ACTIONS OF GLUCOCORTICOIDS.

Glucocorticoids are essential for survival. The term glucocorticoid refers to the glucose-regulating
properties of these hormones. However, glucocorticoids have multiple effects on carbohydrate, lipid,
and protein metabolism. They also regulate immune, circulatory, and renal function. They influence
growth, development, bone metabolism, and central nervous system activity.

In stress situations, glucocorticoid secretion can increase up to 10-fold. This increase is believed to
enhance survival through increased cardiac contractility, cardiac output, sensitivity to the pressor effects
of catecholamines and other pressor hormones, work capacity of the skeletal muscles, and capacity to
mobilize energy stores.

Metabolic Effects

The primary action of the glucocorticoids on carbohydrate metabolism is to increase glucose production
by increasing hepatic gluconeogenesis. Glucocorticoids also increase cellular resistance to insulin,
thereby decreasing entry of glucose into the cell. This inhibition of glucose uptake occurs in adipocytes,
muscle cells, and fibroblasts. In addition to opposing insulin action, glucocorticoids may work in parallel
with insulin to protect against long-term starvation by stimulating glycogen deposition and production in
liver. Both hormones stimulate glycogen synthetase activity and decrease glycogen breakdown.
Glucocorticoid excess may cause hyperglycemia, whereas glucocorticoid deficiency may cause
hypoglycemia

Glucocorticoids increase free fatty acid levels by enhancing lipolysis, decreasing cellular glucose uptake,
and decreasing glycerol production, which is necessary for re-esterification of fatty acids. This increase in
lipolysis is also stimulated through the permissive enhancement of lipolytic action of other factors such
as epinephrine. This action affects adipocytes differently according to their anatomic locations. In the
patient with glucocorticoid excess, fat is lost in the extremities, but it is increased in the trunk
(centripetal obesity), neck, and face (moon facies). This may involve effects on adipocyte differentiation.

Circulatory and Renal Effects.

Glucocorticoids have a positive inotropic influence on the heart, increasing the left ventricular work
index. Moreover, they have a permissive effect on the actions of epinephrine and norepinephrine on
both the heart and the blood vessels. In the absence of glucocorticoids, decreased cardiac output and
shock may develop; in states of glucocorticoid excess, hypertension is frequently observed. This may be
due to activation of the mineralocorticoid receptor (see later), which occurs when renal 11β-
hydroxysteroid dehydrogenase is saturated by excessive levels of glucocorticoids.

Immunologic Effects.

Glucocorticoids play a major role in immune regulation. They inhibit synthesis of glycolipids and
prostaglandin precursors and the actions of bradykinin. They also block histamine and proinflammatory
cytokine (tumor necrosis factor-α, interleukin-1, and interleukin-6) secretion and effects. These actions
diminish the inflammatory process. High doses of glucocorticoids deplete monocytes, eosinophils, and
lymphocytes, especially T cells. They do so at least in part by inducing cell cycle arrest in the G 1 phase
and by activating apoptosis through glucocorticoid receptor-mediated effects. The effects on
lymphocytes are primarily exerted on T helper 1 cells and hence on cellular immunity, whereas the T
helper 2 cells are spared, leading to a predominantly humoral immune response. Pharmacologic doses
of glucocorticoids may also decrease the size of immunologic tissues (spleen, thymus, and lymph nodes).

Glucocorticoids increase circulating polymorphonuclear cell counts, mostly by preventing their egress
from the circulation. Glucocorticoids decrease diapedesis, chemotaxis, and phagocytosis of
polymorphonuclear cells. Thus, the mobility of these cells is altered such that they do not arrive at the
site of inflammation to mount an appropriate immune response. High levels of glucocorticoids decrease
inflammatory and cellular immune responses and increase susceptibility to certain bacterial, viral,
fungal, and parasitic infections.

Effects on Skin, Bone, and Calcium.

Glucocorticoids inhibit fibroblasts, leading to increased bruising and poor wound healing through
cutaneous atrophy. This effect explains the thinning of the skin and striae that are seen in patients with
Cushing syndrome.

Glucocorticoids have the overall effect of decreasing serum calcium and have been used in emergency
therapy for certain types of hypercalcemia. This hypocalcemic effect probably results from a decrease in
the intestinal absorption of calcium and a decrease in the renal reabsorption of calcium and phosphorus.
Serum calcium levels, however, generally do not fall below normal because of the secondary increase in
parathyroid hormone secretion.

The most significant effect of long-term glucocorticoid excess on calcium and bone metabolism is
osteoporosis. Glucocorticoids inhibit osteoblastic activity by decreasing the number and activity of
osteoblasts. Glucocorticoids also decrease osteoclastic activity but to a lesser extent, leading to low
bone turnover with an overall negative balance. The tendency of glucocorticoids to lower serum calcium
and phosphate levels causes secondary hyperparathyroidism. These actions decrease bone accretion
and cause a net loss of bone mineral.

Central Nervous System Effects.