If It Goes Up, Must It Come Down? Chronic Stress and the Hypothalamic-
Pituitary-Adrenocortical Axis in Humans
Gregory E. Miller, Edith Chen, and Eric S. Zhou
University of British Columbia
The notion that chronic stress fosters disease by activating the hypothalamic-pituitary-adrenocortical
(HPA) axis is featured prominently in many theories. The research linking chronic stress and HPA
function is contradictory, however, with some studies reporting increased activation, and others reporting
the opposite. This meta-analysis showed that much of the variability is attributable to stressor and person
features. Timing is an especially critical element, as hormonal activity is elevated at stressor onset but
reduces as time passes. Stressors that threaten physical integrity, involve trauma, and are uncontrollable
elicit a high, flat diurnal profile of cortisol secretion. Finally, HPA activity is shaped by a person’s
response to the situation; it increases with subjective distress but is lower in persons with posttraumatic
Keywords: stress, trauma, cortisol, HPA axis
Exposure to chronic stress markedly increases vulnerability to
adverse medical outcomes. This holds true across a wide variety of
mental and physical conditions. For example, persons facing
chronic stress are more likely to develop an episode of clinical
depression, experience symptoms of an upper respiratory infection
following viral exposure, suffer from a flare up of an existing
allergic or autoimmune condition, and show accelerated progres-
sion of chronic diseases such as acquired immunodeficiency syn-
drome and coronary heart disease (Miller & Cohen, 2005; Monroe
& Hadjiyannakis, 2002; Pereira & Penedo, 2005; Rozanski, Blu-
menthal, & Kaplan, 1999; Wright, Rodriquez, & Cohen, 1998).
This phenomenon is apparent across the entire lifespan. From early
in childhood to late in adulthood, chronic stress is accompanied by
worse health (Coe & Lubach, 2003; Kiecolt-Glaser & Glaser,
2001; Repetti, Taylor, & Seeman, 2002; Taylor, Repetti, & See-
man, 1997), and the magnitude of this effect is substantial: In some
cases, exposure to chronic stress triples or quadruples the chances
of an adverse medical outcome (S. Cohen et al., 1998; Sandberg,
Jarvenpaa, Penttinen, Paton, & McCann, 2004).
Scientists have long been interested in understanding the bio-
logical mechanisms by which chronic stress “gets under the skin”
to affect health outcomes. One potential mechanism that has re-
ceived widespread and persistent attention is the hypothalamic-
pituitary-adrenocortical (HPA) axis. This hormonal response sys-
tem is present in organisms ranging from birds to humans and can
be activated by a broad array of mental and physical stressors
(McEwen, 1998; McEwen & Stellar, 1993; Weiner, 1992). Acti-
vation occurs when neurons in the paraventricular nucleus of the
hypothalamus secrete corticotropin-releasing hormone (CRH).
This molecule travels through the hypophyseal portal circulation to
the anterior pituitary gland, which responds to its presence by
secreting a pulse of adrenocorticotropin hormone (ACTH). The
ACTH signal is carried through the peripheral circulation to the
adrenal glands, which synthesize and release cortisol in a tissue
layer called the zona fasciculata. Of the hormones released as part
of this cascade, cortisol has been the subject of the most research
attention, probably because of its widespread regulatory influ-
ences. Cortisol plays a key role in the central nervous system,
where it is involved in learning, memory, and emotion; in the
metabolic system, where it regulates glucose storage and utiliza-
tion; and in the immune system, where it regulates the magnitude
and duration of the inflammatory responses and the maturation of
lymphocytes (Sapolsky, Romero, & Munck, 2000). Moreover,
these are just the most prominent examples of cortisol’s actions; its
influence also extends to multiple other systems in the body
These observations have prompted scientists to advance numer-
ous theories over the past 50 years linking stressors, cortisol, and
disease. Common to each of these models is the notion that cortisol
is a critical biological intermediary; it is seen as a primary mech-
anism through which chronic stressors get inside the body to bring
about disease. Models of this type have been articulated for psy-
chiatric disorders such as depression and schizophrenia (McEwen,
2000; E. F. Walker & Diforio, 1997); medical conditions such as
cancer, arthritis, and diabetes (Bjorntorp & Rosmond, 1999; Seph-
ton & Speigel, 2003; Heijnen & Kavelaars, 2005); and lifestyle
problems such as obesity (Epel et al., 2000) and fatigue (Bower,
Ganz, & Aziz, 2005). Cortisol has also been implicated as a
primary suspect in more general models of stress and disease (S.
Gregory E. Miller, Edith Chen, and Eric S. Zhou, Department of
Psychology, University of British Columbia (UBC), Vancouver, British
Our efforts on this project were generously supported by the Michael
Smith Foundation for Health Research; the Canadian Institutes of Health
Research; the National Heart, Lung, and Blood Institute; the National
Alliance for Research on Schizophrenia and Depression; and the UBC
Human Early Learning Partnership.
Correspondence concerning this article should be sent to Gregory E.
Miller, Department of Psychology, University of British Columbia, 2136
West Mall Avenue, Vancouver, BC V6K 3R4, Canada. E-mail:
2007, Vol. 133, No. 1, 25–45
Copyright 2007 by the American Psychological Association
Cohen, Kessler, & Underwood, 1995), the idea being that it serves
as a gateway to a broad array of conditions brought on by unde-
In the vast majority of these models, stress triggers disease by
increasing output of cortisol, thereby exposing bodily tissues to
elevated concentrations of the hormone. If sustained, this process
is thought to lead to tissue damage and subsequent dysregulation
of biological systems. In contrast to these models, there also is now
a handful of theories positing that stress-induced declines in cor-
tisol output are the culprit mechanism (Heim, Ehlert, & Hellham-
mer, 2000; Sternberg, Chrousos, Wilder, & Gold, 1992; Yehuda,
2000). These models are generally advanced to explain how stress
could exacerbate conditions in which deficient cortisol signaling
contributes to disease pathogenesis (Raison & Miller, 2003). This
may be the case with rheumatoid arthritis, chronic fatigue syn-
drome, and posttraumatic stress disorder (PTSD). Thus, current
theories view cortisol deviations in both directions as potentially
detrimental; whether elevations or declines are pathogenic depends
on the condition.
Chronic Stress and Cortisol Output
With cortisol so prominently featured in models of stress and
disease, much effort has been devoted to understanding how un-
desirable circumstances modify its secretion. The earliest research
with human subjects indicated that chronic stress (e.g., being a
soldier in combat or having a child with pediatric cancer) was
associated with reduced daily output of cortisol (Bourne, Rose, &
Mason, 1967, 1968; Friedman, Mason, & Hamburg, 1963). These
findings were puzzling to researchers, because they contradicted a
central dogma of the period—that stress markedly increased cor-
tisol secretion. This dogma had emerged from decades of research
in animal models by Selye and his descendants (e.g., see Selye,
1956). As a result, the findings of reduced cortisol output were set
aside, and work in this area languished for 10–15 years. At that
time, new research emerged showing that chronic stresses such as
bereavement, unemployment, and man-made disasters were ac-
companied by elevated levels of cortisol output (Arnetz et al.,
1987; Baum, Gatchel, & Schaeffer, 1983; Kosten, Jacobs, &
Mason, 1984; Schaeffer & Baum, 1984). Perhaps because they
were consistent with the large body of evidence from animal
studies, these findings captivated the attention of researchers and
provided an empirical foundation for models of stress, cortisol, and
disease that followed. For the next 10–15 years, research and
theory in this area flourished, guided by the implicit assumption
that HPA activity increases robustly with stress.
However, in the mid to late 1990s, a series of studies emerged
of patients suffering from PTSD, and they reported the surprising
result that combat veterans, Holocaust survivors, and other trauma
victims had reduced cortisol secretion as well as a host of other
indicators of abnormal HPA activity (Yehuda, Boisonuae, Lowy,
& Giller, 1995; Yehuda, Kahana, et al., 1995; Yehuda, Resnick,
Schmeidler, Yang, & Pitman, 1998; Yehuda, Teicher, Trestman,
Levengood, & Siever, 1996). This pattern was not uniformly
observed in studies of PTSD (see e.g., Hawk, Dougall, Ursano, &
Baum, 2000; Lemieux & Coe, 1995; Pitman & Orr, 1990). The
most robust evidence came from patients who had chronic, intrac-
table PTSD and had been exposed to trauma many years before
cortisol assessment. Nevertheless, this pattern of reduced cortisol
output and blunted HPA activity was sufficiently common that
some researchers began viewing it as a unique feature of (and a
potential cofactor in) PTSD (Yehuda, 2000; Yehuda, Resnick,
Kahana, & Giller, 1993). In the years that followed, broader
evidence of this phenomenon began to emerge; low cortisol output
was documented in chronically stressed but nonpsychiatric popu-
lations, such as victims of domestic violence and caregivers for ill
family members (Miller, Cohen, & Ritchey, 2002; Seedat, Stein,
Kennedy, & Hauger, 2003; Vedhara et al., 2002). Again, not all
studies of chronic stress reported findings in this direction. How-
ever, by 2000, stress-related hypocortisolism had begun to attract
considerable attention, and Heim, Ehlert and Hellhammer (2000)
published a seminal review article on the topic. A number of other
articles on this phenomenon soon followed (Fries, Hesse, Hell-
hammer, & Hellhammer, 2005; Gunnar & Vazquez, 2001; Raison
& Miller, 2003), and today the field is squarely focused on hypo-
Despite the enthusiasm, these findings have created significant
confusion in the field. It is unclear how the recent findings can be
integrated with older studies to arrive at a general conclusion about
how HPA functions are influenced by chronic stress. Does cortisol
output increase, as older work suggests? Or does it decline, as
newer research indicates? Or perhaps more interestingly, is it
capable of doing both? That is, might the nature and direction of
the cortisol response depend on features of the stressor or on
characteristics of the person who is coping with it? The answers to
these questions have significant implications for research and
theory across many areas of inquiry. Hence, the goal of this review
is to synthesize findings over the past 50 years of research and
generate answers to what was once considered a simple question:
How is activity of the HPA axis modified by exposure to chronic
What Shapes HPA Activity Following Exposure to
If chronic stress is capable of increasing or decreasing HPA
activity, what are some of the critical features that govern which
outcome occurs? It is surprising that there has been little effort to
develop psychological hypotheses that can explain this process.
Thus, a second objective of this review is to outline and evaluate
five hypotheses that may help to sort out some of the confusion in
the literature. These hypotheses focus on (1) the time elapsed since
stressor onset, (2) the nature of the threat posed, (3) the core
emotions likely to be elicited by the stressor, (4) the controllability
of the stressor, and (5) the psychiatric characteristics of the person.
1. Time Since Onset
One possibility is that chronic stress both increases and de-
creases HPA activity, but does so at different times over the course
of a threat. Shortly after the stress has begun, the axis may become
activated, resulting in elevated cortisol output. However, with the
passage of time, the body could mount a counter-regulatory re-
sponse such that cortisol output rebounds below normal. This is a
biologically plausible explanation, because the HPA axis is regu-
lated by a potent negative feedback circuit, in which elevated
levels of cortisol suppress output of CRH and ACTH by acting on
glucocorticoid receptors in the hippocampus, hypothalamus, and
MILLER, CHEN, AND ZHOU
pituitary. It is also a plausible explanation for the conflicting
findings in the literature. Although hypotheses about the impor-
tance of timing have been articulated by several researchers (Fries
et al., 2005; Hellhammer & Wade, 1993; Miller et al., 2002), they
have not yet been tested with a proper longitudinal design. Thus,
the existing literature may only seem contradictory because it is
composed of a series of cross-sectional studies, each of which
assesses its participants at a slightly different point in time with
respect to stressor onset. In the current article, we use meta-
analysis to evaluate this hypothesis. To the extent that it is correct,
a correlation should emerge between timing and HPA activity,
with more distant traumas being associated with hypocortisolism,
and the reverse being true of recent-onset stress.
2. Nature of Threat
Another possibility is that different forms of stress elicit differ-
ent patterns of hormonal response. A number of theorists have
argued that biological responses are stressor specific, having been
shaped over time to maximize success at coping (Kemeny, 2003;
Weiner, 1992). For example, a distinction can be made between
forms of stress that pose a threat to the physical self (e.g., being in
the midst of combat) and those that represent a threat to the social
self (e.g., being in the midst of a divorce). According to specificity
hypotheses, these situations should elicit different patterns of HPA
activity because they pose different adaptational demands, which
cortisol helps to support metabolically. Support for this view was
recently obtained in a meta-analysis of cortisol responses to acute
stress: Subjects exposed to laboratory situations that were high in
social threat exhibited robust increases in cortisol secretion (Dick-
erson & Kemeny, 2004). When the situation had few elements of
social threat, little in the way of a cortisol response was evident.
The authors theorized that preserving social standing is a central
motivation of humans; when this standing is threatened by a
demanding situation, the HPA axis is mobilized to help manage the
threat or its longer term consequences. It may also be useful to
differentiate between traumatic and nontraumatic forms of stress.
The former are defined as experiences that involve “actual or
threatened death or serious injury, or a threat to the physical
integrity of self or others” and have a special capacity to elicit
feelings of “intense fear, helplessness, or horror” (American Psy-
chiatric Association, 2000, pp. 427–428). Because they are able to
elicit such intense and distinct emotions, traumas may bring about
more pronounced alterations in HPA function or qualitatively
different profiles of hormonal output than do chronic, but nontrau-
matic, stressors. In the current review, meta-analysis is used to
evaluate whether these distinctions—physical versus social and
trauma versus nontrauma—help to explain the mixed findings in
the literature on chronic stress and HPA outcomes.
3. Emotions Elicited by Stress
A related hypothesis is that the direction and magnitude of the
HPA response is governed by the emotion(s) elicited by the
situation. According to this view, emotions represent the psycho-
logical mechanism connecting stressors to biology, so they should
be the most powerful determinant of changes in HPA functions.
One emotion that has been repeatedly discussed in this regard is
shame. In studies in which subjects are exposed to acute stress in
a laboratory setting, the extent of cortisol reactivity increases in a
linear fashion with shame (Dickerson & Kemeny, 2004; Gru-
enewald, Kemeny, Aziz, & Fahey, 2004). Thus, feelings of shame
appear to foster HPA activation during acute bouts of stress. It is
interesting that the available evidence suggests an opposite pattern
with more long-term, severe stress. At least in combat veterans
who suffer from PTSD, shame is inversely related to daily cortisol
output (Mason et al., 2001). This has led some researchers to
suggest that shame may be a critical mechanism in stressor-related
hypocortisolism. Feelings of loss also have been discussed as
potential moderators. Life stress that involves a major loss has
been shown to predict the onset of major depression (Kendler,
Hettema, Butera, Gardner, & Prescott, 2003), and it has been
argued that it does so by activating the HPA axis to persistently
secrete cortisol (Meinlschmidt & Heim, 2005; Nicolson, 2004;
Petitto, Quade, & Evans, 1992). Thus, the meta-analysis will
examine whether two key emotional themes of chronic stress—
shame and loss—can differentiate between studies that find in-
creases versus decreases in HPA function.
4. Controllability of Stress
Controllability represents another important dimension of
chronic stress that has been proposed to influence HPA axis
responsivity (Heim, Ehlert, & Hellhammer, 2000). In the context
of acute stress, uncontrollability amplifies cortisol secretion, both
in humans and in animals (Dickerson & Kemeny, 2004; Sapolsky,
1998). However, with stress that is more severe and persists
longer, uncontrollability is thought to result in diminished HPA
activity. This blunting may underlie the withdrawal and disengage-
ment behaviors that often accompany uncontrollable chronic stress
(Gold & Chrousos, 2002; Heim, Ehlert, & Hellhammer, 2000;
Mason et al., 2001). Conversely, it may be a manifestation of the
physiological toughening or steeling oneself that can occur when a
person cannot escape from a difficult situation (Dienstbier, 1989;
Gunnar & Vazquez, 2001a). By contrast, stress that has some
element of controllability may activate the HPA axis, as its hor-
monal products provide metabolic support for active coping efforts
(Gunnar & Vazquez, 2001a; Mason et al., 2001). Hence, to the
extent that these theoretical formulations are accurate, the meta-
analysis should yield positive associations between controllability
and HPA products, which would help to explain variability in the
5. Individual Psychiatric Sequelae
A final possibility is that the psychiatric consequences of
chronic stress, rather than features of the stress itself, are what
govern the magnitude and direction of any HPA axis response. For
example, research indicates that if a person exposed to trauma
develops PTSD, he or she is likely to exhibit hypocortisolism
(Yehuda, 2000; Yehuda, Resnick, et al., 1993). In contrast, de-
pression following a trauma has been associated with increased
cortisol output (Kaufman et al., 1997, 1998; Raison & Miller,
2003). Even when a trauma victim does not develop a full-blown
psychiatric condition, research has suggested that the extent of
subjective distress is positively associated with HPA activation
(Baum, Cohen, & Hall, 1993; Davis et al., 2004; Rahe, Karson,
Howard, Rubin, & Poland, 1990). To examine the contribution of
CHRONIC STRESS AND HPA ACTIVITY
psychiatric conditions and normative distress, we also conducted a
separate meta-analysis involving only persons exposed to chronic
stress. It asked the question, do individuals who experience
chronic stress and develop a psychiatric diagnosis, or report greater
subjective distress, differ in HPA function from those who expe-
rience chronic stress but do not develop a diagnosis or report
Defining and Measuring Chronic Stress
Most of the work in this area has relied on stimulus-based
definitions of chronic stress, in which a target population is facing
circumstances that most people would consider troubling and
ongoing. Typical designs feature soldiers in the midst of combat,
refugees displaced by war, victims of sexual assault, family care-
givers for the ill, and people who have lost their jobs or spouses.
Although these situations differ in a number of important respects,
we believe they all can be viewed as chronic forms of stress. By
stress we mean situations that the average person would appraise
as threatening and exceeding his or her ability to cope (Lazarus &
Folkman, 1984). By chronic we mean that the eliciting stimulus
remains in the environment for an extended period of time (e.g.,
the family member who needs care indefinitely) or, alternatively,
that the threat a stimulus poses to the self looms for an extended
period of time (e.g., the sense of danger that follows a sexual
assault), even if the stimulus itself does not. This definition grows
out of the taxonomy proposed by Baum, Cohen, and Hall (1993),
which views chronic stress as being composed of a stimulus from
the environment, a person’s appraisal of that stimulus, and biobe-
havioral responses that support coping efforts. These dimensions
are understood to be independent, and each can vary in duration
from acute to chronic. As a result, this view of chronic stress
encompasses situations in which the stressor persists for an ex-
tended period of time, as well as situations that last for a very short
time but are likely to be seen as threatening for much longer.
Defining and Measuring HPA Activity
HPA activity can be assessed in a variety of ways. The most
common method is to measure output of cortisol. This can be done
by collecting saliva (which contains biologically active cortisol,
unbound to carrier proteins), blood, urine, or cerebrospinal fluid
(all of which contain bound and unbound cortisol). Each of these
fluids provides a slightly different temporal window on cortisol
activity (Baum & Grunberg, 1995). Levels of hormone in blood
and saliva reflect HPA activity in the past 10–60 min. Because it
is usually collected over a 15–24-hr period, urinary cortisol pro-
vides a broader and more integrative profile of activity. In addi-
tion, cortisol has a diurnal rhythm (highest in the early morning,
lowest in the evening), so the timing of assessments is an important
factor. Some studies measure cortisol at specific times of the day
(e.g., morning cortisol, evening cortisol). Others collect samples at
multiple times throughout the day and either average across the
day (as an indication of total cortisol output across the day) or
calculate a slope (as an indication of cortisol’s rhythm across the
day). Studies can also measure hormonal output at different points
in the HPA axis. In addition to cortisol, measures can be taken of
CRH (via cerebrospinal fluid) or ACTH (via blood) as additional
indicators of HPA activity.
An alternative approach is to perform hormonal challenges.
Researchers can introduce molecules such as CRH and ACTH into
the system, as well synthetic versions of cortisol like dexametha-
sone, and measure secretion of downstream hormonal products.
Normally, when cortisol levels are elevated, hypothalamic secre-
tion of CRH declines, and this in turn diminishes ACTH and
cortisol release. Challenge protocols are thus used to evaluate the
sensitivity of the HPA axis’s negative-feedback circuit. Different
molecules are used to assess the integrity of each axis component.
CRH challenges provide a window into pituitary function, whereas
ACTH challenges index sensitivity of the adrenals. Dexametha-
sone acts for the most part at the pituitary. In each of these tests,
a response is considered “normal” when the challenge molecule
suppresses circulating concentrations of the target hormone below
a specified threshold in the hours following administration. For
challenge protocols involving dexamethasone, cortisol is the target
hormone, and it is measured 8–17 hr after drug administration. For
CRH challenges, ACTH and cortisol secretion are measured over
a shorter window, usually 1–2 hr after drug administration. An
“abnormal” response to these protocols occurs when a partici-
pant’s secretion of the target hormone is not influenced (or de-
clines only modestly) following introduction of the challenge
A final approach to measuring the HPA axis involves evaluating
its influence on target tissues. For a hormone like cortisol to
influence a biological system, it must bind to a specific receptor
located inside a cell. The newly formed receptor-hormone complex
translocates to the nucleus, where it is capable of modifying the
cell’s program of genetic expression. To estimate how sensitive
bodily tissues might be to cortisol’s regulatory influence, research-
ers in this area have sometimes measured the number of glucocor-
ticoid receptors. This assessment is typically performed in white
blood cells, as they can be easily extracted from humans and
represent a target tissue of considerable theoretical interest. To the
extent that a person’s cells express higher numbers of receptors, he
or she is assumed to be more sensitive to cortisol’s actions in that
tissue. It also bears noting that receptor expression is directly
influenced by cortisol exposure; when high levels of the hormone
are present, cells typically downregulate receptor numbers to
maintain homeostasis. Thus, number of receptors is also some-
times understood as a marker of a tissue’s recent exposure to
Articles for the meta-analysis were initially identified through searches
of the PubMed, Ovid MEDLINE, PsycInfo, EMBASE, and Evidence-
Based Medicine Reviews databases for the years 1950–2005. Each search
crossed keywords reflecting chronic stress (assault, abuse, bereavement,
caregiver, stress, trauma, unemployed, veteran, and war) with those re-
flecting HPA outcomes (cortisol, ACTH, CRH, adrenocortical). To aug-
ment the yield of the database search, we also combed reference sections
of review articles in the area (Chrousos & Gold, 1992; Dickerson &
Kemeny, 2004; Heim, Ehlert, & Hellhammer, 2000; Raison & Miller,
2003; Yehuda, 2000; Yehuda, Resnick, et al., 1993). As well, we did a
cited-reference search on the ISI Web of Science, which involved entering
the 10 most highly cited studies we found into the database and then having
it locate articles that listed those studies in their reference sections.
MILLER, CHEN, AND ZHOU
To be eligible for inclusion in the meta-analysis, a study had to enroll
subjects exposed to chronic stress, measure an indicator of HPA axis
function, and provide enough data for us to compute effect sizes. We
defined chronic stress as persistent circumstances that would normatively
be appraised as threatening and exceeding coping resources (Lazarus &
Folkman, 1984). To qualify as chronic, either the stressor itself needed to
persist for a period lasting at least 1 month, or the circumstance needed to
involve a brief event such as a natural disaster that was likely to be
appraised as threatening for a similar duration. This definition is consistent
with the broad view of chronic stress proposed by Baum et al. (1993). It
encompasses situations in which the stressor persists for an extended
period of time (e.g., caregiving for a family member with dementia), as
well as situations that last for a very short time but are likely to be seen as
threatening for much longer (e.g., being the victim of a sexual assault). In
summary, for a situation to be included in the meta-analysis, either the
stimulus and/or the presumed threat appraisal had to persist for 1 month.
We also required the chronic stressor to be psychological in nature.
Situations that were undesirable because of their physical health implica-
tions—such as long-term cold, pain, or disease—were excluded from the
meta-analysis for two main reasons. First, our interest was in situations that
primarily involved psychological stress. Second, exposure to stimuli like
cold, pain, and disease can directly modify functions of the HPA axis, and
this makes it difficult (if not impossible) to untangle the relative influences
of the mental versus physical aspects of stress.
With these eligibility criteria in place, our search efforts yielded 171
articles. A sizable number of these articles had to be excluded from the
meta-analysis because they did not focus on a discrete chronic stressor (k ?
24 studies). This created difficulties because the goal of our analysis was
to identify features of chronic stress, such as its core emotional themes, that
give rise to distinct profiles of HPA axis function. If a study included
people facing divergent kinds of chronic stress, such as a job loss and
combat experience, we were unable to assign it codes on these dimensions.
(That is, unless it presented distinct statistics for each form of stress, in
which case it was included in the meta-analysis.) A handful of articles also
had to be excluded because they did not provide sufficient information for
us to compute effect sizes (k ? 13), or they were not designed with an
appropriate control or baseline condition that was free of chronic stress
(k ? 15). To meet our criteria for good design, studies had to include a
control sample free of chronic stress or compare subjects before and after
they encountered difficulties. We also included studies in which all sub-
jects had been exposed to stress, but the focus was on whether psychiatric
symptoms explained variability in HPA outcomes. These studies were used
to perform meta-analyses on the roles of PTSD, major depression, and
normative distress. After studies had been excluded for these reasons, the
pool of eligible articles totaled 119.
The eligible studies were coded to derive features of the participants, the
kinds of stress they faced, and the HPA outcomes being assessed. Coding
was done by consensus of Edith Chen and Gregory E. Miller.
The coder extracted information regarding the
size, mean age, gender balance, and psychiatric condition of the partici-
pants in each study.
Four major features of each form of chronic stress
were coded, corresponding to the hypotheses outlined in the introduction.
To classify the nature of the threat, coders rated each form of stress
according to whether it posed a physical (likely vs. unlikely) and a social
threat (likely vs. unlikely). Physical threats were defined as stimuli that had
the potential to diminish bodily integrity and bring about injury, disease, or
mortality. Social threats were defined as stimuli that could diminish a
person’s social standing or interrupt a major social role that he or she
occupies. Studies were also categorized according to whether they focused
on traumatic stressors (likely vs. unlikely). In line with current diagnostic
standards for PTSD, traumas were defined as situations in which a person
was likely to have experienced or witnessed “events that involved actual or
threatened death or serious injury, or a threat to the physical integrity of
self or others” (American Psychiatric Association, 2000).
To extract the core emotional theme of each form of stress, coders rated
the likelihood that it would result in loss and humiliation. Loss was coded
when there was an actual or potential loss of life to self or a close other or
when the stress threatened an important relationship or social role. Humil-
iation was coded when the stress had the potential to cause shame or
disgrace or leave the victim feeling devalued in the eyes of important
others in his or her life. Ratings were made on a binary scale, with
endpoints of likely and unlikely. The extent of control each kind of stress
afforded participants was also coded. Control was defined as the ability to
end the stress when desired. Because chronic stress never affords much in
the way of control, coders assigned ratings of either uncontrollable or
possibly controllable in this category.
The temporal features of stress were coded in two ways. To estimate the
duration of stress exposure, coders recorded the number of months since
onset, because this is when HPA activity presumably begins. When this
value was not provided, we either requested it from authors or estimated it
using historical knowledge. The latter strategy was mostly used in studies
of combat exposure in Vietnam, for which we estimated duration as months
between the date of article publication and the height of U.S. involvement
in the war (December 1968). Preliminary analyses of this variable revealed
that it was distributed in a nonnormal fashion, so all values were log-10
transformed prior to use in the meta-analysis. To evaluate whether HPA
functions differ according to the persistence of stress, we also recorded
whether the stressor stimulus was present versus absent at the time of
assessment. Circumstances that were still unfolding or required ongoing
coping—such as caregiving for a disabled relative or seeking a job while
unemployed—were rated by coders as being present. Those in which the
outcome had already been determined—such as combat experience 30
years prior or adults who were abused as children—were rated by coders
as being absent.
Meta-analysis is a tool for synthesizing research findings. Its first stage
involves computing an effect size for each study that is identified. The
effect size reflects the magnitude of the relationship between predictor and
outcome variables of interest, in this case, forms of chronic stress and
various HPA axis functions. It is important to note that an effect size
reflects the strength of an association and not its statistical significance; as
such, it is not dependent upon the size of the sample from which it derives.
In the next stage of meta-analysis, article-specific effect sizes are combined
to derive an aggregate estimate across the literature.
Study-level effect sizes.
We used Cohen’s d as the effect size metric in
this meta-analysis. We computed effect sizes for individual studies using
descriptive statistics presented in the original published reports. When
these statistics were not available, we requested them from authors. This
strategy was successful in most circumstances. To compute d from de-
scriptive statistics in between-subjects designs, we subtracted the control
group mean from the chronic stress group mean and divided this value by
the pooled standard deviation (Rosenthal, 1994). To compute d from
descriptive statistics in within-subject designs, we subtracted the group
mean at baseline from the group mean during stress and divided this
quantity by the sample standard deviation at baseline. In cases in which
descriptive statistics were not available, we computed d from inferential
statistics using standard formulae (Rosenthal, 1994). These formulae had to
be modified slightly for studies that used within-subject designs, because
effect sizes are systematically overestimated when they are calculated from
repeated-measures test statistics (Dunlap, Cortina, Vaslow, & Burke,
1996). In these situations, we derived effect size estimates using the
formula d ? tc[2(1 ? r)n]1/2, where tccorresponds to the value of the t
CHRONIC STRESS AND HPA ACTIVITY
statistic for correlated measures, and r corresponds to the value of the
correlation between outcome measures at pretest and posttest (Dunlap et
al., 1996). Because very few studies reported the value of r, we used a
value of .40 to compute effect sizes in this meta-analysis. To ensure that the
meta-analytic findings were robust to variations in r, we conducted
follow-up analyses using r values ranging from .20 to .60. Very similar
findings emerged from these analyses, suggesting that the values we
present below are reliable estimates of effect size.
Aggregate effect sizes.
The study-level effect sizes were subsequently
aggregated by use of fixed-effects models in the software program Com-
prehensive Meta-Analysis Version 2 (Borenstein & Rothstein, 1999). We
chose fixed-effect procedures because they are well suited to the goals of
our review: to take stock of the data that have accumulated in this area over
50 years and to begin testing hypotheses about stressor and person features
that give rise to distinct HPA profiles. When a meta-analysis has aims of
this nature—to sort out existing findings, but not generalize more
broadly—fixed-effects procedures are the method of choice (Hedges &
Vevea, 1998). These models also have the (general) advantage of greater
statistical power (Cohn & Becker, 2003), especially in cases in which the
number of studies being synthesized is small. All that said, some caution
needs to be exercised when the results of fixed-effects analyses are inter-
preted. Although they can help to sort out conflicts among existing studies,
their findings need to be replicated in novel samples before large-scale
generalizations can be made.
Separate fixed-effects models were computed for each HPA outcome
included in the meta-analysis. Each model yielded an aggregate effect size
d, which reflects the difference between chronic stress and control groups
in standard deviation units. d values of .20, .50, and .80 correspond roughly
to small, medium, and large effects, respectively (J. Cohen & Cohen,
1983). Each d statistic was weighted before aggregation by multiplying its
value by the inverse of its variance; this procedure enabled larger studies
to contribute to effect size estimates to a greater extent than smaller ones.
Weighting effect sizes is important because larger studies provide more
accurate estimates of true population parameters (Shadish & Haddock,
1994). After each aggregate d had been derived, we evaluated whether it
was significantly different from zero, using the criteria that its correspond-
ing z value had to be greater than 1.96 and that its 95% confidence intervals
could not include zero (Rosenthal, 1991; Shadish & Haddock, 1994). We
also computed a heterogeneity coefficient with each model to evaluate
whether it was composed of studies with similar findings. The heteroge-
neity coefficient is referred to as Q, and it is chi-square distributed with k ?
1 degrees of freedom, where k is the number of studies included. When a
Q statistic indicated there was significant variability across a group of
studies, we examined whether person or stressor features explained the
disparity. In cases in which the proposed moderator was scaled nominally
or ordinally, we stratified studies using coder ratings and computed sepa-
rate fixed-effects models for each subgroup. When the proposed moderator
was continuous—for example, months since stressor onset—a fixed-effects
meta-regression equation was constructed. These equations are similar to
standard linear regression equations, except that the unit of analysis is
“study” rather than “participant.”
Handling missing data.
scriptive or inferential statistics needed to compute an effect size. In some
of these cases, the authors noted that there was a significant difference
between chronic stress and control groups. When this occurred, we com-
puted effect sizes assuming that p values were equivalent to .05. This
represents a conservative approach because the actual p values were
probably smaller. In other cases, the authors noted that chronic stress and
control groups did not differ with respect to an HPA outcome, but failed to
provide any further statistical information. When this occurred, we com-
puted effect sizes assuming that there was no difference at all between the
groups, that is, a d value of 0.00. Because there is seldom no difference at
all between two groups, this also represents a conservative strategy. Im-
putation was used in ? 5% of cases.
Handling dependent data.
Meta-analysis assumes that each study-level
effect contributing to an aggregate estimate is statistically independent
(Rosenthal, 1991). We took a number of steps to avoid violating this
assumption. First, when the same data appeared to have been published in
multiple articles, we contacted authors to determine the extent of sample
overlap. Second, in a handful of studies, multiple chronic stresses were
assessed, and each was compared with the same pool of control subjects.
In these cases the average d across stresses was used for aggregate
estimates, unless a specific analysis permitted us to use stressor-specific
values in a nondependent fashion. Finally, a small group of studies used
longitudinal designs, assessing HPA outcomes on multiple occasions over
the course of stress. For these studies, we used the average d across
occasions to derive aggregate estimates.
Occasionally studies failed to report the de-
The meta-analysis is based on 107 independent studies from a
total of 119 published manuscripts. A total of 8,521 individuals
participated in these research projects. On average, 53% of partic-
ipants were male, 47% were female, and their average age was
38.39 (SD ? 16.23). They faced many forms of chronic stress: 38
of the studies focused on combat/war experience (35.5%), 27
involved abuse/assault (25.2%), 15 involved death or loss of a
major relationship (14.0%), 10 involved caregiving experiences
(9.3%), 8 involved natural disasters (7.5%), and 5 involved job
loss and/or unemployment (4.7%). Table 1 provides a summary of
how each kind of stress was rated along the various dimensions of
our coding scheme.
With respect to outcomes, the most common HPA indicator was
morning cortisol (k ? 65; 60.7% of studies), followed by daily
output of cortisol (k ? 33; 30.8%), then afternoon/evening cortisol
measures (k ? 31; 29.0%), postdexamethasone cortisol (k ? 21;
19.6%), ACTH (k ? 16; 15.0%), post-CRF cortisol (k ? 7; 6.5%),
post-CRF ACTH (k ? 6; 5.7%), cortisol rhythm (k ? 5; 4.7%),
Ratings of Features for Commonly Assessed Stressors
Months since onset (Mdn, range)
Physical threat rated as likely (%)
Social threat rated as likely (%)
Trauma rated as likely (%)
Rated as likely to be uncontrollable (%)
Feelings of loss rated as likely (%)
Feelings of shame rated as likely (%)
MILLER, CHEN, AND ZHOU
glucocorticoid receptor numbers on lymphocytes (k ? 4; 3.7%),
CRF (k ? 3; 2.8%), and white blood cell function following
glucocorticoid administration (k ? 3; 2.8%). Several outcomes
were included in only 1–2 studies, including post-ACTH cortisol,
postdexamethasone ACTH, postdexamethasone glucocorticoid re-
ceptor numbers, and cortisol or ACTH challenge studies that
administered other types of HPA-challenge molecules. On aver-
age, studies in the meta-analysis reported on two different HPA
indicators (M ? 2.0, SD ? 1.3), though nearly half of them
presented only a single outcome (60 of 119, or 50.4%).
General Findings: Chronic Stress and HPA Functions
Table 2 presents aggregate effect sizes for each outcome. We
have collapsed the findings across stressor and person features, to
provide a general indication of how chronic stress modifies HPA
axis functions. Note that to derive estimates of this nature, we had
to restrict the analyses to studies that included stress and control
conditions and to outcomes that were assessed in three or more
separate studies. The results indicate that exposure to chronic
stress is associated with significantly lower concentrations of
morning cortisol (d ? ?0.08), and more pronounced suppression
of cortisol following dexamethasone challenge (d ? ?0.23). It is
also associated with greater concentrations of afternoon/evening
cortisol (d ? 0.18), a flatter diurnal rhythm (d ? 0.39), and a
higher daily volume of cortisol output (d ? 0.31). Collectively,
these findings suggest that chronic stress is accompanied by a
dysregulated pattern of hormone secretion, with lower than normal
morning output but higher than expected secretion across the rest
of the day. This pattern gives rise to a flattened diurnal rhythm. In
healthy persons not exposed to chronic stress, cortisol usually
displays a robust diurnal rhythm, with values highest in the morn-
ing and lowest in the evening.
Several additional outcomes were assessed in the literature.
Although there was evidence that cerebrospinal fluid concentra-
tions of CRH were significantly increased (d ? 0.66), ACTH
levels in participants facing chronic stress were similar to those in
nonexposed controls. There also were no stress-related differences
in hormonal response to CRH challenge or in the number of
glucocorticoid receptors expressed by white blood cells.
Inspection of the heterogeneity statistics (Q) in Table 2 revealed
significant variability in the studies composing each aggregate d.
This was true in all cases, except diurnal cortisol rhythm and CRH
concentration. Thus, our next step was to explain the sources of
this variability, using the stress–person hypotheses outlined earlier
as a guide. The results of these analyses are presented below. Note
that because only a handful of outcomes have been assessed
regularly in this literature, we limit moderator analyses to catego-
ries in which five or more studies are available. This is the case for
morning, afternoon/evening, and daily volume of cortisol; for
ACTH measured at any time of day; and for the cortisol response
to dexamethasone challenge. With all other outcomes, there were
too few data points to make moderator analysis feasible.
Table 3 summarizes the stressor and person features of studies
that were included in each outcome category. As is evident from
the data in this table, the kind of stress was generally similar across
categories. War/combat and abuse/assault were the most fre-
quently studied difficulties. Experiences with caregiving and be-
reavement were next most common, followed by natural disasters
and job loss, which accounted for only a handful of studies in each
category. On average, a good deal of time had elapsed since the
onset of these stressors, though the range of durations was quite
broad within each category. Stress was more likely to pose a
physical versus social threat, was generally rated as being uncon-
trollable, and was more likely to elicit feelings of loss than shame.
Temporal Features of Stress
To examine the relationship between months since onset and
HPA outcomes, we estimated a series of fixed-effects meta-
regression equations. The results are summarized in Table 4 and
illustrated in Figure 1. Analyses revealed a pattern of inverse
associations for morning cortisol, daily volume, ACTH, and post-
dexamethasone cortisol. As time since the onset of stress in-
creased, effect sizes for each of these outcomes decreased. These
findings are consistent with the hypothesis that when a chronic
Summary of Meta-Analytic Findings Across Studies and Outcomes
CRH: All samples
GC receptor expression
CI ? confidence interval; DST ? dexamethasone suppression test; CRH ? corticotropin releasing hormone;
GC ? glucocorticoid.
Summaries are presented for outcomes assessed in three or more studies. Qwis the heterogeneity statistic.
CHRONIC STRESS AND HPA ACTIVITY
stressor first arises, there is an initial activation of the HPA axis,
which results in elevated levels of ACTH and cortisol. However,
as time passes, this activity diminishes, and cortisol secretion
rebounds to below normal.
As another method of evaluating the impact of timing, we
categorized stressor as present or absent at the time of HPA
assessment. Within-category meta-analyses revealed that in studies
in which the stressor was still present, morning cortisol (d ? 0.12),
afternoon/evening cortisol (d ? 0.18), and daily output of cortisol
(d ? 0.54) were all significantly higher than controls. By contrast,
in studies in which the initial stimulus was no longer present,
morning cortisol (d ? ?0.17) and postdexamethasone cortisol
(d ? ?0.24) were significantly lower, although afternoon/evening
cortisol was higher (d ? 0.21). Similar to the analyses of months
since onset, these findings suggest the possibility that chronic
stress initially boosts cortisol output but that, as time passes and
the initial stimulus is removed, secretion rebounds to below normal
Nature of Stress
Table 5 describes the results of analyses focusing on the nature
of the stress. In studies in which the stress was likely to involve a
threat to the physical self, morning (d ? ?0.16) and postdexam-
ethasone cortisol (d ? ?0.31) were reliably lower, and afternoon/
evening (d ? 0.22) and daily output of cortisol (d ? 0.46) were
reliably higher. Overall, these data suggest the possibility of a
flattened diurnal rhythm in which morning output is somewhat
reduced, but there is less decline across the rest of the day than
would be expected. This pattern results in a significantly elevated
daily volume of secretion. In studies in which physical threat was
rated as unlikely, there was little in the way of reliable findings,
except that morning cortisol was higher (d ? 0.11).
In studies in which the stress was likely to threaten the social
self, morning (d ? 0.27) and afternoon/evening (d ? 0.26) cortisol
output was higher than in nonexposed controls. These findings
suggest that social threats may activate the HPA axis during the
day hours. In contrast, in studies in which social threats were
unlikely, both morning (d ? ?0.17) and postdexamethasone cor-
tisol (d ? ?0.30) were significantly lower, and afternoon/evening
cortisol (d ? 0.15) and daily volume (d ? 0.42) were higher.
These latter findings are difficult to interpret because “unlikely
social threat” is a nonspecific category that tells us little about the
circumstances of the stress.
The studies focusing on traumatic stressors yielded a pattern that
was identical to those focusing on physical threats. They showed
reliably lower morning (d ? ?0.16), and postdexamethasone
Characteristics of Studies in Each Outcome Category
Natural disaster (%)
Months since onset (Mdn, range)
Physical threat rated as likely (%)
Social threat rated as likely (%)
Trauma rated as likely (%)
Rated as likely be uncontrollable (%)
Feelings of loss rated as likely (%)
Feelings of shame rated as likely (%)
Note.DST ? dexamethasone suppression test; ACTH ? adrenocorticotropin hormone.
Meta-Regression of Hypothalamic-Pituitary-Adrenocortical Outcomes On Time From Stressor
CI ? confidence interval; DST ? dexamethasone suppression test.
MILLER, CHEN, AND ZHOU
cortisol (d ? ?0.24), and significantly higher afternoon/evening
(d ? 0.22) and total daily cortisol (d ? 0.51). Again, this pattern
suggests a flat diurnal rhythm in which morning output is reduced,
but there is less decline in the afternoon/evening than would be
expected, leading to higher daily output. In studies in which
trauma was unlikely following a stressor, the only reliable finding
to emerge was higher morning cortisol (d ? 0.16).
Emotions Elicited by Stress
We next examined whether the emotion(s) likely to be elicited
by each form of chronic stress was associated with HPA outcomes.
Table 5 shows that when chronic stress involved a likely loss, both
morning (d ? ?0.09) and post-DST (dexamethasone suppression
test) cortisol (d ? ?0.32) were reliably lower than in nonexposed
controls, whereas afternoon/evening cortisol was reliably higher (d ?
0.20). This pattern suggests that loss is associated with a flatter
cortisol profile across the day. In contrast, for situations in which loss
was unlikely, afternoon/evening cortisol (d ? 0.17) and daily output
(d ? 1.11) were higher.
When chronic stress was likely to involve shame, afternoon/
evening levels of cortisol (d ? 0.16) were significantly higher than
in controls. This suggests that forms of stress likely to elicit shame
activate the HPA axis, similar to what was found for threats to the
social self. By contrast, stress rated as unlikely to elicit shame was
associated with a pattern of lower morning (d ? ?0.17) and
represents an individual study, and its size is directly proportional to its weight in the analysis.
Regression of effect sizes for daily volume on time since stressor onset. Each circle in the plot
Effect Sizes (d) for Hypothalamic-Pituitary-Adrenocortical Outcomes According to Stress Features
Nature of threat
samples Morning samplesPost-DST samples
samples Daily output
d SEd SEd SEd SEd SE
loss, and shame were rated as likely. For controllability, effect sizes are indicated for stress that was uncontrollable and potentially controllable. Dashes
indicate there were too few studies to estimate an effect size. DST ? dexamethasone suppression test; ACTH ? adrenocorticotropin hormone.
**p ? .01.
Values are standardized mean differences (d) with standard errors. Effect sizes are indicated for stress in which physical threat, social threat, trauma,
CHRONIC STRESS AND HPA ACTIVITY
post-DST cortisol (d ? ?0.32) and higher afternoon/evening (d ?
0.20) and daily cortisol output (d ? 0.44). This is the “high–flat”
profile seen with other stress dimensions. However, because un-
likely shame is a nonspecific category, these data are difficult to
Controllability of Stress
Table 5 also presents the results of analyses for controllability.
In studies in which the stress was rated as uncontrollable, there was
evidence of reliably lower morning (d ? ?0.15) and post-DST
cortisol (d ? ?0.24), and reliably greater afternoon/evening cor-
tisol (d ? 0.24) and daily output (d ? 0.43), all relative to
nonexposed controls. Again, these data suggest a flattened rhythm
in which morning output is reduced, but the typical decline across
the day was less than expected, resulting in high overall volume.
By contrast, in studies in which the stress was potentially control-
lable, morning cortisol was reliably higher (d ? 0.21). These
findings suggest that when a person has a chance to control the
outcome of chronic stress, his or her HPA axis is activated in the
Individual Psychiatric Sequelae
Table 6 presents the results of meta-analyses on psychiatric
features of the victim. The studies composing these analyses
generally compared individuals who had or had not developed a
psychiatric condition following exposure to chronic stress. Among
the studies that focused on major depressive disorder, there was
evidence of significantly higher postdexamethasone cortisol (d ?
1.13). These findings suggest that in the context of chronic stress,
clinical depression interferes with the negative-feedback circuit of
the HPA axis, allowing cortisol to partially escape from dexameth-
The analyses also indicated that among people who developed
PTSD after stress exposure, postdexamethasone cortisol (d ?
?0.25) and total daily output (d ? ?0.34) were reliably lower, and
afternoon/evening cortisol was reliably higher (d ? 0.47). These
findings indicate that compared with healthy adults who have been
exposed to identical chronic stress, patients with PTSD are gen-
erally hypocortisolemic and have enhanced sensitivity to mole-
cules that engage the HPA axis negative-feedback circuitry.
Some studies also investigated the role of distress in predicting
HPA outcomes in persons facing chronic stress. These studies
measured subjective distress as an individual difference variable,
and typically correlated distress with HPA outcomes in a sample in
which everyone was facing the same ongoing difficulty. In these
samples more subjective distress was associated with lower morn-
ing (d ? ?0.08), higher afternoon/evening (d ? 0.45), and greater
daily output of cortisol (d ? 0.58). This pattern suggests that
subjective distress is associated with a dysregulated (flat, high)
pattern of cortisol secretion.
Where Is the Action?
The meta-analyses yielded robust support for several of our
hypotheses: (a) Time elapsed since onset was inversely related to
most outcomes; (b) forms of stress that posed a physical threat,
were traumatic in nature, and were uncontrollable elicited a spe-
cific hormonal profile; and (c) there was a consistent pattern of
HPA output among those who developed PTSD after trauma. In an
effort to untangle these findings, and discern the critical determi-
nants of HPA response, we ran a final wave of meta-analyses.
They were guided by three specific questions, each meant to
isolate the influence of a single factor. As a result of the small pool
of studies in this literature, these analyses were limited to the most
frequently assessed outcomes: morning cortisol and daily output.
Question 1: To what extent does PTSD status explain the other
Research in this area has been dominated by a focus on
PTSD, and patients with this disorder were often subjected to
physically threatening and uncontrollable stress, which by diag-
nostic necessity was traumatic in nature. So it could be that
psychiatric diagnosis, rather than stress features, is the critical
determinant of HPA response. Thus, we stratified articles on the
basis of whether patients did versus did not suffer from PTSD, and
then we computed another series of meta-analyses testing the
major hypotheses. The results of these analyses convincingly dem-
onstrated that PTSD does not account for the influences of timing,
stress nature, and controllability. In the subset of studies in which
no patients suffered from PTSD, months since onset remained
negatively associated with morning cortisol (slope ? ?0.11, SE ?
0.05, p ? .02) and with daily output (slope ? ?0.65, SE ? 0.08,
p ? .001). The earlier findings with physically threatening stress
Effect Sizes (d) for Hypothalamic-Pituitary-Adrenocortical (HPA) Outcomes According to Psychiatric Status
samples Morning samples
samplesDaily output Post-DST samples
d SEd SEd SEd SEd SE
over and above stress exposure. Dashes indicate there were too few studies to estimate an effect size. DST ? dexamethasone suppression test; ACTH ?
*p ? .05.
Values are standardized mean differences (d) with standard errors. Effect sizes indicate disparity in HPA outcome attributable to psychiatric status
**p ? .01.
MILLER, CHEN, AND ZHOU
also were preserved: In non-PTSD samples, this kind of stress was
associated with lower morning cortisol (d ? ?0.17, SE ? 0.04,
p ? .001) and with higher daily output (d ? 0.61, SE ? 0.07, p ?
.001). The same was true of the findings for uncontrollability. As
was the case for the larger body of studies, in non-PTSD samples,
uncontrollable stress was accompanied by lower morning cortisol
(d ? ?0.15, SE ? 0.03, p ? .001) and higher daily output (d ?
0.68, SE ? 0.08, p ? .001). Together, these results suggest that the
meta-analytic findings are not simply reducible to the influence of
PTSD on HPA response.1
Question 2: Can the relative influences of physical threat,
trauma exposure, and stressor controllability be separated?
Throughout the meta-analysis, these three factors yielded similar
patterns. They were all associated with lower morning cortisol,
blunted responses to dexamethasone, higher afternoon/evening
cortisol, and greater daily output. Despite attempts to separate the
influence of these factors, they are highly confounded in the
existing literature. Stressors that were rated as physically threat-
ening were almost always rated as traumatic and uncontrollable
and vice versa. This left too few instances of divergence for any
meaningful separation to be achieved. Thus, the pool of studies at
present does not allow us to determine whether it is physical threat,
trauma, controllability, or some combination of these factors that
gives rise to a distinct HPA profile.
Question 3: Is the impact of timing distinct from that of stressor
Readers may wonder whether more distant kinds
of stress, such as combat experience and sexual assault, tended to
be rated as more uncontrollable. If the answer to this question was
yes, isolating the relative influence of these factors would be
important. However, in our coding scheme, controllability was
rated at the time the stressor was present in the victim’s life, not at
the time the cortisol assessment was performed. This prevented
timing and controllability from becoming confounded. This fact is
borne out to some extent by the meta-analytic findings. For ex-
ample, more distant stress was associated with lower daily cortisol
output, whereas the opposite was true of uncontrollable stress.
Nevertheless, to empirically assess whether the contributions of
these variables were independent, we estimated associations be-
tween time since onset and HPA outcomes within the types of
stress that were rated as uncontrollable. These analyses indicated
that months since stressor onset continued to be negatively asso-
ciated with morning cortisol (slope ? ?0.08, SE ? 0.04, p ? .07)
and with daily output (slope ? ?0.71, SE ? 0.07, p ? .001) even
when all the stress was uncontrollable. Thus, timing and control-
lability appear to shape HPA outcomes independently.
We began this article by posing what has long been viewed as
a simple question: How is activity of the HPA axis modified by
exposure to chronic stress? Despite many claims that a simple
answer to this question exists, the meta-analytic findings suggest
that the situation is far more complex. Chronic stress has the
capacity to increase or decrease HPA activity, and the pattern one
sees depends on features of the stress and the person facing it. In
the sections that follow, we discuss each of the stressor and person
features tested in the meta-analysis, focusing on what the available
evidence documents, what still needs to be discovered, and how
researchers can best go about doing that.
Summary and Integration
Time since onset.
meta-analysis was that time since onset was negatively associated
with HPA activity. That is, the more months that had elapsed since
the stress first emerged, the lower a person’s morning cortisol,
daily volume, ACTH, and postdexamethasone cortisol. Similarly,
when chronic stressors were still present in a person’s environment
(e.g., unemployment), morning, afternoon/evening, and daily cor-
tisol output were significantly higher. By contrast, in cases in
which the stressful stimulus was no longer present (e.g., combat
situations), morning cortisol and postdexamethasone cortisol were
significantly lower. These findings are consistent with the hypoth-
esis that when chronic stress first begins, there is an initial acti-
vation of the HPA axis, which results in elevated concentrations of
ACTH and cortisol. However, the findings suggest that as time
passes, this activity diminishes, and cortisol secretion rebounds to
below normal. A time-dependent pattern of this nature is consistent
with theories advanced by several researchers (Fries et al., 2005;
Miller et al., 2002; Hellhammer & Wade, 1993).
Besides revealing the influence of timing on the HPA response,
these findings clarify a major source of confusion in the literature.
Across the last 5 decades, researchers have alternated between
depictions of “hypercortisolism” and “hypocortisolism.” The
meta-analysis indicates that rather than being contradictory, these
depictions are probably all accurate, but simply reflect different
timepoints during the stress process. Studies focusing on recent
and ongoing stress have generally documented increases in HPA
output (Arnetz et al., 1987; Baum et al., 1983; Kosten et al., 1984;
Schaeffer & Baum, 1984), whereas those focusing on distant
traumas have often found the opposite (Yehuda, Teicher, et al.,
1996; Yehuda, Boisonuae, et al., 1995; Yehuda et al., 1998,
Yehuda, Kahana, et al., 1995). Of course, this has not been true
uniformly (Seedat et al., 2003; Miller et al., 2002; Vedhara et al.,
2002), and these exceptions suggest timing is not the only critical
factor. However, the general pattern of the meta-analytic findings
suggests that it is, in the aggregate, a partial determinant of how
the HPA axis responds to chronic stress.
That said, our analysis of timing suffers from an important
limitation. Because of the dearth of longitudinal research in this
area, it relied heavily on studies with cross-sectional designs. Thus,
although the question we sought to answer was whether the pattern
of HPA activity changes as time since onset elapses, the available
research forced us to modify it to “Do studies with shorter intervals
since stress onset show different patterns of HPA activity than
studies with longer intervals?” The difficulty with this sort of
One of the most robust findings of the
1Readers may wonder whether PTSD accounts for the distinct HPA
profile associated with stressors coded as traumatic. Unfortunately, we are
unable to answer this question with the available literature, as nearly all the
studies of trauma involved patients with PTSD. Thus, there was not a
sufficient quantity of trauma studies with non-PTSD subjects to compute
effect sizes and disentangle the influence of these factors. Note also that the
disparate findings for trauma coding in the Nature of Stress section and the
PTSD coding in the Individual Psychiatric Sequelae section are likely due
to the differences in methodology: The trauma analyses compared individ-
uals who experienced a likely trauma with nonexposed controls, whereas
the PTSD analyses compared individuals who did versus did not develop
PTSD after being exposed to stress.
CHRONIC STRESS AND HPA ACTIVITY
analysis is that time and study are confounded; it is therefore
possible that some other study feature is the actual determinant of
HPA response. We view this as an unlikely possibility, but it
cannot be ruled out definitively.2Thus, an important direction for
future research will be to substantiate the meta-analytic findings
using prospective longitudinal designs. So far, only a handful of
research projects have enrolled subjects shortly after stress onset
and followed them over time to determine whether activity of the
HPA axis shifts (Anisman, Griffiths, Matheson, Ravindran, &
Merali, 2001; Gerra et al., 2003; Spratt & Denney, 1991; Theorell
et al., 1992). We recognize that this represents a logistically
difficult undertaking, because most chronic stress arises unexpect-
edly, it takes time to locate and assess victims, and it can be
difficult to keep such participants enrolled for a long time. How-
ever, research of this nature is absolutely necessary if we are to
stringently evaluate the impact of timing and develop realistic
accounts of its influence. This work will need to answer questions
such as the following: At what point in time does HPA activity
begin to decline from its peak? When does it drop below a person’s
baseline? At what point does it reach asymptote and stop declin-
ing? In short, the next wave of studies will need to discern the
shape of the time function, and they can best do so using prospec-
tive longitudinal designs with repeated assessments.
Nature of stress.
The meta-analysis also examined whether
HPA activity varies according to the nature of the threat posed by
the chronic stress. We found that stress that threatens physical
integrity, like combat, elicits a diurnal profile of cortisol secretion
that is high and flat. Although morning output is slightly lower,
secretion in the afternoon/evening and evening is higher, leading to
greater total daily hormone output. An identical pattern was found
for stress that was traumatic in nature. These findings make sense
when viewed from a functional perspective. In the midst of stress
that poses a threat to survival, there would be adaptive value in
maintaining persistently elevated HPA activity. This system’s hor-
monal products facilitate cognitive, metabolic, immunologic, and
behavioral adaptations that maximize the chances of survival
(Sapolsky et al., 2000; Weiner, 1992). When such a threat is not
looming, the organism can afford a diurnal rhythm, in which
hormonal availability declines across the day.
The meta-analysis also indicated that stress posing a threat to the
social self, like divorce, was associated with significantly higher
cortisol at specific times in the day, including the morning and
afternoon/evening. Why might this be the case? One potential
explanation is that activation helps individuals mobilize resources
to preserve their social standing when it is threatened. Researchers
have argued that the need to be part of a social group is a
fundamental human motivation and that people are driven to
behave in ways that further their belongingness and group affili-
ation (Baumeister & Leary, 1995). A recent meta-analysis found
support for this hypothesis by showing that cortisol secretion is
boosted acutely when people are confronted with social evaluative
threats, that is, situations that have the potential to diminish one’s
standing in the eyes of others (Dickerson & Kemeny, 2004). These
findings have been recently extended into a real-world context:
Adults participating in competitive ballroom dancing, which in-
volves a high degree of social evaluation, show marked increases
in cortisol output that are not due to the physical components of
dancing (Beulen, Chen, Rohleder, Wolf, & Kirschbaum, in press).
These increases are much greater than those observed when the
dancers are practicing without an audience. Collectively, these
findings suggest that social stressors, whether they are acute or
chronic, reliably activate the HPA axis. One question that remains
looming in this area of research, however, is why the observed
elevations are not sufficient to yield higher daily cortisol volumes.
Perhaps the hormonal consequences of social threats are limited to
daytime hours, when people are actively coping with them or
ruminating about them. If this was the case, and cortisol excretion
was normal during sleep, it could explain the lack of daily volume
There are several limitations to the evidence provided by the
meta-analysis in this area. Most important is our inability to
determine the relative influences of physical threat, trauma expo-
sure, and stress controllability. These factors overlap almost com-
pletely in the existing research, and this is also likely to be true in
real-world contexts. Nevertheless, research that could isolate the
influence of these dimensions would be extremely valuable. Sec-
ond, although our approach of rating stress according to physical
versus social threat proved to be useful, one should bear in mind
that most studies in the meta-analysis focused on one or the other.
Follow-up research is needed that compares HPA responses uti-
lizing the same measures, taken at the same time points, for both
physical and social stress within the same study. This would allow
direct comparison of the HPA profiles for each type of stress.
Moreover, assessment of the presumptive mediators of these phe-
nomena would advance this research considerably. In the case of
stress that poses a physical threat and is traumatic in nature, the
potential mediators of hormone release might include fearful emo-
tions. For stress that is more social in nature, reduced social
standing would seem to be critical, as would the self-conscious
emotions it elicits. To the extent that the influence of these medi-
ators can be documented, and the concerns identified above can be
addressed, the validity of stressor-specificity hypotheses will be
Controllability of stress.
Many researchers have proposed that
one primary dimension of what makes a situation stressful is its
controllability (Heim, Ehlert, & Hellhammer, 2000; Dickerson &
Kemeny, 2004; Mason et al., 2001; Sapolsky, 1998; Weiner,
1992). We tested this hypothesis by categorizing each kind of
chronic stress as either uncontrollable or potentially controllable.
Uncontrollable stress elicited a flat, high diurnal pattern of cortisol
secretion. This was manifested by a lower morning output and
higher afternoon/evening secretion, which was sufficient to pro-
duce a significant elevation in total daily volume. These findings
are generally consistent with the research on acute stress, which
indicates that situational controllability is inversely related to
cortisol output (Dickerson & Kemeny, 2004). However, they run
counter to a number of recent theories seeking to explain hypo-
cortisolism. These models suggest that when people encounter
chronic stress that is uncontrollable, HPA activity declines mark-
2In an effort to detect evidence of confounding, we examined whether
the timing variable related to other methodological characteristics. There
were no systematic relationships between timing and mean age of partic-
ipants, percent who were female, nature of chronic stress, and type or
quality of cortisol assessment. While these findings do not eliminate the
possibility of confounding, they rule out some of the more plausible
scenarios of it.
MILLER, CHEN, AND ZHOU
edly, and a constellation of withdrawal and disengagement behav-
iors emerge (Gold & Chrousos, 2002; Heim, Ehlert, & Hellham-
mer, 2000; Mason et al., 2001). There also has been speculation
that diminished HPA activity emerges because people have tough-
ened themselves in preparation for later stress (Dienstbier, 1989;
Gunnar & Vazquez, 2001a). Despite the intuitive appeal of these
theories, the meta-analytic findings do not support their basic
prediction. One potential explanation is that most of these theories
were formulated to explain blunted HPA activity in patients suf-
fering from psychiatric disorders like atypical depression and
PTSD (Gold & Chrousos, 2002; Heim, Ehlert, & Hellhammer,
2000; Mason et al., 2001). The theories may apply specifically to
populations with psychiatric disorders, and our meta-analytic find-
ings indicate that these processes may work differently in normal
individuals facing chronic stress. Alternatively, these theories may
have been derived from studies that relied largely on morning
cortisol assessments. As seen in our meta-analysis, morning cor-
tisol was lower for uncontrollable stress; however, across the
whole day, cortisol was higher during uncontrollable stress.
Turning to chronic stress that was rated as potentially control-
lable, the meta-analysis yielded evidence of significantly higher
morning cortisol. This stands in contrast to the lower morning
cortisol observed in conjunction with uncontrollable stress. How
might these findings be explained? When a person is facing a
challenge that is potentially controllable, he or she may engage in
active coping behaviors, with the hope that they will eradicate the
stressor or attenuate its impact. Higher levels of morning cortisol
may help to mobilize biological systems for coping activities that
will occur the rest of the day. Although this explanation is intu-
itively appealing, caution needs to be exercised in this area, as the
findings were restricted to a single index of hormone secretion. It
remains unclear whether controllable stress has effects on cortisol
only at specific times of the day, or whether findings for control-
lable stress are less reliable than for other HPA outcomes. Clearly,
further research is needed to sort this out and evaluate this coping
Two limits of these analyses should be noted. The first is that the
relative influences of uncontrollability, traumatic experience, and
physical threat cannot be separated in this literature. The second is
that our coding system is likely to have some built-in “noise”
because it does not consider individual circumstances. Judgments
of controllability are likely to vary a great deal across people, even
when they are coping with ostensibly similar difficulties. For
example, unemployment is a more controllable situation for a
person with a marketable set of skills holding out for the right job
than it is for someone laid off from an unskilled factory position in
a tight labor market. Because our coding system could not con-
textualize individual ratings in this way, we almost certainly un-
derestimated relations between control and hormonal outcomes.
Future research can circumvent this difficulty and more precisely
evaluate the impact of control by collecting subjective assessments
of this construct from participants.
Emotions elicited by stress.
The meta-analysis also examined
whether feelings of shame or loss were associated with specific
patterns of HPA activity. Situations likely to elicit shame (e.g.,
sexual abuse) were associated with significantly higher afternoon/
evening cortisol, whereas those evoking loss (e.g., death of spouse)
were accompanied by a flattened diurnal profile. This consisted of
lower morning cortisol and higher afternoon/evening cortisol.
What might these findings indicate? For situations that elicit
feelings of shame, high afternoon/evening cortisol may be a result
of troubling social interactions across the day, in which one’s
standing within the social hierarchy has been diminished (Dicker-
son & Kemeny, 2004). It also could reflect rumination about such
interactions. These possibilities would explain why no reliable
shame findings emerge for morning cortisol; within the first hours
of the day, people have not yet had time for rumination or trou-
bling interactions. Nevertheless, the absence of other reliable hor-
monal alterations for shame makes us reluctant to speculate further
or offer definitive conclusions. For stress that evokes feelings of
loss, a flattened cortisol profile may reflect social isolation or a
withdrawal from regular social activities. Social contact with oth-
ers programs many of the body’s circadian rhythms, including
those regulating the secretion of hormones like cortisol (Stetler,
Dickerson, & Miller, 2004; Stetler & Miller, 2005). Thus if major
losses significantly alter an individual’s social activities, this could
result in a dysregulated cortisol rhythm that remains flat across the
day, rather than a diurnal profile that is regulated by social contact.
A major difficulty with the emotion findings is that they were
not robust across outcomes. Shame was associated with only a
single parameter, whereas the effects of loss were somewhat
stronger, extending to three different outcomes. These findings
could reflect what happens in real-world contexts; perhaps emo-
tions are not a central determinant of the HPA response. However,
we are more inclined to believe that the relatively weaker findings
in this area stem from limitations of our coding system. In the same
way that controllability ratings were decontextualized, our emotion
ratings were made for situations more generally and could not
account for individual differences in affective response. Thus,
research would benefit greatly if future studies assessed the degree
to which participants experience shame, loss, and other emotions
during the course of chronic stress. Researchers could then test
whether the intensity and/or frequency of negative emotional ex-
periences is associated with HPA patterns. Future studies should
also compare different negative emotional experiences within one
study to determine whether emotions such as shame, loss, and
sadness have unique HPA signatures.
Individual psychiatric sequelae.
dence that the psychiatric sequelae of chronic stress are reliable
determinants of HPA activity. Individuals who developed a major
depressive episode in the midst of chronic stress showed markedly
higher cortisol after the dexamethasone-suppression test. This ef-
fect was quite large: They showed postdexamethasone cortisol
levels more than one standard deviation greater than healthy adults
who were also in the midst of chronic stress. This finding is
consistent with the larger corpus of evidence on affective disor-
ders, which shows that depression is associated with dexametha-
sone non-suppression, particularly in patients suffering from se-
vere, melancholic subtypes of this disorder (Haskett, 1993).
Despite the robust pattern of findings with dexamethasone, no
other hormonal outcomes were studied in conjunction with depres-
sion. This will be an important undertaking for future research
Individuals who developed PTSD in the aftermath of chronic
stress showed a reliable pattern of hormonal alterations. Compared
with healthy adults who had been exposed to the same form of
chronic stress, they showed lower daily output of cortisol, en-
hanced suppression of cortisol following dexamethasone adminis-
There was consistent evi-
CHRONIC STRESS AND HPA ACTIVITY
tration, and higher levels of cortisol in the afternoon/evening.
These findings parallel the existing literature on PTSD, which
documents hypocortisolism and enhanced sensitivity of the HPA
negative feedback circuit (Yehuda, 2000; Yehuda, Resnick, et al.,
Finally, the meta-analysis provided evidence that subjective
distress is related to the magnitude of HPA alterations. To the
extent that people reported higher levels of distress, they showed
greater total daily output and afternoon/evening cortisol, though
morning levels were somewhat lower. These findings suggest that
even when a person does not develop a full-blown psychiatric
condition, the extent of distress is positively associated with HPA
activation. This is consistent with theories positing that distress is
an important pathway linking stress and endocrine response (S.
Cohen et al., 1995; Baum et al., 1993).
The major limitation of work in this area is that it has been
largely cross-sectional in nature. This design feature makes it
impossible to determine whether hormonal alterations are caused
by an individual’s psychiatric response or simply reflect trait
features of the person that were present before the symptoms (or
perhaps even the chronic stress) emerged. Indeed, research by
Yehuda and colleagues has shown that reduced output of cortisol
is evident in young adults at risk for PTSD, none of whom have
exhibited symptoms of the disorder or have been directly exposed
to trauma (Yehuda et al., 2000). These findings have generated
speculation that blunted hormonal responses to stress may facili-
tate the development of PTSD (Yehuda, 2000; Yehuda, Resnick, et
al., 1993). To the extent that further research shows these hypoth-
eses to be accurate, it will demonstrate that relations between
psychiatric response and HPA activity can play out in multiple
directions. Regardless of how the work on PTSD evolves, future
research in this area needs to be prospective and follow people
over the course of a few years starting shortly after stress onset.
Work of this sort will help untangle the complex relations between
chronic stress, psychiatric response, and HPA activity.
Other potential moderators.
Although the meta-analysis iden-
tified several important features of stressors and persons, it was
unable to consider a number of other potential moderators, which
almost certainly influence the magnitude and direction of the HPA
response. Development is one such factor. Exposure to chronic
stress in the early years of life, when the nervous system is still
developing, may result in a distinct and stable pattern of dysregu-
lation. The importance of considering development has been high-
lighted in studies of rodents, in which early-life experiences have
been shown to program HPA axis functions at the genomic level,
such that they remain altered all the way into adulthood (Liu et al.,
1997; Meaney & Szyf, 2005). At the other end of the develop-
mental spectrum are older adults, who often face chronic stressors
like caregiving, while at same time experiencing age-related
changes in endocrine functions. There are good reasons to believe
these factors will modify their HPA response to chronic stress
(Kiecolt-Glaser & Glaser, 2001; Penedo & Dahn, 2005). Unfortu-
nately, too few of the studies in the meta-analysis provided suffi-
cient information for us to consider development as a moderator.
Nevertheless, this line of inquiry should be a high priority for the
next wave of research in this area. Genetics represents another
potentially important moderator. Polymorphisms that could influ-
ence the HPA response to chronic stress are regularly being
identified; some promising candidates include functional variants
present in the glucocorticoid receptor, the mineralocorticoid recep-
tor, and the serotonin transporter (Barr et al., 2004; DeRijk & de
Kloet, 2005). Though work of this nature is still in its infancy, it
is likely to be a fruitful avenue for research in the years to come.
Finally, the impact of chronic stress on hormonal dynamics is
likely to be moderated by the victim’s previous exposure to stress-
ful circumstances (Yehuda, 2004), ability to call forth effective
coping strategies and social support (e.g., Miller, Cohen, &
Ritchey, 2002), and need to manage other stressors that compete
for his/her attention and resources. For example, a recent study
found that chronic stress was associated with reduced expression
of the glucocorticoid receptor, and this relationship was accentu-
ated when an acute life event was superimposed upon the back-
ground difficulties (Miller & Chen, 2006).
These findings have several important theoretical implications.
The first is that models positing an orderly and uniform HPA
response to chronic stress are no longer appropriate. A new wave
of theories needs to be developed to incorporate the moderating
influences of timing, nature of stress, controllability, and individ-
ual psychiatric response. Such theories must provide answers to
questions such as: What types of chronic stress and individual
responses are required for the HPA axis to become persistently
activated? How are these conditions different from those that
dampen HPA activity? Although the meta-analysis does not pro-
vide sufficient information for this to be done immediately, it has
identified a series of variables that are likely to figure prominently
in any new theories. With further empirical research of the nature
specified earlier, it should be possible to construct more elaborate
and refined theories, which clearly specify the conditions when
HPA activity goes up versus down.
The many theories linking stress, cortisol, and disease outcomes
also will need to be refined. Most of them posit that stress non-
specifically activates the HPA axis, and by doing so, contributes to
the development and progression of medical illnesses. Our results
suggest that the chain of events is unlikely to unfold in such a
simple fashion. Newer models will need to acknowledge that
chronic stress can elicit a variety of HPA responses and that their
impact on disease outcome will depend on the condition being
considered. When a person is early in the course of chronic stress,
for example, he or she may become vulnerable to conditions in
which high cortisol is pathogenic. This seems to be true in psy-
chiatric disorders such as depression and schizophrenia (Nemeroff,
1996; E. F. Walker & Diforio, 1997) and medical illnesses like
heart disease and the metabolic syndrome (Bjorntorp & Rosmond,
1999; G. D. Smith et al., 2005). However, as time passes and
cortisol output declines to below normal, these effects on disease
progression would likely subside (and perhaps reverse). The per-
son may even become vulnerable to conditions in which deficient
cortisol signaling contributes to adverse outcomes, such as rheu-
matoid arthritis, fibromyalgia, and allergic conditions (Heim, Eh-
lert, & Hellhammer, 2000; Raison & Miller, 2003). These are just
simplified theoretical conjectures, of course, and the clinical pic-
ture is likely to be more complex. Nevertheless, they illustrate an
important theoretical lesson—that future theories will need to
match kinds of chronic stress, their likely HPA concomitants, and
MILLER, CHEN, AND ZHOU
disease processes to arrive at biologically plausible hypotheses
regarding the linkages among these constructs.
The findings also highlight the importance of developing more
elaborate psychological hypotheses in this area of inquiry. Some
intriguing relationships were documented between psychosocial
characteristics and HPA activity; however, the cognitive, emo-
tional, and behavioral mechanisms underlying them have yet to be
identified. Future research needs to answer questions such as the
following: Do potentially controllable forms of chronic stress
elevate morning cortisol because of the coping efforts they mobi-
lize? Do shame-eliciting forms of chronic stress increase after-
noon/evening cortisol because of troubling social interactions or
rumination about the stressor? Do loss-related forms of chronic
stress dysregulate cortisol rhythms because of changes in social
circadian rhythms that result from the loss? Once this has been
done, more elaborate mechanistic models linking chronic stress
and HPA function can be developed.
The same issues pertain to biological mechanisms that are more
proximal to the HPA axis. Little theory exists to specify what goes
awry in the system when it faces chronic stress. Is the high, flat
pattern of cortisol secretion across the day a result of dysregulation
in the suprachiasmatic nucleus, the endogenous circadian pace-
maker that regulates HPA rhythms? Or does chronic stress leave
the suprachiasmatic nucleus’s functions intact, and instead modify
downstream structures like the pituitary and/or adrenal glands?
The fact that cortisol was reliably altered by exposure to chronic
stress, and ACTH was not, suggests the possibility that much of
the dysregulation lies at the level of the adrenals. Perhaps chronic
stress modifies the sensitivity of the adrenal glands, such that
cortisol is secreted at volumes disproportionate to ACTH signal-
ing. By making use of ACTH and CRH challenge paradigms,
which respectively evaluate functioning of the adrenals and the
pituitary, future research can test these mechanistic hypotheses and
accelerate the development of theory in this area.
To ensure that further progress is made in this area of inquiry,
the next wave of studies will need to institute a series of method-
ological innovations. As the summary statistics from the meta-
analysis make clear, the field has relied heavily on morning cor-
tisol as an outcome. In 25% of the studies we reviewed, it was the
only HPA outcome to be assessed, and in all but a handful of
studies, this was done on a single occasion. There are obvious
methodological and conceptual limitations to this strategy. Single
measures of a construct are notoriously unreliable, and all evidence
suggests this is the case for cortisol as well (Stewart & Seeman,
2000). If future studies wish to maximize their chances of detect-
ing stress-related disparities, they would be wise to increase the
frequency of sample collection, so that multiple assessments are
made each day for a period of several days. Apart from boosting
statistical power to detect findings, this strategy provides a more
comprehensive portrait of HPA activity. It is difficult to make
accurate inferences about HPA activity being low or high from a
single measure, because as our findings illustrate, the effects of
chronic stress can differ in magnitude and direction over the course
of the day. Guidelines for designing a sampling strategy that
captures the entire diurnal rhythm of cortisol can be found online
(see Stewart & Seeman, 2000).
Progress in this area also will depend on researchers’ capacity to
expand the repertoire of outcome variables. Half of the studies we
reviewed presented findings for only a single indicator of HPA
axis function. Fewer than 15% of the studies assessed ACTH. An
even smaller number assessed CRH, but this is understandable,
given that a medically invasive procedure (lumbar puncture) is
required. Challenge paradigms also were used infrequently, and
when they were, they typically involved dexamethasone suppres-
sion. By more routinely assessing output of ACTH and CRH, and
performing challenge paradigms with these molecules, future re-
search will gain detailed mechanistic insights into how stressors
modify the function of structures comprising the axis. Given that
much work in this area is concerned with hormonal influences on
disease, there also would be much gained by assessing cortisol’s
impact on target tissues. Some work of this nature has already
begun. A recent study found that among people facing a severe
chronic stressor, the immune system’s sensitivity to glucocorti-
coids was diminished (Miller et al., 2002). This was manifested by
a reduction in dexamethasone’s capacity to suppress the produc-
tion of inflammatory molecules in vitro. These findings suggest
that chronic stress interferes with cortisol’s ability to perform an
important regulatory function in the immune system. To the extent
that such a deficit persists, it could enable inflammation to flour-
ish, leading to a variety of adverse medical outcomes. More work
of this nature would be valuable for the field, as it sheds light on
the tissue-level consequences of differential cortisol secretion. In
addition to assessing how immune system functions are influenced
by glucocorticoids (DeRijk, Petrides, Deuster, Gold, & Sternberg,
1996; Rohleder, Schommer, Hellhammer, Engel, & Kirschbaum,
2001), researchers can study these processes in the vascular system
through a noninvasive skin-blanching paradigm (Ebrecht et al.,
2000; B. R. Walker, Best, Shackleton, Padfield, & Edwards, 1996)
and in the nervous system through challenge molecules such as
CRH, ACTH, and dexamethasone.
Statistical power is another design feature that warrants addi-
tional consideration. The studies in our meta-analysis had an
average of 80 participants and for the most part yielded effect sizes
in the .20–.50 range. These represent small- to medium-sized
effects by conventional standards in behavioral science. Even at
the high end of that effect-size range, however, studies need twice
as many participants to have adequate power. Future research will
need to boost enrollment substantially to maximize its chances of
detecting alterations in the HPA axis.
Summary and Conclusions
The notion that stress contributes to disease by activating the
HPA axis is featured prominently in many theories. The research
linking stress and the HPA axis is contradictory, however, with
some studies reporting increased activation and others reporting
the opposite. Our meta-analysis of this area showed that some of
the variability in HPA response is attributable to stressor and
person features. Timing is an especially critical element, as hor-
monal activity is elevated at stress onset but reduced as time
passes. Stress that threatens physical integrity, is traumatic in
nature, and is largely uncontrollable elicits a high, flat diurnal
profile of cortisol secretion. Finally, HPA activity is shaped by the
person’s response to stress; cortisol output increases with the
extent of subjective distress and is generally reduced in those who
CHRONIC STRESS AND HPA ACTIVITY
develop PTSD. These findings highlight the importance of incor-
porating stressor and person features into models of chronic stress
and HPA activity. They also suggest that relations among stress,
cortisol, and disease are likely to be more complex than previously
acknowledged. Because chronic stress can elicit such a wide
variety of HPA responses, its impact on disease outcomes will be
varied and depend on whether high versus low cortisol is patho-
genic. The next wave of models will need to be refined to ac-
knowledge this complexity. With better theories and further re-
search of the nature suggested by the meta-analysis, the pathways
through which chronic stress “gets under the skin” to influence
disease will come into clearer focus.
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Received September 30, 2005
Revision received February 9, 2006
Accepted March 30, 2006 ?
Call for Papers Journal of Experimental Psychology: Learning, Memory,
Special Section on Source Memory: Integrating Cognitive Behavioral
and Cognitive Neuroscience Approaches
The Journal of Experimental Psychology: Learning, Memory, and Cognition invites manuscripts
for a special section on source memory, to be compiled by guest editors Marcia K. Johnson and
Mieke H. Verfaellie, working together with journal Associate Editor John Dunlosky. The goal of the
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memory. We are seeking cognitive behavioral studies that integrate cognitive neuroscience findings
in justifying hypotheses or interpreting results and cognitive neuroscience studies that emphasize
how the evidence informs cognitive theories of source memory. In addition to empirical papers,
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cognitive theory of source memory are also appropriate.
The submission deadline is June 1, 2007. The main text of each manuscript, exclusive of figures,
tables, references, or appendixes, should not exceed 35 double-spaced pages (approximately 7,500
words). Initial inquiries regarding the special section may be sent to John Dunlosky
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