Adrenal

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CORTEX. Cortical cells of the adrenal gland synthesize and secrete steroid hormones. They have abundant smooth endoplasmic reticulum (sER), mitochondria with tubular cristae, and lipid droplets, which are characteristic of all steroid-secreting cells.

A. Zona glomerulosa (ZG)

1. This region constitutes 15% of the cortical volume.

2. Cells in this region synthesize and secrete aldosterone. The secretion of aldosterone is not controlled by corticotropin-releasing factor (CRF) and adrenocorticotropic hormone (ACTH), which are from the hypothalamus and adenohy-pophysis, respectively.

3. The functions of aldosterone include the following:

a. Aldosterone increases sodium ion (Na+) reabsorption from tubular fluid to blood (water follows) by the cortical collecting ducts of the kidneys.

b. Aldosterone increases potassium ion (K+) secretion from blood to tubular fluid by the cortical collecting ducts of the kidneys.

4. Aldosterone has a half-life of 20 minutes because it is metabolized by the liver and excreted as a glucuronide. Urine levels of aldosterone 18-glucuronide are used for diagnostic purposes.

B. Zona fasciculata (ZF)

1. This region constitutes 78% of the cortical volume.

2. Cells in this region synthesize and sccrcte Cortisol. The secretion of Cortisol is controlled by CRF and ACTH from the hypothalamus and adenohypophysis, respectively. Abnormally high levels of ACTH (e.g., tumor of adenohypophysis) cause hypertrophy of the ZF. Abnormally low levels of ACTH (e.g., hypophysectomy) cause atrophy of the ZF.

3. The functions of Cortisol include the following:

a. Cortisol inhibits glucose uptake in adipose tissue and muscle.

b. Cortisol stimulates lipolysis in adipose tissue, which forms glycerol, used by the liver as substrate for gluconeogenesis, and fatty acids, which are metabolized by the liver for energy.

C. Cortisol stimulates proteolysis in muscle, which forms amino acids that are used by the liver as substrate for gluconeogenesis.

d. Cortisol stimulates gluconeogenesis and glycogen synthesis in the liver (overall the most important metabolic effect of Cortisol is the conversion of fat and muscle protein to glycogen).

e. It inhibits bone formation, causing osteoporosis by reducing the synthesis of type I collagen and decreasing the absorption of calcium by the intestinal tract by blocking the action of l,25-(OH2) vitamin D. f. It produces anti-inflammatory and immunosuppressive actions at high concentrations by inhibiting the enzyme phospholipase A2, which releases arachidonic acid (a precursor for many immune mediators).

4. Cortisol has a half-life of 70 minutes because it is metabolized by the liver and excreted in the urine as a glucuronide. Urine levels of 17-hydroxycorticoids are used for diagnostic purposes.

C. Zona reticularis (ZR)

1. This region constitutes 7% of the cortical volume.

2. Cells in this region synthesize and secrete dehydroepiandrosterone (DHEA) and androstenedione. The secretion of DHEA and androstenedione is controlled by CRF and ACTH from the hypothalamus and adenohypophysis, respectively.

3. Although DHEA and androstenedione are weak androgens, they are converted to testosterone by peripheral tissues.

4. The functions of DHEA and androstenedione include the following:

a. In women, DHEA and androstenedione conversion to testosterone is a main source of testosterone. During puberty, DHEA and androstenedione also may serve as substrates for conversion to estrogen.

b. In men, DHEA and androstenedione conversion to testosterone is of little biological significance because the testes produce most of the testosterone.

5. DHEA and androstenedione are metabolized by the liver to 17-ketosteroids. Urine levels of 17-ketosteroids are used for diagnostic purposes.

D. Synthesis of adrenocortical hormones uses cholesterol as a precursor (Figure 23-1).

E. Clinical considerations

1. Primary hyperaldosteronism a. Cause. Elevated levels of aldosterone (i.e., hyperaldosteronism) are commonly caused by an aldosterone-secreting tumor (Conn syndrome) within the

b. Symptoms. Primary hyperaldosteronism is characterized clinically by hypertension, hypernatremia due to increased sodium ion reabsorption, weight gain due to water retention, and hypokalemia due to increased potassium ion secretion.

C. Treatment. It is treated by surgery and/or spironolactone, which is an aldosterone receptor antagonist and therefore an effective antihypertensive and diuretic agent.

2. Cushing syndrome a. Cause. Elevated levels of Cortisol (i.e., hypercortisolism) arc commonly caused by an ACTH-secreting tumor within the adenohypophysis (75% of the cases) or adrenal cortical hyperplasia (25% of the cases).

b. Symptoms. Cushing syndrome is characterized clinically by hypertension, osteoporosis with back pain, central obesity, moon facies, and purple skin striae.

C. Treatment. Ketoconazole is an inhibitor of steroid biosynthesis that is used in the treatment of Cushing syndrome.

3. Congenital adrenal hyperplasia a. Cause. Congenital adrenal hyperplasia is caused most commonly by mutations in genes for enzymes involved in adrenocortical steroid biosynthesis

3ß-dehydrogenase

Progesterone

21-hydroxylase

Deoxycorticosterone

1 W-hydroxylase*

Corticosterone

18-methyloxidase _ ch2oh

ALDOSTERONE

Metabolized

17c<-hydroxylase

17-Hydroxypregnenolone

>

^ 3ß-dehydrogenase

17-Hydroxyprogesterone ■ i

f

Deoxycortisol

11 ß-hydroxylase"

>

r fH*°H > c=o

Desmotase

Desmotase

ANDROSTENEDIONE

Desmotase

Metabolized

Metabolized

Metabolized

Metabolized

Metabolized

Figure 23-1. Synthesis and metabolism of adrenocortical honnones. Synthesis begins with cholesterol as a precursor. The metabolic urine breakdown products (in shaded boxes) are used for diagnostic purposes. 21-hydroxylase (asterisk) and 1 lfi-hydroxylase (double asterisk) are enzymes involved in congenital adrenal hyperplasia.

Figure 23-1. Synthesis and metabolism of adrenocortical honnones. Synthesis begins with cholesterol as a precursor. The metabolic urine breakdown products (in shaded boxes) are used for diagnostic purposes. 21-hydroxylase (asterisk) and 1 lfi-hydroxylase (double asterisk) are enzymes involved in congenital adrenal hyperplasia.

ANDROSTENEDIONE

DHEA

(e.g., 21-hydroxylase deficiency, 11 P-hydroxylase deficiency). In 21-

hydroxylase deficiency (90% of all cases), there is virtually no synthesis of the aldosterone or Cortisol, so that intermediates are funneled into androgen biosynthesis, thereby elevating androgen levels.

b. Symptoms. The elevated levels of androgens lead to virilization of a female fetus ranging from mild clitoral enlargement to complete labioscrotal fusion with a phalloid organ. Because Cortisol cannot be synthesized, negative feedback to the adenohypophysis does not occur, so ACTH continues to stimulate the adrenal cortex, resulting in adrenal hyperplasia.

C. Treatment. Depending on the severity, treatment may include surgical reconstruction and steroid replacement.

4. Primary adrenal insufficiency (Addison disease)

a. Cause. Addison disease is commonly caused by autoimmune destruction of the adrenal cortex.

b. Symptoms. It is characterized clinically by fatigue, anorexia, nausea, weight loss, hypotension, and hyperpigmentation of the skin.

C. Treatment. This condition is managed by steroid replacement therapy.

5. Secondary adrenal insufficiency a. Cause. Secondary adrenal insufficiency is causcd by a disorder of the hypothalamus or adenohypophysis that reduces the secretion of ACTH.

b. Symptoms. It is clinically very similar to Addison disease except there is no hyperpigmentation of the skin.

F. Diagnosis. Table 23-1 shows the laboratory findings used for diagnosis. The dexa-methasone suppression test is based on the ability of dexamethasone (a synthetic glucocorticoid) to inhibit ACTH and Cortisol secretion. If the adcnohypophysis-adrenal cortex axis is normal, dexamethasone will inhibit ACTH and Cortisol secretion by negative feedback.

II. THE MEDULLA contains chromaffin cells, which are modified postganglionic sympathetic neurons. Preganglionic sympathetic axons (via splanchnic nerves) synapse on chromaffin cells, and upon stimulation cause chromaffin cells to secrete catecholamines, epinephrine, and norepinephrine. There are two types of chromaffin cells:

Table 23-1

Laboratory Findings Used to Diagnose Adrenal Gland Disorders

Plasma Levels

Table 23-1

Laboratory Findings Used to Diagnose Adrenal Gland Disorders

Plasma Levels

Clinical Condition

Aldosterone

Cortisol

Androgens

ACTH

Primary hyperaldosteronism (Conn syndrome)

High

N/A

N/A

N/A

Cushing syndrome ACTH tumor Adrenal hyperplasia

N/A N/A

High High

N/A N/A

High Low

Congenital adrenal hyperplasia 21-hydroxylase deficiency llp-hydroxylase deficiency

Low

Low

High

High

Addison disease (primary adrenal insufficiency)

Low

Low

Low

High

Secondary adrenal insufficiency

Normal

Low

Low

Low

ACTH = adrenocorticotropic hormone; N/A - not applicable.

ACTH = adrenocorticotropic hormone; N/A - not applicable.

A. Epinephrine-containing cells comprise a majority of the chromaffin cells in the medulla and contain small, homogeneous, light-staining granules.

1. All of the circulating epinephrine in the blood is derived from the adrenal medulla.

2. Functions of epinephrine a. Stimulates glycogen degradation in the liver, thereby releasing free glucose b. Stimulates glycogen degradation in skeletal muscle, thereby releasing lactic acid

C. Stimulates lipolysis in adipose tissue, thereby releasing free fatty acids d. Inhibits glucose uptake in adipose tissue and muscle so that glucose is available for the brain e. Inhibits insulin secretion f. Affects nonvascular smooth muscle cells

3. Epinephrine has a half-life of 1-3 minutes because it is metabolized by the liver and excreted in the urine as free epinephrine, metanephrine, or as a glucuronide. Urinary free epinephrine or plasma epinephrine levels are used for diagnostic purposes in problems of adrenal medulla function.

B. Norepinephrine-containing cells comprise a minority of the chromaffin cells in the medulla and contain large, electron-dense core granules.

1. The majority of circulating norepinephrine in the blood is derived from the sympathetic nervous system (postganglionic neurons) and brain, with the secretion from the adrenal medulla contributing only a minor portion.

2. Functions of norepinephrine a. Stimulates a-adrcnergic receptors on vascular smooth muscle cells, thereby causing vasoconstriction in resting skeletal musclc b. Stimulates (^-adrenergic receptors on vascular smooth muscle cells, thereby causing vasodilation in resting skeletal muscle

C. Stimulates 3-adrenergic receptors on cardiac myocytes, thereby increasing the heart rate d. Stimulates eccrine sweat glands, producing emotional sweating e. Stimulates apocrine sweat glands, producing pheromones f. Plays a role in anxiety states, panic attacks, and depression g. Affects nonvascular smooth muscle cells

3. Norepinephrine has a half-life of 1-3 minutes, because it is metabolized by the liver and excreted in the urine as free norepinephrine, normetanephrine, a glucuronide, vanillylmandclic acid (VMA), or 3-methoxy-4-bydroxypbenyglycol (MOPEG). Urinary levels of VMA and MOPEG are used for diagnostic purposes in problems of the sympathetic nervous system.

C. Dual blood supply

1. The medulla receives venous blood draining the cortex, which has a high concentration of Cortisol. The synthesis of phenylethanoIamine-N-methyltrans-ferase (a key enzyme in the synthesis of epinephrine) is dependent on high levels of Cortisol received via venous blood from the cortex.

2. The medulla also receives arterial blood from capsular arteries that pass through the cortex to form a capillary network around the chromaffin cells.

Tyrosine

Tyrosine hydroxylase

Dihydroxyphenylalanine

Amino acid decarboxylase

Amino acid decarboxylase

(10%) NOREPINEPHRINE

(90%) EPINEPHRINE

Metabolized

Metabolized

Free normetanephrine Normetanephrine VMA* MOPEG**

Free epinephrine"'' Metanephrine

Figure 23-2. Synthesis and metabolism of adrenomedullary catecholamines. Synthesis begins with tyrosine as a precursor. The metabolic urine breakdown products (in shaded boxes) are used for diagnostic purposes. Vanillylmandelic acid (VMA; asterisk) and 3-methoxy-4-hydroxyphenyglycol (MOPEG; double asterisk) are diagnostic of sympathetic nervous system function. Urinary free epinephrine (danger) or plasma epinephrine levels are diagnostic of adrenal medulla function. When the adrenal medulla is stimulated, the secretion product is 90% epinephrine and 10% norepinephrine. All of the enzymes involved in catecholamine synthesis are found in the cytoplasm except dopamine ^-hydroxylase, which is located within secretion granules. PEMT - phenylethanolamine-N-merhyltransferase.

D. Synthesis of catecholamines uses tyrosine as a precursor (Figure 23-2).

E. Clinical considerations

1. Phcochromocytoma is a relatively rare neoplasm that contains both epinephrine and norepinephrine.

a. Characteristics. Pheochromocytoma occurs mainly in adults. It is generally found in the region of the adrenal gland but also is found in extra-adrenal sites.

b. Symptoms. It is associated with persistent or paroxysmal hypertension, anxiety, tremor, profuse sweating, pallor, chest pain, and abdominal pain.

C. Diagnosis. Increased urine VMA and metanephrine levels, inability to suppress catecholamines with clonidine, and hyperglycemia are common laboratory findings.

d. Treatment. Pheochromocytoma is treated by surgery or phenoxybenzamine (an ct-adrenergic antagonist).

2. Neuroblastoma is a common extracranial neoplasm containing primitive neuroblasts of neural crest origin.

a. Characteristics. Neuroblastomas occur mainly in children. They are found in extra-adrenal sites usually along the sympathetic chain ganglia (60%) or within the adrenal medulla (40%). They metastasize widely.

b. Symptoms. It is associated with opsoclonus (rapid, irregular movements of the eye in horizontal and vertical directions; "dancing eyes").

C. Diagnosis. A neuroblastoma contains small cells arranged in Homer-Wright pseudorosettes. Increased urine VMA and metanephrine levels are found, d. Treatment includes surgical excision, radiation, and chemotherapy.

Figure 23-3. (A) Hyperplasia of the adrenal cortex as might be found in Cushing syndrome. (B) Normal adrenal gland showing the normal thickness of the adrenal cortex. (C) Hypoplasia of the adrenal cortex as might be found in Addison disease. All photomicrographs are taken at the same magnification so that the normal and pathologic changes may be compared. C = adrenal cortex; M = adrenal medulla.

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