Endocrine System


Endocrine System*

Structure and Function

Endocrine glands are collections of specialized cells that synthesize, store, and directly release their secretions, such as polypeptides, steroids, and amino acid derivatives—including catecholamines and thyroid hormones—into the bloodstream, resulting in physiologic effects on target cells distant from the glands. They are sensing and signaling devices located in the extracellular fluid compartment that are capable of responding to changes in the internal and external environments to coordinate a multiplicity of activities that maintain homeostasis.

Signaling molecules are grouped into three general categories according to the source of the signal and the location of the target on which the signal has an effect (Fig. 12-1). In autocrine signaling, cells respond to signals that they themselves secrete. Molecules produced by one cell that act on a neighboring cell are characteristic of paracrine signaling. The final pattern of signaling, which is the focus of this chapter, is endocrine signaling, whereby hormones produced by cells of endocrine organs are released into the circulation and act on distant target cells.

Endocrine cells that produce polypeptide hormones have a well-developed, rough endoplasmic reticulum that assembles the hormone, and a prominent perinuclear Golgi apparatus that packages the hormone into granules for intracellular storage and transport. Secretory granules are unique to polypeptide hormone- and catecholamine-secreting endocrine cells and provide a mechanism for intracellular storage of substantial amounts of preformed active hormone. When the cell receives a signal to secrete a hormone, secretory granules are moved to the periphery of the endocrine cell, most likely by the contraction of microfilaments. After release of the peptides into the bloodstream, they bind to receptors on the surface of target cells, activating a series of intracellular events often mediated by second messengers such as cyclic adenosine monophosphate (cAMP), protein kinases, or calcium.

Steroid hormone–secreting cells are characterized by large cytoplasmic lipid bodies that contain cholesterol and other precursor molecules. The lipid bodies are in close proximity to an extensive smooth endoplasmic reticulum and large mitochondria. The latter have hydroxylase and dehydrogenase enzyme systems that attach various side chains to the basic steroid nucleus. Steroid-producing cells lack secretory granules and do not store significant amounts of preformed hormone. They depend on continued biosynthesis to maintain the normal secretory rate of a particular hormone. Steroid hormones enter target cells by diffusion across the plasma membrane and then bind to nuclear or cytosolic receptors.

In general, endocrine organs are composed of islands of secretory epithelial cells delineated by a fine fibrovascular stroma rich in capillaries. With the exception of thyroid follicular epithelial cells, endocrine cells are arranged in cords or packets. Endocrine cells that secrete polypeptide hormones and catecholamines typically contain abundant, lacy to finely granular, pale eosinophilic cytoplasm, which is immunoreactive for chromogranins and synaptophysin that are present in secretory granules and microvesicles, respectively. Steroid hormone–secreting endocrine cells also contain abundant cytoplasm that appears foamy because of the presence of numerous lipid vacuoles.

Pituitary Gland (Hypophysis)

The adenohypophysis consists of three portions: the pars distalis, pars tuberalis, and pars intermedia (Fig. 12-2). In many animal species, the adenohypophysis completely surrounds the pars nervosa of the neurohypophyseal system. The pars distalis is the largest and is composed of several different endocrine cell populations surrounded by abundant capillaries to facilitate secretion of their trophic hormones (Web Fig. 12-1).

The pars tuberalis is an extension of the adenohypophysis and consists of dorsal projections of parenchymal cells along the infundibular stalk. It primarily functions as a scaffold for the capillary network of the hypophyseal portal system as it courses from the median eminence to the pars distalis. The pars intermedia is located between the pars distalis and pars nervosa; it lines the residual lumen of Rathke’s pouch and has two populations of cells in certain species. In the dog, one of these cell types (B cell) synthesizes and secretes adrenocorticotropic hormone (ACTH).

A specific population of endocrine cells is present in the pars distalis (and also in the pars intermedia of dogs for ACTH secretion) that synthesizes, processes, and secretes each of the pituitary trophic hormones (Fig. 12-3). Secretory cells in the adenohypophysis are classified as acidophils, basophils, and chromophobes based on the reactions of their secretory granules with pH-dependent histochemical stains (Fig. 12-4). Based on contemporary specific immunohistochemical staining, acidophils can be further subclassified functionally into somatotrophs that secrete growth hormone (GH; somatotrophin) and lactotrophs that secrete prolactin. Basophils include gonadotrophs that secrete luteinizing hormone (LH) and follicle-stimulating hormone (FSH), thyrotrophs that secrete thyrotrophic hormone (thyroid-stimulating hormone [TSH]), and ACTH-secreting corticotrophs. Chromophobes are pituitary cells that by light microscopy lack stainable cytoplasmic secretory granules. They include the pituitary cells involved with the synthesis of ACTH and melanocyte-stimulating hormone (MSH) in some species, nonsecretory follicular (stellate) cells, degranulated chromophils (acidophils and basophils) in the actively synthesizing phase of the secretory cycle, and undifferentiated stem cells of the adenohypophysis.

Each type of endocrine cell in the adenohypophysis is under the control of a specific releasing hormone or factor from the hypothalamus (see Fig. 12-3). These releasing hormones are small peptides synthesized and secreted by neurons of the hypothalamus. They are transported by axonal processes to the median eminence, where they are released into capillaries and conveyed by the hypophyseal portal system to specific endocrine cells in the adenohypophysis. Each hormone stimulates the rapid release of secretory granules containing a specific preformed trophic hormone.

The neurohypophysis is subdivided into three anatomic parts. The pars nervosa (posterior lobe) represents the distal component of the neurohypophyseal system. The infundibular stalk joins the pars nervosa to the overlying hypothalamus and is composed of axonal processes from neurosecretory neurons. It also has numerous capillaries, supported by modified glial cells or pituicytes, which are termination sites for the nonmyelinated axonal processes of neurosecretory neurons in the hypothalamus. The neurohypophyseal hormones, oxytocin and antidiuretic hormone (ADH) or vasopressin, are synthesized in the cell body of hypothalamic neurons, packaged into secretory granules, transported by long axonal processes of the hypothalamohypophyseal tract to axons in the pars nervosa, and released into the capillary bed of the hypothalamohypophyseal portal system.

Neurosecretory neurons in the hypothalamus secrete hormone in response to neural input from higher centers, resulting in hormonal secretion. ADH and oxytocin are nonapeptides synthesized by neurons situated either in the supraoptic or paraventricular nuclei of the hypothalamus. ADH and its corresponding neurophysin appear to be synthesized as part of a common larger biosynthetic precursor molecule, termed propressophysin. The hormones are packaged with a corresponding binding protein (i.e., neurophysin) into membrane-limited neurosecretory granules and transported to the pars nervosa for release into the circulation.

Adrenal Gland

Adrenal Cortex

The adrenal glands of mammals consist of two distinct parts that differ not only in morphology and function but also in embryologic origin. Because of their close structural relationships, the outer cortex and inner medulla of the adrenal glands usually have been considered parts of one organ (Fig. 12-5). The adrenal cortex develops from cells of the coelomic epithelium that are of mesodermal origin. The chromaffin tissue and sympathetic ganglion cells of the adrenal medulla are derived from ectoderm of the neural crest.

The adrenal cortex of normal dogs is firm, yellow, and nearly uniformly thick. The soft, brown medulla is surrounded by the cortex. In normal dogs, the cortical-to-medullary ratio is approximately 2 : 1. The adrenal glands are richly vascularized, and a sinusoidal network, which demarcates the cell columns of the adrenal cortex, empties into the venous tree at the periphery of the medulla.

The adrenal cortex microscopically and functionally is subdivided into three layers or zones, although the demarcation between zones often is not distinct. The zona glomerulosa or multiformis (outer zone) adjacent to the capsule is composed of columns of cells that have a sigmoid or arclike arrangement. It represents about 15% of the cortical volume and is responsible for the secretion of mineralocorticoid hormones. The secretory cells of the zona fasciculata (middle zone) are arranged in long anastomosing cords separated by numerous small capillaries. This zone constitutes about 80% of the cortical volume, is composed of cells that contain abundant cytoplasmic lipid, and is responsible for the secretion of the glucocorticoid hormones. The zona reticularis (inner zone) accounts for the remaining 5% of the cortical volume. The secretory cells, arranged in small groups surrounded by capillaries, are responsible for the secretion of sex steroids.

Mineralocorticoids are adrenal steroids that principally affect ion transport by epithelial cells and cause excretion of potassium and conservation of sodium. The most potent and important naturally occurring mineralocorticoid is aldosterone. Enzymatically controlled electrolyte pumps in epithelial cells of the renal tubule and sweat glands respond to mineralocorticoids by conserving sodium and chloride and by excreting potassium. In the distal convoluted tubule of the mammalian nephron, a cation-exchange mechanism is responsible for the resorption of sodium from the glomerular filtrate and secretion of potassium into the lumen (Fig. 12-6). These reactions are accelerated by mineralocorticoids but still proceed, although at a much slower rate in their absence. Lack of mineralocorticoid secretion, such as in the Addison’s-like disease of dogs, can result in lethal retention of potassium and loss of sodium.

Cortisol and lesser amounts of corticosterone are the most important naturally occurring glucocorticoid hormones secreted by the adrenal glands in many animal species. In general, the actions of glucocorticoids on carbohydrate, protein, and lipid metabolism result in sparing of glucose, a tendency to hyperglycemia, and increased glucose production. In addition, glucocorticoids decrease lipogenesis and increase lipolysis in adipose tissue, which results in release of glycerol and free fatty acids.

Glucocorticoids also function to suppress both inflammatory and immunologic responses, thereby reducing the necrosis and fibroplasia that can occur with these responses. However, under the influence of increased concentrations of glucocorticoids, an animal has reduced resistance to bacteria, viruses, and fungi. Glucocorticoids can impair the immunologic response at any stage from the initial interaction and processing of antigens by cells of the monocyte-macrophage system through the induction and proliferation of immunocompetent lymphocytes and subsequent antibody production. Inhibition of a number of functions of lymphoid cells by glucocorticoids forms part of the basis for immunosuppression.

Glucocorticoids exert a profound negative effect on wound healing. Dogs with hypercortisolism can have wound dehiscence (Fig. 12-7). The basic mechanism is inhibition of fibroblast proliferation and collagen synthesis, leading to a decrease in scar tissue formation.

Sex hormones (e.g., progesterone, estrogens, and androgens) are synthesized in small amounts by secretory cells of the zona reticularis of the adrenal cortex. Excessive adrenal sex steroids secreted by a neoplasm arising in the zona reticularis can occur infrequently, resulting in clinical manifestations of virilism, precocious sexual development, or feminization (effects depend on which steroid is secreted in excess, the sex of the patient, and the age at onset).

Adrenal Medulla

The adrenal medulla is derived from neuroectoderm of the neural crest and produces catecholamine hormones. The main biosynthetic pathway for catecholamines in mammals starts with tyrosine that is converted first to 1-dihydroxyphenylalanine (dopa) by tyrosine hydroxylase. Dopa is then decarboxylated by 3,4-amino acid decarboxylase to 3,4-dihydroxyphenylethylamine (dopamine), which subsequently undergoes β-hydroxylation by dopamine β-oxidase to form norepinephrine. In mammals the medulla is completely surrounded by the adrenal cortex, and venous blood from the cortex bathes the medullary cells. This blood has the greatest concentration of corticosteroids of any fluid in the body. This close anatomic association between the adrenal cortex and medulla in mammals is not fortuitous because the N-methylating enzyme, phenylethanolamine-N-methyl transferase, which converts norepinephrine to epinephrine, is corticosteroid hormone dependent.

Thyroid Gland

Thyroid Follicular Cells

The thyroid gland in most animal species has two lobes, one on each lateral surface of the trachea. In pigs, the main lobe of the thyroid gland is on the midline in the ventral cervical region with dorsolateral projections from each side. In dogs, the right lobe of the thyroid gland is situated slightly cranial to the left lobe and almost touches the caudal aspect of the larynx.

The thyroid gland is the largest of the endocrine organs that function exclusively as endocrine glands. The basic histologic structure of the thyroid gland is unique among endocrine glands and consists of follicles of varying size (20 to 250 µm), which contain colloid produced by the follicular cells. The follicular cells are cuboidal to columnar and are orientated so that their secretory pole is directed toward the lumen of the follicle. An extensive network of interfollicular and intrafollicular capillaries provides the follicular cells with an abundant blood supply. Follicular cells have extensive profiles of rough endoplasmic reticulum for synthesis and a large Golgi apparatus for packaging of substantial amounts of protein, which are then transported into the follicular lumen. The luminal side of follicular cells in contact with the colloid has numerous microvilli (Web Fig. 12-2).

The synthesis of thyroid hormones is unique among those of the endocrine glands because the final assembly of hormone occurs extracellularly within the follicular lumen. Follicular cells trap essential raw materials, such as iodide from the blood, by a sodium-iodide symporter in the basolateral plasma membrane and then transport them rapidly against a concentration gradient to the lumen, where the iodide is oxidized by thyroid peroxidase in the microvilli to iodine (I2) (Fig. 12-8). The assembly of thyroid hormones within the follicular lumen is made possible by a unique protein, thyroglobulin. Thyroglobulin is a high molecular weight (600,000 to 750,000 Da) glycoprotein synthesized in successive subunits on the ribosomes of the endoplasmic reticulum in follicular cells. The constituent amino acids (tyrosine and others) and carbohydrates (e.g., mannose, fructose, galactose) are derived from the circulation. Recently synthesized thyroglobulin (17S) leaves the Golgi apparatus and is packaged into apical vesicles that are extruded into the follicular lumen (see Fig. 12-8). The amino acid tyrosine, an essential component of thyroid hormones, is incorporated within the molecular structure of thyroglobulin. Iodine is bound to tyrosyl residues in thyroglobulin at the apical surface of follicular cells to form monoiodotyrosine (MIT) and diiodotyrosine (DIT) (see Fig. 12-8). The resulting MIT and DIT combine to form the two biologically active iodothyronines, T4 and T3, secreted by the thyroid gland.

The secretion of thyroid hormones into the bloodstream from colloid is initiated by elongation of microvilli and formation of pseudopodia on the luminal surface of follicular cells. In response to TSH, these extend into the follicular lumen and indiscriminately phagocytose the adjacent colloid. Colloid droplets within follicular cells fuse with numerous lysosomes. T3 and T4 are released from the thyroglobulin molecule, diffuse across the follicular cell basement membrane, and enter into adjacent capillaries. Negative feedback control of thyroid hormone secretion is accomplished by the coordinated response of the adenohypophysis and certain hypothalamic nuclei to concentrations of T4 and T3 in the blood.

TSH is delivered to thyroid follicular cells where it binds to the basilar aspect of the cell, activates adenyl cyclase, and increases the rate of all biochemical reactions concerned with the biosynthesis and secretion of thyroidal hormones. If the secretion of TSH is sustained (hours or days), thyroid follicular cells become more columnar and follicular lumina become smaller as a result of increased uptake of colloid by endocytosis (Fig. 12-9). Numerous periodic acid–Schiff (PAS)-positive colloid droplets are present in the luminal aspect of the hypertrophied follicular cells. The converse occurs in the thyroid gland in response to increases in circulating T4 and T3, which cause a corresponding decrease in TSH. Thyroid follicles become enlarged and distended with colloid as a result of decreased TSH-mediated endocytosis of colloid. Follicular cells lining the involuted follicles become low cuboidal, with only a few endocytic vacuoles at the interface between the colloid and follicular cells (Fig. 12-10).

T4 and T3, once released into the circulation, act on many different target cells in the body. The overall functions of T4 and T3 are similar, although much of the biologic activity appears to be the result of monodeiodination of T4 to 3,5,3′-triiodothyronine (T3) before they interact with high-affinity nuclear receptors in target cells. In certain conditions, such as protein starvation during the neonatal period, hepatic and renal disease, and fever, T4 is preferentially monodeiodinated to 3,3′,5′-triiodothyronine (reverse T3). Because reverse T3 produced by target cells is biologically inactive, monodeiodination to form reverse T3 provides a mechanism by which the overall metabolic effects of thyroid hormones are attenuated. The subcellular mechanism of action of thyroid hormones resembles that of steroids, in that free hormone enters target cells and binds initially to cytosol-binding proteins and subsequently to high-affinity nuclear receptors. Binding of thyroid hormone to receptors on the inner mitochondrial membrane is responsible for the early activation of energy metabolism and increased oxidative phosphorylation.

Thyroid C (Parafollicular) Cells

Calcitonin is secreted by a second endocrine cell population, C or parafollicular cells, in the mammalian thyroid gland. These cells are situated either in the follicular wall, within the basement membrane between follicular cells, or in small groups adjacent to interfollicular capillaries between follicles (Web Fig. 12-3). C cells do not border the follicular colloid directly, and their secretory pole is oriented toward the interfollicular capillaries. The distinctive feature of C cells is the presence of numerous small, membrane-limited, cytoplasmic secretory granules, which are immunoreactive for calcitonin.

Calcitonin is a polypeptide hormone secreted according to the calcium ion concentration in plasma and extracellular fluids. The rate of calcitonin secretion is upregulated in response to increased blood calcium concentrations.

C cells store substantial amounts of calcitonin in their cytoplasm, and the hormone is discharged rapidly into interfollicular capillaries in response to hypercalcemia (Fig. 12-11). C cells respond to long-term hypercalcemia by hyperplasia. When the blood calcium concentration is reduced, the stimulus for calcitonin secretion is diminished, and numerous secretory granules accumulate in the cytoplasm of C cells (see Fig. 12-11). Calcitonin exerts its function by interacting with target cells located primarily in bone and kidneys. The actions of parathyroid hormone (PTH) and calcitonin are antagonistic on bone resorption, but synergistic in decreasing the renal tubular reabsorption of phosphorus.

Parathyroid Glands

Parathyroid glands in most animal species consist of two pairs of glands situated in the cranial cervical region. The dog and cat have both external and internal parathyroid glands located near the thyroid gland. Other animal species, such as the pig, have only a single pair of parathyroid glands cranial to the thyroid gland, embedded either in the thymus in young animals or in adipose connective tissue in adult animals. In cattle and sheep, the larger external parathyroid gland is located a considerable distance cranial to the thyroid gland in the loose connective tissue along the common carotid artery. The smaller internal parathyroid glands are situated on the dorsal and medial surface of the thyroid gland. In horses, the larger (“lower”) parathyroid gland is located a considerable distance from the thyroid gland in the caudal cervical region, near the bifurcation of the bicarotid trunk at the level of the first rib, whereas the smaller (“upper”) parathyroid gland is situated near the thyroid gland.

The parathyroid glands of animals are composed predominantly of chief cells in different stages of secretory activity (Fig. 12-12). Oxyphil cells, often forming nodules, are also present in parathyroid glands of senile horses and cattle. They are larger than chief cells, and their abundant cytoplasm is filled with numerous large, often bizarre-shaped mitochondria and few secretory granules. Although their presence has been associated with hyperparathyroidism in certain species, the extent of their functional capacity remains controversial.

Biologically active PTH secreted by chief cells is a straight-chain polypeptide consisting of 84 amino acid residues, with a molecular weight of approximately 9500 Da. Secretory cells in the parathyroid glands of most animals store relatively small amounts of preformed hormone but are capable of responding to minor fluctuations in calcium ion concentration rapidly, by altering the rate of hormonal secretion, and more slowly, by altering the rate of hormonal synthesis (Fig. 12-13). In contrast to most endocrine organs that are under complex control, the parathyroid glands have a unique feedback control system based primarily on the concentration of calcium and, to a lesser extent, of magnesium ions in blood. Calcium ion concentration controls not only the rate of biosynthesis and secretion of PTH but also other metabolic and intracellular degradative processes within chief cells. Increased calcium ion concentration in extracellular fluids rapidly inhibits the uptake of amino acids by chief cells, and consequently synthesis of proPTH, its conversion to PTH, and secretion of stored PTH (see Fig. 12-13).

PTH is the principal hormone involved in the minute-to-minute, fine regulation of blood calcium concentration (total and ionic calcium) in mammals. It does this by directly influencing the function of target cells located primarily in bone and the kidneys, and indirectly acting in the intestine to maintain plasma calcium concentration sufficient to ensure the optimal functioning of a wide variety of body cells. The overall action of PTH on bone is to mobilize calcium into extracellular fluids (Fig. 12-14). Bone responds to PTH by increasing the activity of osteoclasts and osteocytes existing in bone.

PTH has a rapid (within 5 to 10 minutes) and direct effect on renal tubular function, leading to decreased reabsorption of phosphorus and consequently the development of phosphaturia. The site of action where PTH blocks tubular reabsorption of phosphorus has been determined to be the proximal tubule. The ability of PTH to enhance the renal absorption of calcium also is of considerable importance in the maintenance of calcium homeostasis. This effect of PTH on tubular reabsorption of calcium appears to be a result of a direct action on the distal convoluted tubule. Calcitonin and PTH, acting in concert, provide a dual negative feedback control mechanism to maintain the concentration of calcium in extracellular fluids within narrow limits.

The third major hormone involved in the regulation of calcium metabolism and skeletal remodeling is cholecalciferol or vitamin D3 (see Fig. 12-14). Cholecalciferol is ingested in small amounts in the diet and can be synthesized in the epidermis from precursor molecules (e.g., 7-dehydrocholesterol) through a provitamin D3 intermediate form in response to ultraviolet light. The active metabolites of vitamin D increase the absorption of calcium and phosphorus from the intestine and thereby maintain adequate concentrations of these electrolytes in the extracellular fluids as required for the appropriate mineralization of bone matrix. From a functional point of view, vitamin D brings about the retention of sufficient mineral ions to ensure mineralization of bone matrix, whereas PTH maintains the proper ratio of calcium to phosphorus in extracellular fluids. The major target tissue for 1,25-(OH)2D3 is the mucosa of the small intestine, where it increases the active transcellular transport of calcium (cranial small intestine) and phosphorus (caudal small intestine).

Pancreatic Islets

The endocrine function of the pancreas is performed by small groups of cells, the islets of Langerhans (Fig. 12-15), which are completely surrounded by acinar or exocrine cells that produce digestive enzymes. During embryonic development of the pancreas, a close relationship exists between the endocrine and exocrine portions. Evidence suggests that islet, acinar, and ductal cells arise from a common multipotential precursor cell. In early embryonic development, the endocrine cells are integrated within the exocrine matrix of the pancreatic bud. They subsequently accumulate in nonvascularized clusters and later become separated from the exocrine tissue and then independently vascularized.

The pancreatic islets of normal animals contain multiple types of cells. The predominant secretory cells are the β cells, which function in the biosynthesis of insulin but co-secrete islet amyloid polypeptide. The glucagon-secreting α cells are less numerous than β cells. δ Cells and F, or PP, cells in the islets secrete somatostatin and pancreatic polypeptide, respectively. The different cell types of the endocrine pancreatic cells can be differentiated by cytochemical and immunohistochemical techniques, and by electron microscopy (Web Fig. 12-4). The α, β, and δ cells have well-developed rough endoplasmic reticulum and Golgi complexes that participate in the biosynthesis of polypeptide hormones, as well as numerous secretory granules in the cytoplasm. Each type of endocrine cell in the pancreatic islets has secretory granules with distinct ultrastructural characteristics, which can be used to identify the cell types; however, immunohistochemical identification of the specific islet hormone is a more accurate method of identifying different cell types in the pancreatic islets.

The major physiologic stimulus for the release of insulin from β cells is glucose. An appropriate concentration of calcium ion in extracellular fluids is required for induction of insulin release from β cells. Insulin is a powerful hormone with broad biologic influences that either directly or indirectly affects the structure and function of every organ in the body. Tissues especially responsive to insulin include skeletal and cardiac muscle, adipose tissue, fibroblasts, hepatocytes, leukocytes, mammary glands, cartilage, bone, skin, aorta, pituitary gland, and peripheral nerves. The principal function of insulin is to stimulate anabolic reactions involving carbohydrates, lipids, proteins, and nucleic acids. It catalyzes the formation of macromolecules used in cell structure, energy stores, and regulation of many cell functions. Hepatocytes, adipose cells, and muscle are three principal target sites for insulin. In general, insulin increases the transfer of glucose and certain other monosaccharides, some amino acids and fatty acids, and potassium and magnesium ions across the plasma membrane of target cells. In addition, it enhances glucose oxidation and glycogenesis and stimulates lipogenesis and the formation of adenosine triphosphate (ATP), DNA, and RNA. Insulin also decreases the rate of lipolysis, proteolysis, ketogenesis, and gluconeogenesis.

Glucagon is a hormone that stimulates energy release from target cells and is secreted in response to a reduction in blood glucose concentration. It mobilizes stores of energy-yielding nutrients by increasing glycogenolysis, gluconeogenesis, and lipolysis, thereby increasing the blood concentration of glucose. At physiologic concentrations, glucagon increases both hepatic glycogenolysis and gluconeogenesis. Insulin and glucagon act in concert to maintain the concentration of glucose in extracellular fluids within relatively narrow limits. A glucose sensor in the pancreatic islets controls the relative proportion of these two biologic antagonists. Glucagon controls glucose influx into the extracellular space from the hepatocytes, and insulin controls glucose efflux from the extracellular space into such insulin-sensitive cells as adipocytes, myocytes, and hepatocytes.

Chemoreceptor Organs

Chemoreceptor tissue is present at several sites in the body, including the carotid body, aortic bodies, nodose ganglion of the vagus nerve, ciliary ganglion in the orbit, pancreas, bodies on the internal jugular vein below the middle ear, and glomus jugular along the recurrent branch of the glossopharyngeal nerve. The chemoreceptor organs are sensitive indicators of changes in the blood carbon dioxide content, pH, and oxygen tension, thereby aiding in the regulation of respiration and circulation. Carotid and aortic bodies can initiate an increase in the depth, minute volume, and rate of respiration via parasympathetic nerves, and an increase in heart rate and elevation of arterial blood pressure via the sympathetic nervous system. The bodies are composed of parenchymal (chemoreceptor) and stellate (sustentacular) cells. Nerve endings with synaptic vesicles, as well as nerve fibers, occur in close association with the chemoreceptor cells.

Portals of Entry

The portals of entry for the inflammatory agents affecting endocrine glands include hematogenous spread and direct extension. Autoimmune and infectious inflammatory diseases affect various endocrine glands. The pathogenesis of autoimmune diseases typically involves autoreactive T lymphocytes and autoantibodies, both of which gain access to the endocrine gland via the blood. Bacterial, viral, and fungal diseases preferentially restricted to individual endocrine glands rarely occur; however, endocrine glands are equally vulnerable to involvement in systemic diseases. Endocrine glands, such as the pituitary and pineal glands and the thyroid and parathyroid glands, can also become secondarily involved through direct extension from the meninges and larynx, respectively.

The endocrine system is unique in the fact that many of the disease processes affecting it involve disturbances of growth such as hyperplasia and neoplasia. The histopathologic differentiation among nodular hyperplasia, adenoma, and carcinoma is often more difficult in endocrine glands than in most other organs of the body. However, criteria used to differentiate these proliferative lesions should be established and applied in a uniform manner in the evaluation of proliferative lesions in endocrine glands. For many endocrine glands, there appears to be a continuous spectrum of proliferative lesions derived from a specific population of secretory cells between focal or nodular hyperplasia and adenomas.

Excessive focal growth of endocrine cells is the consequence of aberrant secretion of growth- and/or function-stimulating hormone(s) and has been referred to as nonneoplastic endocrine hyperplasia. Nodules arising in hyperplastic endocrine glands can be polyclonal and of clonal origin. Hyperfunction and cellular hypertrophy caused by nonneoplastic endocrine hyperplasia are considered to be largely reversible on cessation of the inciting stimulus; however, chronic and severe hyperplasia of endocrine tissues is not always fully reversible.

Endocrine glands appear predisposed to the development of an increased incidence of neoplasms after prolonged stimulation of a population of secretory cells. Long-continued stimulation can lead to the development of clones of cells within the hyperplastic endocrine glands that grow more rapidly and are consequently more susceptible to genetic alterations, resulting in neoplastic transformation on exposure to the appropriate combination of promoting agents.

Responses to Injury

Pathogenic Mechanisms of Endocrine Diseases

Although injury of cells in endocrine glands is often attributable to processes, such as necrosis, inflammation, and autoimmunity, discussed in Chapters 1, 3, and 5, respectively, many diseases of endocrine glands are characterized by dramatic functional disturbances and characteristic clinicopathologic alterations affecting one or more body systems. The affected animal can have changes primarily involving the skin (alopecia caused by hypothyroidism), nervous system (seizures caused by hyperinsulinism), urinary system (polyuria caused by diabetes mellitus, diabetes insipidus, and hyperadrenocorticism), or skeletal system (fractures induced by hyperparathyroidism). There are several mechanisms that can disrupt normal endocrine function, with the majority of processes resulting in insufficient or excessive hormone production.

Primary Hypofunction of an Endocrine Gland

Hormone secretion is subnormal because of extensive destruction of secretory cells by a disease process, the failure of an endocrine gland to develop properly, or the result of a specific biochemical defect in the synthetic pathway of a hormone. In animals, immune-mediated injury characterized by notable infiltration of lymphocytes and plasma cells and deposition of electron-dense immune complexes along basement membranes causes hypofunction via progressive destruction of secretory parenchyma in one or more endocrine glands.

Failure of development also results in primary hypofunction of an endocrine gland. The classic example of this mechanism in animals is the failure of oropharyngeal ectoderm to differentiate completely into trophic hormone–secreting cells of the adenohypophysis in dogs, resulting in pituitary dwarfism (see the section on Disorders of Dogs).

Secondary Hypofunction of an Endocrine Gland

In secondary hypofunction of an endocrine gland, a destructive lesion in one organ, such as the pituitary gland, interferes with the secretion of a trophic hormone. This results in hypofunction of the target endocrine gland. Large, endocrinologically inactive pituitary neoplasms in adult dogs, cats, and other animals can interfere with the secretion of multiple pituitary trophic hormones and result in clinically detectable hypofunction of the adrenal cortex (Fig. 12-16), follicular cells of the thyroid gland, and gonads.

Primary Hyperfunction of an Endocrine Gland

Primary hyperfunction of an endocrine gland is one of the most important pathologic mechanisms of endocrine disease in animals. The cells of a lesion, often a neoplasm derived from endocrine cells, autonomously synthesize and secrete a hormone at a rate in excess of the body’s ability to use and degrade it, thereby resulting in a syndrome caused by hormone excess. Examples are summarized in Table 12-1.

Secondary Hyperfunction of an Endocrine Gland

In this mechanism of endocrine disease, a lesion in one organ (e.g., adenohypophysis) secretes an excess of a trophic hormone that leads to long-term stimulation and hypersecretion of a hormone by a target organ. The classic example in animals is the ACTH-secreting neoplasm derived from pituitary corticotrophs in dogs and cats (Fig. 12-17). The functional disturbances and lesions are caused by increased blood cortisol concentrations resulting from the ACTH-stimulated hypertrophy and hyperplasia of the cells of the zonae fasciculata and reticularis of the adrenal cortex. In some aging dogs with notable adrenal cortical enlargement and functional disturbances of cortisol excess, no gross or histopathologic evidence of a neoplasm is present in the pituitary gland. These animals can have a change in negative feedback control as the result of an age-related increase in monoamine oxidase-β in the hypothalamus and increased metabolism of dopamine. The outcome is reduced inhibition of ACTH production by the pars intermedia of the pituitary gland leading to severe corticotroph hyperplasia, increased ACTH concentration in the blood, and long-term stimulation of the adrenal cortex, resulting in the syndrome of cortisol excess.

Hypersecretion of Hormones or Hormonelike Factors by Nonendocrine Neoplasms

Certain neoplasms of nonendocrine tissue in animals secrete either new humoral substances or hormones that share chemical and/or biologic characteristics with the “native” hormones secreted by an endocrine gland. Most of the recently discovered humoral substances secreted by nonendocrine neoplasms are peptides rather than steroids, iodothyronines, or catecholamines. The nonpeptide hormones require more complex biosynthetic pathways and are infrequently produced by cancer cells. Pseudohyperparathyroidism or humoral hypercalcemia of malignancy is a clinical syndrome primarily produced by the autonomous hypersecretion of PTH–related peptide (PTHrP) by cancer cells. PTHrP interacts with the parathyroid hormone receptor in target cells (e.g., bone and kidneys) and results in persistent, often life-threatening hypercalcemia. A well-characterized example of this disease mechanism in animals is the adenocarcinoma of the apocrine glands of the anal sac in dogs (see the section on Disorders of Dogs). These neoplasms produce PTHrP, which mimics the action of PTH and results in an accelerated mobilization of calcium from bone by osteoclasts leading to the development of persistent hypercalcemia. Serum PTH concentrations are lower in dogs with apocrine carcinomas than in controls, and PTH concentrations are undetectable in neoplastic tissue.

Endocrine Hyperactivity Caused by Diseases of Other Organs

The best-characterized example of endocrine hyperactivity caused by disease of other organs is the hyperparathyroidism that develops as a result of chronic renal failure or nutritional imbalance. In the renal form, hyperphosphatemia occurs because of a decreased glomerular filtration rate, resulting in a reciprocal decline in serum calcium and parathyroid stimulation. Subsequently the progressive destruction of cells of the proximal convoluted tubules interferes with the metabolic activation of vitamin D by 1α-hydroxylase in the kidneys, leading to decreased intestinal calcium absorption and continued parathyroid stimulation. This rate-limiting step in the metabolism of vitamin D is controlled by multiple factors, including levels of PTH, serum phosphorus, and several other hormones. The intestinal absorption of calcium is impaired and results in the development of progressive hypocalcemia; the hypocalcemia leads to long-term parathyroid gland stimulation and subsequently to the development of generalized demineralization of the skeleton. Nutritional hyperparathyroidism develops in animals fed abnormal diets that are either too low in calcium, too high in phosphorus, or deficient in cholecalciferol.

Iatrogenic Syndromes of Hormone Excess

The administration of an exogenous hormone can influence the activity of target cells either directly or indirectly and result in important functional disturbances. It is well recognized that the chronic administration of potent preparations of adrenal cortical steroids at inappropriately large daily doses (for the symptomatic treatment of various diseases) can produce most of the functional disturbances that are secondary to an endogenous hypersecretion of cortisol. Increased concentrations of exogenous cortisol result in notable atrophy of the adrenal cortex, particularly the ACTH-dependent zonae fasciculata and reticularis (Fig. 12-18). Similarly the administration of excessively large doses of insulin can result in hypoglycemia, and an excess of T4 or T3 can result in hyperthyroidism, especially in certain species, such as cats, which have limited capacities to conjugate T4 with glucuronic acid and thus enhance its biliary excretion.

The administration of progestogens to dogs indirectly results in a syndrome of growth hormone excess. For example, the injection of medroxyprogesterone acetate for the prevention of estrus in dogs stimulates the expression of the growth hormone gene in the mammary glands and results in elevated circulating growth hormone concentrations, producing many of the clinical manifestations of acromegaly. The excessive skinfolds (Fig. 12-19), expansion of interdigital spaces, and abdominal enlargement in dogs with iatrogenic acromegaly are related to the protein anabolic effects of growth hormone. Elongation of bones in response to exogenous progestogens requires functional growth plates and osteogenic surfaces.

Defense Mechanisms

The primary defense mechanism employed by the endocrine system is the hierarchy of hormonal regulation known as the hypothalamic-pituitary-target gland axis (see Fig. 12-3). The hypothalamus produces a number of releasing and inhibitory hormones in response to sensory input from the central nervous system (CNS). These releasing and inhibitory hormones act on anterior or posterior portions of the pituitary gland to stimulate or prevent the release of trophic hormones. Trophic hormones act on specific endocrine glands, stimulating them to produce hormones that exert ultimate actions on downstream tissues. Under normal circumstances, the action of a hormone is self-limiting because of the existence of negative feedback loops for each hormone series in which secretion of a particular hormone ultimately leads to inhibition of its subsequent secretion. Negative feedback from target endocrine glands can be directed at the hypothalamus, the pituitary gland, or both.

Disorders of Domestic Animals

Disorders known or thought to have a genetic basis and/or be inherited are listed in Web Table 12-1.

Disorders of the Adenohypophysis

Hypopituitarism and Neoplasms of the Adenohypophysis

Endocrinologically Inactive Chromophobe Adenomas: Nonfunctional pituitary neoplasms occur in dogs and cats but are uncommon in other species. Although chromophobe adenomas seem endocrinologically inactive, they can cause significant functional disturbances and clinical signs by compressing and causing atrophy of adjacent portions of the pituitary gland, as well as dorsal extension into the overlying brain (Fig. 12-20). The clinical disturbances result either from the lack of secreted pituitary trophic hormones and subsequent diminished target organ function (e.g., adrenal cortex; see Fig. 12-16) or from dysfunction of the CNS. Affected animals often have decreased spontaneous activity, incoordination, and disturbances of balance; are weak; and sometimes collapse after exercise. Chronically affected animals are blind and have dilated and fixed pupils because of compression and disruption of the optic nerves by dorsal extension of the pituitary neoplasms (see Fig. 12-20). Endocrinologically inactive pituitary adenomas often become large before they cause clinical signs or kill the animal (see Figs. 12-16 and 12-20).

Clinical signs reported with nonfunctional pituitary adenomas and hypopituitarism are not specific and could be confused with other disorders of the CNS, such as brain neoplasms and encephalitis, or with chronic renal disease. There is no effect on body stature secondary to compression of the pars distalis and interference with growth hormone secretion because these neoplasms usually arise in adult animals that have already completed their growth. However, atrophy of the skin and loss of muscle mass could be related in part to a lack of the protein anabolic effects of growth hormone. Impaired secretion of pituitary trophic hormones often leads to a reduced basal metabolic rate because of decreased TSH secretion and hypoglycemia secondary to trophic atrophy of the adrenal cortex (see Fig. 12-16).

Pituitary Gland Carcinomas: Pituitary gland carcinomas are uncommon neoplasms compared with adenomas but have been seen in older dogs and cattle. They usually are endocrinologically inactive but can cause significant functional disturbances by destroying the pars distalis and neurohypophyseal system, leading to panhypopituitarism and diabetes insipidus. Carcinomas are large and invade extensively into the overlying brain, along the ventral aspect of the cranial cavity, and into the basisphenoid bone where they cause osteolysis. Metastases occur infrequently to cervical lymph nodes or distant sites such as the spleen or liver. Carcinomas are highly cellular and often have large areas of hemorrhage and necrosis. Giant cells, nuclear pleomorphism, and mitotic figures are encountered more frequently than in adenomas.

Craniopharyngiomas (Intracranial Germ Cell Tumors): Craniopharyngiomas are benign neoplasms derived from epithelial remnants of the oropharyngeal ectoderm of the craniopharyngeal duct (Rathke’s pouch). They often occur in animals younger than those with other types of pituitary neoplasms and are present in either suprasellar or infrasellar locations. Craniopharyngioma is associated with dwarfism in young dogs because it causes subnormal secretion of somatotrophin and other trophic hormones at an early age, before closure of the growth plates.

The reclassification of some pleomorphic neoplasms in the suprasellar region of younger dogs from craniopharyngiomas to germ cell tumors has recently been proposed. The diagnosis of germ cell tumors was based on three criteria: (1) midline suprasellar location, (2) presence within the tumor of several distinct cell types (one population resembles a seminoma or dysgerminoma and others suggest teratomatous differentiation into secretory glandular and squamous elements), and (3) α-fetoprotein immunoreactivity.

Craniopharyngiomas and suprasellar germ cell tumors often are large and grow along the ventral aspect of the brain, where they can surround several cranial nerves. In addition, they extend dorsally into the hypothalamus and thalamus (Fig. 12-21). The resulting clinical signs often occur because of a combination of the following:

Microscopically, craniopharyngiomas have alternating solid and cystic areas. The solid areas are composed of nests of cuboidal, columnar, or squamous epithelial cells with focal areas of mineralization. The cystic spaces are lined by either columnar or squamous cells and contain keratin debris and colloid.

Hyperpituitarism and Neoplasms of the Adenohypophysis

Pars Intermedia Adenomas: Adenomas derived from cells of the pars intermedia are the most common type of pituitary gland neoplasm in horses and the second most common type in dogs, but they are rare in other species. Adenomas develop in older horses, more frequently in females. Nonbrachycephalic breeds of dogs have adenomas of the pars intermedia more often than brachycephalic breeds.

Adenomas of the pars intermedia in dogs are either functionally inactive and result in varying degrees of hypopituitarism and diabetes insipidus, or endocrinologically active and secrete excessive levels of ACTH, leading to bilateral adrenal cortical hyperplasia and a syndrome of cortisol excess. Endocrinologically active (ACTH-secreting) adenomas of the pars intermedia in dogs have prominent groups of corticotrophs that have abundant eosinophilic cytoplasm and more widely scattered follicles.

Two cell populations have been identified in the pars intermedia of normal dogs by immunohistochemistry. The predominant cell type (A cell) is strongly immunoreactive for α-MSH, as in the pars intermedia of other species, whereas the second cell type (B cell) in the canine pars intermedia is strongly immunoreactive for ACTH. This second cell population accounts for the high bioactive ACTH concentration found in the pars intermedia of dogs and most likely gives rise to corticotroph adenomas of the pars intermedia in dogs with the syndrome of cortisol excess.

The clinical syndrome reported with neoplasms of the pars intermedia in horses is characterized by polyuria, polydipsia, polyphagia, muscle weakness, somnolence, intermittent hyperpyrexia, and generalized hyperhidrosis. The affected horses often develop hirsutism because of a failure to seasonally shed hair. The hair over most of the trunk and extremities is long (up to 10 to 12 cm), abnormally thick and wavy, and often matted (Fig. 12-22). Horses with larger neoplasms sometimes have insulin-resistant hyperglycemia and glycosuria, probably resulting from the downregulation of insulin receptors on target cells induced by chronic excessive intake of feed and hyperinsulinemia. The disturbances in carbohydrate metabolism, ravenous appetite, hypertrichosis, and hyperhidrosis reflect deranged hypothalamic function caused by compression of the overlying hypothalamus by the large pituitary neoplasms. The hypothalamus is the primary center for homeostatic regulation of body temperature, appetite, and cyclic shedding of hair.

In addition to their space-occupying effects, some adenomas of the pars intermedia are endocrinologically active. Plasma cortisol and immunoreactive adrenocorticotropin (iACTH, molecular weight 4500 Da) concentrations can be modestly elevated in horses with pars intermedia adenomas. The cortisol concentrations often lack normal diurnal rhythm and are not suppressed by either large or small doses of dexamethasone. The modest increases of plasma iACTH appear to be caused by the different processing of proopiomelanocortin (POMC) in neoplasms derived from cells of the pars intermedia. This could explain the normal or slightly increased blood cortisol concentrations and normal or mildly hyperplastic adrenal cortices observed in some horses with adenomas of the pars intermedia. The concentrations of ACTH in the neoplasm have been reported to be six times that of the normal pars intermedia and only approach the concentrations found in the pars distalis of normal horses. The plasma and neoplasm concentrations of pars intermedia–derived peptides (corticotrophin-like intermediate lobe peptide [CLIP], α-MSH, β-MSH, and β-endorphin [β-END]) are disproportionately increased (40 times or more) compared with those of ACTH, apparently as the result of selective posttranslational processing of POMC in a manner similar to that of the normal pars intermedia.

Adenomas of the pars intermedia have immunohistochemical staining similar to that of the nonneoplastic equine pars intermedia. The findings include a strong, diffuse cytoplasmic reaction for POMC, a moderately strong reaction for α-MSH and β-END, a weak reaction for ACTH, and negative immunostaining for prolactin, glial fibrillary acidic protein, and neuron-specific enolase. Two antisera directed against different parts of the N-terminal fragment of human (h) POMC differ in their immunoreactivity. Immunostaining of neoplastic cells was stronger with anti-h1-48 N-POMC antisera than with anti-h1-76 N-POMC antisera. These immunohistochemical findings support the biochemical studies that suggest horses with pituitary adenomas derived from the cells of the pars intermedia develop a unique clinical syndrome that is the result of hypothalamic and neurohypophyseal derangement and an autonomous production of excess amounts of POMC-derived peptides. Although many of the functional disturbances in horses with pituitary adenomas (e.g., diabetes insipidus, polyphagia, hyperpyrexia, hyperhidrosis, and hirsutism) appear to be the result of hypothalamic or neurohypophyseal dysfunction, other behavioral signs (e.g., docility and diminished responsiveness to painful stimuli) could be related to increased plasma and cerebrospinal fluid concentrations of β-END. The clinical syndrome in horses with pituitary neoplasms is distinctly different from that of Cushing’s disease in dogs and cats.

In dogs, adenomas of the pars intermedia result in only a moderate enlargement of the pituitary gland. The pars distalis is readily identifiable and sharply demarcated from the anterior margin of the neoplasm, usually by an incomplete layer of condensed stroma. The neoplasm can extend across the residual hypophyseal lumen and result in compression atrophy, but it usually does not invade the pars distalis. The posterior lobe is incorporated within the neoplasm, but the infundibular stalk is intact. Histologically, canine pars intermedia adenomas are composed of numerous large colloid-filled follicles lined by partially ciliated simple columnar epithelium scattered among nests of variably sized chromophobic cells.

In horses, adenomas of the pars intermedia often are large neoplasms that extend out of the fossa hypophysialis and severely compress the overlying hypothalamus (Fig. 12-23). The adenomas are yellow to white and multinodular and enclose the pars nervosa. When the neoplasm is incised, the pars distalis usually can be identified as a compressed subcapsular rim of tissue on the anterior margin. A sharp line of demarcation remains between the neoplasm and the compressed pars distalis. The neoplastic cells are arranged in cords and nests along the capillaries and connective tissue septae and are large, cylindrical, spindle-shaped, or polyhedral with oval hyperchromatic nuclei (Fig. 12-24). The pattern is often reminiscent of that of the prominent pars intermedia of normal horses. Ribbons of more cuboidal to columnar neoplastic cells occasionally form follicular structures that have dense eosinophilic colloid.

Sep 17, 2016 | Posted by in GENERAL | Comments Off on Endocrine System
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