The two adrenals (suprarenal glands) are located on top of each kidney. Each gland can be divided histologically and biochemically into two major subglands:
– The adrenal cortex
–The adrenal medulla
The adrenal medulla is a modified autonomic ganglion synthesizing mainly epinephrine and some norepinephrine. The adrenal cortex has three zones, each of which synthesizes a specific steroid hormone or hormones (Fig. 27.1).
Fig. 27.1 
Adrenal gland.
Secretion of hormones from the adrenal cortex is under hypothalamic and pituitary control. The adrenal medulla is stimulated to release catecholamines by activation of the sympathetic nervous system. Both controlling mechanisms are activated by stress. Hyperkalemia and angiotensin II stimulate the release of aldosterone. Adrenocortical hormones cause feedback inhibition of their upstream regulatory hormones. Cortisol also acts in a paracrine fashion to stimulate catecholamine release. Epinephrine and norepinephrine act on the pituitary to stimulate the release of adrenocorticotropic hormone (ACTH). (CRH, corticotropin-releasing hormone)
Embryology of the adrenal gland
The adrenal cortex, which comprises 80% of the gland, is derived from mesothelium; whereas the adrenal medulla (20%) is derived from neural crest cells. The sympathetic nervous system is also derived from neural crest cells, which explains the link between this system and the adrenal medulla and their common functionality.
Hypothalamic-Anterior Pituitary Control of Adrenocortical Hormones
Corticotropin-releasing hormone (CRH) secreted from the hypothalamus acts on the anterior pituitary to synthesize pro-opiomelanocortin (POMC), which is the precursor of adrenocorticotropic hormone (ACTH). ACTH secreted from the anterior pituitary activates cholesterol desmolase in the adrenal cortex. This stimulates the conversion of cholesterol to pregnenolone, which is the precursor of all adrenocortical hormones.
The cascade showing the synthesis of all of the adrenocortical and androgen hormones from cholesterol is shown in Fig. 27.2.
Fig. 27.2 Synthesis of mineralocorticoids, glucocorticoids, and androgens.
(ACTH, adrenocorticotropic hormone)
27.1 Adrenocortical Hormones
Aldosterone
Synthesis
The synthesis of aldosterone is shown in Fig. 27.2 (red box).
Regulation of Secretion
Aldosterone secretion is mainly regulated by the renin–angiotensin system (RAS) and by serum [K+]. ACTH maintains tonic control.
– Renin is an enzyme produced by juxtaglomerular (JG) cells of the afferent arteriole of the kidney. It is released when blood pressure (BP) is reduced in the renal artery, usually due to a decrease in circulating blood volume (hypovolemia). It is also released in response to sympathetic nervous system activation or decreased NaCl load at the macula densa. Renin cleaves angiotensinogen to angiotensin I; angiotensin I is acted upon by angiotensin-converting enzyme (ACE) to form angiotensin II. Angiotensin II increases the conversion of corticosterone to aldosterone, which increases the renal reabsorption of Na+ and water, thus restoring blood volume to normal (Fig. 27.3).
Fig. 27.3 Renin–angiotensin−aldosterone system.
The renin–angiotensin−aldosterone system regulates sodium balance, fluid volume, and blood pressure (BP). Renin is released by the kidneys in response to reduced perfusion (due to decreased plasma volume and BP). Renin then stimulates angiotensinogen to convert angiotensin I to angiotensin II in the lungs. Angiotensin II causes vasoconstriction and stimulates the secretion of aldosterone from the adrenal cortex. Aldosterone causes sodium (and water) reabsorption, thus increasing fluid volume, BP, and renal perfusion. Angiotensin II and aldosterone cause feedback inhibition of renin secretion. Renin is also inhibited by normalization of renal perfusion. (GFR, glomerular filtration rate; RBF, renal blood flow)
– Hyperkalemia causes increased aldosterone production, which increases the renal excretion of K+.
Table 27.1 summarizes the factors that stimulate and inhibit aldosterone secretion.
Atrial natriuretic peptide
Atrial natriuretic peptide (ANP) is a 27 amino acid peptide secreted by atrial myocytes. It is involved in the long-term homeostasis of sodium and water, BP, and arterial pressure. It is secreted in response to atrial distention, sympathetic stimulation of β receptors, hypernatremia (indirect effect), angiotensin II, and endothelin secretion (a vasoconstrictor). It acts by two mechanisms. First, it causes direct vasodilation of vascular smooth muscle. This decreases cardiac output by increasing venous capacitance, which decreases preload, and by decreasing peripheral resistance, which decreases afterload. Second, ANP acts on the kidney to inhibit renin secretion and the reabsorption of sodium. Overall, ANP provides counter-regulation to the renin–angiotensin−aldosterone system.
α1 Blockers and renin release
Alpha1 blockers (e.g., prazosin, terazosin, and doxazosin) act selectively on the post-synaptic α1 receptor of vascular smooth muscle, causing vasodilation and lowering total peripheral resistance. They are used in the treatment of hypertension or heart failure. However, their effects will cause counter-regulatory activation of the renin–angiotensin−aldosterone system (unwanted); thus, they are often combined with ACE inhibitors or β blockers. Orthostatic (postural) hypotension is common with the first dose.
Angiotensin-converting enzyme inhibitors
ACE inhibitors (e.g., captopril, enalapril, and lisinopril) prevent the activation of angiotensin I to angiotensin II in the lung by inhibiting ACE. In doing so, they prevent the direct vasoconstrictive effects of angiotensin II on blood vessels, causing decreased peripheral vascular resistance and decreased sympathetic tone. They also prevent aldosterone release from the adrenal cortex, which prevents sodium and water reabsorption, thus decreasing preload. ACE inhibitors prevent the degradation of bradykinin (ACE also acts as a kininase). Bradykinin is a vasodilator, and increasing its level may contribute to the effect of ACE inhibitors. These drugs provide symptomatic improvement and reduce mortality in hypertension and heart failure. Common side effects include a persistent cough, hyperkalemia, firstdose hypotension, and taste disturbances.
Actions
Aldosterone acts on the distal tubule and collecting duct of the kidney to regulate BP and blood volume via the following mechanisms:
– ↑Na+ (and water) reabsorption
– ↑K+ secretion
– ↑H+ secretion
Fig. 27.4 summarizes the secretion, effects, and degradation of aldosterone.
Fig. 27.4 Secretion, effects, and degradation of aldosterone.
Aldosterone is secreted by the zona glomerulosa of the adrenal cortex partly in response to stimulation by ACTH from the anterior pituitary. Aldosterone secretion increases mainly in response to drops in BP and blood volume (mediated by angiotensin II) and by hyperkalemia. Aldosterone leads to retention of Na+, a moderate increase in H+ secretion, and increased K+ excretion. It also increases the number of Na+−K+−ATPase molecules in the target cells. Aldosterone is degraded by glucuronidation in the liver and excreted into bile and feces. (GFR, glomerular filtration rate; RBF, renal blood flow)
Pathophysiology
Aldosterone deficiency. Aldosterone deficiency may be a part of overall adrenocortical insufficiency (Addison disease), which is discussed on page 275. It is a major problem due to loss of Na+ and retention of K+.
Aldosterone excess. Primary aldosteronism and secondary aldosteronism are summarized in Tables 27.2 and 27.3. respectively.
Cortisol
Synthesis
The synthesis of cortisol is shown in Fig. 27.2 (yellow box).
Regulation of secretion
Negative-feedback control: When cortisol decreases, CRH and ACTH increase, producing cortisol release. An increase in cortisol decreases CRH and ACTH concentrations (Figs. 27.1 and 27.5).
Cortisol levels follow a circadian rhythm of secretion, with a peak in its concentration occurring just after awakening in the morning (Fig. 27.6).
Fig. 27.5 Regulation of cortisol and epinephrine concentrations in plasma.
The hypothalamus is stimulated to release corticotropin-releasing hormone (CRH) by the limbic system. This then causes the downstream release of adrenocorticotropic hormone (ACTH) from the anterior pituitary and cortisol release from the adrenal cortex. Cortisol may, in turn, stimulate the release of epinephrine and norepinephrine from the adrenal medulla. Autonomic centers in the medulla may also directly stimulate the adrenal medulla to produce epinephrine and norepinephrine via postganglionic sympathetic nerves. Epinephrine and norepinephrine may positively feed back on the anterior pituitary to stimulate the release of ACTH and thus amplify the original signal. Cortisol negatively feeds back on the limbic system, hypothalamus, and anterior pituitary. ACTH may also negatively feed back on the hypothalamus. This allows the original signal to be inhibited when plasma levels of ACTH or cortisol become too high. (ADH, antidiuretic hormone)
Fig. 27.6 Circadian rhythm of adrenocorticotropic hormone (ACTH) and cortisol secretion.
Peak plasma cortisol concentration is observed at ~8:00 a.m., and the lowest concentration is at ~8:00 p.m. There are fluctuations around the mean concentration, with some secondary peaks occurring throughout the day. The rhythm for release of ACTH is similar to that for cortisol. (CRH, corticotropin-releasing hormone; ADH, antidiuretic hormone)
Dosing regimen of glucocorticoid drugs
The dosing regimen of glucocorticoid drugs can minimize adrenocortical atrophy, e.g., if they are given when normal cortical secretion is high, and feedback inhibition is low (late morning), the glucocorticoid drug is eliminated during daytime, and normal endogenous cortisol production starts early the following morning.
Actions
Cortisol coordinates the body’s response to stress and is essential for life. It regulates the expression of a large number of genes, enzymes, and proteins and is generally considered “permissive,” allowing the actions of other hormones.
The actions of cortisol are summarized in Table 27.4. These actions may also be elicited by synthetic glucocorticoids.
The respiratory burst
The respiratory burst is the rapid release of reactive oxygen species (superoxide radical and hydrogen peroxide) from phagocytes (neutrophils and monocytes) when a microbe is encountered and phagocytosed. It is one of the mechanisms by which phagocytes exert their microbicidal effects and is an important immune defense. The reactive oxygen species are generated by the partial reduction of oxygen in the respiratory chain (electron transport chain). They combine with Cl− to form hypochlorous acid, which dissociates to form hypochlorite ions, which kill the microbes. Cortisol (and exogenous corticosteroids) inhibits the respiratory burst and so may predispose an individual to infection.
Perinatal role of cortisol
The most important perinatal role of cortisol is its effects on lung maturation. It is essential for production of lung surfactant, development of the alveoli, flattening of the lining cells, and thinning of the lung septa. Cortisol is also essential for the maturation of digestive enzyme capacity of the intestinal mucosa. This permits the neonate to utilize disaccharides present in milk.
Stress and the hypothalamic-pituitary-adrenocortical axis
The hypothalamic-pituitary-adrenocortical (HPA) axis and the sympathetic nervous system are involved in maintaining homeostasis in response to physiological or psychological stress. Sympathetic (catecholaminergic) mechanisms provide short-term, rapid changes in response to perturbations in homeostasis, whereas the HPA axis (via elevations in cortisol) provides a longer-term mechanism that allows continued resistance to homeostatic perturbations. The major physiological stressors are hypoglycemia, hypotension, hypovolemia, hypo- or hyperthermia, and pain. Psychological stressors are more difficult to identify but may include novel environments (change), unpredictability of situation, conflict, sleep deprivation, and psychological “pressure.” The magnitude of the HPA response is determined by past experience or exposure (coping or adapting) to these stressors. Many of the actions of glucocorticoids (especially at high levels) are damaging, so prolonged exposure to stressors can cause an emergence of stress-related disease. Under “normal” regulation, cortisol provides negative feedback, which rapidly terminates HPA axis activation following exposure to a stressor, but chronic or repeated exposure to a stressor dampens cortisol negative feedback, allowing “hypersecretion” of cortisol at basal levels and following acute stress. Activation of the HPA axis in stress may also alter the pulsa-tile and episodic release of other hormones (via disruption of circadian rhythms) and may disrupt feedback inhibition.
Inactivation
Cortisol can be inactivated by conversion to cortisone, an inactive metabolite of cortisol, by the enzyme 11-β-hydroxysteroid dehydrogenase (11-β-HSD). This enzyme is expressed by miner-alocorticoid receptor (MR)−responsive cells in the kidney.
Uses of Exogenous Corticosteroids (e.g., hydrocortisone)
– Endocrine uses:
– Adrenocortical insufficiency (Addison disease)
– Congenital adrenal hyperplasia (to suppress ACTH release)
– Nonendocrine uses:
–Rheumatoid arthritis
–Leukemia
–Lymphoma
–Allergic reactions
–Asthma
–Inflammatory and autoimmune disorders
–Immunosuppression for transplantation
–Collagen disorders
–Cerebral edema
–Bacterial meningitis
Pathophysiology
Adrenocortical insufficiency. Adrenocortical insufficiency, or Addison disease, is summarized in Table 27.5.
Acute adrenal crisis (Addisonian crisis)
Acute adrenal crisis (addisonian crisis) is due to acute insufficiency of adrenal steroids, mainly cortisol. It usually occurs in people with known Addison disease who undergo some form of stress, such as surgery, trauma, or infection, but it may also occur when someone on long-term steroids abruptly stops them or forgets to take their medication. The main sign of acute adrenal crisis is shock (hypotension, tachycardia, and oliguria), but there may also be acute abdominal pain, diarrhea, vomiting, hypoglycemia, fever, weakness, and confusion. It may progress to seizures, coma, and death if untreated. If there is a high index of suspicion for acute adrenal crisis, treatment should begin before any laboratory results are in. Treatment involves giving intravenous (IV) fluids, IV hydrocortisone, antibiotics, and IV glucose if necessary. In the longer term, the patient can be switched to oral steroids, and the precipitating factor should be treated.
Perioperative steroid coverage
Patients who have been on long-term steroids or who have stopped steroids in the last few months will have some adrenal suppression (due to feedback inhibition of ACTH secretion by exogenous steroids). Consequently, the perioperative administration of steroids prior to undergoing the stress of surgery is necessary to prevent adrenal crisis (addisonian crisis), the major effect of which is shock.
Adrenocortical excess. Adrenocortical excess, or Cushing syndrome, is summarized in Table 27.6. Note that Cushing disease is adrenocortical excess that is caused by an ACTH- secreting tumor.
Congenital virilizing adrenal hyperplasia
Congenital virilizing adrenal hyperplasia (adrenogenital syndrome) is a deficiency of both aldosterone and cortisol biosynthesis. It is associated with a defect in adrenal steroidogenesis, most commonly with 21-hydroxylase, but defects with 3-β-hydrox-ysteroid dehydrogenase (3-β-HSD) may also occur. When these enzymes are not expressed or nonfunctional, then steroido-genesis proceeds through androgen formation in all zones of the cortex, but there is little or no synthesis of cortisol and aldosterone. Because cortisol is not being synthesized, there is no feedback on the HPA axis, leading to hypersecretion of ACTH. The high levels of ACTH induce adrenocortical hyperplasia, which augments the already elevated androgen production. The individual appears “masculinized” or virilized (male secondary features), allowing the disease to be diagnosed more easily in female neonates than male neonates, in whom it is typically missed. Treatment involves replacement of the deficient hormones.
Role of cortisol in fasting states
Cortisol is essential for survival during fasting states because of its proteolytic effects. During fasting, liver glycogen stores quickly become depleted. Gluconeogenesis continues using amino acids (from protein catabolism) in the presence of cortisol. However, if cortisol is deficient, death from hypoglycemia occurs. Plasma levels of cortisol during fasting are only slightly to moderately elevated (usually relative to the degree of initial hypoglycemia), but this elevation of cortisol is sufficient because cortisol has a permissive effect on key metabolic enzymes. During fasting, the body also breaks down adipose tissue into glycerol and fatty acids. Glycerol can then be converted to glucose in the liver. Cortisol enhances this lipolysis.
Androgens
Synthesis
The synthesis of androgens is shown in Fig. 27.2 (blue and purple boxes).
27.2 Adrenal Medullary Hormones
Epinephrine (and norepinephrine)
The adrenal medulla is a modified sympathetic ganglion. It is innervated by preganglionic sympathetic axons that stimulate the release of two catecholamines:
– Epinephrine (80%)
– Norepinephrine (20%)
Fig. 27.7 
Biosynthesis of catecholamines.
Note: Most norepinephrine released in the body comes from sympathetic ganglia rather than the chromaffin cells of the adrenal medulla.
Synthesis
The synthesis of epinephrine and norepinephrine is shown in Fig. 27.7. The conversion of tyrosine to dihydroxyphenylalanine (Dopa) by the enzyme tyrosine hydroxylase is the rate-limiting step and is well regulated.
Mechanism of Norepinephrine Secretion
Acetylcholine, released from preganglionic sympathetic neurons, reacts with nicotinic receptors on chromaffin cells in the adrenal medulla, causing increased Na+ and Ca2+ permeability. Increased cytosolic Ca2+ moves granules to the membrane and causes exocytosis of norepinephrine.
Regulation of Secretion
The secretion of epinephrine and norepinephrine is controlled by the sympathetic nervous system, the HPA axis (via cortisol), and feedback inhibition of enzymes caused by high levels of norepinephrine.
– Acutely high levels of norepinephrine stimulate the release of tyrosine hydroxylase.
– Chronically elevated norepinephrine stimulates the release of tyrosine hydroxylase and dopamine hydroxylase, as well as PNMT (via cortisol).
Refer to Figs. 27.1 and 27.5.
Actions
Epinephrine mobilizes energy for “fight or flight.” Its principal actions are summarized in Table 27.7, but these are covered in detail in Chapter 4 on the autonomic nervous system.
Inactivation
The half-life of catecholamines is only 1 to 2 minutes in the circulation. Catecholamines are largely inactivated by catechol-O-methyltransferase (COMT) in the liver, or they may be deaminated by monoamine oxidase (MAO) within nerve terminals.
Pathophysiology
Epinephrine and norepinephrine. An excess of epinephrine and norepinephrine results from an adrenal tumor known as a pheochromocytoma (see Table 27.8).
