Embryology

The gland is made of two embryologically and functionally distinct units: the cortex (outer layer and endocrine) and medulla (inner layer and neurocrine). The cortex is derived from the intermediate mesoderm of the urogenital ridge in the fifth week of gestation as mesenchymal cells proliferate to form the outer layer of the fetal adrenal. These cells become encapsulated at the end of the eighth week by cells from the peritoneal mesothelium. The medulla is derived from neural crest cells located in the sympathetic ganglia, which become enveloped by the cortex by the ninth week and ends by week 18. At birth the gland is twice the weight of the adult gland and continues to develop until 12 months of age.

Unilateral agenesis is rare, and bilateral agenesis is incompatible with life. However, because of the differences in embryologic development of the kidney and adrenal glands, in cases of renal agenesis, malrotation, or malascent, the adrenal glands will be in their normal anatomic location but more discoid in shape. Other embryologic anomalies include heterotopia (adrenal rests), which can be found anywhere along the path of gonadal descent in the retroperitoneum. These rests can be found in up to 50% of neonates but because of atrophy, only 1% of adults. In cases of congenital adrenal hyperplasia (CAH), rests may lie in the testis, manifesting as a testis mass. This needs to be considered prior to orchiectomy in patients with CAH.

Anatomy

The glands weigh 4–5 g each, are 4–6 cm in length and are 2–3 cm wide and lie at the level of the 11th and 12th ribs. The right gland is triangular and is bordered medially by the inferior vena cava (IVC), superiorly and anteriorly by the liver, inferiorly by the kidney and renal vein, posteriorly by the psoas muscle, and laterally by the body wall. The left is crescent shaped and is bordered medially by the aorta; superiorly and anteriorly by the spleen, stomach, and splenic vessels; inferiorly by the kidney and renal vein, posteriorly by the psoas muscle; and laterally by the body wall. The blood supply is variable but arises from three arteries: superior adrenal (inferior phrenic artery), middle adrenal (aorta), and inferior (ipsilateral renal artery). The short right adrenal vein drains directly into the IVC; the left vein is longer and drains into the renal vein. Extensive collateral vasculature allows for partial adrenalectomy when indicated. Right lymphatic drainage is via the paracaval chain, and the left is drained by the paraaortic chain. Autonomic innervation is by preganglionic sympathetic fibers off the sympathetic trunk directly to the chromaffin cells of the medulla, whereas postganglionic fibers from the splanchnic ganglia supply the cortex ( Figs. 30.1 and 30.2 ).

Adrenal vascular supply demonstrating inflow from the superior, middle, and inferior adrenal arteries bilaterally. Whereas the right (R.) adrenal vein drains directly into the posterior inferior vena cava, the left (L.) adrenal vein often communicates with the inferior phrenic vein before draining into the left renal vein.

(Courtesy of the University of Kentucky.)

Vascular supply of adrenal glands. a, Artery; L, left; R, right; v, vein.

Adrenal cortex physiology

Much of the hormone synthesis in the adrenal gland arises from the common precursor, cholesterol. Low-density lipoprotein (LDL) serves as the primary source of cholesterol for the adrenals. The cortex is composed of three major zones: the zona glomerulosa (mineralocorticoid), zona fasciculate (glucocorticoid) and reticularis (androgen). The zone layers can best be remembered as “salt, sugar, sex” ( Fig. 30.3 ).

Steroid hormone synthesis beginning with cholesterol and resulting in mineralocorticoid, glucocorticoid, and androgen production in the adrenal cortex. Enzymes are listed in boxes and genes in parentheses.

(From Hyun G, Kolon TF. A practical approach to intersex in the newborn period. Urol Clin North Am 2004;31:435-443.)

Adrenal medulla

The medulla composes 10% of adrenal mass but is integral to the autonomic nervous system. Chromaffin cells in the medulla are innervated by preganglionic sympathetic fibers of T11 to L2 similar to the sympathetic ganglia. The systemic stress response is modulated by catecholamines that are produced from the amino acid tyrosine and consist of epinephrine (E) (80%), norepinephrine (NE) (19%), and dopamine (1%).

The majority of catecholamine metabolism occurs in the adrenal medulla. The metabolites metanephrine, normetanephrine, and vanillylmandelic acid (VMA) and the enzymes catechol- O -methyltransferase (COMT) and monoamine oxidase (MAO) are the most important. More than 90% of metanephrine and 20% of normetanephrine in the bloodstream are produced in the medulla. These can be important in the diagnosis of pheochromocytoma. These metabolites are also excreted in the urine in a sulfonated form, making them measurable in urine collections.

Cushing syndrome

Pathophysiology

Cushing syndrome (CS) is rare and is defined as hypercortisolism secondary to excessive production of glucocorticoids by the adrenal cortex. Corticotropic cells of the anterior pituitary gland secrete ACTH, also known as corticotropin, under the influence of the hypothalamus ( Fig. 30.4 ). Physiologically, the most important promoter of ACTH release is corticotropin-releasing hormone (CRH), but oxytocin and vasopressin also play a role. Stress is the most important variable in modulating the hypothalamus-pituitary-adrenal (HPA) axis. Glucocorticoids bind receptors in the hypothalamus and the pituitary gland and complete the negative feedback loop by inhibiting production of CRH and ACTH by these structures, respectively. Given the sophistication of the HPA axis, hypercortisolism can result from a number of different pathologies that result in oversecretion of cortisol by the adrenal glands. Causes of CS can be divided into three main groups: (1) exogenous, (2) ACTH dependent, and (3) ACTH independent.

Clinically relevant causes of excess cortisol production. ACTH, Adrenocorticotropic hormone; CRH, corticotropin-releasing hormone.

Clinical characteristics

Clinical characteristics of CS vary considerably. The classic symptoms of hypercortisolism, such as central obesity, moon facies, buffalo hump, proximal muscle weakness, easy bruisability, and abdominal striae, are nonspecific. CS also results in systemic symptomatology that is identical to the common metabolic syndrome, such as central obesity, dyslipidemia, insulin resistance, and hypertension (HTN). Many men with CS have erectile dysfunction and may present with decreased libido and hypogonadism. Up to 50% of CS patients have urolithiasis. Patients who exhibit cushingoid features should be worked up for hypercortisolism.

Diagnostic tests

The two most frequently used tests to diagnose CS are the 24-hour urinary free cortisol (UFC) test and the overnight low-dose dexamethasone suppression test (LD-DST). When evaluating incidentalomas, the UFC test may be inadequate because of its low sensitivity. In normal patients, dexamethasone stimulates the corticotropic cells of the anterior pituitary, which in turn suppresses ACTH production and results in lower serum cortisol levels. A patient’s failure to suppress cortisol after dexamethasone administration is indicative of CS.

The UFC test is a 24-hour direct measurement of bioavailable cortisol. Late-night salivary cortisol and midnight plasma cortisol measurements take advantage of a common feature of all causes of CS—a perturbation and in some cases complete disruption in the diurnal variation of cortisol levels. The abnormality is the inability to suppress cortisol levels at night. Peak morning cortisol levels in patients with CS are often within the normal range; however, persistent elevation at night may signal the loss of diurnal variance associated with CS. Although midnight plasma cortisol measurements are clinically impractical in an outpatient setting, late-night salivary cortisol measurements are becoming a popular diagnostic tool for identification of hypercortisolism.

Treatment

Pathophysiology

The release of renin from the JG cells is the rate-limiting step in the RAAS cascade. Normally, renin release is stimulated by low renal perfusion pressure, increased renal sympathetic nervous activity, and low sodium concentration sensed by the macula densa. Renin then cleaves angiotensinogen to angiotensin I, which in turn is cleaved by angiotensin-converting enzyme (ACE) to angiotensin II. Angiotensin II functions as a potent vasoconstrictor and triggers the release of aldosterone from the zona glomerulosa. Additional regulators of aldosterone release include potassium and ACTH. In Conn syndrome, aldosterone secretion is independent of the RAAS, and plasma renin levels will be suppressed. This finding is in contrast with patients who have secondary hyperaldosteronism, in whom elevated renin levels are the cause of elevations in aldosterone secretion. There are subtypes of primary aldosteronism that differ in their therapy. Idiopathic hyperplasia and aldosterone-producing adenomas account for >95% of cases. Clinically, patients with idiopathic hyperplasia have less severe HTN and are less likely to be hypokalemic compared with patients with aldosterone-producing adenomas. Whereas both adrenal glands are responsible for increased aldosterone production in idiopathic hyperplasia, unilateral adrenalectomy is not therapeutic. Unilateral adrenal hyperplasia is distinctly uncommon but, when appropriately diagnosed, is potentially curable with adrenalectomy. In comparison with idiopathic hyperplasia, aldosterone-producing adenomas are associated with more profound HTN and hypokalemia ( Fig. 30.5 ).

Subtypes of primary aldosteronism.

(Modified from Young WF. Primary aldosteronism: renaissance of a syndrome. Clin Endocrinol [Oxf] 2007;66:607-618.)

Familial hyperaldosteronism (FH) type I, also called glucocorticoid-remediable aldosteronism, is autosomal dominant and is manifested by aldosterone being secreted to the circadian rhythm of ACTH instead of the RAAS. Patients often have early-onset severe HTN or cerebral vascular accidents and/or a family history of HTN.

Type II is autosomal dominant and presents with either hyperplasia or adenomas indistinct from the sporadic type of hyperaldosteronism. FH type III is characterized by bilateral adrenal hyperplasia, refractory HTN, severe hypokalemia, and the overproduction of hybrid steroids. Genetic testing for types I and III is recommended ( Box 30.1 ).

Clinical characteristics

Virtually all patients present with refractory HTN. Hypokalemia is classically a hallmark of the disease but may only be present 10%–50% of the time. Cardiac and renal disease may be present because of the HTN. Stroke, atrial fibrillation, cardiac events, proteinuria, and renal failure are all increased in hyperaldosteronism.

Screening

Hypokalemia needs correction and significant medications discontinued prior to screening the patient ( Fig. 30.6 ). Alpha or calcium channel blockers should be employed as first line to treat HTN. Patients should be encouraged to take sodium and avoid licorice and chewing tobacco. Obtain a morning (between 8–10 am ) plasma aldosterone concentration (PAC) and pra . From these, the PAC and aldosterone-to-renin ratio (ARR) can determine autonomous aldosterone secretion. PAC >20 ng/dL and PRA below the detection level are abnormal. All patients suspected of primary hyperaldosteronism should get cross-sectional imaging. Hyperaldosteronomas are typically unilateral, low-density, nonenhancing lesion <10 Hounsfield units (HU), with an average size of 1.6–1.8 cm and a normal-appearing contralateral adrenal gland.

Primary aldosteronism diagnosis and treatment algorithm. CT, Computed tomography; FH, familial hyperaldosteronism; PA, primary aldosteronism; PAC, plasma aldosterone concentration; PRA, plasma renin activity.

Confirmatory testing

If there is HTN, hypokalemia, PRA below detection and PAC >20 ng/dL, no confirmatory testing is needed. The flurocortisone suppression test involves 0.1 mg every 6 hours in addition to NaCl 2 g every 8 hours, both for 4 days. PAC is measured in the upright position. Failure to suppress PAC to less than 6 ng/dL is diagnostic of primary aldosteronism.

The oral sodium loading test is conducted by administering a high-sodium diet and NaCl for 3 days followed by 24-hour urine measurements of aldosterone, sodium, and creatinine. The diagnosis of primary aldosteronism is made when the 24-hour aldosterone is >12 μg/day.

The intravenous (IV) saline infusion test spares the patient from several days of sodium loading by the administration of 2 L of 0.9% sodium chloride intravenously over 4 hours. The infusion is performed in the morning after an overnight fast while the patient is in a recumbent position. After the IV infusion of saline, PAC is measured; a level >5 ng/dL is diagnostic of primary aldosteronism, and levels >10 ng/dL are suggestive of aldosterone-producing adenomas.

Adrenal vein sampling (AVS) can be useful. Proper patient preparation is essential and includes 1 hour of recumbency, correction of hypokalemia, and discontinuation of antihypertensive agents. AVS is performed in the morning after an overnight fast. Percutaneous samples are collected from three sites: right adrenal vein, left adrenal vein, and IVC. Aldosterone and the cortisol concentrations are determined. Appropriate specimen collection from the adrenal vein is determined by comparing the cortisol concentrations from the adrenal vein with the cortisol concentration from the IVC. The ratio of adrenal vein to IVC cortisol should be >1.1−5 : 1, depending on the use of cosyntropin stimulation. If cosyntropin stimulation is used, a higher ratio is expected in properly collected samples. AVS that demonstrates adrenal vein–to–IVC ratios below the cutoff, on either side, should be considered “nonselective” and discarded. An adrenal vein–to–IVC ratio above the cutoff, bilaterally, is considered “selective,” and comparisons between aldosterone concentrations can be made to determine the presence of lateralization.

Treatment and prognosis

When total or partial adrenalectomy is feasible, this is the procedure of choice. The majority undergoing adrenalectomy will have improvement in HTN, and most will discontinue some or all medications, a significant portion will have no change in blood pressure. Potassium is corrected in the vast majority of patients.

Medical therapy is successful at normalizing both HTN and potassium and consists of aldosterone receptor agonists spironolactone and eplerenone. Spironolactone is initiated at doses of 25–50 mg/day and can be titrated up to 400 mg/day, depending on blood pressure, serum potassium levels, and side effects. Side effects include gynecomastia, impotence, and menstrual disturbances. Eplerenone is better tolerated because of increased selectivity for the aldosterone receptor. Treatment should be initiated with 25 mg/day and titrated up to 100 mg/day ( Table 30.1 ).

Table 30.1

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