Figure 777

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Beta Switch Program by Sue Heintze

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Typical pattern of cortisol concentration during the day. Note the oscillations in secretion as well as a daily secretory surge an hour or so after awaking in the morning.

stimulating hormone (MSH), p-lipotropin, p-endor-phin, and a few others (Figure 77-8). Under normal conditions, none of these hormones is secreted in enough quantity by the pituitary to have a significant effect on the human body, but when the rate of secretion of ACTH is high, as may occur in Addison's disease, formation of some of the other POMC-derived hormones may also be increased.

The POMC gene is actively transcribed in several tissues, including the corticotroph cells of the anterior pituitary, POMC neurons in the arcuate nucleus of the hypothalamus, cells of the dermis, and lymphoid tissue. In all of these cell types, POMC is processed to form a series of smaller peptides. The precise type of POMC-derived products from a particular tissue depends on the type of processing enzymes present in the tissue. Thus, pituitary corticotroph cells express prohormone convertase 1 (PC1), but not PC2, resulting in the production of N-terminal peptide, joining peptide, ACTH, b-endorphin, and b-lipotropin. In the hypothalamus, the expression of PC2 leads to the production of a-, b-, and g-MSH, but not ACTH. As discussed in Chapter 71, a-MSH formed by neurons of the hypothalamus plays a major role in appetite regulation.

In melanocytes located in abundance between the dermis and epidermis of the skin, MSH stimulates formation of the black pigment melanin and disperses it to the epidermis. Injection of MSH into a person over 8 to 10 days can greatly increase darkening of the skin. The effect is much greater in people who have genetically dark skins than in light-skinned people.

In some lower animals, an intermediate "lobe" of the pituitary gland, called the pars intermedia, is highly developed, lying between the anterior and posterior pituitary lobes. This lobe secretes an especially large

Figure 77-8

Proopiomelanocortin (POMC) processing by prohormone con-vertase 1 (PC1, red arrows) and PC 2 (blue arrows). Tissue specific expression of these two enzymes results in different pep-tides produced in various tissues. The anterior pituitary expresses PC1, resulting in formation of N-terminal peptide, joining peptide, ACTH, and ß-lipotropin. Expression of PC2 within the hypothalamus leads to the production of a-, ß-, and g-melanocyte stimulating hormone (MSH), but not ACTH. CLIP, corticotropin-like intermediate peptide.

amount of MSH. Furthermore, this secretion is independently controlled by the hypothalamus in response to the amount of light to which the animal is exposed or in response to other environmental factors. For instance, some arctic animals develop darkened fur in the summer and yet have entirely white fur in the winter.

ACTH, because it contains an MSH sequence, has about 1/30 as much melanocyte-stimulating effect as MSH. Furthermore, because the quantities of pure MSH secreted in the human being are extremely small, whereas those of ACTH are large, it is likely that ACTH normally is more important than MSH in determining the amount of melanin in the skin.

Adrenal Androgens

Several moderately active male sex hormones called adrenal androgens (the most important of which is dehydroepiandrosterone) are continually secreted by the adrenal cortex, especially during fetal life, as discussed more fully in Chapter 83. Also, progesterone and estrogens, which are female sex hormones, are secreted in minute quantities.

Normally, the adrenal androgens have only weak effects in humans. It is possible that part of the early development of the male sex organs results from childhood secretion of adrenal androgens. The adrenal androgens also exert mild effects in the female, not only before puberty but also throughout life. Much of the growth of the pubic and axillary hair in the female results from the action of these hormones.

In extra-adrenal tissues, some of the adrenal andro-gens are converted to testosterone, the primary male sex hormone, which probably accounts for much of their androgenic activity. The physiologic effects of andro-gens are discussed in Chapter 80 in relation to male sexual function.

Abnormalities of Adrenocortical Secretion

Hypoadrenalism-Addison's Disease

Addison's disease results from failure of the adrenal cortices to produce adrenocortical hormones, and this in turn is most frequently caused by primary atrophy of the adrenal cortices. In about 80 per cent of the cases, the atrophy is caused by autoimmunity against the cortices. Adrenal gland hypofunction is also frequently caused by tuberculous destruction of the adrenal glands or invasion of the adrenal cortices by cancer. The disturbances in Addison's disease are as follows.

Mineralocorticoid Deficiency. Lack of aldosterone secretion greatly decreases renal tubular sodium reabsorption and consequently allows sodium ions, chloride ions, and water to be lost into urine in great profusion. The net result is a greatly decreased extracellular fluid volume. Furthermore, hyponatremia, hyperkalemia, and mild acidosis develop because of failure of potassium and hydrogen ions to be secreted in exchange for sodium reabsorption.

As the extracellular fluid becomes depleted, plasma volume falls, red blood cell concentration rises markedly, cardiac output decreases, and the patient dies in shock, death usually occurring in the untreated patient 4 days to 2 weeks after cessation of mineralo-corticoid secretion.

Glucocorticoid Deficiency. Loss of cortisol secretion makes it impossible for a person with Addison's disease to maintain normal blood glucose concentration between meals because he or she cannot synthesize significant quantities of glucose by gluconeogenesis. Furthermore, lack of cortisol reduces the mobilization of both proteins and fats from the tissues, thereby depressing many other metabolic functions of the body. This sluggishness of energy mobilization when cortisol is not available is one of the major detrimental effects of glucocorticoid lack. Even when excess quantities of glucose and other nutrients are available, the person's muscles are weak, indicating that glucocorticoids are needed to maintain other metabolic functions of the tissues in addition to energy metabolism.

Lack of adequate glucocorticoid secretion also makes a person with Addison's disease highly susceptible to the deteriorating effects of different types of stress, and even a mild respiratory infection can cause death.

Melanin Pigmentation. Another characteristic of most people with Addison's disease is melanin pigmentation of the mucous membranes and skin. This melanin is not always deposited evenly but occasionally is deposited in blotches, and it is deposited especially in the thin skin areas, such as the mucous membranes of the lips and the thin skin of the nipples.

The cause of the melanin deposition is believed to be the following: When cortisol secretion is depressed, the normal negative feedback to the hypothalamus and anterior pituitary gland is also depressed, therefore allowing tremendous rates of ACTH secretion as well as simultaneous secretion of increased amounts of MSH. Probably the tremendous amounts of ACTH cause most of the pigmenting effect because they can stimulate formation of melanin by the melanocytes in the same way that MSH does.

Treatment of People with Addison's Disease. An untreated person with total adrenal destruction dies within a few days to a few weeks because of weakness and usually circulatory shock. Yet such a person can live for years if small quantities of mineralocorticoids and glucocorti-coids are administered daily.

Addisonian Crisis. As noted earlier in the chapter, great quantities of glucocorticoids are occasionally secreted in response to different types of physical or mental stress. In a person with Addison's disease, the output of glucocorticoids does not increase during stress. Yet whenever different types of trauma, disease, or other stresses, such as surgical operations, supervene, a person is likely to have an acute need for excessive amounts of glucocorticoids and often must be given 10 or more times the normal quantities of glucocorticoids to prevent death.

This critical need for extra glucocorticoids and the associated severe debility in times of stress is called an addisonian crisis.

Hyperadrenalism-Cushing's Syndrome

Hypersecretion by the adrenal cortex causes a complex cascade of hormone effects called Cushing's syndrome. Most of the abnormalities of Cushing's syndrome are ascribable to abnormal amounts of cortisol, but excess secretion of androgens may also cause important effects. Hypercortisolism can occur from multiple causes, including (1) adenomas of the anterior pituitary that secrete large amounts of ACTH, which then causes adrenal hyperplasia and excess cortisol secretion; (2) abnormal function of the hypothalamus that causes high levels of corticotropin-releasing hormone (CRH), which stimulates excess ACTH release; (3) "ectopic secretion" of ACTH by a tumor elsewhere in the body, such as an abdominal carcinoma; and (4) adenomas of the adrenal cortex. When Cushing's syndrome is secondary to excess secretion of ACTH by the anterior pituitary, this is referred to as Cushing's disease.

Excess ACTH secretion is the most common cause of Cushing's syndrome and is characterized by high plasma levels of ACTH as well as cortisol. Primary overproduction of cortisol by the adrenal glands accounts for about 20 to 25 per cent of clinical cases of Cushing's syndrome and is usually associated with reduced ACTH levels due to cortisol feedback inhibition of ACTH secretion by the anterior pituitary gland.

Administration of large doses of dexamethasone, a synthetic glucocorticoid, can be used to distinguish between ACTH-dependent and ACTH-independent Cushing's syndrome. In patients who have overproduction of ACTH due to an ACTH-secreting pituitary adenoma or to hypothalamic-pituitary dysfunction, even large doses of dexamethasone usually do not suppress ACTH secretion. In contrast, patients with primary adrenal overproduction of cortisol (ACTH-independent) usually have low or undetectable levels of ACTH. The dexamethasone test, although widely used, can sometimes give an incorrect diagnosis, because some ACTH-secreting pituitary tumors respond to dexamethasone with suppressed ACTH secretion. Therefore, it is usually considered to be a first step in the differential diagnosis of Cushing's syndrome.

Cushing's syndrome can also occur when large amounts of glucocorticoids are administered over prolonged periods for therapeutic purposes. For example, patients with chronic inflammation associated with diseases such as rheumatoid arthritis are often treated with glucocorticoids and may develop some of the clinical symptoms of Cushing's syndrome.

A special characteristic of Cushing's syndrome is mobilization of fat from the lower part of the body, with concomitant extra deposition of fat in the thoracic and upper abdominal regions, giving rise to a buffalo torso. The excess secretion of steroids also leads to an ede-matous appearance of the face, and the androgenic potency of some of the hormones sometimes causes acne and hirsutism (excess growth of facial hair). The appearance of the face is frequently described as a "moon face," as demonstrated in the untreated patient with Cushing's syndrome to the left in Figure 77-8. About 80 per cent of patients have hypertension, presumably because of the slight mineralocorticoid effects of cortisol.

Effects on Carbohydrate and Protein Metabolism. The abundance of cortisol secreted in Cushing's syndrome can cause increased blood glucose concentration, sometimes to values as high as 200 mg/dl after meals-as much as twice normal. This results mainly from enhanced glu-coneogenesis and decreased glucose utilization by the tissues.

The effects of glucocorticoids on protein catabolism are often profound in Cushing's syndrome, causing greatly decreased tissue proteins almost everywhere in the body with the exception of the liver; the plasma proteins also remain unaffected. The loss of protein from the muscles in particular causes severe weakness. The loss of protein synthesis in the lymphoid tissues leads to a suppressed immune system, so that many of these patients die of infections. Even the protein collagen fibers in the subcutaneous tissue are diminished so that the subcutaneous tissues tear easily, resulting in development of large purplish striae where they have torn apart. In addition, severely diminished protein deposition in the bones often causes severe osteoporosis with consequent weakness of the bones.

Treatment of Cushing's Syndrome. Treatment of Cushing's syndrome consists of removing an adrenal tumor if this is the cause or decreasing the secretion of ACTH, if this is possible. Hypertrophied pituitary glands or even small tumors in the pituitary that oversecrete ACTH can sometimes be surgically removed or destroyed by radiation. Drugs that block steroidogenesis, such as metyrapone, ketoconazole, and aminoglutethimide, or that inhibit ACTH secretion, such as serotonin antagonists and GABA-transaminase inhibitors, can also be used when surgery is not feasible. If ACTH secretion cannot easily be decreased, the only satisfactory treatment is usually bilateral partial (or even total) adrena-lectomy, followed by administration of adrenal steroids to make up for any insufficiency that develops.

Primary Aldosteronism (Conn's Syndrome)

Occasionally a small tumor of the zona glomerulosa cells occurs and secretes large amounts of aldosterone; the resulting condition is called "primary aldosteronism" or "Conn's syndrome." Also, in a few instances, hyperplastic adrenal cortices secrete aldosterone rather than cortisol. The effects of the excess aldosterone are discussed in detail earlier in the chapter. The most important effects are hypokalemia, slight increase in extracellular fluid volume and blood volume, very slight increase in plasma sodium concentration (usually not more than a 4 to 6 mEq/L increase), and, almost always, hypertension. Especially interesting in primary aldosteronism are occasional periods of muscle paralysis caused by the hypokalemia. The paralysis is caused by a depressant effect of low extracellular potassium concentration on action potential transmission by the nerve fibers, as explained in Chapter 5.

One of the diagnostic criteria of primary aldostero-nism is a decreased plasma renin concentration. This results from feedback suppression of renin secretion caused by the excess aldosterone or by the excess extracellular fluid volume and arterial pressure resulting from the aldosteronism. Treatment of primary aldos-teronism is usually surgical removal of the tumor or of most of the adrenal tissue when hyperplasia is the cause.

Adrenogenital Syndrome

An occasional adrenocortical tumor secretes excessive quantities of androgens that cause intense masculinizing effects throughout the body. If this occurs in a female, she develops virile characteristics, including growth of a beard, a much deeper voice, occasionally baldness if she also has the genetic trait for baldness, masculine distribution of hair on the body and the pubis, growth of the clitoris to resemble a penis, and deposition of proteins in the skin and especially in the muscles to give typical masculine characteristics.

In the prepubertal male, a virilizing adrenal tumor causes the same characteristics as in the female plus rapid development of the male sexual organs, as shown in Figure 77-9, which depicts a 4-year-old boy with adrenogenital syndrome. In the adult male, the viriliz-ing characteristics of adrenogenital syndrome are usually obscured by the normal virilizing characteristics of the testosterone secreted by the testes. It is often difficult to make a diagnosis of adrenogenital syndrome in the adult male. In adrenogenital syndrome, the excretion of 17-ketosteroids (which are derived from andro-gens) in the urine may be 10 to 15 times normal. This finding can be used in diagnosing the disease.

Figure 77-9

A person with Cushing's syndrome before (left) and after (right) subtotal adrenalectomy. (Courtesy Dr. Leonard Posey.)

A person with Cushing's syndrome before (left) and after (right) subtotal adrenalectomy. (Courtesy Dr. Leonard Posey.)

Before After Cushing

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