Chapter 20 Endocrine Glands PDF

VetBooks.ir C H A P T E R 20 PITUITARY GLAND (HYPOPHYSIS) The Hypothalamic-Hypophyseal Tract & Blood Supply Adenohypophysis (Anterior Pituitary) Control of Hormone Secretion in the Anterior Pituitary Neurohypophysis (Posterior Pituitary) ADRENAL GLANDS Adrenal Cortex Adrenal Medulla S Endocrine Glan...

VetBooks.ir C H A P T E R 20 PITUITARY GLAND (HYPOPHYSIS) The Hypothalamic-Hypophyseal Tract & Blood Supply Adenohypophysis (Anterior Pituitary) Control of Hormone Secretion in the Anterior Pituitary Neurohypophysis (Posterior Pituitary) ADRENAL GLANDS Adrenal Cortex Adrenal Medulla S Endocrine Glands 413 416 417 420 421 423 424 425 ecretory cells of endocrine glands release their products, signaling molecules called hormones, into the neighboring vascularized compartment for uptake by capillaries and distribution throughout the body. There is no secretory duct as in exocrine glands. Endocrine cells are typically epithelial, at least in origin, and aggregated as cords or clusters. Besides the specialized endocrine glands discussed in this chapter, many other organs specialized for other functions, such as the heart, thymus, gut, kidneys, testis, and ovaries, contain various endocrine cells (Figure 20–1). Distribution by the circulation allows hormones to act on target cells with receptors for those hormones at a distance from the site of their secretion. As discussed briefly in Chapter 2, other endocrine cells produce hormones that act on target cells only a short distance away. This may involve paracrine secretion, with localized dispersal in interstitial fluid or through short loops of blood vessels, as when gastrin made by pyloric G cells reaches target cells in the fundic glands, or juxtacrine secretion, in which a signaling molecule remains on the secreting cell’s surface or adjacent extracellular matrix and affects target cells when the cells make contact. Juxtacrine signaling is particularly important in embryonic and regenerative tissue interactions. In autocrine secretion, cells may produce molecules that act on themselves or on cells of the same type. For example, insulin-like growth factor (IGF) produced by several cell types may act on the same cells that produced it. Endocrine glands are often also target organs for other hormones that can establish a feedback mechanism to control hormone secretion and keep blood hormonal levels within strict limits. Hormones, like neurotransmitters, are frequently hydrophilic molecules such as proteins, glycoproteins, peptides, or PANCREATIC ISLETS 427 DIFFUSE NEUROENDOCRINE SYSTEM 429 THYROID GLAND Production of Thyroid Hormone & Its Control PARATHYROID GLANDS 429 430 432 PINEAL GLAND 434 SUMMARY OF KEY POINTS 437 ASSESS YOUR KNOWLEDGE 437 modified amino acids with receptors on the surface of target cells. Alternatively, hydrophobic steroid and thyroid hormones must circulate on transport proteins but can diffuse through the cell membranes and activate cytoplasmic receptors in target cells (see Chapter 2). ››PITUITARY GLAND (HYPOPHYSIS) The pituitary gland, or hypophysis (Gr. hypo, under + physis, growth), weighs about 0.5 g in adults and has dimensions of about 10 × 13 × 6 mm. It lies below the brain in a small cavity on the sphenoid bone, the sella turcica (Figure 20–2). The pituitary is formed in the embryo partly from the developing brain and partly from the developing oral cavity (Figure 20–3). The neural component is the neurohypophyseal bud growing down from the floor of the future diencephalon as a stalk (or infundibulum) that remains attached to the brain. The oral component arises as an outpocketing of ectoderm from the roof of the primitive mouth and grows cranially, forming a structure called the hypophyseal (Rathke) pouch. The base of this pouch eventually constricts and separates from the pharynx. Its anterior wall then thickens greatly, reducing the pouch’s lumen to a small fissure (Figure 20–3). Because of its dual origin, the pituitary actually consists of two glands—the posterior neurohypophysis and the anterior adenohypophysis—united anatomically but with different functions. The neurohypophysis retains many histologic features of brain tissue and consists of a large part, the pars nervosa, and the smaller infundibulum stalk attached to the hypothalamus at the median eminence (Figures 20–2 and 20–4). The adenohypophysis, derived from the oral 413 20_Mescher_ch20_p413-438.indd 413 26/04/18 11:53 am VetBooks.ir 414 CHAPTER 20 FIGURE 20–1 Endocrine Glands Locations of the major endocrine glands. Major endocrine glands Organs containing endocrine cells Hypothalamus Parathyroid glands Pituitary gland Pineal gland Posterior surface of thyroid gland Thyroid gland Adrenal cortex Adrenal medulla Skin Thymus Adrenal gland Adrenal glands Heart Liver Stomach Pancreas Small intestine Kidney Gonads Testes (male) Ovaries (female) In addition to the major endocrine glands shown at the left here, there are widely distributed endocrine cells as well as various other tissues in organs (right) throughout the body with endocrine 20_Mescher_ch20_p413-438.indd 414 functions. Not shown are adipocytes, which exert important endocrine functions, and the many tissues in which paracrine signaling is important. 26/04/18 11:53 am 415 FIGURE 20–2 Pituitary gland. C H A P T E R VetBooks.ir Pituitary Gland (Hypophysis) Hypothalamus Mammillary body Optic chiasm Anterior pituitary Pars intermedia Posterior pituitary Infundibular stalk Pars distalis Pars nervosa Hypophyseal fossa in sella turcica of sphenoid bone FIGURE 20–3 Formation of the pituitary gland. Diencephalon Neuroectoderm Neurohypophyseal bud Oral ectoderm Hypophyseal pouch Endocrine Glands Pituitary Gland (Hypophysis) Infundibulum Pars tuberalis The pituitary gland is composed of an anterior part and a posterior part that is directly attached to the hypothalamus region of the brain by an infundibular stalk. The gland occupies a fossa of the sphenoid bone called the sella turcica (L. Turkish saddle). 2 0 Median eminence Neurohypophyseal bud (future posterior pituitary) Hypophyseal pouch (future anterior pituitary) Pharynx Stomodeum (future mouth) (a) Week 3: Hypophyseal pouch and neurohypophyseal bud form Anterior pituitary Infundibulum Pars tuberalis Neurohypophyseal bud Hypophyseal pouch Pars intermedia Pars nervosa Pars distalis (b) Late second month: Hypophyseal pouch loses contact with roof of pharynx The pituitary gland forms from two separate embryonic structures. (a) During the third week of development, a hypophyseal pouch (or Rathke pouch, the future anterior pituitary) grows from the roof of the pharynx, while a neurohypophyseal bud (future posterior pituitary) forms from the diencephalon. 20_Mescher_ch20_p413-438.indd 415 Posterior pituitary Median eminence (c) Fetal period: Anterior and posterior parts of pituitary have formed (b) By late in the second month, the hypophyseal pouch detaches from the roof of the pharynx and merges with the neurohypophyseal bud. (c) During the fetal period, the anterior and posterior parts of the pituitary complete development. 26/04/18 11:53 am VetBooks.ir 416 CHAPTER 20 FIGURE 20–4 Endocrine Glands Pituitary gland. IS PT PD PI Histologically the two parts of the pituitary gland reflect their origins, as seen in this low-magnification section of an entire gland. The infundibular stalk (IS) and pars nervosa (PN) of the ectoderm, has three parts: a large pars distalis or anterior lobe; the pars tuberalis, which wraps around the infundibulum; and the thin pars intermedia adjacent to the posterior pars nervosa (Figures 20–2 and 20–4). The Hypothalamic-Hypophyseal Tract & Blood Supply The pituitary gland’s neural connection to the brain and its blood supply are both of key importance for its function (Figures 20–4 and 20–5). Embryologically, anatomically, and functionally, the pituitary gland is connected to the hypothalamus at the base of the brain. In addition to the vascular portal system carrying small regulatory peptides from the hypothalamus to the adenohypophysis, a bundle of axons called the hypothalamic-hypophyseal tract courses into the neurohypophysis from two important hypothalamic 20_Mescher_ch20_p413-438.indd 416 PN neurohypophysis resemble CNS tissue, while the adenohypophysis’ pars distalis (PD), pars intermediate (PI), and pars tuberalis (PT) are typically glandular in their level of staining. (X30; H&E) nuclei. The peptide hormones ADH (antidiuretic hormone) and oxytocin are synthesized by large neurons in the supraoptic and the paraventricular nuclei, respectively. Both hormones undergo axonal transport and accumulate temporarily in the axons of the hypothalamic-hypophyseal tract before their release and uptake by capillaries branching from the inferior arteries. The blood supply derives from two groups of vessels coming off the internal carotid artery and drained by the hypophyseal vein. The superior hypophyseal arteries supply the median eminence and the infundibular stalk; the inferior hypophyseal arteries provide blood mainly for the neurohypophysis. The superior arteries divide into a primary plexus of fenestrated capillaries that irrigate the stalk and median eminence. These capillaries then rejoin to form venules that branch again as a larger secondary capillary plexus in the adenohypophysis (Figure 20–5). These vessels 26/04/18 11:54 am FIGURE 20–5 417 The hypothalamic-hypophyseal tract and portal system. Paraventricular nucleus (produces oxytocin) C H A P T E R VetBooks.ir Pituitary Gland (Hypophysis) Hypothalamus Supraoptic nucleus (produces ADH) 2 0 Posterior pituitary Infundibulum Hypothalamic-hypophyseal tract Pars nervosa (With axons storing oxytocin and ADH) (a) Hypothalamus Infundibulum Superior hypophyseal artery Hypophyseal portal veins Primary plexus of the hypothalamic-hypophyseal portal system Anterior pituitary (a) The hypothalamic-hypophyseal tract consists of axons extending from the hypothalamic supraoptic and paraventricular nuclei, through the infundibulum and into the pars nervosa of the posterior pituitary, where peptide hormones they carry are released for capillary uptake. (b) The hypothalamic-hypophyseal portal system, with blood from the superior hypophyseal artery, consists of two capillary networks connected by the hypophyseal portal vein. The primary plexus surrounds the infundibulum and median eminence, and the second is throughout the pars distalis and drains into the hypophyseal veins. Hypophyseal veins Hypophyseal vein Secondary plexus of the hypothalamic-hypophyseal portal system Endocrine Glands Pituitary Gland (Hypophysis) Optic chiasm Posterior pituitary Hypophyseal vein (b) make up the hypothalamic-hypophyseal portal system that has great importance because it carries neuropeptides from the median eminence the short distance to the adenohypophysis where they either stimulate or inhibit hormone release by the endocrine cells there. Adenohypophysis (Anterior Pituitary) The three parts of the adenohypophysis are derived embryonically from the hypophyseal pouch. Pars Distalis The pars distalis accounts for 75% of the adenohypophysis and has a thin fibrous capsule. The main components are cords of well-stained endocrine cells interspersed with fenestrated capillaries and supporting reticular connective tissue (Figures 20–4 and 20–6). Common stains suggest two broad groups of cells in the pars distalis with different staining affinities: chromophils 20_Mescher_ch20_p413-438.indd 417 Inferior hypophyseal artery and chromophobes. Chromophils are secretory cells in which hormone is stored in cytoplasmic granules. They are also called basophils and acidophils, based on their affinities for basic and acidic dyes, respectively (Figure 20–6). Subtypes of basophilic and acidophilic cells are identified by their granular morphology in the TEM or more easily by immunohistochemistry (Figure 20–7). Specific cells are usually named according to their hormone’s target cells (Table 20–1). Acidophils secrete either growth hormone (somatotropin) or prolactin (PRL) and are called somatotrophs and lactotrophs (or somatotropic cells and lactotropic cells), respectively. The basophilic cells are the corticotrophs, gonadotrophs, and thyrotrophs, with target cells in the adrenal cortex, gonads, and thyroid gland, respectively. Somatotrophs typically constitute about half the cells of the pars distalis in humans, with thyrotrophs the least abundant. With two exceptions, each type of anterior pituitary cell makes one kind of hormone (Table 20–1). Gonadotrophs 26/04/18 11:54 am VetBooks.ir 418 CHAPTER 20 FIGURE 20–6 Endocrine Glands Pars distalis: Acidophils, basophils, and chromophobes. C S S A C A A B C B C S B A a S C b A B S S A C B (a, b) Most general staining methods simply allow the parenchymal cells of the pars distalis to be subdivided into acidophil cells (A), basophils (B), and chromophobes (C) in which the cytoplasm is poorly stained. Also shown are capillaries and sinusoids (S) in the second capillary plexus of the portal system. Cords of acidophils and basophils vary in distribution and number in different regions of the pars distalis, but are always closely associated with microvasculature that carries off secreted hormones into the general circulation. (X400; H&E) (c) The same area is seen after staining with Gomori trichrome. (X400) c secrete two different glycoproteins: follicle-stimulating hormone (FSH) and luteinizing hormone (LH) (called interstitial cell-stimulating hormone [ICSH] in men). The main protein synthesized in corticotrophs is pro-opiomelanocortin (POMC), which is cleaved posttranslationally into the polypeptide hormones adrenocortical trophic hormone (ACTH) and β-lipotropin(β-LPH). Hormones produced by the pars distalis have widespread functional activities. They regulate almost all other endocrine glands, ovarian function and sperm production, milk production, and the metabolism of muscle, bone, and adipose tissue (Table 20–1; Figure 20–8). Chromophobes stain weakly, with few or no secretory granules, and also represent a heterogeneous group, 20_Mescher_ch20_p413-438.indd 418 including stem and undifferentiated progenitor cells as well as any degranulated cells present. Pars Tuberalis The pars tuberalis is a smaller funnel-shaped region surrounding the infundibulum of the neurohypophysis (Figures 20–2 and 20–4). Most of the cells of the pars tuberalis are gonadotrophs. Pars Intermedia A narrow zone lying between the pars distalis and the pars nervosa, the pars intermedia contains basophils (corticotrophs), chromophobes, and small, colloid-filled cysts 26/04/18 11:54 am FIGURE 20–7 419 Ultrastructure and immunohistochemistry of somatotropic cells. C H A P T E R VetBooks.ir Pituitary Gland (Hypophysis) 2 0 N a b (a) Ultrastructurally, cytoplasm of all chromophil cells is shown to have well-developed Golgi complexes (G), euchromatic nuclei (N), and cytoplasm filled with secretory granules, as seen here in a somatotroph, the most common acidophil. The arrow indicates the cell membrane. Specific chromophils are more easily identified using immunohistochemistry and antibodies against the hormone products. (X10,000) (b) The micrograph shows somatotrophs stained using an antibody against somatotropin. (X400; Hematoxylin counterstain) Endocrine Glands Pituitary Gland (Hypophysis) G TABLE 20–1    Major cell types of the anterior pituitary and their major functions. Cell Type % of Total Cells Hormone Produced Major Function Somatotrophs 50 Somatotropin (growth hormone, GH), a 22-kDa protein Stimulates growth in epiphyseal plates of long bones via insulin-like growth factors (IGFs) produced in liver Lactotrophs (or mammotrophs) 15-20 Prolactin (PRL), a 22.5-kDa protein Promotes milk secretion Gonadotrophs 10 Follicle-stimulating hormone (FSH) and luteinizing hormone (LH; interstitial cellstimulating hormone [ICSH] in men), both 28-kDa glycoprotein dimers, secreted from the same cell type FSH promotes ovarian follicle development and estrogen secretion in women and spermatogenesis in men; LH promotes ovarian follicle maturation and progesterone secretion in women and interstitial cell androgen secretion in men Thyrotrophs 5 Thyrotropin (TSH), a 28-kDa glycoprotein dimer Stimulates thyroid hormone synthesis, storage, and liberation Corticotrophs 15-20 Adrenal corticotropin (ACTH), a 4-kDa polypeptide Stimulates secretion of adrenal cortex hormones Lipotropin (LPH) Helps regulate lipid metabolism 20_Mescher_ch20_p413-438.indd 419 26/04/18 11:54 am VetBooks.ir 420 CHAPTER 20 FIGURE 20–8 Endocrine Glands Hormones of the pars distalis and their targets. Hypothalamus Regulatory hormones of hypothalamus Tropic hormones of anterior pituitary Releasing hormones: TRH, PRH, GnRH, CRH, GHRH Inhibiting hormones: PIH, GIH Infundibulum Anterior pituitary Posterior pituitary Muscle TSH Thyroid-stimulating hormone (TSH) stimulates the thyroid gland to release thyroid hormone (TH). Growth hormone (GH) acts on all body tissues, especially cartilage, bone, muscle, and adipose connective tissue to stimulate growth. GH Thyroid Bone PRL Adipose connective tissue Mammary gland Adrenal cortex Prolactin (PRL) acts on mammary glands to stimulate milk production. ACTH Adrenocorticotropic hormone (ACTH) acts on the adrenal cortex to cause release of corticosteroids (eg, cortisol). FSH and LH Adrenal gland Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) act on gonads (testes and ovaries) to stimulate development of gametes (sperm and oocyte). Testis Ovary The anterior pituitary secretes six major tropic hormones controlling the activities of their target organs. Release of these hormones derived from the lumen of the embryonic hypophyseal pouch (Figure 20–9). Best-developed and active during fetal life, corticotrophs of the pars intermedia express POMC but cleave it differently from cells in the pars distalis, producing mainly smaller peptide hormones, including two forms of melanocyte-stimulating hormone (MSH), γ-LPH, and β-endorphin. MSH increases melanocyte activity, but the overall functional significance of the pars intermedia remains uncertain. Control of Hormone Secretion in the Anterior Pituitary The activities of the cells of the anterior pituitary are controlled primarily by peptide-related hypothalamic hormones produced by small neurons near the third ventricle, discharged from axons in the median eminence, and transported by 20_Mescher_ch20_p413-438.indd 420 is regulated primarily by hypothalamic factors carried by the hypothalamic-hypophyseal blood supply. capillaries of the portal system throughout the anterior pituitary. As shown in Table 20–2, most of these hormones are releasing hormones that stimulate secretion by specific anterior pituitary cells. Two of the hypothalamic factors, however, are inhibiting hormones, which block hormone secretion in specific cells of the adenohypophysis (Table 20–2). Because of the strategic position of the hypothalamic neurons and the control they exert on the adenohypophysis and therefore on many bodily functions, many sensory stimuli coming to the brain or arising within the central nervous system (CNS) can affect pituitary function and then also quickly affect activities of many other organs and tissues. Another mechanism controlling activity of anterior pituitary cells is negative feedback by hormones from the target organs on secretion of the relevant hypothalamic factors and on hormone secretion by the relevant pituitary cells. Figure 20–10 illustrates this mechanism, using the thyroid 26/04/18 11:54 am FIGURE 20–9 421 All these mechanisms allow the fine tuning of hormone secretion by cells of the anterior pituitary. Pars intermedia. › ›› MEDICAL APPLICATION B PD PI C PN C The pars intermedia (PI) is a narrow region lying between the pars distalis (PD) and the pars nervosa (PN), with many of its basophils (B) often invading the latter. Remnants of the embryonic hypophyseal pouch’s lumen are usually present in this region as colloid-filled cysts (C) of various sizes. Function of this region in humans is not clear. (X56; H&E) as an example, and shows the complex chain of events that begins with the action of neural stimuli in the hypothalamus and ends with the effects of hormones from the pituitary’s target organs. Finally, hormone secretion in the anterior pituitary is affected by other hormones from outside the feedback loop or even outside the major target tissues. Examples include the polypeptide ghrelin produced mainly in the stomach mucosa, which also acts as a releasing hormone for somatotropin secretion, and oxytocin, released in the posterior pituitary during breast-feeding, which increases secretion of prolactin. 20_Mescher_ch20_p413-438.indd 421 Neurohypophysis (Posterior Pituitary) The neurohypophysis consists of the pars nervosa and the infundibular stalk (Figures 20–2 and 20–4) and, unlike the adenohypophysis, does not contain the cells that synthesize its two hormones. It is composed of neural tissue, containing some 100,000 unmyelinated axons of large secretory neurons with cell bodies in the supraoptic and paraventricular nuclei of the hypothalamus (Figure 20–5). Also present are highly branched glial cells called pituicytes that resemble astrocytes and are the most abundant cell type in the posterior pituitary (Figure 20–11). The secretory neurons have all the characteristics of typical neurons, including the ability to conduct an action potential, but have larger-diameter axons and well-developed synthetic components related to the production of the 9-amino acid peptide hormones antidiuretic hormone (ADH)—also called arginine vasopressin—and oxytocin. Transported axonally into the pars nervosa, these hormones accumulate in axonal dilations called neurosecretory bodies or Herring bodies, visible in the light microscope as faintly eosinophilic structures (Figure 20–11). The neurosecretory bodies contain membrane-enclosed granules with either oxytocin or ADH bound to 10-kDa carrier proteins called neurophysin I and II, respectively. The hormoneneurophysin complex is synthesized as a single protein and then cleaved to produce the peptide hormone and its binding protein. Nerve impulses along the axons trigger the release of the peptides from the neurosecretory bodies for uptake by the fenestrated capillaries of the pars nervosa, and the hormones are then distributed to the general circulation. Axons from the supraoptic and paraventricular nuclei mingle in the neurohypophysis but are mainly concerned with ADH and oxytocin secretion, respectively. ADH is released in response to increased blood tonicity, sensed by osmoreceptor cells in the hypothalamus, which then stimulate ADH synthesis in supraoptic neurons. ADH increases the permeability of the renal collecting ducts to water (see Chapter 19) so that more water is reabsorbed from the filtrate in these tubules and osmotic balance of body fluids is restored (Table 20–3). Endocrine Glands Pituitary Gland (Hypophysis) C 2 0 Benign pituitary adenomas often produce excessive numbers of functional acidophils or basophils. Adenomas involving somatotropic cells can cause gigantism if occurring in children before closure of the long bones’ epiphyseal plates or acromegaly in adults, with musculoskeletal, neurologic, and other medical consequences. C H A P T E R VetBooks.ir Pituitary Gland (Hypophysis) 26/04/18 11:54 am VetBooks.ir 422 CHAPTER 20 Endocrine Glands TABLE 20–2     Hypothalamic hormones regulating cells of the anterior pituitary. Hormone Chemical Form Functions Thyrotropin-releasing hormone (TRH) 3-amino acid peptide Stimulates release of thyrotropin (TSH) Gonadotropin-releasing hormone (GnRH) 10-amino acid peptide Stimulates the release of both follicle-stimulating hormone (FSH) and luteinizing hormone (LH) Somatostatin 14-amino acid peptide Inhibits release of both somatotropin (GH) and TSH Growth hormone-releasing hormone (GHRH) 40- or 44-amino acid polypeptides (2 forms) Stimulates release of GH Dopamine Modified amino acid Inhibits release of prolactin (PRL) Corticotropin-releasing hormone (CRH) 41-amino acid polypeptide Stimulates synthesis of pro-opiomelanocortin (POMC) and release of both β-lipotropic hormone (β-LPH) and corticotropin (ACTH) FIGURE 20–10 Negative feedback loops affecting anterior pituitary secretion. Hypothalamus 1 A stimulus (eg, low body temperature) causes the hypothalamus to secrete thyrotropin-releasing hormone (TRH), which acts on the anterior pituitary. stimulatory inhibitory Negative feedback inhibition TRH 5 Increased body temperature is detected by the hypothalamus, and secretion of TRH by the hypothalamus is inhibited. TH also blocks TRH receptors on the thyrotropic cells, inhibiting synthesis and release of TSH. Both effects indirectly dampen TH production in the thyroid. 2 Thyrotropic cells in the anterior pituitary release thyroid-stimulating hormone (TSH). Anterior pituitary Target organs in body TSH 4 TH stimulates target cells to increase metabolic TH activities, resulting in an increase in basal body temperature. 3 TSH stimulates follicular cells of the thyroid gland to release thyroid hormone (TH). Relationship between the hypothalamus, the anterior pituitary, and its target organs is shown, using the thyroid as an example. Hypothalamic thyrotropin-releasing hormone (TRH) stimulates secretion of thyroid-stimulating hormone or thyrotropin (TSH), 20_Mescher_ch20_p413-438.indd 422 which stimulates synthesis and secretion of thyroid hormone (TH). In addition to their effects on target organs, TH inhibits TSH secretion from the pars distalis and TRH secretion from the hypothalamus by negative feedback. 26/04/18 11:54 am FIGURE 20–11 Pars nervosa: neurosecretory bodies and pituicytes. 423 Oxytocin stimulates contraction of uterine smooth muscle during childbirth and the myoepithelial cells in the mammary gland (Table 20–3). A nursing infant induces oxytocin secretion by stimulating sensory tracts that act on the hypothalamus in a neurohormonal reflex causing rapid ejection of milk. Oxytocin also produces psychological effects, such as promotion of pair bonding behavior. 2 0 The adrenal (or suprarenal) glands are paired organs lying near the superior poles of the kidneys, embedded in the pararenal adipose tissue and fascia (Figures 20–1 and 20–12). They are flattened structures with a half-moon shape, about 4-6-cm long, 1-2-cm wide, and 4-6-mm thick in adults. Together, they weigh about 8 g, but their weight and size vary with the age and physiologic condition of the individual. Adrenal glands are each covered by a dense connective tissue capsule that P C NB NB FIGURE 20–12 adrenal glands. Location and blood supply of the Endocrine Glands Adrenal Glands ››ADRENAL GLANDS C C H A P T E R VetBooks.ir Adrenal Glands Left inferior phrenic artery Left superior suprarenal arteries The pars nervosa of the posterior pituitary consists of modified neural tissues containing unmyelinated axons supported and ensheathed by glia cells called pituicytes (P), the most numerous cell present. The axons run from the supraoptic and paraventricular hypothalamic nuclei, and have swellings called neurosecretory (Herring) bodies (NB) from which either oxytocin or vasopressin is released upon neural stimulation. The released hormones are picked up by capillaries (C) for distribution. (X400; H&E) Left middle suprarenal artery Left adrenal gland Left inferior suprarenal arteries Left suprarenal vein    Hormones of the posterior TABLE 20–3 pituitary. Hormone Function Vasopressin/antidiuretic hormone (ADH) Increases water permeability of renal collecting ducts Oxytocin Stimulates contraction of mammary gland myoepithelial cells and uterine smooth muscle › ›› MEDICAL APPLICATION Posterior pituitary function can be adversely affected by heritable mutations in the gene for vasopressin (ADH)-neurophysin, by compression from a tumor in adjacent tissues, and by head trauma. By lowering levels of vasopressin, such conditions can produce diabetes insipidus, a disorder characterized by inability to concentrate urine, which leads to frequent urination (polyuria) and increased thirst (polydipsia). 20_Mescher_ch20_p413-438.indd 423 Abdominal aorta The paired adrenal glands are located at the superior pole of each kidney and each consists of an outer cortex producing a variety of steroid hormones and an inner medulla producing epinephrine and norepinephrine. This anterior view of the left adrenal gland and kidney shows the blood vessels supplying these glands. 26/04/18 11:54 am VetBooks.ir 424 CHAPTER 20 Endocrine Glands sends thin trabeculae into the gland’s parenchyma. The stroma consists mainly of reticular fibers supporting the secretory cells and microvasculature. Each gland has two concentric regions: a yellowish adrenal cortex and a reddish-brown central adrenal medulla. The adrenal cortex and medulla can be considered two different organs with distinct embryonic origins, functions, and morphologic characteristics that become united during embryonic development. The cortex arises from mesoderm and the medulla from the neural crest. The general histologic appearance of the adrenal gland is typical of an endocrine gland in which cells of both cortex and medulla are grouped in cords along wide capillaries. The adrenal gland lacks a hilum; superior, middle, and inferior suprarenal arteries arising from larger abdominal arteries penetrate the capsule independently (Figure 20–12) and branch immediately to form a subcapsular arterial plexus. From this plexus arterioles for the adrenal cortex and medulla emerge separately to form rich networks of fenestrated capillaries and sinusoids. Cortical capillaries irrigate endocrine cells of the cortex and then drain into the microvasculature of the medulla. The adrenal medulla thus has a dual blood supply: arterial blood from the medullary arterioles and venous blood from capillaries of the cortex. Venous drainage from the glands occurs via the suprarenal veins (Figure 20–12). Adrenal Cortex Cells of the adrenal cortex have characteristic features of steroid-secreting cells: acidophilic cytoplasm rich in lipid droplets, with central nuclei. Ultrastructurally their cytoplasm shows an exceptionally profuse smooth ER (SER) of interconnected tubules, which contain the enzymes for cholesterol synthesis and conversion of the steroid prohormone pregnenolone into specific active steroid hormones. The mitochondria are often spherical, with tubular rather than shelflike cristae (Figure 20–13). These mitochondria not only synthesize ATP but also contain the enzymes for converting cholesterol to pregnenolone and for some steps in steroid synthesis. The function of steroid-producing cells involves close collaboration between SER and mitochondria. Steroid hormones are not stored in granules like proteins nor undergo exocytosis. As small lipid-soluble molecules, steroids diffuse freely from cells through the plasma membrane. The adrenal cortex has three concentric zones in which the cords of epithelial steroid-producing cells are arranged somewhat differently and which synthesize different classes of steroid hormones (Figure 20–14): FIGURE 20–13 adrenalocytes. L G A M 20_Mescher_ch20_p413-438.indd 424 SER N TEM of two adjacent steroid-secreting cells from the zona fasciculate shows features typical of steroid-producing cells: lipid droplets (L) containing cholesterol esters, mitochondria (M) with tubular and vesicular cristae, abundant SER, and autophagosomes (A), which remove mitochondria and SER between periods of active steroid synthesis. Also seen are the euchromatic nuclei (N), a Golgi apparatus (G), RER, and lysosomes. (X25,700) The zona glomerulosa, immediately inside the cap- sule and comprising about 15% of the cortex, consists of closely packed, rounded or arched cords of columnar or pyramidal cells with many capillaries (Figure 20–15). The steroids made by these cells are called mineralocorticoids because they affect uptake of Na+, K+, and water by cells of renal tubules. The principal product is aldosterone, the major regulator of salt balance, Ultrastructure of cortical which acts to stimulate Na+ reabsorption in the distal convoluted tubules (see Chapter 19). Aldosterone secretion is stimulated primarily by angiotensin II and also by an increase in plasma K+ concentration, but only weakly by ACTH. The middle zona fasciculata, occupies 65%-80% of the cortex and consists of long cords of large polyhedral cells, one or two cells thick, separated by fenestrated sinusoidal capillaries (Figure 20–15). The cells are filled with lipid droplets and appear vacuolated in routine histologic preparations. These cells secrete glucocorticoids, especially cortisol, which affect carbohydrate metabolism by stimulating gluconeogenesis in many cells and glycogen synthesis in the liver. Cortisol also suppresses many immune functions and can induce fat mobilization and muscle proteolysis. Secretion is controlled by ACTH with negative feedback proportional to the concentration of circulating glucocorticoids (Figure 20–10). Small amounts of weak androgens are also produced here. The innermost zona reticularis comprises about 10% of the cortex and consists of smaller cells in a network of irregular cords interspersed with wide capillaries (Figure 20–15). The cells are usually more heavily stained than those of the other zones because they contain fewer lipid droplets and more lipofuscin pigment. Cells of 26/04/18 11:54 am FIGURE 20–14 425 Adrenal gland. Capsule C H A P T E R VetBooks.ir Adrenal Glands Capsule Zona glomerulosa Capsule Adrenal cortex 2 0 Adrenal medulla Zona fasciculata Zona reticularis Adrenal medulla Inside the capsule of each adrenal gland is an adrenal cortex, formed from embryonic mesodermal cells, which completely surrounds an innermost adrenal medulla derived embryologically from neural crest cells. Both regions are very well vascularized with the zona reticularis also produce cortisol but primarily secrete the weak androgens, including dehydroepiandrosterone (DHEA) that is converted to testosterone in both men and women. Secretion by these cells is also stimulated by ACTH with regulatory feedback. › ›› MEDICAL APPLICATION Addison disease or adrenal cortical insufficiency is a disorder, usually autoimmune in origin, which causes degeneration in any layer of adrenal cortex, with concomitant loss of glucocorticoids, mineralocorticoids, or androgen production. Adrenal Medulla The adrenal medulla is composed of large, pale-staining polyhedral cells arranged in cords or clumps and supported by a reticular fiber network (Figure 20–16). A profuse supply of sinusoidal capillaries intervenes between adjacent cords and a few parasympathetic ganglion cells are present. Medullary parenchymal cells, known as chromaffin cells, arise from neural crest cells, as do the postganglionic neurons of sympathetic and parasympathetic ganglia. Chromaffin cells can be considered modified sympathetic postganglionic neurons, lacking axons and dendrites and specialized as secretory cells. 20_Mescher_ch20_p413-438.indd 425 Adrenal medulla 35x fenestrated sinusoidal capillaries. Cortical cells are arranged as three layers: the zona glomerulosa near the capsule, the zona fasciculata (the thickest layer), and the zona reticularis. Endocrine Glands Adrenal Glands Adrenal cortex › ›› MEDICAL APPLICATION In the adrenal medulla, benign pheochromocytomas periodically secrete high levels of catecholamines that cause swings in blood pressure between hypertension and hypotension. Unlike cells of the adrenal cortex, chromaffin cells contain many electron-dense granules, 150-350 nm in diameter, for storage and secretion of catecholamines, either epinephrine or norepinephrine. The granules of epinephrine-secreting cells are less electron-dense and generally smaller than those of norepinephrine-secreting cells (Figure 20–16). Both catecholamines, together with Ca2+ and ATP, are bound in granular storage complexes with 49-kDa proteins called chromogranins. Norepinephrine-secreting cells are also found in paraganglia (collections of catecholamine-secreting cells adjacent to the autonomic ganglia) and in various viscera. The conversion of norepinephrine to epinephrine (adrenalin) occurs only in chromaffin cells of the adrenal medulla. About 80% of the catecholamine secreted from the adrenal is epinephrine. Medullary chromaffin cells are innervated by preganglionic sympathetic neurons, which trigger epinephrine and norepinephrine release during stress and intense emotional reactions. Epinephrine increases heart rate, dilates bronchioles, and dilates arteries of cardiac and skeletal muscle. Norepinephrine constricts vessels of the digestive system and skin, increasing blood flow to the heart, muscles, and brain. 26/04/18 11:54 am VetBooks.ir 426 CHAPTER 20 FIGURE 20–15 Endocrine Glands Adrenal cortex. C G C a b c d F R M e M The steroid-secreting cells of the adrenal cortex are arranged differently to form three fairly distinct concentric layers, the zonae glomerulosa (G), fasciculata (F), and reticularis (R), surrounding the medulla (M). As with all endocrine glands, the layers of the adrenal cortex all contain a rich microvasculature. Shown here are sections from two adrenal glands, stained with H&E (left) and Mallory trichrome, in which the sparse collagen appears blue (right). (a, b) Immediately beneath the capsule (C), the zona glomerulosa consists of rounded clusters of columnar or pyramidal cells principally secreting the mineral corticoid aldosterone. Blood-filled regions are parts of the subcapsular arterial plexus. 20_Mescher_ch20_p413-438.indd 426 f M (c, d) The thick middle layer, the zona fasciculata, consists of long cords of large, spongy-looking cells mainly secreting glucocorticoids such as cortisol. (e, f) Cells of the innermost zona reticularis, next to the medulla (M), are small, have fewer lipid droplets and are therefore better stained, arranged in a close network and secrete mainly sex steroids, including the androgen precursor DHEA. Cells of all the layers are closely associated with capillaries and sinusoids. Left: (X20); a–f: (X200) 26/04/18 11:55 am FIGURE 20–16 427 Adrenal medulla. C H A P T E R VetBooks.ir Pancreatic Islets NE 2 0 Endocrine Glands Pancreatic Islets E a The hormone-secreting cells of the adrenal medulla are chromaffin cells, which resemble sympathetic neurons. (a) The micrograph shows that they are large pale-staining cells, arranged in cords interspersed with wide capillaries. Faintly stained cytoplasmic granules can be seen in most chromaffin cells. (X200; H&E) Both hormones stimulate glycogen breakdown, elevating blood glucose levels. Together these effects augment the capability for defensive reactions or escape of stressors, the fightor-flight response. During normal activity the adrenal medulla continuously secretes small quantities of these hormones. ››PANCREATIC ISLETS The pancreatic islets (islets of Langerhans) are compact spherical or ovoid masses of endocrine cells embedded within the acinar exocrine tissue of the pancreas (Figure 20–17). Most islets are 100-200 μm in diameter and contain several hundred cells, but some have only a few cells. The pancreas has more than 1 million islets, mostly in the gland’s narrow tail region, but they only constitute 1%-2% of the organ’s total volume. A very thin reticular capsule surrounds each islet, separating it from the adjacent acinar tissue. Pancreatic islets have the same embryonic origin as the pancreatic acinar tissue: in epithelial outgrowths from endoderm of the developing gut. The cells of islets are polygonal or rounded, smaller, and more lightly stained than the surrounding acinar cells, arranged in cords separated by fenestrated capillaries (Figure 20–17). Routine stains or trichrome stains show that most islet cells are acidophilic or basophilic with fine cytoplasmic granules (Figure 20–17). Ultrastructural features are those of active 20_Mescher_ch20_p413-438.indd 427 b (b) TEM reveals that the granules of norepinephrine-secreting cells (NE) are more electron-dense than those of cells secreting epinephrine (E), which is due to the chromogranins binding the catecholamines. Most of the hormone produced is epinephrine, which is only made in the adrenal medulla. (X33,000) polypeptide-secreting cells, with secretory granules that vary in size, morphology, and electron density from cell to cell. The major islet cells are most easily identified and studied by immunohistochemistry: α or A cells secrete primarily glucagon and are usually located peripherally. β or B cells produce insulin (L. insula, island), are the most numerous, and are located centrally. δ or D cells, secreting somatostatin, are scattered and much less abundant. › ›› MEDICAL APPLICATION Diabetes mellitus is characterized by loss of the insulin effect and a subsequent failure of cells to take up glucose, leading to elevated blood sugar or hyperglycemia. Type 1 diabetes or insulin-dependent diabetes mellitus (IDDM) is caused by loss of the β cells from autoimmune destruction and is treated by regular injections of insulin. In type 2 diabetes or non–insulindependent diabetes mellitus (NIDDM), β cells are present but fail to produce adequate levels of insulin in response to hyperglycemia and the peripheral target cells “resist” or no longer respond to the hormone. Type 2 diabetes commonly occurs with obesity, and poorly understood, multifactorial genetic components are also important in this disease’s onset. 26/04/18 11:55 am VetBooks.ir 428 CHAPTER 20 FIGURE 20–17 Endocrine Glands Pancreatic islets. C C a b C C c d Pancreatic islet cells Pancreatic acinus Blood capillary α cell Pancreatic islets are clumped masses of pale-staining endocrine cells embedded in the exocrine acinar tissue of the pancreas. β cell (a) The islets are clusters of cells smaller and lighter staining than cells of the surrounding tissue. (X12.5; H&E) δ cell PP cell (b) At higher magnification an islet’s capillary system can be seen. Several arterioles enter each islet, branch into fenestrated capillaries (C) among the peripheral islet cells, then converge centrally before leaving the islet as efferent capillaries carrying blood to the acini surrounding the islet. This local vascular system allows specific islet hormones to help control secretion of other islet cells and the neighboring acini. (X40; H&E) (c) With H&E staining all cells of an islet appear similar, although differences in cell size and basophilia may be apparent. Capillaries (C) are also apparent. (X55; H&E) (d) An islet prepared with a modified aldehyde fuchsin stain shows that granules in the peripheral α cells are a deep brownish purple and the central β cells granules are brownish orange. Reticulin connective tissue of the islet capsule and along the capillaries stains green in this preparation. Immunohistochemistry with antibodies against the various islet polypeptide hormones allows definitive identification of each islet cell type. (X300; Modified aldehyde fuchsin and light green) e 20_Mescher_ch20_p413-438.indd 428 (Figure 20-17d, used with permission from Dr Arthur A. Like, Department of Pathology, University of Massachusetts Medical School, Worcester.) (e) The diagram shows the four major islet hormones and the cells secreting them: α cells making glucagon, β cells making insulin, δ cells making somatostatin, and PP cells making pancreatic polypeptide. 26/04/18 11:55 am 429 TABLE 20–4    Major cell types and hormones of pancreatic islets. C H A P T E R VetBooks.ir Thyroid Gland Hormone Produced Hormone Structure and Size Hormone Function α ~20 Glucagon Polypeptide; 3500 Da Acts on several tissues to make energy stored in glycogen and fat available through glycogenolysis and lipolysis; increases blood glucose content β ~70 Insulin Dimer of α and β chains with S-S bridges; 5700-6000 Da Acts on several tissues to cause entry of glucose into cells and promotes decrease of blood glucose content δ or D 5-10 Somatostatin Polypeptide; 1650 Da Inhibits release of other islet cell hormones through local paracrine action; inhibits release of GH and TSH in anterior pituitary and HCl secretion by gastric parietal cells PP Rare Pancreatic polypeptide Polypeptide; 4200 Da Stimulates activity of gastric chief cells; inhibits bile secretion, pancreatic enzyme and bicarbonate secretion, and intestinal motility A minor fourth cell type, more common in islets located within the head of the pancreas, are PP cells, which secrete pancreatic polypeptide. Table 20–4 summarizes the types, quantities, and main functions of the major pancreatic hormones. Pancreatic islets also normally contain a few enterochromaffin cells, like those of the digestive tract, which are also scattered in the pancreatic acini and ducts and which secrete other hormones affecting the digestive system. Activity of α and β cells is regulated largely by blood glucose levels above or below the normal level of 70 mg/dL. Increased glucose levels stimulate β cells to release insulin and inhibit α cells from releasing glucagon; decreased glucose levels stimulate α cells to release glucagon. Opposing actions of these hormones help to precisely control blood glucose concentration, an important factor in homeostasis (Table 20–4). These hormones and somatostatin from the δ cells also act in a paracrine manner to affect hormone release within an islet as well as activity of the neighboring acinar cells. Sympathetic and parasympathetic nerve endings are closely associated with about 10% of α, β, and δ cells and can also function as part of the control system for insulin and glucagon secretion. Gap junctions transfer the autonomic neural stimulus to the other cells. Sympathetic fibers increase glucagon release and inhibit insulin release; parasympathetic fibers increase secretion of both glucagon and insulin. ››DIFFUSE NEUROENDOCRINE SYSTEM The enterochromaffin cells scattered in both the islets and small ducts of the pancreas are similar to those of the digestive tract (see Chapter 15). Collectively these dispersed cells, 20_Mescher_ch20_p413-438.indd 429 as well as similar cells in the respiratory mucosa, make up the diffuse neuroendocrine system (DNES). Like the pancreatic islets, most of these cells are derived from endodermal cells of the embryonic gut or bronchial buds. These secretory cells are considered neuroendocrine because they produce many of the same polypeptides and neurotransmitter-like molecules, such as serotonin (5-hydroxytryptamine), also released by neurosecretory cells in the CNS. Several such cells, along with their hormones and major functions, are summarized in Table 15–1 with the digestive system. Most of these hormones are polypeptides and act in a paracrine manner, affecting primarily the activities of neighboring contractile cells and secretory cells (both exocrine and endocrine). Enteroendocrine cells of the stomach and small bowel are shown ultrastructurally in Figures 15–20, 15–24c, and 15–27. Many cells of the DNES are stained by solutions of chromium salts and have therefore been called enterochromaffin cells, while those staining with silver nitrate are sometimes called argentaffin cells. DNES cells secreting serotonin or certain other amine derivatives demonstrate amine precursor uptake and decarboxylation and are often referred to acronymically as APUD cells. Such names are still widely used, but, as indicated in Table 15–1, they have been largely replaced by letter designations like those used for pancreatic islet cells. Whatever name is used, cells of the DNES are highly important due to their role in regulating motility and secretions of all types within the digestive system. Endocrine Glands Thyroid Gland Quantity (%) 2 0 Cell Type ››THYROID GLAND The thyroid gland, located anterior and inferior to the larynx, consists of two lobes united by an isthmus (Figure 20–18). 26/04/18 11:55 am VetBooks.ir 430 CHAPTER 20 FIGURE 20–18 Endocrine Glands Thyroid gland. Cricoid cartilage Inferior thyroid artery Inferior thyroid veins The thyroid is a highly vascular, butterfly-shaped gland surrounding the anterior surface of the trachea just below the larynx. Thyrocytes have apical junctional complexes and rest on a basal lamina (Figure 20–20). The cells exhibit organelles indicating active protein synthesis and secretion, as well as phagocytosis and digestion. The nucleus is generally round and central. Basally the cells are rich in rough ER and apically, facing the follicular lumen, are Golgi complexes, secretory granules, numerous phagosomes and lysosomes, and microvilli. Another endocrine cell type, the parafollicular cell, or C cell, is also found inside the basal lamina of the follicular epithelium or as isolated clusters between follicles (Figure 20–20). Derived from the neural crest, parafollicular cells are usually somewhat larger than follicular cells and stain less intensely. They have a smaller amount of rough ER, large Golgi complexes, and numerous small (100-180 nm in diameter) granules containing calcitonin (Figure 20–20). Secretion of calcitonin is triggered by elevated blood Ca2+ levels, and it inhibits osteoclast activity, but this function in humans is less important than the roles of parathyroid hormone and vitamin D in the regulation of normal calcium homeostasis. › ›› MEDICAL APPLICATION It originates in early embryonic life from the foregut endoderm near the base of the developing tongue. It synthesizes the thyroid hormones thyroxine (tetra-iodothyronine or T4) and tri-iodothyronine (T3), which help control the basal metabolic rate in cells throughout the body, as well as the polypeptide hormone calcitonin. The parenchyma of the thyroid is composed of millions of rounded epithelial thyroid follicles of variable diameter, each with simple epithelium and a central lumen densely filled with gelatinous acidophilic colloid (Figure 20–19). The thyroid is the only endocrine gland in which a large quantity of secretory product is stored. Moreover, storage is outside the cells, in the colloid of the follicle lumen, which is also unusual. There is sufficient hormone in follicles to supply the body for up to 3 months with no additional synthesis. Thyroid colloid contains the large glycoprotein thyroglobulin (660 kDa), the precursor for the active thyroid hormones. The thyroid gland is covered by a fibrous capsule from which septa extend into the parenchyma, dividing it into lobules and carrying blood vessels, nerves, and lymphatics. Follicles are densely packed together, separated from one another only by sparse reticular connective tissue (Figure 20–19), although this stroma is very well vascularized with fenestrated capillaries for transfer of released hormone to the blood. The follicular cells, or thyrocytes, range in shape from squamous to low columnar (Figure 20–19), their size and other features varying with their activity, which is controlled by thyroid-stimulating hormone (TSH) from the anterior pituitary. Active glands have more follicles of low columnar epithelium; glands with mostly squamous follicular cells are hypoactive. 20_Mescher_ch20_p413-438.indd 430 Chronic dietary iodine deficiencies inhibit thyroid hormone production, causing thyrotropic cells of the anterior pituitary gland to produce excess TSH. This leads to excessive growth of thyroid follicles and enlargement of the thyroid gland, a condition known as goiter. Production of Thyroid Hormone & Its Control Production, storage, and release of thyroid hormones involve an unusual, multistage process in the thyrocytes, with both an exocrine phase and an endocrine phase. Both phases are promoted by TSH and occur in the same cell, as summarized in Figure 20–21. The major activities of this process include the following: 1. The production of thyroglobulin, which is similar to that in other glycoprotein-exporting cells, with synthesis in the rough ER and glycosylation in the Golgi apparatus. Thyroglobulin has no hormonal activity itself but contains 140 tyrosyl residues critical for thyroid hormone synthesis. The glycoprotein is released as an exocrine product from apical vesicles of thyrocytes into the follicular lumen. 2. The uptake of iodide from blood by Na/I symporters (NIS) in the thyrocytes’ basolateral cell membranes, which allows for 30-fold concentration of dietary iodide in thyroid tissue relative to plasma. Decreased levels of circulating iodide trigger synthesis of NIS, increasing iodide uptake and compensating for the lower plasma concentration. An apical iodide/chloride transporter (also called pendrin) pumps I– from thyrocytes into the colloid. 26/04/18 11:55 am 431 FIGURE 20–19 Thyroid follicular cells and parafollicular cells. C C H A P T E R VetBooks.ir Thyroid Gland L S 2 0 S L C Endocrine Glands Thyroid Gland a b T T C C C C C c d (a) A low-power micrograph of thyroid gland shows the thin capsule (C), from which septa (S) with the larger blood vessels, lymphatics, and nerves enter the gland. The parenchyma of the organ is distinctive, consisting of colloid-filled epithelial follicles of many sizes. The lumen of each follicle is filled with a lightly staining colloid of a large gelatinous protein called thyroglobulin. (X12; H&E) (b) The lumen (L) of each follicle is surrounded by a simple epithelium of thyrocytes in which the cell height ranges from squamous to low columnar. Also present are large pale-staining parafollicular 3. Iodination of tyrosyl residues in thyroglobulin with either one or two atoms occurs in the colloid after oxidation of iodide to iodine by membrane-bound thyroid peroxidase on the microvilli surfaces of thyrocytes. 4. Formation of T3 and T4 (also called thyroxine) occurs as two iodinated tyrosines, still part of colloidal thyroglobulin, which are covalently conjugated in coupling reactions. 5. Endocytosis of iodinated thyroglobulin by the thyrocytes involves both fluid-phase pinocytosis and receptormediated endocytosis. The endocytic vesicles fuse with lysosomes, and the thyroglobulin is thoroughly degraded by lysosomal proteases, freeing active thyroid hormone as both T3 and T4. 20_Mescher_ch20_p413-438.indd 431 e T or C cells (C) secreting calcitonin, a polypeptide involved with calcium metabolism. (X200; H&E) (c-e) C cells may be part of the follicular epithelium or present singly or in groups outside of follicles. Thyrocytes (T) can usually be distinguished from parafollicular C cells (C) by their smaller size and darker staining properties. Unlike thyrocytes, C cells seldom vary in their size or pale staining characteristics. C cells are somewhat easier to locate in or between small follicles. c and d: (X400;H&E); e: (X400; Mallory trichrome) 6. Secretion of T4 and T3 at the basolateral domains of thyrocytes occurs in an endocrine manner: both molecules are immediately taken up by capillaries. Nearly all of both thyroid hormones are carried in blood tightly bound to thyroxine-binding globulin or albumen. T4 is the more abundant compound, constituting 90% of the circulating thyroid hormone. Both molecules bind the same intracellular receptors of target cells, but T3 is 2- to 10-fold more active than T4. The half-life of T3 is 1.5 days in comparison with a week for T4. Both thyroid hormones increase the number and size of mitochondria and stimulate mitochondrial protein synthesis, helping to enhance metabolic activity. 26/04/18 11:55 am VetBooks.ir 432 CHAPTER 20 FIGURE 20–20 Endocrine Glands Ultrastructure of thyroid follicular and parafollicular cells. L T G T T C a BM (a) TEM of the follicular epithelium shows pseudopodia and microvilli extending from the follicular thyrocytes (T) into the colloid of the lumen (L). The cells have apical junctional complexes, much RER, well-developed Golgi complexes, and many lysosomes. Inside the basement membrane (BM) of the follicle, but often not contacting the colloid in the lumen, are occasional C cells (C). To the The major regulator of the anatomic and functional state of thyroid follicles is TSH (thyrotropin) from the anterior pituitary (Figure 20–8). With TSH receptors abundant on the basal cell membrane of thyrocytes, this tropic hormone increases cell height in the follicular epithelium and stimulates all stages of thyroid hormone production and release. Thyroid hormones inhibit the release of TSH, maintaining levels of circulating T4 and T3 within the normal range (Figure 20–10). Secretion of TSH in the pituitary is also increased by exposure to cold and decreased by heat and stressful stimuli. › ›› MEDICAL APPLICATION Graves disease is an autoimmune disorder in which antibodies produce chronic stimulation of the follicular cells and release of thyroid hormones (hyperthyroidism), which causes a hypermetabolic state marked by weight loss, nervousness, sweating, heat intolerance, and other features. Hypothyroidism, with reduced thyroid hormone levels, can be caused by local inflammation (thyroiditis) or inadequate secretion of TSH by the anterior pituitary gland and is often manifested by tiredness, weight gain, intolerance of cold, and decreased ability to concentrate. 20_Mescher_ch20_p413-438.indd 432 b left and right of the two C cells seen here are capillaries intimately associated with the follicular cells, but outside the basement membrane. (X2000) (b) A TEM of a C cell, with its large Golgi apparatus (G), extensive RER, and cytoplasm filled with small secretory granules containing calcitonin. (X5000) ››PARATHYROID GLANDS The parathyroid glands are four small ovoid masses—each 3 × 6 mm—with a total weight of about 0.4 g. They are located on the back of the thyroid gland, usually embedded in the larger gland’s capsule (Figure 20–22). The microvasculature of each arises from the inferior thyroid arteries. Each parathyroid gland is contained within a thin capsule from which septa extend into the gland. A sparse reticular stroma supports dense elongated clusters of secretory cells. The parathyroid glands are derived from the embryonic pharyngeal pouches—the superior glands from the fourth pouch and the inferior glands from the third pouch. Their migration to the developing thyroid gland is sometimes misdirected so that the number and locations of the glands are somewhat variable. Up to 10% of individuals may have parathyroid tissue attached to the thymus, which originates from the same pharyngeal pouches. The endocrine cells of the parathyroid glands, called principal (chief) cells, are small polygonal cells with round nuclei and pale-staining, slightly acidophilic cytoplasm (Figure 20–23). Irregularly shaped cytoplasmic granules contain the polypeptide 26/04/18 11:55 am 433 FIGURE 20–21 Thyrocyte activities in thyroid hormone synthesis. Thyroid I–/Cl– MIT transporter peroxidase (pendrin) 4 Thyroglobulin 3 Pre-T3 synthesis Colloid DIT Tyr Tyr Tyr C H A P T E R VetBooks.ir Parathyroid Glands Tyr Pre-T4 I MIT I I DIT I I DIT I 2 0 I DIT Endocrine Glands Parathyroid Glands 1 5 Tyr Tyr MIT DIT DIT DIT Tyr Tyr Pre-T3 Pre-T4 Lysome 2 Colloid reabsorption droplets Triiodothyronine (T3) I O HO rER I 6 CH2CHCOOH NH2 I Thyroxine (T4) Capillary lumen Iodide Thyroglobulin Na+/I– symporter (NIS) Iodine Synthesis I T3 T4 The diagram shows the multistep process by which thyroid hormones are produced via the stored thyroglobulin intermediate. In an exocrine phase of the process, (1) the glycoprotein thyroglobulin is made and secreted into the follicular lumen and (2) iodide is pumped across the cells into the lumen. In the lumen (3) iodide is converted to iodine by membrane-bound thyroid peroxidase and added to tyrosine residues of thyroglobulin (4) to form parathyroid hormone (PTH), an important regulator of blood calcium levels. PTH has three major targets: Osteoblasts respond to PTH by producing an osteoclast- stimulating factor, which increases the number and activity of osteoclasts. The resulting resorption of the calcified bone matrix and release of Ca2+ increase the concentration of circulating Ca2+, which suppresses PTH production. The effect of PTH on blood levels of Ca2+ is thus opposite to that of calcitonin. 20_Mescher_ch20_p413-438.indd 433 O HO I Reabsorption I CH2CHCOOH I NH2 monoiodotyrosine (MIT) or diiodotyrosine (DIT), which are then covalently coupled to form T3 and T4 still within the glycoprotein. The iodinated thyroglobulin is then (5) endocytosed by the thyrocytes and degraded by lysosomes, (6) releasing free active T3 and T4 to the adjacent capillaries in an endocrine manner. Detailed steps are given in the text. Both phases are promoted by TSH and may occur simultaneously in the same cell. In the distal convoluted tubules of the renal cortex, PTH stimulates Ca2+ reabsorption (and inhibits phosphate reabsorption in the proximal tubules). PTH also indirectly increases the Ca2+ absorption in the small intestine by stimulating vitamin D activation. With increasing age, many secretory cells are replaced with adipocytes, which may constitute more than 50% of the gland in older people. 26/04/18 11:55 am VetBooks.ir 434 CHAPTER 20 FIGURE 20–22 Endocrine Glands Parathyroid glands. FIGURE 20–23 Parathyroid principal cells. P S Thyroid gland (posterior aspect) O Parathyroid glands a Esophagus Trachea Posterior view The parathyroid glands are four small nodules normally embedded in the capsule on the posterior surface of the thyroid gland. C b Much smaller populations of oxyphil cells, often clustered, are sometimes also present in parathyroid glands, more commonly in older individuals. These are much larger than the principal cells and are characterized by very acidophilic cytoplasm filled with abnormally shaped mitochondria. Accumulating with age, oxyphil cells are degenerated derivatives of principal cells, with some still exhibiting low levels of PTH synthesis. (a) A small lobe of parathyroid gland, surrounded by connective tissue septa (S), shows mainly densely packed cords of small principal cells (P). Older parathyroid glands show increasing numbers of much larger and acidophilic nonfunctional oxyphil cells (O) that may occur singly or in clumps of varying sizes. (X60; H&E) (b) Higher magnification shows that principal cells have round central nuclei and pale-staining cytoplasm. Cords of principal cells secreting PTH surround capillaries (C). (X200; H&E) › ›› MEDICAL APPLICATION In hypoparathyroidism, diminished secretion of PTH can cause bones to become more mineralized and denser and striated muscle to exhibit abnormal contractions due to inadequate calcium ion concentrations. Excessive PTH produced in hyperparathyroidism stimulates osteoclast number and activity, leading to increased levels of blood calcium that can be deposited pathologically in cartilage, arteries, or the kidneys. 20_Mescher_ch20_p413-438.indd 434 ››PINEAL GLAND The pineal gland, also known as the epiphysis cerebri, regulates the daily rhythms of bodily activities. A small, pine cone-shaped organ, approximately 5-8 mm by 3-5 mm, the pineal gland develops from neuroectoderm in the posterior wall of the third ventricle and remains attached to the brain by a short stalk. The pineal gland is 26/04/18 11:55 am Pineal gland. V P S Endocrine Glands Pineal Gland FIGURE 20–24 Melatonin release from pinealocytes is promoted by darkness and inhibited by daylight. The resulting diurnal fluctuation in blood melatonin levels induces rhythmic changes in the activity of the hypothalamus, pituitary gland, and other endocrine tissues that characterize the circadian (24 hours, day/night) rhythm of physiological functions and behaviors. In humans and other mammals, the cycle of light and darkness is detected within the retinas and transmitted to the pineal via the retinohypothalamic tract, the suprachiasmatic nucleus, and the tracts of sympathetic fibers entering the pineal. The pineal gland acts, therefore, as a neuroendocrine transducer, converting sensory input regarding light and darkness into variations in many hormonal functions. 2 0 covered by connective tissue of the pia mater, from which septa containing small blood vessels emerge and subdivide variously sized lobules. Prominent and abundant secretory cells called pinealocytes have slightly basophilic cytoplasm and irregular euchromatic nuclei (Figure 20–24). Ultrastructurally pinealocytes are seen to have secretory vesicles, many mitochondria, and long cytoplasmic processes extending to the vascularized septa, where they end in dilatations near capillaries, indicating an endocrine function. These cells produce melatonin, a low-molecular-weight tryptophan derivative. Unmyelinated sympathetic nerve fibers enter the pineal gland and end among pinealocytes, with some forming synapses. 435 C H A P T E R VetBooks.ir Pineal Gland A V A S CA CA a (a) The micrograph shows a group of pinealocytes surrounded by septa (S) containing venules (V) and capillaries (arrows). Also seen is an extracellular mineral deposit called a corpus arenaceum (CA) of unknown physiologic significance but an excellent marker for the pineal. (X200; H&E) (b) At higher magnification the numerous large pinealocytes (P) with euchromatic nuclei can be compared to much fewer astrocytes (A) that have darker, more elongated nuclei and are located mainly within septa and near small blood vessels (V). Capillaries 20_Mescher_ch20_p413-438.indd 435 P b (arrow) are not nearly as numerous as in other endocrine glands. At the lower left is a part of a very large corpus arenaceum (CA), the calcified structures also known as brain sand. Along the septa run unmyelinated tracts of sympathetic fibers, associated indirectly with photoreceptive neurons in the retinas and running to the pinealocytes to stimulate melatonin release in periods of darkness. Levels of circulating melatonin are one factor determining the diurnal rhythms of hormone release and physiologic activities throughout the body. (X400; H&E) 26/04/18 11:55 am VetBooks.ir 436 CHAPTER 20 Endocrine Glands The pineal gland also has interstitial glial cells that are modified astrocytes, staining positively for glial fibrillary acidic protein, which represent about 5% of the cells. These have elongated nuclei more heavily stained than those of pinealocytes and are usually found in perivascular areas and between the groups of pinealocytes. A characteristic feature of the pineal gland is the presence of variously sized concretions of calcium and magnesium salts called corpora arenacea, or brain sand, formed by mineralization of extracellular protein deposits. Such concretions may appear during childhood and gradually increase in number and size with age, with no apparent effect on the gland’s function. › ›› MEDICAL APPLICATION Densely calcified corpora arenacea can be used as landmarks for the midline location of the pineal gland in various radiological examinations of the brain. Tumors originating from pinealocytes are very rare, but they can be either benign or highly malignant Table 20–5 summarizes the major endocrine cells, hormones, and functions of the adrenal gland, pancreatic islets, thyroid, parathyroid, and pineal glands. TABLE 20–5     Cells, important hormones, and functions of other major endocrine organs. Gland Endocrine Cells Major Hormones Major Functions Adrenal glands: Cortex Cells of zona glomerulosa Mineralocorticoids Stimulate renal reabsorption of water and Na+ and secretion of K+ to maintain salt and water balance Cells of zona fasciculata Glucocorticoids Influence carbohydrate metabolism; suppress immune cell activities Cells of zona reticularis Weak androgens Precursors for testosterone or estrogen Chromaffin cells Epinephrine Increases heart rate and blood pressure Norepinephrine Constricts vessels; increases heart rate and blood pressure α Cells Glucagon Raises blood glucose levels β Cells Insulin Lowers blood glucose levels δ Cells Somatostatin Inhibits secretion of insulin, glucagon, and somatotropin PP cells Pancreatic polypeptide Inhibits secretion of pancreatic enzymes and HCO3– Follicular cells Thyroid hormones (T3 and T4) Increases metabolic rate Parafollicular or C cells Calcitonin Lowers blood Ca2+ levels by inhibiting osteoclast activity Parathyroid glands Chief cells Parathyroid hormone (PTH) Raises blood Ca2+ levels by stimulating osteoclast activity Pineal gland Pinealocytes Melatonin Regulates circadian rhythms Adrenal glands: Medulla Pancreatic islets Thyroid glands 20_Mescher_ch20_p413-438.indd 436 26/04/18 11:55 am