Glucocorticoids are hormones that are produced by the zona fasciculata of the adrenal cortex. The name "glucocorticoid" derives from their effects on glucose metabolism, and the fact that they are steroid hormones of the the adrenal cortex. Cortisol is the principal glucocorticoid that is secreted.
Like other steroid hormones, cortisol binds to an intracellular receptor (the glucocorticoid receptor), which
mediates its effects by changing gene expression. As
indicated in the figure below, most cells in the body express
glucocorticoid receptors, and are thus targets of cortisol.
Cortisol has many diverse effects, but in general its role is to
ensure that cells in the body have an adequate response to stress. More specifically,
cortisol stimulates gluconeogenesis
in the liver, and promotes fat and protein breakdown.
Another important effect of cortisol is that it reduces inflammation and inhibits immune
function. For this reason,
glucocorticoids are important and widely used drugs in the
treatment of inflammatory disorders (e.g. asthma, inflammatory
bowel disease, psoriasis) and autoimmune diseases (e.g. lupus,
rheumatoid arthritis).
As shown in the figure at
right, cortisol is regulated by tropic hormones released
by the hypothalamus and anterior pituitary. The
hypothalamic hormone, CRH
(corticotropin releasing hormone) stimulates secretion of the
anterior pituitary hormone ACTH
(adrenocorticotropic hormone), which then stimulates cortisol
secretion.
A distinctive feature of these hormones is that they regulate their own secretion through negative feedback. What this means is that cortisol binds to its receptor on cells in the hypothalamus and anterior pituitary, and has the effect of inhibiting secretion of its tropic hormones. Less tropic hormone secretion leads to less stimulation of cortisol secretion by cells in the adrenal cortex.
The usefulness of negative feedback inhibition is that it works to keep hormone levels within a particular appropriate physiological range. Consider a case where one adrenal gland is damaged. This will cause decreased secretion of cortisol, and there will be a decrease in the degree of negative feedback inhibition on the hypothalamus and anterior pituitary. The reduced negative feedback inhibition means that more CRH and ACTH will be secreted. More ACTH will stimulate the remaining adrenal tissue to grow and to secrete more cortisol. This will have the effect of bringing cortisol back up towards its normal daily level of secretion.
In order to accurately
determine the cause of abnormal cortisol secretion, one needs to
look not only at cortisol levels, but also at the level of its
tropic hormone, ACTH. It is also important to consider the
effect of negative feedback regulation. The table at right
summarizes the hormone levels that indicate particular diagnoses.
Cushing's syndrome (also called Cushing syndrome) is the name given to hypersecretion of cortisol (or hypercortisolism). Cushing's syndrome causes a very characteristic type of central obesity. There is weight gain in the trunk and face, but a loss of muscle mass and adipose tissue in the arms and legs. Hypercortisolism also causes insulin resistance (which can lead to the development of type 2 diabetes mellitus), excessive bone resorption (which can lead to osteoporosis), and hypertension.
The most common type of Cushing's syndrome is iatrogenic Cushing's syndrome.
"Iatrogenic" means caused by a medical treatment. Iatrogenic
Cushing's syndrome occurs in patients who must use high doses of
glucocorticoid drugs. Treatment with glucocorticoid drugs is
also the major cause of secondary adrenal insufficiency (see
below). Whenever a patient presents with symptoms of
hypercortisolism, a first step in diagnosis is to ask about drug
history in order to determine whether the cause is iatrogenic.
When Cushing's syndrome is due to a tumor in the adrenal cortex, increased negative feedback has the effect of decreasing secretion of tropic hormones. Therefore, the level of ACTH will be low. This is illustrated in the figure at right.
Alternatively, Cushing's syndrome might result because of hypersecretion of ACTH. In fact, Cushing's syndrome is more commonly caused by a pituitary adenoma (a pituitary tumor) than by an adrenal tumor. Cushing's syndrome caused by a pituitary adenoma is known as Cushing's disease. The pituitary adenoma hypersecretes ACTH and is relatively insensitive to feedback inhibition by cortisol. In Cushing's disease due to a pituitary tumor, both ACTH and cortisol levels will be high.
Hyposecretion of cortisol is known as adrenal insufficiency. Primary adrenal insufficiency is called Addison's disease. ("Primary" is the term used for an adrenal disorder when the problem originates in the adrenal gland.) Addison's disease is most often due to an autoimmune disorder but it can also result from infections such as tuberculosis. Note that generalized damage to the adrenal cortex will affect both the zona glomerulosa and the zona fasciculata. So in Addison's disease there is hyposecretion of both cortisol and aldosterone, the steroid hormone that regulates Na+ and K+ balance in the extracellular fluid.
In primary adrenal insufficiency, decreased cortisol secretion causes a release from negative feedback, and consequently, ACTH levels are high. In practice, physicians will often use a challenge test to make the diagnosis. The challenge test measures the ability of the adrenal gland to secrete cortisol in response to exogenously administered ACTH.
Secondary
adrenal insufficiency (or hypopituitary
adrenal insufficiency) describes the situation
where abnormally low ACTH levels lead to hyposecretion of
cortisol. Interestingly, the major cause of this disorder is high
dose glucocorticoid therapy. As mentioned above, glucocorticoids
are used therapeutically to treat inflammatory and autoimmune
diseases.
The diagram at left illustrates how glucocorticoids cause hypopituitary adrenal insufficiency. Chronic high levels of glucocorticoids lead to a suppression of ACTH secretion that can sometimes persist for several months after glucocorticoid treatment stops. When the glucocorticoid therapy is discontinued, the result is hypocortisolism.
Because of this, an important component of treatment with glucocorticoid drugs is that they are never stopped abruptly. Instead, patients are instructed to gradually reduce the dosage of glucocorticoid as they end therapy. Tapering the drug dosage allows the pituitary gland to recover.