in an
unstable dominance hierarchy is reported to accelerate atherosclerotic plaque formation
(17). Blood pressure surges accompany the social confrontations and catecholamines are
elevated during those surges. Together, the blood pressure and catecholamine elevations
accelerate atherosclerosis, as shown by the fact that the acceleration of atherosclerosis
in dominant monkeys was prevented by beta adrenergic blocking drugs (18).
The concept of allostasis and allostatic load envisions a
cascade of cause and effect that begins with primary stress mediators, such as
catecholamines and cortisol, and leading to primary effects and then to secondary and
tertiary outcomes, as will be described below. In order to begin to understand this
formulation, Figure 1 summarizes four key features of the model.
Figure 1. The Stress Response and Development of
Allostatic Load
Perception of stress is influenced by one's experiences, genetics, and behavior. When the
brain perceives an experience as stressful, physiologic and behavioral responses are
initiated leading to allostasis and adaptation. Over time, allostatic load can accumulate,
and the overexposure to neural, endocrine, and immune stress mediators can have adverse
effects on various organ systems, leading to disease. Reprinted from McEwen (22) by
permission from the New England Journal of Medicine. Copyright 1998 Massachusetts
Medical Society. All rights reserved.
First, the brain is the integrative center for coordinating
the behavioral and neuroendocrine responses (hormonal, autonomic) to challenges, some of
which qualify as "stressful" but others of which are related to the diurnal
rhythm and its ability to coordinate waking and sleeping functions with the environment.
Second, there are considerable individual differences in coping with challenges, based
upon interacting genetic, developmental and experiential factors. There is a cascading
effect of genetic predisposition and early developmental events, such as abuse and neglect
or other forms of early life stress, to predispose the organism to over-react
physiologically and behaviorally to events throughout life. Third, inherent within the
neuroendocrine and behavioral responses to challenge is the capacity to adapt (allostasis,
meaning to achieve stability, or homeostasis, through change); and, indeed, the
neuroendocrine responses are set up to be protective in the short-run. For the
neuroendocrine system, turning on and turning off responses efficiently is vital (see
Figure 2); inefficiency in allostasis leads to cumulative effects over long time
intervals, as will be describe below.
Fourth, allostasis has a price (allostatic load, referring to
cumulative negative effects, or the price the body pays for being forced to adapt to
various psychosocial challenges and adverses environments) that is related to how
inefficient the response is, or how many challenges an individual experiences (ie, a lot
of stressful events). Thus allostatic load is more than "chronic stress" and
encompasses many aspects of an individual's life that affect the regulation and level of
the mediators of allostasis. Among the many factors that contribute to allostatic load are
genes and early development, as well as learned behaviors reflecting life style choices of
diet, exercise, smoking and drinking. All of these factors influence the reactivity of the
systems that produce the physiological stress mediators. Thus allostatic load reflects, in
part, genetically- or developmentally-programmed inefficiency in handling the normal
challenges of daily life related to the sleep-wake cycle and other daily experiences, as
well as the adverse physiological consequences of a fat-rich diet, drinking or smoking.
 |
Figure 2. Allostasis in the Autonomic
Nervous System and the Hypothalamic- pituitary-adrenal Axis
Allostatic systems respond to stress (upper panel) by initiating the adaptive response,
sustaining it until the stress ceases, and then shutting it off (recovery). Allostatic
responses are initiated (lower panel) by an increase in circulating catecholamines from
the autonomic nervous system and glucocorticoids from the adrenal cortex. This sets into
motion adaptive processes that alter the structure and function of a variety of cells and
tissues. These processes are initiated via intracellular receptors for steroid hormones,
plasma membrane receptors, and second messenger systems for catecholamines. Cross-talk
between catecholamines and glucocorticoid receptor signaling systems can occur (see text).
Reprinted from McEwen (22) by permission from the New England Journal of Medicine.
Copyright 1998 Massachusetts Medical Society. All rights reserved. |
Many of the same considerations apply to behavioral, as
opposed to physiological, responses to challenge, and there are also protective and
damaging aspects to one's behavior. Individuals can act to increase or decrease further
risk for harm or disease - for example, antisocial responses such as hostility and
aggression vs. cooperation and conciliation; risk taking behaviors such as smoking,
drinking, and physical risk-taking vs. self protection; poor diet and health practices vs.
good diet, exercise, etc. The linkage of "allostasis" and "allostatic
load" probably applies to behavioral responses as well to physiological responses to
challenge in so far as the behavioral response, such as smoking or alcohol consumption,
may have at least perceived adaptive benefits in the short run but produce damaging
effects in the long run.
Allostatic Load Requires Understanding of
Physiological Mechanisms
Although allostasis and allostatic load are general concepts to be applied across
physiological and behavioral responses, they require in each case an understanding of
underlying mechanisms in each system of the body. This understanding begins with the
mediators that produce organ- and tissue-specific effects by acting via receptors that are
common throughout the body (see Figure 2). The mediators of allostasis include adrenal
steroids and catecholamines, primarily, but also other hormones like DHEA, prolactin,
growth hormones and the cytokines related to the immune system, as well as local tissue
mediators like the excitatory amino acids. In Figure 2, the actions of two mediators, the
glucocorticoids and the catecholamines, are shown, acting via receptors that trigger
changes throughtout the target cell in processes, including both rapid effects and changes
in gene expression that have long-lasting consequences for cell function. Thus, whenever a
hormone is secreted, there are to be considered both the short-term and long-term
consequences of hormone action on cell function.
For each system of the body, there are both short-term adaptive actions (allostasis) that
are protective and long-term effects that can be damaging (allostatic load). For the
cardiovascular system, a prominent example of allostasis is the role of catecholamines in
promoting adaptation by adjusting heart rate and blood pressure to sleeping, waking,
physical exertion (33). Yet, repeated surges of blood pressure in the face of job stress
or the failure to shut off blood pressure surges efficiently accelerates atherosclerosis
and synergizes with metabolic hormones to produce Type II diabetes, and this constitutes a
type of allostatic load (see (22)). Closely related to this is the role of adrenal
steroids in metabolism. Whereas adrenal steroids promote allostasis by enhancing food
intake and facilitating the replenishment of energy reserves, the overactivity of this
system involving repeated HPA activity in stress or elevated evening cortisol leads to
allostatic load in terms of insulin resistance, accelerating progression towards Type II
diabetes, including abdominal obesity, atherosclerosis, and hypertension (4;5).
In the brain, actions of adrenal steroids and catecholamines that are related to
allostasis include promoting retention of memories of emotionally-charged events, both
positive and negative. Yet, overactivity of the HPA axis together with overactivity of the
excitatory amino acid neurotransmitters promotes a form of allostatic load, consisting of
cognitive dysfunction by a variety of mechanisms that involve reduced neuronal
excitability, neuronal atrophy and, in extreme cases, death of brain cells, particularly
in the hippocampus (21;23).
For the immune system, adrenal steroids promote allostasis together with catecholamines by
promoting "trafficking", ie., movement, of immune cells to organs and tissues
where they are needed to fight an infection or other challenge, and they also modulate the
expression of the hormones of the immune systems, the cytokines and chemokines (24). With
chronic overactivity of these same mediators, allostatic load results, consisting of
immunosuppressive effects when these mediators are secreted chronically or not shut off
properly (24). Yet, some optimal levels of these mediators is required to maintain a
functional balance within the competing forces of the immune system, and the absence of
sufficient levels of glucocorticoids and catecholamines allows other immune mediators to
over-react and increases the risk of autoimmune and inflammatory disorders (34).
Therefore, an inadequate response of the HPA axis and autonomic nervous system is another
type of allostatic load, in which the disregulation of other mediators, normally contained
by cortisol and catecholamines, is a primary factor in a disorder.
Thus, allostatic load may be subdivided into at least 4 subtypes, as summarized in Figure
3.
Figure 3. Four Types of Allostatic Load
The top panel illustrates the normal allostatic response, in which a response is initiated
by a stressor, sustained for an appropriate interval, and then turned off. The remaining
panels illustrate four conditions that lead to allostatic load: 1) Repeated
"hits" from multiple novel stressors; 2) Lack of adaptation; 3) Prolonged
response due to delayed shut down; and 4) inadequate response that leads to compensatory
hyperactivity of other mediators: e.g., inadequate secretion of glucocorticoid, resulting
in increased levels of cytokines that are normally counter-regulated by glucocorticoids).
Figure drawn by Dr. Firdaus Dhabhar, Rockefeller University. Reprinted from McEwen
(22) by permission from the New England Journal of Medicine. Copyright 1998 Massachusetts
Medical Society. All rights reserved.
The first type is simply too much "stress" in the
form of repeated, novel events that cause repeated elevations of stress mediators over
long periods of time. For example, the amount and freqency of economic hardship predicts
decline of physical and mental functioning as well as increased mortality (16). Yet not
all types of allostatic load deal with chronic stress. A second type of allostatic load
depicted in Fig. 3 involves a failure to habituate or adapt to the same stressor. This
leads to the over-exposure to stress mediators because of the failure of the body to
dampen or eliminate the hormonal stress response to a repeated event. An example of this
is the finding that repeated public speaking challenges, in which most individuals
habituated their cortisol response, led a significant minority of individuals to fail to
habituate and continue to show cortisol response (14).
A third and related type of allostatic load, also depicted in Fig. 3, involves the failure
to shut off either the hormonal stress response or to display the normal trough of the
diurnal cortisol pattern. One example of this is blood pressure elevations in work-related
stress which turn off slowly in some individuals with a family history of hypertension
(11). Another example of perturbing the normal diurnal rhythm is that of sleep deprivation
leading to elevated evening cortisol and hyperglycemia within 5d (36) and depressive
illness leading to chronically elevated cortisol and loss of bone mineral mass (27).
The fourth type of allostatic load depicted in Figure 3 involves an inadequate hormonal
stress response which allows other systems, such as the inflammatory cytokines, to become
overactive. The Lewis rat is an example of an animal strain in which increased
susceptibility to inflammatory and autoimmune disturbances is related to inadequate levels
of cortisol (34;35).
Validation of Allostatic Load
Assessment of allostatic load would optimally incorporate information on
"resting" or "usual" levels of allostatic mediators for each
individual, as well as assessments of system dynamics (i.e., alterations in the
"operating range" of the system parameters in response to stimulation, so as to
tap into the 4 types of allostatic load depicted in Figure 3); and it would include
information for parameters of all major physiological regulatory systems. Such a goal is
rather ambitious, but a first step was made in that direction using available data from
the MacArthur Successful Aging Study. Using this data, we previously reported on an
initial operational measure of allostatic load which reflects information on levels of
physiologic activity across a range of important regulatory systems, including the
hypothalamic-pituitary-adrenal and sympathetic nervous systems as well as the
cardiovascular system and metabolic processes (32). Our measure of allostatic load
reflects only one of the two aspects of physiologic activity postulated to contribute to
allostatic load, namely, higher, chronic, steady state levels of activity related to the
diurnal variation as well as any residual activity reflecting chronic stress or failure to
shut-off responses to acute stressors. Specifically, available data on physiologic
activity represent single measures of activity levels rather than assessments of the
dynamics of these systems in response to challenge.
Available data from the MacArthur Study provided information on the following parameters
(32):
- Systolic and diastolic blood pressure, indices of cardiovascular activity.
- Waist-hip ratio, an index of more chronic levels of metabolism and adipose tissue
deposition, thought to be influenced by increased glucocorticoid activity.
- Serum HDL and total cholesterol, related to the development of atherosclerosis --
increased risks being seen with higher levels in the case of total cholesterol and lower
levels in the case of HDL.
- Blood plasma levels of glycosylated hemoglobin, an integrated measure of glucose
metabolism over several days time.
- Serum dihydroepiandrosterone sulfate (DHEA-S), a functional HPA axis antagonist.
- Over-night urinary cortisol excretion, an integrated measure of 12-hr HPA axis activity.
- Overnight urinary norepinephrine and epinephrine excretion levels, integrated indices of
12-hr SNS activity.
Our initial measure of allostatic load was created by summing across indices of subjects'
status with respect to these ten components of allostatic load. For each of the ten
indicators, subjects were classified into quartiles based on the distribution of scores in
the high function cohort (see (32)). The decision to use distributions in the high
function cohort was based on the fact that analyses of relationships between allostatic
load and health outcomes were based on longitudinal data for this latter group. Allostatic
load was measured by summing the number of parameters for which the subject fell into the
"highest" risk quartile (i.e., top quartile for all parameters except HDL
cholesterol and DHEA-S for which membership in the lowest quartile corresponds to highest
risk).
Several alternative criteria for calculating allostatic load were also examined. One such
alternative using a stricter criterion was based on a sum of the number of parameters for
which the subject fell into the top (or bottom) 10% of the distribution (i.e., the group
at highest "risk"). Another measure of allostatic load was based on averaging
z-scores for each of the parameters. In each case, analyses yielded essentially the same
results as the measure based on the quartile criteria, though the latter showed the
strongest effects. These concurrent results suggest to us that the disease risks
associated with allostatic load derive (as the original conceptualization would argue)
from being relatively higher on various measures of physiologic regulation rather than
only at the most extreme levels. At the same time, simply averaging levels of activity
across systems may tend to obscure the impact of elevations in a subset of systems that
contribute to higher allostatic load. Thus, we selected an algorithm for allostatic load
that avoids the problem of averaging, using instead a count of the number of parameters
for which subjects exhibited relatively elevated levels. The 10 components were equally
weighted since, based on factor analysis, indicators from physiologic systems defined
different factors, and the component loadings on the relevant factors were virtually the
same. This measure of allostatic load was then examined for its ability to predict health
outcomes over a 2.5 year follow-up. Higher baseline allostatic load scores were found to
predict significantly increased risks for incident cardiovascular disease as well as
increased risks for decline in physical and cognitive functioning and for mortality (32).
Further Refinement of Allostatic Load
One of the problems with the original conceptualization of allostatic load and its
measurement is that the components were not organized and categorized with regard to what
each measure represents in the cascade of events that lead from allostasis to allostatic
load. Nor was there any suggested organization in choosing those original measure that
would facilitate systematically relating measures to specific disease outcomes or
systematically adding new measures. Allostasis and allostatic load are concepts that are
mechanistically based and only as good as the information about mechanisms that lead to
disease. A new way of classifying the measures must provide a handle for relating what is
measured to a pathophysiological process and allow for the incorporation of new measures
as more is known about underlying mechanisms leading to disease. Below we summarize a new
formulation, based upon the notion of primary mediators leading to primary effects and
then to secondary outcomes, which lead, finally, to tertiary outcomes that represent
actual diseases.
Primary mediators - chemical messengers that are released as part of allostasis.
At present, we have four such mediators (cortisol, noradrenalin, epinephrine, DHEA). . In
general, the primary mediators have very widespread influences throughout the body and are
very useful, when measured correctly, in predicting a variety of secondary and tertiary
outcomes. Cortisol is a glucocorticoid with wide-ranging effects throughout the body.
Glucocorticoid receptors are present in virtually every tissue and organ in the body and
mediate effects ranging from induction of liver enzymes involved in energy metabolism to
regulating trafficking of immune cells and cytokine production to facilitating formation
of fear-related memories (25;30). DHEA is a functional antagonist of cortisol (20;37)
which may also have effects via other signalling pathways (3); generally, low DHEA is
considered deleterious, as is chronically high cortisol (29). As already noted, it is
important to emphasize that the acute effects of stress mediators are generally adaptive
(allostasis) and it is the chronic elevation or disregulation of these mediators over long
times that causes problems, ie., allostatic load.
Catecholamines (adrenalin, noradrenalin) are released by the adrenal medulla and
sympathetic nervous system, respectively, and they produce widespread effects throughout
the body, ranging from vasoconstriction and acceleration of heart rate to trafficking of
immune cells to targets, as well as enhancement of fear-related memory formation (6).
Adrenergic receptors are widespread throughout the body, in blood vessels and target
organs such as the liver, pancreas, as well as the brain which is not accessible to
circulating catecholamines. However, catecholamines signal the brain through the sensory
vagus and the nucleus of the solitary tract, as in learned fear (6).
Primary effects - cellular events, like enzymes, receptors, ion channels or structural
proteins induced genomically or phosphorylated via second messenger systems, that are
regulated as part of allostasis by the primary mediators.
We do not presently measure primary effects, and it may be desirable to study primary
effects as the basis for the secondary and tertiary outcomes - this, in fact, is the
mechanistic research that is supported by the NIH! Glucocorticoids regulate gene
expression via several pathways, involving interactions with DNA via the glucocorticoid
response elements (GRE's) and also via protein-protein interactions with other
transcriptional regulators (28). As noted above, DHEA antagonizes glucocorticoid actions
in a number of systems. Catecholamines act via alpha and beta adrenergic receptors, and
beta receptors stimulate the formation of the intracellular second messenger, cyclic AMP,
which, in turn, regulates intracellular events via phosphorylation, including
transcription regulators via the CREB family of proteins.
In some cases, the glucocorticoid and cAMP pathways converge at the level of gene
expression (e.g, see (38)). Therefore it is not surprising that secondary outcomes (see
below) are the result of more than one primary mediator. Primary effects are organ and
tissue specific in many cases. Hence, at this level and even more for the secondary and
tertiary outcomes we must become more organ and disease specific!
Secondary outcomes - integrated processes that reflect the cumulative outcome of the
primary effects in a tissue/organ specific manner in response to the primary mediators,
often reflecting the actions of more than one primary medator, including the ones
described above as well as others not yet measured.
As already noted above, we measure the following secondary outcomes, which are all related
to abnormal metabolism and risk for cardiovascular disease: WHR, blood pressure,
glycosylated hemoglobin, cholesterol/HDL ratio, HDL cholesterol. As noted above, WHR and
glycosylated hemoglobin both reflect the effects of sustained elevations in glucose and
the insulin resistance that develops as a result of elevated cortisol and elevated
sympathetic nervous system activity. Blood pressure elevation is part of the
pathophysiologal pathway of the metabolic syndrome, but is also a more primary indication
of the allostatic load that can lead to accelerated atherosclerosis as well as insulin
resistance . Cholesterol and HDL cholesterol are measures of metabolic imbalance in
relation to obesity and atherosclerosis and also reflect the operation of the same primary
mediators as well as other metabolic hormones.
In general, in the future, we feel that we need to expand the secondary outcomes in two
directions. First, there is need for more specific outcomes related to the damage pathway
in cardiovascular disease and risk for MI (e.g., nitric oxide, fibrinogen). Fibrinogen has
already been used as an allostatic load measure in relation to job stress and
socioeconomic status (19). Second, we need outcomes related to other systems such as the
brain and the immune system. For the brain, assessments of declarative and spatial memory
have been employed to see individual differences in brain aging, reflecting atrophy of the
hippocampus and progressive elevation of cortisol (15). For the immune system, integrated
measures of the immune response such as delayed type hypersensitivity (9;10) and
immunization challenge (12) should reveal the impact of allostatic load on cellular and
humoral immune function and help distinguish between the immunoenhancing effects of acute
stress and immunosuppressive effects of chronic stress. Moreover, assessment of the
frequency and severity of the common cold (7;8) is another indirect way of assessing
immune function, and this might be considered a secondary outcome.
Teritary outcomes - these are the actual diseases or disorders which are the result of the
allostatic load that is predictd from the extreme values of the secondary outcomes and of
the primary mediators.
Thus far, we have utilized cardiovascular disease, decreased physical capacity and severe
cognitive decline as outcomes in the successful aging studies (31;32), but some
redefinition of outcomes is needed. That is, a stricter criterion based upon the new
definitions of primary, secondary and tertiary outcomes would assign cognitive decline as
a secondary outcome, although Alzheimer's disease or vascular dementia would be a tertiary
outcomes when there is clearly a serious and permanent disease. By the same token, cancer
would be a tertiary outcome, whereas the common cold would be a secondary outcome and an
indirect measure, in part, of immune system efficacy, as discussed above.
This new classification of the existing measures of allostatic load should permits the
following next steps:
- 1) relating progression of pathophysiology from primary mediators to secondary outcomes
and then to tertiary, i.e., disease outcomes;
- 2) identifying clusters of secondary outcomes that are relevant to particular diseases;
- 3) moving to earlier ages in measuring allostatic load by relying more on secondary
outcomes that are known to be risk factor for later disease; tertiary outcomes generally
appear later in life, at least for dementia and cardiovascular disease, and an important
question for future studies is whether secondary outomes in younger subjects can be used
as a surrogate for tertiary outcomes.
References
1. Adler, N., W. T. Boyce, M. Chesney, S.
Folkman, and L. Syme. Socioeconomic inequalities in health: No easy solution.
J.Amer.Med.Assoc. 269: 3140-3145, 1993.
2. Adler, N. E., T. Boyce, M. A. Chesney, S.
Cohen, S. Folkman, R. L. Kahn, and L. S. Syme. Socioeconomic status and health: the
challenge of the gradient. American Psychologist 49: 15-24, 1994.
3. Araneo, B. and R. Daynes.
Dehydropepiandrosterone functions as more than an antiglucocorticoid in preserving
immunocompetence after thermal injury. Endorinology 136: 393-401, 1995.
4. Bjorntorp, P. Editorial: "Portal"
adipose tissue as a generator of risk factors for cardiovascular disease and diabetes.
Atherosclerosis 10: 493-496, 1990.
5. Brindley, D. N. and Y. Rolland. Possible
connections between stress, diabetes, obesity, hypertension and altered lipoprotein
metabolism that may result in atherosclerosis. Clin.Science 77: 453-461, 1989.
6. Cahill, L., B. Prins, M. Weber, and J. L.
McGaugh. Beta-Adrenergic activation and memory for emotional events. Nature 371: 702-704,
1994.
7. Cohen, S., S. Line, S. B. Manuck, B. S.
Rabin, E. R. Heise, and J. R. Kaplan. Chronic stocial stress, social status, and
susceptibility to upper respiratory infections in nonhuman primates. Psychosomat.Med. 59:
213-221, 1997.
8. Cohen, S., D. A. J. Tyrrell, and A. P.
Smith. Psychological stress and susceptibility to the common cold. N.Engl.J.Med. 325:
606-612, 1991.
9. Dhabhar, F. and B. McEwen. Enhancing versus
suppressive effects of stress hormones on skin immune function. Proc.Natl.acad.Sci.USA 96:
1059-1064, 1999.
10. Dhabhar, F. S. and McEwen, B. S. Moderate
stress enhances, and chronic stress suppresses, cell-mediated immunity in vivo. Abstracts,
Soc.Neurosci. 22, #536.3-p 1350. 96.
11. Gerin, W. and T. G. Pickering. Association
between delayed recovery of blood pressure after acute mental stress and parental history
of hypertension. Journal of Hypertension 13: 603-610, 1995.
12. Kiecolt-Glaser, J. K., Glaser, R.,
Gravenstein, S., Malarkey, W. B., and Sheridan, J. Chronic stress alters the immune
response to influenza virus vaccine in older adults. Proc.Natl.acad.Sci.USA 93, 3043-3047.
96.
13. Kirschbaum, C., B. M. Kudielka, J. Gaab, N.
C. Schommer, and D. H. Hellhammer. Impact of gender, menstrual cycle phase and oral
contraceptive use on the activity of the hypothalamo-pituitary-adrenal axis. Psychsom.
Med. 61: 154-162, 1999.
14. Kirschbaum, C., J. C. Prussner, A. A.
Stone, I. Federenko, J. Gaab, D. Lintz, N. Schommer, and D. H. Hellhammer. Persistent High
Cortisol Responses to Repeated Psychological Stress in a Subpopulation of Healthy Men.
Psychosomatic Medicine 57: 468-474, 1995.
15. Lupien, S. J., M. J. DeLeon, S. De Santi,
A. Convit, C. Tarshish, N. P. V. Nair, M. Thakur, B. S. McEwen, R. L. Hauger, and M. J.
Meaney. Cortisol levels during human aging predict hippocampal atrophy and memory
deficits. Nature Neuroscience 1: 69-73, 1998.
16. Lynch, J. W., G. A. Kaplan, and S. J.
Shema. Cumulative impact of sustained economic hardship on physical, cognitive,
psychological, and social functioning. NEJM 337: 1889-1895, 1997.
17. Manuck, S. B., J. R. Kaplan, M. R. Adams,
and T. B. Clarkson. Studies of psychosocial influences on coronary artery atherosclerosis
in cynomolgus monkeys. Health Psychol. 7: 113-124, 1995.
18. Manuck, S. B., J. R. Kaplan, M. F. Muldoon,
M. R. Adams, and T. B. Clarkson. The behavioral exacerbation of atherosclerosis and its
inhibition by propranolol. In McCabe, P. M., N. Schneiderman, T. M. Field, and J. S.
Skyler, eds. Stress, Coping And Disease. Hove and London, Lawrence Erlbaum Associates.
1991, 51-72.
Notes: Chapter Num: 3.
19. Markowe, H. L. J., M. G. Marmot, M. J.
Shipley, C. J. Bulpitt, T. W. Meade, Y. Stirling, M. V. Vickers, and A. Semmence.
Fibrinogen: a possible link between social class and coronary heart disease. Brit.Med.Jnl
291: 1312-1314, 1985.
20. May, M., E. Holmes, W. Rogers, and M. Poth.
Protection from Glucocorticoid Induced Thymic Involution by Dehydroepiandrosterone. Life
Sciences 46: 1627-1631, 1990.
21. McEwen, B. S. Possible mechanisms for
atrophy of the human hippocampus. Molecular Psychiatry 2: 255-262, 1997.
22. McEwen, B. S. Protective and Damaging
Effects of Stress Mediators. New England J.Med. 338: 171-179, 1998.
23. McEwen, B. S. Stress and hippocampal
plasticity. Annu.Rev.Neurosci. 22: 105-122, 1999.
24. McEwen, B. S., C. A. Biron, K. W. Brunson,
K. Bulloch, W. H. Chambers, F. S. Dhabhar, R. H. Goldfarb, R. P. Kitson, A. H. Miller, R.
L. Spencer, and J. M. Weiss. Neural-endocrine-immune interactions: the role of
adrenocorticoids as modulators of immune function in health and disease. Brain Res.Rev.
23: 79-133, 1997.
25. McEwen, B. S., R. R. Sakai, and R. L.
Spencer. Adrenal steroid effects on the brain: versatile hormones with good and bad
effects. In Schulkin, J., ed. Hormonally-Induced Changes in Mind and Brain. San Diego,
Academic Press. 1993, 157-189.
26. McEwen, B. S. and E. Stellar. Stress and
the Individual: Mechanisms leading to disease. Archives of Internal Medicine 153:
2093-2101, 1993.
27. Michelson, D., C. Stratakis, L. Hill, J.
Reynolds, E. Galliven, G. Chrousos, and P. Gold. Bone mineral density in women with
depression. N.Engl.J.Med. 335: 1176-1181, 1996.
28. Miner, J. N., M. I. Diamond, and K. R.
Yamamoto. Joints in the regulatory lattice: Composite regulation by steroid receptor-AP1
complexes. Cell Growth & Differentiation 2: 525-530, 1991.
29. Morales, A. J., J. J. Nolan, J. C. Nelson,
and S. S. C. Yen. Effects of Replacement Dose of Dehydroepiandrosterone in Men and Women
of Advancing Age. J Clin Endocrin Metab 78: 1360-1367, 1994.
30. Quirarte, G. L., B. Roozendaal, and J. L.
McGaugh. Glucocorticoid enhancement of memory storage involves noradrenergic activation in
the basolateral amygdala. Proc.Natl.acad.Sci.USA 94: 14048-14053, 1997.
31. Seeman, T. E., B. S. McEwen, B. H. Singer,
M. S. Albert, and J. W. Rowe. Increase in Urinary Cortisol Excretion and Memory Declines:
MacArthur Studies of Successful Aging. J.Clin.Endocrinol.Metab. 82: 2458-2465, 1997.
32. Seeman, T. E., B. H. Singer, J. W. Rowe, R.
I. Horwitz, and B. S. McEwen. Price of adaptation--allostatic load and its health
consequences: MacArthur studies of successful aging. Arch Intern Med 157: 2259-2268, 1997.
33. Sterling, P. and J. Eyer. Allostasis: A New
Paradigm to Explain Arousal Pathology. In Fisher, S. and J. Reason, eds. Handbook of Life
Stress, Cognition and Health. New York, John Wiley & Sons. 1988, 629-649.
Notes: Chapter Num: 34.
34. Sternberg, E. M. Neural-immune interactions
in health and disease. The Journal of Clinical Investigation 100: 2641-2647, 1997.
35. Sternberg, E. M., J. M. Hill, and G. P.
Chrousos. Inflammatory mediator-induced hypothalamic-pituitary-adrenal axis activation is
defective in streptococcal cell wall arthritis susceptible Lewis rats. Proc.Natl.Acad.Sci
86: 2374-2378, 1996.
36. Van Cauter, E., K. S. Polonsky, and A. J.
Scheen. Roles of circadian rhythmicity and sleep in human glucose regulation. Endocr.Rev.
18: 716-738, 1997.
37. Wright, B. E., J. R. Porter, E. Browne, and
F. Svec. Antiglucocorticoid action of dehydroepiandrosterone in young obese Zucker rats.
Int J Obesity 16: 579-593, 1992.
38. Yamada, K., Duong, D. T., Scott, D. K.,
Wang, J.C., and Granner, D. K. CCAAT/Enhancer-binding protein · is an accessory factor
for the glucocorticoid response from the cAMP response element in the rat
phosphoenolpyruvate carboxykinase gene promoter. J.Biol.Chem. 274, 5880-5887. 99.
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