Endocrine Anatomy and Physiology

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Chapter 31

Endocrine Anatomy and Physiology

Mary E. Lough

Maintaining dynamic equilibrium among the various cells, tissues, organs, and systems of the human body is a highly complex and specialized process. Two systems regulate these critical relationships: the nervous system and the endocrine system. The nervous system communicates by nerve impulses that control skeletal muscle, smooth muscle tissue, and cardiac muscle tissue. The endocrine system controls and communicates by distributing potent hormones throughout the body. Figure 31-1 lists the endocrine glands and their hormones, target tissues, and actions. When stimulated, the endocrine glands secrete hormones into surrounding body fluids. In the circulation, these hormones travel to specific target tissues, where they exert a pronounced effect. Receptors found on or within these specialized target tissue cells are equipped with molecules that recognize the hormone and bind it to the cell, producing a specific response.

FIGURE 31-1 Location of endocrine glands with the hormones they produce, target cells or organs, and hormonal actions.

Pancreas

In the pancreas, clusters of cells that appear to form tiny islands among the exocrine cells accomplish the pancreatic endocrine functions. These clusters are known as the islets of Langerhans and are composed of four distinct cell types: alpha, beta, delta, and PP. The locations of the cells that produce these hormones are shown in Figure 31-2. Alpha cells secrete glucagon, beta cells secrete insulin, delta cells secrete somatostatin, and PP cells secrete pancreatic polypeptide hormone. Glucagon, insulin, somatostatin, and polypeptide hormones are released into the surrounding capillaries to empty into the portal vein, where they are distributed to target cells in the liver. The hormones then travel into general circulation to reach other target cells.

FIGURE 31-2 Macroscopic and microscopic structures of the pancreas and the islets of Langerhans.

Insulin

Insulin is a potent anabolic hormone produced by the beta cells of the pancreas. Elevated levels of blood glucose stimulate insulin production. Insulin is the only hormone produced in the body that directly lowers blood glucose levels. Insulin is responsible for the storage of carbohydrate, protein, and fat nutrients. Insulin also augments the transport of potassium into the cells, decreases the mobilization of fats, and stimulates protein synthesis (Table 31-1). Box 31-1 defines the terms commonly used when discussing glucose and insulin balance. The major stimulant for insulin secretion is an elevation of serum glucose. The greater the rise in blood glucose, the more insulin the normal pancreas produces. Other hormones inhibit the release of insulin (Table 31-2).

Box 31-1 Terms Used for Insulin and Glucose Imbalance

• Anabolism—constructive phase of metabolism in which the body converts simple substances into more complex compounds in the presence of energy

• Catabolism—destructive phase of metabolism in which the body breaks down complex substances to form simpler substances in the presence of energy

• Gluconeogenesis—formation of glucose from noncarbohydrate nutrients (e.g., fats, protein), which occurs in the liver

• Glycogen—storage form of glucose in liver and muscles

• Glycogenesis—formation of glycogen from glucose and adenosine triphosphate after a meal when both are plentiful

• Glycogenolysis—conversion of glycogen stored in the liver and muscles into usable glucose

• Osmolality—measurement of the number of particles in a solution or the concentration of a solution

TABLE 31-1

PANCREATIC ENDOCRINE CELLS, HORMONES, STIMULANT RELEASE FACTOR, TARGET TISSUE, AND RESPONSE OR ACTION

CELL	HORMONE	STIMULANT RELEASE FACTOR	TARGET TISSUE	RESPONSE OR ACTION
Alpha	Glucagon	↓ Glucose	Hepatocyte	↑ Glucose in bloodstream
		Exercise	Myocyte	↑ Gluconeogenesis
		↑ Amino acids		↑ Glycogenolysis
		SNS stimulation		↑ Fat mobilization
				↑ Protein mobilization
Beta	Insulin	Glucose	Skeletal cells	↓ Blood glucose
			Muscle cells	↓ Fat mobilization
			Cardiac cells	↑ Fat storage
				↓ Protein mobilization
				↑ Protein synthesis
				↑ Glucogenesis
Delta	Somatostatin	Hyperglycemia	Alpha cells	↓ Blood glucose
			Beta cells	↓ Glycogen secretion
				↓ Insulin secretion
PP	Pancreatic polypeptide	Acute hypoglycemia	Gallbladder	↑ Gallbladder contraction
			Smooth muscle	↓ Pancreatic enzyme

SNS, Sympathetic nervous system; ↑, increases; ↓, decreases.

TABLE 31-2

AGENTS THAT PROMOTE OR INHIBIT INSULIN RELEASE

INSULIN RELEASE (MAJOR STIMULANT: HIGH BLOOD GLUCOSE)	INSULIN INHIBITION (MAJOR INHIBITOR: LOW BLOOD GLUCOSE)
Hormones
Glucagon	Somatostatin
Corticotropic hormone	Norepinephrine
Thyrotropin	Epinephrine
Somatotropin
Glucocorticoids
Incretins
Medications
Beta-adrenergic stimulators	Beta-adrenergic blocking agents
Sulfonylurea	Diazoxide
Theophylline	Phenytoin
Acetylcholine	Thiazide or sulfonamide diuretics

Blood Glucose

Blood glucose is reported in millimoles per liter (mmol/L), which is the System International (SI) unit of measure used throughout the world. In the United States, blood glucose is measured in milligrams per deciliter (mg/dL). The normal blood glucose range is 70 to 100 mg/dL (3.9 to 5.6 mmol/L). To convert mmol/L of glucose to mg/dL, multiply the mmol/L value by 18. To convert mg/dL of glucose to mmol/L, divide the mg/dL value by 18.

In patients who have symptoms of diabetes, pancreatic beta cell destruction has already occurred. In type 1 diabetes, all of the beta cells are nonfunctional. In type 2 diabetes, about 50% of the beta cells are destroyed by the time the patient exhibits signs and symptoms of diabetes. The destruction of the beta cells disrupts homeostatic ability to regulate blood glucose.

Carbohydrate Anabolism.

Glucose is admitted to the skeletal, cardiac, and adipose cells for use as energy in the presence of effective insulin facilitated by the glucose transporter 4 (GLUT4), as described below. The movement of glucose from the circulation into the intracellular compartment reduces the concentration of glucose in the bloodstream and helps preserve the blood’s osmolality. Simultaneously, glucose is available to the cell as its main energy source. Excess glucose in the form of glycogen is stored in the hepatic and muscle cells for use as fuel at a later time. In skeletal muscle, 90% of the glucose in the cell is converted to glycogen for longer-term storage.¹ Liver glycogen contributes up to 10% of total liver weight when fully replete.¹

Fat Anabolism.

Adequate, effective insulin levels affect fat metabolism. Dyslipidemias are strongly associated with type 2 diabetes. Type 2 diabetes is characterized by overproduction of large, triglyceride-rich, very-low-density lipoproteins (VLDLs).² Disorders of carbohydrate and fat metabolism are also associated with metabolic syndrome, a precursor to diabetes and cardiovascular disease.³

Protein Conservation.

Insulin and the GLUTs (see below) together facilitate the transfer of glucose across the cell wall. By having glucose (carbohydrate) available as the body’s fuel source, protein is spared from use as energy. Protein is then available for critical protein synthesis and for amino acid transport into the cells. Protein metabolism also benefits from an adequate insulin supply. Only in acute hyperglycemia of diabetic ketoacidosis (DKA) or in starvation states does the body use protein for energy sources.

Glucagon

Glucagon, synthesized by alpha cells in the pancreas, has the opposite effect of insulin. Glucagon is released during hypoglycemia to induce hepatic glucose output. Because glucagon counter-regulates insulin levels and raises blood glucose levels, it is a potent gluconeogenic hormone. By means of gluconeogenesis, glucagon can form glucose from noncarbohydrate sources such as fat and protein when required. Glucagon release from the pancreas is stimulated by low blood glucose levels, starvation, exercise, or stimulation of the sympathetic nervous system (SNS), as listed in Box 31-2.^4,5 Glucagon release protects the brain from the consequences of hypoglycemia.⁵

Box 31-2 Effects of the Insulin-to-Glucagon Ratio on Carbohydrate, Fat, and Protein Metabolism

BALANCED INSULIN AND GLUCAGON	DECREASED INSULIN AND INCREASED GLUCAGON
↑ Use of glucose by cells	↓ Use of glucose by cells
↑Movement of potassium intracellularly	↓ Movement of potassium intracellularly
↑ Carbohydrate metabolism	↑ Blood glucose
↓ Gluconeogenesis	↑ Gluconeogenesis
↑ Glycogen storage	↓ Glycogen storage
↓ Glycogenolysis	↑ Glycogenolysis
↓ Lipolysis	↑ Lipolysis
↓ Fat mobilization	↑ Fat mobilization
↑ Fat storage	↓ Fat stores
↓ Protein mobilization	↑ Hepatic metabolism fats
↑ Protein synthesis	↑ Ketogenesis
	↑ Mobilization of protein
	↑ Proteolysis
	↑ Lipoprotein

To meet short-term energy requirements, glucagon stimulates the release of glycogen stores from liver and muscle cells. Through a process called glycogenolysis, the glycogen stored in the liver is converted into a glucose form that can be used by the cells.⁵

For long-term energy needs, glucagon stimulates glucose release through the more complex process of gluconeogenesis. In gluconeogenesis, fat and protein nutrients are rapidly broken down into end products that are then changed into glucose.⁵

A normal blood glucose level is maintained in the healthy body by the insulin-to-glucagon ratio. When the blood glucose level is high, insulin is released, and glucagon is inhibited. When blood glucose levels are low, glucagon rather than insulin is released to raise the blood glucose level. The brain has a very limited supply of glucose, and glucagon release is essential to protect the brain from the effects of hypoglycemia.⁶

Somatostatin

Somatostatin is a hormone that is produced in the pancreatic delta cells. Somatostatin decreases glucagon secretion, and in high quantities, it decreases insulin release (see Table 31-1). Hyperglycemia stimulates the activity of the delta cells. It is theorized that the release of insulin enables somatostatin to control beta cell activity. Somatostatin may be involved in the regulation of the postprandial influx of glucose into cells.

Pancreatic Polypeptide

The role of pancreatic polypeptide, synthesized by the PP cells within the islets of Langerhans, is not completely understood. Pancreatic polypeptide release can be stimulated by acute hypoglycemia or by an intake that is high in protein and low in carbohydrate. The effect of hypersecretion or hyposecretion of this hormone has not been identified. The hormone represses pancreatic enzyme secretion and relaxes the smooth muscle tissue of the gallbladder.

Glucose Transporters

Human cells take up glucose by means of facultative glucose-transport proteins known by the term glucose transporter (GLUT). These proteins are specialized by tissue distribution and function as described in Table 31-3.⁷ At the cellular level, glucose crosses the cell plasma membrane through aqueous pores formed by GLUT transporters. At this time, 14 GLUTs have been identified.⁸ The GLUT number indicates the order in which the molecular sequence and GLUT tissue locations were identified.⁸ The functions of a few key GLUTs are described in more detail below.

TABLE 31-3

GLUCOSE TRANSPORTERS

GLUCOSE TRANSPORTER (GLUT)	ANATOMIC LOCATIONS	FUNCTION
GLUT1	Erythrocytes, endothelial cells of brain	Basal glucose uptake
	Transport across blood–brain barrier
GLUT2	Pancreatic beta bells, liver, kidney, small intestine	High-capacity, low-affinity GLUT
		Can transport fructose
GLUT3	Brain cells, nerve cells	Transports glucose into neural tissue
GLUT4	Striated muscle and adipose tissue	Insulin-regulated transport in muscle and fat
GLUT5	Intestine, kidney, testis	Transports fructose
GLUT6	Spleen, leukocytes, brain
GLUT7	Small intestine, colon, testis	Transports fructose
GLUT8	Testis, brain, muscle, adipocytes	Fuel supply of mature spermatozoa
GLUT9	Liver, kidney
GLUT10	Liver, pancreas	Muscle-specific fructose transporter
GLUT11	Heart, muscle
GLUT12	Heart, prostate, mammary gland

The central nervous system (CNS) is freely permeable to glucose transported by GLUT1 and GLUT3.6,9 The CNS does not rely on insulin for transport of glucose across the neural cell membrane. The brain and other CNS cells require a constant source of glucose because they retain minimal glucose and glycogen stores.

GLUT2.

The GLUT2 proteins are associated with glucose sensing and facilitate rapid entry of glucose into specialized cells such as the pancreatic beta cells and into the glucose-sensing cells in the hepatoportal vein area.⁸ In the intestine, in the presence of a high-glucose meal, GLUT2 proteins may translocate to the apical cell surface to increase glucose absorption from the gut to the bloodstream.⁸

GLUT4.

The GLUT4 protein plays a pivotal role in the way glucose moves from the bloodstream into the cell.¹⁰ After a meal, the levels of sugars and amino acids in the bloodstream rise. This increase signals pancreatic beta cells to release insulin into the bloodstream. As the insulin circulates in the vascular system, it activates an insulin receptor on the plasma membrane of cells, primarily peripheral muscle and adipose cells. This receptor initiates signaling cascades inside the cell to activate GLUT4, which resides within the cells in clathrin-coated pits until needed. GLUT4 translocates (travels) from intracellular storage sites to the plasma membrane in response to the signal from the insulin receptor.^10,11 At the cell surface, GLUT4 facilitates the passive transport of glucose along a concentration gradient into striated muscle and fat cells.

In the baseline state (between meals with normal blood glucose) only 4% to 10% GLUT4 are on the cell surface, whereas 90% are within the cell.¹² Within 10 to 15 minutes of insulin stimulation of muscle cells, GLUT4 levels at the cell surface double as rapid translocation from the interior to the cell surface occurs.¹² Between meals, the liver normally provides sufficient glucose output to maintain constant circulating blood glucose levels within the normal range.

GLUT5.

Fructose absorption is the target for GLUT5 proteins, which are found on the apical membrane of intestinal cells.⁸ GLUT5 is of interest because of the high levels of fructose in many modern processed foods and the link between high-fructose foods and obesity.

Incretins

The incretins, which are hormones that are released from the GI tract after a meal, increase the production of insulin from the pancreatic beta cells. Two incretins are of particular clinical importance: 1) glucagon-like-peptide 1 (GLP-1) and 2) glucose-dependent insulinotropic polypeptide (GIP). The physiology of the incretins has been used to develop new medicines that reduce postprandial blood glucose levels in type 2 diabetes as listed in Table 33-3 in Chapter 33. More insulin is released following oral glucose ingestion than in response to the same amount of intravenous glucose because of release of the gut incretins.^13,14 The increase in insulin section caused by stimulation from the incretins may make up to 70% of the insulin response, depending on the size of the meal.^13,14 This incretin-effect is impaired in patients with type 2 diabetes.^13,14 The physiologic effects of GIP and GLP-1 are listed in Table 31-4.

TABLE 31-4

INCRETINS IMPACT ON METABOLISM

ACTIONS	GIP	GLP-1
Pancreas	Stimulates insulin synthesis and release from pancreatic beta cells after a meal when BG is elevated	Stimulates insulin synthesis and release from pancreatic beta cells after a meal when BG is elevated
	Maintains beta cell mass and function Decreases beta cell death (apoptosis)	Maintains beta cell mass and function Decreases beta cell death (apoptosis)
	Increases GLUT2 expression in pancreas	Increases GLUT2 expression in pancreas
		Increases somatostatin release from the pancreatic delta cells
		Decreases glucagon release from the pancreas
Liver		Decreases release of glucose from the liver
Gastrointestinal system		Delays gastric emptying
Central nervous system		Decreases appetite, sense of satiety after a meal
Muscle		Increases glucose uptake in muscle
Adipose tissue		Increases glucose uptake and free fatty acid synthesis to triglycerides
Bone	Increases bone formation Decreases bone resorption	Increases bone formation Decreases bone resorption

BG, Blood glucose; GIP, glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like-peptide 1; GLUT2, glucose transporter 2.

The incretins have other beneficial physiologic effects, including proliferation of pancreatic beta cells, decrease in beta cell death (apoptosis), and increase in GLUT2 proteins in the islets of Langerhans. Incretins augment the effects of insulin to increase glucose and fatty-acid uptake and storage in triglycerides.¹⁵

Glucose-Dependent Insulinotropic Polypeptide.

GIP is synthesized and predominantly released from the K-cells of the duodenum. GIP acts directly on pancreatic beta cells to increase insulin secretion.

Glucagon-Like-Peptide 1.

GLP-1 is synthesized and released from the L-cells of the ileum and colon.¹³ When blood glucose levels are high, GLP-1 stimulates insulin release from the pancreas and inhibits glucagon release from the liver. GLP-1 has a short half-life of less than 2 minutes because it is rapidly broken down by the enzyme dipeptidyl peptidase-4 (DPP-4).¹⁶ Gliptins are medicines that have been developed to inhibit the DPP-4 enzyme and slow the inactivation of endogenous GLP-1 to reduce postprandial glucose elevation after a meal.

GLP-I exerts other beneficial effects, including decreased gastric emptying and the feeling of satiety (feeling of being full) after a meal. When blood glucose levels are within normal range, GLP-1 inhibits the release of somatostatin from the pancreatic delta cells and glucagon from the liver.¹⁴

Pituitary Gland and Hypothalamus

Anatomy

The hypothalamus is linked to the pituitary gland in two distinct ways: 1) a vascular network connects the anterior portion of the pituitary with the hypothalamus and 2) a separate pathway of nerve fibers connects the posterior pituitary with the hypothalamus. Understanding the proximity of the hypothalamus and the pituitary gland to each other is necessary to appreciate the correlation that exists between these organs.

The hypothalamus lies in the base of the brain, superior to the pituitary gland. It is composed of specialized nervous tissue responsible for the integrated functioning of the nervous system and endocrine system, which is called neuroendocrine control. The hypothalamus weighs approximately 4 grams (g) and forms the walls and lower portion of the third ventricle of the brain. The area composing the floor of the ventricle thickens in the center and elongates. It is from this funnel-shaped portion, called the infundibular stalk or stem, that the pituitary gland is suspended, as illustrated in Figure 31-3. The infundibular stalk contains a rich vascular supply and a network of communicating neurons that travel from the hypothalamus to the pituitary. The vascular network and neural pathways transport chemical and neural signals and maintain constant communication between the nervous system and the endocrine system.

FIGURE 31-3 Anatomy of the hypothalamus and the pituitary gland and their locations in the skull. (From Thompson JM, et al. *Mosby’s Clinical Nursing*. 5th ed. St. Louis: Mosby; 2002.)

The pituitary gland is also called the hypophysis. It is attached below the hypothalamus and is found recessed in the base of the cranial cavity in a hollow depression of the sphenoid bone known as the sella turcica. Secured in such a protected environment, the pituitary is one of the most inaccessible endocrine glands in humans. However, because of this location, the pituitary gland is susceptible to injury from surgical and accidental trauma to the face and head. The pituitary is composed of the anterior lobe and the posterior lobe (see Fig. 31-3). Each component within the pituitary has its own origin, morphology, and function.

Anterior Pituitary

The anterior lobe of the pituitary, also called the adenohypophysis, is the largest portion of the gland. It communicates with the hypothalamus by means of a vascular network. The glandular tissue of the anterior pituitary produces several hormones, including adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), growth hormone (GH), and prolactin. Information about all the hormones, their target tissues, and their actions is found in Figure 31-1.

Posterior Pituitary

The posterior lobe of the pituitary gland is also known as the neurohypophysis. It retains its continuity with the hypothalamus by means of neural fibers running through the infundibular stalk. The neurohypophysis has no glandular properties but functions as an extension of the hypothalamus. It collects, stores, and later releases hormones that are produced in the hypothalamus. Oxytocin and antidiuretic hormone (ADH) are manufactured in the hypothalamus and stored in the posterior pituitary.

Physiology

The hypothalamus gland is known as the “master gland” because of the influence it has over all areas of body functioning. The hypothalamus controls pituitary gland action and response by secreting substances called release-inhibiting factors. These factors control the release or inhibition of hormones. Thyrotropin-releasing hormone (TRH) is an example of a release-inhibiting factor. Virtually every function necessary to maintaining the human body in a state of dynamic equilibrium is regulated in this manner. One of the most important hormones to understand in caring for the critically ill patient is ADH.

Antidiuretic Hormone

ADH, known also as arginine vasopressin, is an important hormone responsible for regulating fluid balance within the body. ADH acts through specialized vasopressin receptors (V receptors) in specific target tissue:

V₁ receptors in arterial walls

V₂ receptors in kidney collecting ducts

V₃ receptors in pituitary tissue

ADH has two functions: 1) by means of the V₁ receptors, it constricts smooth muscles within the arterial wall and 2) through V₂ receptors, it regulates fluid balance by altering the permeability of the kidney tubule to water. ADH also contributes to control of the sodium level in the extracellular fluid by control of plasma osmolality. The sodium ion concentration in the plasma largely determines plasma osmolality. Osmoreceptors, located in the hypothalamus are sensitive to changes in the circulating plasma osmolality.¹⁷

Disorders of water metabolism are divided into hyperosmolar and hypo-osmolar states. Hyperosmolar disorders have a deficit of body water relative to body solute. Hypo-osmolar disorders have an excess of body water relative to total body solute.¹⁸

Sodium and water metabolism are regulated by different but complementary systems within the body. Sodium metabolism is predominately regulated by the renin–angiotensin–aldosterone system (RAAS), and water metabolism is primarily controlled by arginine vasopressin.

A low sodium level is associated with a low serum osmolality (hypo-osmolar state). When sodium levels rise, plasma osmolality increases (hyperosmolar state). ADH is then released to stimulate water resorption at the nephron to maintain sodium balance. This process decreases water loss from the body and subsequently concentrates and reduces urine volume. Fluid conserved in this manner is returned to the circulating plasma, where it dilutes the concentration (osmolality) of plasma, as shown in Figure 31-4.

FIGURE 31-4 Physiology of the release and restriction of antidiuretic hormone.

The release of ADH increases with hypovolemia. Primarily, the plasma osmotic pressure and the volume of circulating blood regulate the release of ADH. Stretch receptors located in the left atrium are sensitive to volume changes in the plasma that may be caused by vomiting, diarrhea, or blood loss. Hemorrhage that is sufficient to lower the blood pressure or emesis that is sufficient to reduce fluid volume stimulates the release of ADH. Other factors capable of influencing ADH secretion are pain, stress, malignant disease, surgical intervention, alcohol, and some medications. Table 31-5 lists additional factors that affect ADH levels.

TABLE 31-5

FACTORS AFFECTING ANTIDIURETIC HORMONE

ANTIDIURETIC HORMONE STIMULATION	ANTIDIURETIC HORMONE RESTRICTION
Increased serum osmolality	Decreased serum osmolality
Emesis	Hypervolemia
Hypovolemia	Water intoxication
Hemorrhage	Cold
Pain	Congenital defect
	Carbon dioxide inhalation
Hypothalamic-Pituitary System Damage
Accidental trauma	Accidental trauma
Surgical trauma	Surgical trauma
Pathologic trauma	Pathologic trauma
Stress: physical and emotional
Acute infections
Malignancies
Nonmalignant pulmonary disorders
Stimulated pulmonary baroreceptors
Nocturnal sleep
Medications
Nicotine	Phenytoin
Barbiturates	Chlorpromazine
Oxytocin	Reserpine
Glucocorticoids	Norepinephrine
Anesthetics	Ethanol
Acetaminophen	Opioids
Amitriptyline	Lithium
Carbamazepine	Demeclocycline
Cyclophosphamide	Tolazamide
Chlorpropamide
Potassium-depleting diuretics
Vincristine
Isoproterenol

Thyroid Gland

Anatomy

The thyroid gland weighs 15 to 25 g in the adult human.¹⁹ The size of the adult gland varies according to the availability of dietary iodine in different geographic regions. The gland partially encases the trachea, is wrapped around the second to fourth tracheal rings anteriorly and laterally, and is located at the level of the sixth and seventh cervical vertebrae posteriorly. The thyroid gland lies inferior the thyroid cartilage and the articulating surface of the cricoid cartilage. This bow tie–shaped gland has two lateral lobes that are partially covered by the sternohyoid and sternothyroid muscles. The thyroid isthmus, the band of narrow thyroid tissue that connects the lateral lobes, lies directly inferior to the cricoid cartilage, as shown in Figure 31-5.

Two important nerves associated with speech and swallowing pass close to the thyroid gland. The recurrent laryngeal nerve and superior laryngeal nerve are branches of the vagus nerve. The considerable anatomic variety in the location of these nerves increases the risk of injury during surgical procedures such as thyroidectomy.¹⁹

The thyroid gland has a rich blood supply from the superior and inferior thyroid arteries. The superior thyroid artery is the first branch of the external carotid artery.¹⁹ Venous drainage is from the superior, middle, and inferior thyroid veins. Lymphatic drainage follows the route of the thyroid veins.¹⁹ The functional units of the thyroid gland are spherical cells called follicles. Follicles are filled with the protein thyroglobulin.²⁰

The parathyroid glands (usually four) are intimately associated with the posterior surface of the thyroid gland. The parathyroid glands derive their name from their anatomic proximity to the thyroid, although they have a completely different function. The parathyroid glands maintain calcium homeostasis.

Through a complex process, dietary iodine is absorbed and concentrated in the thyroid follicles. About 100 microgram (mcg) of iodide is needed on a daily basis to generate sufficient quantities of thyroid hormone. In the United States, dietary ingestion of iodide ranges from 200 to 500 mcg per day. The iodine is oxidized to iodide by the enzyme thyroid peroxidase. Through active transport, the amino acid tyrosine binds the iodide to thyroglobulin, eventually yielding triiodothyronine (T₃) and thyroxine (T₄). More than 99% of T₃ and T₄ circulates in the bloodstream bound to transport proteins: thyroxin-binding globulin, prealbumin, and albumin. The minute amount of free thyroid hormone that is not protein bound is responsible for activating thyroid responses throughout the body.

Thyroglobulin

Thyroglobulin (Tg) is a key precursor in the biosynthesis of thyroid hormone. Thyroglobulin is stored in the thyroid follicles until needed. TSH release stimulates thyroglobulin secretion into the bloodstream.²⁰

Triiodothyronine and Thyroxine

TSH prompts the thyroid cells to produce thyroid hormones (T₃ and T₄) in the presence of iodine in the thyroid follicles. In the normal thyroid gland, 90% of the thyroid hormone that is produced is in the form of thyroxine (T₄) and 10% as triiodothyronine (T₃). These hormones are named according to the number of iodine atoms in their structure; T₃ has three iodine atoms and T₄ has four iodine atoms.²⁰

Most T₄ is subsequently converted into the more biologically active T₃. Most T₃ in the bloodstream is the result of the conversion of T₄ to T₃ in the peripheral tissues, liver, and kidneys. T₃ acts more rapidly on target tissues compared with T₄, and it is more actively potent. Both thyroid hormones impact the rate at which oxygen is used in the body and, thus, affect all metabolic processes in the body.

Calcitonin

The thyroid gland produces a third hormone, thyrocalcitonin, also called calcitonin. This hormone is produced by the parafollicular cells, or C-cells, found scattered among the thyroid follicular cells. Calcitonin acts in concert with parathyroid hormone to maintain normal calcium blood levels. Calcitonin lowers calcium levels in the blood through urinary excretion and by promoting calcium absorption in the bone. In contrast, parathyroid hormone limits urinary loss and stimulates bones to release calcium. Throughout the remainder of this discussion, thyroid hormone refers collectively to T₃ and T₄, not calcitonin.

Hypothalamic–Pituitary–Thyroid Axis Feedback Loop

The hypothalamic–pituitary–thyroid axis regulates the mechanism for the synthesis and secretion of thyroid hormone. The production and secretion of thyroid hormone is regulated by a feedback mechanism that limits the amount of hormone circulating to the cellular need at that time, as illustrated in Figure 31-6.

FIGURE 31-6 Hypothalamus-pituitary-thyroid axis feedback loop.

In response to decreased circulating levels of T₃ and T₄, the hypothalamus releases TRH. TRH activates TSH in the anterior pituitary and TSH stimulates the thyroid gland to manufacture and release the thyroid hormones T₃ and T₄ in the presence of iodine.²⁰ When serum blood levels of T₃ and T₄ become high, the pituitary inhibits the production of additional TSH. When levels of T₃ and T₄ become too low, the pituitary is stimulated to secrete additional TSH.

T₄ prompts the activation of beta-adrenergic receptors in widespread areas of the body. These receptors trigger an SNS response and release norepinephrine at sympathetic nerve endings.²¹ The effect is stimulation of the cardiac tissue, nervous tissue, and smooth muscle tissue, as well as an increase in metabolism and thermogenesis (increased body heat). Box 31-3 lists the major actins of thyroid hormones in more detail.

Box 31-3 Major Functions of Thyroid Hormones

• Interact with growth hormone

• Maturation of skeletal system

• Development of central nervous system

• Stimulate carbohydrate metabolism

• Increase the rate of glucose absorption from the gastrointestinal tract

• Increase the rate of glucose use by the cells

• Accelerate the rate of fat metabolism

• Increase cholesterol degradation in the liver

• Decrease serum cholesterol levels

• Increase protein anabolism and catabolism

• Mobilize protein and release amino acids into circulation

• Increase energy from protein nutrients through gluconeogenesis

• Increase the body’s demand for vitamins

• Increase oxygen consumption and use

• Increase basal metabolic rate

• Have marked chronotropic and inotropic effects on heart

• Increase cardiac output

• Stimulate contractility and excitability of myocardium

• Increase blood volume

• Expand respiratory rate and depth necessary for normal hypoxic and hypercapnic drive

• Promote sympathetic overactivity

• Boost erythropoiesis

• Increase metabolism and clearance of various hormones and pharmacologic agents

• Stimulate bone resorption

Adrenal Gland

Anatomy

The adrenal glands, also called suprarenal glands, are small, yellowish, bilateral, pyramidal or semilunar-shaped organs located at the superior pole of the kidney. As a neighbor to the kidney, they are retroperitoneal and embedded in the fat pad of the kidney. The normal adrenal gland is 3 to 4 cm in its longest axis and weighs approximately 5 g in the adult (Fig. 31-7). Functionally and histologically, two glands exist within the suprarenal gland: 1) the outer cortex and 2) the inner medulla. Both regions secrete hormones that are integral to the body’s response to stress.

FIGURE 31-7 Adrenal Gland.
A, Cross section of the adrenal gland showing the outer cortex and inner medulla. B, Anatomical relationship of the adrenal glands to the kidneys.

Adrenal Cortex

The adrenal cortex is the thicker outer region, and it makes up 85% of the gland. The cortex is composed of three different layers of cells, each with a specific endocrine function: 1) the zona glomerulosa, 2) the zona fasciculata, and 3) the zona reticularis. The cortex secretes cortisol, it regulates fluid homeostasis by means of aldosterone, and it secretes androgens.

Adrenal Medulla

The inner region is called the adrenal medulla. The inner medulla is a part of the SNS, and it resembles a cluster of neurons more than an endocrine gland. The adrenal medulla contains clusters of specialized chromaffin cells, which are modified preganglionic sympathetic neurons.22,23 Different sets of chromaffin cells contain chromaffin granules that are specific for each of catecholamines epinephrine or norepinephrine.²² The granules for each catecholamine appear in different sets of cells within the adrenal medulla. A chromaffin cell usually contains granules only for one catecholamine or the other.²²

The adrenal medulla is stimulated by the SNS by preganglionic bundles of sympathetic nerve fibers that originate in the spinal cord.²² The role of the chromaffin cells is to secrete the catecholamines epinephrine and norepinephrine. Under physiologic stress, these hormones produce a widespread excitatory effect described as a “surge of adrenaline” or as the “fight-or-flight response.”²³

Adrenal Blood Supply

The rich arterial blood supply comes to the adrenal gland from three sources (see Fig. 31-7): (1) the superior suprarenal artery is a branch of the inferior phrenic artery; (2) the middle suprarenal artery branches directly off of the aorta; and (3) the inferior suprarenal artery branches off the renal artery.

Venous drainage is usually achieved through a single vein from each adrenal gland. The vein from the right adrenal gland drains into the inferior vena cava, and the vein from the left adrenal gland empties into the left renal vein.