Negative Feedback

Cortisol exerts a negative feedback inhibition of corticotropin-releasing hormone (CRH) secretion by binding to specific steroid receptors in the CNS. It also inhibits both ACTH secretion and proopiomelanocortin (POMC) gene transcription. Systemic hypoperfusion, with decreased adrenal blood flow and certain drugs, may also inhibit cortisol synthesis.

Circadian Pattern of Secretion

It is estimated that human cortisol production is approximately 5 to 10 mg/m per day. This amount is the equivalent of about 20 to 30 mg/day of hydrocortisone or 5 to 7 mg/day of oral prednisone. The range of the circadian pattern of cortisol production varies more than threefold. Peak levels of ACTH and cortisol secretion occur between 4 and 8 a.m. There is minimal production of cortisol during the evening, and the lowest levels are observed between 8 p.m. and 12 a.m. In abnormal sleep-wake cycles, this diurnal pattern will adjust, so that peak cortisol levels occur just prior to awakening.

CNS Control of Secretion

Baroreceptor and chemoreceptor afferent inputs to the medulla are transmitted via the pons to the hypothalamus. Nociceptive afferent signals activate both the medulla and thalamus, which independently activate the hypothalamus via the paleocortex limbic system. Emotional triggers also activate the hypothalamus through the paleocortex limbic system. The arrival of afferent input into the hypothalamic paraventricular nucleus stimulates the synthesis of CRH, which is secreted into the hypophyseal portal system to the anterior pituitary, causing ACTH release. In addition to afferent signals, other substances can stimulate the hypothalamus to secrete CRH and cause ACTH release. These include the proinflammatory cytokines IL-1β, IL-6, and tumor necrosis factor α (TNF-α). Other substances that influence CRH and ACTH secretion include vasopressin, angiotensin II, norepinephrine (NE), prostaglandin F _2α (PGF _2α ), and thromboxane A ₂ (TXA ₂ ). Cortisol synthesis can increase 5- to 10-fold during severe stress, to a maximal level of approximately 100 mg/m per day.

Endogenous Corticosteroids

Cortisol levels increase within minutes of stress, whether physical (trauma, surgery, exercise), psychological (anxiety, depression), or physiologic (hypoglycemia, infection). Pain, fever, and hypovolemia all cause a sustained increase in ACTH and cortisol secretion. Surgery is associated with elevations in ACTH and cortisol levels, which usually persist for 24 to 48 hours. The magnitude of the stress response is directly proportional to the extent of surgical trauma. Less extensive procedures such as surgery on the joints, breasts, or neck produce a 36% increase in cortisol levels, whereas laparotomy is associated with an 84% increase in the serum cortisol level for 2 days postoperatively. Adult adrenal glands produce about 50 mg of cortisol/24 hours during minor surgery and 75 to 150 mg/24 hours during major surgery.

Elevated levels of circulating cytokines, which appear within minutes of trauma, stimulate the HPA axis to increase production of cortisol. Increased tissue corticosteroid levels are an important protective and life-sustaining response in these settings. Corticosteroids improve survival in stress by reducing the duration of shock, decreasing the severity of inflammation, improving vessel contractility and hemodynamics, and preventing inflammatory cell recruitment, proliferation, and release of proinflammatory mediators. Corticosteroids also improve outcome by modulating α-receptor responsiveness to catecholamines. GCs both increase the number of α receptors and prevent uncoupling of the α receptor from adenylate cyclase.

Exogenous Corticosteroids

The introduction of cortisone, a purified glucocorticoid preparation, revolutionized the treatment of a number of medical diseases and provided physiologic replacement in patients with adrenal insufficiency. Shortly thereafter, a number of case reports and studies appeared describing the catastrophic effects of inadequate corticosteroid supplementation in glucocorticoid-treated patients with medical or surgical stresses. Glucocorticoid therapy is the most common cause of secondary adrenal insufficiency. Initially, glucocorticoid administration suppresses CRH and ACTH stimulation. Over time, tertiary iatrogenic adrenal insufficiency develops as the adrenal gland atrophies. Adrenal atrophy may persist for months, following even short courses of corticosteroid therapy.

The dose and duration of corticosteroid administration are only fair predictors of the extent of adrenal suppression, because ACTH and cortisol production vary greatly among individuals. The time to recovery from HPA suppression is highly variable, ranging from 2 to 5 days to 9 to 12 months. The hypothalamus is the first to be suppressed by steroid dosing but the first to recover (normalizing ACTH in several months), whereas the adrenal glands are the last to be suppressed and the slowest to recover, a process that may take 6 to 12 months. Data regarding corticosteroid-induced adrenal suppression are varied. Suppression of the HPA axis should be anticipated in any patient who has been receiving more than 30 mg/day of hydrocortisone (or 7.5 mg of prednisolone or 0.75 mg of dexamethasone) for more than 3 weeks.

Given the large variation in cortisol production in healthy patients, it is difficult to predict the need for GC supplementation during stress. Also, the adrenal response to acute medical illness is variable. An intact HPA axis is paramount to survival during periods of major stress and critical illness. Adrenal insufficiency with decreased GC levels is associated with a significantly increased mortality in these settings. Adrenal suppression should be suspected in patients receiving corticosteroids, and these patients should receive replacement GCs when facing major surgery or critical illness.

Expert recommendations have suggested lower doses and shorter duration of glucocorticoid administration ( Table 44.1 ). Patients undergoing minor procedures such as routine dental work, skin biopsy, inguinal repair, or minor orthopaedic surgery only require their normal daily dose of replacement, and not a supplemental dose. Some clinicians have advocated using hydrocortisone continuous infusions to limit the rapid clearance and peaks and nadirs of bolus therapy. Others have suggested using longer-acting glucocorticoid agents, such as methylprednisolone or dexamethasone.

Effects on Cytokines

Cytokines are important mediators of inflammation, and the pattern of their expression largely determines the magnitude and persistence of the inflammatory response. Steroids have potent inhibitory effects on cytokine transcription and synthesis, especially the ones relevant in chronic inflammation (IL-1, IL-3, IL-4, IL-5, IL-6, IL-8, TNF-α, and granulocyte-macrophage colony-stimulating factor). Steroids interfere with cytokine synthesis by blocking their synthesis. They inhibit the synthesis of the IL-2 receptor and oppose the induction of IL-2 and T-lymphocyte activation and proliferation.

Effects on Inflammatory Mediators

The activation of phospholipase A ₂ leads to the hydrolysis of arachidonic acid from membrane phospholipids and the production of arachidonic acid metabolites. Arachidonic acid metabolism via the cyclooxygenase pathway produces prostaglandins and thromboxanes, and through the lipoxygenase pathway it produces leukotrienes. Steroids increase the synthesis of lipocortin (annexin) 1, a phospholipase A ₂ inhibitor, and thus decrease the production of inflammatory mediators such as leukotrienes, prostaglandins, and platelet-activating factor. GCs also upregulate the transcription of other anti-inflammatory genes such as neutral endopeptidase and inhibitors of plasminogen activator.

The primary anti-inflammatory effect of steroids appears to be the suppression of transcription of genes involved in inflammation such as collagenase, elastase, plasminogen activator, cyclooxygenase (COX)-2, and most chemokines. Steroids directly inhibit the transcription of a cytosolic form of phospholipase A ₂ induced by cytokines, and they inhibit the gene expression of cytokine-induced COX-2 in monocytes. Cortisol, 6-methylprednisolone, and dexamethasone suppress lipopolysaccharide-induced synthesis of PGE ₂ and cyclooxygenase-2 expression and activity in human monocytes. In addition, steroids inhibit the synthesis of early genes c-fos and c-jun triggered by increased levels of mediators of inflammation such as leukotriene B ₄ and platelet-activating factor.

Effects on Inflammatory Cells

GCs interfere with macrophage activity by impairing phagocytosis, intracellular digestion of antigens, and macrophage release of IL-1 and TNF-α. By inhibiting the expression of chemokines, GCs prevent the activation and recruitment of inflammatory cells, including eosinophils, basophils, and lymphocytes. Steroids also markedly decrease the survival of certain inflammatory cells, such as eosinophils. Eosinophil activity is dependent on the presence of cytokines IL-3, IL-5, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interferon-γ. The presence of these cytokines promotes prolonged eosinophil survival, increased adhesion molecule expression, potentiated eosinophil degranulation, and movement of eosinophils across an endothelial barrier. Steroid administration blocks these cytokine effects, leading to programmed cell death, or apoptosis. GCs cause an expansion in the number of circulating neutrophils secondary to decreased adherence to vascular endothelium (demargination) and stimulation of bone marrow production. GCs interfere with T-cell mediated immunity. They inhibit the production of T lymphocytes by downregulating T-cell growth factors IL-1β and IL-2, and they inhibit the release of various T-lymphocyte cytokines.

Effects on Nitric Oxide Synthase

Various cytokines induce nitric oxide synthase (NOS), resulting in increased nitric oxide production. Nitric oxide increases plasma exudation in inflammatory sites. Steroids potently inhibit the inducible form of NOS in macrophages, and steroid pretreatment prevents the induction of NOS expression by endotoxin.

Effects on Adhesion Molecules

Adhesion molecules facilitate the trafficking of inflammatory cells to sites of inflammation. The expression of the adhesion molecules E-selectin, P-selectin, and intracellular adhesion molecule-1 on the surface of endothelial cells is induced by the cytokines IL-1β and TNF-α. These adhesion molecules enable the endothelium to recruit leukocytes actively and nonselectively, including neutrophils, eosinophils, mononuclear cells, and basophils from the circulation. GCs are effective and potent inhibitors of TNF-α and IL-1 release from macrophages, monocytes, and other infiltrating cells. There is a second class of cytokines that selectively activate the endothelium—IL-4 and IL-13, two cytokines associated with allergic diseases. Their release causes the endothelial expression of vascular cell adhesion molecule-1 only. Consequently, only circulating basophils, eosinophils, monocytes, and lymphocytes, but not neutrophils, can bind to the endothelial surface.

Other Anti-inflammatory Effects

Steroids inhibit plasma exudation from postcapillary venules at inflammatory sites. This effect is delayed, suggesting that gene transcription and protein synthesis are involved. It appears that the antipermeability effect is linked to the synthesis of vasocortin. In addition to nuclear anti-inflammatory effects, GCs also have direct effects on cells and cell membranes. Cortisol stabilizes lysosomal membranes, thus inhibiting lysosomal enzyme release. GCs prevent the sequestration of water intracellularly and the swelling and destruction of cells. GCs inhibit leukocyte accumulation and complement-induced polymorphonuclear neutrophil (PMN) aggregation and decrease PMN chemotaxis, T-cell and B-cell proliferation, and the differentiation and function of macrophages.

Other Mechanisms of Pain Relief

Following peripheral nerve injury, a number of morphologic and biochemical changes occur at the injury site including the formation of neuromas, which leads to increased electrical excitability. Ectopic discharge from the injury site leads to a persistent afferent barrage, which maintains neuralgic pain and paresthesias. GCs have been demonstrated to suppress spontaneous ectopic neural discharge originating in experimental neuromas and prevent the later development of ectopic impulse discharge in freshly cut nerves. The topical application of methylprednisolone was noted to block transmission of C-fibers but not the A-β fibers.

Cushing’s Syndrome

Cushing’s syndrome is characterized by sudden weight gain, hypertension, glucose intolerance, oligomenorrhea, decreased libido, and spontaneous ecchymoses. There is centripetal weight gain, involving thickening of the facial fat that rounds the facial contour (moon facies), enlargement of the dorsocervical fat pad (buffalo hump), and truncal obesity. The development of multiple striae wider than 1 cm on the abdomen or proximal extremities is almost unique to Cushing’s syndrome. Mild hirsutism, acne, personality changes, depression, insomnia, and edema also occur. Despite the external signs of excess GC production, patients receiving GCs develop adrenal atrophy and are at risk for adrenal crisis in the setting of stress. Laboratory tests reveal low blood ACTH and cortisol and low urinary cortisol levels.

Skeletal Effects

Osteoporosis, aseptic necrosis, and growth retardation are all potential complications of long-term GC therapy. Osteoporosis occurs in as many as 50% of patients treated with long-term supraphysiologic doses of prednisone. Trabecular bone, found in the axial skeleton (vertebrae and ribs), is more susceptible to demineralization due to high metabolic turnover rate (eight times more) when compared with that of cortical bone. Corticosteroid-induced osteoporosis (CIOP) has a multifactorial cause–impaired intestinal absorption of calcium coupled with its increased renal excretion, increased osteoclast activity with resultant bone resorption, inhibition of osteoblast activity with decreased bone synthesis, and secondary hyperparathyroidism. The incidence of fractures in patients receiving GCs has been reported to be between 10% and 20%. Patients at greatest risk for corticosteroid-induced osteoporosis are postmenopausal women, children, immobilized patients, and patients with rheumatoid arthritis. Agents such as activated vitamin D products, hormone replacement therapy, fluoride, calcitonin, and bisphosphonates have been shown to maintain or improve bone mineral density in corticosteroid-induced osteoporosis.

Aseptic necrosis is a severe musculoskeletal complication of GC therapy. It occurs with greater incidence in alcoholics, patients with systemic lupus erythematosus, patients with fatty degeneration of the liver, patients with altered lipid metabolism, and renal transplantation patients. The mechanism is related to deposits of fat in terminal arterioles of certain sites of bone. The femoral head is the site most commonly affected, although the humeral head or knee may also be involved. Bone pain is almost always the first symptom and precedes radiologic signs of osteonecrosis by up to 6 months.

Muscle Effects

The incidence of myopathy secondary to high-dose GC therapy has been reported to vary from 7% to 60%. There is no consistent relationship between the dose and duration of steroid administration and the occurrence of myopathy, but the condition develops more often with the use of potent fluorinated steroids such as triamcinolone, dexamethasone, and betamethasone. Symptoms include skeletal muscle weakness, tenderness, and pain with proximal or pelvic muscles typically affected. Recovery may take months to 1 year; treatment includes a reduction in the GC dose and physical therapy with a rehabilitation exercise program.

Ophthalmologic Effects

Cataracts and glaucoma may occur with chronic GC therapy. Steroid-induced cataracts occur in the posterior subcapsular region of the lens and may be asymptomatic until well formed. Children are at greatest risk for this complication. Glaucoma is caused by swelling of collagen strands at the angle of the anterior chamber of the eye, with resistance to the outflow of aqueous humor. The process is usually reversible after GC therapy is discontinued.

Gastrointestinal Effects

Nausea and vomiting are not uncommon with oral steroid therapy. Peptic ulcer disease is slightly increased with GC therapy and is more likely to be gastric than duodenal. GCs cause a decrease in mucus production and mucosal cell renewal. Concomitant use of aspirin and nonsteroidal anti-inflammatory drugs increase this risk and should be avoided, along with tobacco and alcohol, which also are ulcerogenic.

Metabolic Effects

Hyperglycemia results from GC effects of increased hepatic glucose synthesis and increased gluconeogenesis. GCs also antagonize peripheral insulin effects and can occasionally produce insulin resistance. Exacerbation of glucose intolerance is common, but the development of new cases of diabetes mellitus is not, and ketoacidosis is rare. Weight gain is a common side effect of GC therapy and may be the result of increased appetite or fluid retention. Facial edema and fat are estimated to occur in 10% to 25% of patients on steroid therapy for 2 months.

Hyperlipidemia is another metabolic consequence of GC therapy and is likely secondary to relative insulin resistance. Increased plasma triglyceride levels are more common than increased cholesterol levels. Patients with previous lipid level elevations are at higher risk for this side effect. Electrolyte abnormalities such as hypokalemic alkalosis may also occur, usually with GCs possessing strong mineralocorticoid properties.

Cardiovascular Effects

Hypertension, edema, and atherosclerosis may occur with GC therapy. Elevations in blood pressure occur because of increased sodium retention and vasoconstriction. GCs cause vasoconstriction by potentiating the effect of norepinephrine and opposing the effect of endogenous vasodilators such as histamine. This side effect occurs more frequently in patients with preexisting hypertension, older adults, GCs with high mineralocorticoid potency, and high-dose or prolonged (longer than 2 weeks) glucocorticoid treatment courses. Edema occurs from fluid retention secondary to sodium retention. With initial GC dosing, there is a paradoxical diuresis caused by an early blockade of antidiuretic hormone release.

Hematologic Effects

Blood cell effects, immunosuppression, and impaired fibroplasia occur with steroid therapy. Immunosuppression is produced by GCs at many levels. GCs increase the release of granulocytes from bone marrow, thus increasing the number of circulating leukocytes. Lymphopenia occurs, with predominant depression of T-cell production and decreased eosinophil counts with enhanced eosinophil destruction. Tissue inflammation is reduced by inhibition of cytokine production and by impaired chemotaxis of macrophages, neutrophils, basophils, and eosinophils. There is inhibition of the metabolism of arachidonic acid into prostaglandin and leukotriene mediators, as well as a direct inhibition of COX-2. Steroid therapy increases susceptibility to many bacterial, fungal, viral, and parasitic infections. Wound healing is delayed by GC inhibition of fibroblasts, collagen production, and suppression of wound reepithelialization.

Nervous System Effects

Mood changes, nervousness, euphoria, insomnia, and headache are common side effects of GC therapy and are dose related. Psychosis is an uncommon side effect and is seen more commonly in patients with previous psychiatric disorders.

Cutaneous Effects

Skin changes typical of the hyperadrenal state may occur; these include purpura, telangiectasia, atrophy, striae, pseudo-scars, and facial plethora. The skin becomes thin and fragile. Hair growth changes include transient scalp hair loss and hirsutism on other parts of the body. Hyperpigmentation or hypopigmentation may occur, as well as acneiform eruptions. Steroid acne commonly presents on the back and chest as fine, uniform papulopustules.

Pregnancy and Lactation

There appears to be no teratogenic contraindication to corticosteroid therapy in pregnancy. However, intrauterine growth retardation has been reported, and steroid use late in pregnancy may cause adrenal suppression in the fetus. Corticosteroids are secreted in small amounts into breast milk, thus exposing the infant to the risk of adrenal suppression.