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).
Introduction
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 compounds.
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 the threat.
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 arthritis.
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.
Stress-Related Disorders
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 affected.
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 the 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.
Therapeutic
Dosage
