Adrenal Glands

Chapter 120

Adrenal Glands

The widespread availability of abdominal ultrasonography has led to increased detection of adrenal masses in human and veterinary medicine. In fact, frequent diagnosis of adrenal masses unrelated to the primary complaint has resulted in a new term in both disciplines—the adrenal incidentaloma.27 Unfortunately, the complex anatomy and physiology of the adrenal gland present a variety of challenges at every level, from diagnosis of disease conditions to decision making, perioperative care, and surgery itself. Thus, modern veterinary surgeons are often faced with the difficult task of weighing the risks and benefits of elective adrenalectomy, a procedure with significant perioperative mortality. Despite challenges associated with surgery, it is generally agreed that adrenalectomy is indicated in animals with functional tumors and those with characteristics of malignancy.27 In these instances, proper knowledge of adrenal physiology and perioperative care can improve the chances of a successful patient outcome.19


The paired adrenal glands are located in the retroperitoneal space, closely associated with the aorta and vena cava in the cranial abdomen (Figure 120-1).20 The left adrenal gland is located medial to the cranial pole of the left kidney and is loosely adhered to fascia of the psoas minor muscle and transverse process of the second lumbar vertebra. The left adrenal gland is adjacent to the left side of the abdominal aorta medially, and its caudal aspect borders the left renal artery. The right adrenal, which is further cranial than the left, is located ventral to the thirteenth thoracic vertebra and is adhered to the right side of the vena cava. In many instances, the adrenal capsule is actually contiguous with vascular adventitia.20 The right adrenal gland is covered by the caudal extension of the right lateral liver lobe; access to the region can be further complicated by hepatomegaly that accompanies hyperadrenocorticism. Both adrenal glands are also obscured by adipose tissue that accumulates in this region of the retroperitoneal space; however, they are easily identified by the beige appearance of the adrenal cortical tissue and by the phrenicoabdominal vein that crosses the ventral surface of each gland.

The microscopic anatomy of the adrenal glands reflects developmental origin and the physiologic function of this endocrine organ. The adrenal cortex is derived from a mass of mesodermal cells that arise near the genital ridges during embryonic development.20 These cells differentiate into polygonal to columnar shapes, with varying lipid content.20 The cortex takes on a laminar architecture adapted to serve specific endocrine functions, including regulation of renal fluid and electrolyte balance (aldosterone synthesis) and chronic stress adaptation and carbohydrate metabolism (steroid hormone synthesis). This mesodermal mass is later invaded by neural crest ectoderm, which migrates to the center of the gland and forms the adrenal medulla.20 As indicated by its developmental origin, the adrenal medulla is essentially a sympathetic ganglion, consisting of postsynaptic neurons that are modified to release their neurotransmitters (epinephrine and norepinephrine) into the systemic circulation through the adrenal gland’s rich vasculature.

The arterial supply to the adrenal glands consists of 20 to 30 small branches arising from the phrenicoabdominal, renal, and cranial abdominal arteries and directly from the adjacent aorta.20 These arteries form a plexus, which is visible through the thick adrenal capsule, and send penetrating branches into the cortex and medulla. Venous blood is collected in sinusoids and drains into a single adrenal vein. The right adrenal vein empties directly into the vena cava, and the left adrenal vein empties into the left renal vein.


The adrenal cortex is divided into three zones: the outer zona glomerulosa, which secretes mineralocorticoids, and the central zona fasciculata and inner zona reticularis, which secrete glucocorticoids and sex steroids. The majority of glucocorticoids are produced within the zona fasciculata. Adrenal corticoids are synthesized from cholesterol. Enzymatic cleavage of a carbon side chain within mitochondria produces the C-21 steroid pregnenolone. Within cells of the zona fasciculata and zona reticularis, pregnenolone is hydroxylated at C-17 to form the glucocorticoid molecule. Zona glomerulosa cells lack 17α-hydroxylase; absence of a hydroxyl group on C-17 is the major difference between aldosterone and cortisol.

Because steroid hormones are lipids, transport through blood relies on binding to plasma proteins. Corticosteroid-binding globulin, or transcortin, has a high affinity to cortisol. Consequently, 75% of cortisol in the plasma is bound to transcortin and 15% to albumin, with approximately 10% unbound. Transcortin transports only 10% of aldosterone; the majority is transported bound to albumin (50%) or remains in its free state (40%). Transcortin is affected by a variety of physiologic states, including pregnancy, which increases its hepatic synthesis, and liver dysfunction, which decreases it. Clearance half-lives of cortisol and aldosterone are 60 and 20 minutes, respectively. The liver is important for metabolism of these hormones into their less active states.


The primary function of glucocorticoids is regulation of metabolism, particularly by stimulation of hepatic gluconeogenesis. Other effects include inhibition of glucose uptake and metabolism in peripheral tissues (especially muscle and adipose cells), stimulation of lipolysis, inhibition of protein synthesis, enhancement of protein catabolism, increase of glomerular filtration rate, inhibition of vasopressin, stimulation of gastric acid secretion, and suppression of the inflammatory response and immune system. Control of glucocorticoid secretion is by a negative feedback system. Glucocorticoids inhibit release of hypothalamic corticotropin-releasing hormone, which in turn decreases corticotropin secretion by the pituitary gland. Glucocorticoids may also have some negative feedback on the pituitary gland itself. Stress can modify glucocorticoid feedback control.


The major functions of the mineralocorticoid aldosterone are electrolyte balance and blood pressure homeostasis. Release of aldosterone is influenced primarily by the renin-angiotensin-aldosterone system and blood potassium concentrations. Renin, which is produced by the juxtaglomerular apparatus of the kidney, is a proteolytic enzyme that splits circulating angiotensinogen, which is synthesized in the liver, into angiotensin I. Within the pulmonary capillary endothelium, angiotensin I is converted to angiotensin II by angiotensin-converting enzyme. Angiotensin II stimulates peripheral vasoconstriction and secretion of aldosterone by the zona glomerulosa. Aldosterone in turn promotes sodium, chloride, and water reabsorption and potassium excretion, particularly at the renal tubules.


Chromaffin cells within the adrenal medulla synthesize catecholamines from tyrosine and, to a lesser extent, phenylalanine. The specific biosynthetic pathway includes conversion of tyrosine to dopa, dopamine, norepinephrine, and finally epinephrine. In most mammals, epinephrine is the major catecholamine secreted by the adrenal medulla. The rate-limiting enzyme in catecholamine formation is tyrosine hydroxylase, which is inhibited by all the products of tyrosine metabolism listed above. Regulation of the adrenal medulla occurs through sympathetic nerve stimulation and typically coincides with simultaneous direct sympathetic stimulation of other organs via sympathetic nerves. Although direct sympathetic nerve stimulation causes only brief effects on target organs, the adrenal medulla releases catecholamines (~80% epinephrine and 20% norepinephrine) into the blood, where their duration of activity is extended up to 10 times, until they are metabolized by the liver and excreted by the kidneys. Interestingly, this complementary system allows for continued sympathetic function even in the face of bilateral adrenalectomy.

The primary actions of catecholamines include response to acute stress and regulation of intermediary metabolism, particularly in response to hypoglycemia. Actions are mediated through alpha- and beta-adrenergic receptors on target tissues. Alpha-1 and alpha-2 receptors control catecholamine release from presynaptic and postsynaptic sympathetic nerve endings. Beta-1 receptors primarily affect the heart, and beta-2 receptors affect intermediary metabolism and smooth muscle contraction. Epinephrine is about 10 times more potent on beta-2 receptors than norepinephrine, so it is more important in controlling metabolism. At beta-2 receptors, epinephrine increases blood glucose concentrations, particularly by promoting hepatic glycogenolysis and gluconeogenesis. Epinephrine also stimulates glycogenolysis in skeletal muscle, with subsequent production of lactate that is converted by the liver to glucose. Epinephrine inhibits insulin secretion (via alpha-2 receptors), stimulates pancreatic glucagon secretion to increase blood glucose concentrations, and promotes lipolysis to increase free fatty acid concentrations in the blood.

Epinephrine and norepinephrine interact with beta-1 receptors to increase the force of cardiac contraction and, by shortening the duration of diastolic depolarization, increase heart rate. Although alpha-2 stimulation promotes arteriolar constriction, epinephrine’s affinity for beta-2 receptors causes vasodilation in skeletal muscle arterioles, coronary arteries, and all veins. Although reduced peripheral resistance should decrease diastolic pressure, minimal change in blood pressure is usually noted because of concurrent increase in cardiac output secondary to an increased heart rate. Other effects of catecholamines include bronchial and gastrointestinal smooth muscle relaxation (epinephrine on beta-2 receptors), uterine relaxation (epinephrine on beta-2 receptors) or contraction (epinephrine and norepinephrine on alpha-2 receptors), urine retention from relaxation of the body of the bladder (epinephrine on beta-2 receptors) and contraction of the bladder neck (epinephrine and norepinephrine on alpha-2 receptors), and pupil dilatation (epinephrine causing alpha-1 stimulated contraction of iris radial muscles and beta-2 relaxation of lens ciliary muscles). Epinephrine also causes central nervous system excitation (alpha-2), sweating and piloerection (alpha-2), ejaculation and tumescence (alpha-2), and increased renin secretion (beta-1).

Identification of An Adrenal Mass

Adrenal masses are most commonly identified during ultrasound examination of the abdomen and less commonly with computed tomography (CT) or magnetic resonance imaging (MRI) (Figure 120-2). Clinical signs, findings on physical examination, results of routine blood and urine tests, or a combination of these may suggest adrenal disease (e.g., hyperadrenocorticism) and the need for diagnostic imaging. Alternatively, the adrenal mass may be an unexpected finding during abdominal ultrasonography that is performed for another reason (e.g., persistent vomiting). Regardless of how an adrenal mass is discovered, determining the functional status of the mass is critical to ensure appropriate perioperative management of the case and to improve the likelihood of a successful outcome after adrenalectomy.

Before proceeding with therapeutics, one of the first considerations is to confirm that an adrenal mass exists. Because of the subtlety of findings in ultrasound examination of the adrenal glands, the authors typically recommend repeating abdominal imaging to confirm that the mass is a repeatable finding and that therapy is warranted. Bulbous enlargement of the cranial or caudal pole of the adrenal gland is common in dogs with normal adrenal glands and can often be misinterpreted as an adrenal mass. The diagnosis of an adrenal mass is made when the maximum width of the adrenal gland exceeds 1.5 cm, the gland loses its typical “kidney-bean” shape, and the gland is asymmetric in shape and size compared with the contralateral adrenal gland.5,17

Adrenal asymmetry may represent a functional neoplasm; however, other differential diagnoses include hypertrophy of normal tissue, granuloma, cyst, hemorrhage, or an inflammatory nodule. Adrenalectomy is the treatment of choice if an adrenal mass is malignant and has not metastasized, but adrenalectomy may not be indicated if the mass is benign, small, and hormonally inactive and has not invaded surrounding structures. Unfortunately, it is not easy to determine if an adrenal mass is malignant or benign before surgical removal and histopathologic evaluation. Guidelines to suggest malignancy include mass size, invasion of the mass into surrounding tissues and blood vessels, and identification of additional mass lesions with abdominal ultrasonography and thoracic radiography. The bigger the mass, the more likely it is malignant and the more likely metastasis has occurred, regardless of findings on abdominal ultrasonography and thoracic radiography.

Diagnosis of Functional Adrenal Tumors

Adrenal tumors may secrete a hormone or may be nonfunctional. Excess secretion of cortisol, catecholamines, aldosterone, progesterone, and steroid hormone precursors have been documented in dogs and cats (Table 120-1). Clinical presentation and results of routine blood and urine tests often provide clues to the functional status of the adrenal tumor. The most common functional adrenal tumors in dogs secrete cortisol or catecholamines.

Cortisol-Secreting Adrenal Tumors

Dogs with a cortisol-secreting adrenal tumor have clinical signs of hyperadrenocorticism, including polyuria, polydipsia, polyphagia, panting, abdominal enlargement, endocrine alopecia, mild muscle weakness, and lethargy.12 Findings on routine blood and urine tests include the presence of a stress leukogram, increased serum alkaline phosphatase activity, hypercholesterolemia, isosthenuria or hyposthenuria, and proteinuria.12 Abdominal ultrasonography will reveal a variably sized adrenal mass, typically ranging from 1.5 to greater than 8 cm in maximum width. The mass may compress or invade adjacent blood vessels and organs; these findings are suggestive of carcinoma (see Figure 120-2).23 Asymmetry in the size of the adrenal glands is typical. Ideally, the contralateral unaffected adrenal gland is small or undetectable (maximum width, typically <0.3 cm) as a result of adrenocortical atrophy induced by hypercortisolism. However, a normal-size contralateral adrenal gland does not rule out hyperadrenocorticism caused by an adrenal tumor. Rarely, bilateral cortisol-secreting adrenal tumors are present.

Low-Dose Dexamethasone Suppression Test

A total of 80% to 85% of dogs with naturally occurring hyperadrenocorticism have the pituitary dependent form (pituitary-dependent hyperadrenocorticism). In these dogs, excessive secretion of adrenocorticotropic hormone (ACTH) by the pituitary gland causes bilateral adrenal hyperplasia and excessive glucocorticoid secretion. Functional adrenal adenomas and carcinomas, however, secrete excessive amounts of cortisol independent of pituitary control. Negative feedback by cortisol will suppress hypothalamic cortisol releasing hormone and circulating plasma ACTH concentrations; however, it will not suppress cortisol secretion of functional tumors. As a result, the cortex of the uninvolved adrenal gland and the normal cells of the affected adrenal gland should atrophy.

The low-dose dexamethasone suppression test is used to establish the diagnosis of hyperadrenocorticism. Suppression is defined as a 4-hour postdexamethasone serum cortisol concentration below 1.5 µg/dL, a 4-hour postdexamethasone serum cortisol concentration less than 50% of the baseline concentration, or an 8-hour postdexamethasone serum cortisol concentration less than 50% of the baseline concentration.13 Serum cortisol concentrations do not suppress during the low-dose dexamethasone suppression test in dogs with adrenal-dependent hyperadrenocorticism. Failure of serum cortisol concentrations to suppress does not by itself confirm adrenal-dependent hyperadrenocorticism, however; approximately 40% of dogs with pituitary-dependent hyperadrenocorticism also fail to suppress during the low-dose dexamethasone suppression test.13 In a dog with an adrenal mass and clinical signs of hyperadrenocorticism, suppression of serum cortisol during the low-dose dexamethasone suppression test strongly supports the presence of a non–cortisol-secreting adrenal tumor (e.g., pheochromocytoma) in a dog with pituitary-dependent hyperadrenocorticism, especially if the contralateral adrenal gland is normal in size and appearance. Determination of a single baseline plasma ACTH concentration may aid in distinguishing dogs with adrenal-dependent hyperadrenocorticism from those with pituitary-dependent hyperadrenocorticism after the diagnosis of hyperadrenocorticism has been established with the low-dose dexamethasone suppression test.17,32 Dogs with a functional adrenal tumor are likely to have low (e.g., <10 pg/mL) or undetectable concentrations of endogenous ACTH. Dogs with iatrogenic hyperadrenocorticism also have low endogenous ACTH; however, these patients have subnormal baseline cortisol concentrations.

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Jul 18, 2016 | Posted by in PHARMACOLOGY, TOXICOLOGY & THERAPEUTICS | Comments Off on Adrenal Glands
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