THE ENDOCRINE SYSTEM

Your body cells have dynamic adventures on the microscopic level all the time. For instance, when insulin molecules leave the blood and bind tightly to protein receptors on nearby cells, the response is dramatic: bloodborne glucose molecules begin to enter the cells, and cellular activity accelerates. Such is the power of the second great control system of the body, the endocrine system. Along with the nervous system, it coordinates and directs the activity of the body’s cells.

The speed of control in these two regulating systems is very different. The nervous system is “built for speed.” It uses nerve impulses to prod the muscles and glands into immediate action rapid adjustments can be made in response to changes occurring both inside and outside the body. By contrast, the endocrine system acts more slowly by using chemical messengers called hormones, which are released into the blood to be transported throughout the body.

Hormones have widespread effects and control several major processes: reproduction; growth and development; mobilizing body defenses against stressors; maintaining electrolyte, water, and nutrient balance of the blood; and regulating cellular metabolism and energy balance. As you can see, the endocrine system regulates processes that go on for relatively long periods and, in some cases, continuously. The scientific study of hormones and endocrine organs is called endocrinology.

9.1 The Endocrine System and Hormone Function— An Overview

Compared to other organs of the body, the organs of the endocrine system are small and unimpressive. The endocrine system also lacks the structural or anatomical continuity typical of most organ systems. Instead, bits and pieces of endocrine tissue are tucked away in separate regions of the body (see Figure 9.3, p. 328). However, functionally the endocrine organs are impressive, and when their role in maintaining body homeostasis is considered, they are

9.1a The Chemistry of Hormones

Hormones are chemical substances secreted by endocrine cells into the extracellular fluids that regulate the metabolic activity of other cells in the body. Although the body produces many different hormones, nearly all of them can be classified chemically as either amino acid–based molecules (including proteins, peptides, and amines) or steroids. Steroid hormones (made from cholesterol) include the sex hormones made by the gonads (ovaries and testes) and the hormones produced by the adrenal cortex. All other hormones are nonsteroidal amino acid derivatives. If we also consider the hormones that act locally, called prostaglandins (pros”tah-glan’dinz), we must add a third chemical class. (Prostaglandins are described later in the chapter—see Table 9.2, p. 346). The prostaglandins are made from highly active lipids released from nearly all cell membranes.

9.1b Hormone Action

Although hormones circulate to all the organs of the body via blood, a given hormone affects only certain tissue cells or organs, referred to as its target cells or target organs. For a target cell to respond to a hormone, specific protein receptors to which that hormone can attach must be present on the cell’s plasma membrane or in its interior. Only when this binding occurs can the hormone influence the workings of a cell.

The term hormone comes from a Greek word meaning “to arouse.” In fact, the body’s hormones do just that. They “arouse,” or bring about their effects on, the body’s cells primarily by altering cellular activity—that is, by increasing or decreasing the rate of a normal metabolic process rather than by stimulating performance of a new one. The precise change(s) that follow hormone binding depend on the specific hormone and the target cell type.

Hormones can:

Change plasma membrane permeability or membrane potential (electrical state) by opening or closing ion channels • Activate or inactive enzymes

Stimulate or inhibit cell division

Promote or inhibit secretion of a product

Turn on or turn off transcription of certain genes (such as those encoding proteins or regulatory molecules)

Direct Gene Activation

Despite the huge variety of hormones, there are really only two mechanisms by which hormones trigger changes in cells. Steroid hormones (and, strangely, thyroid hormone) can use the mechanism of direct gene activation (Figure 9.1a, p. 326). Because they are lipidsoluble molecules, the steroid hormones can diffuse through the plasma membranes of their target cells.

1 . Once inside, the steroid hormone enters the nucleus 2. and binds to a specific hormone receptor 3 . In this specific example, the hormone-receptor complex then binds to specific sites on the cell’s DNA 4 , activating certain genes to transcribe messenger RNA (mRNA) 5 . The mRNA is translated in the cytoplasm 6 , resulting in the synthesis of new proteins. Alternatively, the steroid hormone may bind to receptors in the cytoplasm, and then the complex moves into the nucleus to activate certain genes. Instead of turning genes on, some hormones turn genes off in step 4.

Second-Messenger System

Steroid hormones can influence cell activity either by direct gene activation or by the indirect pathway of activating a second messenger. Protein and peptide hormones, however, are usually water-soluble and are unable to enter target cells directly. Instead, they bind to hormone receptors situated on the target cell’s plasma membrane and use a secondmessenger system. In these cases (Figure 9.1b), the hormone (first messenger) binds to the receptor protein on the membrane, 1 and the activated receptor sets off a series of reactions (a cascade) that activates an enzyme 2 . The enzyme, in turn, catalyzes reactions that produce second-messenger molecules.

3 (in this case, cyclic AMP, also known as cAMP, or cyclic adenosine monophosphate) that oversee additional intracellular changes that promote the typical response of the target cell to the hormone 4 . Think of a postal service employee (first messenger) delivering a letter to campus, and a college mailroom employee (second messenger) carrying the letter from the college mailbox (cell membrane) to your dorm mailbox (DNA). As you might guess, the same hormone may have a variety of possible second messengers (including cyclic guanosine monophosphate, or cGMP, and calcium ions) and many possible target cell responses, depending on the tissue type stimulated.

9.1c Stimuli for Control of Hormone Release

Recall that negative feedback mechanisms are the chief means of regulating blood levels of nearly all hormones (see Chapter 1, p. 41). In such systems, some internal or external stimulus triggers hormone secretion; then, a rising level of the hormone inhibits further hormone release (even while promoting a response in the target organ). As a result, blood levels of many hormones vary within a very narrow range. With hormones, “a little goes a long way”! The stimuli that activate endocrine glands fall into three major categories—hormonal, humoral, and neural (Figure 9.2). These three mechanisms represent the most common systems that control hormone release, but they by no means explain all of them. Some endocrine organs respond to many different stimuli.

Hormonal Stimuli

The most common stimulus is a hormonal stimulus, in which endocrine organs are prodded into action by other hormones. For example, hormones of the hypothalamus stimulate the anterior pituitary gland to secrete its hormones, and many anterior pituitary hormones stimulate other endocrine organs to release their hormones into the blood (Figure 9.2a). As the hormones produced by the final target glands increase in the blood, they “feed back” to inhibit the release of anterior pituitary hormones and thus their own release. Hormone release promoted by this mechanism tends to be rhythmic, with hormone blood levels rising and falling again and again.

Humoral Stimuli

Changing blood levels of certain ions and nutrients may also stimulate hormone release. Such stimuli are referred to as humoral (hyoo-moral) stimuli to distinguish them from hormonal stimuli, which are also bloodborne chemicals. The term humoral refers to the ancient use of the word humor to indicate the various body fluids (blood, bile, and others). For example, a decreasing blood calcium ion level in the capillaries serving the parathyroid glands prompts the release of parathyroid hormone (PTH). Because PTH acts by several routes to reverse that decline, the blood Ca2+ level soon rises, ending the stimulus for PTH release (Figure 9.2b). Other hormones released in response to humoral stimuli include calcitonin, released by the thyroid gland, and insulin, produced by the pancreas.

Neural Stimuli

In isolated cases, nerve fibers stimulate hormone release, and the endocrine cells are said to respond to neural stimuli. The classic example is sympathetic nervous system stimulation of the adrenal medulla to release the catecholamines norepinephrine and epinephrine during periods of stress (Figure 9.2c).

9.2 The Major

Endocrine Organs

The major endocrine organs of the body include the pituitary, pineal, thyroid, parathyroid, thymus and adrenal glands, pancreas, and gonads (ovaries and testes) (Figure 9.3). The hypothalamus, which is part of the nervous system, is also recognized as a major endocrine organ because it produces several hormones. Some hormone-producing glands (the anterior pituitary, thyroid, parathyroids, and adrenals) have purely endocrine functions, but others (pancreas and gonads) have both endocrine and exocrine functions and are thus mixed glands.

Both types of glands are formed from epithelial tissue, but the endocrine glands are ductless glands that produce hormones that they release into the blood or lymph. (As you might expect, the endocrine glands have a rich blood supply.) Conversely, the exocrine glands release their products at the body’s surface or into body cavities through ducts (exocrine glands have an exit).

9.2a Pituitary Gland and Hypothalamus

The pituitary gland is approximately the size of a pea. It hangs by a stalk from the inferior surface of the hypothalamus of the brain, where it is snugly surrounded by the sella turcica (“Turk’s saddle”) of the sphenoid bone. It has two functional lobes—the anterior pituitary (glandular tissue) and the posterior pituitary (nervous tissue).

Pituitary-Hypothalamus Relationships

Despite its relatively small size, the anterior pituitary gland controls the activity of so many other endocrine glands that it has often been called the “master endocrine gland.” Its removal or destruction has a dramatic effect on the body. The adrenal and thyroid glands and the gonads atrophy, and results of hyposecretion by those glands quickly become obvious. However, the anterior pituitary is not as all-powerful as it might appear, because the release of each of its hormones is controlled by releasing hormones and inhibiting hormones produced by the hypothalamus.

The hypothalamus liberates these regulatory hormones into the blood of the portal circulation, which connects the blood supply of the hypothalamus with that of the anterior pituitary. (In a portal circulation, two capillary beds are connected by one or more veins; in this case, the capillaries of the hypothalamus are drained by veins that empty into the capillaries of the anterior pituitary.)

The hypothalamus also makes two additional hormones, oxytocin and antidiuretic hormone, which are transported along the axons of the hypothalamic neurosecretory cells to the posterior pituitary for storage (Figure 9.4). They are later released endocrine glands. A summary of the endocrine organs and their hormones’ main actions and regulatory factors appears in Table 9.1, pp. 343–345. into the blood in response to nerve impulses from the hypothalamus.

Posterior Pituitary and Hypothalamic

Hormones

The posterior pituitary is not an endocrine gland in the strict sense because it does not make the peptide hormones it releases. Instead, it acts as a storage area for hormones made by hypothalamic neurons

Oxytocin is released in significant amounts only during childbirth and nursing. It stimulates powerful contractions of the uterine muscle during sexual relations, during labor, and during breastfeeding. It also causes milk ejection (the let-down reflex) in a nursing woman. Both natural and synthetic oxytocic drugs are used to induce labor or to hasten labor that is progressing at a slow pace. Less often, oxytocics are used to stop postpartum bleeding (by causing constriction of the ruptured blood vessels at the placental site) and to stimulate the let-down reflex.

The second hormone released by the posterior pituitary is antidiuretic hormone (ADH). Diuresis is urine production. Thus, an antidiuretic is a chemical that inhibits or prevents urine production. ADH causes the kidneys to reabsorb more water from the forming urine; as a result, urine volume decreases, and blood volume increases. Water is a powerful inhibitor of ADH release. In larger amounts, ADH also increases blood pressure by causing constriction of the arterioles (small arteries). For this reason, it is sometimes referred to as vasopressin.

Drinking alcoholic beverages inhibits ADH secretion and results in output of large amounts of urine. The dry mouth and intense thirst experienced “the morning after” reflect this dehydrating effect of alcohol. Certain drugs, classed together as diuretics, antagonize the effects of ADH, causing water to be flushed from the body. These drugs are used to manage the edema (water retention in tissues) typical of congestive heart failure.

Anterior Pituitary Hormones

The anterior pituitary produces several hormones that affect many body organs (Figure 9.5). Two of the six anterior pituitary hormones in the figure-growth hormone and prolactin-exert their major effects on nonendocrine targets. The remaining four-follicle-stimulating hormone, luteinizing hormone, thyrotropic hormone, and adrenocorticotropic hormone are all tropic hormones.

Tropic (= turn on) hormones stimulate their target organs, which are also endocrine glands, to secrete their hormones, which in turn exert their effects on other body organs and tissues. All anterior pituitary hormones (1) are proteins (or peptides), (2) act through secondmessenger systems, and (3) are regulated by hormonal stimuli and, in most cases, negative feedback.

Growth hormone (GH) is a general metabolic hormone. However, its major effects are directed to the growth of skeletal muscles and long bones of the body, and thus it plays an important role in determining final body size. GH is a protein-sparing and anabolic hormone that causes the building of amino acids into proteins and stimulates most target cells to grow in size and divide. At the same time, it causes fats to be broken down and used for energy while it spares glucose, helping to maintain blood sugar homeostasis.

Prolactin (PRL) is a protein hormone structurally similar to growth hormone. Its only known target in humans is the breast (pro = for; lact = milk). After childbirth, it stimulates and maintains milk production by the mother’s breasts. Its function in men is not known.

The gonadotropic (go”nad-o-tro’pik) hormones regulate the hormonal activity of the gonads (ovaries and testes). In women, the gonadotropin follicle stimulating hormone (FSH) stimulates follicle development in the ovaries. As the follicles mature, they produce estrogen, and eggs are readied for ovulation. In men, FSH stimulates sperm development by the testes. Luteinizing (lu’te-in-i”zing) hormone (LH) triggers ovulation of an egg from the ovary and causes the ruptured follicle to produce progesterone and some estrogen. In men, LH stimulates testosterone production by the interstitial cells of the testes.

Thyrotropic hormone (TH) , also called thyroidstimulating hormone (TSH), influences the growth and activity of the thyroid gland. Adrenocorticotropic (adre”no-kor”tı-ko-tro’pik) hormone (ACTH) regulates the endocrine activity of the cortex portion of the adrenal gland.

9.2b Pineal Gland

The pineal gland is a small, cone-shaped gland that hangs from the roof of the third ventricle of the brain (see Figure 9.3). The endocrine function of this tiny gland is still somewhat of a mystery. Although many chemical substances have been identified in the pineal gland, only the hormone melatonin appears to be secreted in substantial amounts. The level of melatonin rises and falls during the course of the day and night. The peak level occurs at night and makes us drowsy; the lowest level occurs during daylight around noon.

Melatonin is believed to be a “sleep trigger” that plays an important role in establishing the body’s sleepwake cycle. It is believed to coordinate the hormones of fertility and to inhibit the reproductive system (especially the ovaries of females) until the body matures.

9.2c Thyroid Gland

The thyroid gland is located at the base of the throat, just inferior to the Adam’s apple, where it is easily palpated during a physical examination. It is a fairly large gland consisting of two lobes joined by a central mass, or isthmus (Figure 9.6a). The thyroid gland makes two hormones, one called thyroid hormone, the other called calcitonin (produced by the parafollicular cells). Internally, the thyroid gland is composed of hollow structures called follicles (Figure 9.6b), which store a sticky colloidal material. Thyroid hormone is derived from this colloid.

Thyroid hormone, often referred to as the body’s major metabolic hormone, is actually two active iodine-

containing hormones, thyroxine, or T4, and triiodothyronine, or T3. Thyroxine is the major hormone secreted by the thyroid follicles. Most triiodothyronine is formed at the target tissues by conversion of thyroxine to triiodothyronine. These two hormones are very much alike. Each is constructed from two tyrosine amino acids linked together, but thyroxine has four bound iodine atoms, whereas triiodothyronine has three (thus, T4 and T3, respectively).

Thyroid hormone controls the rate at which glucose is “burned,” or oxidized, and converted to body heat and chemical energy (ATP). Because all body cells depend on a continuous supply of ATP to power their activities, every cell in the body is a target. Thyroid hormone is also important for normal tissue growth and development, especially in the reproductive and nervous systems.

The second important hormone product of the thyroid gland, calcitonin, decreases the blood calcium ion level by causing calcium to be deposited in the bones. It acts antagonistically to parathyroid hormone, the hormone produced by the parathyroid glands. Whereas thyroxine is made and stored in follicles before it is released to the blood, calcitonin is made by the parafollicular cells found in the connective tissue between the follicles (see Figure 9.6b). It is released directly to the blood in response to an increasing level of blood calcium ions. Few effects of hypo- or hypersecretion of calcitonin are known, and calcitonin production is meager or ceases entirely in adults. This may help to explain (at least in part) the progressive decalcification of bones that accompanies aging.

9.2d Parathyroid Glands

The parathyroid glands are tiny masses of glandular tissue most often found on the posterior surface of the thyroid gland (look back at Figure 9.3). Typically, there are two parathyroid glands on each thyroid lobe, that is, a total of four parathyroids; but as many as eight have been reported, and some may be in other regions of the neck or even in the thorax. The parathyroids secrete parathyroid hormone (PTH), which is the most important regulator of calcium ion (Ca2+) homeostasis of the blood. When the blood calcium ion concentration drops below a certain level, the parathyroids release PTH, which stimulates bone destruction cells (osteoclasts) to break down bone matrix and release calcium ions into the blood.

Thus, PTH is a hypercalcemic hormone (that is, it acts to increase the blood level of calcium ions), whereas calcitonin is a hypocalcemic hormone. (The negative feedback interaction between these two hormones as they control the blood calcium ion level during youth is illustrated in Figure 9.7.) Although the skeleton is the major PTH target, PTH also stimulates the kidneys and intestine to absorb more calcium ions (from urinary filtrate and foodstuffs, respectively).

9.2e Thymus