Endocrine Glands and Their Function



Endocrine Glands and Their Function



Key Points


The thyroid gland


1. The thyroid hormones are synthesized from two connected tyrosine molecules that contain three or four iodine molecules.


2. Thyroid hormones are stored outside the cell and attached to thyroglobulin in the form of colloid.


3. The release of thyroid hormones involves transport of thyroglobulin with attached thyroid hormones into the cell, cleavage of the thyroid hormones from thyroxine-binding globulin, and release into the interstitial tissues.


4. Thyroid hormones are transported in the plasma attached to plasma proteins.


5. The main routes of metabolism of thyroid hormones are through deiodination or the formation of glucuronides and sulfates via hepatic mechanisms.


6. Thyroid hormones are the primary factors for the control of basal metabolism.


7. The ingestion of compounds that inhibit the uptake or organic binding of iodine blocks the thyroid’s ability to secrete thyroid hormones and causes goiter.


The adrenal glands


1. The adrenal glands are composed of two organs: the outer gland (cortex) and the inner gland (medulla).


The adrenal cortex


1. The adrenal cortex has three zones: the zona glomerulosa, which secretes mineralocorticoids, and the zona fasciculata and the zona reticularis, which secrete glucocorticoids and sex steroids.


2. Adrenal corticoids are synthesized from cholesterol; the critical difference in the activity of these corticoids is related to the hydroxyl group on C-17 of glucocorticoids.


3. Adrenocortical hormones are carried in plasma in association with specific binding globulins (corticosteroid-binding globulin).


4. The metabolism of adrenocortical hormones involves the reduction of double bonds and conjugation of the steroids to glucuronides and sulfates.


5. One of the most important functions of glucocorticoids is control of metabolism, in particular the stimulation of hepatic gluconeogenesis.


6. Corticotropin is the pituitary hormone that regulates glucocorticoid synthesis by the adrenal cortex.


7. One of the most important clinical uses of glucocorticoids is the suppression of the inflammatory response.


The adrenal medulla


1. The synthesis of catecholamines is from tyrosine; the main catecholamine synthesized by the adrenal medulla is epinephrine.


2. The primary actions of catecholamines are on metabolism, especially effects that increase the concentration of glucose.


3. The main factors that stimulate catecholamine secretion are hypoglycemia and conditions that produce stress.


Hormones of the pancreas


1. The synthesis of insulin is biphasic: an acute phase involves the release of preformed insulin, and a chronic phase involves the synthesis of protein.


2. The metabolism of insulin involves splitting the A and B chains and reducing the chains to amino acids and peptides.


3. The main metabolic functions of insulin are anabolic.


4. Insulin deficiency produces diabetes mellitus, which can culminate in diabetic ketoacidosis.


5. Dietary management is an important consideration in therapy for feline type 2 diabetes.


6. The most important functions of glucagon are to decrease glycogen synthesis, increase glycogenolysis, and increase gluconeogenesis.


7. Glucagon synthesis is stimulated by decreased glucose concentrations in the blood.


8. The main functions of somatostatin are to inhibit the secretion of hormones produced by the pancreas (insulin, glucagon, pancreatic polypeptide).


Calcium and phosphate metabolism


1. Calcium is important for many intracellular reactions, including muscle contraction, nerve cell activity, release of hormones through exocytosis, and activation of enzymes.


2. Phosphate is important for the structure of bone and teeth, and organic phosphate serves as part of the cell membrane and several intracellular components.


3. The most important body pool of calcium involved in homeostasis is the extracellular fluid component.



The Thyroid Gland


In most mammals the thyroid gland is located caudal to the trachea at the level of the first or second tracheal ring. The thyroid gland is composed of two lobes lying on either side of the trachea and connected by a narrow piece of tissue called the isthmus.


The thyroid gland is the most important endocrine gland for metabolic regulation. The glandular tissue has cells formed in a circular arrangement called a follicle (Figure 34-1). The follicles are filled with a homogeneous-staining substance called colloid, which is the main storage form of the thyroid hormones. The follicular cells are cuboidal when the secretion is basal and are elongated when the cells are stimulated to release hormone. Another important endocrine cell, the parafollicular cell, or C cell, is located outside the follicles. This cell secretes calcitonin, a hormone important for the regulation of calcium. The activity of this hormone is discussed in the section on calcium metabolism.


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FIGURE 34-1 Histological features of the normal thyroid gland of the rat. All normal thyroid glands are structurally similar, although slight variations occur with age, diet, habitation, and sexual status (neutered or intact). The normal animals of the colony to which this rat belonged were maintained on a high-protein ration, which probably accounts for the slight hypertrophic condition of the secretory epithelium. (From Turner CD, Bagnara JT: General endocrinology, ed 6, Philadelphia, 1976, Saunders.)


The Thyroid Hormones Are Synthesized from Two Connected Tyrosine Molecules That Contain Three or Four Iodine Molecules


The synthesis of thyroid hormone is unusual because a large amount of the active hormone is stored as a colloid outside the follicle cells, within the lumen (or acinus) created by the circular arrangement of glandular cells. Two molecules are important for thyroid hormone synthesis: tyrosine and iodine. Tyrosine is a part of a large molecule (molecular weight, 660,000 D) called thyroglobulin that is formed within the follicle cell and secreted into the lumen of the follicle. Iodine is converted to iodide in the intestinal tract and then is transported to the thyroid, where the follicle cells effectively trap the iodide through an active transport process. This allows intracellular iodide concentrations to be 25 to 200 times higher than extracellular concentrations.


As iodide passes through the apical wall of the cell, it attaches to the ring structures of the tyrosine molecules, which are part of the thyroglobulin amino acid sequence. The tyrosyl ring can accommodate two iodide molecules; if one iodide molecule attaches, it is called monoiodotyrosine, and if two attach, it is called diiodotyrosine. The coupling of two iodinated tyrosine molecules results in the formation of the main thyroid hormones; two diiodotyrosine molecules form tetraiodothyronine, or thyronine (T4), and one monoiodotyrosine and one diiodotyrosine molecule form triiodothyronine (T3) (Figure 34-2). A key enzyme in the biosynthesis of thyroid hormones is thyroperoxidase (which works in concert with an oxidant, hydrogen peroxide). Thyroperoxidase catalyzes the iodination of the tyrosyl residues of thyroxine-binding globulin (TBG) and the formation of T3 and T4. In addition to the unusual molecular storage form of the hormone, thyroid hormones are also unique in that they are the only hormones that contain a halide (i.e., iodine).


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FIGURE 34-2 Production of tetraiodothyronine (thyronine, T4) and triiodothyronine (T3) by the coupling of iodinated tyrosyl residues with thyroglobulin molecule. DIT, Diiodotyrosine; MIT, monoiodotyrosine. (From Hedge GA, Colby HD, Goodman RL: Clinical endocrine physiology, Philadelphia, 1987, Saunders.)



The Release of Thyroid Hormones Involves Transport of Thyroglobulin with Attached Thyroid Hormones into the Cell, Cleavage of the Thyroid Hormones from Thyroxine-Binding Globulin, and Release into the Interstitial Tissues


For thyroid hormones to be released from the thyroid gland, thyroglobulin with its attached monoiodotyrosine, diiodotyrosine, T3, and T4 molecules must be translocated into the follicle cell, and the hormones must be cleaved from thyroglobulin (Figure 34-3). Key enzymes in this transfer are found in the lysosomes. On entering the cell, the TBG molecules fuse with lysosomes, and lysosomal enzymes cleave both the iodinated tyrosine molecules and the iodinated thyronines from the thyroglobulin molecule. The thyronines are released through the basal cell membrane (they freely pass through the cell membrane); monoiodotyrosine and diiodotyrosine are deiodinated by an enzyme called iodotyrosine dehalogenase; and both the iodide and the remaining tyrosine molecules are recycled to form new hormone in association with thyroglobulin.


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FIGURE 34-3 Depiction of follicular cell showing steps in the synthesis and release of triiodothyronine (T3) and thyronine (T4). The numbers identify the major steps: 1, trapping of iodide; 2, oxidation of iodide; 3, exocytosis of thyroglobulin; 4, iodination of thyroglobulin; 5, coupling of iodotyrosines; 6, endocytosis of thyroglobulin; 7, hydrolysis of thyroglobulin; 8, release of T3 and T4; 9, deiodination of monoiodotyrosine (MIT) and diiodotyrosine (DIT); and 10, recycling of iodide. TBG, Thyroxine-binding globulin; TP, thyroperoxidase. (From Hedge GA, Colby HD, Goodman RL: Clinical endocrine physiology, Philadelphia, 1987, Saunders.)

The majority of T3 formation occurs outside the thyroid gland by deiodination of T4. Tissues that have the highest concentration of deiodinating enzymes are those of the liver and kidneys, although muscle tissue produces more T3 on the basis of relative size. The enzyme that is involved in the removal of iodide from the outer phenolic ring of T4 in the formation of T3 is called 5′-monodeiodinase (Figure 34-4). Another type of T3 in which an iodide molecule is removed from the inner phenolic ring of T4, a compound called reverse T3, is also formed. Reverse T3 has little of the biological effects of thyroid hormones and is formed only by the action of extrathyroidal deiodinating enzymes and not by activity of the thyroid gland.


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FIGURE 34-4 Structure and nomenclature of thyroxine and its conversion to the two triiodothyronines by 5′-monodeiodinase and 5-monodeiodinase (MD). Shaded squares indicate the sites of deiodination. (From Hedge GA, Colby HD, Goodman RL: Clinical endocrine physiology, Philadelphia, 1987, Saunders.)


Thyroid Hormones Are Transported in the Plasma Attached to Plasma Proteins


As indicated in Chapter 33, lipid-soluble hormones are transported in the vascular system through association with specific binding plasma proteins. There is considerable species variation in the proteins that bind thyroid hormones. The most important carrier protein is TBG, which has high affinity for T4, although it also has low capacity because of its low concentration. TBG also is an important carrier protein for T3. TBG has been reported in all domestic animals except the cat. Albumin is also involved in the transport of thyroid hormones; however, albumin has low affinity for T3 and T4 but high capacity because of its high concentration in plasma. In the absence of TBG, albumin is the most important carrier of thyroid hormones. All species have a third plasma protein, thyroxine-binding prealbumin, which is specific for T4 and has a specificity and capacity that are intermediate between those of TBG and albumin. The term prealbumin refers to the migration of the protein during electrophoresis, not to synthesis of the molecule.


As with all lipid-soluble hormones that are transported in plasma, most of the T3 and T4 is bound; little is free to interact with receptors on the cells of the target tissues. The amount of thyroid hormone that is free in plasma is remarkably low (e.g., in humans, 0.03% of T4 and 0.3% of T3). In dogs the amount of free hormone is somewhat greater (slightly less than 1.0% for T4 and slightly more than 1.0% for T3) because of less affinity between plasma-binding proteins and thyroid hormones in canine plasma than in human plasma. The equilibrium between free and bound hormone is easily shifted because of physiological or pharmacological situations, such as the increase in estrogen concentrations that occurs during pregnancy. Estrogens cause increased synthesis of TBG by the liver, resulting in a shift toward the bound form. Adjustments to maintain a normal amount of free hormone occur rapidly, with a decline in the rate of metabolism or with stimulation of thyroid hormone production through the release of thyroid-stimulating hormone (TSH).



The Main Routes of Metabolism of Thyroid Hormones Are Through Deiodination or the Formation of Glucuronides and Sulfates via Hepatic Mechanisms


The main form of metabolism of thyroid hormones involves the removal of iodide molecules. Except for the T3 formed from T4, none of the deiodinated thyronine derivatives has any significant metabolic activity. The two enzymes involved in T3 and reverse T3 synthesis, 5′-deiodinase and 5-deiodinase, are also involved in the catabolism of thyroid hormones. Only these two enzymes are needed for catabolism because they do not differentiate between the 3 and 5 positions of the phenolic rings of the thyronines. Skeletal muscle, liver, and kidney tissues are important tissues involved in the catabolism of thyroid hormones through deiodination. The formation of thyroid hormone conjugates represents another form of inactivation; sulfates and glucuronides are formed mainly in the liver and kidneys. Conjugation is less common than deiodination as a means of metabolism of thyroid hormones. Another form of metabolism involves modification of the alanine moiety of the thyronines by either transamination or decarboxylation. The deiodinated and conjugated forms of the thyronines are eliminated primarily in the urine; unmetabolized thyronines are excreted with feces through bile secretion. Degradation of the conjugate forms in the feces results in the production of iodide molecules, which are reabsorbed as part of the enterohepatic cycle. Humans are more efficient than dogs in recovery of iodide both intrathyroidally and enterohepatically.


One of the striking aspects of thyroid hormones is their long half-lives in humans; T3 has a half-life of 1 day and T4 of 6 to 7 days, whereas most other hormones have half-lives of seconds or minutes. One reason for these long half-lives is the large percentage of the circulating thyronines that are bound to the plasma proteins, which protects them from degradation. The difference in half-lives between T3 and T4 results from the tighter T4 protein binding compared with T3 and the resultant reduction in free circulating hormone. In contrast, the half-life for T4 is relatively short in certain domestic species; dogs and cats exhibit a T4 half-life of less than 24 hours.



Thyroid Hormones Are the Primary Factors for the Control of Basal Metabolism


The mechanism of action of thyroid hormones at the cellular level is based on their ability to penetrate the cell membrane even though they are amino acids; in essence, they are lipophilic. Although it is thought that thyroid hormones interact directly with the nucleus to initiate the transcription of messenger ribonucleic acid (mRNA) (Figure 34-5), the presence of T3 receptors has been reported on mitochondria.


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FIGURE 34-5 Proposed subcellular mechanism of thyroid hormone action. mRNA, Messenger ribonucleic acid; R, receptor. (From Hedge GA, Colby HD, Goodman RL: Clinical endocrine physiology, Philadelphia, 1987, Saunders.)

Thyroid hormones are likely the primary determinants of basal metabolism. It is difficult to define their precise physiological effects, however, because many of the effects of thyroid hormones have been demonstrated through the creation of hypothyroid or hyperthyroid states. Nevertheless, it has long been recognized that thyroid hormones increase oxygen consumption of tissues and, as a result, heat production. This effect is known as the calorigenic effect. One site of action of the calorigenic effect of thyroid hormones is within the mitochondrion.


Thyroid hormones affect carbohydrate metabolism in several ways, including increasing intestinal glucose absorption and facilitating the movement of glucose into both fat and muscle. Furthermore, thyroid hormones facilitate insulin-mediated glucose uptake by cells. Glycogen formation is facilitated by small amounts of thyroid hormones; however, glycogenolysis occurs after larger dosages.


Thyroid hormones in concert with growth hormone are essential for normal growth and development. This is accomplished in part by the enhancement of amino acid uptake by tissues and enzyme systems that are involved in protein synthesis.


Whereas thyroid hormones affect all aspects of lipid metabolism, the emphasis is placed on lipolysis. One particular effect of thyroid hormones is the tendency to reduce plasma cholesterol levels. This appears to involve both increased cell uptake of low-density lipoproteins (LDLs) with associated cholesterol molecules and a tendency for increased degradation of both cholesterol and LDL. These effects on lipid metabolism are usually seen in pathophysiological situations involving hypersecretion of thyroid hormone or in thyroid deficiency states in which hypercholesterolemia is a hallmark of thyroid deficiency. In this same context, the effects of thyroid hormones on metabolic processes, including carbohydrate, protein, and lipid metabolism, are often described as catabolic.


Thyroid hormones have noteworthy effects on the nervous and cardiovascular systems. The effects of the sympathetic nervous system are enhanced by the presence of thyroid hormones. This is thought to occur through thyroid stimulation of β-adrenergic receptors in tissues that are targets for the catecholamines, such as epinephrine and norepinephrine. In the central nervous system (CNS), thyroid hormones are important for normal development of tissues in the fetus and neonate; inhibition of mental activity occurs when thyroid hormone exposure is inadequate. In humans, persons with hypothyroid activity are mentally dull and lethargic, which suggests that normal CNS function in the adult depends on the presence of adequate amounts of thyroid hormone.


Thyroid hormones increase the heart rate and force of contraction, probably through their interaction with the catecholamines. This interaction is caused by an increase in tissue responsiveness through the induction of catecholaminergic β receptors by thyroid hormones. Blood pressure is elevated because of increased systolic pressure, with no change in diastolic pressure; the end result is an increase in cardiac output. These responses are most easily observed in situations of increased thyroid activity. In regard to the effect of thyroid hormones on cardiovascular activity, it may be concluded that they are important for maintaining normal contractile activity of cardiac muscle, including the transmission of nerve impulses.


Thyroid hormone was used in classic experiments involving the metamorphosis of amphibian larvae. Thyroxine administration causes the differentiation of tadpoles into frogs, whereas thyroidectomy results in development into large tadpoles. Thyroid-induced metamorphosis is limited to amphibians, but thyroid hormones are important for many (subtle) aspects of differentiation in other classes of animals.


Thyroid hormone activity is usually defined in terms of tissue or organ responses to inadequate or excessive amounts of hormone. A more balanced view is that thyroid hormones are important for the normal metabolic activity of all tissues.


TSH, or thyrotropin, is the most important regulator of thyroid activity. It acts through the initiation of cyclic adenosine 3′,5′-monophosphate (cAMP) formation and the phosphorylation of protein kinases. Thyrotropin secretion is regulated by thyroid hormones through negative-feedback inhibition of the synthesis of thyrotropin-releasing hormone (TRH) at the level of the hypothalamus and by inhibition of TSH activity at the level of the pituitary gland (Figure 34-6).


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FIGURE 34-6 Hypothalamopituitary-thyroid axis. Plus signs indicate stimulation; minus signs indicate inhibition. T3, Triiodothyronine; T4, thyronine; TRH, thyrotropin-releasing hormone; TSH, thyroid-stimulating hormone. (From Hedge GA, Colby HD, Goodman RL: Clinical endocrine physiology, Philadelphia, 1987, Saunders.)


The Ingestion of Compounds That Inhibit the Uptake or Organic Binding of Iodine Blocks the Thyroid’s Ability to Secrete Thyroid Hormones and Causes Goiter


An inability to secrete adequate amounts of thyroid hormone often leads to the enlargement of the thyroid gland, a condition known as goiter. In many places in the world, this condition is, or has been, caused by a deficiency of iodine in the diet. This has largely been corrected through the use of iodized salt. Certain plants, such as cruciferous plants (e.g., cabbage, kale, rutabaga, turnip, rapeseed), contain a potent antithyroid compound called progoitrin, which is converted into goitrin within the digestive tract. Goitrin interferes with the organic binding of iodine. Many of the goitrogenic feeds also contain thiocyanates, which interfere with the trapping of iodine by the thyroid gland. The feeding of excess iodine can sometimes overcome the effects of thiocyanate but has less influence on overcoming the effects of goitrin. Studies of these phenomena have led to the development of compounds for the treatment of hyperthyroidism, the most potent being the thiocarbamides, thiourea and thiouracil. Other antithyroid drugs include sulfonamides, p-aminosalicylic acid, phenylbutazone, and chlorpromazine.



Hypothyroidism in Dogs


Hypothyroidism is most common in the dog, and the usual etiology of primary hypothyroidism is lymphocytic thyroiditis. Congenital hypothyroidism may be caused by thyroid dysgenesis, dyshormonogenesis, T4 transport defects, goitrogens, or in rare cases, iodine deficiency. Secondary hypothyroidism may be a secondary effect of pituitary tumors, radiation therapy, or ingestion of endogenous or exogenous glucocorticoids. Tertiary hypothyroidism can be acquired, as in the case of hypothalamic tumors, or can be congenital as a result of defective TRH or TRH receptor defects.


The signalment of hypothyroid dogs carries a distinct breed predisposition; high-risk breeds manifest symptoms as early as 2 to 3 years of age, and low-risk breeds manifest symptoms at a slightly older age (4 to 6 years of age). Breeds predisposed to hypothyroidism include golden retrievers, Doberman pinschers, dachshunds, Irish setters, miniature schnauzers, Great Danes, miniature poodles, boxers, Shetland sheepdogs, Newfoundlands, chow chows, English bulldogs, Airedale terriers, cocker spaniels, Irish wolfhounds, giant schnauzers, Scottish deerhounds, and Afghan hounds.


Clinical signs of hypothyroidism are gradual and subtle in onset; lethargy and obesity are most common. Dermatological evidence of hypothyroidism is the next most common clinical finding. Symmetric truncal or tail head alopecia is a classic finding in hypothyroid dogs. The skin is often thickened because of myxedematous accumulations in the dermis. Common hair coat changes seen in the hypothyroid dog include dull dry hair, poor hair regrowth after clipping, and presence or retention of puppy hair.


Cardiovascular signs of hypothyroidism include bradycardia, decreased cardiac contractility, and atherosclerosis, but these are uncommon presenting complaints. Neuromuscular signs such as myopathies and megaesophagus are also uncommon manifestations of canine hypothyroidism. Neuropathies, including bilateral or unilateral facial nerve paralysis, vestibular disease, and lower motor neuron disorders, are occasionally seen in hypothyroid dogs. Myxedema coma is an unusual finding in hypothyroid dogs and is secondary to myxedematous fluid accumulations in the brain and severe hyponatremia. Less common signs of hypothyroidism include reproductive disorders in female dogs, such as prolonged interestrous intervals, silent heat, and delivery of weak or stillborn puppies. Corneal lipid deposits and gastrointestinal problems such as constipation are occasionally observed in hypothyroid dogs.


Clinicopathological findings, such as anemia resulting from erythropoietin deficiency, decreased bone marrow activity, and decreased serum iron and iron-binding capacity, are observed in about 25% to 30% of hypothyroid dogs. Hypercholesterolemia is seen in approximately 75% of hypothyroid dogs because of altered lipid metabolism, decreased fecal excretion of cholesterol, and decreased conversion of lipids to bile acids. Hyponatremia, a common finding in humans with hypothyroidism, is observed as a mild decrease in serum sodium in about 30% of hypothyroid dogs in one study. Hyponatremia is caused by an increase in total body water as a result of impaired renal excretion of water and by retention of water by hydrophilic deposits in tissues. An unusual clinicopathological feature of hypothyroidism is increased serum creatine phosphokinase levels, possibly as a result of hypothyroid myopathy.


Diagnosis is based on measurement of serum basal total thyroxine (T4) and triiodothyronine (T3) concentrations, serum free T4 and T3 concentrations, and endogenous canine serum thyrotropin (TSH) levels (Table 34-1) and/or results of dynamic thyroid function tests, including the TRH and TSH stimulation tests. The many variables that affect T4 include age, breed, environmental and body temperature, diurnal rhythm, obesity, and malnutrition. Specifically, affected greyhounds have approximately half the normal total thyroxine (TT4) and free thyroxine (unbound) (FT4) concentrations of normal dogs. Obese dogs have mild increases in serum TT4 concentrations. In puppies the serum TT4 concentration is two to five times higher than in adult dogs. Furthermore, there is an age-related decline in serum TT4 concentrations and response to TSH stimulation in dogs. Euthyroid sick syndrome is characterized by a decrease in serum TT4 and increase in reverse T3. Concurrent illnesses such as diabetes mellitus, chronic renal failure, hepatic insufficiency, and infections can cause euthyroid sick syndrome, resulting in decreases in serum TT4 concentrations. Drugs such as anesthetics, phenobarbital, primidone, diazepam, trimethoprim-sulfa, quinidine, phenylbutazone, salicylates, and glucocorticoids can also decrease serum basal TT4 concentrations.



Free thyroid hormone concentrations, or unbound T4 and T3, are used in human medicine to differentiate between euthyroid sick syndrome and true hypothyroidism. In humans the diagnostic accuracy of a single FT4 measurement is approximately 90%. Measurement of FT4 concentrations is achieved by equilibrium dialysis (gold standard) or analogue immunoassays. Theoretically, FT4 is not subject to spontaneous or drug-induced changes that occur with TT4. Results of early studies, classifying dogs as hypothyroid on the basis of TSH stimulation tests, indicated that FT4 measurements by equilibrium dialysis were 90% accurate, whereas other FT4 assays (analogue assays) were no better than TT4. Glucocorticoids decrease both FT4 fraction and TT4 in dogs.


With the advent of the endogenous canine TSH assay, veterinarians now have a method of assessing the thyroid-pituitary axis in dogs without dynamic testing. With thyroid gland failure, decreases in serum FT4 and TT4 are sensed by the pituitary gland, resulting in an increase in serum endogenous TSH concentration. Initial studies in dogs with experimentally induced hypothyroidism have been encouraging. In humans, when endogenous TSH concentrations are increased and FT4 concentrations are decreased, diagnostic accuracy for primary hypothyroidism approaches 100%. As FT4 concentration falls, there is a logarithmic increase in serum endogenous TSH concentration, which makes the TSH assay the most sensitive test for the detection of early hypothyroidism. The use of endogenous TSH alone is not recommended as a method of assessing thyroid function.


The antithyroglobulin autoantibody test (ATAA) appears promising on the basis of initial study results. The presence of antithyroglobulin antibodies theoretically presages the onset of hypothyroidism in dogs with autoimmune thyroiditis. It is hoped that this test will identify dogs with hereditary thyroid disease before breeding. However, no large studies of dogs with naturally occurring thyroid disease have been performed to evaluate this assay.


For many years the TSH stimulation test was considered the gold standard for diagnosis of hypothyroidism in dogs. Unfortunately, this test does not differentiate between early hypothyroidism and euthyroid sick syndrome and does not identify dogs with secondary or tertiary hypothyroidism. Furthermore, exogenous bovine TSH is no longer commercially available. Other thyroid function tests include the TRH stimulation test, thyroid scan, and thyroid biopsy. However, each test has drawbacks (expense, inaccuracy, or invasiveness).


In summary, diagnosis of canine hypothyroidism is based on signalment, historical findings, physical examination findings, clinicopathological features, and confirmation with a battery of thyroid function tests. The author uses TT4 and endogenous TSH (eTSH) initially, followed by FT4 by dialysis. If all measurements are abnormal, the dog is hypothyroid. If two of the three are abnormal, secondary hypothyroidism (low FT4, low TSH) or early primary hypothyroidism (high TSH, low FT4) is possible. If only one of the three thyroid measurements is abnormal, the dog should be reevaluated in 3 to 6 months.



Hyperthyroidism in Cats


Hyperthyroidism is the most common endocrinopathy of cats and is caused by adenomatous hyperplasia of the thyroid gland. Middle-aged to older cats are typically affected, and there is no predilection for breed or gender.


Balanced pet foods normally provide sufficient iodine but vary widely in iodine content. The effects of this feed variation have been theorized to be important in cats, but there is no data to support or refute the theory. Although acute changes in dietary iodine have been associated with changes in FT4 in cats, most chronic changes in dietary iodine are associated with “adaptation” of the thyroid gland and therefore are unlikely to be the cause of feline hyperthyroidism.


As noted earlier, goitrogens can result in hypothyroidism. However, some have theorized that chronic exposure to goitrogens can lead to toxic nodular goiter resulting in hyperthyroidism. Flavinoids from soy proteins have been suggested to play a role in the pathogenesis of hyperthyroidism in cats. Polyphenolic soy isoflavones, such as genistein and daidzein, were identified in almost 60% of dry cat foods tested. This contradicts the epidemiologic data which shows that hyperthyroidism is less common in cats fed dry foods. Some dry foods contain isoflavone contents consistent with levels shown to interfere with thyroid function by inhibiting thyroperoxidase in rats and 5′-deiodinase activity in cats. In a prospective study of 18 clinically normal cats eating a soy diet (400 mg isoflavones/kg diet), total T4 and FT4 concentrations were modestly, but significantly, increased while T3 concentrations were unchanged. However, many studies in humans have shown no detrimental effect of soy isoflavones on thyroid function particularly when incorporated into a balanced diet with adequate iodine intake.


Canned cat food has been implicated as a cause of feline hyperthyroidism in multiple epidemiological studies. The suspected goitrogen is bisphenol-A-diglycidyl ether (BADGE), a substance used in making the liner of easy-open “pop-top” cans. It is suspected that this compound can leach into the foods and be consumed by cats. Although this BADGE-based lining is generally considered safe and is used for foods for human consumption, cats may be more susceptible to toxic effects of this compound because they have a greatly reduced ability to detoxify it via hepatic glucuronidation. Bisphenol A also reduces triiodothyronine binding and causes increased TSH secretion resulting in hyperthyroidism and goiter in rats and some humans. While cat studies may not be available, rodent studies show a very high safety margin. It should be noted that epidemiological studies showing associations are not the same as cause and effect. More than 90% of cats in the United States consume commercial pet foods as their primary nutritional source, and relatively few develop hyperthyroidism.


More recently, investigators have honed in on the molecular aspects of feline hyperthyroidism. The disease in cats is more similar to toxic nodular goiter in humans and is characterized by autonomous growth of thyroid follicles. The pathogenesis of toxic nodular goiter is an abnormality in the signal transduction of the thyroid cell. The TSH receptor on the thyroid cells activates receptor-coupled guanosine triphosphate-binding proteins (G proteins; see Chapter 1). Uniquely, the thyroid cell proliferation and hormone production are both controlled by the TSH receptor-G-protein-cAMP signaling. Overexpression of stimulatory G proteins and underexpression of inhibitory G proteins have been demonstrated in some humans with toxic nodular goiter. Mutations of the TSH receptor that result in the receptor remaining activated without ligand (i.e., TSH) have also been reported in humans with toxic nodular goiter.


In hyperthyroid cats, the same abnormalities have been investigated and it appears that activation mutation (activation without ligand) of the TSH receptor may be part of the pathogenesis of feline hyperthyroidism in some cats. Furthermore, abnormalities of G proteins, specifically significantly decreased G inhibitory protein expression, have been described in tissues from hyperthyroid cats.


Although cat litter was associated with an increased risk of hyperthyroidism, the use of litter may simply be a marker of cats that are kept indoors. Indoor cats are likely to live longer and hence have a higher risk of developing hyperthyroidism. Exposure to pesticides and herbicides has been associated with thyroid abnormalities in other species. In particular, the use of flea control products was associated with an increased risk of developing hyperthyroidism; however, no specific product or ingredient could be identified.


One recent report implicated brominated flame retardants (BFRs) as carcinogens/goitrogens possibly associated with feline hyperthyroidism. Coincidently BFRs were introduced 30 years ago at the same time that feline hyperthyroidism emerged. Bromide, a halide, is an intriguing agent to implicate in feline hyperthyroidism because of the unique composition of thyroid hormones which contain the halide iodide. In this report, serum levels of lipid-adjusted serum polybrominated diphenyl ethers (PBDE) were ten- to four-hundred-fold higher than those found in humans. It has been theorized that findings of higher than human polybrominated diphenyl ether (PBDE) serum levels in cats is in accord with the most consistently identified risk factor, which is indoor living. The authors also propose that cats are at increased risk because of meticulous grooming behavior and increased exposure to flame retardants in furniture and carpets. The smaller size of cats, relative to humans, is also a possible risk factor for increased serum levels of PBDEs.


Hyperthyroidism is characterized by hypermetabolism; therefore, polyphagia, weight loss, polydipsia, and polyuria are the most prominent features of the disease. Activation of the sympathetic nervous system is also seen; hyperactivity, tachycardia, pupillary dilation, and behavioral changes are characteristic of the disease in cats. Long-standing hyperthyroidism leads to hypertrophic cardiomyopathy, high-output heart failure, and cachexia, which may lead to death.


Clinicopathological features of hyperthyroidism include erythrocytosis and an excitement leukogram (neutrophilia, lymphocytosis) caused by increased circulating catecholamine concentrations. Increased catabolism of muscle tissue in hyperthyroid cats may result in increased levels of blood urea nitrogen (BUN) but not creatinine. In fact, glomerular filtration rate (GFR) is increased in hyperthyroid cats, and this increase may mask underlying renal insufficiency. Although hyperthyroidism increases GFR, the effect of thyroid hormone excess on the urinalysis is variable. Most cats, however, have decreased urine specific gravity, particularly if they are exhibiting polyuria as a clinical sign. Increased metabolic rate results in liver hypermetabolism; therefore, serum activities of liver enzymes (alanine aminotransferase, aspartate aminotransferase) increase in 80% to 90% of hyperthyroid cats. Serum cholesterol decreases, not because of decreased synthesis, but rather because of increased hepatic clearance mediated by thyroid hormone excess.


Feline hyperthyroidism is diagnosed through measurement of TT4; TT3 measurement is generally noncontributory to a diagnosis. Because the disease has become more common and recognized in its early stages, FT4 concentrations have been shown to be more diagnostic of early or “occult” hyperthyroidism. However, FT4 concentrations should be interpreted in light of the TT4 because nonthyroidal illness (chronic renal failure) can result in spurious elevations of FT4 as well. Free triiodothyronine (FT3) concentrations do not provide any further advantage over FT4.



The Adrenal Glands


The Adrenal Glands Are Composed of Two Organs: the Outer Gland (Cortex) and the Inner Gland (Medulla)


The adrenal glands are two bilaterally symmetric endocrine organs located just anterior to the kidneys. Each gland is divided into two separate entities, a medulla and a cortex (Figure 34-7), each of which produces different types of hormones. These adrenal tissues have different embryonic origins. The medulla arises from the neuroectoderm and produces amines such as norepinephrine and epinephrine. The cortex arises from the mesodermal coelomic epithelium and produces steroid hormones such as cortisol, corticosterone, sex steroids, and aldosterone. The utility of placing two such disparate tissues together is not apparent. The one common factor is that both sets of hormones are important for adaptation to adverse environmental conditions (i.e., stress).


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FIGURE 34-7 Depiction of comparable sections through the adrenal glands of A, normal rats, and B, hypophysectomized rats. Because the functional capacity of the adrenal cortex is conditioned by the release of corticotropin, hypophysectomy results in tremendous shrinkage of the cortex. The medulla is not influenced by hypophysectomy. Both sections are drawn to scale. (From Turner CD, Bagnara JT: General endocrinology, ed 6, Philadelphia, 1976, Saunders.)

Interest in the function of the adrenal cortex was heightened in the 1930s because of the research of Hans Selye. He published a series of papers on the effects of adrenalectomy and the ability of the surgically treated animal to defend itself against injury. Selye’s hypothesis was termed the general adaptation syndrome, which he divided into three parts: the alarm reaction, the stage of resistance, and the stage of exhaustion. The critical aspect of this theory was that in addition to specific responses to injury, animals responded in nonspecific ways to combat injury, and the adrenal cortex was the most important organ in leading the nonspecific response. One example of the beneficial effects of glucocorticoids in a situation of injury is the mobilization of glucose, a readily usable source of energy for running away or healing injury. The adaptation of animals to stressful environments is often accompanied by enlargement of the adrenal cortex, such as in domestic chickens raised in crowded conditions and wild animals living in relatively high density.



The Adrenal Cortex


The Adrenal Cortex Has Three Zones: the Zona Glomerulosa, Which Secretes Mineralocorticoids, and the Zona Fasciculata and the Zona Reticularis, Which Secrete Glucocorticoids and Sex Steroids


The adrenal cortex is organized into three zones in mammals (see Figure 34-7). The outer zone, the zona glomerulosa, is relatively narrow, and its cells are organized in a whorl-type arrangement. The middle zone, the zona fasciculata, is relatively wide, and its cells are organized in columns. In the cow and sheep, the zona fasciculata is further divided into inner and outer layers. The inner zone of the adrenal cortex, the zona reticularis, which is adjacent to the adrenal medulla, is intermediate in size, and cells are more randomly organized.


All the cells of the adrenal cortex have intracellular features characteristic of steroid hormone synthesis: an abundance of lipid droplets (containing cholesterol esters), mitochondria, and smooth endoplasmic reticulum. Human adrenal glands have an additional zone, the fetal zone, that is present during fetal life and for the first year of life. The fetal zone participates with the placenta in the production of estrogen during gestation. Immature mice and rabbits have an inner X zone that becomes the zona reticularis at puberty.


The adrenal cortex produces two major types of steroid hormones: the mineralocorticoids and the glucocorticoids. These hormones have distinctly different functions. The mineralocorticoids, produced by the zona glomerulosa, play an important role in electrolyte balance and therefore are important in the regulation of blood pressure (see later discussion). The major mineralocorticoid is aldosterone. The glucocorticoids, produced by the zona fasciculata (which accounts for the majority of glucocorticoid production) and zona reticularis, are important in the regulation of all aspects of metabolism, either directly or through an interaction with other hormones. The major glucocorticoid is cortisol.



Adrenal Corticoids Are Synthesized from Cholesterol; the Critical Difference in the Activity of These Corticoids Is Related to the Hydroxyl Group on C-17 of Glucocorticoids


The synthesis of adrenal steroids involves the classic pathways for steroid biosynthesis. As indicated previously, cholesterol is the major starting material for the synthesis of steroid hormones. Cholesterol is readily available to the steroid-synthesizing cells because it is stored in large quantities in ester form within lipid droplets in these cells. One of the initial steps in steroid formation is the hydrolysis of the ester. The first step in steroid synthesis involves an enzyme that cleaves the carbon side chain from the steroid molecule, leaving a C-21 steroid known as pregnenolone. This step occurs within the mitochondrion (Figure 34-8). The synthesis of all steroid hormones, regardless of their form, utilizes pregnenolone in the synthetic pathway (see Figure 33-5).


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FIGURE 34-8 Mechanism of action of corticotropin (adrenocorticotropic hormone, ACTH) on adrenocortical steroidogenesis. The numbers indicate the processes stimulated (indicated by plus signs) by corticotropin as follows: 1, stimulation of the uptake of low-density lipoproteins (LDL), which are further processed to free cholesterol; 2, stimulation of the hydrolysis of stored cholesterol esters to generate free cholesterol; 3, stimulation of the transport of cholesterol into mitochondria, where cleavage of the cholesterol side chain occurs; and 4, promotion of the binding of cholesterol to the enzyme. AC, Adenyl cyclase; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; R, receptor. (From Hedge GA, Colby HD, Goodman RL: Clinical endocrine physiology, Philadelphia, 1987, Saunders.)

The critical aspect of adrenal corticoid synthesis, which differentiates adrenal corticoids from the progesterone family of steroids, is a hydroxylation step at C-21 (directed by a C-21 hydroxylase). The difference between the mineralocorticoids (aldosterone) and the glucocorticoids (cortisol) is a hydroxyl group on C-17, which is part of the glucocorticoid molecule. As expected, cells of the zona fasciculata and zona reticularis have the hydroxylating enzyme for C-17 (17α-hydroxylase), whereas cells of the zona glomerulosa do not have this enzyme. Both aldosterone and cortisol have hydroxyl groups on C-11. Because of the marked difference in biological activity of the mineralocorticoids and glucocorticoids, it is useful to view the zona glomerulosa as an endocrine organ that is distinct from the zona fasciculata and zona reticularis.


Two intermediate compounds in the synthesis of aldosterone have significant adrenocortical activity. 11-Deoxycorticosterone has significant mineralocorticoid activity, although it is secreted in relatively small amounts. Corticosterone, the immediate precursor to aldosterone, is a relatively important glucocorticoid in animals, although its potency is less than that of cortisol.


In adrenal cortical cells, biosynthetic pathways allow some synthesis of androgens and estrogens. Although the amount of sex steroids produced by the adrenal cortex under normal conditions is low, significant amounts can be synthesized under pathological conditions.



Adrenocortical Hormones Are Carried in Plasma in Association with Specific Binding Globulins (Corticosteroid-Binding Globulin)


Steroid hormones, as indicated previously, are lipids and depend on binding to plasma proteins for transport in the blood. A specific globulin that has a high affinity for cortisol has been identified: corticosteroid-binding globulin, or transcortin. Of the cortisol carried in plasma, 75% is bound to transcortin and 15% to albumin, leaving 10% in the unbound, or free, state. This amount of free hormone is large compared with thyroid hormones: less than 0.1% of T4 is free. The transport of aldosterone is mainly associated with albumin (50%), and only 10% is associated with transcortin, leaving a very large amount (40%) in the free state.


Changes in physiological or pathophysiological states can influence the amount of binding proteins present in plasma. Estrogen produced in increasing amounts by the fetoplacental unit during pregnancy results in an increase in hepatic synthesis of transcortin, whereas liver dysfunction can result in lower concentrations of transcortin. The large pool of hormone present in the bound state during pregnancy gives animals a good reserve from which to make appropriate adjustments in the amount of free hormone available for influencing biological activity. Because the total amount of glucocorticoid is determined in the assay of plasma concentrations, the veterinary clinician needs to be aware that total concentrations not only reflect secretion rate, but also can be influenced by the amount of glucocorticoid-binding plasma proteins.



The Metabolism of Adrenocortical Hormones Involves the Reduction of Double Bonds and Conjugation of the Steroids to Glucuronides and Sulfates


The clearance half-life of cortisol is about 60 minutes, and that of aldosterone is about 20 minutes. This difference is attributable to the observed difference in protein binding of these hormones within the plasma. In general, metabolism of mineralocorticoid and glucocorticoid hormones involves the reduction of double bonds and ketone configurations, which reduces the biological activity of the molecules. The liver, an organ important for modification of these hormones, is also an important site for the conjugation of these steroids with sulfates and glucuronides; this reduces their biological potency and renders them water soluble for passage in the urine.



One of the Most Important Functions of Glucocorticoids Is Control of Metabolism, in Particular the Stimulation of Hepatic Gluconeogenesis


The mechanism of action of adrenal hormones is similar to that of other lipophilic hormones: they are able to penetrate the cell membrane and interact in the cytoplasm with specific cytosolic receptors. This complex is transferred to the nucleus, resulting in transcription of certain genes and the synthesis of specific proteins that affect the biological action of the adrenal hormones.


As emphasized previously, adrenocortical hormones are classified as either glucocorticoid or mineralocorticoid in their activity. Before the biological actions of each class are discussed, it is important to realize that there is overlap of activity (Table 34-2). For example, whereas cortisol is the dominant glucocorticoid hormone, it also has mineralocorticoid effects, although at a reduced potency.



The glucocorticoid hormones are important mediators of intermediary metabolism. One of the important specific effects of glucocorticoids is the stimulation of hepatic gluconeogenesis, which involves the conversion of amino acids to carbohydrates. The net result is an increase in hepatic glycogen and a tendency to increase blood glucose levels. These effects on glycogen metabolism are observed mainly in animals that have excessive glucocorticoid secretion (hyperadrenocorticism) or an insulin deficiency. The effect of glucocorticoids on carbohydrate metabolism is “permissive”; that is, their presence is required for the gluconeogenic and glycogenolytic actions of glucagon and epinephrine, respectively.


Whereas glucocorticoids and insulin have similar effects on liver glycogen metabolism, their effects on the peripheral use of glucose are different. Glucocorticoids inhibit glucose uptake and metabolism in the peripheral tissues, particularly in muscle and adipose cells. This effect has been termed the anti-insulin effect. The chronic administration of glucocorticoids can lead to the development of a syndrome called steroid diabetes because of the hyperglycemic effect produced at the level of the liver; use of glucose decreases in the peripheral tissues because of insulin antagonism.


Whereas the actions of glucocorticoids on fat metabolism tend to be complex, the direct effect on adipose tissue is to increase the rate of lipolysis and to redistribute fat into the liver and abdomen. This fat redistribution leads to the classic “potbelly” appearance of animals and humans with hyperadrenocorticism.


Protein synthesis is inhibited by glucocorticoids; in fact, protein catabolism is enhanced, with an accompanying release of amino acids. This process supports hepatic gluconeogenesis. Two tissues, cardiac and brain, are spared from the effect of glucocorticoids on protein catabolism. Chronic administration of glucocorticoids results in muscle wasting and the weakening of bone. The mobilization and incorporation of amino acids into glycogen result in an increase in urinary excretion of nitrogen and a negative nitrogen balance.


Glucocorticoids play a role in water diuresis (i.e., the enhancement of water excretion). Whereas glucocorticoids inhibit vasopressin activity in the distal tubule, the most important effect is to increase the GFR. Table 34-3 summarizes the effects of glucocorticoids.




Corticotropin Is the Pituitary Hormone that Regulates Glucocorticoid Synthesis by the Adrenal Cortex


The control of the secretion of the glucocorticoids by the zona fasciculata and zona reticularis is by the tropic hormone (corticotropin) (Figure 34-9). A negative-feedback system exists, whereby glucocorticoids inhibit the release of hypothalamic corticotropin–releasing hormone, which in turn results in decreased corticotropin secretion by the pituitary gland. Some evidence indicates that glucocorticoids also have a negative-feedback effect at the level of the pituitary gland. The potency of a glucocorticoid in negative-feedback inhibition of corticotropin is directly related to its glucocorticoid potency; for example, cortisol has more potent negative-feedback effects than corticosterone and has more potent glucocorticoid effects.


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FIGURE 34-9 Regulation of cortisol secretion by the hypothalamopituitary axis. Plus signs indicate stimulation; minus signs indicate inhibition. CRH, Corticotropin-releasing hormone. (From Hedge GA, Colby HD, Goodman RL: Clinical endocrine physiology, Philadelphia, 1987, Saunders.)
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Jul 18, 2016 | Posted by in PHARMACOLOGY, TOXICOLOGY & THERAPEUTICS | Comments Off on Endocrine Glands and Their Function

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