Glucocorticoids

In contrast to loss of mineralocorticoids, failure to produce glucocorticoids is not acutely life-threatening. Nevertheless, loss or profound diminishment of glucocorticoid secretion leads to a state of deranged metabolism and an inability to deal with stressors which, if untreated, is fatal.

In addition to their physiologic importance, glucocorticoids are also among the most frequently used drugs, and often prescribed for their anti-inflammatory and immunosuppressive properties.

Cortisol and Glucocorticoid Receptors

The vast majority of glucocorticoid activity in most mammals is from cortisol, also known as hydrocortisone. Corticosterone, the major glucocorticoid in rodents, is another glucocorticoid.

Cortisol binds to the glucocorticoid receptor in the cytoplasm and the hormone-receptor complex is then translocated into the nucleus, where it binds to its DNA response element and modulates transcription from a battery of genes, leading to changes in the cell's phenotype.

Only about 10% of circulating cortisol is free. The remaining majority circulates bound to plasma proteins, particularly corticosteroid-binding globulin (transcortin). This protein binding likely decreases the metabolic clearance rate of glucocorticoids and, because the bound steroid is not biologically active, tends to act as a buffer and blunt wild fluctuations in cortisol concentration.

Physiologic Effects of Glucocorticoids

There seem to be no cells that lack glucocorticoid receptors and as a consequence, these steroid hormones have a huge number of effects on physiologic systems. That having been said, it can be stated that the best known and studied effects of glucocorticoids are on carbohydrate metabolism and immune function.

Effects on Metabolism

The name glucocorticoid derives from early observations that these hormones were involved in glucose metabolism. In the fasted state, cortisol stimulates several processes that collectively serve to increase and maintain normal concentrations of glucose in blood. These effects include:

• Stimulation of gluconeogenesis, particularly in the liver: This pathway results in the synthesis of glucose from non-hexose substrates such as amino acids and lipids and is particularly important in carnivores and certain herbivores. Enhancing the expression of enzymes involved in gluconeogenesis is probably the best known metabolic function of glucocorticoids.
• Mobilization of amino acids from extrahepatic tissues: These serve as substrates for gluconeogenesis.
• Inhibition of glucose uptake in muscle and adipose tissue: A mechanism to conserve glucose.
• Stimulation of fat breakdown in adipose tissue: The fatty acids released by lipolysis are used for production of energy in tissues like muscle, and the released glycerol provide another substrate for gluconeogenesis.

Effects on Inflammation and Immune Function

Glucocorticoids have potent anti-inflammatory and immunosuppressive properties. This is particularly evident when they administered at pharmacologic doses, but also is important in normal immune responses. As a consequence, glucocorticoids are widely used as drugs to treat inflammatory conditions such as arthritis or dermatitis, and as adjunction therapy for conditions such as autoimmune diseases.

Other Effects of Glucocorticoids

Glucocorticoids have multiple effects on fetal development. An important example is their role in promoting maturation of the lung and production of the surfactant necessary for extrauterine lung function. Mice with homozygous disruptions in the corticotropin-releasing hormone gene (see below) die at birth due to pulmonary immaturity.

Several aspects of cognitive function are known to both stimulate glucocorticoid secretion and be influenced by glucocorticoids. Fear provides an interesting example of this. Fear-inducing stimuli lead to secretion of glucocorticoids from the adrenal gland, and treatment of phobic individuals with glucocorticoids prior to a fear-inducing stimulus can blunt the fear response.

Excessive glucocorticoid levels resulting from administration as a drug or hyperadrenocorticism have effects on many systems. Some examples include inhibition of bone formation, suppression of calcium absorption and delayed wound healing. These observations suggest a multitide of less dramatic physiologic roles for glucocorticoids.

Control of Cortisol Secretion

Cortisol and other glucocorticoids are secreted in response to a single stimulator: adrenocorticotropic hormone (ACTH) from the anterior pituitary. ACTH is itself secreted under control of the hypothalamic peptide corticotropin-releasing hormone (CRH). The central nervous system is thus the commander and chief of glucocorticoid responses, providing an excellent example of close integration between the nervous and endocrine systems.

Virtually any type of physical or mental stress results in elevation of cortisol concentrations in blood due to enhanced secretion of CRH in the hypothalamus. This fact sometimes makes it very difficult to assess glucocorticoid levels, particularly in animals. Observing the approach of a phlebotomist, and especially being restrained for blood sampling, is enough stress to artificially elevate cortisol levels several fold!

Cortisol secretion is suppressed by classical negative feedback loops. When blood concentrations rise above a certain theshold, cortisol inhibits CRH secretion from the hypothalamus, which turns off ACTH secretion, which leads to a turning off of cortisol secretion from the adrenal. The combination of positive and negative control on CRH secretion results in pulsatile secretion of cortisol. Typically, pulse amplitude and frequency are highest in the morning and lowest at night.

ACTH binds to receptors in the plasma membrane of cells in the zona fasiculata and reticularis of the adrenal. Hormone-receptor engagement activates adenyl cyclase, leading to elevated intracellular levels of cyclic AMP which leads ultimately to activation of the enzyme systems involved in biosynthesis of cortisol from cholesterol.

Disease States

The most prevalent disorder involving glucocorticoids in man and animals is hyperadrenocorticism or Cushings disease. Excessive levels of glucocorticoids are seen in two situations:

• Excessive endogenous production of cortisol, which can result from a primary adrenal defect (ACTH-independent) or from excessive secretion of ACTH (ACTH-dependent).
• Administration of glucocorticoids for theraputic purposes. This is a common side-effect of these widely-used drugs.

Cushing's disease has widespread effects on metabolism and organ function, which is not surprising considering the ubiquitous distribution of glucocorticoid receptors. A diverse set of clinical manifestations accompany this disorder, including hypertension, apparent obesity, muscle wasting, thin skin, and metabolic aberrations such as diabetes.

Insufficient production of cortisol, often accompanied by an aldosterone deficiency, is called hypoadrenocorticism or Addison's disease. Most commonly, this disease is a result of infectious disease (e.g. tuberculosis in humans) or autoimmune destruction of the adrenal cortex. As with Cushing's disease, numerous diverse clincial signs accompany Addison's disease, including cardiovascular disease, lethargy, diarrhea, and weakness. Aldosterone deficiency can be acutely life threatening due to disorders of electrolyte balance and cardiac function.