C h a p t e r 9
Stress and Adaptation
211
of adrenocorticotropic hormone (ACTH) from the
anterior pituitary gland into the systemic circulation.
Adrenocorticotropic hormone, in turn, stimulates the
adrenal gland to synthesize and secrete glucocorticoid
hormones (e.g., cortisol).
25
Cortisol is the primary glucocorticoid in humans,
representing a major subclass of steroid hormones that
regulate metabolic, cardiovascular, immune, and behav-
ioral responses. A glucocorticoid negative feedback sys-
tem exists, whereby the HPA axis is subject to feedback
inhibition from circulating glucocorticoids. These gluco-
corticoids have a number of direct or indirect physiologic
effects that mediate the stress response, enhance the action
of other stress hormones, or suppress other components of
the stress system. In this regard, cortisol acts not only as a
mediator of the stress response but also as an inhibitor so
that overactivation of the stress response does not occur.
21,23
Cortisol maintains blood glucose levels and enhances the
effect of catecholamines on the cardiovascular system.
Blood glucose levels are elevated rapidly, in part by mobi-
lization of glucose stores and by inhibition of further stor-
age through the antagonizing effects of insulin.
21
Cortisol
also suppresses osteoblast activity, hematopoiesis, protein
and collagen synthesis, and immune responses. All of these
functions are meant to protect the organism against the
effects of a stressor and to focus energy on regaining bal-
ance in the face of an acute challenge to homeostasis.
Angiotensin II.
Stimulation of the SNS also activates the
peripheral renin-angiotensin-aldosterone system (RAAS),
which mediates a peripheral increase in vascular tone and
renal retention of sodium and water (see Chapter 18).
These changes contribute to the physiologic alterations
that occur with the stress response; if prolonged, they
may contribute to pathologic changes. Angiotensin II,
peripherally delivered or locally produced, also has CNS
effects; angiotensin II type 1 (AT
1
) receptors are widely dis-
tributed in the hypothalamus and locus ceruleus. Through
these receptors, angiotensin II enhances CRF formation
and release, contributes to the release of ACTH from the
pituitary, enhances stress-induced release of vasopressin
from the posterior pituitary, and stimulates release of nor-
epinephrine from the locus ceruleus. Results from animal
studies on the effect of AT
1
receptor blockade suggest
that receptor antagonists attenuate activation of the stress
response and may be an effective treatment for chronic
stimulation of the stress response.
26,27
Other Hormones.
A wide variety of other hormones,
including growth hormone, thyroid hormone, and
reproductive hormones, are responsive to stressful situa-
tions as well.
16,17,28
Systems responsible for reproduction,
growth, and immunity are directly linked to the stress
system, and hormonal effects of the stress response pro-
foundly influence these systems.
Although growth hormone is initially elevated with the
onset of stress, prolonged presence of cortisol leads to sup-
pression of growth hormone, insulin-like growth factor 1
(IGF-1), and other growth factors, exerting a chronically
inhibitory effect on growth. In addition, CRF directly
increases somatostatin, which in turn inhibits growth hor-
mone secretion. Although the connection is speculative,
effects of stress on growth hormone may provide one of
the vital links to understanding failure to thrive in children.
Stress-induced cortisol secretion also is associ-
ated with decreased levels of thyroid-stimulating hor-
mone and inhibition of conversion of thyroxine (T
4
)
to the more biologically active triiodothyronine (T
3
) in
peripheral tissues (see Chapter 32). Both changes may
serve as a means to conserve energy at times of stress.
Locus
ceruleus
Pituitary
ACTH
Adrenal
gland
Autonomic
nervous system
manifestations
CRF
Immune system
(cytokines)
Cortisol
Hypothalamus
Brain stem
FIGURE 9-3.
Neuroendocrine–immune
system regulation of the stress response.
ACTH, adrenocorticotropic hormone; CRF,
corticotropin-releasing factor.
