alterations in pituitary, thyroid, parathyroid, and ... · in secondary disorders of endocrine...

538

CHAPTER

31Alterations in Pituitary,

Thyroid, Parathyroid, and Adrenal Function

General Aspects of Altered Endocrine FunctionHypofunction and HyperfunctionPrimary, Secondary, and Tertiary Disorders

Pituitary and Growth Hormone DisordersHypopituitarismGrowth and Growth Hormone Disorders

Growth HormoneShort Stature and Growth Hormone Deficiency

in ChildrenGrowth Hormone Deficiency in AdultsTall Stature and Growth Hormone Excess in ChildrenGrowth Hormone Excess in Adults

Isosexual Precocious PubertyThyroid Disorders

Control of Thyroid FunctionActions of Thyroid HormoneTests of Thyroid Function

Alterations in Thyroid FunctionHypothyroidism

Congenital HypothyroidismAcquired Hypothyroidism and Myxedema

HyperthyroidismGraves’ DiseaseThyroid Storm

Parathyroid Hormone DisordersHypoparathyroidismHyperparathyroidism

Disorders of Adrenal Cortical FunctionControl of Adrenal Cortical Function

Biosynthesis, Transport, and MetabolismAdrenal Sex HormonesMineralocorticoids

GlucocorticoidsSuppression of Adrenal FunctionTests of Adrenal Function

Congenital Adrenal HyperplasiaAdrenal Cortical Insufficiency

Primary Adrenal Cortical InsufficiencySecondary Adrenal Cortical InsufficiencyAcute Adrenal Crisis

Glucocorticoid Hormone Excess (Cushing’s Syndrome)

T he endocrine system affects all aspects of body function,including growth and development, energy metabolism,muscle and adipose tissue distribution, sexual develop-

ment, fluid and electrolyte balance, and inflammation and im-mune responses. This chapter focuses on disorders of pituitaryfunction, growth and growth hormone levels, thyroid function,and adrenocortical function.

GENERAL ASPECTS OF ALTEREDENDOCRINE FUNCTION

Hypofunction and HyperfunctionDisturbances of endocrine function usually can be divided intotwo categories: hypofunction and hyperfunction. Hypofunctionof an endocrine gland can occur for a variety of reasons. Congen-ital defects can result in the absence or impaired developmentof the gland or the absence of an enzyme needed for hormonesynthesis. The gland may be destroyed by a disruption in bloodflow, infection, inflammation, autoimmune responses, or neo-plastic growth. There may be a decline in function with aging,or the gland may atrophy as the result of drug therapy or forunknown reasons. Some endocrine-deficient states are associ-ated with receptor defects: hormone receptors may be absent,the receptor binding of hormones may be defective, or the cel-lular response to the hormone may be impaired. It is suspectedthat in some cases a gland may produce a biologically inactive

539Chapter 31: Alterations in Pituitary, Thyroid, Parathyroid, and Adrenal Function

hormone or that an active hormone may be destroyed by cir-culating antibodies before it can exert its action.

Hyperfunction usually is associated with excessive hor-mone production. This can result from excessive stimulationand hyperplasia of the endocrine gland or from a hormone-producing tumor of the gland. An ectopic tumor can producehormones; for example, certain bronchogenic tumors producehormones such as antidiuretic hormone (ADH) and adreno-corticotropic hormone (ACTH).

Primary, Secondary, and Tertiary DisordersEndocrine disorders in general can be divided into primary,secondary, and tertiary groups. Primary defects in endocrinefunction originate in the target gland responsible for produc-ing the hormone. In secondary disorders of endocrine function,the target gland is essentially normal, but its function is alteredby defective levels of stimulating hormones or releasing fac-tors from the pituitary system. For example, adrenalectomyproduces a primary deficiency of adrenal corticosteroid hor-mones. Removal or destruction of the pituitary gland elimi-nates ACTH stimulation of the adrenal cortex and brings abouta secondary deficiency. A tertiary disorder results from hypo-thalamic dysfunction (as may occur with craniopharyngiomasor cerebral irradiation); thus, both the pituitary and targetorgan are understimulated.

cold intolerance. However, ACTH deficiency (secondary adre-nal failure) is the most serious endocrine deficiency, leading toweakness, nausea, anorexia, fever, and postural hypotension.Hypopituitarism is associated with increased morbidity andmortality.

Anterior pituitary hormone loss tends to follow a typicalsequence, especially with progressive loss of pituitary reservecaused by tumors or previous pituitary radiation therapy(which may take 10 to 20 years to produce hypopituitarism).Usually GH secretion is lost first, then LH and FSH, followedby TSH deficiency. ACTH is usually the last to become deficient.

Treatment of hypopituitarism includes treating any identi-fied underlying cause. Hormone deficiencies are treated withreplacement of the target gland hormone. Cortisol replacementis started when ACTH deficiency is present; thyroid replace-ment when TSH deficiency is detected; and sex hormone re-placement when LH and FSH are deficient. GH replacement isbeing used increasingly to treat GH deficiency.

Growth and Growth Hormone DisordersSeveral hormones are essential for normal body growth andmaturation, including growth hormone (GH), insulin, thyroidhormone, and androgens. In addition to its actions on carbo-hydrate and fat metabolism, insulin plays an essential role ingrowth processes. Children with diabetes, particularly thosewith poor control, often fail to grow normally even though GHlevels are normal. When levels of thyroid hormone are lowerthan normal, bone growth and epiphyseal closure are delayed.Androgens such as testosterone and dihydrotestosterone exertanabolic growth effects through their actions on protein syn-thesis. Glucocorticoids at excessive levels inhibit growth, ap-parently because of their antagonistic effect on GH secretion.

Growth HormoneGrowth hormone, also called somatotropin, is a 191–amino-acid polypeptide hormone synthesized and secreted by specialcells in the anterior pituitary called somatotropes. For many

In summary, endocrine disorders are the result of hypo-function or hyperfunction of an endocrine gland. They canoccur as a primary defect in hormone production by a targetgland or as a secondary or tertiary disorder resulting from adefect in the hypothalamic-pituitary system that controls atarget gland’s function.

PITUITARY AND GROWTH HORMONE DISORDERS

The anterior lobe of the pituitary gland produces ACTH, thy-roid stimulating hormone (TSH), growth hormone (GH), thegonadotrophic hormones (follicle stimulating hormone [FSH]and luteinizing hormone [LH]), and prolactin (see Chapter 30,Fig. 30-4). Four of these, ACTH, TSH, LH, and FSH control thesecretion of hormones from other endocrine glands. ACTHcontrols the release of cortisol from the adrenal gland and TSHthe secretion of thyroid hormone from the thyroid gland; LHregulates sex hormones, and FSH regulates fertility.

HypopituitarismHypopituitarism, which is characterized by a decreased secre-tion of pituitary hormones, is a condition that affects many ofthe other endocrine systems. Typically, 70% to 90% of theanterior pituitary must be destroyed before hypopituitarismbecomes clinically evident.1 The cause may be congenital or re-sult from a variety of acquired abnormalities (Chart 31-1). Themanifestations of hypopituitarism usually occur gradually, butit can present as an acute and life-threatening condition.Patients usually report being chronically unfit, with weakness,fatigue, loss of appetite, impairment of sexual function, and

CHART 31-1 Causes of Hypopituitarism

■ Tumors and mass lesions—pituitary adenomas, cysts,metastatic cancer, and other lesions

■ Pituitary surgery or radiation■ Infiltrative lesions and infections—hemochromatosis,

lymphocytic hypophysitis■ Pituitary infarction—infarction of the pituitary gland after

substantial blood loss during childbirth (Sheehan’ssyndrome)

■ Pituitary apoplexy—sudden hemorrhage into the pituitarygland

■ Genetic diseases—rare congenital defects of one or morepituitary hormones

■ Empty sella syndrome—an enlarged sella turcica that isnot entirely filled with pituitary tissue

■ Hypothalamic disorders—tumors and mass lesions (e.g., craniopharyngiomas and metastatic malignancies),hypothalamic radiation, infiltrative lesions (e.g., sarcoido-sis), trauma, infections

years, it was thought that GH was produced primarily duringperiods of growth. However, this has proved to be incorrect be-cause the rate of GH production in adults is almost as great asin children. GH is necessary for growth and contributes to theregulation of metabolic functions (Fig. 31-1).2,3 All aspects ofcartilage growth are stimulated by GH; one of the most strikingeffects of GH is on linear bone growth, resulting from its actionon the epiphyseal growth plates of long bones. The width ofbone increases because of enhanced periosteal growth; visceraland endocrine organs, skeletal and cardiac muscle, skin, andconnective tissue all undergo increased growth in response toGH. In many instances, the increased growth of visceral andendocrine organs is accompanied by enhanced functional ca-pacity. For example, increased growth of cardiac muscle is ac-companied by an increase in cardiac output.

In addition to its effects on growth, GH facilitates the rate ofprotein synthesis by all of the cells of the body; it enhances fattyacid mobilization and increases the use of fatty acids for fuel;and it maintains or increases blood glucose levels by decreas-ing the use of glucose for fuel. GH has an initial effect of in-creasing insulin levels. However, the predominant effect of pro-longed GH excess is to increase glucose levels despite an insulinincrease. This is because GH induces a resistance to insulin inthe peripheral tissues, inhibiting the uptake of glucose by mus-cle and adipose tissues.

Many of the effects of GH depend on a family of peptidescalled insulin-like growth factors (IGF), also called somatomedins,which are produced mainly by the liver. GH cannot directlyproduce bone growth; instead, it acts indirectly by causing the

liver to produce IGF. These peptides act on cartilage and boneto promote their growth. At least four IGFs have been identi-fied; of these, IGF-1 appears to be the more important in termsof growth, and it is the one that usually is measured in labo-ratory tests. The IGFs have been sequenced and have structuresthat are similar to that of proinsulin. This undoubtedly ex-plains the insulin-like activity of the IGFs and the weak actionof insulin on growth. IGF levels are themselves influenced bya family of at least six binding factors called IGF-binding pro-teins (IGFBPs).

GH is carried unbound in the plasma and has a half-life ofapproximately 20 to 50 minutes. The secretion of GH is regu-lated by two hypothalamic hormones: GH-releasing hormone(GHRH), which increases GH release, and somatostatin, whichinhibits GH release. A third hormone, the recently identifiedghrelin, also may be important. These hypothalamic influences(i.e., GHRH and somatostatin) are tightly regulated by neural,metabolic, and hormonal factors. The secretion of GH fluctu-ates during a 24-hour period, with peak levels occurring 1 to 4 hours after onset of sleep (i.e., during sleep stages 3 and 4).The nocturnal sleep bursts, which account for 70% of daily GHsecretion, are greater in children than in adults.4

GH secretion is stimulated by hypoglycemia, fasting, star-vation, increased blood levels of amino acids (particularly argi-nine), and stress conditions such as trauma, excitement, emo-tional stress, and heavy exercise. GH is inhibited by increasedglucose levels, free fatty acid release, cortisol, and obesity.Impairment of secretion, leading to growth retardation, is notuncommon in children with severe emotional deprivation.

540 Unit Eight: Alterations in the Endocrine System

Increasedlineargrowth

Increasedsize andfunction

Increasedlean muscle

mass

Anteriorpituitary

Hypothalamus

Growth hormoneGrowth-promoting actions

Liver

Anti-insulin effects

Increased protein synthesis

Bone andcartilage

Bodyorgans Muscle

Adiposetissue

Carbohydratemetabolism

Decreasedglucose use

Increased bloodglucose

Increased lipolysisIncreased FFA use

Decrease inadiposity

IGF-1

■ FIGURE 31-1 ■ Growth-promoting and anti-insulin ef-fects of growth hormone. IGF-1,insulin growth factor 1.

CHART 31-2 Causes of Short StatureVariants of Normal

Genetic or “familial” short statureConstitutional short stature

Low Birth Weight (e.g., intrauterine growth retardation)

Endocrine Disorders

Growth hormone (GH) deficiencyPrimary GH deficiency

Idiopathic GH deficiencyPituitary agenesis

Secondary GH deficiency (panhypopituitarism)Biologically inactive GH productionDeficient IGF-1 production in response to normal or

elevated GH (Laron-type dwarfism)HypothyroidismDiabetes mellitus in poor controlGlucocorticoid excess

Endogenous (Cushing’s disease)Exogenous (glucocorticoid drug treatment)

Abnormal mineral metabolism (e.g., pseudohypopara-thyroidism)

Chronic Illness and Malnutrition

Chronic organic or systemic disease (e.g., asthma, especiallywhen treated with glucocorticoids; heart or renal disease)

Nutritional deprivationMalabsorption syndrome

Functional Endocrine Disorders (Psychosocial Dwarfism)

Chromosomal Disorders (e.g., Turner’s Syndrome)

Skeletal Abnormalities (e.g.., achondroplasia)Short Stature and Growth Hormone Deficiencyin Children

Short stature is a condition in which the attained height iswell below the fifth percentile or linear growth is below nor-mal for age and gender. Short stature, or growth retardation,has a variety of causes, including chromosomal abnormalitiessuch as Turner’s syndrome (see Chapter 4), GH deficiency, hypo-thyroidism, and panhypopituitarism. Other conditions knownto cause short stature include protein-calorie malnutrition,chronic diseases such as renal failure and poorly controlleddiabetes mellitus, malabsorption syndromes, and certain ther-apies such as corticosteroid administration. Emotional dis-turbances can lead to functional endocrine disorders, causingpsychosocial dwarfism. The causes of short stature are sum-marized in Chart 31-2.

Accurate measurement of height is an extremely importantpart of the physical examination of children. Completion of thedevelopmental history and growth charts is essential. Growthcurves and growth velocity studies also are needed. Diagnosisof short stature is not made on a single measurement but isbased on actual height and on velocity of growth and parentalheight. The diagnostic procedures for short stature include teststo exclude nonendocrine causes. Extensive hormonal testingprocedures are initiated in cases where an endocrine cause issuspected. Usually, tests to determine GH and IGF-1 levels aredone. Radiologic films are used to assess bone age, which most

often is delayed. Lateral skull x-rays may be used to evaluate thesize and shape of the sella turcica (i.e., depression in the sphe-noid bone that contains the pituitary gland) and determine ifa pituitary tumor exists. Magnetic resonance imaging (MRI) orcomputed axial tomography (CT) scans of the hypothalamic-pituitary area may be done if a pituitary lesion is suspected.After the cause of short stature has been determined, treatmentcan be initiated.

Genetic and Constitutional Short Stature. Two forms of shortstature, genetic short stature and constitutional short stature,are not disease states but variations from population norms.5

Genetically short children tend to be well proportioned and tohave a height close to the midparental height of their parents.The midparental height for boys can be calculated by adding13 cm (5 inches) to the height of the mother, adding thefather’s height, and dividing the total by two. For girls, 13 cm (5 inches) is subtracted from the father’s height, the result isadded to the mother’s height, and the total is divided by two.Ninety-five percent of normal children are within 8.5 cm of themidparental height.

Constitutional short stature is a term used to describe children(particularly boys) who have moderately short stature, thin


KEY CONCEPTS

GROWTH HORMONE

■ Growth hormone (GH), which is produced by soma-totropes in the anterior pituitary, is necessary for lin-ear bone growth in children. It also stimulates cellsto increase in size and divide more rapidly; it en-hances amino acid transport across cell membranesand increases protein synthesis; and it increases therate at which cells use fatty acids and decreases therate at which they use carbohydrates.

■ The effects of GH on cartilage growth require insulin-like growth factors (IGFs), also called somato-medins, which are produced mainly by the liver.

■ In children, GH deficiency interferes with linear bonegrowth, resulting in short stature or dwarfism. In arare condition called Laron-type dwarfism, GH levelsare normal or elevated, but there is a hereditarydefect in IGF production.

■ GH excess in children results in increased linear bonegrowth, or gigantism. In adults, GH excess results inovergrowth of the cartilaginous parts of the skele-ton, enlargement of the heart and other organs ofthe body, and metabolic disturbances resulting inaltered fat metabolism and impaired glucosetolerance.

build, delayed skeletal and sexual maturation, and absence ofother causes of decreased growth. Catch-up growth is a term usedto describe an abnormally high growth rate that occurs as achild approaches normal height for age. It occurs after the ini-tiation of therapy for GH deficiency and hypothyroidism andthe correction of chronic diseases.

Psychosocial Dwarfism. Psychosocial dwarfism involves afunctional hypopituitarism and is seen in some emotionallydeprived children. These children usually present with poorgrowth, potbelly, and poor eating and drinking habits.5,6 Ty-pically, there is a history of disturbed family relationships inwhich the child has been severely neglected or disciplined.Often, the neglect is confined to one child in the family. GHfunction usually returns to normal after the child is removedfrom the constraining environment. The prognosis depends onimprovement in behavior and catch-up growth. Family therapyusually is indicated, and foster care may be necessary.

Growth Hormone Deficiency in Children. There are se-several forms of GH deficiency that present in childhood.Children with idiopathic GH deficiency lack the hypothalamicGHRH but have adequate somatotropes, whereas children withpituitary tumors or agenesis of the pituitary lack somatotropes.The term panhypopituitarism refers to conditions that cause adeficiency of all of the anterior pituitary hormones. In a rarecondition called Laron-type dwarfism, GH levels are normal orelevated, but there is a hereditary defect in IGF production thatcan be treated directly with IGF-1 replacement.7

Congenital GH deficiency is associated with normal birthlength, followed by a decrease in growth rate that can be iden-tified by careful measurement during the first year and thatbecomes obvious by 1 to 2 years of age. Persons with classicGH deficiency have normal intelligence, short stature, obesitywith immature facial features, and some delay in skeletal mat-uration (Fig. 31-2). Puberty often is delayed, and males withthe disorder have microphallus (abnormally small penis), es-pecially if the condition is accompanied by gonadotropin-releasing hormone (GnRH) deficiency. In the neonate, GHdeficiency can lead to hypoglycemia and seizures; if adreno-corticotropic hormone (ACTH) deficiency also is present, thehypoglycemia often is more severe. Acquired GH deficiencydevelops in later childhood; it may be caused by a hypothalamic-pituitary tumor, particularly if it is accompanied by other pitu-itary hormone deficiencies.

When short stature is due to a GH deficiency, GH replace-ment therapy is the treatment of choice. GH is species specific,and only human GH (hGH) is effective in humans. HumanGH, which is synthesized by recombinant DNA techniques, isnow available in adequate supply. It is administered subcuta-neously in multiple weekly doses during the period of activegrowth, and its use can be continued into adulthood.

Children with short stature due to Turner’s syndrome andchronic renal insufficiency also are treated with hGH.8 hGHtherapy may be considered for children with short stature butwithout GH deficiency. Several studies suggest that short-termtreatment with GH increases the rate of growth in these chil-dren. Although the effect of GH on adult height is not great,it can result in improved psychological well-being. There areconcerns about misuse of the drug to produce additionalgrowth in children with normal GH function who are of near-

normal height. Guidelines for use of the hormone continueto be established.

Growth Hormone Deficiency in AdultsThere are two categories of GH deficiency in adults: (1) GH de-ficiency that was present in childhood, and (2) GH deficiencythat developed during adulthood, mainly as the result of hypo-pituitarism resulting from a pituitary tumor or its treatment.GH levels also can decline with aging, and there has been in-terest in the effects of declining GH levels in the elderly (de-scribed as the somatopause).

Several studies have shown that cardiovascular mortality isincreased in GH-deficient adults.9 Increased arterial intima-media thickness and a higher prevalence of atheroscleroticplaques and endothelial dysfunction have been reported inboth childhood and adult GH deficiency. The GH deficiencysyndrome is associated with a cluster of cardiovascular risk fac-tors, including central adiposity (increased waist-hip ratio), in-creased visceral fat, insulin resistance, and dyslipidemia. Thesefeatures also are associated with the metabolic syndrome (syn-drome X; see Chapter 32). In addition to these so-called tradi-tional cardiovascular risk factors, nontraditional cardiovascu-lar risk factors (e.g., C-reactive protein and interleukin-6, whichare markers of the inflammatory pathway) also are elevated.

The diagnosis of GH deficiency in adults is made by findingsubnormal serum GH responses to two stimulation tests thatmeasure GH reserve. Measurements of the serum IGF-1 or basalGH do not distinguish reliably between normal and subnor-mal GH secretion in adults. Insulin-induced hypoglycemia isthe gold standard test for GH reserve. The L-dopa test probablyis the next best test. Other stimulation tests involve the use ofarginine or arginine plus GHRH, clonidine (an α-adrenergicagonist), glucagon, or GHRH.

GH replacement obviously is important in the growingchild; however, the role in adults (especially for the somato-


pause) is being assessed. Adults with documented GH defi-ciency may be treated with hGH. In the United States, personswith GH deficiency acquired as an adult must meet at least twocriteria for therapy: a poor GH response to at least two standardstimuli, and hypopituitarism caused by pituitary or hypothal-amic damage.8

Tall Stature and Growth Hormone Excess in Children

Tall Stature. Just as there are children who are short for theirage and sex, there also are children who are tall for their age andsex. Normal variants of tall stature include genetic tall statureand constitutional tall stature. Children with exceptionally tallparents tend to be taller than children with shorter parents. Theterm constitutional tall stature is used to describe a child who istaller than his or her peers and is growing at a velocity that iswithin the normal range for bone age.5,10 Other causes of tallstature are genetic or chromosomal disorders, such as Marfan’ssyndrome or XYY syndrome (see Chapter 4). Endocrine causesof tall stature include sexual precocity because of early onset ofestrogen and androgen secretion and excessive GH.

Exceptionally tall children (i.e., genetic tall stature and con-stitutional tall stature) can be treated with sex hormones—estrogens in girls and testosterone in boys—to effect early epi-physeal closure. Such treatment is undertaken only after fullconsideration of the risks involved. To be effective, such treat-ment must be instituted 3 to 4 years before expected epiphysealfusion.

Gigantism. Growth hormone excess occurring before pubertyand the fusion of the epiphyses of the long bones results in gi-gantism (Fig. 31-3). Excessive secretion of GH by somatotropeadenomas causes gigantism in the prepubertal child. It occurswhen the epiphyses are not fused and high levels of IGF stimu-late excessive skeletal growth. Fortunately, the condition is rarebecause of early recognition and treatment of the adenoma.

Growth Hormone Excess in AdultsWhen GH excess occurs in adulthood or after the epiphyses ofthe long bones have fused, the condition is referred to asacromegaly.11 Acromegaly results from excess levels of GH thatstimulate the hepatic secretion of IGF-1, which causes most ofthe clinical manifestations of acromegaly. The annual inci-dence of acromegaly is 3 to 4 cases per 1 million people, witha mean age at the time of diagnosis of 40 to 45 years.

The most common cause of acromegaly is a somatotropeadenoma. Approximately 75% of persons with acromegalyhave large expansive tumors that erode the sella turcica and im-pinge on adjacent cranial structures, and most of the remainderhave small tumors contained within the pituitary gland. Othercauses of acromegaly (<5%) are excess secretion of GHRH byhypothalamic tumors, ectopic GHRH secretion by nonendo-crine tumors such as carcinoid tumors or small cell lung can-cers, and ectopic secretion of GH by nonendocrine tumors.

The disorder usually has an insidious onset, and symptomsoften are present for a considerable period before a diagnosisis made. When the production of excessive GH occurs after theepiphyses of the long bones have closed, as in the adult, theperson cannot grow taller, but the soft tissues continue to grow.Enlargement of the small bones of the hands and feet and ofthe membranous bones of the face and skull results in a pro-

nounced enlargement of the hands and feet, a broad and bul-bous nose, a protruding lower jaw, and a slanting forehead. Theteeth become splayed, causing a disturbed bite and difficulty inchewing. The cartilaginous structures in the larynx and respira-tory tract also become enlarged, resulting in a deepening of thevoice and tendency to develop bronchitis. Vertebral changesoften lead to kyphosis, or hunchback. Bone overgrowth oftenleads to arthralgias and degenerative arthritis of the spine, hips,and knees. Virtually every organ of the body is increased in size.Enlargement of the heart and accelerated atherosclerosis maylead to an early death.

The metabolic effects of excess levels of GH include alter-ations in fat and carbohydrate metabolism. GH causes in-creased release of free fatty acids from adipose tissue, leadingto increased concentration of free fatty acids in body fluids. Inaddition, GH enhances the formation of ketones and the uti-lization of free fatty acids for energy in preference to use ofcarbohydrates and proteins. GH exerts multiple effects on car-bohydrate metabolism, including decreased glucose uptakeby tissues such as skeletal muscle and adipose tissue, in-creased glucose production by the liver, and increased insulinsecretion. Each of these changes results in GH-induced in-sulin resistance (see Chapter 32). This leads to glucose intol-erance, which stimulates the beta cells of the pancreas to pro-duce additional insulin. Long-term elevation of GH results in


overstimulation of the beta cells, causing them literally to“burn out.” Impaired glucose tolerance occurs in as many as50% to 70% of persons with acromegaly; overt diabetes mel-litus subsequently can result.

The pituitary gland is located in the pituitary fossa of thesphenoid bone (i.e., sella turcica), which lies directly belowthe optic nerve. Enlargement of the pituitary gland eventuallycauses erosion of the surrounding bone, and because of its lo-cation, this can lead to headaches, visual field defects resultingfrom compression of the optic nerve, and palsies of cranialnerves III, IV, and VI. Compression of other pituitary structurescan cause secondary hypothyroidism, hypogonadism, and adre-nal insufficiency. Other manifestations include excessive sweat-ing with an unpleasant odor, oily skin, heat intolerance, mod-erate weight gain, muscle weakness and fatigue, menstrualirregularities, and decreased libido. Hypertension is relativelycommon. Paresthesias may develop because of nerve entrap-ment and compression caused by excess soft tissue and accu-mulation of subcutaneous fluid (especially carpal tunnel syn-drome). Acromegaly also is associated with an increased risk ofcolonic polyps and colorectal cancer. The mortality rate of pa-tients with acromegaly is two to three times the expected rate,mostly from cardiovascular diseases and cancer. The cardio-vascular disease results from the combination of cardiomyo-pathy, hypertension, insulin resistance and hyperinsulinemia,and hyperlipidemia.

Acromegaly often develops insidiously, and only a smallnumber of persons seek medical care because of changes inappearance. The diagnosis of acromegaly is facilitated by thetypical features of the disorder—enlargement of the hands andfeet and coarsening of facial features. Laboratory tests to detectelevated levels of GH not suppressed by a glucose load are usedto confirm the diagnosis. CT and MRI scans can detect and lo-calize the pituitary lesions. Because most of the effects of GHare mediated by IGF-1, IGF-1 levels may provide informationabout disease activity.

The treatment goals for acromegaly focus on the correctionof metabolic abnormalities and include normalization of theGH response to an oral glucose load; normalization of IGF-1levels to age- and gender-matched control levels; removal or re-duction of the tumor mass; relieving the central pressure ef-fects; improvement of adverse clinical features; and normaliza-tion of the mortality rate.12 Pituitary tumors can be removedsurgically using the transsphenoidal approach or, if that is notpossible, a transfrontal craniotomy. Radiation therapy may beused, but remission (reduction in GH levels) may not occur forseveral years after therapy. Radiation therapy also significantlyincreases the risk of hypopituitarism, hypothyroidism, hypo-adrenalism, and hypogonadism.5

Medications used for the treatment of acromegaly includethe somatostatin analogs, which produce feedback inhibitionof GH. Sustained-release preparations, which effectively inhibitGH secretion for 30 days after a single intramuscular injection,are now available.4

Isosexual Precocious PubertySexual development is considered precocious and warrants in-vestigation when it occurs before 8 years of age for girls and be-fore 9 years of age for boys. Precocious sexual development maybe idiopathic or may be caused by gonadal, adrenal, or hypo-

thalamic tumors. True isosexual precocious puberty is causedby early activation of the hypothalamic-pituitary-gonadal axis.The gonadotropin-mediated increase in size and activity of thegonads leads to increasing sex hormone production with earlydevelopment of sexual characteristics and fertility.13,14 Benignand malignant tumors of the central nervous system (CNS)can cause precocious puberty. These tumors are thought to re-move the inhibitory influences normally exerted on the hypo-thalamus during childhood. Gonadotropin-independent causesof precocious puberty include functioning ovarian tumorsand feminizing adrenal tumors in girls and congenital adrenalhyperplasia and Leydig cell tumors in boys.13

Diagnosis of precocious puberty is based on physical find-ings of early thelarche (i.e., beginning of breast development),adrenarche (i.e., beginning of augmented adrenal androgenproduction), and menarche (i.e., beginning of menstrual func-tion) in girls. The most common sign in boys is early genitalenlargement. Radiologic findings may indicate advanced boneage. Persons with precocious puberty usually are tall for theirage as children but short as adults because of the early closureof the epiphyses. CT or MRI should be used to exclude intra-cranial lesions.

Depending on the cause of precocious puberty, the treat-ment may involve surgery, medication, or no treatment. Thetreatment of choice for gonadotropin-dependent precociouspuberty is administration of a long-acting GnRH agonist.Constant levels of the hormone cause a decrease in pituitary re-sponsiveness to GnRH, leading to decreased secretion of go-nadotropic hormones and sex steroids. Parents often need ed-ucation, support, and anticipatory guidance in dealing withtheir feelings and the child’s physical needs and in relating to achild who appears older than his or her years.


In summary, hypopituitarism, which is characterized bya decreased secretion of pituitary hormones, is a conditionthat affects many of the other endocrine systems. Dependingon the extent of the disorder, it can result in decreased levelsof GH, thyroid hormones, adrenal corticosteroid hormones,and testosterone in the male and of estrogens and proges-terone in the female.

A number of hormones are essential for normal bodygrowth and maturation, including GH, insulin, thyroid hor-mone, and androgens. GH exerts its growth effects through agroup of IGFs. GH also exerts an effect on metabolism and isproduced in the adult and in the child. Its metabolic effectsinclude a decrease in peripheral use of carbohydrates and anincreased mobilization and use of fatty acids.

In children, alterations in growth include short stature, tallstature, and isosexual precocious puberty. Short stature is acondition in which the attained height is well below the fifthpercentile or the linear growth velocity is below normal for achild’s age or gender. Short stature can occur as a variant ofnormal growth (i.e., genetic short stature or constitutionalshort stature) or as the result of endocrine disorders, chronicillness, malnutrition, emotional disturbances, or chromosomaldisorders. Short stature resulting from GH deficiency can betreated with human GH preparations. In adults, GH deficiencyrepresents a deficiency carried over from childhood or onethat develops during adulthood as the result of a pituitarytumor or its treatment. GH levels also can decline with aging,

THYROID DISORDERS

Control of Thyroid FunctionThe thyroid gland is a shield-shaped structure located immedi-ately below the larynx in the anterior middle portion of theneck. It is composed of a large number of tiny, saclike structurescalled follicles (Fig. 31-4). These are the functional units of thethyroid. Each follicle is formed by a single layer of epithelial(follicular) cells and is filled with a secretory substance calledcolloid, which consists largely of a glycoprotein-iodine complexcalled thyroglobulin.

The thyroglobulin that fills the thyroid follicles is a largeglycoprotein molecule that contains 140 tyrosine amino acids.In the process of thyroid synthesis, iodine is attached to these

tyrosines. Both thyroglobulin and iodide are secreted into thecolloid of the follicle by the follicular cells.

The thyroid is remarkably efficient in its use of iodide. Adaily absorption of 100 to 200 µg of dietary iodide is sufficientto form normal quantities of thyroid hormone. In the processof removing it from the blood and storing it for future use,iodide is pumped into the follicular cells against a concentra-tion gradient. As a result, the concentration of iodide in thenormal thyroid gland is approximately 30 times that in theblood.2

Once inside the follicle, most of the iodide is oxidized by theenzyme peroxidase in a reaction that facilitates combinationwith a tyrosine molecule to form monoiodotyrosine and thendiiodotyrosine (Fig. 31-5). Two diiodotyrosine residues arecoupled to form thyroxine (T4), or a monoiodotyrosine and adiiodotyrosine are coupled to form triiodothyronine (T3). OnlyT4 (93%) and T3 (7%) are released into the circulation.2 Thereis evidence that T3 is the active form of the hormone and thatT4 is converted to T3 before it can act physiologically.

Thyroid hormones are bound to thyroid-binding globulinand other plasma proteins for transport in the blood. Only thefree hormone enters cells and regulates the pituitary feedbackmechanism. Protein-bound thyroid hormone forms a largereservoir that is slowly drawn on as free thyroid hormone isneeded. There are three major thyroid-binding proteins: thy-roid hormone-binding globulin (TBG), thyroxine-binding pre-albumin (TBPA), and albumin. More than 99% of T4 and T3 iscarried in the bound form. TBG carries approximately 70% ofT4 and T3; TBPA binds approximately 10% of circulating T4 andlesser amounts of T3; and albumin binds approximately 15%of circulating T4 and T3.

A number of disease conditions and pharmacologic agentscan decrease the amount of binding protein in the plasma orinfluence the binding of hormone. Congenital TBG deficiency


and there has been interest in the effects of declining GHlevels in the elderly (described as the somatopause).

Tall stature refers to the condition in which children aretall for their age and gender. It can occur as a variant of nor-mal growth (i.e., genetic tall stature or constitutional tallstature) or as the result of a chromosomal abnormality or GHexcess. GH excess in adults results in acromegaly, which in-volves proliferation of bone, cartilage, and soft tissue alongwith the metabolic effects of excessive hormone levels.

Isosexual precocious puberty defines a condition of earlyactivation of the hypothalamic-pituitary-gonadal axis (i.e., be-fore 8 years of age in girls and 9 years of age in boys), result-ing in the development of appropriate sexual characteristicsand fertility. It causes tall stature during childhood but resultsin short stature in adulthood because of the early closure ofthe epiphyses.

Superior parathyroid

Inferiorparathyroid

Lateral lobeof thyroid

Lateral viewFront view

Thyroid gland

Lateral lobe

Isthmus

Follicularcells

Colloid

Thyroidfollicle

■ FIGURE 31-4 ■ The thyroid gland and the follicular structure.

Coldtemperature

Hypothalamus

Anteriorpituitary

Thyroid gland

Target organs

Thyrotropin-Releasing Hormone (TRH)

TSH

T3 and T4

Sleep Stress

Inhi

bitio

n

■ FIGURE 31-6 ■ The hypothalamic-pituitary-thyroid feedbacksystem, which regulates the body levels of thyroid hormone.

is an X-linked trait that occurs in 1 of every 2500 live births.Corticosteroid medications and systemic disease conditionssuch as protein malnutrition, nephrotic syndrome, and cirrho-sis decrease TBG concentrations. Medications such as pheny-toin, salicylates, and diazepam may bind to TBG, displacing T4

and T3, effectively producing a low TBG state.The secretion of thyroid hormone is regulated by the hypo-

thalamic-pituitary-thyroid feedback system (Fig. 31-6). In thissystem, thyrotropin-releasing hormone (TRH), which is pro-duced by the hypothalamus, controls the release of thyroid-stimulating hormone (TSH) from the anterior pituitary gland.TSH, in turn, increases the overall activity of the thyroid glandby promoting the release of thyroid hormone into the blood-stream and increasing T4 and T3 synthesis. The effect of TSH onthe release of thyroid hormones occurs within approximately30 minutes, but the other effects require days or weeks.

Increased levels of thyroid hormone act in the feedbackinhibition of TRH or TSH. High levels of iodide (e.g., from

iodide-containing cough syrup or kelp tablets) also cause atemporary decrease in thyroid activity that lasts for severalweeks, probably through a direct inhibition of TSH on the thy-roid. Cold exposure is one of the strongest stimuli for increasedthyroid hormone production and probably is mediated throughTRH from the hypothalamus. Various emotional reactions alsocan affect the output of TRH and TSH and therefore indirectlyaffect secretion of thyroid hormones.

Actions of Thyroid HormoneAll the major organs in the body are affected by altered levelsof thyroid hormone. Thyroid hormone has two major func-tions: it increases metabolism and protein synthesis, and it isnecessary for growth and development in children, includingmental development and attainment of sexual maturity.

Metabolic Rate. Thyroid hormone increases the metabolismof all body tissues except the retina, spleen, testes, and lungs.The basal metabolic rate can increase by 60% to 100% abovenormal when large amounts of T4 are present.2 As a result ofthis higher metabolism, the rate of glucose, fat, and protein useincreases. Lipids are mobilized from adipose tissue, and the ca-tabolism of cholesterol by the liver is increased. Blood levels ofcholesterol are decreased in hyperthyroidism and increased inhypothyroidism. Muscle proteins are broken down and used asfuel, probably accounting for some of the muscle fatigue thatoccurs with hyperthyroidism. The absorption of glucose fromthe gastrointestinal tract is increased. Because vitamins are es-sential parts of metabolic enzymes and coenzymes, an increasein the metabolic rate “speeds up” the use of vitamins and tendsto cause vitamin deficiency.

Cardiovascular Function. Cardiovascular and respiratory func-tions are strongly affected by thyroid function. With an increasein metabolism, there is an increase in oxygen consumption andproduction of metabolic end-products, with an accompanyingincrease in vasodilatation. Blood flow to the skin, in particular,is augmented as a means of dissipating the body heat that re-sults from the higher metabolism. Blood volume, cardiac out-put, and ventilation all are increased as a means of maintain-


KEY CONCEPTS

THYROID HORMONE

■ Thyroid hormone increases the metabolism and pro-tein synthesis in nearly all of the tissues of the body.

■ Hypothyroidism produces a decrease in metabolicrate, an accumulation of a hydrophilic mucopolysac-charide substance (myxedema) in the connectivetissues throughout the body, and an elevation inserum cholesterol.

■ Hyperthyroidism has an effect opposite that of hypo-thyroidism. It produces an increase in metabolic rateand oxygen consumption, increased use of meta-bolic fuels, and increased sympathetic nervousystem responsiveness.

HO CH2CH COOH NH2

Tyrosine

HO CH2CH COOH NH2

CH2CH COOH NH2

Monoiodotyrosine Triiodothyronine (T3)

HO CH2CH COOH NH2

Diiodotyrosine

HO O

CH2CH COOH NH2

Thyroxine (T4)

HO O

■ FIGURE 31-5 ■ Chemistry of thyroid hormone production.

ing blood flow and oxygen delivery to body tissues. Heart rateand cardiac contractility are enhanced as a means of maintain-ing the needed cardiac output. However, blood pressure islikely to change little because the increase in vasodilatationtends to offset the increase in cardiac output.

Gastrointestinal Function. Thyroid hormone enhances gastro-intestinal function, causing an increase in motility and pro-duction of gastrointestinal secretions that often results in diar-rhea. An increase in appetite and food intake accompanies thehigher metabolic rate that occurs with increased thyroid hor-mone levels. At the same time, weight loss occurs because ofthe increased use of calories.

Neuromuscular Effects. Thyroid hormone has marked effectson neural control of muscle function and tone. Slight eleva-tions in hormone levels cause skeletal muscles to react morevigorously, and a drop in hormone levels causes muscles toreact more sluggishly. In the hyperthyroid state, a fine muscletremor is present. The cause of this tremor is unknown, but itmay represent an increased sensitivity of the neural synapses inthe spinal cord that control muscle tone.

In the infant, thyroid hormone is necessary for normalbrain development. The hormone enhances cerebration; inthe hyperthyroid state, it causes extreme nervousness, anxiety,and difficulty in sleeping.

Evidence suggests a strong interaction between thyroid hor-mone and the sympathetic nervous system. Many of the signsand symptoms of hyperthyroidism suggest overactivity of thesympathetic division of the autonomic nervous system, such astachycardia, palpitations, and sweating. Tremor, restlessness,anxiety, and diarrhea also may reflect autonomic nervous sys-tem imbalances. Drugs that block sympathetic activity haveproved to be valuable adjuncts in the treatment of hyper-

thyroidism because of their ability to relieve some of these un-desirable symptoms.

Tests of Thyroid FunctionThe diagnosis of thyroid disorders is based on tests of T3, T4,and TSH levels, radioiodine uptake studies, thyroid scans,ultrasound, and CT or MRI scans.15 Measures of T3, T4, andTSH have been made available through immunoassay meth-ods. The free T4 test measures the unbound portion of T4 that isfree to enter cells to produce its effects. Ultrasensitive TSH mea-surements are used to diagnose hyperthyroidism and hypo-thyroidism, as well differentiate between primary and sec-ondary thyroid disorders. T3, T4, and free T4 levels are low inprimary hypothyroidism, and the TSH level (via negative feed-back) is elevated.

The radioiodine (123I) uptake test measures the ability of thethyroid gland to remove and concentrate iodine from theblood. Thyroid scans (i.e., 123I, 99mTc-pertechnetate) can be usedto detect thyroid nodules and determine the functional activityof the thyroid gland. Ultrasonography can be used to differen-tiate cystic from solid thyroid lesions, and CT and MRI scansare used to demonstrate tracheal compression or impingementon other neighboring structures.

Alterations in Thyroid FunctionAn alteration in thyroid function can represent a hypofunc-tional or a hyperfunctional state. The manifestations of thesetwo altered states are summarized in Table 31-1. Disorders ofthe thyroid may be caused by a congenital defect in thyroid de-velopment, or they may develop later in life, with a gradual orsudden onset.

Goiter is an increase in the size of the thyroid gland. It canoccur in hypothyroid, euthyroid, and hyperthyroid states.


Manifestations of Hypothyroid and Hyperthyroid StatesTABLE 31-1

Basal metabolic rate

Sensitivity to catecholamines

General features

Blood cholesterol levels

General behavior

Cardiovascular function

Gastrointestinal function

Respiratory function

Muscle tone and reflexes

Temperature tolerance

Skin and hair

Weight

Decreased

Decreased

Myxedematous featuresDeep voiceImpaired growth (child)

Increased

Mental retardation (infant)Mental and physical sluggishnessSomnolence

Decreased cardiac outputBradycardia

ConstipationDecreased appetite

Hypoventilation

Decreased

Cold intolerance

Decreased sweatingCoarse and dry skin and hair

Gain

Level of Organization Hypothyroidism Hyperthyroidism

Increased

Increased

ExophthalmosLid lagDecreased blinking

Decreased

Restlessness, irritability, anxietyHyperkinesisWakefulness

Increased cardiac outputTachycardia and palpitations

DiarrheaIncreased appetite

Dyspnea

Increased, with tremor and fibrillatory twitching

Heat intolerance

Increased sweatingThin and silky skin and hair

Loss

Goiters may be diffuse, involving the entire gland without evi-dence of nodularity, or they may contain nodules. Diffuse goi-ters usually become nodular. Goiters may be toxic, producingsigns of extreme hyperthyroidism, or thyrotoxicosis, or theymay be nontoxic. Diffuse nontoxic and multinodular goitersare the result of compensatory hypertrophy and hyperplasia offollicular epithelium from some derangement that impairs thy-roid hormone output (Fig. 31-7).

The degree of thyroid enlargement usually is proportionalto the extent and duration of thyroid deficiency. Multinodulargoiters produce the largest thyroid enlargements and often areassociated with thyrotoxicosis. When sufficiently enlarged, they

may compress the esophagus and trachea, causing difficulty inswallowing, a choking sensation, and inspiratory stridor. Suchlesions also may compress the superior vena cava, producingdistention of the veins of the neck and upper extremities, edemaof the eyelids and conjunctiva, and syncope with coughing.

HypothyroidismHypothyroidism can occur as a congenital or an acquired de-fect. Congenital hypothyroidism develops prenatally and ispresent at birth. Acquired hypothyroidism develops later in lifebecause of primary disease of the thyroid gland or secondary todisorders of hypothalamic or pituitary origin.

Congenital HypothyroidismCongenital hypothyroidism is a common cause of preventablemental retardation. It affects approximately 1 of 4000 infants.16

Hypothyroidism in the infant may result from a congenital lackof the thyroid gland, abnormal biosynthesis of thyroid hor-mone, or deficient TSH secretion. With congenital lack of thethyroid gland, the infant usually appears normal and functionsnormally at birth because of the transplacental passage of mod-erate amounts of maternal T4. The manifestations of untreatedcongenital hypothyroidism are referred to as cretinism. How-ever, the term does not apply to the normally developing infantin whom replacement thyroid hormone therapy was institutedshortly after birth.

Thyroid hormone is essential for normal brain develop-ment and growth, almost half of which occurs during the first6 months of life. If untreated, congenital hypothyroidism causesmental retardation and impairs growth. Fortunately, neonatalscreening tests have been instituted to detect congenital hypo-thyroidism during early infancy. Screening usually is done in the hospital nursery. In this test, a drop of blood is takenfrom the infant’s heel and analyzed for T4 and TSH.

Transient congenital hypothyroidism has been recognizedmore frequently since the introduction of neonatal screening.It is characterized by high TSH levels and low thyroid hormonelevels. The fetal and infant thyroids are sensitive to iodine ex-cess. Iodine crosses the placenta and mammary glands and isreadily absorbed by infant skin. Transient hypothyroidism maybe caused by maternal or infant exposure to substances such astopical iodine-containing disinfectants (e.g., iodine-containingdouches or nursery disinfectants). Antithyroid drugs such aspropylthiouracil, methimazole, and carbimazole also cross theplacenta and block fetal thyroid function.

Congenital hypothyroidism is treated by hormone replace-ment. Evidence indicates that it is important to normalize T4

levels as rapidly as possible (in the first 6 weeks of life) becausea delay is accompanied by poorer psychomotor and mental de-velopment. Dosage levels are adjusted as the child grows. In-fants with transient hypothyroidism usually can have the re-placement therapy withdrawn at 6 to 12 months. When earlyand adequate treatment regimens are followed, the risk of men-tal retardation in infants detected by screening programs essen-tially is nonexistent.

Acquired Hypothyroidism and MyxedemaAcquired hypothyroidism in older children and adults repre-sents a decrease in thyroid function resulting from destruction ordysfunction of the thyroid gland (i.e., primary hypothyroidism)


■ FIGURE 31-7 ■ (A) Middle-aged woman with a nontoxic (nodu-lar) goiter that has enlarged to produce a conspicuous neck mass.(B) Microscopic view of one of the macroscopic nodules showsmarked variation in size of the follicles. (Rubin E., Farber J.L.[1999]. Pathology [3rd ed., p. 1164]. Philadelphia: LippincottWilliams & Wilkins)

A

B

or impaired hypothalamic or pituitary function (i.e., secondaryhypothyroidism).

Primary hypothyroidism is much more common than sec-ondary hypothyroidism. It may result from thyroidectomy(i.e., surgical removal) or ablation of the gland with radiation.Certain goitrogenic agents, such as lithium carbonate (i.e., usedin the treatment of manic-depressive states) and the anti-thyroid drugs propylthiouracil and methimazole in continu-ous dosage can block hormone synthesis and produce hypo-thyroidism with goiter. Iodine-containing drugs (e.g., kelptablets, iodide-containing cough syrups, radiographic contrastmedia) also can block thyroid hormone production, particu-larly in persons with autoimmune thyroid disease. Amiodarone(an antiarrhythmic drug), which contains 75 mg of iodine per200-mg tablet, is being increasingly implicated in causing thy-roid problems. Iodine deficiency, which can cause goiter andhypothyroidism, is rare in the United States because of thewidespread use of iodized salt and other iodide sources.

Hashimoto’s thyroiditis is an autoimmune disorder in whichthe thyroid gland may be totally destroyed by an immunologicprocess.1 It is the major cause of goiter and hypothyroidism inchildren and adolescents.16 Hashimoto’s thyroiditis is pre-dominantly a disease of women, with a female-to-male ratio of10�1 to 20�1.1 The course of the disease varies. At the onset,only a goiter may be present. In time, hypothyroidism usuallybecomes evident. Although the disorder usually causes hypo-thyroidism, a hyperthyroid state may develop midcourse in thedisease. The transient hyperthyroid state is caused by leakage ofpreformed thyroid hormone from damaged cells of the gland.

Clinical Manifestations. The clinical manifestations of hypo-thyroidism can range from mild nonspecific complaints asso-ciated with subclinical hypothyroidism to those associatedwith overt hypothyroidism.17 The manifestations of the overthypothyroidism are related largely to two factors: the hypo-metabolic state resulting from thyroid hormone deficiency,and myxedematous involvement of body tissues.

The hypometabolic state is characterized by a gradual onsetof weakness and fatigue, a tendency to gain weight despite aloss of appetite, and cold intolerance. As the condition pro-gresses, the skin becomes dry and rough and acquires a paleyellowish cast, which primarily results from carotene deposi-tion, and the hair becomes coarse and brittle. There can be lossof the lateral one third of the eyebrows. Gastrointestinal motil-ity is decreased, producing constipation, flatulence, and abdo-minal distention. Nervous system involvement is manifestedin mental dullness, lethargy, and impaired memory.

Myxedema represents the presence of a nonpitting mucoustype of edema caused by an accumulation of a hydrophilicmucopolysaccharide substance in the connective tissuesthroughout the body. As a result of myxedematous fluid ac-cumulation, the face takes on a characteristic puffy look, espe-cially around the eyes, the tongue becomes enlarged, and thevoice hoarse and husky (Fig. 31-8). Mucopolysaccharide de-posits in the heart can cause generalized cardiac dilatation,bradycardia, and other signs of altered cardiac function. Thesigns and symptoms of hypothyroidism are summarized inTable 31-1.

Diagnosis and Treatment. Diagnosis of hypothyroidism isbased on history and physical examination and laboratory mea-

surement of TSH and free T4 levels. The condition is treatedwith replacement therapy using synthetic preparations of T3 orT4. Most people are treated with T4. Serum TSH levels are usedto estimate the adequacy of T4 replacement therapy.

Myxedematous Coma. Myxedematous coma is a life-threatening, end-stage expression of hypothyroidism. It ischaracterized by coma, hypothermia, cardiovascular collapse,hypoventilation, and severe metabolic disorders that includehyponatremia, hypoglycemia, and lactic acidosis.18 It occursmost often in elderly women who have chronic hypothyroid-ism from a spectrum of causes. It occurs more frequently in thewinter months, which suggests that cold exposure may be aprecipitating factor. The severely hypothyroid person is unableto metabolize sedatives, analgesics, and anesthetic drugs, andbuildup of these agents may precipitate coma.

Treatment includes aggressive management of precipitat-ing factors; supportive therapy such as management of cardio-respiratory status, hyponatremia, and hypoglycemia; and thy-roid replacement therapy. Prevention is preferable to treatmentand entails special attention to high-risk populations, such aswomen with a history of Hashimoto’s thyroiditis. These per-sons should be informed about the signs and symptoms of se-vere hypothyroidism and the need for early medical treatment.

HyperthyroidismHyperthyroidism, or thyrotoxicosis, results from excessive de-livery of thyroid hormone to the peripheral tissues. The mostcommon cause of hyperthyroidism is Graves’ disease, which isaccompanied by ophthalmopathy (exophthalmos, i.e., bulgingof the eyeballs) and goiter. Other causes of hyperthyroidism


are multinodular goiter, adenoma of the thyroid, and occa-sionally, ingestion of excessive thyroid hormone. Thyroid cri-sis, or storm, is an acutely exaggerated manifestation of thehyperthyroid state.

Many of the manifestations of hyperthyroidism are relatedto the increase in oxygen consumption and use of metabolicfuels associated with the hypermetabolic state, as well as tothe increase in sympathetic nervous system activity. With thehypermetabolic state, there are frequent complaints of ner-vousness, irritability, and fatigability. Weight loss is common,despite a large appetite. Other manifestations include tachy-cardia, palpitations, shortness of breath, excessive sweating,muscle cramps, and heat intolerance. The person appears rest-less and has a fine muscle tremor. Even in persons without ex-ophthalmos, there is an abnormal retraction of the eyelids andinfrequent blinking such that they appear to be staring. Thehair and skin usually are thin and have a silky appearance. Thesigns and symptoms of hyperthyroidism are summarized inTable 31-1.

The treatment of hyperthyroidism is directed toward reduc-ing the level of thyroid hormone. This can be accomplishedwith eradication of the thyroid gland with radioactive iodine,through surgical removal of part or all of the gland, or the useof drugs that decrease thyroid function and thereby the effectof thyroid hormone on the peripheral tissues. Destruction ofthyroid tissue with radioactive iodine is used more frequentlythan surgery. The β-adrenergic–blocking drug propranolol maybe used to block the effects of the hyperthyroid state on sym-pathetic nervous system function. It is given in conjunctionwith other antithyroid drugs such as propylthiouracil and me-thimazole. These drugs prevent the thyroid gland from con-verting iodine to its organic (hormonal) form and block theconversion of T4 to T3 in the tissues.

Graves’ DiseaseGraves’ disease is a state of hyperthyroidism, goiter, and oph-thalmopathy (or, less commonly, dermopathy).19,20 The onsetusually is between the ages of 20 and 40 years, and women arefive times more likely to experience the disease than men.Graves’ disease is an autoimmune disorder characterized by ab-normal stimulation of the thyroid gland by thyroid-stimulatingantibodies (thyroid-stimulating immunoglobulins [TSI]) thatact through the normal TSH receptors. It may be associatedwith other autoimmune disorders, such as myasthenia gravisand pernicious anemia. The disease is associated with humanleukocyte antigen (HLA)-DR3 and HLA-B8, and a familial ten-dency is evident.

The exophthalmos, which occurs in as many as one third ofpersons with Graves’ disease, is thought to result from thyroid-stimulating antibodies sensitized to interact with antigensfound in fibroblasts in orbital tissue behind the eyeball andin the extraocular muscles that move the eyeball.21,22 The oph-thalmopathy of Graves’ disease can cause severe eye prob-lems, including paralysis of the extraocular muscles; involve-ment of the optic nerve, with some visual loss; and cornealulceration because the lids do not close over the protrudingeyeball. The exophthalmos usually tends to stabilize after treat-ment of the hyperthyroidism. Unfortunately, not all of the oc-ular changes are reversible with treatment. Smoking tends toaggravate the condition. Figure 31-9 depicts a woman withGraves’ disease.

Thyroid StormThyroid storm, or crisis, is an extreme and life-threatening formof thyrotoxicosis, rarely seen today because of improved diag-nosis and treatment methods. When it does occur, it is seenmost often in undiagnosed cases or in persons with hyper-thyroidism who have not been adequately treated. It often isprecipitated by stress such as an infection (usually respiratory),diabetic ketoacidosis, physical or emotional trauma, or ma-nipulation of a hyperactive thyroid gland during thyroidec-tomy. Thyroid storm is manifested by a very high fever, extremecardiovascular effects (i.e., tachycardia, congestive failure, andangina), and severe CNS effects (i.e., agitation, restlessness, anddelirium). Thyroid storm requires rapid diagnosis and imple-mentation of treatment.


■ FIGURE 31-9 ■ Graves’ disease. A young woman with hyper-thyroidism presented with a mass in the neck and exophthalmos.(Rubin E., Farber J.L. [1999]. Pathology [3rd ed., p. 1167].Philadelphia: Lippincott Williams & Wilkins)

In summary, thyroid hormones play a role in the meta-bolic process of almost all body cells and are necessary fornormal physical and mental growth in the infant and youngchild. Alterations in thyroid function can manifest as a hypo-thyroid or a hyperthyroid state. Hypothyroidism can occur asa congenital or an acquired defect. Congenital hypothyroid-ism leads to mental retardation and impaired physical growthunless treatment is initiated during the first months of life.Acquired hypothyroidism leads to a decrease in metabolicrate and an accumulation of a mucopolysaccharide substancein the intercellular spaces; this substance attracts water andcauses a mucous type of edema called myxedema. Hyper-thyroidism causes an increase in metabolic rate and alter-ations in body function similar to those produced by en-hanced sympathetic nervous system activity. Graves’ disease,which is caused by thyroid-stimulating antibodies, is charac-terized by hyperthyroidism, goiter, and ophthalmopathy.

PARATHYROID HORMONE DISORDERS

Parathyroid hormone (PTH), a major regulator of serum cal-cium and phosphate, is secreted by the parathyroid glands.There are four parathyroid glands located on the dorsal surfaceof the thyroid gland.1 The dominant regulator of PTH is a de-crease in serum calcium concentration. A unique calcium re-ceptor within the parathyroid cell membrane responds rapidlyto changes in serum calcium levels. The response to a decreasein serum calcium is prompt, occurring within seconds. Phos-phate does not exert a direct effect on PTH secretion. Instead, itacts indirectly by complexing with calcium and decreasingserum calcium concentration.

The secretion, synthesis, and action of PTH are also influ-enced by magnesium. Magnesium serves as a cofactor in thegeneration of cellular energy and is important in the functionof second messenger systems. Magnesium’s effects on the syn-thesis and release of PTH are thought to be mediated throughthese mechanisms.23 Because of its function in regulating PTHrelease, severe and prolonged hypomagnesemia can markedlyinhibit PTH levels.

The main function of PTH is to maintain the calcium con-centration of the extracellular fluids. It performs this functionby promoting the release of calcium from bone, increasing theactivation of vitamin D as a means of enhancing intestinal ab-sorption of calcium, and stimulating calcium conservation bythe kidney while increasing phosphate excretion (Fig. 31-10).

Parathyroid hormone acts on bone to accelerate the mobi-lization and transfer of calcium to the extracellular fluid. Theskeletal response to PTH is a two-step process. There is an im-mediate response in which calcium that is present in bone fluidis released into the extracellular fluid and a second more slowlydeveloping response in which completely mineralized bone isresorbed resulting in the release of both calcium and phos-phate The actions of PTH in terms of bone resorption requirenormal levels of both vitamin D and magnesium.

The activation of vitamin D by the kidney is enhanced bythe presence of PTH; it is through the activation of vitamin Dthat PTH increases intestinal absorption of calcium and phos-phate. PTH acts directly on the kidney to increase tubular re-absorption of calcium and magnesium while increasing phos-phate elimination. The accompanying increase in phosphateelimination ensures that calcium released from bone does notproduce hyperphosphatemia and increase the risk of soft tissuedeposition of calcium/phosphate crystals.

HypoparathyroidismHypoparathyroidism reflects deficient PTH secretion resultingin hypocalcemia. PTH deficiency may be caused by a congeni-tal absence of all of the parathyroid glands, such as occurs inDiGeorge syndrome.24 An acquired deficiency of PTH mayoccur after neck surgery, particularly if the surgery involves re-moval of a parathyroid adenoma, thyroidectomy, or bilateralneck resection for cancer. Hypoparathyroidism may also havean autoimmune origin. Antiparathyroid antibodies have beendetected in some persons with hypoparathyroidism, particu-larly those with multiple endocrine disorders. Other causes ofhypoparathyroidism include heavy metal damage, such as oc-curs with Wilson’s disease, metastatic tumors, and infection.

Functional impairment of parathyroid function occurs withmagnesium deficiency. Correction of the hypomagnesemia re-sults in rapid disappearance of the condition.

Manifestations of acute hypoparathyroidism that resultfrom a decrease in serum calcium include tetany with musclecramps, carpopedal spasm, and convulsions (see discussion ofhypocalcemia in Chapter 6). Paresthesias, such as tingling ofthe circumoral area and in the hands and feet, are almost al-ways present. There may be prolongation of the QT intervalcaused by low calcium levels, resistance to digitalis, hypoten-sion, and refractory heart failure. Symptoms of chronic defi-ciency include lethargy, anxiety state, and personality changes.There may be blurring of vision caused by cataracts, which de-velop during an extended period of time. Extrapyramidalsigns, such as those seen with Parkinson’s disease, may occurbecause of calcification of the basal ganglia. Successful treat-ment of the hypocalcemia may improve the disorder and issometimes associated with decreases in basal ganglia calcifica-tion on x-ray. Teeth may be defective if the disorder occurs dur-ing childhood.

Diagnosis of hypoparathyroidism is based on low serumcalcium levels, high serum phosphate levels, and low serumPTH levels. Serum magnesium levels are usually measured toexclude hypomagnesemia as a cause of the disorder.


Decreasedserumcalcium

Parathyroid hormone

Activatedvitamin D

Bonereleaseof calcium

Intestineincreasedcalciumabsorption

Kidney decreased calcium elimination and increasedphosphateelimination

Increasedserumcalcium

Feedback

■ FIGURE 31-10 ■ Regulation of serum calcium concentration byparathyroid hormone.

Acute hypoparathyroid tetany is treated with intravenouscalcium gluconate followed by oral administration of calciumsalts and vitamin D. Magnesium supplementation is used whenthe disorder is caused by magnesium deficiency. Persons withchronic hypoparathyroidism are treated with oral calcium andvitamin D. Serum calcium levels are monitored at regular in-tervals (at least every 3 months) as a means of maintainingserum calcium within a slightly low but asymptomatic range.Maintaining serum calcium within this range helps to preventhypercalciuria and kidney damage.

Pseudohypoparathyroidism is a rare familial disorder char-acterized by target tissue resistance to PTH. It is characterizedby hypocalcemia, increased parathyroid function, and a varietyof congenital defects in the growth and development of theskeleton, including short stature and short metacarpal andmetatarsal bones. There are variants in the disorders, with somepersons having the pseudohypoparathyroidism with the con-genital defects and others having the congenital defects withnormal calcium and phosphate levels. The manifestations ofthe disorder are primarily attributable to hypocalcemia. Treat-ment is similar to that for hypoparathyroidism.

HyperparathyroidismHyperparathyroidism is caused by hypersecretion of parathy-roid hormone. Hyperparathyroidism can manifest as a primarydisorder caused by hyperplasia, an adenoma, or carcinoma ofthe parathyroid glands or as a secondary disorder seen in per-sons with renal failure.25

Primary hyperparathyroidism is seen more commonly afterage 50 years and is more common in women than men.Primary hyperparathyroidism causes hypercalcemia and an in-crease in calcium in the urine filtrate, resulting in hypercalcuriaand the potential for development of kidney stones. Chronicbone resorption may produce diffuse demineralization, patho-logic fractures, and cystic bone lesions. Signs and symptoms ofthe disorder are related to skeletal abnormalities, exposure ofthe kidney to high calcium levels, and elevated serum calciumlevels (see hypercalcemia). Diagnostic procedures includeserum calcium and parathyroid hormone levels. Imaging stud-ies of the parathyroid area may be used to identify a para-thyroid adenoma.

Secondary hyperparathyroidism involves hyperplasia of theparathyroid glands and occurs primarily in persons with renalfailure (see Chapter 24).25 In early renal failure, an increase inPTH results from decreased serum calcium and activated vita-min D levels. As the disease progresses, there is a decrease in vit-amin D and calcium receptors, making the parathyroid glandsmore resistant to vitamin D and calcium. At this point, elevatedphosphate levels induce hyperplasia of the parathyroid glandsindependent of calcium and activated vitamin D.

The bone disease seen in persons with secondary hyper-parathyroidism caused by renal failure is known as renal osteo-dystrophy. Treatment includes resolving the hypercalcemiawith large fluid intake. Persons with mild disease are advised tokeep active and drink adequate fluids. They also are advised toavoid calcium-containing antacids, vitamin D, and thiazide di-uretics, which increase reabsorption of calcium by the kidney.Bisphosphonates (e.g., pamidronate and alendronate), whichare potent inhibitors of bone resorption, may be used tem-porarily to treat the hypercalcemia of hyperparathyroidism.

Parathyroidectomy may be indicated in persons with sympto-matic hyperthyroidism, kidney stones, or bone disease.

DISORDERS OF ADRENAL CORTICAL FUNCTION

Control of Adrenal Cortical FunctionThe adrenal glands are small, bilateral structures that weigh ap-proximately 5 g each and lie retroperitoneally at the apex ofeach kidney (Fig. 31-11). The medulla or inner portion of thegland secretes epinephrine and norepinephrine and is part ofthe sympathetic nervous system. The cortex forms the bulk ofthe adrenal gland and is responsible for secreting three types of hormones: the glucocorticoids, the mineralocorticoids, andthe adrenal sex hormones. Because the sympathetic nervoussystem also secretes epinephrine and norepinephrine, adrenalmedullary function is not essential for life, but adrenal corticalfunction is.

Biosynthesis, Transport, and MetabolismMore than 30 hormones are produced by the adrenal cortex. Ofthese hormones, aldosterone is the principal mineralocorti-coid, cortisol (hydrocortisone) is the major glucocorticoid, andandrogens are the chief sex hormones.1 All of the adrenal cor-tical hormones have a similar structure in that all are steroidsand are synthesized from acetate and cholesterol. Each of thesteps involved in the synthesis of the various hormones re-quires a specific enzyme (Fig. 40-11). The secretion of the glu-cocorticoids and the adrenal androgens is controlled by theACTH secreted by the anterior pituitary gland.

Cortisol and the adrenal androgens are secreted in an un-bound state and bind to plasma proteins for transport in thecirculatory system. Cortisol binds largely to corticosteroid-binding globulin and to a lesser extent to albumin. Aldosteronecirculates mostly bound to albumin. It has been suggested thatthe pool of protein-bound hormones may extend the durationof their action by delaying metabolic clearance.

The main site for metabolism of the adrenal cortical hor-mones is the liver, where they undergo a number of metabolicconversions before being conjugated and made water soluble.They are then eliminated in either urine or bile.


Zonaglomerulosa

Zonafasciculata

Zonareticularis

Cortex

Medulla

■ FIGURE 31-11 ■ The adrenal gland, showing the medulla andthe three layers of the cortex. The zona glomerulosa is the outerlayer of the cortex and is primarily responsible for mineralocorti-coid production. The middle layer, the zona fasciculata, and theinner layer, the zona reticularis, produce the glucocorticoids andthe adrenal sex hormones.

Adrenal Sex HormonesThe adrenal sex hormones are synthesized primarily by the zonareticularis and the zona fasciculata of the cortex (see Fig. 31-12).These sex hormones probably exert little effect on normal sex-ual function. However, there is evidence that the adrenal sexhormones (the most important of which is dehydroepiandros-terone) contribute to the pubertal growth of body hair, particu-larly pubic and axillary hair in women. They also may play arole in the steroid hormone economy of the pregnant womanand the fetal-placental unit.

MineralocorticoidsThe mineralocorticoids play an essential role in regulatingpotassium and sodium levels and water balance. They are pro-duced in the zona glomerulosa, the outer layer of cells of theadrenal cortex. Aldosterone secretion is regulated by the renin-angiotensin mechanism and by blood levels of potassium.Increased levels of aldosterone promote sodium retention bythe distal tubules of the kidney while increasing urinary lossesof potassium. The influence of aldosterone on fluid and elec-trolyte balance is discussed in Chapter 6, and its effect on bloodpressure is discussed in Chapter 16.

GlucocorticoidsThe glucocorticoid hormones, mainly cortisol, are synthesizedin the zona fasciculata and the zona reticularis of the adrenalgland. The blood levels of these hormones are regulated bynegative feedback mechanisms of the hypothalamic-pituitary-adrenal (HPA) system (Fig. 31-13). The hypothalamus releasescorticotropin-releasing hormone, which is important in con-trolling the release of ACTH from the pituitary.1 Cortisol levels


KEY CONCEPTS

ADRENAL CORTICAL HORMONES

■ The adrenal cortex produces three types of steroidhormones: the mineralocorticoids (principally aldo-sterone), which function in sodium, potassium, andwater balance; the glucocorticoids (principally corti-sol), which aid in regulating the metabolic functionsof the body and in controlling the inflammatory re-sponse, and are essential for survival in stress situa-tions; and the adrenal sex hormones (principallyandrogens), which serve mainly as a source of an-drogens for women.

■ The manifestations of adrenal cortical insufficiencyare related mainly to mineralocorticoid deficiencyand glucocorticoid deficiency.

■ The manifestations of adrenal cortical excess are re-lated to mineralocorticoid excess, glucocorticoid ex-cess with derangements in glucose metabolism andimpaired ability to respond to stress because of inhi-bition of inflammatory and immune responses, andsigns of increased androgen levels, such as hirsutismin women.

increase as ACTH levels rise and decrease as ACTH levels fall.There is considerable diurnal variation in ACTH levels, whichreach their peak in the early morning (around 6 to 8 AM) anddecline as the day progresses (Fig. 31-14). This appears to be at-tributable to rhythmic activity in the CNS, which causes burstsof corticotropin-releasing hormone (CRH) secretion and, inturn, ACTH secretion. This diurnal pattern is reversed in peo-ple who work during the night and sleep during the day. Therhythm also may be changed by physical and psychologicalstresses, endogenous depression, manic-depressive psychosis,and liver disease or other conditions that affect cortisol metab-olism. One of the earliest signs of Cushing’s syndrome, a dis-order of cortisol excess, is the loss of diurnal variation in CRHand ACTH secretion.

The glucocorticoids perform a necessary function in re-sponse to stress and are essential for survival. When producedas part of the stress response, these hormones aid in regulatingthe metabolic functions of the body and in controlling the in-flammatory response. The actions of cortisol are summarizedin Table 31-2.

Metabolic Effects. Cortisol stimulates glucose production bythe liver, promotes protein breakdown, and causes mobiliza-tion of fatty acids. As body proteins are broken down, aminoacids are mobilized and transported to the liver, where theyare used in the production of glucose (i.e., gluconeogenesis).Mobilization of fatty acids converts cell metabolism from theuse of glucose for energy to the use of fatty acids. As glucoseproduction by the liver increases and peripheral glucose use de-creases, a moderate resistance to insulin develops. In personswith diabetes and those who are diabetes prone, this has the ef-fect of raising the blood glucose level.

Psychological Effects. The glucocorticoid hormones appear tobe involved directly or indirectly in emotional behavior. Re-ceptors for these hormones have been identified in brain tissue,which suggests that they play a role in the regulation of behav-ior. Persons treated with adrenal cortical hormones have beenknown to display behavior ranging from mildly aberrant topsychotic.

Immunologic and Inflammatory Effects. Cortisol influencesmultiple aspects of immunologic function and inflammatoryresponsiveness. It blocks inflammation at an early stage bydecreasing capillary permeability and stabilizing the lyso-somal membranes so that inflammatory mediators are notreleased. Cortisol suppresses the immune response by reduc-ing humoral and cell-mediated immunity. With this lessenedinflammatory response comes a reduction in fever. Duringthe healing phase, cortisol suppresses fibroblast activity andthereby lessens scar formation. Cortisol also inhibits prosta-glandin synthesis, which may account in large part for its anti-inflammatory actions. Large quantities of cortisol are requiredfor an effective anti-inflammatory action. This is achieved bythe administration of pharmacologic, rather than physio-logic, doses of synthetic cortisol.

Suppression of Adrenal FunctionA highly significant aspect of long-term therapy with pharma-cologic preparations of the adrenal cortical hormones is adre-nal insufficiency on withdrawal of the drugs. The deficiency

results from suppression of the HPA system. Chronic sup-pression causes atrophy of the adrenal gland, and the abruptwithdrawal of drugs can cause acute adrenal insufficiency.Recovery to a state of normal adrenal function may be pro-longed, requiring 12 months or more.

Tests of Adrenal FunctionSeveral diagnostic tests can be used to evaluate adrenal corti-cal function and the HPA system. Blood levels of cortisol,aldosterone, and ACTH can be measured using immunoassaymethods. A 24-hour urine specimen measures the excretionof 17-ketosteroids, 17-ketogenic steroids, and 17-hydroxy-corticosteroids. These metabolic end-products of the adrenalhormones and the male androgens provide informationabout alterations in the biosynthesis of the adrenal corticalhormones. The 24-hour urinary free cortisol is an excellentscreening test for Cushing’s syndrome.

Suppression and stimulation tests afford a means of assess-ing the state of the HPA feedback system. For example, a testdose of ACTH can be given to assess the response of the adrenal

cortex to stimulation. Similarly, administration of dexametha-sone, a synthetic glucocorticoid drug, provides a means of mea-suring negative feedback suppression of ACTH. Adrenal tumorsand ectopic ACTH-producing tumors usually are unresponsiveto ACTH suppression by dexamethasone. CRH tests can be usedto diagnose a pituitary ACTH-secreting tumor (i.e., Cushing’sdisease), especially when combined with inferior petrosal ve-nous sampling (this allows the blood drainage of the pituitaryto be sampled directly). Metyrapone (Metopirone) blocks thefinal step in cortisol synthesis, resulting in the production of11-dehydroxycortisol, which does not inhibit ACTH. This testmeasures the ability of the pituitary to release ACTH. The goldstandard test for assessing the HPA axis is the insulin hypo-glycemic stress test.

Congenital Adrenal HyperplasiaCongenital adrenal hyperplasia (CAH), or the adrenogenitalsyndrome, describes a congenital disorder caused by an auto-somal recessive trait in which a deficiency exists in any of the


HO

Pregnenolone

A

B

C

BProgesterone

17 α Hydroxyprogesterone

17 α Hydroxypregnenolone

Androgen synthesis(reticularis)

Cholesterol

Aldosteronesynthesis

(glomerulosa)

11-Deoxycorticosterone Dehydroepiandrosterone

AndrostenedioneCortisolCorticosterone

AldosteroneTestosterone

11-Deoxycortisol

D A

C

D

E

Site of enzyme action

A) 3-beta-dehydrogenaseB) 17-hydroxylaseC) 21-hydroxylaseD) 11-beta-hydroxylaseE) 18-hydroxylase

■ FIGURE 31-12 ■ Predominant biosynthetic pathwaysof the adrenal cortex. Critical enzymes in the biosyntheticprocess include 11-beta-hydroxylase and 21-hydroxylase.A deficiency in one of these enzymes blocks the synthe-sis of hormones dependent on that enzyme and routesthe precursors into alternative pathways.

enzymes necessary for the synthesis of cortisol.26,27 A commoncharacteristic of all types of CAH is a defect in the synthesis ofcortisol that results in increased levels of ACTH and adrenalhyperplasia. The increased levels of ACTH overstimulate thepathways for production of adrenal androgens. Mineralocor-ticoids may be produced in excessive or insufficient amounts,depending on the precise enzyme deficiency. Infants of bothgenders are affected. The condition is seldom diagnosed inmales at birth unless they have enlarged genitalia or lose salt

and manifest adrenal crisis. In female infants, an increase in an-drogens is responsible for creating the virilization syndrome ofambiguous genitalia, with an enlarged clitoris, fused labia, andurogenital sinus (Fig. 31-15). In male and female children,other secondary sex characteristics are normal, and fertility isunaffected if appropriate therapy is instituted.

The two most common enzyme deficiencies are 21-hydroxylase (accounting for >90% of cases) and 11-β-hydroxylase deficiency. The clinical manifestations of bothdeficiencies are largely determined by the functional proper-ties of the steroid intermediates and the completeness of theblock in the cortisol pathway.

A spectrum of 21-hydroxylase deficiency states exists, rang-ing from simple virilizing CAH to a complete salt-losing en-zyme deficiency. Simple virilizing CAH impairs the synthesis ofcortisol, and steroid synthesis is shunted to androgen produc-tion. Persons with these deficiencies usually produce sufficientaldosterone or aldosterone intermediates to prevent signs andsymptoms of mineralocorticoid deficiency. The salt-losing formis accompanied by deficient production of aldosterone and itsintermediates. This results in fluid and electrolyte disordersafter the fifth day of life, including hyponatremia, hyperkale-mia, vomiting, dehydration, and shock.

The 11-β-hydroxylase deficiency is rare and manifests a spec-trum of severity. Affected persons have excessive androgen pro-duction and impaired conversion of 11-deoxycorticosterone tocorticosterone. The overproduction of 11-deoxycorticosterone,which has mineralocorticoid activity, is responsible for thehypertension that accompanies this deficiency. Diagnosis ofadrenogenital syndrome depends on the precise biochemicalevaluation of metabolites in the cortisol pathway and on clini-cal signs and symptoms.

Medical treatment of adrenogenital syndrome includes oralor parenteral cortisol replacement. Fludrocortisone acetate, amineralocorticoid, also may be given to children who are saltlosers. Depending on the degree of virilization, reconstructivesurgery during the first 2 years of life is indicated to reduce thesize of the clitoris, separate the labia, and exteriorize the vagina.Surgery has provided excellent results and does not impair sex-ual function.


Hypothalamus

Anteriorpituitary

Adrenalcortex

Target organs

Synthetichormones

Corticotropin-releasing hormone (CRH)

ACTH

Cortisol

Inhi

bitio

n

HypoglycemiaPain

InfectionStress

TraumaHemorrhage

Sleep

■ FIGURE 31-13 ■ The hypothalamic-pituitary-adrenal (HPA)feedback system that regulates glucocorticoid (cortisol) levels.Cortisol release is regulated by ACTH. Stress exerts its effects oncortisol release through the HPA system and the corticotropin-releasing hormone (CRH), which controls the release of ACTHfrom the anterior pituitary gland. Increased cortisol levels incite anegative feedback inhibition of ACTH release. Pharmacologicdoses of synthetic steroids inhibit ACTH release by way of thehypothalamic CRH.

200

180

160

140

120

100

80

60

40

20

0Noon 4PM 8PM Mid-

night4AM 8AM Noon

Pla

sma

AC

TH

(

)

5

10

15

20

25

30

35

40

Plasm

a glucocorticoids ( )

Sleep0

■ FIGURE 31-14 ■ Pulsatile changesin the concentration of adrenocorti-cotropic hormone (ACTH) and glu-cocorticoids over a 24-hour period.The amplitude of the pulses of ACTHand glucocorticoids is lower in theevening hours and then increasesgreatly during the early morninghours. This is due to the diurnal os-cillation of the hypothalamic-pituitaryaxis. (Modified from Krieger D.T.[1979]. Rhythms of CRF, ACTH andcorticosteroids. In Krieger D.T. [Ed.],Endocrine rhythms [pp. 123–142]. NewYork: Raven)

Adrenal Cortical InsufficiencyThere are two forms of adrenal insufficiency: primary and sec-ondary. Primary adrenal insufficiency, or Addison’s disease, iscaused by destruction of the adrenal gland. Secondary adrenalinsufficiency results from a disorder of the HPA system.

Primary Adrenal Cortical InsufficiencyIn 1855, Thomas Addison, an English physician, provided thefirst detailed clinical description of primary adrenal insuffi-ciency, now called Addison’s disease. The use of this term is re-served for primary adrenal insufficiency in which adrenal cor-tical hormones are deficient and ACTH levels are elevatedbecause of lack of feedback inhibition.28–30

Addison’s disease is a relatively rare disorder in which all thelayers of the adrenal cortex are destroyed. Autoimmune de-struction is the most common cause of Addison’s disease in theUnited States. Before 1950, tuberculosis was the major cause ofAddison’s disease in the United States, and it continues to be amajor cause of the disease in countries where it is more prev-alent. Rare causes include metastatic carcinoma, fungal infec-tion (particularly histoplasmosis), cytomegalovirus infection,amyloid disease, and hemochromatosis. Bilateral adrenal hem-orrhage may occur in persons taking anticoagulants, duringopen heart surgery, and during birth or major trauma. Adrenalinsufficiency can be caused by acquired immunodeficiency syn-drome (AIDS), in which the adrenal gland is destroyed by a va-riety of opportunistic infectious agents.

Addison’s disease, like type 1 diabetes mellitus, is a chronicmetabolic disorder that requires lifetime hormone replacementtherapy. The adrenal cortex has a large reserve capacity, and themanifestations of adrenal insufficiency usually do not becomeapparent until approximately 90% of the gland has been de-stroyed. These manifestations are related primarily to miner-alocorticoid deficiency, glucocorticoid deficiency, and hyper-pigmentation resulting from elevated ACTH levels. Althoughlack of the adrenal androgens (i.e., DHEAS) exerts few effectsin men because the testes produce these hormones, womenhave sparse axillary and pubic hair.31

Mineralocorticoid deficiency causes increased urinary lossesof sodium, chloride, and water, along with decreased excre-tion of potassium. The result is hyponatremia, loss of extra-cellular fluid, decreased cardiac output, and hyperkalemia.There may be an abnormal appetite for salt. Orthostatic hypo-tension is common. Dehydration, weakness, and fatigue arecommon early symptoms. If loss of sodium and water is ex-treme, cardiovascular collapse and shock ensue. Because of alack of glucocorticoids, the person with Addison’s disease has


■ FIGURE 31-15 ■ A female infant with congenital adrenal hyper-plasia demonstrating virilization of the genitalia with hypertrophyof the clitoris and partial fusion of labioscrotal folds. (Rubin E.,Farber J.L. [1999]. Pathology [3rd ed., p. 1186]. Philadelphia:Lippincott Williams & Wilkins)

Actions of CortisolTABLE 31-2

Glucose metabolism

Protein metabolism

Fat metabolism

Anti-inflammatory action (pharmacologic levels)

Psychic effect

Permissive effect

Stimulates gluconeogenesisDecreases glucose use by the tissues

Increases breakdown of proteinsIncreases plasma protein levels

Increases mobilization of fatty acidsIncreases use of fatty acids

Stabilizes lysosomal membranes of the inflammatory cells, preventing the release ofinflammatory mediators

Decreases capillary permeability to prevent inflammatory edemaDepresses phagocytosis by white blood cells to reduce the release of inflammatory

mediatorsSuppresses the immune response

Causes atrophy of lymphoid tissueDecreases eosinophilsDecreases antibody formationDecreases the development of cell-mediated immunity

Reduces feverInhibits fibroblast activity

May contribute to emotional instability

Facilitates the response of the tissues to humoral and neural influences, such as that ofthe catecholamines, during trauma and extreme stress

Major Influence Effect on Body

poor tolerance to stress. This deficiency causes hypoglycemia,lethargy, weakness, fever, and gastrointestinal symptoms,such as anorexia, nausea, vomiting, and weight loss.

Hyperpigmentation results from elevated levels of ACTH.The skin looks bronzed or suntanned in exposed and un-exposed areas, and the normal creases and pressure points tendto become especially dark. The gums and oral mucous mem-branes may become bluish-black. The amino acid sequence ofACTH is strikingly similar to that of melanocyte-stimulatinghormone; hyperpigmentation occurs in more than 90% of per-sons with Addison’s disease and is helpful in distinguishing theprimary and secondary forms of adrenal insufficiency.

The daily regulation of the chronic phase of Addison’s dis-ease usually is accomplished with oral replacement therapy,with higher doses being given during periods of stress. The phar-macologic agent that is used should have both glucocorticoidand mineralocorticoid activity. Mineralocorticoids are neededonly in primary adrenal insufficiency. Hydrocortisone usuallyis the drug of choice. In mild cases, hydrocortisone alone maybe adequate. Fludrocortisone (a mineralocorticoid) is used forpersons who do not obtain a sufficient salt-retaining effectfrom hydrocortisone. DHEAS replacement also may be helpfulin the female patient.

Because persons with the disorder are likely to have epi-sodes of hyponatremia and hypoglycemia, they need to have aregular schedule for meals and exercise. Persons with Addison’sdisease also have limited ability to respond to infections,trauma, and other stresses. Such situations require immediatemedical attention and treatment. All persons with Addison’sdisease should be advised to wear a medical alert bracelet ormedal.

Secondary Adrenal Cortical InsufficiencySecondary adrenal insufficiency can occur as the result of hypo-pituitarism or because the pituitary gland has been surgicallyremoved. Tertiary adrenal insufficiency results from a hypo-thalamic defect. However, a far more common cause thaneither of these is the rapid withdrawal of glucocorticoids thathave been administered therapeutically. These drugs suppressthe HPA system, with resulting adrenal cortical atrophy andloss of cortisol production. This suppression continues longafter drug therapy has been discontinued and can be criticalduring periods of stress or when surgery is performed.

Acute Adrenal CrisisAcute adrenal crisis is a life-threatening situation. If Addison’sdisease is the underlying problem, exposure to even a minor ill-ness or stress can precipitate nausea, vomiting, muscular weak-ness, hypotension, dehydration, and vascular collapse. The on-set of adrenal crisis may be sudden, or it may progress during aperiod of several days. The symptoms may occur suddenly inchildren with salt-losing forms of the adrenogenital syndrome.Massive bilateral adrenal hemorrhage causes an acute fulmina-ting form of adrenal insufficiency. Hemorrhage can be causedby meningococcal septicemia (i.e., Waterhouse-Friderichsensyndrome), adrenal trauma, anticoagulant therapy, adrenalvein thrombosis, or adrenal metastases.

Acute adrenal insufficiency is treated with intravenous flu-ids and corticosteroid replacement therapy. Corticosteroid re-placement is accomplished through the intravenous adminis-tration of either dexamethasone or hydrocortisone.

Glucocorticoid Hormone Excess (Cushing’s Syndrome)The term Cushing’s syndrome refers to the manifestations ofhypercortisolism from any cause. Three important forms ofCushing’s syndrome result from excess glucocorticoid produc-tion by the body. One is a pituitary form, which results fromexcessive production of ACTH by a tumor of the pituitarygland. This form of the disease was the one originally describedby Cushing; therefore, it is called Cushing’s disease.32,33 The sec-ond form is the adrenal form, caused by a benign or malignantadrenal tumor. The third form is ectopic Cushing’s, caused bya nonpituitary ACTH-secreting tumor.34 Certain extrapituitarymalignant tumors such as small cell carcinoma of the lung maysecrete ACTH or rarely CRH and produce Cushing’s syndrome.Cushing’s syndrome also can result from long-term therapywith one of the potent pharmacologic preparations of gluco-corticoids; this form is called iatrogenic Cushing’s syndrome.

The major manifestations of Cushing’s syndrome representan exaggeration of the many actions of cortisol (see Table 31-2).Altered fat metabolism causes a peculiar deposition of fat char-acterized by a protruding abdomen; subclavicular fat pads or“buffalo hump” on the back; and a round, plethoric “moonface” (Fig. 31-16). There is muscle weakness, and the extremi-ties are thin because of protein breakdown and muscle wasting.In advanced cases, the skin over the forearms and legs becomesthin, having the appearance of parchment. Purple striae, orstretch marks, from stretching of the catabolically weakenedskin and subcutaneous tissues are distributed over the breast,thighs, and abdomen. Osteoporosis may develop because ofdestruction of bone proteins and alterations in calcium metab-olism, resulting in back pain, compression fractures of the ver-tebrae, and rib fractures. As calcium is mobilized from bone,renal calculi may develop.

Derangements in glucose metabolism are found in approx-imately 75% of patients, with clinically overt diabetes mellitusoccurring in approximately 20%. The glucocorticoids possessmineralocorticoid properties; this causes hypokalemia as a re-sult of excessive potassium excretion and hypertension resulting


■ FIGURE 31-16 ■ Cushing’s syndrome. A woman who sufferedfrom a pituitary adenoma that produced ACTH exhibits a moonface, buffalo hump, increased facial hair, and thinning of the scalphair. (Rubin E., Farber J.L. [1999]. Pathology [3rd ed., p. 1193].Philadelphia: Lippincott Williams & Wilkins)

from sodium retention. Inflammatory and immune responsesare inhibited, resulting in increased susceptibility to infection.Cortisol increases gastric acid secretion, which may provokegastric ulceration and bleeding. An accompanying increase inandrogen levels causes hirsutism, mild acne, and menstrualirregularities in women. Excess levels of the glucocorticoidsmay give rise to extreme emotional lability, ranging from mildeuphoria and absence of normal fatigue to grossly psychoticbehavior.

Diagnosis of Cushing’s syndrome depends on the findingof cortisol hypersecretion. The determination of 24-hour ex-cretion of cortisol in urine provides a reliable and practicalindex of cortisol secretions. One of the prominent features ofCushing’s syndrome is loss of the diurnal pattern of cortisolsecretion. Cortisol determinations often are made on threeblood samples: one taken in the morning, one in late after-noon or early evening, and a third drawn the following morn-ing after a midnight dose of dexamethasone. Measurement ofthe plasma levels of ACTH, measurement of 24-hour urinary17-ketosteroids, 17-ketogenic steroids, and 17-hydroxycorti-costeroids, and suppression or stimulation tests of the HPAsystem often are made. MRI or CT scans afford a means forlocating adrenal or pituitary tumors.

Untreated, Cushing’s syndrome produces serious morbid-ity and even death. The choice of surgery, irradiation, or phar-macologic treatment is determined largely by the cause of thehypercortisolism. The goal of treatment for Cushing’s syn-drome is to remove or correct the source of hypercortisolismwithout causing any permanent pituitary or adrenal damage.Transsphenoidal removal of a pituitary adenoma or a hemi-hypophysectomy is the preferred method of treatment forCushing’s disease. This allows removal of only the tumor,rather than the entire pituitary gland. After successful removal,the person must receive cortisol replacement therapy for 6 to12 months or until adrenal function returns. Patients also mayreceive pituitary radiation therapy, but the full effects of treat-ment may not be realized for 3 to 12 months. Unilateral or bi-lateral adrenalectomy may be done in the case of adrenal ade-noma. When possible, ectopic ACTH-producing tumors areremoved. Pharmacologic agents that block steroid synthesis(i.e., etomidate, mitotane, ketoconazole, metyrapone, andaminoglutethimide) may be used to treat persons with ec-topic tumors that cannot be resected. Many of these patientsalso require Pneumocystis carinii pneumonia prophylaxis be-cause of the profound immunosuppression caused by the ex-cessive glucocorticoid.

REVIEW QUESTIONS■ Use thyroid hormone as an example for describing the etiol-ogy of primary, secondary, and tertiary hypothyroidism.

■ Differentiate genetic short stature from constitutional shortstature.

■ State the mechanisms of short stature in hypothyroidism,poorly controlled diabetes mellitus, treatment with adrenalglucocorticosteroid hormones, malnutrition, and psychosocialdwarfism.

■ List three causes of tall stature.

■ Relate the functions of growth hormone to the manifesta-tions of acromegaly.

■ Explain why children with isosexual precocious puberty aretall-statured children but short-statured adults.

■ Diagram the hypothalamic-pituitary-thyroid feedback system.

■ Relate the functions of thyroid hormone to hypothyroidismand hyperthyroidism.

■ Explain how a defect in a single step of corticosteroid hor-mone synthesis produces the manifestations of the adreno-genital syndrome.

■ Relate the functions of the adrenal cortical hormones toAddison’s disease (i.e., adrenal insufficiency) and Cushing’ssyndrome (i.e., cortisol excess).

Visit the Connection site at connection.lww.com/go/porthfor links to chapter-related resources on the Internet.

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In summary, the adrenal cortex produces three types ofhormones: mineralocorticoids, glucocorticoids, and adrenalsex hormones. The mineralocorticoids along with the renin-angiotensin mechanism contribute to the control of body lev-els of sodium and potassium. The glucocorticoids have anti-inflammatory actions and aid in regulating glucose, protein,and fat metabolism during periods of stress. These hormonesare under the control of the HPA system. The adrenal sex hor-mones exert little effect on daily control of body function, butthey probably contribute to the development of body hair inwomen. The adrenogenital syndrome describes a genetic de-fect in the cortisol pathway resulting from a deficiency of one

of the enzymes needed for its synthesis. Depending on theenzyme involved, the disorder causes virilization of femaleinfants and, in some instances, fluid and electrolyte distur-bances because of impaired mineralocorticoid synthesis.

Chronic adrenal insufficiency (Addison’s disease) can becaused by destruction of the adrenal gland or by dysfunctionof the HPA system. Adrenal insufficiency requires replacementtherapy with cortical hormones. Acute adrenal insufficiency isa life-threatening situation. Cushing’s syndrome refers to themanifestations of excessive cortisol levels. This syndrome maybe a result of pharmacologic doses of cortisol, a pituitary oradrenal tumor, or an ectopic tumor that produces ACTH. Theclinical manifestations of Cushing’s syndrome reflect the veryhigh level of cortisol that is present.

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alterations in pituitary, thyroid, parathyroid, and ... · in secondary disorders of endocrine...

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