National Institues of Health September 9, 2002
System Malfunction Could Lead to Serious, Life Threatening Disease
Whether from a charging lion, or a pending deadline, the body's response to
stress can be both helpful and harmful. The stress response gives us the
strength and speed to ward off or flee from an impending threat. But when it
persists, stress can put us at risk for obesity, heart disease, cancer, and a
variety of other illnesses.
Perhaps the greatest understanding of stress and its effects has resulted
from a theory by George Chrousos, M.D., Chief of the Pediatric and Reproductive
Endocrinology Branch at the National Institute of Child Health and Human
Development (NICHD), and Philip Gold, MD, of the Clinical Neuroendocrinology
Branch at the National Institute of Mental Health (NIMH).
A threat to your life or safety triggers a primal physical response from the
body, leaving you breathless, heart pounding, and mind racing. From deep within
your brain, a chemical signal speeds stress hormones through the bloodstream,
priming your body to be alert and ready to escape danger. Concentration becomes
more focused, reaction time faster, and strength and agility increase. When the
stressful situation ends, hormonal signals switch off the stress response and
the body returns to normal.
But in our modern society, stress doesn't always let up. Many of us now
harbor anxiety and worry about daily events and relationships. Stress hormones
continue to wash through the system in high levels, never leaving the blood and
tissues. And so, the stress response that once gave ancient people the speed and
endurance to escape life-threatening dangers runs constantly in many modern
people and never shuts down.
Research now shows that such long-term activation of the stress system can
have a hazardous, even lethal effect on the body, increasing risk of obesity,
heart disease, depression, and a variety of other illnesses.
Much of the current understanding of stress and its effects has resulted from
the theory by Drs. Chrousos and Gold. Their theory explains the complex
interplay between the nervous system and stress hormones--the hormonal system
known as the hypothalamic-pituitary-adrenal (HPA) axis. Over the past 20 years,
Dr. Chrousos and his colleagues have employed the theory to understand a variety
of stress-related conditions, including depression, Cushing's syndrome, anorexia
nervosa, and chronic fatigue syndrome.
The Stress Circuit
The HPA axis is a feedback loop by which signals from the brain trigger the
release of hormones needed to respond to stress. Because of its function, the
HPA axis is also sometimes called the "stress circuit."
Briefly, in response to a stress, the brain region known as the hypothalamus
releases corticotropin-releasing hormone (CRH). In turn, CRH acts on the
pituitary gland, just beneath the brain, triggering the release of another
hormone, adrenocorticotropin (ACTH) into the bloodstream. Next, ACTH signals the
adrenal glands, which sit atop the kidneys, to release a number of hormonal
These compounds include epinephrine (formerly known as adrenaline),
Norepinephrine (formerly known as noradrenaline) and cortisol. All three
hormones enable the body to respond to a threat. Epinephrine increases blood
pressure and heart rate, diverts blood to the muscles, and speeds reaction time.
Cortisol, also known as glucocorticoid, releases sugar (in the form of glucose)
from the body reserves so that this essential fuel can be used to power the
muscles and the brain.
Normally, cortisol also exerts a feedback effect to shut down the stress
response after the threat has passed, acting upon the hypothalamus and causing
it to stop producing CRH.
This stress circuit affects systems throughout the body. The hormones of the
HPA axis exert their effect on the autonomic nervous system, which controls such
vital functions as heart rate, blood pressure, and digestion.
The HPA axis also communicates with several regions of the brain, including
the limbic system, which controls motivation and mood, with the amygdala, which
generates fear in response to danger, and with the hippocampus, which plays an
important part in memory formation as well as in mood and motivation. In
addition, the HPA axis is also connected with brain regions that control body
temperature, suppress appetite, and control pain.
Similarly, the HPA axis also interacts with various other glandular systems,
among them those producing reproductive hormones, growth hormones, and thyroid
hormones. Once activated, the stress response switches off the hormonal systems
regulating growth, reproduction, metabolism, and immunity. Short term, the
response is helpful, allowing us to divert biochemical resources to dealing with
Stress, heredity, and the environment
According to Dr. Chrousos, this stress response varies from person to person.
Presumably, it is partially influenced by heredity. For example, in most people
the HPA axis probably functions appropriately enough, allowing the body to
respond to a threat, and switching off when the threat has passed. Due to
differences in the genes that control the HPA axis, however, other people may
fail to have a strong enough response to a threat, while still others may over
respond to even minor threats.
Beyond biological differences, the HPA axis also can alter its functioning in
response to environmental influences. The HPA axis may permanently be altered as
a result of extreme stress at any time during the life cycle-during adulthood,
adolescence, early childhood, or even in the womb.
If there are major stresses in early childhood, the HPA feedback loop becomes
stronger and stronger with each new stressful experience. This results in an
individual who, by adulthood, has an extremely sensitive stress circuit in
place. In life threatening situations-such as life in an area torn by war-this
exaggerated response would help an individual to survive. In contemporary
society, however, it usually causes the individual to overreact hormonally to
comparatively minor situations.
Effects on the body
Stress and the Reproductive system
Stress suppresses the reproductive system at various levels, says Dr.
Chrousos. First, CRH prevents the release of gonadotropin releasing hormone (GnRH),
the "master" hormone that signals a cascade of hormones that direct
reproduction and sexual behavior. Similarly, cortisol and related glucocorticoid
hormones not only inhibit the release of GnRH, but also the release of
luteinizing hormone, which prompts ovulation and sperm release. Glucocorticoids
also inhibit the testes and ovaries directly, hindering production of the male
and female sex hormones testosterone, estrogen, and progesterone.
The HPA overactivity that results from chronic stress has been shown to
inhibit reproductive functioning in anorexia nervosa and in starvation, as well
as in highly trained ballet dancers and runners. For example, in one study,
Chrousos found that men who ran more than 45 miles per week produced high levels
of ACTH and cortisol in response to the stress of extreme exercise. These male
runners had low LH and testosterone levels. Other studies have shown that women
undertaking extreme exercise regimens had ceased ovulating and menstruating.
However, the interaction between the HPA axis and the reproductive system is
also a two way street. The female hormone estrogen exerts partial control of the
gene that stimulates CRH production. This may explain, why, on average, women
have slightly elevated cortisol levels. In turn, higher cortisol levels, in
combination with other, as yet unknown, factors, may be the reason why women are
more vulnerable than men to depression, anorexia nervosa, panic disorder,
obsessive compulsive disorder, and autoimmune diseases like lupus and rheumatoid
Growth and stress
The hormones of the HPA axis also influence hormones needed for growth.
Prolonged HPA activation will hinder the release of growth hormone and
insulin-like growth factor 1 (IGF-1), both of which are essential for normal
growth. Glucocorticoids released during prolonged stress also cause tissues to
be less likely to respond to IGF-1. Children with Cushing's syndrome-which
results in high glucocorticoid levels-lose about 7.5 to 8.0 centimeters from
their adult height.
Similarly, premature infants are at an increased risk for growth retardation.
The stress of surviving in an environment for which they are not yet suited,
combined with the prolonged stress of hospitalization in the intensive care
unit, presumably activates the HPA axis. Growth retarded fetuses also have
higher levels of CRH, ACTH, and cortisol, probably resulting from stress in the
womb or exposure to maternal stress hormones.
Old research has also shown that the stress from emotional deprivation or
psychological harassment may result in the short stature and delayed physical
maturity of the condition known as psychosocial short stature (PSS).
PSS was first discovered in orphanages, in infants who failed to thrive and
grow. When these children were placed in caring environments in which they
received sufficient attention, their growth resumed. The children's cortisol
levels were abnormally low, a seeming contradiction, which Chrousos investigated
by studying a small, non-human primate, the common marmoset. These monkeys live
in small family groups in which infants are cared for by both parents. As in
human society, the infants are sometimes well cared for, but sometimes abused.
Like humans, the abused monkeys showed evidence of PSS.
The researchers determined that the stressed and abused monkeys appeared to
respond normally to stress, but seemed unable to "switch off" the
stress response by secreting appropriate cortisol levels, thereby remaining in a
state of prolonged stress arousal as compared to their peers.
The gastrointestinal tract and stress
As many of us know, stress can also result in digestive problems. The stress
circuit influences the stomach and intestines in several ways. First, CRH
directly hinders the release of stomach acid and emptying of the stomach.
Moreover, CRH also directly stimulates the colon, speeding up the emptying of
its contents. In addition to the effects of CRH alone on the stomach, the entire
HPA axis, through the autonomic nervous system, also hinders stomach acid
secretion and emptying, as well as increasing the movement of the colon.
Also, continual, high levels of cortisol-as occur in some forms of
depression, or during chronic psychological stress-can increase appetite and
lead to weight gain. Rats given high doses of cortisol for long periods had
increased appetites and had larger stores of abdominal fat. The rats also ate
heavily when they would normally have been inactive. Overeating at night is also
common among people who are under stress.
The immune system and stress
The HPA axis also interacts with the immune system, making you more
vulnerable to colds and flu, fatigue and infections.
In response to an infection, or an inflammatory disorder like rheumatoid
arthritis, cells of the immune system produce three substances that cause
inflammation: interleukin 1 (IL-1), interleukin 6 (IL-6), and tumor necrosis
factor (TNF). These substances, working either singly or in combination with
each other, cause the release of CRH. IL-6 also promotes the release of ACTH and
cortisol. Cortisol and other compounds then suppress the release of IL-1, IL-6,
and TNF, in the process switching off the inflammatory response.
Ideally, stress hormones damp down an immune response that has run its
course. When the HPA axis is continually running at a high level, however, that
damping down can have a down side, leading to decreased ability to release the
interleukins and fight infection.
In addition, the high cortisol levels resulting from prolonged stress could
serve to make the body more susceptible to disease, by switching off
disease-fighting white blood cells. Although the necessary studies have not yet
been conducted, Dr. Chrousos considers it possible that this same deactivation
of white blood cells might also increase the risk for certain types of cancer.
Conversely, there is evidence that a depressed HPA Axis, resulting in too
little corticosteroid, can lead to a hyperactive immune system and increased
risk of developing autoimmune diseases-diseases in which the immune system
attacks the body's own cells. Overactivation of the antibody-producing B cells
may aggravate conditions like lupus, which result from an antibody attack on the
body's own tissues.
One of the major disorders characteristic of an overactive HPA axis is
melancholic depression. Chrousos' research has shown that people with depression
have a blunted ability to "counterregulate," or adapt to the negative
feedback of increases in cortisol. The body turns on the "fight or
flight" response, but is prevented from turning it off again. This produces
constant anxiety and overreaction to stimulation, followed by the paradoxical
response called "learned helplessness," in which victims apparently
lose all motivation.
Hallmarks of this form of depression are anxiety, loss of appetite, loss of
sex drive, rapid heart beat, high blood pressure, and high cholesterol and
triglyceride levels. People with this condition tend to produce
higher-than-normal levels of CRH. The high levels of CRH are probably due to a
combination of environmental and hereditary causes, depending on the person
However, rather than producing higher amounts of ACTH in response to CRH,
depressed people produce smaller amounts of this substance, presumably because
their hippocampuses have become less sensitive to the higher amounts of CRH. In
an apparent attempt to switch off excess CRH production, the systems of people
with melancholic depression also produce high levels of cortisol. However,
by-products of cortisol, produced in response to high levels of the substance,
also depress brain cell activity. These by-products serve as sedatives, and
perhaps contribute to the overall feeling of depression.
Other conditions are also associated with high levels of CRH and cortisol.
These include anorexia nervosa, malnutrition, obsessive-compulsive disorder,
anxiety disorder, alcoholism, alcohol and narcotic withdrawal, poorly controlled
diabetes, childhood sexual abuse, and hyperthyroidism.
The excessive amount of the stress hormone cortisol produced in patients with
any of these conditions is responsible for many of the observed symptoms. Most
of these patients share psychological symptoms including sleep disturbances,
loss of libido, and loss of appetite as well as physical problems such as an
increased risk for accumulating abdominal fat and hardening of the arteries and
other forms of cardiovascular disease. These patients may also experience
suppression of thyroid hormones, and of the immune system. Because they are at
higher risk for these health problems, such patients are likely to have their
life spans shortened by 15 to 20 years if they remain untreated.
Although many disorders result from an overactive stress system, some result
from an under active stress system. For example, in the case of Addison's
disease, lack of cortisol causes an increase of pigment in the skin, making
patient appear to have a tan. Other symptoms include fatigue, loss of appetite,
weight loss, weakness, loss of body hair, nausea, vomiting, and an intense
craving for salt. Lack of the hormone CRH also results in the feelings of
extreme tiredness common to people suffering from chronic fatigue syndrome. Lack
of CRH is also central to seasonal affective disorder (SAD), the feelings of
fatigue and depression that plague some patients during winter months.
Chrousos and his team, showed that sudden cessation of CRH production may
also result in the depressive symptoms of postpartum depression. In response to
CRH produced by the placenta, the mother's system stops manufacturing its own
CRH. When the baby is born, the sudden loss of CRH may result in feelings of
sadness or even severe depression for some women.
Recently, Dr. Chrousos and his coworkers uncovered evidence that frequent
insomnia is more than just having difficulty falling asleep. The researchers
found that, when compared to a group of people who did not have difficulty
falling asleep, the insomniacs had higher ACTH and cortisol levels, both in the
evening and in the first half of the night. Moreover, the insomniacs with the
highest cortisol levels tended to have the greatest difficulty falling asleep.
The researchers theorized that, in many cases, persistent insomnia may be a
disorder of the stress system. From their ACTH and cortisol levels, it appears
that the insomniacs have nervous systems that are on overdrive, alert and ready
to deal with a threat, when they should otherwise be quieting down. Rather than
prescribing drugs known as hypnotics to regulate the sleep system, the
researchers suggested that physicians might have more success prescribing
antidepressants, to help calm an overactive stress system. Behavior therapy, to
help insomniacs relax in the evening, might also be useful.
After conducting many years of research into the functioning of the HPA axis,
Dr. Chrousos concluded that chronic stress should not be taken lightly or
accepted as a fact of life.
"Persistent, unremitting stress leads to a variety of serious health
problems," Dr. Chrousos said. "Anyone who suffers from chronic stress
needs to take steps to alleviate it, either by learning simple techniques to
relax and calm down, or with the help of qualified therapists.
National Institues of Health September 9, 2002
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