Glucocorticoid hormone action

Abstract

The glucocorticoid hormones have glucose-regulating properties (for which they) were named) and also influence many other metabolic functions in a number of tissues. These actions are coordinated in many respects. The pharmacological effects of these hormones form the basis for steroid use in therapy of numerous disorders. The molecular basis for most physiological and pharmacological actions of glucocorticoids (both catabolic and anabolic) and of other classes of steroid hormones are probably very similar. The steroid readily penetrates the cell membrane (and probably does not require transport mechanisms) and reversibly binds to specific proteins—termed cytoplasmic receptors. Associated with this interaction are conformational changes in the receptor which result in receptor-glucocorticoid steroid complex binding to DNA-containing sites in the cell nucleus. The latter reaction results in influences on the synthesis of specific messenger RNAs which code for proteins that are ultimately responsible for the glucocorticoid response.

Catabolism is observed in muscle, adipose tissue, connective tissue, skin and lymphoid tissue. In general, this involves increased degradation and decreased synthesis of proteins, fat, DNA and RNA and decreased uptake of glucose, and amino and nucleic acids. These catabolic actions are probably responsible for certain deleterious effects of pharmacological dosages such as the inhibition of growth observed in children, osteoporosis, bruising, impaired wound healing and enhanced susceptibility to infections. Conversely, these same actions also provide the rationale for glucocorticoid employment in immunosuppression as in treatment of transplant rejection and of the autoimmune diseases. A number of tissues, particularly brain, heart and red blood cells, are in general spared the catabolic actions, but in some of these, there are glucocorticoid-induced alterations in certain functions. In liver there is a general increase in protein and RNA synthesis with a general enhancement in the gluconeogenic capacity. The later, combined with an elevated plasma level of gluconeogenic precursors, results in an increased glucose production which, combined with decreased uptake of glucose in peripheral tissues, results in an enhanced tendency to hyperglycemia. This is ordinarily countered by secondary hyperinsulinism. The latter combined with enhanced enzyme capacity in the liver also leads to glycogen deposition. The tendency to make glucose available for tissues such as heart, brain and blood cells at the expense of other tissues could be considered in terms of a hormonal preparation of the host for nutritional deprivation. In many respects, this ‘stress response’ parallels the responses to stimuli which activate adenyl cyclase, and the ‘permissive’ actions of glucocorticoids facilitate actions of other hormones which are frequently those which stimulate adenyl cyclase. Other glucocorticoid actions, e.g. on vascular and other responses, can also be considered in terms of a stress response even though the central relation to glucose metabolism is not obvious. Although coordinate responses—as for example decreased synthesis combined with increased degradation—are frequent, it appears that these result from individual regulation by receptor-glucocorticoid complexes of numerous separate functions rather than from a general secondary signal producing the coordinate responses. For example, in liver, where the response is generally anabolic, there is an inhibition of DNA synthesis, and in lymphoid tissue, where the response is overwhelmingly catabolic, there may be induction of enzymes apparently unrelated to catabolism.

Glucocorticoid responsiveness arises in development by unknown mechanisms; however, in several systems the receptors are present before responsiveness emerges. Also, responsive tissues may become unresponsive. This is particularly evident in the immunological system where steroid-resistant precursor cells become steroid-sensitive. Then, after antigenic challenge, cells become steroid-resistant. Developmental resistance contrasts with that which follows glucocorticoid treatment (as for example of lymphoblastic leukemia) which is probably due to mutation. Resistance, which may involve any of a number of the steps in glucocorticoid action, is frequently due to loss of the specific glucocorticoid receptors. Resistance to glucocorticoid therapy may also result from poor absorption or enhanced metabolism of the drug. There may also exist states of enhanced glucocorticoid responsiveness.