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Histology_Ross.  Intracellular receptors, which are localized within the cell (mainly within the nucleus), are used by steroids and thyroid hormones that can easily penetrate both plasma and nuclear membranes. Their receptors consist of large multi-protein complexes of chaperones containing three binding domains: a hormone-binding region, a DNA-binding


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Histology_Ross. FIGURE 21.2 • General mechanisms of hormone action. a. This schematic diagram shows the basis for protein hormone action involving cell surface receptors. Hormone molecules bind to the receptor and initiate synthesis of second-messenger molecules. These molecules, in turn, activate a cascade of reactions that produce hormone-specific responses in the stimulated cell. b. This diagram shows the mechanism of action of steroid hormones, which use intracellular receptors. Binding of the hormone to this receptor causes allosteric transformation of the receptor into a form that binds to DNA. This binding leads to mRNA transcription and production of new proteins that produce hormone-specific responses in the stimulated cell.


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Histology_Ross. region, and an amino-terminal region. Binding of the hormone to these receptors causes allosteric transformation of the receptor into a form that binds to chromosomal DNA and activates RNA polymerase activity. This in turn increases transcription of mRNA, resulting in the production of new proteins that regulate cell metabolism. Therefore, hormones acting on intracellular receptors infuence gene expression directly, without the help of a second messenger (see Fig. 21.2). Regulation of Hormone Secretion and Feedback Mechanism Regulation of hormonal function is controlled by feedback mechanisms.


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Histology_Ross. Regulation of Hormone Secretion and Feedback Mechanism Regulation of hormonal function is controlled by feedback mechanisms. Hormonal production is often controlled through feedback mechanisms from the target organ. In general, feedback occurs when the response to a stimulus (action of a hormone) has an effect on the original stimulus (hormone-secreting cell). The nature of this response determines the type of feedback. Two types of feedback are recognized; a negative feedback occurs when the response diminishes the original stimulus. It is much more common than a positive feedback, which occurs when the response enhances the original stimulus.


Histology_Ross

Histology_Ross. To better understand the function of feedback mechanisms, one can point to an air-conditioning system, which also uses a simple negative feedback system. When the compressor produces enough cold air to lower the temperature below the set point of the thermostat, the thermostat is triggered and shuts off the compressor. In this negative feedback system, the lower temperature is then fed back to the compressor and diminishes its response (it shuts off its production of cold air). When the temperature rises back above the set point, the negative feedback is abolished and the compressor comes back on (for more information on negative feedback, see Folder 21.1, Functional Considerations: Regulation of Pituitary Gland Secretion).


Histology_Ross

Histology_Ross. Activities of hormones are constantly monitored on many levels beginning with molecular biosynthetic processes to the final end points of hormonal action. Several examples of feedback mechanisms are discussed in the sections on the pituitary, hypothalamus, and thyroid gland. Hormone-secreting cells are present in many organs to regulate their activity.


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Histology_Ross. Hormone-secreting cells are present in many organs to regulate their activity. This chapter primarily describes the discrete endocrine glands that release their hormones for delivery to the bloodstream for transport to target cells and organs. In other chapters, the endocrine function of adipose tissue as well as individual cells within the gonads, liver, pancreas, kidney, and gastrointestinal system is discussed. The cells of the diffuse neuroendocrine (DNES) system (see page 581) constitute a collection of endocrine cells in the body. In addition to their endocrine function, cells of DNES system exercise autocrine and paracrine control of the activity of their own and adjacent epithelial cells by diffusion of peptide secretions through the extracellular spaces.


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Histology_Ross. The pituitary gland and the hypothalamus, the portion of the brain to which the pituitary gland is attached, are morphologically and functionally linked in the endocrine and neuroendocrine control of other endocrine glands. Because they play central roles in a number of regulatory feedback systems, they are often called the “master organs” of the endocrine system. In the past, the control of pituitary hormone secretion by the hypothalamus was classically regarded as the major function of the neuroendocrine system. However, the field of neuroendocrinology today has expanded to encompass multiple reciprocal interactions between the central nervous system (CNS), autonomic nervous system (ANS), endocrine system, and immune system in the regulation of homeostasis and behavioral responses to environmental stimuli. For example, the neuroendocrine axes in maintaining energy homeostasis were discussed in Chapter 9 (Adipose Tissue).


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Histology_Ross.  FOLDER 21.1 Functional Considerations: Regulation of Pituitary Gland Secretion


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Histology_Ross. The release of hormones from the anterior lobe of the pituitary gland is carefully regulated by three tiers of control mechanisms that include the following:  Tier I: hypothalamic secretion of hypothalamic-regulating hormones. The pituitary gland is under signif-icant control by the hypothalamus, which regulates release of hypothalamic-regulating hormones into the hypophyseal portal veins. The hypothalamic-regulating hormones are produced by the cells of the hypothalamus in response to circulating levels of systemic hormones and impulses from the CNS. These hormones act directly on the highly spe-cific G protein–linked receptors on the plasma mem-branes of cells residing in the anterior lobe of the pituitary gland. Activation of receptors elicits positive or negative signals that affect gene transcription and lead to stimula-tion or inhibition of pituitary hormone secretion. Most of the tropic hormones produced by the anterior lobe of the pitu-itary gland are regulated by


Histology_Ross

Histology_Ross. affect gene transcription and lead to stimula-tion or inhibition of pituitary hormone secretion. Most of the tropic hormones produced by the anterior lobe of the pitu-itary gland are regulated by polypeptide-releasing hor-mones, with the notable exception of dopamine. Prolactin (PRL) production is primarily regulated by the inhibitory ef-fect of dopamine (i.e., PRL secretion is tonically inhibited by the release of dopamine from the hypothalamus).  Tier II: Paracrine and autocrine secretions of the pituitary cells. Release of hormones from the pituitary gland is also regulated by soluble growth factors and cy-tokines produced by the cells residing in the pituitary gland.  Tier III: Feedback effect of circulating hormones. The level of hormones in the systemic circulation regu-lates the secretion of cells in the anterior lobe of the pituitary gland. This is primary achieved by negative feedback regulation of hormones secreted by the pitu-itary gland by target hormones. For instance,


Histology_Ross

Histology_Ross. secretion of cells in the anterior lobe of the pituitary gland. This is primary achieved by negative feedback regulation of hormones secreted by the pitu-itary gland by target hormones. For instance, secretion of TSH is inhibited by thyroid hormones produced in the thyroid gland under TSH influence. To better understand the mechanism of negative regula-tion, consider a simple negative feedback system that controls the synthesis and discharge of T3 and T4 thyroid hormones (see Fig. 21.6). The secretion of thyroid hor-mones is controlled by the release of TSH from the anterior lobe of the pituitary gland into the bloodstream. If blood lev-els of T3 and T4 are high, TRH is not produced or released. If blood levels of T3 and T4 are low, the hypothalamus dis-charges TRH into the hypothalamohypophyseal portal sys-tem. Release of TRH stimulates specific cells within the anterior lobe of the pituitary gland to produce TSH, which in turn stimulates the thyroid to produce and release more


Histology_Ross

Histology_Ross. portal sys-tem. Release of TRH stimulates specific cells within the anterior lobe of the pituitary gland to produce TSH, which in turn stimulates the thyroid to produce and release more thyroid hormones. As the thyroid hormone levels rise, the negative feedback system stops the hypothalamus from discharging TRH. Using the same mechanism of negative feedback regulation, thyroid hormones also act on the thy-rotropes in the anterior lobe of the pituitary gland to inhibit their secretion of TSH.


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Histology_Ross. The pituitary gland is composed of glandular epithelial tissue and neural (secretory) tissue. The pituitary gland [Lat. pituta, phlegm—reflecting its nasopharyngeal origin] is a pea-sized, compound endocrine gland that weighs 0.5 g in males and 1.5 g in multiparous women (i.e., a woman who has given birth two or more times). It is centrally located at the base of the brain, where it lies in a saddle-shaped depression of the sphenoid bone called the sella turcica. A short stalk, the infundibulum, and a vascular network connect the pituitary gland to the hypothalamus. The pituitary gland has two functional components (Fig. 21.3):  Anterior lobe (adenohypophysis), the glandular epithe lial tissue  Posterior lobe (neurohypophysis), the neural secretory


Histology_Ross

Histology_Ross. The pituitary gland has two functional components (Fig. 21.3):  Anterior lobe (adenohypophysis), the glandular epithe lial tissue  Posterior lobe (neurohypophysis), the neural secretory These two portions are of different embryologic origin. The anterior lobe of the pituitary gland is derived from an evagination of the ectoderm of the oropharynx toward the brain (Rathke’s pouch). The posterior lobe of the pituitary gland is derived from a downgrowth (the future infundibulum) of neuroectoderm of the foor of the third ventricle (the diencephalon) of the developing brain (Fig. 21.4).


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Histology_Ross. The anterior lobe of the pituitary gland consists of three derivatives of Rathke’s pouch:  Pars distalis, which comprises the bulk of the anterior lobe of the pituitary gland and arises from the thickened anterior wall of the pouch Pars intermedia, a thin remnant of the posterior wall of the pouch that abuts the pars distalis  Pars tuberalis, which develops from the thickened lateral walls of the pouch and forms a collar or sheath around the infundibulum The embryonic infundibulum gives rise to the posterior lobe of the pituitary gland. The posterior lobe of the pituitary gland consists of the following:  Pars nervosa, which contains neurosecretory axons and their endings.  Infundibulum, which is continuous with the median eminence and contains the neurosecretory axons forming the hypothalamohypophyseal tracts Knowledge of the unusual blood supply of the pituitary gland is important to understanding its functions. The


Histology_Ross

Histology_Ross. Knowledge of the unusual blood supply of the pituitary gland is important to understanding its functions. The FIGURE 21.4 • Development of the pituitary gland. This diagram shows sequential stages (a to c) in the development of the pituitary gland. FIGURE 21.3 • Pituitary gland. a. Photomicrograph of a pituitary gland. The pituitary gland lobes can be identified on the basis of their appearance, location, and relation to each other. 7. b. Drawing of a pituitary and related regions of the hypothalamus. The anterior lobe of the pituitary gland consists of the pars distalis, pars tuberalis, and pars intermedia; the posterior lobe of the pituitary gland consists of the infundibulum and pars nervosa.


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Histology_Ross. pituitary blood supply is derived from two sets of vessels The hypothalamohypophyseal portal system provides the (Fig. 21.5): crucial link between the hypothalamus and the pituitary  Superior hypophyseal arteries supply the pars tuber-gland. alis, median eminence, and infundibulum. These vessels The arteries that supply the pars tuberalis, median eminence, arise from the internal carotid arteries and posterior com-and infundibulum give rise to fenestrated capillaries (the primunicating artery of the circle of Willis. mary capillary plexus). These capillaries drain into portal  Inferior hypophyseal arteries primarily supply the pars veins, called the hypophyseal portal veins, which run nervosa. These vessels arise solely from the internal carotid along the pars tuberalis and give rise to a second fenestrated arteries. An important functional observation is that most sinusoidal capillary network (the secondary capillary plexus). of the anterior lobe of the pituitary gland has no


Histology_Ross

Histology_Ross. to a second fenestrated arteries. An important functional observation is that most sinusoidal capillary network (the secondary capillary plexus). of the anterior lobe of the pituitary gland has no direct This system of vessels carries the neuroendocrine secretions arterial supply. of hypothalamic nerves from their sites of release in the


Histology_Ross

Histology_Ross. FIGURE 21.5 • Diagram of the blood supply to the pituitary gland. The hypophyseal portal veins begin in the capillary beds of the median eminence and infundibulum and end in the capillaries of the pars distalis. median eminence and infundibulum directly to the cells of the pars distalis. Most of the blood from the pituitary gland drains into the cavernous sinus at the base of the diencephalon and then into the systemic circulation. Some evidence suggests, however, that blood can flow via short portal veins from the pars distalis to the pars nervosa and that blood from the pars nervosa may flow toward the hypothalamus. These short pathways provide a route by which the hormones of the anterior lobe of the pituitary gland could provide feedback directly to the brain without making the full circuit of the systemic circulation.


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Histology_Ross. The nerves that enter the infundibulum and pars nervosa from the hypothalamic nuclei are components of the posterior lobe of the pituitary gland (see the section that follows on the posterior lobe). The nerves that enter the anterior lobe of the pituitary gland are postsynaptic fibers of the autonomic nervous system and have vasomotor function. Structure and Function of the Pituitary Gland Anterior Lobe of the Pituitary Gland (Adenohypophysis) The anterior lobe of the pituitary gland regulates other endocrine glands and some nonendocrine tissues. Most of the anterior lobe of the pituitary gland has the typical organization of endocrine tissue. The cells are organized in clumps and cords separated by fenestrated sinusoidal capillaries of relatively large diameter. These cells respond to signals from the hypothalamus and synthesize and secrete a number of pituitary hormones. Four hormones of the anterior


Histology_Ross

Histology_Ross. FIGURE 21.6 • Interaction of the hypothalamus, anterior lobe of the pituitary gland, and thyroid gland. Production of thyroid hormones is regulated through a negative feedback system. The thyroid hormone can feed back on the system and inhibit further release of thyroid hormones. Such inhibition occurs at the level of the anterior lobe and the hypothalamus. The system is activated in response to low thyroid hormone levels or in response to metabolic needs. TRH, thyrotropin-releasing hormone; TSH, thyroid-stimulating hormone (thyrotropin).


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Histology_Ross. lobe—adrenocorticotropic hormone (ACTH), thyroid-stimulating (thyrotropic) hormone (TSH, thyrotropin), follicle-stimulating hormone (FSH), and luteinizing hormone (LH)—are called tropic hormones because they regulate the activity of cells in other endocrine glands throughout the body (Fig. 21.6). The two remaining hormones of the anterior lobe, growth hormone (GH) and prolactin (PRL), are not considered tropic because they act directly on target organs that are not endocrine. The general character and effects of the pituitary hormones of the anterior lobe are summarized in Table 21.1.


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Histology_Ross. Pars Distalis. The cells within the pars distalis vary in size, shape, and staining properties. The cells are arranged in cords and nests with interweaving capillaries. Early descriptions of the cells within the pars distalis were based solely on the staining properties of secretory vesicles within the cells. Using mixtures of acidic and basic dyes (Fig. 21.7), histologists identified three types of cells according to their staining reaction, namely, basophils (10%), acidophils (40%),and chromophobes (50%). However, this classification contains no information regarding the hormonal secretory activity or functional role of these cells.


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Histology_Ross. TABLE Hormones of the Anterior Lobe of the Pituitary Gland 21.1 Hormone Composition MW (kDa) Major Functions Growth hormone (somatotropin, GH) Straight-chain protein (191 aa) 21,700 Stimulates liver and other organs to synthesize and secrete insulin-like growth factor I (IGF-I), which in turn stimulates division of progenitor cells located in growth plates and in skeletal muscles, resulting in body growth Prolactin (PRL) Straight-chain protein (198 aa) 22,500 Promotes mammary gland development; initiates milk formation; stimulates and maintains secretion of casein, lactalbumin, lipids, and carbohydrates into the milk Adrenocorticotropic hormone (ACTH) Small polypeptide (39 aa) 4,000 Maintains structure and stimulates secretion of gluco-corticoids and gonadocorticoids by the zona fasciculata and zona reticularis of the adrenal cortex Follicle-stimulating hormone (FSH) 2-chain glycoproteina (, 92 aa; , 111 aa) 28,000 Stimulates follicular development in the ovary and spermato-genesis


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Histology_Ross. and zona reticularis of the adrenal cortex Follicle-stimulating hormone (FSH) 2-chain glycoproteina (, 92 aa; , 111 aa) 28,000 Stimulates follicular development in the ovary and spermato-genesis in the testis Luteinizing hormone (LH) 2-chain glycoproteina (, 92 aa; , 116 aa) 28,300 Regulates final maturation of ovarian follicle, ovulation, and corpus luteum formation; stimulates steroid secretion by follicle and corpus luteum; in males, essential for maintenance of and androgen secretion by the Leydig (interstitial) cells of the testis Thyrotropic hormone (TSH) 2-chain glycoproteina (, 92 aa; , 112 aa) 28,000 Stimulates growth of thyroid epithelial cells; stimulates production and release of thyroglobulin and thyroid hormones aThe chains of FSH, LH, and TSH are identical and encoded by a single gene; the chains are specific for each hormone. kDa, kilodaltons; aa, amino acids.


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Histology_Ross. Five functional cell types are identified in the pars distalis on the basis of immunocytochemical reactions.


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Histology_Ross. All known hormones of the anterior lobe of the pituitary gland are small proteins or glycoproteins. This important fact has led to definitive identification of specific cell types by immunocytochemistry (Table 21.2). These studies have classified cells of the anterior lobe of the pituitary gland into five cell types:  Somatotropes (GH cells) are most commonly found within the pars distalis and constitute approximately 50% of the parenchymal cells in the anterior lobe of the pituitary gland. These medium-sized, oval cells exhibit round, centrally located nuclei and produce growth hormone (GH; somatotropin). The presence of eosinophilic vesicles in their cytoplasm classifies them as acidophils. Three hormones regulate the release of GH from somatotropes. Two of these hormones are opposing hypothalamic-releasing hormones: growth hormone–releasing hormone (GHRH), which stimulates GH release from the somatotropes, and somatostatin, which inhibits GH release from the somatotropes.


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Histology_Ross. hypothalamic-releasing hormones: growth hormone–releasing hormone (GHRH), which stimulates GH release from the somatotropes, and somatostatin, which inhibits GH release from the somatotropes. Recently, a third hormone, a 28-amino acid peptide ghrelin, was isolated from the stomach. It is a potent stimulator of GH secretion and appears to coordinate food intake with GH secretion. Hormonally active tumors that originate from somatotropes are associated with hypersecretion of GH and cause gigantism in children and acromegaly in adults.


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Histology_Ross.  Lactotropes (PRL cells, mammotropes) constitute 15% to 20% of the parenchymal cells in the anterior lobe of the pituitary gland. These are large, polygonal cells with oval nuclei. They produce prolactin (PRL). In their storage phase, lactotropes exhibit numerous acidophilic vesicles (the histologic feature of an acidophil). When the content of these vesicles is released, the cytoplasm of the lactotrope does not stain (the histologic feature of a chromophobe). Secretion of PRL is under inhibitory control by dopamine, the catecholamine produced by the hypothalamus. However, thyrotropin-releasing hormone (TRH) and vasoactive inhibitory peptide (VIP) are known to stimulate synthesis and secretion of PRL. During pregnancy and lactation, these cells undergo hypertrophy and hyperplasia, causing the pituitary gland to increase in size. These processes account for the larger size of the pituitary gland in multiparous women.


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Histology_Ross.  Corticotropes (ACTH cells) also constitute 15% to 20% of the parenchymal cells in the anterior lobe of the pituitary gland. These polygonal, medium-sized cells with round and eccentric nuclei produce a precursor molecule of adrenocorticotropic hormone (ACTH), known as proopiomelanocortin (POMC). Corticotropes stain as basophils and also exhibit a strong positive reaction with periodic acid–Schiff (PAS) reagent, because of the carbohydrate moieties associated with POMC. POMC is further cleaved by proteolytic enzymes within the corticotrope into several fragments, namely ACTH, -lipotrophic hormone (-LPH), melanocyte-stimulating hormone (MSH), -endorphin, and enkephalin. ACTH release is regulated


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Histology_Ross. FIGURE 21.7 • Pars distalis. This specimen of the pars distalis is stained with brilliant crystal scarlet, aniline blue, and Martius yellow to distinguish the various cell types and connective tissue stroma. The cords of cells are surrounded by a delicate connective tissue stroma stained blue. The sinusoidal capillaries are seen in close association with the parenchyma and contain erythrocytes stained yellow. In the region shown here, the acidophils (Ac) are the most numerous cell type present. Their cytoplasm stains cherry red. The basophils (Bas) stain blue. The chromophobes (Ch), although few in number in this particular region, are virtually unstained. 640. by corticotropin-releasing hormone (CRH) produced by the hypothalamus.


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Histology_Ross. by corticotropin-releasing hormone (CRH) produced by the hypothalamus.  Gonadotropes (FSH and LH cells) constitute about 10% of the parenchymal cells in the anterior lobe of the pituitary gland. These small, oval cells with round and eccentric nuclei produce both luteinizing hormone (LH) and follicle-stimulating hormone (FSH). They are scattered throughout the pars distalis and stain intensely with both basic stains (thus classifying them as the basophil cell type) and PAS reagent. Many gonadotropes are capable of producing both FSH and LH. However, immunocytochemical studies indicate that some gonadotropes may produce only one hormone or the other. The release of FSH and LH is regulated by gonadotropin-releasing hormone (GnRH) produced by the hypothalamus. Both FSH and LH play an important role in male and female reproduction, which is discussed in Chapters 22 and 23.


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Histology_Ross.  Thyrotropes (TSH cells) constitute about 5% of the parenchymal cells in the anterior lobe of the pituitary gland. These large, polygonal cells with round and eccentric nuclei produce thyrotropic hormone called thyroid-stimulating hormone (TSH), which acts on the follicular cells of the thyroid gland to stimulate production of thyroglobulin and thyroid hormones. Thyreotropes exhibit cytoplasmic basophilia (basophils) and stain positively with PAS reagent. Release of TSH is under the hypothalamic control of thyrotropin-releasing hormone (TRH), which also stimulates secretion of PRL. Distinctive characteristics of the five cell types of the anterior lobe of the pituitary gland are readily seen with transmission electron microscopy (TEM). These characteristics are summarized in Table 21.3. In addition to the five types of hormone-producing cells, anterior lobe of the pituitary gland contains folliculostellate cells.


Histology_Ross

Histology_Ross. Folliculo-stellate cells present in the anterior lobe of the pituitary gland are characterized by a starlike appearance with their cytoplasmic processes encircling hormone-producing cells. They have the ability to make cell clusters or small follicles, and they do not produce hormones. Folliculostellate cells are interconnected by gap junctions containing connexin-43 protein. Based on immunocytochemical and electrophysiological studies, it is hypothesized that the network of folliculo-stellate cells interconnected by gap junctions transmits signals from the pars tuberalis to pars distalis. These signals may regulate hormone release throughout the anterior lobe of the pituitary gland. Thus, the folliculo-stellate network may appear to function in addition to the hypophyseal portal vein system. Recent in vitro findings of gap junctions interconnecting not only folliculo-stellate cells but also hormone-producing cells support this proposed signaling mechanism in the anterior lobe of the


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Histology_Ross. Recent in vitro findings of gap junctions interconnecting not only folliculo-stellate cells but also hormone-producing cells support this proposed signaling mechanism in the anterior lobe of the pituitary gland.


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Histology_Ross. Pars Intermedia. The pars intermedia surrounds a series of small cystic cavities that represent the residual lumen of Rathke’s pouch. The parenchymal cells of the pars intermedia surround colloid-filled follicles. The cells lining these follicles appear to be derived either from folliculo-stellate cells or various hormone-secreting cells. TEM reveals that these cells form apical junctional complexes and have vesicles larger than those found in the pars distalis. The nature of this follicular colloid is yet to be determined; however, often cell debris is found within it. The pars intermedia contains basophils and chromophobes (Fig. 21.8). Frequently, the basophils and cystic cavities extend into the pars nervosa.


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Histology_Ross. The function of the pars intermedia cells in humans remains unclear. From studies of other species, however, it is known that basophils have scattered vesicles in their cytoplasm that contain either or -endorphin (a morphine-related compound). In frogs, the basophils produce MSH, which stimulates pigment production in melanocytes and pigment dispersion in melanophores. In humans, MSH is not a distinct, functional hormone but is a byproduct of LPH posttranslational processing. Because MSH is found in the human pars intermedia in small amounts, the basophils of the pars intermedia are assumed to be corticotropes.


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Histology_Ross. TABLE Staining Characteristics of Cells Found in the Anterior Lobe of the Pituitary Gland 21.2 Cell Type Percentage of Total Cells General Staining Specific Staining Product Somatotrope (GH cell) 50 Acidophil Orange G (PAS ) Growth hormone (GH) Lactotrope (PRL cell) 15–20 Acidophil Orange G (PAS ) Herlant’s erythrosin Brooke’s carmosine Prolactin (PRL) Corticotrope (ACTH cell) 15–20 Basophil Lead hematoxylin (PAS ) Proopiomelanocortin (POMC), which is cleaved in human into adrenocorticotropic hormone (ACTH) and -lipotrophic hormone (-LPH) Gonadotrope (FSH and LH cells) 10 Basophil Aldehyde-fuchsin Aldehyde-thionine (PAS ) Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) Thyrotrope (TSH cell) 5 Basophil Aldehyde-fuchsin Aldehyde-thionine (PAS ) Thyrotropic hormone (TSH)


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Histology_Ross. Pars Tuberalis. The pars tuberalis is an extension of the anterior lobe along the stalklike infundibulum. It is a highly vascular region containing veins of the hypothalamohypophyseal system. The parenchymal cells are arranged in small clusters or cords in association with the blood vessels. Nests of squamous cells and small follicles lined with cuboidal cells are scattered in this region. These cells often show immunoreactivity for ACTH, FSH, and LH. Posterior Lobe of the Pituitary Gland (Neurohypophysis) The posterior lobe of the pituitary gland is an extension of the central nervous system (CNS) that stores and releases secretory products from the hypothalamus. The posterior lobe of the pituitary gland, also known as the neurohypophysis, consists of the pars nervosa and the infundibulum that connects it to the hypothalamus.


Histology_Ross

Histology_Ross. The posterior lobe of the pituitary gland, also known as the neurohypophysis, consists of the pars nervosa and the infundibulum that connects it to the hypothalamus. TABLE Electron Microscopic Characteristics of Cells Found in the Anterior Lobe of the Pituitary Gland21.3 Cell Type Size/Shape Nucleus/Location Secretory Vesicle Size/ Characteristics Other Cytoplasmic Characteristics Somatotrope Medium/oval Round/central, with prominent nucleoli Dense: 350 nm, closely packed None Lactotrope Large/polygonal Oval/central Inactive: 200 nm, sparse Active: dense, pleomorphic, 600 nm, sparse Lysosomes increase after lactation Corticotrope Medium/polygonal Round/eccentric 100–300 nm Lipid droplets, large lysosomes, perinu-clear bundles of intermediate filaments Gonadotrope Small/oval Round/eccentric Dense: 200–250 nm Prominent Golgi apparatus, distended rER cisternae Thyrotrope Large/polygonal Round/eccentric Dense: 150 nm Prominent Golgi apparatus with numerous vesicles


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Histology_Ross. FIGURE 21.8 • Photomicrograph of the pars intermedia of an adult human pituitary gland. This photomicrograph of a toluidine blue–stained specimen shows the pars intermedia located between the pars distalis (on the left) and pars nervosa (on the right). In humans, this portion of the gland is somewhat rudimentary. However, a characteristic feature of the pars intermedia is the presence of different-sized follicles filled with colloid (CF ) and small groups of cells consisting of chromophobes and basophils. 120.


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Histology_Ross. The pars nervosa, the neural lobe of the pituitary, contains the nonmyelinated axons and their nerve endings of approximately 100,000 neurosecretory neurons whose cell bodies lie in the supraoptic nuclei and paraventricular nuclei of the hypothalamus. The axons form the hypothalamohypophyseal tract and are unique in two respects. First, they do not terminate on other neurons or target cells but end in close proximity to the fenestrated capillary network of the pars nervosa. Second, they contain secretory vesicles in all parts of the cells, i.e., the cell body, axon, and axon terminal. Because of their intense secretory activity, the neurons have well-developed Nissl bodies and in this respect resemble ventral horn and ganglion cells.


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Histology_Ross. The posterior lobe of the pituitary gland is not an endocrine gland. Rather, it is a storage site for neurosecretions of the neurons of the supraoptic and paraventricular nuclei of the hypothalamus. The nonmyelinated axons convey neurosecretory products to the pars nervosa. Other neurons from the hypothalamic nuclei (described below) also release their secretory products into the fenestrated capillary network of the infundibulum, the first capillary bed of the hypothalamohypophyseal portal system. Electron microscopy reveals three morphologically distinct neurosecretory vesicles in the nerve endings of the pars nervosa.


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Histology_Ross. Electron microscopy reveals three morphologically distinct neurosecretory vesicles in the nerve endings of the pars nervosa. Three sizes of membrane-bounded vesicles are present in the pars nervosa:  Neurosecretory vesicles with diameters ranging between 10 and 30 nm accumulate in the axon terminals. They also form accumulations that dilate portions of the axon near the terminals (Fig. 21.9). These dilations, called Herring bodies, are visible in the light microscope (Plate 81, page 774). In the electron microscope, Herring bodies in addition to abundant neurosecretory vesicles, contain mitochondria, few micro-tubules and profiles of SER (Fig. 21.10).  Nerve terminals also contain 30-nm vesicles that contain acetylcholine. These vesicles may play a specific role in the release of neurosecretory vesicles.


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Histology_Ross.  Larger 50to 80-nm vesicles that resemble the dense core vesicles of the adrenal medulla and adrenergic nerve endings are present in the same terminal as the other membrane-bound vesicles. The membrane-bound neurosecretory vesicles that aggregate to form Herring bodies contain either oxytocin or antidiuretic hormone (ADH; also called vasopressin; Table 21.4). Each hormone is a small peptide of nine amino acid residues. The two hormones differ in only two of these residues. Each vesicle also contains ATP and a neurophysin, a protein that binds to the hormone by noncovalent bonds. Oxytocin and ADH are synthesized as part of a large molecule that includes the hormone and its specific neurophysin. The large molecule is proteolytically cleaved into the hormone and neurophysin as it travels from the nerve cell body to the axon terminal. Immunocytochemical staining demonstrates that oxytocin and ADH are secreted by different cells in the hypothalamic nuclei.


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Histology_Ross. ADH facilitates resorption of water from the distal tubules and collecting ducts of the kidney by altering the permeability of the cells to water. ADH’s original name, vasopressin, was derived from the observation that large nonphysiologic doses increase blood pressure by promoting the contraction of smooth muscle in small arteries and arterioles. However, the physiologic levels of ADH have only minimal effects on blood pressure. ADH is the main hormone involved in regulation of water homeostasis and osmolarity of body fuids. The primary physiologic effect of ADH on the kidney is the insertion of water channels (aquaporins) into cells of the distal convoluted tubules and collecting ducts, which increases the permeability for water. Insertion of aquaporin-2 (AQP-2) into the apical domain and aquaporin-3 (AQP-3) into the basolateral domain of these cells is responsible for rapid resorption of water across the tubule epithelium.


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Histology_Ross. ADH acts through its specific V2 receptor on the basolateral domain of cells lining the distal convoluted tubules and collecting ducts; mutation of this receptor is responsible for nephrogenic diabetes insipidus (Folder 21.3). Plasma osmolality and blood volume are monitored by specialized receptors of the cardiovascular system (e.g., carotid bodies and juxtaglomerular apparatus). An increase


Histology_Ross

Histology_Ross. Abnormalities in the signaling mechanisms that coordinate and control the function of multiple organs and biological processes are the bases of many endocrine diseases. Classical biochemistry, physiology, and advances in cell and molecular biology and genetics combined with clinical observations are able to explain the mechanisms of hor-monal action and endocrine diseases. Endocrine diseases can be classified into four major categories:  Hormone overproduction. The most common cause of hormone overproduction is an increase in the total num-ber of cells producing a specific hormone. An example of this mechanism is hyperthyroidism (Graves’ disease; see Folder 21.4). Briefly, the presence of abnormal antibodies that mimic the action of TSH stimulates a dramatic in-crease in the number of thyroid cells. In some instances, increased hormone secretion is related to genetic abnor-mality that affects regulation of hormone synthesis and re-lease. In addition, mutation in tumor suppressor


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Histology_Ross. thyroid cells. In some instances, increased hormone secretion is related to genetic abnor-mality that affects regulation of hormone synthesis and re-lease. In addition, mutation in tumor suppressor genes and protooncogenes may lead to proliferation of mutant cells that produce the specific hormone. This commonly occurs in cells of the anterior lobe of the pituitary gland.  Hormone underproduction. Underproduction of hor-mones may result from destruction of an endocrine organ by a disease process (e.g., tuberculosis of the adrenal glands) or autoimmunity (e.g., Hashimoto’s disease in which abnormal antibodies target and destroy thyroid hormone–producing cells). Also, genetic abnormalities that lead to abnormal development of endocrine glands (e.g., hypogonadotropic hypogonadism), abnormal hormone synthesis (e.g., deletion of the GH gene), or abnormal reg-ulation of hormone secretion (e.g., hypoparathyroidism associated with mutation of the calcium-sensing receptor expressed on


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Histology_Ross. hormone synthesis (e.g., deletion of the GH gene), or abnormal reg-ulation of hormone secretion (e.g., hypoparathyroidism associated with mutation of the calcium-sensing receptor expressed on parathyroid cells) can cause decreased serum levels or lack of active hormones. Iatrogenic injury to endocrine glands such as occurs when the parathyroid gland is removed during thyroidectomy (thyroid gland removal) may also be responsible.  Altered tissue responses to hormones. This cate-gory of endocrine disease is often cause by a variety of genetic mutation in hormone receptors (e.g., TSH, LH, and PTH). In diabetic patients, the resistance to insulin in muscles and the liver is mainly caused by signals origi-nating from adipose tissue (see Chapter 9).  Tumors of endocrine glands. Most of the tumors of endocrine gland are hormonally active and are responsi-ble for hormone overproduction. However, some tumors of endocrine glands do not produce hormones, but com-press neighboring organs or


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Histology_Ross. tumors of endocrine gland are hormonally active and are responsi-ble for hormone overproduction. However, some tumors of endocrine glands do not produce hormones, but com-press neighboring organs or cause destructions of other organs due to metastasis. An example of such a tumor is thyroid cancer that can metastasize throughout the body without presenting signs of thyroid hormone overpro-duction (hyperthyroidism). Hormones are used to treat endocrine diseases. A com-mon use is as hormone replacement therapies when a specific endocrine gland is not developed or ceases to produce the required hormone. Hormones and their syn-thetic analogs can be used to suppress the effects of other hormones. In general, thyroid and steroid hormones can be administered orally, whereas protein hormones (e.g., insulin, GH) need to be injected. Recent technological innovations including computerized mini-pumps and depot intramuscular injections have made therapy more manage-able for patients.


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Histology_Ross.  FOLDER 21.2 Clinical Correlation: Principles of Endocrine Diseases in osmolality or a decrease in blood volume stimulates ADH release. Additionally, the cell bodies of the hypothalamic secretory neurons may also serve as osmoreceptors, initiating ADH release. Pain, trauma, emotional stress, and drugs such as nicotine also stimulate release of ADH. Oxytocin promotes contraction of smooth muscle of the uterus and myoepithelial cells of the breast. Oxytocin is a more potent promoter of smooth muscle contraction than is ADH. Its primary effect includes promotion of contraction of  uterine smooth muscle during orgasm, menstruation, and parturition. As parturition approaches, uterine smooth muscle cells demonstrate about a 200-fold increase in the responsiveness to oxytocin. This is accompanied by increased formation of gap junctions between smooth muscle cells and increased density of oxytocin receptors.


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Histology_Ross.  myoepithelial cells of the secretory alveoli and alveolar ducts of the mammary gland. Oxytocin secretion is triggered by neural stimuli that reach the hypothalamus. These stimuli initiate a neurohumoral reflex that resembles a simple sensorimotor reflex. In the uterus, the neurohumoral reﬂex is initiated by distension of the vagina and cervix. In the breast, the reﬂex is initiated by breastfeeding (suckling). Contraction of the myoepithelial cells that surround the base of the alveolar secretory cells and cells of the larger ducts cause milk to be released and pass through the ducts that open onto the nipple (i.e., milk ejection; see page 867). Synthetic analogs of oxytocin are often used in intravenous infusion pumps to initiate and strengthen uterine contractions during active labor and delivery. Nasal preparations of oxytocin are also used to promote lactation in breastfeeding women. The pituicyte is the only cell specific to the posterior lobe of the pituitary gland.


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Histology_Ross. The pituicyte is the only cell specific to the posterior lobe of the pituitary gland. In addition to the numerous axons and terminals of the hypothalamic neurosecretory neurons, the posterior lobe of the pituitary gland contains fibroblasts, mast cells, and specialized glial cells called pituicytes associated with the fenestrated capillaries. These cells are irregular in shape, with many branches, and resemble astroglial cells. Their nuclei are round or oval, and pigment vesicles are present in the cytoplasm. Like astroglia, they possess specific intermediate filaments assembled from glial fibrillary acidic proteins (GFAP). Pituicytes often have processes that terminate in the perivascular space. Because of their many processes and relationships to the blood, the pituicyte serves a supporting role similar to that of astrocytes in the rest of the CNS (see page 367).


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Histology_Ross. FIGURE 21.9 • Electron micrograph of Herring bodies of rat posterior lobe. Dilated portions of axons near their terminals called Herring bodies (HB) contain numerous neurosecretory vesicles filled with either oxytocin or ADH. They are surrounded by the specialized glial cells called pituicytes (P). Note that Herring bodies reside in a close proximity to blood vessels (BV), mainly fenestrated capillaries, lined by endothelial cells (En). 6,000. (Courtesy of Dr. Holger Jastrow). The hypothalamus regulates pituitary gland activity.


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Histology_Ross. The hypothalamus regulates pituitary gland activity. The hypothalamus is located in the middle of the base of the brain, and it encapsulates the ventral portion of the third ventricle. It coordinates most endocrine functions of the body and serves as one of the major controlling centers of the autonomic nervous system. Some of the functions that it regulates include blood pressure, body temperature, fluid and electrolyte balance, body weight, and appetite. The hypothalamus produces numerous neurosecretory products. In addition to oxytocin and ADH, hypothalamic neurons secrete polypeptides that promote and inhibit the secretion and release of hormones from the anterior lobe of the pituitary gland (Table 21.5). These hypothalamic polypeptides also accumulate in nerve endings near the median eminence and infundibulum and are released into the capillary bed of the hypothalamohypophyseal portal system for transport to the pars distalis of the pituitary gland.


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Histology_Ross. A feedback system regulates endocrine function at two levels: hormone production in the pituitary gland and hypothalamic releasing hormone production in the hypothalamus. The circulating level of a specific secretory product of a target organ, a hormone or its metabolite, may act directly on the cells of the anterior lobe of the pituitary gland or the hypothalamus to regulate the secretion of hypothalamic releasing hormones (see Fig. 21.6). The two levels of feedback FIGURE 21.10 • Electron micrograph of rat posterior lobe.


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Histology_Ross. FIGURE 21.10 • Electron micrograph of rat posterior lobe. Neurosecretory granules and small vesicles are present in the terminal portions of the axonal processes of the hypothalamohypophyseal tract fibers. Capillaries with fenestrated endothelium are present in close proximity to the nerve endings. 20,000. (Courtesy of Drs. Sanford L. Palay and P. Orkland.) allow exquisite sensitivity in the control of secretory function. The hormone itself normally regulates the secretory activity of the cells in the hypothalamus and pituitary gland that regulate its secretion.


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Histology_Ross. In addition, information from most physiologic and psychologic stimuli that reach the brain also reaches the hypothalamus. The hypothalamohypophyseal feedback loop provides a regulatory path whereby general information from the CNS contributes to the regulation of the anterior lobe of the pituitary gland and, consequently, to the regulation of the entire endocrine system. The secretion of hypothalamic regulatory peptides is the primary mechanism by which changes in emotional state are translated into changes in the physiologic homeostatic state.


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Histology_Ross. The pineal gland (pineal body, epiphysis cerebri) is an endocrine or neuroendocrine gland that regulates daily body rhythm. It develops from neuroectoderm of the posterior portion of the roof of the diencephalon and remains attached to the brain by a short stalk. In humans, it is located at the posterior wall of the third ventricle near the center of the brain. The pineal gland is a flattened, pine cone–shaped structure, hence its name (Fig. 21.11). It measures 5 to 8 mm high and 3 to 5 mm in diameter and weighs between 100 and 200 mg. The pineal gland contains two types of parenchymal cells: pinealocytes and interstitial (glial) cells.


Histology_Ross

Histology_Ross. The pineal gland contains two types of parenchymal cells: pinealocytes and interstitial (glial) cells. Pinealocytes are the chief cells of the pineal gland. They are arranged in clumps or cords within lobules formed by connective tissue septa that extend into the gland from the pia mater that covers its surface. These cells have a large, deeply infolded nucleus with one or more prominent nucleoli and contain lipid droplets within their cytoplasm. When examined with the TEM, pinealocytes show typical cytoplasmic


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Histology_Ross. TABLE Hormones of the Posterior Lobe of the Pituitary Gland21.4 Hormone Composition Source Major Functions Oxytocin Polypeptide containing 9 amino acids Cell bodies of neurons located in the supraoptic and paraventricular nuclei of the hypothalamusa Stimulates activity of the contractile cells around the ducts of the mammary glands to eject milk from the glands; stimulates contraction of smooth muscle cells in the pregnant uterus Antidiuretic hormone (ADH; vasopressin) Polypeptide containing 9 amino acids; two forms: arginine-ADH (most common in humans) and lysine-ADH Cell bodies of neurons located in the supraoptic and paraventricular nuclei of the hypothalamusa Decreases urine volume by increasing reabsorption of water by collecting ducts of the kidney; decreases the rate of perspiration in response to dehydration; increases blood pressure by stimulating contractions of smooth muscle cells in the wall of arterioles a Immunocytochemical studies indicate that oxytocin and ADH are


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Histology_Ross. in response to dehydration; increases blood pressure by stimulating contractions of smooth muscle cells in the wall of arterioles a Immunocytochemical studies indicate that oxytocin and ADH are produced by separate sets of neurons within the supraoptic and paraventricular nuclei of the hypothalamus. Biochemical studies have demonstrated that the supraoptic nucleus contains equal amounts of both hormones, whereas the paraventricular nucleus contains more oxytocin than ADH, but less than the amount found in the supraoptic nucleus.


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Histology_Ross.  FOLDER 21.3 Clinical Correlation: Pathologies Associated with ADH Secretion chapter 21 Endocrine Organs PI N EAL G LAN D 753 The absence or reduced production of ADH leads to a condition known as diabetes insipidus, which is char-acterized by polyuria (production of large volumes of di-luted urine—up to 20 L per day) with hypotonic and tasteless (insipid) urine. Individuals with this condition have extreme thirst, which allows them to counteract the loss of water by drinking large amounts of fluids. This dis-ease commonly results from head injuries, tumors, or other lesions that can damage the hypothalamus or pos-terior lobe of the pituitary gland. This form of the disease is classified as hypothalamic diabetes insipidus in contrast to nephrogenic diabetes insipidus, in which secretion of the ADH is normal or elevated, but there is a lack of renal response to circulating levels of ADH. Nephrogenic diabetes is usually a congenital disorder re-lated to the mutation of the aquaporins-2


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Histology_Ross. the ADH is normal or elevated, but there is a lack of renal response to circulating levels of ADH. Nephrogenic diabetes is usually a congenital disorder re-lated to the mutation of the aquaporins-2 (AQP-2) water channels gene or different ADH V2 receptor mutations in kidney tubules. Hypothalamic diabetes insipidus is usu-ally treated by administration of synthetic analogs of ADH (desmopressin), whereas the treatment of the nephro-genic type of this disease is aimed at reducing the volume of urine output. Abnormally high levels of ADH are found in the syn-drome of inappropriate antidiuretic hormone secre-tion (SIADH), which is characterized by hyponatremia (low serum levels of sodium), decreased serum osmolality asso-ciated with excessive urine sodium excretion, and elevated urine osmolality. In SIADH, the elevated level of ADH in-creases the absorption of water, thereby leading to produc-tion of concentrated urine, inability to excrete water, and hyponatremia that results from excess


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Histology_Ross. In SIADH, the elevated level of ADH in-creases the absorption of water, thereby leading to produc-tion of concentrated urine, inability to excrete water, and hyponatremia that results from excess water rather than sodium deficiency. The increase in ADH secretion may be related to CNS disorders (tumors, injuries, infections, or cerebrovascular accidents); pulmonary diseases (pneumo-nia, chronic obstructive pulmonary disease, a lung abscess, or tuberculosis); tumors that secrete ADH (small-cell carci-noma of the lung, tumors of the pancreas, thymoma, or lym-phomas); and certain drugs (anti-inflammatories, nicotine, diuretics, and many others). Treatment of SIADH depends on the underlying etiology and includes fluid restrictions as well as pharmacological treatment. An ADH V2–receptor antagonist (Conivaptan) is now available to improve hy-ponatremia and to increase the free water diuresis without loss of other ions in the urine of patients with SIADH. TABLE Hypothalamic Regulating


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Histology_Ross. antagonist (Conivaptan) is now available to improve hy-ponatremia and to increase the free water diuresis without loss of other ions in the urine of patients with SIADH. TABLE Hypothalamic Regulating Hormones21.5 Hormone Composition Source Major Functions Growth hormone– releasing hormone (GHRH) Two forms in human: polypeptides containing 40 and 44 amino acids Cell bodies of neurons located in the arcuate nucleus of hypothalamus Stimulates secretion and gene expression of GH by somatotropes Somatostatin Two forms in human: polypeptides containing 14 and 28 amino acids Cell bodies of neurons located in the periventricular, paraven-tricular, and arcuate nuclei of the hypothalamus Inhibits secretion of GH by somatotropes, inhibits insulin secretion by B cells of pancreatic islets Dopamine Catecholamine (amino acid derivative) Cell bodies of neurons located in the arcuate nucleus of hypothalamus Inhibits secretion of PRL by lactotropes Corticotropin-releasing hormone (CRH) Polypeptide


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Histology_Ross. Catecholamine (amino acid derivative) Cell bodies of neurons located in the arcuate nucleus of hypothalamus Inhibits secretion of PRL by lactotropes Corticotropin-releasing hormone (CRH) Polypeptide containing 41 amino acids Cell bodies of neurons located in the arcuate, periventricular, and medial paraventricular nuclei of hypothalamus Stimulates secretion of ACTH by corticotropes; stimulates gene expression for POMC in corticotropes Gonadotropin-releasing hormone (GnRH) Polypeptide containing 10 amino acids Cell bodies of neurons located in the arcuate, ventromedial, dorsal, and paraventricular nuclei of hypothalamus Stimulates secretion of LH and FSH by gonadotropes Thyrotropin-releasing hormone (TRH) Polypeptide containing 3 amino acids Cell bodies of neurons located by the ventromedial, dorsal, and paraventricular nuclei of hypothalamus Stimulates secretion and gene expression of TSH by thyrotropes; stimulates synthesis and secretion of PRL


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Histology_Ross. FIGURE 21.11 • Photomicrograph of infant pineal gland. This H&E–stained section is from a median cut through the pine cone–shaped gland. The conical anterior end of the gland is at the top of the micrograph. The arrows indicate the part of the gland that connects with the posterior commissure. The gland is formed by an evagination of the posterior portion of the roof of the third ventricle (diencephalon). The dark areas indicated by asterisks are caused by bleeding within the gland. 25. organelles along with numerous, dense-core, membrane-bounded vesicles in their elaborate, elongated cytoplasmic processes. The processes also contain numerous parallel bundles of microtubules. The expanded, clublike endings of the processes are associated with the blood capillaries. This feature strongly suggests neuroendocrine activity.


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Histology_Ross. The interstitial (glial) cells constitute about 5% of the cells in the gland. They have staining and ultrastructural features that closely resemble those of astrocytes and are reminiscent of the pituicytes of the posterior lobe of the pituitary gland. In addition to the two cell types, the human pineal gland is characterized by the presence of calcified concretions, called corpora arenacea or brain sand (Fig. 21.12). These concretions appear to be derived from precipitation of calcium phosphates and carbonates on carrier proteins that are released into the cytoplasm when the pineal secretions are


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Histology_Ross. FIGURE 21.12 • Photomicrograph of human pineal gland. This higher-magnification photomicrograph shows the characteristic concretions called brain sand or corpora arenacea. Pinealocytes (chief cells of the pineal gland) account for the majority of the cells seen in the specimen. They are arranged in clumps or cords. Those blood vessels (BV ) that contain red blood cells are readily apparent; numerous other blood vessels are also present but are not recognized at this magnification without evidence of the blood cells. 250. exocytosed. The concretions are recognizable in childhood and increase in number with age. Because they are opaque to X-rays and located in the midline of the brain, they serve as convenient markers in radiographic and computed tomography (CT) studies. The human pineal gland relates light intensity and duration to endocrine activity.


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Histology_Ross. The human pineal gland relates light intensity and duration to endocrine activity. The pineal gland is a photosensitive organ and an important timekeeper and regulator of the day/night cycle (circadian rhythm). It obtains information about light and dark cycles from the retina via the retinohypothalamic tract, which connects in the suprachiasmatic nucleus with sympathetic neural tracts traveling into the pineal gland. During the day, light impulses inhibit the production of the major pineal gland hormone, melatonin. Therefore, pineal activity, as measured by changes in the plasma level of melatonin, increases during darkness and decreases during light. In humans, these circadian changes of melatonin secretion play an important role in regulating daily body rhythms.


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Histology_Ross. TABLE Hormones of the Pineal Gland21.6 Hormone Composition Source Major Functions Melatonin Indolamine (N-acetyl-5-methoxytryptamine) Pinealocytes Regulates daily body rhythms and day/night cycle (circadian rhythms); inhibits secretion of GnRH and regulates steroidogenic activity of the gonads particularly as related to the menstrual cycle; in animals, influences seasonal sexual activity


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Histology_Ross. Melatonin is released in the dark and regulates reproductive function in mammals by inhibiting the steroidogenic activity of the gonads (Table 21.6). Production of gonadal steroids is decreased by the inhibitory action of melatonin on neurosecretory neurons located in the hypothalamus (arcuate nucleus) that produce GnRH. Inhibition of GnRH causes a decrease in the release of FSH and LH from the anterior lobe of the pituitary gland. In addition to melatonin, extracts of pineal glands from many animals contain numerous neurotransmitters, such as serotonin, norepinephrine, dopamine,and histamine, and hypothalamic-regulating hormones, such as somatostatin and TRH. Clinically, tumors that destroy the pineal gland are associated with precocious (early-onset) puberty.


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Histology_Ross. Animal studies demonstrate that information relating to the length of daylight reaches the pineal gland from photoreceptors in the retina. The pineal gland thus influences seasonal sexual activity. Recent studies in humans suggest that the pineal gland has a role in adjusting to sudden changes in day length, such as those experienced by travelers who suffer from jet lag. In addition, the pineal gland may play a role in altering emotional responses to the reduced length of day during winter in temperate and subarctic zones known as seasonal affective disorder (SAD). The thyroid gland is located in the anterior neck region adjacent to the larynx and trachea.


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Histology_Ross. The thyroid gland is located in the anterior neck region adjacent to the larynx and trachea. The thyroid gland is a bilobate endocrine gland located in the anterior neck region and consists of two large lateral lobes connected by an isthmus, a thin band of thyroid tissue. The two lobes, each approximately 5 cm in length, 2.5 cm in width, and 20 to 30 g in weight, lie on either side of the larynx and upper trachea. The isthmus crosses anterior to the upper part of the trachea. A pyramidal lobe often extends upward from the isthmus. A thin connective tissue capsule surrounds the gland. It sends trabeculae into the parenchyma that partially outline irregular lobes and lobules. Thyroid follicles constitute the functional units of the gland. The thyroid gland develops from the endodermal lining of the floor of the primitive pharynx.


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Histology_Ross. The thyroid gland begins to develop during the fourth week of gestation from a primordium originating as an endodermal thickening of the floor of the primitive pharynx. The primordium grows caudally and forms a ductlike invagination known as the thyroglossal duct. The thyroglossal duct descends through the tissue of the neck to its final destination in front of the trachea, where it divides into two lobes. During this downward migration, the thyroglossal duct undergoes atrophy, leaving an embryologic remnant, the pyramidal lobe of the thyroid, which is present in about 40% of the population. About the ninth week of gestation, endodermal cells differentiate into plates of follicular cells that become arranged into follicles. By week 14, well-developed follicles lined by the follicular cells contain colloid in their lumen. During week 7, epithelial cells lining the invagination of the fourth branchial pouches (sometimes called the fifth branchial pouches), known as the ultimobranchial


Histology_Ross

Histology_Ross. contain colloid in their lumen. During week 7, epithelial cells lining the invagination of the fourth branchial pouches (sometimes called the fifth branchial pouches), known as the ultimobranchial bodies, start their migration toward the developing thyroid gland and become incorporated into the lateral lobes. After fusing with the thyroid, ultimobranchial body cells disperse among the follicles, giving rise to parafollicular cells that become incorporated into the follicular epithelium.


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Histology_Ross. The thyroid follicle is the structural and functional unit of the thyroid gland. A thyroid follicle is a roughly spherical cystlike compartment with a wall formed by a simple cuboidal or low columnar epithelium, the follicular epithelium. Hundreds of thousands of follicles that vary in diameter from about 0.2 to 1.0 mm constitute nearly the entire mass of the human thyroid gland. The follicles contain a gel-like mass called colloid (Fig. 21.13). The apical surfaces of the follicular cells are in contact with the colloid, and the basal surfaces rest on a typical basal lamina. Follicular epithelium contains two types of cells: follicular and parafollicular cells.


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Histology_Ross. Follicular epithelium contains two types of cells: follicular and parafollicular cells. The parenchyma of the thyroid gland is composed of epithelium containing two types of cells:  Follicular cells (principal cells) are responsible for pro duction of the thyroid hormones T4 and T3. These cells vary in shape and size according to the functional state of the gland. In routine hematoxylin and eosin (H&E) prepa rations, follicular cells exhibit a slightly basophilic basal cy toplasm with spherical nuclei containing one or more FIGURE 21.13 • Thyroid gland. This photomicrograph of a human thyroid is from a section stained with H&E. It shows the colloid-containing follicles of the gland. Each follicle consists of a single layer of epithelial cells surrounding a central mass of colloid. The arrows indicate some of the blood capillaries between the follicles. 500.


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Histology_Ross. prominent nucleoli. The Golgi apparatus has a supranuclear position. Lipid droplets and PAS-positive droplets can be identified with appropriate staining. At the ultrastructural level, the follicle cells reveal organelles commonly associated with both secretory and absorptive cells (Fig. 21.14), including typical junctional complexes at the apical end of the cell and short microvilli on the apical cell surface. Numerous profiles of rough-surfaced endoplasmic reticulum (rER) are present in the basal region. Small vesicles present in the apical cytoplasm are morphologically similar to vesicles associated with the Golgi apparatus. Abundant endocytotic vesicles, identified as colloidal resorption droplets, and lysosomes are also present in the apical cytoplasm.


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Histology_Ross.  Parafollicular cells (C cells) are located in the periphery of the follicular epithelium and lie within the follicle basal lamina. These cells have no exposure to the follicle lumen. They secrete calcitonin, a hormone that regulates calcium metabolism. In routine H&E preparations, C cells are pale staining and occur as solitary cells or small clusters of cells. Human parafollicular cells are difficult to identify with light microscopy. At the electron microscope level, the parafollicular cells reveal numerous small secretory vesicles, which range in diameter from 60 to 550 nm, and a prominent Golgi apparatus (Fig. 21.15).


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Histology_Ross. FIGURE 21.14 • Electron micrograph of follicular cells in rat thyroid gland. This electron micrograph shows a single layer of epithelium containing low columnar follicular cells. The apical surfaces with visible microvilli (Mv) are in contact with the colloid, whereas basal surfaces of follicular cells rest on the basal lamina (FBL). A narrow extracellular connective tissue space separates the follicular cells from the lumen of the capillary. Note that the fenestrated endothelial cells (En) lining capillary lumen rest on the basal lamina (EBL). Accumulation of lysosomes (L) and colloid resorption droplets (CRD), extensive Golgi apparatus (G), rough endoplasmic reticulum (rER), and presence of enlarged intercellular spaces are indicative of intensive activity of follicular cells. N, nucleus; JC, junctional complex. 14,000. (Courtesy of Dr. Holger Jastrow).


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Histology_Ross. An extensive network of fenestrated capillaries derived from the superior and inferior thyroid arteries surrounds the follicles. Blind-ended lymphatic capillaries are present in the interfollicular connective tissue and may also provide a second route for conveying the hormones from the gland. Thyroid gland function is essential to normal growth and development. The thyroid gland produces three hormones, each of which is essential to normal metabolism and homeostasis (Table 21.7):  Thyroxine (tetraiodothyronine, T4) and triiodothyronine (T3) are synthesized and secreted by the follicular cells. Both hormones regulate cell and tissue basal metabolism and heat production and influence body growth and development. Secretion of these hormones is regulated by TSH released from the anterior lobe of the pituitary gland.


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Histology_Ross.  Calcitonin (thyrocalcitonin) is synthesized by the parafollicular cells (C cells) and is a physiologic antagonist to parathyroid hormone (PTH). Calcitonin has an important role in regulating serum calcium levels in lower animals; however, its physiological role in humans remains elusive. Calcitonin lowers blood calcium levels by suppressing the


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Histology_Ross. FIGURE 21.15 • Electron micrograph of a parafollicular cell. Cytoplasmic processes of follicular cells (arrows) partially surround the parafollicular cell (PC), which contains numerous electron-dense granules and a prominent Golgi apparatus (G). A basal lamina (BL) is associated with the follicular cells (FC). A portion of the central mass of colloidal material (C) in two adjacent follicles can be seen in the left corners of the micrograph. 12,000. (Courtesy of Dr. Emmanuel-Adrien Nunez.) resorptive action of osteoclasts and promotes calcium deposition in bones by increasing the rate of osteoid calcification. Secretion of calcitonin is regulated directly by blood calcium levels. High levels of calcium stimulate secretion; low levels inhibit it. Secretion of calcitonin is unaffected by the hypothalamus and pituitary gland. Calcitonin is secreted by several endocrine tumors (e.g., a medullary carcinoma of the thyroid); therefore, it is used as a tumor marker to monitor progress of


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Histology_Ross. the hypothalamus and pituitary gland. Calcitonin is secreted by several endocrine tumors (e.g., a medullary carcinoma of the thyroid); therefore, it is used as a tumor marker to monitor progress of recovery after surgical resection of the tumor. Although calcitonin is used to treat patients with several disorders associated with excess bone resorption (e.g., osteoporosis and Paget’s disease), no clinical disease has been associated with its deficiency or even its absence after total thyroidectomy.


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Histology_Ross. The principal component of colloid is thyroglobulin, an inactive storage form of thyroid hormones. The principal component of colloid is a large (660 kilodalton) iodinated glycoprotein called thyroglobulin containing about 120 tyrosine residues. Colloid also contains several enzymes and other glycoproteins. It stains with both basic and acidic dyes and is strongly PAS positive. Thyroglobulin is not a hormone. It is an inactive storage form of the thyroid hormones. Active thyroid hormones are liberated from thyroglobulin and released into the fenestrated blood capillaries that surround the follicles only after further cellular processing. The thyroid is unique among endocrine glands because it stores large amounts of its secretory product extracellularly. Synthesis of thyroid hormone involves several steps. The synthesis of the two major thyroid hormones, thyroxine (T4) and T3 takes place in the thyroid follicle in a series of discrete steps (Fig. 21.16): 1.


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Histology_Ross. The synthesis of the two major thyroid hormones, thyroxine (T4) and T3 takes place in the thyroid follicle in a series of discrete steps (Fig. 21.16): 1. Synthesis of thyroglobulin. The precursor of thyroglobulin is synthesized in the rER of the follicular epithelial cells. Thyroglobulin is posttranslationally glycosylated in the rER and the Golgi apparatus before it is packaged into vesicles and secreted by exocytosis into the lumen of the follicle. 2.


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Histology_Ross. Resorption, diffusion, and oxidation of iodide. Follicular epithelial cells actively transport iodide from the 758 The most common symptom of thyroid disease is a goiter, the enlargement of the thyroid gland. It may indicate either hypothyroidism or hyperthyroidism. Hypothyroidism can be caused by insufficient dietary iodine (iodine-defciency goiter, endemic goiter) or by one of several inherited autoimmune diseases, such as autoimmune thyroiditis (Hashimoto’s thyroiditis). Autoimmune thyroiditis is characterized by the presence of abnormal autoimmunoglobulins directed against thyroglobu-lin (TgAb), thyroid peroxidase (TPOAb), and the TSH recep-tor (TSHAb). The results are thyroid cell apoptosis and follicular destruction. The low levels of circulating thyroid hormone stimulate release of excessive amounts of TSH, which cause hypertrophy of the thyroid through synthesis of more thyroglobulin. Adult hypothyroidism, formerly called myxedema (due to the puffy appearance of the skin) is


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Histology_Ross. excessive amounts of TSH, which cause hypertrophy of the thyroid through synthesis of more thyroglobulin. Adult hypothyroidism, formerly called myxedema (due to the puffy appearance of the skin) is char-acterized by mental and physical sluggishness. The edema that occurs in the severe stages of hypothyroidism is caused by the accumulation of large amounts of hyaluronan in the extracellular matrix of the connective tissue of the dermis. In hyperthyroidism (toxic goiter or Graves’ dis-ease), excessive amounts of thyroid hormones are re-leased into the circulation. Individuals with Graves’ disease have detectable levels of autoantibodies. These abnormal immunoglobulins (IgG) bind to the TSH receptors on the follicular cells and stimulate adenylate cyclase activity. As a result, increased levels of cAMP in follicular cells lead to continuous stimulation of the cells and increased thyroid hormone secretion. Because of negative feedback, the lev-els of TSH in the circulation are usually


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Histology_Ross. levels of cAMP in follicular cells lead to continuous stimulation of the cells and increased thyroid hormone secretion. Because of negative feedback, the lev-els of TSH in the circulation are usually normal. However, under such stimulation the thyroid gland undergoes hyper-trophy, and the thyroid hormone is secreted at abnormally high rates, causing increased metabolism. Most of the clin-ical futures are associated with increased metabolic rate and increased sympathetic nerve activities. These include weight loss, excessive sweating, tachycardia, and nervous-ness. Noticeable features include protrusion of the eyeballs and retraction of the eyelids, resulting from increased sym-pathetic activity and increased deposition of extracellular matrix in the adipose tissue located behind the eyeball (Fig. F21.4.1a). The thyroid gland is enlarged. Microscopic features include the presence of columnar follicular cells lin-ing the thyroid follicles. Because of the high utilization of col-loid,


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Histology_Ross. (Fig. F21.4.1a). The thyroid gland is enlarged. Microscopic features include the presence of columnar follicular cells lin-ing the thyroid follicles. Because of the high utilization of col-loid, the follicle tends to be depleted in the areas of contact with the apical surface of follicular cells (Fig. F21.4.1b). The treatment for Graves’ disease is either surgical to remove the thyroid gland or radiotherapy by ingestion of radioactive iodine (131I), which destroys most active follicular cells.


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Histology_Ross.  FOLDER 21.4 Clinical Correlation: Abnormal Thyroid Function aaabbbFIGURE F21.4.1 • Hyperthyroidism. a. A young woman with signs of hyperthyroidism. Note the enlarged mass on the neck and the typical ocular symptoms known as exophthalmos. b. Photomicrograph of a thyroid gland specimen from an individual with Graves’ disease. Due to the increased utilization of colloid, there is a lack of staining at the periphery of the colloid near the apical surface of the follicular cell. Note that the majority of the cells are columnar in shape. (Reprinted with permission from Rubin E, Gorstein F, Rubin R, Schwarting R, Strayer D. Rubin’s Pathology, Clinicopathologic Foundations of Medicine, 4th ed. Baltimore: Lippincott Williams & Wilkins, 2005.)


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Histology_Ross. TABLE 21.7 Hormones of the Thyroid Gland carbohydrate use, protein synthesis and degradation, and fat synthesis and degradation); regulates heat production; influences body and tissue growth and development of the nervous system in the fetus and young childb; increases absorption of carbohydrates from the intestine Decreases blood calcium levels by inhibiting bone resorption and stimulating absorption of calcium by the bones Thyroxine (tetraiodothyronine, T4) and aThyroid gland secretes substantially more T4 than T3; however, about 40% of T4 is peripherally converted to T3, which acts more rapidly and is a more potent hormone. bDeficiency of T3 and T4 during development results in fewer and smaller neurons, defective myelination, and mental retardation.


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Histology_Ross. blood into their cytoplasm using ATPase-dependent lishing an intracellular concentration of iodide that is 30 sodium/iodide symporters (NIS). The NIS is the to 40 times greater than that of the serum. Iodide ions 87-kilodalton transmembrane protein that mediates ac-then diffuse rapidly toward the apical cell membrane. tive iodide uptake in the basolateral membrane of the From here iodide ions are transported to the lumen of follicular epithelial cells. These cells are capable of estab-the follicle by the 86 kilodalton iodide/chloride receptor FIGURE 21.16 • Diagram of steps in thyroid hormone synthesis. This diagram 5L depicts two follicular cells: one in the process of thyroglobulin synthesis (on the left with red pathways) and the other in the process of thyroglobulin resorption (on the right with blue pathways). The numbers, which are described more fully in the text, indicate the sequential steps that occur: 1, synthesis and secretion of thyroglobulin; 2, uptake and concentration


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Histology_Ross. right with blue pathways). The numbers, which are described more fully in the text, indicate the sequential steps that occur: 1, synthesis and secretion of thyroglobulin; 2, uptake and concentration of iodide from the blood by sodum/iodide symporters (NIS), release of iodide into the colloid via iodide/chloride (pendrin) 6 transporters, and oxidation of iodide to iodine by thyroid peroxidase; 3, iodination of thyroglobulin in the colloid; 4, formation of T3 and T4 hormones in the colloid by oxidative coupling reactions; 5L, resorption pathway); 5TE, resorption of colloid via pathway; and 6, release of T4 and T3 from synthesis resorption the cell into the circulation.


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Histology_Ross. transporter called pendrin located in the apical cell membrane. Iodide is then immediately oxidized to iodine, the active form of iodide. This process occurs in the colloid and is catalyzed by membrane-bound thyroid peroxidase (TPO). 3. Iodination of thyroglobulin. One or two iodine atoms are then added to the specific tyrosine residues of thyroglobulin. This process occurs in the colloid at the microvillar surface of the follicular cells and is also catalyzed by thyroid peroxidase (TPO). Addition of one iodine atom to a single tyrosine residue forms monoiodotyrosine (MIT). Addition of a second iodine atom to the MIT residue forms a diiodotyrosine (DIT) residue. 4.


Histology_Ross

Histology_Ross. 4. Formation of T3 and T4 by oxidative coupling reactions. The thyroid hormones are formed by oxidative coupling reactions of two iodinated tyrosine residues in close proximity. For example, when neighboring DIT and MIT residues undergo a coupling reaction, T3 is formed; when two DIT residues react with each other, T4 is formed. After iodination, T4 and T3 as well as the DIT and MIT residues that are still linked to a thyroglobulin molecule are stored as the colloid within the lumen of the follicle.


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Histology_Ross. 5. Resorption of colloid. In response to TSH, follicular cells take up thyroglobulin from the colloid by a process of receptor-mediated endocytosis. After endocytosis, thyroglobulin follows at least two different intracellular pathways. In the lysosomal pathway, thyreoglobulin is internalized and transported within endocytotic vesicles to early endosomes. They eventually mature into lysosomes or fuse with existing lysosomes. Resorption of thyroglobulin at this stage can be confirmed by the presence of large endocytic vesicles called colloidal resorption droplets in the apical region of the follicular cells. Thyroglobulin is then degraded by lysosomal proteases into constituent amino acids and carbohydrates, leaving free T4, T3, DIT, and MIT molecules (see 5L labeled pathway in Fig 21.16). Under physiological condition, this is a major pathway of colloid resorption.


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Histology_Ross.  In the transepithelial pathway, thyroglobulin is transported intact from the apical to the basolateral surface of follicular cells. To enter this pathway thyroglobulin binds to its receptor megalin, a 330-kilodalton member of the LDL endocytic receptor family. Megalin is a transmembrane protein expressed at the apical surface of follicular epithelial cells directly facing colloid. Thyreoglobulin internalized by megalin avoids the lysosomal pathway and endocytic vesicles are delivered to the basolateral membrane of follicular cells (see 5TE labeled pathway in Fig 21.16). In pathologic conditions of high TSH or TSH-like stimulation, megalin expression is increased and large amounts of thyroglobulin follow the transepithelial pathway. This pathway may reduce the extent of T4 and T3 release by diverting thyroglobulin away from the lysosomal pathway.


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Histology_Ross. Patients with Graves’ and other thyroid diseases have detectable amounts of circulating thyroglobulin that contains portion of megalin receptor. If the levels of TSH remain high, the amount of colloid in the follicle is reduced because it is synthesized, secreted, iodinated, and resorbed too rapidly to accumulate.


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Histology_Ross. 6. Release of T4 and T3 into the circulation and recycling processes. Majority of T4 and T3 are liberated from thyroglobulin in the lysosomal pathway in a T4 to T3 ratio of 20:1. They cross the basal membrane and enter the blood and lymphatic capillaries. Most of the released hormones are immediately bound to either a specific plasma protein (54 kilodalton), thyroxinbinding protein (70%), or a nonspecific prealbumin fraction of serum protein (25%), leaving only small amounts (~5%) of free circulating hormones that are metabolically active. Very small amounts of T4 to T3 are released bound to thyroglobulin. Only the follicular cells are capable of producing T4, whereas most T3, which is five times more active than T4, is produced through conversion from T4 by organs such as the kidney, liver, and heart. The free circulating hormones also function in the feedback system that regulates the secretory activity of the thyroid. Once uncoupled from thyroglobulin, DIT and MIT molecules are


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Histology_Ross. liver, and heart. The free circulating hormones also function in the feedback system that regulates the secretory activity of the thyroid. Once uncoupled from thyroglobulin, DIT and MIT molecules are further deiodinated within the cytoplasm of the follicular cells to release the amino acid tyrosine and iodide, which are then available for recycling.


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Histology_Ross. Thyroid hormones play an essential role in normal fetal development.


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Histology_Ross. In humans, thyroid hormones are essential to normal growth and development. In normal pregnancy, both T3 and T4 cross the placental barrier and are critical in the early stages of brain development. In addition, the fetal thyroid gland begins to function during the 14th week of gestation and also contributes additional thyroid hormones. Thyroid hormone deficiency during fetal development results in irreversible damage to the central nervous system (CNS), causing reduced numbers of neurons, defective myelination, and mental retardation. If maternal thyroid deficiency is present before the development of the fetal thyroid gland, the mental retardation is severe. Recent studies reveal that thyroid hormones also stimulate gene expression for GH in the somatotropes. Therefore, in addition to neural abnormalities, a generalized stunted body growth is typical. The combination of these two abnormalities is called congenital hypothyroidism.


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Histology_Ross. The parathyroid glands are small endocrine glands closely associated with the thyroid. They are ovoid, a few millimeters in diameter, and arranged in two pairs, constituting the superior and inferior parathyroid glands. They are usually located in the connective tissue on the posterior surface of the lateral lobes of the thyroid gland. However, the number and location may vary. In 2% to 10% of individuals, additional glands are associated with the thymus. Structurally, each parathyroid gland is surrounded by a thin connective tissue capsule that separates it from the thyroid. Septa extend from the capsule into the gland to divide it into poorly defined lobules and to separate the densely packed cords of cells. The connective tissue is more evident in the adult, with the development of fat cells that increase with age and ultimately constitute as much as 60% to 70% of the glandular mass.


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Histology_Ross. The glands receive their blood supply from the inferior thyroid arteries or from anastomoses between the superior and inferior thyroid arteries. Typical of endocrine glands, rich networks of fenestrated blood capillaries and lymphatic capillaries surround the parenchyma of the parathyroids. Parathyroid glands develop from the endodermal cells derived from the third and fourth branchial pouches. Embryologically, the inferior parathyroid glands (and the thymus) are derived from the third branchial pouch; the superior glands, from the fourth branchial pouch. Normally, the inferior parathyroids separate from the thymus and come to lie below the superior parathyroids. Failure of these structures to separate results in the atypical association of the parathyroids with the thymus in the adult. The principal (chief) cells differentiate during embryonic development and are functionally active in regulating fetal calcium metabolism. The oxyphil cells differentiate later at puberty.


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Histology_Ross. Principal cells and oxyphil cells constitute the epithelial cells of the parathyroid gland.  Principal (chief) cells, the more numerous of the parenchymal cells of the parathyroid (Fig. 21.17), are responsible for regulating the synthesis, storage, and secretion of large amounts of PTH. They are small, polygonal cells, with a diameter of 7 to 10 m and a centrally located nucleus. The pale-staining, slightly acidophilic cytoplasm contains lipofuscin-containing vesicles, large accumulations of glycogen, and lipid droplets. Small, dense, membrane-limited vesicles seen with the TEM or after using special stains with the light microscope are thought to be the storage form of PTH. Principal cells can replicate when they are chronically stimulated by changes in blood calcium levels.


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Histology_Ross.  Oxyphil cells constitute a minor portion of the parenchymal cells and are not known to have a secretory role. They are found singly or in clusters; the cells are more rounded, considerably larger than the principal cells, and have a distinctly acidophilic cytoplasm (see Fig. 21.17). Mitochondria, often with bizarre shapes and sizes, almost fill the cytoplasm and are responsible for the strong acidophilia of these cells. No secretory vesicles and little if any rER are present. Cytoplasmic inclusion bodies consist of occasional lysosomes, lipid droplets, and glycogen distributed among the mitochondria. Parathyroid hormone regulates calcium and phosphate levels in the blood. The parathyroids function in the regulation of calcium and phosphate levels. Parathyroid hormone (PTH) is essential


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Histology_Ross. Parathyroid hormone regulates calcium and phosphate levels in the blood. The parathyroids function in the regulation of calcium and phosphate levels. Parathyroid hormone (PTH) is essential FIGURE 21.17 • Photomicrograph of human parathyroid gland. This H&E–stained specimen shows the gland with part of its connective tissue capsule (Cap). The blood vessels (BV) are located in the connective tissue septum between lobes of the gland. The principal cells are arranged in two masses (top and bottom) and are separated by a large cluster of oxyphil cells (center). The oxyphil cells are the larger cell type with prominent eosinophilic cytoplasm. They may occur in small groups or in larger masses, as seen here. The principal cells are more numerous. They are smaller, having less cytoplasm, and consequently exhibit closer proximity of their nuclei. Adipose cells (AC) are present in variable, although limited, numbers. 175.


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Histology_Ross. for life. Therefore, care must be taken during thyroidectomy to leave some functioning parathyroid tissue. If the glands are totally removed, death will ensue because muscles, including the laryngeal and other respiratory muscles, go into tetanic contraction as the blood calcium level falls. PTH is an 84–amino acid linear peptide (Table 21.8). It binds to a specific PTH receptor on target cells that interacts with G protein to activate a second-messenger system. PTH release causes the level of calcium in the blood to increase. Simultaneously, it reduces the concentration of serum phosphate. Secretion of PTH is regulated by the serum calcium level through a simple feedback system. When parathyroid calcium-sensing receptors on principal cells detect low serum


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Histology_Ross. TABLE Parathyroid Hormone 21.8 Hormone Composition Source Major Functions Parathyroid hormone (PTH) Polypeptide containing 84 amino acids Principal (chief cells)a Increases blood calcium level in three ways: (1) promotes calcium release from bone (acting on osteoblasts via RANK-RANKL signaling system, it increases the relative number of osteoclasts); (2) acts on the kidney to stimulate calcium reabsorption by the distal tubule while inhibiting phos-phate reabsorption in the proximal tubule; and (3) increases formation of hormonally active 1,25-dihydroxycholecalciferol (1,25-(OH)2 vitamin D3) in the kidney, which promotes tubular reabsorption of calcium. aSome evidence suggests that oxyphil cells, which first appear in the parathyroid gland at about 4 to 7 years of age and increase in number after puberty, may also produce PTH.


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Histology_Ross. calcium levels, they stimulate secretion of PTH; high levels of serum calcium inhibit its secretion. PTH functions at several sites:  Action on bone tissue. For years, the bone resorption has been considered the major effect of PTH action on bone. However, the actions of PTH on bone are more complicated. PTH acts directly and indirectly on several cell types. Receptors for PTH are found on osteoprogenitor cells, osteoblasts, osteocytes, and bone lining cells. Surprisingly, the bone-resorbing osteoclasts do not have PTH receptors; thus, they are indirectly activated by the RANKRANKL signaling mechanism of osteoblasts (page 228). The binding of PTH to its receptors on osteoblasts increases local RANK production and decreases osteoprotegerin (OPG) secretion. These changes then stimulate osteoclast differentiation, which leads to increased bone resorption and release of calcium and phosphates into the extracellular fluid. PTH also has an anabolic effect on bone that leads to increased


Histology_Ross

Histology_Ross. differentiation, which leads to increased bone resorption and release of calcium and phosphates into the extracellular fluid. PTH also has an anabolic effect on bone that leads to increased bone mass; therefore, it is utilized in the treatment of osteoporosis (see Folder 8.2 in Chapter 8 on page 233).


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Histology_Ross.  Kidney excretion of calcium is decreased by PTH stimulation of tubular reabsorption, thus conserving calcium.  Urinary phosphate excretion is increased by PTH secretion, thus lowering phosphate concentration in the blood and extracellular fluids.  Kidney conversion of 25-OH vitamin D3 to hormonally active 1,25-(OH)2 vitamin D3 is regulated primarily by PTH, which stimulates activity of 1-hydroxylase and increases the production of active hormone.  Intestinal absorption of calcium is increased under the influence of PTH. Vitamin D3, however, has a greater effect than PTH on intestinal absorption of calcium. PTH and calcitonin have reciprocal effects in the regulation of blood calcium levels.


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Histology_Ross. PTH and calcitonin have reciprocal effects in the regulation of blood calcium levels. Although PTH increases blood calcium levels, the peak increase after its release is not reached for several hours. PTH appears to have a rather slow, long-term homeostatic action. Calcitonin, however, rapidly lowers blood calcium levels and has its peak effect in about 1 hour; therefore, it has a rapid, acute homeostatic action. The adrenal (suprarenal) glands secrete both steroid hormones and catecholamines. They have a flattened triangular shape and are embedded in the perirenal fat at the superior poles of the kidneys.


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Histology_Ross. The adrenal (suprarenal) glands secrete both steroid hormones and catecholamines. They have a flattened triangular shape and are embedded in the perirenal fat at the superior poles of the kidneys. The adrenal glands are covered with a thick connective tissue capsule from which trabeculae extend into the parenchyma, carrying blood vessels and nerves. The secretory parenchymal tissue is organized into two distinct regions (Fig. 21.18):  The cortex is the steroid-secreting portion. It lies beneath the capsule and constitutes nearly 90% of the gland by weight.  The medulla is the catecholamine-secreting portion. It lies deep to the cortex and forms the center of the gland. Parenchymal cells of the cortex and medulla are of different embryologic origin.


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Histology_Ross. Parenchymal cells of the cortex and medulla are of different embryologic origin. Embryologically, the cortical cells originate from mesodermal mesenchyme, whereas the medulla originates from neural crest cells that migrate into the developing gland (Fig. 21.19). Although embryologically distinct, the two portions of the adrenal gland are functionally related (see below). The parenchymal cells of the adrenal cortex are controlled in part by the anterior lobe of the pituitary gland and function in regulating metabolism and maintaining normal electrolyte balance (Table 21.9).


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Histology_Ross. The adrenal glands are supplied with blood by the superior, middle, and inferior suprarenal arteries. These vessels branch before entering the capsule, to produce many small arteries that penetrate the capsule. In the capsule, the arteries branch to give rise to three principal patterns of blood distribution (Figs. 21.20 and 21.21). The vessels form a system that consists of  capsular capillaries that supply the capsule. the cortex and then drain into the fenestrated medullary capillary sinusoids.  medullary arterioles that traverse the cortex, traveling within the trabeculae, and bring arterial blood to the medullary capillary sinusoids. sympathetic ganglion (from neural crest) cortical primordium aorta of fetal cortex chromaffin aorta cells of future medulla


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Histology_Ross. sympathetic ganglion (from neural crest) cortical primordium aorta of fetal cortex chromaffin aorta cells of future medulla FIGURE21.18 • Photomicrograph of the adrenal gland. This low-power micrograph of an H&E–stained specimen shows the full thickness of the adrenal gland with the cortex seen on both surfaces and a central region containing the medulla. Within the medulla are profiles of the central vein. Note that the deeper portion of the cortex stains darker than the outer portion, a reflection of the washed-out lipid in the zona glomerulosa and outer region of the zona fasciculata. This section also includes a cross section of the adrenal vein, which is characterized by the longitudinally arranged bundles of smooth muscle in its wall. 20.


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Histology_Ross. The medulla thus has a dual blood supply: arterial blood from the medullary arterioles and “venous” blood from the cortical sinusoidal capillaries that have already supplied the cortex. The venules that arise from the cortical and medullary sinusoids drain into the small adrenomedullary collecting veins that join to form the large central adrenomedullary vein, which then drains directly into the inferior vena cava on the right side and into the left renal vein on the left side. In humans, the central adrenomedullary vein and its tributaries are unusual in that they have a tunica media containing conspicuous, longitudinally oriented bundles of smooth muscle cells. Synchronous contraction of longitudinal smooth muscle bundles along the central adrenomedullary vein and its tributaries cause the volume of the adrenal gland to decrease. This volume decrease enhances the efflux of hormones from the adrenal medulla into the circulation, an action comparable to squeezing a wet sponge.


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Histology_Ross. Lymphatic vessels are present in the capsule and the connective tissue around the larger blood vessels in the gland. FIGURE21.19 • Development of the adrenal gland. a. In this early stage, the cortex is shown developing from cells of the intermediate mesoderm, and the medulla is shown differentiating from cells in the neural crest and migrating from the neighboring sympathetic ganglion. Note that the gland develops between the root of the dorsal mesentery of the primitive gut and the developing urogenital ridges. b. Mesodermal cells from the fetal cortex surround the cells of the developing medulla. c. At this stage (about 7 months of development), the fetal cortex occupies about 70% of the cortex. The permanent cortex develops outside the fetal cortex. d. The fully developed adrenal cortex is visible at the age of 4 months. The permanent cortex replaces the fetal cortex, which at this age has completely disappeared. Note the fully developed zonation of the permanent cortex.


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Histology_Ross. TABLE Hormones of the Adrenal Glands 21.9 Hormone Composition Source Major Functions Adrenal cortex Mineralocorticoids (95% of mineralocorticoid activity in aldosterone) Steriod hormones (cholesterol derivatives) Parenchymal cells of the zona glomerulosa Aid in controlling electrolyte homeostasis (act on distal tubule of kidney to increase sodium reabsorption and decrease potassium reabsorp-tion); function in maintaining the osmotic balance in the urine and in preventing serum acidosis Glucocorticoids (cortico -sterone, and cortisol; 95% of glucocorticoid activity in cortisol) Steriod hormones (cholesterol derivatives) Parenchymal cells of the zona fasciculata (and to a lesser extent of the zona reticularis) Promote normal metabolism, particularly carbohy-drate metabolism (increase rate of amino acid transport to live, promote removal of protein from skeletal muscle and its transport to liver, reduce rate of glucose metabolism by cells and stimulate glycogen synthesis by liver,


Histology_Ross

Histology_Ross. rate of amino acid transport to live, promote removal of protein from skeletal muscle and its transport to liver, reduce rate of glucose metabolism by cells and stimulate glycogen synthesis by liver, stimulate mobilization of fats from storage deposits for energy use); provide resistance to stress; suppress inflammatory response and some allergic reactions Gonadocorticoids (dehydroepiandrosterone [DHEA] is a major sex steroid produced in both men and women) Steriod hormones (cholesterol derivatives) Parenchymal cells of the zona reticularis (and to a lesser extent of the zona fasciculata) Induce weak masculinizing effect; at normal serum levels usually their function is insignificant Adrenal medulla Norepinephrine and epinephrine (in human, 80% epinephrine) Catecholamines (amino acid derivatives) Chromaffin cells Sympathomimetic (produce effects similar to those induced by the sympathetic division of the autonomic nervous system)a; increase heart rate, increase blood pressure, reduce


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Histology_Ross. Chromaffin cells Sympathomimetic (produce effects similar to those induced by the sympathetic division of the autonomic nervous system)a; increase heart rate, increase blood pressure, reduce blood flow to viscera and skin; stimulate conversion of glycogen to glucose; increase sweating; induce dilation of bronchioles; increase rate of respiration; decrease digestion; decrease enzyme production by digestive system glands; decrease urine production a The catecholamines influence the activity of glandular epithelium, cardiac muscle, and smooth muscle located in the walls of blood vessels and viscera.