The adrenal glands consist of two functionally distinct parts: the adrenal cortex, which secretes steroids, and the adrenal medulla, which secretes catecholamines.
Structure of the Adrenal Glands
Each kidney has an adrenal gland located above its upper pole. An adrenal gland consists of two distinct parts: an outer cortex and an inner medulla. The adrenal cortex secretes steroid hormones from three distinct zones (Figure 8-19):
The glomerulosa layer is the outermost zone and secretes aldosterone.
The fasciculata layer is the middle zone and secretes cortisol and androgens.
The reticularis layer is the inner zone and continues from the fasciculata layer to the corticomedullary boundary. The reticularis layer secretes cortisol and androgens.
The adrenal gland. The adrenal cortex and the adrenal medulla are distinct structures visible in a cross-section of the adrenal gland. The adrenal cortex has three cellular layers, the zona glomerulosa, the zona fasciculata, and the zona reticularis. The adrenal medulla is composed of chromaffin cells, which receive a rich preganglionic sympathetic innervation and a portal blood supply from the adrenal cortex.
The adrenal medulla is distinct from the adrenal cortex and consists of chromaffin cells, which are embryologically derived from the neuronal precursor (neural crest) cells. The adrenal medulla is richly innervated by preganglionic sympathetic neurons, which release acetylcholine as their neurotransmitter. Chromaffin cells are the functional equivalent of the postganglionic neurons of the sympathetic nervous system (see Chapter 2). Chromaffin cells mainly secrete epinephrine plus a small amount of norepinephrine in response to preganglionic stimulation. The chromaffin cells receive high concentrations of adrenal steroids because the adrenal medulla receives a direct portal venous blood supply from the adrenal cortex (Figure 8-20). High concentrations of cortisol stimulate epinephrine synthesis, which aids in the coordination of the stress response. In fact, significant cortisol deficiency, such as occurs in an Addisonian crisis, can result in potentially fatal hypotension due to the loss of catecholamine potentiation from cortisol.
Synthesis of adrenocortical steroids.
Synthesis and Secretion of Adrenocortical Hormones
The three functional categories of steroid hormone are:
Mineralocorticoids (aldosterone) regulate electrolyte balance in several organs, particularly the kidney.
Glucocorticoids (cortisol), so named because one of their several functions is to increase the blood glucose concentration.
Sex steroids (androgens, estrogens, and progestins) are found only in the adrenal gland and produce the weak androgens androstenedione and dehydroepiandrosterone (DHEA).
Steroid synthesis begins with cholesterol. All steroid-producing tissues, with the exception of the placenta, can synthesize cholesterol from acetate. However, circulating cholesterol, derived from low-density lipoproteins, is usually needed to produce adequate amounts of steroid hormone. The rate-limiting step in steroid synthesis is conversion of cholesterol to pregnenolone, which occurs in mitochondria via the side-chain cleavage enzyme (also called cholesterol 20, 22 desmolase).
The identity of the final steroid hormone that is synthesized depends on which other enzymes are expressed in a given steroid-producing cell (see Figure 8-20). In the adrenal cortex, the following primary steroid products are produced:
Aldosterone is only produced in the glomerulosa cells because these cells are the only ones that express the enzyme aldosterone synthase.
Cortisol is produced by the fasciculata and reticularis cells because these cells are the primary source of the required enzyme 17 α-hydroxylase.
Weak androgens are the sex steroids produced by the adrenal glands because the cells lack the enzymes needed to produce testosterone and estrogens. Progesterone is produced as an intermediate but is used in the synthesis of cortisol and aldosterone rather than being secreted by the adrenal gland.
Cortisol affects many cell types due to the wide expression of glucocorticoid receptors. Free cortisol molecules diffuse into the target cells and bind to the cytoplasmic glucocorticoid receptors. The activated receptors enter the nucleus and alter gene expression via interactions with the glucocorticoid response elements found on DNA. Less than 5% of plasma cortisol is free to diffuse into the target cells, with about 90% bound to the corticosteroid-binding protein (transcortin) and a further 5% bound to albumin.
Cortisol is secreted in response to virtually all forms of stress, including trauma, infection, illness, temperature change, and mental stress; in the absence of cortisol, even minor illnesses can be fatal. Cortisol mobilizes glucose, amino acids, and fatty acids, and resists inflammatory and immune responses. The “glucocorticoid” action of cortisol (to increase blood glucose) occurs by several mechanisms, including stimulation of hepatic gluconeogenesis, mobilization of amino acids from muscle cells, reduced cellular metabolism of glucose, and reduced sensitivity to insulin (see Endocrine Pancreas).
Synthetic corticosteroids (e.g., prednisone and dexamethasone) exhibit different levels of glucocorticoid and mineralocorticoid activity. Corticosteroids with stronger anti-inflammatory and immunosuppressant (glucocorticoid) effects are widely used in an attempt to control chronic inflammatory conditions such as arthritis, chronic obstructive pulmonary disease, and inflammatory bowel disease. In adrenal insufficiency, corticosteroids are used to replace the cortisol (glucocorticoid) and aldosterone (mineralocorticoid). Table 8-3 compares the estimated relative glucocorticoid and mineralocorticoid potencies of several commonly used corticosteroids.
Table 8-3Estimated Relative Potencies of Common Corticosteroids ||Download (.pdf) Table 8-3Estimated Relative Potencies of Common Corticosteroids
Control of Cortisol Secretion
The hypothalamic-pituitary-adrenal axis describes a cascade of hormones that begins with hypothalamic CRH stimulating the release of ACTH from the anterior pituitary, which in turn stimulates cortisol release from the adrenal cortex. Cortisol exerts negative feedback control over its own production by suppressing the secretion of both CRH and ACTH (Figure 8-21A).
Cortisol secretion. A. Hierarchical negative feedback control operates via the hypothalamic-pituitary-adrenal axis. B. Cortisol secretion is driven by pulsatile adrenocorticotropic hormone (ACTH) secretion and has a circadian rhythm, with the greatest secretion in the early morning. ACTH secretion is driven by corticotropin-releasing hormone (CRH) from the hypothalamus. Other peaks of cortisol concentration occur in response to stress, when higher parts of the central nervous system drive greater CRH secretion.
Cortisol secretion has a circadian variation, with hormone levels highest in the early morning hours and lower during late afternoon and evening. The circadian rhythm of cortisol helps the body in becoming active and alert in the morning and in reducing activity prior to sleep. Variations in cortisol secretion reflect the pulsatile release of CRH and ACTH (see Figure 8-21B). In addition to the circadian rhythm inherent in the CRH-ACTH-cortisol axis, the secretion of CRH is under the control of higher brain centers, demonstrated by peaks of CRH (and ACTH) release in response to stress.
Synthesis and Actions of ACTH
Anterior pituitary corticotropes synthesize ACTH by the posttranslational processing of a large precursor protein called pro-opiomelanocortin (POMC). Several other peptide hormones of uncertain physiologic importance are generated from POMC, including β-lipotropin, β-endorphin, and melanocyte-stimulating hormone (MSH) (Figure 8-22). The administration of large doses of MSH stimulates the production of the dark skin pigment melanin, by melanocytes in skin; thus the name MSH.
Processing of pro-opiomelanocortin (POMC) to produce various peptide hormones. ACTH, adrenocorticotropic hormone; MSH, melanocyte-stimulating hormone.
The primary action of ACTH is stimulation of cortisol secretion from the adrenal cortex, although receptors for ACTH are present in all three cortical cell layers. Cortisol secretion is only stimulated in the fasciculata and reticularis layers because these are the sites of 17 α -hydroxylase expression. Aldosterone secretion is primarily controlled by angiotensin II (see Renin-angiotensin System) and is only weakly stimulated by ACTH.
Excess ACTH can occur in many conditions, including as a result of an ACTH-secreting pituitary adenoma; as a paraneoplastic syndrome associated with small cell lung carcinoma; or from the lack of negative feedback inhibition in the setting of primary adrenocortical insufficiency. ACTH is a trophic hormone; an excess causes growth of the adrenal glands. Increased skin pigmentation is a characteristic of ACTH hypersecretion and is thought to be either due to higher levels of MSH secretion or due to ACTH acting as an agonist at the MSH receptor.
ACTH deficiency causes secondary failure of cortisol secretion and atrophy of the fasciculata and reticularis layers of the adrenal cortex. The glomerulosa cells are spared because they are also supported by a trophic effect from angiotensin II.
Aldosterone is required for the maintenance of normal extracellular fluid volume through the conservation of Na+. The main action of aldosterone is stimulation of Na+ reabsorption and K+ secretion at the distal renal tubule, although similar actions occur in other epithelia (e.g., distal colon, sweat glands, and salivary glands). The effect is to conserve Na+ in the extracellular fluid and promote K+ excretion. In the total absence of aldosterone, there is severe Na+ depletion and K+ retention; without treatment, the condition is fatal.
The effects of aldosterone are mediated via the mineralocorticoid receptor. Cells that express mineralocorticoid receptors also express the enzyme 11 β-hydroxysteroid dehydrogenase, which deactivates cortisol through its conversion to cortisone. This is necessary to prevent cortisol from acting as an agonist at the mineralocorticoid receptor (Figure 8-23). Fluid retention is a side effect of excess cortisol production or of therapy with glucocorticoid drugs because the amount of substrate overwhelms the level of endogenous 11 β-hydroxysteroid dehydrogenase activity.
Metabolism of glucocorticoids by the enzyme 11β-hydroxysteroid dehydrogenase (HSD) in the mineralocorticoid target cells.
Licorice inhibits the activity of 11β-hydroxysteroid dehydrogenase, which allows cortisol to bind to the mineralocorticoid receptors and to activate them. The resulting excess mineralocorticoid activity causes hypertension, hypokalemia, and metabolic alkalosis.
Control of Aldosterone Secretion
The renin-angiotensin system is the most important stimulus for aldosterone secretion. Renin is secreted from the granular juxtaglomerular cells of the renal juxtaglomerular apparatus in response to low effective circulating blood volume. The stimulus for renin release is provided by three mechanisms acting together:
Reduced distension of the renal afferent arteriole.
Tubuloglomerular feedback signaling due to the low glomerular filtration rate and the low renal tubular fluid flow (see Chapter 6).
Stimulation of the renal sympathetic nerves due to activation of the baroreceptor reflex by decreased blood pressure (see Chapter 4).
The secretion of renin results in an increase in plasma angiotensin II and aldosterone concentrations as follows (Figure 8-24):
Renin acts on the circulating precursor protein angiotensinogen, which is produced by the liver. Angiotensinogen is cleaved by renin to the inactive decapeptide angiotensin I.
Angiotensin I is cleaved to produce the octapeptide angiotensin II by the action of angiotensin-converting enzyme (ACE). ACE is present on the vascular endothelial cells, with about 50% of ACE activity localized in the lung.
Angiotensin II binds to its AT1 receptor in the adrenal cortical glomerulosa cells, which stimulates aldosterone secretion.
The renin-angiotensin-aldosterone system. Steps 1–3 are fully described in the text. (1) Renin cleaves circulating angiotensinogen to produce angiotensin I; (2) angiotensin-converting enzyme (ACE) converts angiotensin I to angiotensin II; (3) angiotensin II stimulates aldosterone secretion from the adrenal cortex.
The combined responses of angiotensin II and aldosterone result in the restoration of the normal effective circulating volume; for example, through increased Na+ and water retention in the kidney (see Chapter 6). This completes a cycle of negative feedback, removing the stimulus for further renin secretion.
An increase in plasma [K+] is a secondary stimulus for aldosterone secretion and works directly through depolarization of the glomerulosa cell membrane potential. A negative feedback cycle occurs in which increased aldosterone secretion results in increased urinary K+ excretion, which decreases plasma [K+] and removes stimulation of aldosterone secretion.
ACTH is a very weak stimulus for aldosterone secretion; aldosterone does not exert any negative feedback control over ACTH secretion.
Disorders of the Adrenal Cortex
Most cases of adrenocortical insufficiency (Addison's disease) are due to primary failure of the entire adrenal cortex rather than to secondary or tertiary causes. One of the most common causes of primary failure is autoimmune adrenalitis.
The following major signs and symptoms of adrenocortical insufficiency result from the loss of cortisol and aldosterone:
Cortisol deficiency causes hypoglycemia between meals, due to low rates of hepatic gluconeogenesis, and hypotension, as a result of the lack of potentiation of catecholamines. Patients typically experience weakness and fatigue. They may become severely debilitated by the inability to produce cortisol in response to stress, and are then described as being in Addisonian crisis.
Aldosterone deficiency results in hypovolemia and hyponatremia as a result of urinary losses of NaCl and water. Hyperkalemia and metabolic acidosis result from reduced urinary excretion of K+ and H+.
In primary adrenal insufficiency, lack of negative feedback results in high levels of ACTH and a characteristic increase in skin pigmentation (Figure 8-25).
Deficiency of adrenal androgens in females is likely to result in reduced libido and thinning of the pubic hair. These effects do not occur in males due to secretion of the gonadal androgens (see Chapter 9, Male Reproductive Physiology).
Characteristic features of a patient with chronic primary adrenocortical insufficiency (Addison's disease).
Chronic systemic glucocorticoid therapy, such as that used in the treatment of rheumatologic conditions (e.g., rheumatoid arthritis) or chronic inflammation, can suppress the hypothalamic-pituitary-adrenal axis through feedback inhibition. Adrenal insufficiency may occur if treatment is abruptly stopped. To avoid adrenal insufficiency, the steroid dose can be slowly tapered down, allowing time for the hypothalamic-pituitary-adrenal axis to become active again. When concerned about adrenal insufficiency in the acutely ill patient, the hypothalamic-pituitary-adrenal axis can be quickly tested using the ACTH stimulation test. After administration of an ACTH analogue (e.g., cosyntropin), the serum cortisol levels should increase appropriately; failure to do so indicates adrenocortical insufficiency.
Hypercortisolism, or Cushing's syndrome, is characterized by the following signs and symptoms, which result from an excess of glucocorticoids (Figure 8-26):
Hyperglycemia is due to enhanced gluconeogenesis.
Muscle wasting and weakness are due to protein catabolism.
Truncal obesity and a characteristic rounding of the face called moon face are caused by redistribution of body fat.
Hypertension is common due to the mineralocorticoid effects of excess glucocorticoids.
Characteristic features of a patient with Cushing's syndrome.
Cushing's syndrome is caused by endogenous or exogenous sources such as use of glucocorticoid therapy. Cushing's syndrome is classified as primary, secondary, and tertiary. The different patterns of plasma cortisol and ACTH concentration in these disorders are summarized in Table 8-4 and as follows:
Primary hypercortisolism may be due to an adenoma of the adrenal cortex.
Secondary hypercortisolism is due to excess ACTH and may result from a pituitary adenoma; it is specifically called Cushing's disease. Secondary hypercortisolism can also result from an ectopic source of ACTH secretion (e.g., small cell lung carcinoma).
Tertiary hypercortisolism results from excess CRH.
Synthetic glucocorticoids (e.g., used in the chronic treatment of rheumatoid arthritis).
Table 8-4Levels of Cortisol and Adrenocorticotropic Hormone (ACTH) in Cushing's Syndrome ||Download (.pdf) Table 8-4Levels of Cortisol and Adrenocorticotropic Hormone (ACTH) in Cushing's Syndrome
|Disorder ||Endogenous Cortisol Levels ||ACTH Levels |
|Primary hypercortisolism (e.g., adrenal adenoma) ||↑ ||↓ |
|Secondary hypercortisolism (e.g., Cushing's disease) ||↑ ||↑ |
|Tertiary hypercortisolism ||↑ ||↑ |
|Exogenous glucocorticoid treatment ||↓ ||↓ |
Exogenous use of glucocorticoids is the most common cause of Cushing's syndrome. However, an ACTH-secreting pituitary adenoma (Cushing's disease) is the most common endogenous cause.
The signs and symptoms of hyperaldosteronism arise from the effects of excessive mineralocorticoids. Conn's syndrome is also known as primary hyperaldosteronism and is the result of an aldosterone-producing adrenal adenoma. Symptoms include:
Hypertension due to excessive retention of Na+ and fluids by the kidney.
Hypokalemia due to increased urinary K+ excretion.
Metabolic alkalosis due to increased urinary H+ excretion.
Secondary hyperaldosteronism occurs in response to activation of the renin-angiotensin-aldosterone axis. Conditions that activate this axis are far more common than those causing primary hyperaldosteronism (Conn's syndrome). Examples of conditions that result in secondary hyperaldosteronism include renal artery stenosis, cirrhosis, and congestive heart failure.
In most disorders of the adrenal cortex, the clinical picture is dominated by the consequences of inappropriate levels of glucocorticoids and mineralocorticoids. The adrenal androgens have weak effects compared to the effects of testosterone produced by the male gonads. Therefore, an excess or a deficiency of the adrenal androgens has little impact on adult males. The effects of the adrenal androgens are more apparent in children and women since they do not secrete gonadal androgens. Tumors of the adrenal cortex can secrete an excess of adrenal androgens; children and adult females develop male secondary sex characteristics, and there is marked growth of the clitoris or the penis, called the adrenogenital syndrome.
Mutations of enzymes in the steroid biosynthetic pathway can occur, resulting in failure to manufacture a given hormone. In this event, there is an accumulation of the precursor steroids proximal to the enzyme defect in the synthetic pathway. The most common congenital error in adrenal steroid metabolism is 21 α-hydroxylase deficiency. Loss of 21 α -hydroxylase function causes the following complications (Figure 8-27):
Symptoms of primary adrenal insufficiency due to the inability to synthesize cortisol or aldosterone.
Massive accumulation of adrenal androgens, as steroid precursors are shunted along the androgen synthesis pathway.
Adrenal hyperplasia, due to high levels of ACTH caused by loss of negative feedback inhibition from cortisol.
Shunting of adrenal steroid synthesis toward androgen production in 21α-hydroxylase deficiency.
The clinical syndrome caused by 21α-hydroxylase deficiency is called virilizing congenital adrenal hyperplasia. This congenital defect is most readily apparent in female infants because the influence of androgens in utero produces ambiguous genitalia.
Synthesis and Secretion of Catecholamines
As a part of the stress response, the adrenal medulla secretes catecholamines in concert with activation of the sympathetic nervous system. The adrenal medulla synthesizes epinephrine and norepinephrine, which are derived from the amino acid tyrosine via a series of enzymatically controlled reactions (Figure 8-28). The rate limiting step is the production of L-dopa from tyrosine via the enzyme tyrosine hydroxylase. The final conversion from norepinephrine to epinephrine is catalyzed by phenylethanolamine-N-methyltransferase and only occurs in the chromaffin cells; in the sympathetic postganglionic neurons, the pathway ends with the production of norepinephrine. Epinephrine and norepinephrine are stored within the dense granules of the chromaffin cells in association with the binding protein chromogranin.
Catecholamine synthesis in the adrenal medulla. ACTH, adrenocorticotropic hormone.
The release of catecholamines by the adrenal medulla is controlled by the central nervous system (CNS) via the preganglionic sympathetic neurons. The neurotransmitter acetylcholine is released and acts at the nicotinic cholinergic receptors on the chromaffin cells. The steps in the catecholamine synthetic pathway from tyrosine to norepinephrine are stimulated by ACTH and by stimulation of the sympathetic nerves (Figure 8-28). Cortisol is delivered via the portal vessels directly from the adrenal cortex and stimulates the final enzyme in the pathway necessary for epinephrine secretion. Thus, the stress response sensed in the hypothalamic-pituitary-adrenocortical axis sustains epinephrine secretion by the adrenal medulla.
Actions of Circulating Catecholamines
The CNS-epinephrine axis complements the effects of the sympathetic nervous system (see Chapter 2). Responses in the target cells depend on the specific adrenergic receptor type that is expressed. There are five major receptor types:
The α1 receptors are coupled to the Gαq G proteins, which give rise to increased intracellular [Ca2+] in the target cells.
The α2 receptors suppress cAMP responses through coupling to Gαi.
The β1, β2, and β3 receptors all increase cAMP via Gαs.
The major endocrine product released by the adrenal medulla is epinephrine, whereas the major sympathetic neurotransmitter released is norepinephrine. Epinephrine has a similar binding affinity to norepinephrine at the α receptors but has greater affinity at the β1 and β2 receptors. Stress results in the enhanced secretion of catecholamines from the adrenal medulla and the secretion of cortisol from the adrenal cortex. Catecholamines coordinate a short-term response, which includes increased cardiac output, bronchodilation, and elevated blood glucose concentration (Table 8-5). Cortisol initiates a longer response, which includes the mobilization of glucose, fatty acids, and amino acids, and suppression of the immune system.
Table 8-5Selected Effector Organ Responses to Adrenal Medullary Hormones and Sympathetic Nerve Stimulation ||Download (.pdf) Table 8-5Selected Effector Organ Responses to Adrenal Medullary Hormones and Sympathetic Nerve Stimulation
|Organ ||Receptor Type ||Response |
|Heart || || |
|Sinoatrial node ||β1 ||Increased heart rate |
|Atrioventricular node and the His-Purkinje system ||β1 ||Increased conduction speed |
|Myocardium ||β1 ||Increased contractility |
|Vascular smooth muscle ||α1 ||Constriction in skin, abdominal viscera, and kidney |
| ||β2 ||Dilation in skeletal muscle |
|Bronchiolar smooth muscle ||β2 ||Relaxation |
|Gastrointestinal tract || || |
|Circular smooth muscle ||α2, β2 ||Reduced motility |
|Sphincters ||α1 ||Constriction |
|Secretion ||α2 ||Inhibition |
|Liver ||β2 ||Glycogenolysis and gluconeogenesis |
|Adipose tissue ||β1, β3 ||Lipolysis |
|Kidney ||β1 ||Renin secretion |
|Urinary bladder || || |
|Detrusor wall ||β2 ||Relaxation of bladder |
|Sphincter ||α1 ||Constriction |
|Male sex organs ||α1 ||Ejaculation |
Understanding the pharmacologic effects of adrenergic agonists and antagonists requires knowledge of the different adrenergic receptor types and their locations. For example, administering a β2 agonist, such as albuterol, a drug that is often used in the treatment of asthmatic episodes, will result in relaxation of the smooth muscle in the lung. A knowledge of adrenergic receptor types can also be helpful in predicting the potential side effects of a drug. For example, using a selective α1 antagonist such as prazosin in the setting of benign prostatic hyperplasia allows more complete bladder emptying by relaxing the urinary sphincter; however, as a result of blocking the α1 receptors on the blood vessels, prazosin can also cause postural hypotension or reflex tachycardia.
Inactivation of Circulating Catecholamines
Circulating catecholamines are rapidly broken down by a series of enzymatic reactions, as illustrated in Figure 8-29. Endothelial cells in the heart, liver, and kidney express the enzyme catecholamine-O-methyltransferase (COMT), which converts epinephrine to metanephrine and norepinephrine to normetanephrine. A second enzyme, monoamine oxidase (MAO), converts both of these metabolites to vanillylmandelic acid (VMA), which is excreted in the urine. Catecholamine production by the adrenal medulla is assessed by measuring the levels of catecholamines, metanephrines, and VMA in the urine.
Degradation of circulating catecholamines. MAO, monoamine oxidase; COMT, catechol-O-methyltransferase.
Patients with pheochromocytoma, a secretory tumor of the adrenal medulla, hypersecrete catecholamines. Episodes of dramatic surges in the release of catecholamines result in transient hypertension, palpitations, sweating, increased body temperature, and increased blood glucose concentration. Diagnosis is aided by measuring the increased concentrations of catecholamines and their breakdown products in the urine.