One of the Most Important Clinical Uses of Glucocorticoids Is the Suppression of the Inflammatory Response

Glucocorticoids have valuable clinical effects, particularly the inhibition of the inflammatory response, including the pre­vention of capillary dilation, extravasation of fluid into tissue spaces, leukocyte migration, fibrin deposition, and connective tissue synthesis.

FIGURE 34-11 Chemical structures of some clinically useful glucocorticoid analogues. (From Martin CR: Endocrine physiology, London, 1985, Oxford University Press.)

functional tissue with fibrous connective tissue, with a resultant loss of function. For example, inflammatory proc­esses in the mammary gland often result in the isolation of the injurious agent by the laying down of connective tissue as a part of the defense mechanism; however, the gland may lose much of its functional capacity as a result. Administration of glucocorticoids, in conjunction with antibiotic therapy, can help reduce the loss of functional tissue by inhibiting the development of connective tissue. Figure 34-11 shows the chemical structures of some of the synthetic glucocorticoids used in clinical practice.

One of the ways in which glucocorticoids inhibit the inflam­matory response is through the inhibition of the formation of substances that promote inflammation. Glucocorticoids inhibit the synthesis of inflammatory mediators, such as prosta­glandins, thromboxanes, and leukotrienes, that arise as a result of arachidonic acid metabolism. This effect is mediated through the stabilization of lysosomal membranes and the prevention of phospholipase A₂ activation. Glucocorticoids are also used to inhibit allergic reactions. This action occurs through the inhibition of the release of certain biogenic amines, such as histamine, from the granules of mast cells.

Hyperadrenocorticism

Hyperadrenocorticism (Cushings syndrome) in the dog may be caused by a pituitary tumor, pituitary hyperplasia, adrenal tumors, adrenal hyperplasia, or nonendocrine tumors (usually of the lung), or it may be iatrogenic. Approximately 85% of dogs with Iiyperadrenocorticism have pituitary gland-dependent dis­ease, whereas 15% exhibit adrenal tumors. Hyperadrenocorti- cism is a disease of middle-aged and older dogs (7-12 years). Breeds typically affected by pituitary-dependent hyperadreno- corticism include miniature poodles, dachshunds, boxers, Boston terriers, and beagles. Adrenal tumors are seen more frequently in large-breed dogs, and there is a predilection for females (3:1 ratio with males). Hyperadrenocorticism is a rare endocrine disorder of cats and is usually pituitary in origin in that species.

The most common clinical signs associated with canine hyperadrenocorticism are polydipsia, polyuria, polyphagia, heat intolerance, lethargy, abdominal enlargement or “pot­belly,” panting, obesity, muscle weakness, and recurrent urinary tract infections (UTIs). Dermatological manifesta­tions of canine hyperadrenocorticism can include alopecia (especially truncal), thin skin, phlebectasias, comedones, bruising, cutaneous hyperpigmentation, calcinosis cutis, pyo­derma, dermal atrophy (especially around scars), seborrhea, and secondary demodicosis. Thin skin is the hallmark of feline hyperadrenocorticism. Cats with Cushing’s syndrome develop such severe thinning of the epidermis that they may incur open wounds just by grooming themselves.

Attempts to diagnose hyperadrenocorticism can be chal­lenging. Uncommon clinical manifestations of hyperadreno­corticism in dogs can include signs such as hypertension, congestive heart failure, bronchial calcification, pulmonary thromboembolism, polyneuropathy, polymyopathy, pseudo­myotonia, behavioral changes, and blindness. Evidence of increased collagenase activity caused by hypercortisolemia may result in nonhealing corneal ulceration and bilateral cranial cruciate rupture (in small dogs).

Serum chemistry abnormalities associated with hyper- Cortisolemia in dogs include increased serum activities of alkaline phosphatase and alanine aminotransferase, hyper­cholesterolemia, hyperglycemia, and decreased BUN. The hemogram is often characterized by evidence of erythroid regeneration (nucleated red blood cells) and a classic “stress leukogram.” Basophilia is occasionally observed. Many dogs with hyperadrenocorticism have evidence of UTI without pyuria. Proteinuria resulting from glomerulosclerosis is also common. Urine specific gravity is usually decreased and may be hyposthenuric. Thyroid status is often affected in animals with hyperadrenocorticism, as evidenced by (1) decreases in TT₄ and TT₃ caused by euthyroid sick syndrome and (2) a response to TSH stimulation that is attenuated as a result of overcrowding of pituitary thyrotrophs by adrenocortico- trophs. Overt diabetes mellitus may result from the insulin antagonism caused by hypercortisolemia in about 15% of dogs with hyperadrenocorticism and 85% of cats with hyper­adrenocorticism. Conversely, hyperadrenocorticism can be a cause of insulin resistance and poor glycemic control in diabetic animals.

'Γhe diagnosis of hyperadrenocorticism should be based on suggestive clinical signs and supporting minimal database abnormalities (e.g., high serum cholesterol, increased serum alkaline phosphatase activity) and confirmed by an appro­priate screening test. If screening test results are inconclusive, the dog should be retested at a later date (3-6 months) rather than be subjected to treatment without a definitive diagnosis.

Screening tests for hyperadrenocorticism, such as the low- dose dexamethasone suppression (LDDS) test and the cortico­tropin stimulation test, work on the principle of suppression or stimulation of the pituitary-adrenal axis.

The LDDS test has traditionally been the screening test of choice for canine hyperadrenocorticism. It is sensitive (92%- 95%); only 5% to 8% of dogs with pituitary dependent hyper­adrenocorticism exhibit suppressed cortisol concentrations at 8 hours (i.e., 5%-10% false-negative results). In addition, 30% of dogs with pituitary-dependent hyperadrenocorticism exhibit suppression at 3 or 4 hours, followed by “escape” of sup­pression at 8 hours; this pattern is diagnostic for pituitary­dependent disease and makes further testing unnecessary. The major disadvantage of the LDDS test is the lack of specificity in dogs with nonadrenal illness. It is recommended that a dog be allowed to recover from the nonadrenal illness before being assessed for hyperadrenocorticism with the LDDS test.

Mineralocorticoids

The mineralocorticoids, produced in the outer zone (zona glomerulosa) of the adrenal cortex, have surprisingly different functions compared with glucocorticoids; the functions are surprising because both types of hormones are produced by tissues that are part of the same gland. As indicated previously, electrolyte balance and blood pressure homeostasis repre­sent the principal physiological effects of mineralocorticoids (Table 34-4). These actions are carried out at the level of the distal tubules in the kidney. The effect of the mineralocorti­coids is to promote retention of sodium and secretion of potassium and hydrogen.

Table 34-4

Mineralocorticoid Effects and Target Tissues

From Hedge GA, Colby HD, Goodman RL: Clinical endocrine physiology, Philadelphia, 1987, Saunders.

meability of the luminal cell surface to sodium influx from the renal filtrate and increases sodium/potassium-adenosinetri- phosphatase (Na⁺,K⁺-ATPase) activity in the contraluminal cell surface, which allows movement of Na⁺ out of the cell into the interstitial tissue (Figure 34-12).

The control of secretion of K⁺ by mineralocorticoids is passive in the sense that K⁺ is retained in the renal filtrate to maintain the osmolality of urine. However, evidence suggests that mineralocorticoids have an effect on Na⁺ secretion that is

FIGURE 34-12 Mechanisms of action of aldosterone on sodium transport in the renal tubular cell.The numbered arrows indicate the three putative sites of action of aldosterone: 7_z increasing the permeability of the luminal membrane to sodium; 2, increasing mitochondrial adenosine triphosphate (ATP) production; and (3) increasing Na⁺,K⁺-ATPase activity in the contraluminal membrane. Plus signs indicate stimulation. A_t Aldosterone; ADP_t adenosine diphosphate; mRNA_t messenger ribonucleic acid; R_t receptor.

FIGURE 34-13 Regulation of aldosterone secretion by the zona glomerulosa of the adrenal cortex. Plus signs indicate stimulation. ACTH_t Corticotropin (adrenocorticotropic hormone); ECF_t extracellular fluid. (From Hedge GA, Colby HD, Goodman RL: Clinical endocrine physiology, Philadelphia, 1987, Saunders.)

independent of Na‘ retention. The secretion of K' continues to be influenced by mineralocorticoids after mineralo­corticoid administration, whereas Na⁺ retention decreases within a few days.

In situations of excessive mineralocorticoid production, the effects of increased Na' retention are to increase the extra­cellular fluid volume and to cause hypertension; conversely, low blood pressure (hypotension) occurs as a result of inadequate secretion of mineralocorticoids. Hypersecretion of mineralocorticoids can also lead to excessive hydrogen ion (H⁺) loss and metabolic alkalosis, whereas hyposecretion can result in increased retention of H* and metabolic acidosis.

The regulation of mineralocorticoid secretion, in contrast to glucocorticoid secretion, is not controlled by tropic hor­mones from the pituitary gland (Figure 34-13). In the case of mineralocorticoids, the main controlling factors are produced in the target organ, the kidney. Cells in the juxtaglomerular apparatus of the kidney produce an enzyme, renin, in response to decreases in blood pressure. Renin acts on αngiotensinogen_t an α₂ globulin produced by the liver and present in the circulation, and this results in the production of angiotensin I_t a decapeptide. Angiotensin I is further hydrolyzed to angio­tensin II_t an octapeptide, by angiotensin-converting enzyme. Angiotensin Il stimulates the zona glomerulosa to produce mineralocorticoids. Angiotensin II also increases peripheral resistance of the blood vascular system by causing vasocon­striction of smooth muscle of the blood vessels. Angiotensin II, if present on a long-term basis, also increases the size of the zona glomerulosa.

Evidence indicates that cells of the macula densa, groups of specialized cells located at the origin of the kidney’s distal tubule (Figure 34-14), exert control on the renin-angiotensin system. This is done through the sensing of changes in Na⁺

FIGURE 34-14 Diagrammatic representation of juxtaglomerular apparatus. (From Martin CR: Endocrine physiology, London, 1985, Oxford University Press.)

concentrations in tissue fluids; increased Na^, results in decreased renin release» and decreased Na⁺ results in increased renin release. In either case, the change produced tends to restore the mineralocorticoid concentrations to normal. In addition to the effect of sodium, the macula densa may control changes in the renin-angiotensin system through the sensing of changes in chloride ion (CΓ) concentrations in tissue fluids.

Another major regulatory factor in the control of mineralo­corticoid secretion is the blood potassium concentration. An increase in K⁺ concentration stimulates the zona glomerulosa to secrete mineralocorticoids, whereas a decline in K⁺ has the opposite effect. This stimulation is independent of the renin­angiotensin system.

It has been thought that corticotropin has minimal effect on control of the zona glomerulosa, because experimental studies showed that hypophysectomy has little effect on the zona glomerulosa. More recent studies have shown that cells of the zona glomerulosa have receptors for corticotropin, and corticotropin may play some role, although minor, in the control of mineralocorticoid secretion.

In contrast to the sodium-conserving effect of mineralo­corticoids, the 28-amino acid atrial natriuretic peptide (ANP) reduces Na⁺ retention by the kidneys. ANP also causes pe­ripheral vasodilation and thus a lowering of blood pressure. ANP may inhibit the production of mineralocorticoids and renin as well. ANP is produced by cells of the cardiac atria, but it is also produced in other sites, including the brain.

Hypoadrenocorticism

Hypoadrenocorticism, caused by lack of mineralocorticoids and glucocorticoids, is most often diagnosed in young female dogs and usually has an immune-mediated etiology. Certain breeds, such as Leonbergers, standard poodles, and Portu­guese water dogs, are at increased risk for the disease; however, hypoadrenocorticism may be diagnosed in any breed. Historical findings compatible with hypoadrenocorticism include inter­mittent vomiting, diarrhea, weight loss, Iethargy^r, anorexia, and weakness. These symptoms often resolve with fluid therapy and corticosteroid treatment. Physical examination of animals in an acute hypoadrenal crisis reveals weak pulse, bradycardia, pro­longed capillary refill time, severe mental slowness, and pro­found muscle weakness. Clinical features of hypoadreno­corticism that should raise suspicion include a normal or slow heart rate in the presence of circulatory shock and the “waxing and waning ’ course of disease before collapse.

Electrolyte abnormalities consisting of severe hypo­natremia and hypochloremia associated with hyperkalemia are the hallmarks of hypoadrenocorticism. Azotemia and hyperphosphatemia also accompany primary hypoadreno­corticism, which makes it difficult to differentiate it from acute renal failure. Azotemia may be prerenal as a result of dehydration and hypovolemia, or increase in BUN may be caused by gastrointestinal hemorrhage. Hematological abnor­malities consist of eosinophilia and lymphocytosis, or eosino­phil and lymphocyte counts may be normal in the presence of severe metabolic stress. The anemia of hypoadrenocorticism has classically been attributed to lack Ofglucocorticoid effects on the bone marrow. However, more recent studies have sug­gested that hemorrhagic gastroenteritis contributes signifi­cantly to the anemia. Although hypoglycemia is more common with secondary or atypical hypoadrenocorticism, it is rarely seen with typical hypoadrenocorticism.

Urine specific gravity is frequently low, attributable to medullary washout (inadequate medullary gradient caused by sodium depletion) and decreased medullary blood flow. Dilute urine in the presence of azotemia and hyperkalemia may easily be mistaken for acute renal failure. I Iormonal assays are necessary to confirm the presence or absence of adrenal disease and to differentiate between hypoadrenocorticism and renal failure.

Diagnosis of primary hypoadrenocorticism is based on clinical signs, classic electrolyte imbalances, and confirmation with a corticotropin response test. The baseline cortisol sample should be collected with the initial blood work, and synthetic corticotropin (Cosyntropin ∣Cortrospi], 0.25 mg) should be administered intravenously during the initial fluid therapy. A l-hour, postcorticotropin sample may then be drawn, and glucocorticoids may be administered after the 1-hour sample is taken. Intramuscular injection of corticotropin (gel or synthetic) may not be absorbed in animals in circulatory shock; therefore, intravenous administration of synthetic corticotropin is preferred. If glucocorticoids must be administered before the measurement of cortisol, dexamethasone sodium phosphate is preferred because it does not interfere with the cortisol assay. Endogenous plasma corticotropin may be measured to deter­mine whether the hypoadrenocorticism is primary or secondary.

Dogs and cats with primary hypoadrenocorticism exhibit a subnormal response to corticotropin administration. Both the baseline and the postcorticotropin cortisol concentrations are usually low or undetectable. Endogenous plasma cortico-

FIGURE 34-15 Stimulus-secretion coupling in the adrenal chromaffin cell. Note that cytosolic calcium may be derived from intracellular or extracellular sources. Circled plus signs indicate stimulation. A, Acetylcholine; R_z receptor. (From Hedge GA_z Colby HD_z Goodman RL: Clinical endocrine physiology, Philadelphia, 1987, Saunders.)

tropin concentrations are dramatically increased in animals with primary hypoadrenocorticism as a result of loss of negative feedback to the pituitary gland, caused by decreased serum cortisol concentrations. In the case of secondary hypo­adrenocorticism, caused by a pituitary deficiency of cortico­tropin, the endogenous corticotropin concentrations are typically decreased (PK, protein kinase; PK-C, protein kinase C; PLC, phospholipase C. (From Hedge GA, Colby HD, Goodman RL: Clinical endocrine physiology, Philadelphia, 1987, Saunders.)

affect mainly the heart, and β₂ receptors affect smooth muscle contraction and intermediary metabolism. Whereas all adrenergic receptors are responsive to both epinephrine and norepinephrine, the responses to the two catecholamines are different. In addition, the receptor types on various tissues vary in number, which, together with the different responses of adrenergic receptors on tissues, results in variable adrenergic responses being produced by a particular catecholamine.

The metabolic effects of catecholamines are mediated mainly by β₂ receptors. Because epinephrine is 10 times more potent than norepinephrine with β₂ receptors, epinephrine plays a much more important role in the control of inter­mediary metabolism than does norepinephrine. The effects of epinephrine on glucose metabolism are similar to those of glucagon and opposite to those of insulin. Epinephrine increases blood glucose concentrations, with the effect mainly in the liver; that is, epinephrine promotes both hepatic glyco­genolysis and gluconeogenesis. Epinephrine also stimulates glycogenolysis in skeletal muscle, which in this situation is in contrast with the action of glucagon. Because glucose-6- phosphatase is not present in skeletal muscle, lactate is pro­duced instead of glucose; the liver takes up lactate and con­verts it to glucose. Additional effects on glucose metabolism include the inhibition of insulin secretion (through α receptors) and stimulation of glucagon secretion by the pancreas; both actions increase blood glucose concentrations.

Epinephrine promotes lipolysis through interaction with two receptors on adipose cells. Activation of a lipase enzyme results in an increase in free fatty acids in the blood. Gluco­corticoids potentiate the effect of epinephrine on lipolysis.

Catecholamines stimulate cardiac function. Both epineph­rine and norepinephrine interact with β₁ receptors to increase both the force of contraction and the heart rate, the latter resulting from the promotion of a shorter period of diastolic depolarization. Whereas both catecholamines promote arteriolar constriction through interaction with α receptors, epinephrine, through its high affinity for β₂ receptors, causes the dilation of blood vessels both in the heart and in skeletal muscle. The end result is that total peripheral resistance is decreased by the action of epinephrine, with a concomitant decline in diastolic pressure; however, blood pressure is mini­mally changed, and cardiac output increases because of the increase in heart rate. The action of epinephrine to increase cardiac output is an obvious beneficial effect in situations that are described as “fight or flight.”

Catecholamines affect smooth muscle. Epinephrine causes relaxation of bronchial smooth muscle, particularly when the muscle is in a contracted state. Because the action is mediated through β₂ receptors, norepinephrine has little effect on bronchial smooth muscle. Epinephrine causes relaxation of the smooth muscle of the gastrointestinal (Gl) tract through interaction with β₂ receptors. Catecholamine stimulation of β-adrenergic receptors results in contraction of uterine smooth muscle, and stimulation of β₂ receptors results in relaxation. Because of its dominant effect on β₂ receptors, epinephrine causes relaxation of the uterus, whereas both epinephrine and norepinephrine interact with α receptors to cause contraction.

The effects of the catecholamines on bladder smooth muscle depend on different locations of α and β receptors; α-adrenergic receptors are located within the neck of the bladder, and β-adrenergic receptors are located within the body of the bladder. Epinephrine relaxes the body and contracts the neck of the bladder; norepinephrine contracts the neck of the bladder. The net effect is retention of urine.

Although the parasympathetic nervous system is the principal system involved in penile erection, the sympathetic nervous system may also play a role. Epinephrine promotes erection through vasodilation of the vasculature mediated by β receptors. Higher concentrations of epinephrine (and nor­epinephrine) can cause ejaculation through α-receptor interaction and vasoconstriction.

In the eye, epinephrine causes relaxation of the lens through stimulation of β receptors on the ciliary muscles. It causes dilation of the pupil through stimulation of α receptors, with resultant contraction of the radial muscle of the iris.

Table 34-5

Responses of Target Tissues to Catecholamines

From Hedge GA, Colby HD, Goodman RL: Clinical endocrine physiology, Philadelphia, 1987, Saunders.

The effects of epinephrine on the CNS are excitatory. Drugs that affect the CNS probably do so by modulation of catecholamine concentrations» whereby sedation is associated with lower values of epinephrine. Other effects of catecholamine include the promotion of sweating and piloerection. Epi­nephrine also increases renin production by the renal juxta­glomerular cells. Table 34-5 summarizes the effects of catecholamines.