Handbook of Psychology

Stress 177

Through positive and negative feedback of hormone levels,
up- and down-regulation of postsynaptic receptors, and
activation and inhibition of the immune system, the body is
able to recover homeostasis during and after stressful per-
turbations. However, when dysregulation of any of these
mechanisms occurs, homeostasis is more dif“cult to sustain,
recovery of the balance of physiological processes takes
longer, and disease may result. Thus, biological stress sys-
tems are crucial components of the diathesis-stress model;
individuals with a preexisting weakness at any point in the
stress system may experience inadequate or interminable re-
sponses to stress. Moreover, stress response dysregulation
appears to be a shared feature of many chronic illnesses.

HPAAxis

A signi“cant body of research on the biological aspects of
stress has focused on the HPA axis and its role in suppression
of immune function. Stress activates the CNS, causing the
release of corticotropin-releasing hormone (CRH) from the
hypothalamus. CRH then stimulates the release of adrenal
corticotrophic hormone (ACTH) from the anterior pituitary,
which in turn triggers release of cortisol from the adrenal cor-
tex (Figure 8.1). In the healthy individual, cortisol is believed

to reduce in”ammation by suppressing cellular immune

function. Thus, via cortisol secretion, stress serves an anti-

in”ammatory purpose.

The anti-in”ammatory ef fects of cortisol have led investi-

gators to believe that HPA axis dysregulation could be a

source of the in”ammation observed in RA. There is a grow-

ing body of evidence to suggest that RA is the endpoint of a

continuum of psychological, endocrine, and immune dysreg-

ulation (Chrousos & Gold, 1992). The hormonal responses

intrinsic to psychological stress are thought to trigger a

cascade of dysregulated endocrine and immune activity that

ultimately results in the in”ammation seen in RA.

Given the extreme in”ammation seen in RA, we would

expect that either the in”ammation in RA is a result of low

cortisol levels or, alternatively, that cortisol levels are inef-

fectively compensating for the degree of in”ammation.

Consistent with these expectations, some studies have re-

vealed blunted cortisol responses to stimulation and de-

creased cortisol secretion associated with a disease ”are (van

den Brink, Blankenstein, Koppeschaar, & Bijlsma, 1993).

Yet, while some studies have found blunted cortisol re-

sponses, others have demonstrated relatively normal cortisol

levels in response to stress in RA patients (Huyser & Parker,

1998; Neeck, Federlin, Graef, Rusch, & Schmidt, 1990).

However, as cortisol serves an anti-in”ammatory purpose,

normal cortisol levels in an in”ammatory disease such as RA

may not be adaptive. These “ndings have led investigators to

hypothesize that the magnitude of cortisol responses may not

be proportional to the stimulation of in”ammatory processes

in RA patients. The lack of a dose-dependent cortisol re-

sponse to in”ammation may be due to feedback failure at

several levels (Templ et al., 1996). In other words, after

chronically elevated circulating levels of cortisol are stimu-

lated by the in”ammatory process, tar get organs may down-

regulate cortisol receptor density to compensate. As a result,

the same level of cortisol may not be as effective as it once

was. This is analogous to insulin-resistant diabetes, in which

chronically elevated insulin levels cause down-regulation of

insulin receptors. There is evidence to support this decreased

cortisol sensitivity hypothesis in RA. For instance, re-

searchers have documented decreased cortisol receptor den-

sities on peripheral blood mononuclear cells in patients with

RA (Morand, Jefferiss, Dixey, Mitra, & Goulding, 1994).

HPA dysregulation has also been hypothesized to be asso-

ciated with FM symptoms. Some investigators have found ev-

idence for HPA hyperactivity in FM patients. For instance,

one study found a trend toward increased cortisol in FM pa-

tients compared to RA and low back pain patients in response

to dexamethasone administration (Ferraccioli et al., 1990).

However, in another study, although both FM and RA patients

Figure 8.1 Hypothalamic-Pituitary-Adrenal (HPA) Axis:Stress activates
the CNS, causing the release of corticotropin-releasing hormone (CRH)
from the hypothalamus. CRH then stimulates the release of adrenal corti-
cotrophic hormone (ACTH) from the anterior pituitary, which in turn trig-
gers release of cortisol from the adrenal cortex. Cortisol then suppresses
lymphocyte production. Cortisol also feeds back to the anterior pituitary,
suppressing the release of more ACTH.
Sympathetic-Adrenal-Medullary (SAM) Axis:In the SAM axis, stress
stimulates nerves that directly innervate the adrenal medulla, which in turn
releases norepinephrine (NE) and epinephrine (EPI) into the bloodstream.
The SAM axis promotes lymphocyte proliferation.
Immune Feedback:The immune system also feeds back onto the HPA
axis. Cytokines stimulate the HPA axis.

ACTH

Cortisol

NE and EPI

Lymphocytes

Cytokines

Hypothalamus

Anterior Pituitary

CRH

HPA Axis

SAM Axis

Immune Feedback