Development of the thyroid gland

The thyroid gland (Greek thyreos, shield; eidos, form) develops as a median endodermal downgrowth at the base of the tongue. A transient structure, the thyroglossal duct, connects the developing gland to its point of origin, the foramen cecum, at the back of the tongue.

The thyroglossal duct disappears completely, leaving the thyroid to develop as a ductless gland. Persistent thyroglossal duct tissue remnants may give rise to cysts.

The thyroid gland responds to thyroid-stimulating hormone (TSH) at about week 22 in the fetus. The congenital absence of the thyroid gland causes irreversible neurologic damage in the infant (cretinism).

The thyroid gland consists of two lobes connected by a narrow band of thyroid tissue called the isthmus.

The thyroid gland is located below the larynx and the lobes rest on the sides of the trachea. The larynx provides a convenient landmark for locating the thyroid gland. The thyroid gland is surrounded by a double connective tissue capsule. Two pairs of parathyroid glands are located on the posterior surface of the thyroid gland, between or outside the two capsules.

Histologic organization of the thyroid gland

Each lobe of the thyroid gland consists of numerous follicles. The thyroid follicle, or acinus, is the structural and functional unit of the gland. It consists of a single layer of cuboidal epithelial cells, the follicular epithelium (Figures 19-1 and 19-2), enclosing a central lumen containing a colloid substance rich in thyroglobulin, an iodinated glycoprotein, yielding a periodic acid–Schiff (PAS)–positive reaction.

Figure 19-1 Histology of the thyroid gland

Figure 19-2 Structure of the thyroid follicular cells

The follicular epithelium also contains about 10% of scattered parafollicular cells, also called C cells. C cells, derived from the neural crest, contain small cytoplasmic granules representing the stored hormone calcitonin (hence the designation C cells).

When the thyroid gland is hypoactive, as in dietary iodide deficiency, the follicle is enlarged with colloid. Because no triiodothyronine (T₃) or thyroxine (T₄) is made to exert a negative feedback, TSH synthesis and secretion increase. TSH stimulates growth and vascularization of the thyroid gland. Consequently, the gland enlarges.

When the thyroid gland is active, the follicular epithelium is columnar, and colloid droplets may be seen within the cells as well as large apical pseudopodia and microvilli (see Figure 19-2).

The thyroid epithelium is surrounded by a basal lamina and reticular fibers. A network of vasomotor and sympathetic nerve fibers and blood vessels, including fenestrated capillaries, can be observed in the connective tissue among thyroid follicles.

Function of the thyroid gland

In contrast to other endocrine organs, which have a limited storage capacity, the production of thyroid hormones depends on the follicular storage of the prohormone thyroglobulin in the colloid.

A characteristic feature of the thyroid follicular epithelium is its ability to concentrate iodide from the blood and synthesize the hormones thyroxine and triiodothyronine.

The synthesis and secretion of thyroid hormones involve two phases (Figure 19-3): (1) an exocrine phase and (2) an endocrine phase.

Figure 19-3 Synthesis and secretion of thyroid hormones T₃ and T₄

Both phases are regulated by TSH by a mechanism that includes receptor binding and cyclic adenosine monophosphate (cAMP) production, as discussed in Chapter 3, Cell Signaling.

The exocrine phase (see Figure 19-3) consists of (1) the uptake of inorganic iodide from the blood, (2) the synthesis of thyroglobulin, and (3) the incorporation of iodine into tyrosyl residues of thyroglobulin by thyroid peroxidase.

The uptake of iodide requires an adenosine triphosphate (ATP)–driven iodide pump present in the basal plasma membrane of the follicular cells. This active transport system is referred to as the iodide trap. Intracellular iodide rapidly diffuses against both its concentration and electrical gradients to end up extracellularly in the colloid. Anions, such as perchlorate (ClO₄⁻), are used clinically as a competitive inhibitor of the iodide pump to block iodide uptake by the thyroid follicular cell.

The rough endoplasmic reticulum and Golgi apparatus are sites involved in the synthesis and glycosylation of thyroglobulin, a 660-kd glycoprotein composed of two identical subunits. Thyroglobulin is packed in secretory vesicles and released by exocytosis into the colloidal lumen. Thyroglobulin contains about 140 tyrosine residues available for iodination.

Thyroid peroxidase, the enzyme responsible for the iodination of thyroglobulin, is a heme-containing glycoprotein anchored in the membrane of the same secretory vesicle that contains thyroglobulin. After exocytosis, thyroid peroxidase is exposed at the luminal surface of the thyroid cell.

Thyroid peroxidase is activated during exocytosis. Activated thyroid peroxidase oxidizes iodide to iodine within the colloid; the iodine is then transferred to acceptor tyrosyl residues of thyroglobulin. Thyroid peroxidase activity and the iodination process can be inhibited by propylthiouracil and methyl mercaptoimidazole (MMI). These antithyroid drugs are used to inhibit the production of thyroid hormones by hyperactive glands.

The endocrine phase starts with the TSH-stimulated endocytosis of iodinated thyroglobulin into the follicular cell (see Figure 19-3):

T₃ has a shorter half-life (18 hours), is more potent, and less abundant than T₄. The half-life of T₄ is 5 to 7 days and represents about 90% of the secreted thyroid hormones.

Thyroid hormones increase the basal metabolic rate. The primary site of action of T₃, and to a lesser extent T₄, is the cell nucleus. T₃ binds to thyroid hormone receptor bound to a specific DNA region, called thyroid hormone–responsive element (TRE), to induce specific gene transcription. In cardiocytes (heart), thyroid hormone regulates the expression of genes encoding phospholamban in the sarcoplasmic reticulum, β-adrenergic receptors, Ca²⁺-ATPase, and others. In the absence of T₃, unoccupied nuclear receptors bound to the TRE repress genes that are positively regulated by thyroid hormone.

Clinical significance: Hyperthyroidism (Graves’ disease) and hypothyroidism

Graves’ disease is an autoimmune disease in which the thyroid gland is hyperfunctional (Figure 19-4). Autoantibodies (called thyroid-stimulating immunoglobulins or TSIs), produced by plasma cells derived from sensitized T cells against TSH receptors present at the basal surface of thyroid follicular cells, bind to the receptor and mimic the effect of TSH, stimulating cAMP production.

Figure 19-4 Graves’ disease: Unregulated synthesis and secretion of thyroid hormones T₃ and T₄

As a result, thyroid follicular cells become columnar and secrete large amounts of thyroid hormones in the blood circulation in an unregulated fashion. Enlargement of the thyroid gland (goiter), bulging of the eyes (exophthalmos; see Figure 19-4), tachycardia, warm skin, and fine finger tremors are typical clinical features.

In the adult, hypothyroidism is generally caused by a thyroid disease, and a decrease in the basal metabolic rate, hypothermia, and cold intolerance are observed. Decreased sweating and cutaneous vasoconstriction make the skin dry and cool. Afflicted individuals tend to feel cold in a warm room. In the adult, hypothyroidism is manifested by coarse skin with a puffy appearance due to the accumulation of proteoglycans and retention of fluid in the dermis of the skin (myxedema) and muscle. Cardiac output is reduced, and the pulse rate slows down. Except for developmental disturbances, most symptoms are reversed when the thyroid disorder is corrected.

In the fetus, a lack of thyroid hormone causes cretinism. This condition is observed in iodide-deficient geographic areas. The symptoms of hypothyroidism in newborns can include respiratory distress syndrome, poor feeding, umbilical hernia, and retarded bone growth. Untreated hypothyroidism in children results in mental retardation.

Hashimoto’s disease is an autoimmune disease associated with hypothyroidism.

It is caused by autoantibodies targeted to thyroid peroxidase and thyroglobulin. Antibodies to thyroid peroxidase are known as antimicrosomal antibodies. A progressive destruction of the thyroid follicles leads to a decrease in the function of the thyroid gland.

Calcium regulation

Ca²⁺ is found inside and outside cells, is a major component of the skeleton, is required for muscle contraction, blood clotting, nerve impulse transmission, and enzymatic activities. Ca²⁺ is an essential mediator in cell signaling (for example, through calcium-binding calmodulin).

The maintenance of Ca²⁺ homeostasis is regulated by (1) parathyroid hormone, (2) calcitonin, and (3) vitamin D (calcitriol, or 1,25-dihydroxycholecalciferol).

Parathyroid hormone acts on bone and the kidneys to raise Ca²⁺ levels in serum. Calcitonin, secreted by C cells in the thyroid follicle, lowers Ca²⁺ levels. Vitamin D is produced in the kidneys and increases the intestinal absorption of Ca²⁺ by stimulating synthesis of Ca²⁺-binding protein by intestinal epithelial cells (enterocytes). These two aspects will be discussed later in this chapter.

Development of the parathyroid glands

The four parathyroid glands derive from the third and fourth branchial pouches. The third branchial pouch differentiates into the inferior parathyroid glands and the thymus. The fourth branchial pouch develops into the superior parathyroid glands and the ultimobranchial body.

Parathyroid glands are found on the posterior surface of the thyroid gland, between its capsule and the surrounding cervical connective tissue. In addition to the four parathyroid glands, accessory glands may be found in the mediastinum or in the neck.

The accidental removal of the normal parathyroid glands during thyroid surgery (thyroidectomy) causes tetany, characterized by spasms of the thoracic and laryngeal muscles, leading to asphyxia and death.

Histologic organization of the parathyroid glands

The parenchyma of the parathyroid glands consists of two cell populations supplied by sinusoidal capillaries (Figure 19-5): (1) the more numerous chief or principal cell, and (2) the oxyphil or acidophilic cell. Cells are arranged in cordlike or follicular-like clusters.

Figure 19-5 Structure and function of the parathyroid gland

Chief or principal cells contain cytoplasmic granules with parathyroid hormone, an 84-amino-acid peptide derived from a large precursor of 115 amino acids (preproparathyroid hormone). This precursor gives rise to proparathyroid hormone (90 amino acids), which is processed by a proteolytic enzyme in the Golgi apparatus into parathyroid hormone. Parathyroid hormone is stored in secretory granules. Glycogen inclusions are also observed in chief cells.

The Ca²⁺-sensing receptor (CaSR) is associated to G protein in the plasma membrane of chief cells. Serum Ca²⁺ binding to the extracellular region of the CaSR triggers the release of intracellular signals suppressing the secretion of parathyroid hormone, with the consequent decrease in the serum Ca²⁺ concentration. When the serum Ca²⁺ concentration decreases, the secretion of parathyroid hormone is stimulated, resulting in an increase in serum Ca²⁺. In most cells, Ca²⁺ enters a cell through a membrane-associated channel. Chief parathyroid cells are rather unusual because Ca²⁺ is a ligand for the CaSR resulting in the activation of G protein.

Oxyphil or acidophilic cells contain abundant mitochondria, which give this cell its typical stain. This cell type may represent transitional chief cells.

Function of the parathyroid hormone

Parathyroid hormone regulates the Ca²⁺ and PO₄^3- balance in blood by acting on two main sites:

An increase in serum Ca²⁺ levels (hypercalcemia) suppresses the release of parathyroid hormone from chief cells. A decrease in Ca²⁺ levels (hypocalcemia) stimulates parathyroid hormone release by chief cells.

When Ca²⁺ levels are low, parathyroid hormone reestablishes homeostasis by acting on osteoblasts, which induce osteoclasts to reabsorb bone.

Parathyroid hormone binds to a cell surface receptor of the osteoblast to regulate the synthesis of three proteins essential for the differentiation and function of osteoclasts (Figure 19-6; see also the discussion of osteoclasts in Chapter 4, Connective Tissue):

Figure 19-6 Parathyroid hormone regulates osteoclastogenesis

You should be aware that RANKL not only regulates osteoclastogenesis but also is expressed by dendritic cells, T and B cells, components of the immune system. This is an important consideration in anti-RANKL treatment of some forms of osteoporosis, as discussed under Bone in Chapter 4, Connective Tissue.

Clinical significance: Hyperparathyroidism, hypoparathyroidism, and CaSR mutations

Hyperparathyroidism is caused by a functional benign tumor of the gland (adenoma). An abnormal increase in the secretion of parathyroid hormone causes:

Inactivating mutations of one allele of the CaSR prevent parathyroid chief cells to sense increases in serum Ca²⁺, which results in an increase of parathyroid hormone secretion. This condition, called familial benign hypercalcemia, can be severe when two inactivated CaSR alleles exist. This condition, detected in newborns, requires immediate parathyroidectomy.

Idiopathic hypoparathyroidism results in a failure of tissues to respond to parathyroid hormone. An activating mutation of the CaSR leads the parathyroid gland into assuming that the Ca²⁺ serum level is elevated when it is not. This condition determines a reduction in serum Ca²⁺ and parathyroid hormone levels.

CaSR can also be a target of autoimmunity and either activate (causing hypoparathyroidism) or inactivate the CaSR (causing a syndrome similar to familial benign hypercalcemia). Calcimimetic drugs, which activate CaSR, reduce pathologic elevations of parathyroid hormone. CaSR-blocking drugs, called calcilytics, may be useful for the treatment of osteoporosis.

Clinical significance: Multiple endocrine neoplasia syndrome

Tumors of C cells (medullary carcinoma of the thyroid gland) result in excessive production of calcitonin. However, calcium levels in serum are normal, with no apparent bone damage.

The presence of a calcitonin-producing tumor of the thyroid gland may be associated with pheochromocytoma, a tumor of the adrenal medulla (multiple endocrine neoplasia [MEN] syndrome).

Clinical significance: Rickets and osteomalacia

In children, a deficiency of vitamin D causes rickets. In adults, the corresponding clinical condition is osteomalacia. The calcification of the bone matrix osteoid is deficient in both conditions.

In rickets, bone remodeling is defective. The ends of the bones bulge (rachitic rosary at the costochondral junctions), and poor calcification of the long bones causes bending (bowlegs or knock-knees).

In osteomalacia, pain, partial bone fractures, and muscular weaknesses are typical in the adult.

Chronic renal failure or a congenital disorder—resulting in the lack of lα-hydroxylase—can also cause rickets or osteomalacia.

Hypercalcemia is frequently found in patients with metastasis causing bone destruction or in patients with tumors secreting a parathyroid hormone–related peptide.

Development of the adrenal gland

During the fifth week of fetal development, proliferating mesothelium-derived cells infiltrate the retroperitoneal mesenchyme at the cranial end of the mesonephros and give rise to the primitive adrenal cortex. A second proliferation of mesothelial-derived cells surrounds the primitive cortex and forms the cortex of the future adult gland.

At the seventh week of development, the mesothelial cellular mass is invaded at its medial region by neural crest–derived chromaffinoblast cells, which differentiate into the two classes of chromaffin cells of the adrenal medulla. The adrenal medulla is homologous to a diffuse sympathetic ganglion without postganglionic processes.

Mesenchymal cells surrounding the fetal cortex differentiate into fibroblasts and form the capsule of the adrenal gland. At this time, blood vessels and nerves of the adrenal gland develop.

At the end of fetal life, the adrenal glands are relatively larger than they are in the adult. At birth, the zonae glomerulosa and fasciculata are developed under the control of adrenocorticotropic hormone (ACTH) secreted by the fetal pituitary gland. The fetal cortex regresses, disappears within the first year of life, and is replaced by the definitive cortex.

Ectopic adrenocortical or medullary tissue may be found retroperitoneally, inferior to the kidneys, along the aorta, and in the pelvis. Aggregates of ectopic chromaffin cells, called paraganglia, can be a site of tumor growth (pheochromocytoma).

Functions of the fetal adrenal cortex

During the early stage of gestation, the adrenal cortex synthesizes dehydroepiandrosterone, a precursor of the synthesis of estrogen by the placenta. A lack of 3β-hydroxysteroid dehydrogenase activity prevents the synthesis of progesterone, glucocorticoids, and androstenedione. The interaction between the fetal adrenal cortex and the placenta is known as the fetoplacental unit (see Chapter 23, Fertilization, Placentation, and Lactation).

Glucocorticoids, either of maternal origin or synthesized from placental progesterone by the fetus, are essential for three main developmental events: (1) the production of surfactant by type II alveolar cells after the eighth month of fetal life; (2) the development of a functional hypothalamopituitary axis; and (3) the induction of thymic involution.

Histologic organization of the adrenal cortex

The adrenal glands (Latin ad, near; ren, kidney) are associated with the superior poles of the kidneys. Each gland consists of a yellowish outer cortex (80% to 90% of the gland) and a reddish inner medulla (10% to 20%). The adrenal cortex is of mesodermal origin and produces steroid hormones. The adrenal medulla is of neuroectodermic origin and produces catecholamines.

The adrenal cortex consists of three concentric zones (Figures 19-9 and 19-10). (1) The outermost layer of the cortex is the zona glomerulosa. (2) The middle layer of the cortex is the zona fasciculata. (3) The innermost layer of the cortex is the zona reticularis.

Figure 19-9 Histologic organization of the adrenal gland

Figure 19-10 Fine structure of steroid-producing cells of the adrenal cortex (zona fasciculata)

Cells of the zona glomerulosa produce the mineralocorticoid aldosterone (Figures 19-11 and 19-12). Although the zona fasciculata is often associated with glucocorticoid production—mainly cortisol—and the zona reticularis with androgen production, the functional distinctions between the two layers are not precise and they appear as a functional unit. In addition, these two layers are stimulated by corticotropin (ACTH), whereas the zona glomerulosa is primarily angiotensin II–dependent. Angiotensin II stimulates both the growth of the zona glomerulosa and the synthesis of aldosterone (see Figure 19-12).

Figure 19-11 Fine structure of steroid-producing cells of the adrenal cortex (zona reticularis)

Figure 19-12 Steroidogenic pathway

Angiotensin II is an octapeptide derived from the conversion of the angiotensin I decapeptide in the pulmonary circulation by angiotensin-converting enzyme (see Chapter 14, Urinary System). Aldosterone has a half-life of 20 to 30 minutes and acts directly on the distal convoluted tubule and collecting tubule, where it increases Na⁺ reabsorption and excretion of K⁺.

The zona glomerulosa (Latin glomus, ball) has the following characteristics (see Figure 19-9): (1) it lies under the capsule; (2) it represents 10% to 15% of the cortex; (3) its cells aggregate into a glomerulus-like arrangement and have a moderate amount of lipid droplets in the cytoplasm; and (4) it lacks the enzyme 17α-hydroxylase and, therefore, cannot produce cortisol or sex steroids.

During aldosterone action, aldosterone binds to intracellular receptor proteins to activate transcription factors that enhance the expression of specific genes. Aldosterone-responsive cells do not respond to the glucocorticoid cortisol because cortisol is converted to cortisone by the enzyme 11β-hydroxysteroid dehydrogenase and cortisone does not bind to the aldosterone receptor.

Aldosterone stimulates the retention of Na⁺ in the kidneys, the retention of water (as a consequence of Na⁺ reabsorption), and renal secretion of K⁺ and H⁺.

The zona fasciculata (Latin fascis, bundle) makes up 75% of the cortex. It is formed by cuboid cells, with the structural features of steroid-producing cells (see Figure 19-10), arranged in longitudinal cords separated by cortical fenestrated capillaries, or sinusoids (see Figure 19-11).

The cytoplasm of zona fasciculata cells shows three components that characterize their steroidogenic function: (1) the steroid hormone precursor cholesterol stored in abundant lipid droplets (see Figure 19-11); when lipids are extracted during histologic preparation or are unstained by the standard hematoxylin-eosin (H&E) procedures, the cells of the zona fasciculata display a foamy appearance and are called spongiocytes; (2) mitochondria with tubular cristae containing steroidogenic enzymes; and (3) well-developed smooth endoplasmic reticulum, also with enzymes involved in the synthesis of steroid hormones (see Figure 19-11).

Cells of the zona fasciculata and zona reticularis cannot produce aldosterone but contain 17α –hydroxylase necessary for the production of glucocorticoids—cortisol—and cortisol—and the enzyme 17, 20-hydroxylase, required for the production of sex hormones.

Cortisol is not stored in cells and new synthesis, stimulated by ACTH, is required for achieving a hormonal increase in blood circulation. Cortisol is converted in hepatocytes to cortisone.

Cortisol has two major effects: (1) A metabolic effect: Cortisol’s effects are opposite to those of insulin. In the liver, cortisol stimulates gluconeogenesis to increase the concentration of glucose in blood. (2) An anti-inflammatory effect: Cortisol suppresses tissue responses to injury and decreases cellular and humoral immunity.

The zona reticularis (Latin rete, net) makes up 5% to 10% of the cortex. Cells of the zona reticularis form an anastomosing network of short cellular cords separated by fenestrated capillaries.

The cells of this zone are acidophilic, due to abundant lysosomes, large lipofuscin granules, and fewer lipid droplets (see Figure 19-11). Although cells of the zona fasciculata can synthesize androgens, the primary site of adrenal sex hormone production is the zona reticularis. Dehydroepiandrosterone (DHEA) and androstenedione are the predominant androgens produced by the cortex of the adrenal gland (see Figures 19-12 and 19-13). DHEA sulfate is synthesized in the zona reticularis.

Figure 19-13 Synthesis of steroids in the adrenal cortex

Although DHEA and androstenedione are weak androgens, they can be converted to testosterone and even to estrogen in peripheral tissues. The adrenal gland is the major source of androgens in women; these androgens stimulate the growth of pubic and axillary hair during puberty.

Adrenal medulla

The adrenal medulla contains chromaffin cells, so named because of their ability to acquire a brown coloration when exposed to an aqueous solution of potassium dichromate. This reaction is due to the oxidation of catecholamines by chrome salts to produce a brown pigment.

Chromaffin cells (Figure 19-14) are modified sympathetic postganglionic neurons—without postganglionic processes—derived from the neural crest and forming epithelioid cords surrounded by fenestrated capillaries. The cytoplasm of chromaffin cells contains membrane-bound dense granules consisting in part of matrix proteins, called chromogranins, and one class of catecholamine, either epinephrine or norepinephrine (adrenaline or noradrenaline). Some granules contain both epinephrine and norepinephrine. Minimal secretion of dopamine also occurs, but the role of adrenal dopamine is not known.

Figure 19-14 Synthesis of catecholamines

Catecholamines are secreted into the blood instead of being secreted into a synapse, as in postganglionic terminals. The adrenal medulla is innervated by sympathetic preganglionic fibers that release acetylcholine.

Two different chromaffin cell types are present. About 80% of the cells produce epinephrine and 20% synthesize norepinephrine. These two cell populations can be distinguished at the electron microscope level by the morphology of the membrane-bound granules. Norepinephrine is stored in granules with a dense eccentric core. Epinephrine-containing granules are smaller and occupy the less dense central core. Note an important difference with cells of the adrenal cortex: cells from the adrenal cortex do not store their steroid hormones in granules.

Catecholamines are synthesized from tyrosine to DOPA (3,4-dihydroxyphenylalanine) in the presence of tyrosine hydroxylase (see Figure 19-14). DOPA is converted to dopamine by DOPA decarboxylase. Dopamine is transported into existing granules and converted inside them by dopamine β-hydroxylase to norepinephrine. The membrane of the granules contains the enzymes required for catecholamine synthesis and ATP-driven pumps for the transport of substrates.

Once synthesized, norepinephrine leaves the granule to enter the cytosol, where it is converted to epinephrine in a reaction driven by the enzyme phenylethanolamine N-methyltransferase (PNMT). The synthesis of PNMT is induced by glucocorticoids transported from the cortex to the medulla by the adrenocortical capillary system. When the conversion step to epinephrine is completed, epinephrine moves back to the membrane-bound granule for storage.

The degradation of catecholamines in the presence of the enzymes monoamine oxidase (MAO) and catechol O-methyltransferase (COMT) yields the main degradation products vanillylmandelic acid (VMA) and metanephrine, which are eliminated in urine. Urinary VMA and metanephrine are used clinically to determine the level of catecholamine production in a patient.

Actions of catecholamines are mediated by α and β adrenergic receptors

Catecholamines bind to α- and β-adrenergic receptors in target cells. There are α₁-, α₂-, β₁-, and β₂-adrenergic receptors. Epinephrine has greater binding affinity for β₂-adrenergic receptors than norepinephrine. Both hormones have similar binding affinity for β₁-, α₁-, and α₂-adrenergic receptors.

The stimulation of α-adrenergic receptors of blood vessels causes vasoconstriction. In blood vessels of skeletal muscle, activation of β2-adrenergic receptors causes vasodilation. Epinephrine acting through α-adrenergic receptors causes vasoconstriction, but when it activates β-adrenergic receptors in skeletal muscle it causes vasodilation. The adrenergic receptors of the cardiac muscle are β₁-adrenergic receptors, and both epinephrine and norepinephrine have comparable effects.

Blood supply to the adrenal gland

Similar to all endocrine organs, the adrenal glands are highly vascularized. Arterial blood derives from three different sources (Figure 19-15): (1) the inferior phrenic artery, which gives rise to the superior adrenal artery; (2) the aorta, from which the middle adrenal artery branches out; and (3) the renal artery, which gives rise to the inferior adrenal artery.

Figure 19-15 Blood supply to the adrenal gland

All three adrenal arteries enter the adrenal gland capsule and form an arterial plexus. Three sets of branches emerge from the plexus: (1) One set supplies the capsule. (2) The second set enters the cortex forming straight fenestrated capillaries (also called sinusoids), percolating between the zonae glomerulosa and fasciculata, and forming a capillary network in the zona reticularis before entering the medulla. (3) The third set generates medullary arteries traveling along connective tissue trabeculae of the cortex without branching and supplying blood only to the medulla.

This blood vessel distribution results in (1) dual blood supply to the adrenal medulla; (2) the transport of cortisol to the medulla, necessary for the synthesis of PNMT and required for the conversion of norepinephrine to epinephrine; and (3) the supply of fresh blood to the adrenal medulla, required for rapid responses to stress.

There are no veins or lymphatics in the adrenal cortex. The adrenal cortex and medulla are drained by the central vein, present in the adrenal medulla.

Clinical significance: Abnormal secretory activity of the adrenal cortex

Zona glomerulosa: A tumor localized in the zona glomerulosa can cause excessive secretion of aldosterone. This rare condition is known as primary aldosteronism, or Conn’s syndrome. A more common cause of hyperaldosteronism is an increase in renin secretion (secondary hyperaldosteronism).

Zona fasciculata: An increase in aldosterone, cortisol, and adrenal androgen production—secondary to ACTH production—occurs in Cushing’s disease. Cushing’s disease is caused by an ACTH-producing tumor of the anterior hypophysis. A functional tumor of the adrenal cortex can also result in overproduction of cortisol, as well as of aldosterone and adrenal androgens. This clinical condition is described as Cushing’s syndrome (as opposed to Cushing’s disease). The symptoms of Cushing’s syndrome reflect the multiple actions of glucocorticoids, in particular, on the carbohydrate metabolism. Cortisol’s effects are opposite to those of insulin.

Zona reticularis: When compared with the gonads, the zona reticularis secretes insignificant amounts of androgens. Androgen hypersecretion becomes important when there is an adrenal disorder resulting in reproductive abnormalities.

An acute destruction of the adrenal gland by meningococcal septicemia in infants is the cause of Waterhouse-Friderichsen syndrome. A chronic destruction of the adrenal cortex by an autoimmune process or tuberculosis results in the classic Addison’s disease. In Addison’s disease, ACTH secretion increases because of the cortisol deficiency. ACTH can cause an increase in skin pigmentation, in particular in the skin folds and gums. The loss of mineralocorticoids leads to hypotension and circulatory shock. A loss of cortisol decreases vasopressive responses to catecholamines and leads to an eventual drop in peripheral resistance, thereby contributing to hypotension. A deficiency in cortisol causes muscle weakness (asthenia).

Clinical significance: Hypersecretory activity of the adrenal medulla

Tumors of the adrenal medulla (pheochromocytomas) cause sustained or episodic hypertension. When pheochromocytomas are associated with other endocrine tumors, they are a component of the multiple endocrine neoplasia (MEN) syndrome. The presence of large amounts of VMA in urine has diagnostic relevance.

Clinical significance: Congenital adrenal hyperplasia

Congenital adrenal hyperplasia is a familial inherited condition in which a mutation in the gene encoding steroidogenic acute regulatory protein (StAR), causes a deficiency in adrenocortical and gonadal steroidogenesis. StAR regulates the synthesis of steroids by transporting cholesterol across the outer mitochondrial membrane. A steroidogenic deficiency increases ACTH secretion, leading to adrenal hyperplasia.

Adrenal hyperplasia is seen in individuals with a deficiency of the enzyme 21-hydroxylase who cannot produce cortisol or mineralocorticoids. These individuals are hypotensive because of a difficulty in retaining salt and maintaining extracellular volume. A deficiency in the enzyme 11-hydroxylase (CYP11) results in the synthesis and accumulation of the mineralocorticoid deoxycorticosterone (DOC). Patients with this deficiency retain salt and water and become hypertensive.

See Figure 19-12 for the roles of 21-hydroxylase (CYP21) and 11-hydroxylase (CYP11) in the synthesis of cortisol and mineralocorticoids.

Development of the pancreas

By week 4, two outpocketings from the endodermal lining of the duodenum develop as the ventral and dorsal pancreas, each with its own duct. The ventral pancreas forms the head of the pancreas and associates with the common bile duct. The dorsal pancreas forms part of the head, body, and tail of the pancreas. By week 12, pancreatic acini develop from the ducts. The endocrine pancreas develops at the same time as the exocrine pancreas. Endocrine cells are first observed along the base of the differentiating exocrine acini by weeks 12 to 16.

Islets of Langerhans

The pancreas has two portions (Figures 19-16 and 19-17):

Figure 19-16 Blood supply to the islets of Langerhans and cell distribution

Figure 19-17 Islet of Langerhans

Each islet of Langerhans is formed by two components:

An independent vascular system, the acinar vascular system, supplies blood directly to the exocrine pancreatic acini.

A cells (α cells) produce glucagon, beta cells synthesize insulin, delta cells secrete gastrin and somatostatin, and F cells produce pancreatic polypeptide.

Glucagon, a 29-amino-acid peptide, is stored in granules that are released by exocytosis when there is a decrease in the plasma levels of glucose. Glucagon increases glucose blood levels by increasing hepatic glycogenolysis. Glucagon binds to a specific membrane-bound receptor and this binding results in the synthesis of cAMP.

B cells (β cells) produce insulin, a 6-kd polypeptide consisting of two chains (Figure 19-18): (1) chain A, with 21 amino acids; and (2) chain B, with 30 amino acids. Chains A and B are linked by disulfide bonds.

Figure 19-18 Synthesis and secretion of insulin by B cells of an islet of Langerhans

Insulin derives from a large single-chain precursor, preproinsulin, encoded by a gene located on the short arm of chromosome 11. Preproinsulin is synthesized in the rough endoplasmic reticulum and is processed in the Golgi apparatus.

The large precursor gives rise to proinsulin (9 kd; 86 amino acids) in which C peptide connects A and B chains. Removal of C peptide by specific proteases results in (1) the separation of chains A and B and (2) the organization of a crystalline core consisting of a hexamer and zinc atoms. C peptide surrounds the crystalline core.

An increase in blood glucose stimulates the release of both insulin and C peptide stored in secretory granules. Glucose is taken up by B cells by an insulin-independent, glucose transporter protein-2 (GLUT-2), and stored insulin is released in a Ca²⁺ — dependent manner.

If glucose levels remain high, new synthesis of insulin occurs. GLUT-2 is also present in hepatocytes. Insulin is required for increasing the transport of glucose in cells (predominantly in hepatocytes, skeletal and cardiac muscle, fibroblasts, and adipocytes). This is accomplished by (1) the transmembrane transport of glucose and amino acids, (2) the formation of glycogen in hepatocytes and skeletal and cardiac muscle cells, and (3) the conversion of glucose to triglycérides in adipose cells (Figure 19-19).

Figure 19-19 Adipose cell, lipid storage, and insulin

Insulin initiates its effect by binding to the α sub unit of its receptor. The insulin receptor consists of two subunits, α and β. The intracellular domain of the β subunit has tyrosine kinase activity, which autophosphorylates and triggers a number of intracellular responses. One of these responses is the translocation of glucose transporter protein-4 (GLUT-4) from the Golgi apparatus to the plasma membrane to facilitate the uptake of glucose. GLUT-4 is insulin-dependent and is present in adipocytes and skeletal and cardiac muscle.

Note the functional difference between GLUT-2 and GLUT-4: (1) GLUT-2 is insulin-independent and serves to transport glucose to insular B cells and hepatocytes; (2) GLUT-4 is insulin-dependent and serves to remove glucose from blood.

A (α) cells produce glucagon, a 29-amino-acid peptide (3.5 kd) derived from a large precursor, preproglucagon, encoded by a gene present on chromosome 2. In addition to the pancreas, glucagon can be found in the gastrointestinal tract (enteroglucagon) and brain. About 30% to 40% of glucagon in blood derives from the pancreas; the remainder comes from the gastrointestinal tract. Circulating glucagon, of pancreatic and gastrointestinal origin, is transported to the liver and about 80% is degraded before reaching the systemic circulation. The liver is the primary target site of glucagon. Glucagon induces hyperglycemia by its glycogenolytic activity in hepatocytes.

Neither C peptide nor zinc is present in glucagon-containing secretory granules.

The actions of glucagon are antagonistic to those of insulin. The secretion of glucagon is stimulated by (1) a fall in the concentration of glucose in blood, (2) an increase of arginine and alanine in serum, and (3) stimulation of the sympathetic nervous system.

D (δ) cells produce gastrin (see discussion of enteroendocrine cells in Chapter 15, Upper Digestive Segment) and somatostatin. Somatostatin is a 14 amino-acid peptide identical to somatostatin produced in the hypothalamus. Somatostatin inhibits the release of insulin and glucagon in a paracrine manner.

Somatostatin also inhibits the secretion of HCl by parietal cells of the fundic stomach, the release of gastrin from enteroendocrine cells, the secretion of pancreatic bicarbonate and enzymes, and the contraction of the gallbladder. Somatostatin is also produced in the hypothalamus and inhibits the secretion of growth hormone from the anterior hypophysis.

Pancreatic polypeptide is a 36-amino-acid peptide that inhibits the secretion of somatostatin. Pancreatic polypeptide also inhibits the secretion of pancreatic enzymes and blocks the secretion of bile by inhibiting contraction of the gallbladder. Its function is to conserve digestive enzymes and bile between meals. Cholecystokinin stimulates the release of pancreatic polypeptide.

Cell types in the islets of Langerhans can be identified by (1) immunocytochemistry, using antibodies specific for each cell product; (2) electron microscopy, to distinguish the size and structure of the secretory granules; and (3) the cell distribution in the islet. B cells are centrally located (core distribution) and surrounded by the other cell types (mantle distribution; see Figure 19-16).

Clinical significance: ATP-sensitive K+ channel and insulin secretion

The ATP-sensitive potassium (K_ATP) channel, a complex of the sulfonylurea receptor 1 (SUR1) and the inward-rectifying K+ channel (Kir6.2) subunits, is the key regulator of insulin release. SUR1 is encoded by the KCNJ11 (potassium channel J member 11) gene. Kir6.2 is encoded by the ABCC8 (ATP-binding cassette, subfamily C, member 8) gene.

K_ATP channel modulates the influx of Ca²⁺ through voltage-gated Ca²⁺ channels. In the normal resting state, the K_ATP channel is open and the voltage-gated Ca²⁺ channel remains closed. No insulin is secreted. When glucose is taken up by B cells by GLUT-2, the K_ATP channel closes utilizing ATP derived from glucose metabolism. K+ accumulates in the cell, the Ca²⁺ channel opens by membrane depolarization, and the influx of Ca²⁺ triggers insulin exocytosis (see Figure 19-18).

The clinical significance of this mechanism is highlighted by mutations in SUR1 and Kir6.2 genes. Gain-of-function mutations of SUR1 and Kir6.2 cause K_ATP channels to remain open, thereby decreasing insulin secretion and leading to neonatal diabetes mellitus. Loss-of-function mutations of SUR1 and Kir6.2 genes cause K_ATP channels to remain closed, thereby causing unregulated secretion of insulin leading to neonatal hyperinsulinemic hypoglycemia.

Clinical significance: Insulin and diabetes

When blood glucose levels rise in a normal person, the immediate release of insulin ensures a return to normal levels within 1 hour. In a diabetic individual, increased blood glucose levels (hyperglycemia) remain high for a prolonged period of time.

Hyperglycemia can be the result of the following (Figure 19-20):

Figure 19-20 Diabetes mellitus: Clinical forms

The symptoms and consequences of type 1 and type 2 diabetes are generally similar. Hyperglycemia, polyuria (increased frequency of micturition and urine volume), and polydipsia (sensation of thirst and increased fluid intake) are the three characteristic symptoms. The clinical forms of diabetes mellitus are summarized in Figure 19-20. The late complications of diabetes mellitus are summarized in Figure 19-21.

Figure 19-21 Clinical aspects of types 1 and 2 diabetes: Late complications

Concept mapping

Endocrine System