Medical Physiology, 3rd Edition

Principles of Endocrine Function

Chemical signaling can occur through endocrine, paracrine, or autocrine pathways

As shown in Figure 3-1A, in classic endocrine signaling, a hormone carries a signal from a secretory gland across a large distance to a target tissue. Hormones secreted into the extracellular space can also regulate nearby cells without ever passing through the systemic circulation. This regulation is referred to as paracrine action of a hormone (see Fig. 3-1B). Finally, chemicals can also bind to receptors on or in the cell that is actually secreting the hormone and thus affect the function of the hormone-secreting cell itself. This action is referred to as autocrine regulation (see Fig. 3-1C). All three mechanisms are illustrated for individual endocrine systems in subsequent chapters. At the outset, it can be appreciated that summation of the endocrine, paracrine, and autocrine actions of a hormone can provide the framework for a complex regulatory system.

Endocrine Glands

The major hormones of the human body are produced by one of seven classic endocrine glands or gland pairs: the pituitary, the thyroid, the parathyroids, the testes, the ovaries, the adrenals (cortex and medulla), and the endocrine pancreas. In addition, other tissues that are not classically recognized as part of the endocrine system produce hormones and play a vital role in endocrine regulation. These tissues include the central nervous system (CNS), particularly the hypothalamus, as well as the gastrointestinal tract, adipose tissue, liver, heart, and kidney.

In some circumstances, particularly with certain neoplasms, nonendocrine tissues can produce hormones that are usually thought to be made only by endocrine glands (Box 47-1).

Box 47-1

Neoplastic Hormone Production

The ability of nonendocrine tissue to produce hormones first became apparent with the description of clinical syndromes in which some patients with lung cancer were found to make excessive amounts of AVP, a hormone usually made by the hypothalamus. Shortly afterward, people with other lung or gastrointestinal tumors were found to make ACTH, which is normally made only in the pituitary. Subsequently, many hormone-secreting neoplastic tissues were described. As the ability to measure hormones in tissues has improved and, in particular, as the capability of measuring mRNA that codes for specific peptide hormones has developed, it has become clear that hormone production by neoplastic tissue is quite common, although most tumors produce only small amounts that may have no clinical consequence.

The production of hormones by nonendocrine neoplastic cells has been most clearly defined for cancers of the lung. Several different types of lung cancer occur, each deriving from a different cell line, and yet each is capable of producing one or several hormones. The clinical syndromes that result from secretion of these hormones are often called paraneoplastic syndromes. Thus, lung cancers arising from squamous cells are sometimes associated with hypercalcemia, which results from the secretion of a protein—parathyroid hormone–related peptide—that can mimic the activity of PTH (see p. 1069). Small-cell lung cancers are notorious for their ability to secrete numerous hormones, including AVP (with resultant hyponatremia; see Box 38-3), ACTH (with resultant Cushing syndrome; see Box 50-1), and many others. Still other types of lung cancer produce other paraneoplastic syndromes.

Nearly all these ectopic, neoplastic sources of hormone produce peptide hormones. Other sources of hormone production, in addition to lung cancer, include gastrointestinal tumors, renal and bladder cancer, neural tumors, unique tumors called carcinoid tumors that can arise almost anywhere in the body, and even lymphomas and melanomas. In some patients, the symptoms and signs resulting from ectopic hormone production may appear before any other reason exists to suspect an underlying neoplasm, and these symptoms may be the key clues to the correct diagnosis.

Paracrine Factors

Numerous specialized tissues that are not part of the classic endocrine system release “factors” into the extracellular fluid that can signal neighboring cells to effect a biological response. The interleukins, or lymphokines, are an example of such paracrine factors, as are several of the growth factors, such as platelet-derived growth factor (PDGF), fibroblast growth factor, and others. These factors are not hormones in the usual sense. They are not secreted by glandular tissue, and their sites of action are usually (but not always) within the local environment. However, these signaling molecules share many properties of the classic peptide and amine hormones in that they bind to surface receptors and regulate one or more of the specific intracellular signaling mechanisms described in Chapter 3.

The distinction between the hormones of the classic endocrine systems and other biologically active secreted peptides blurs even further in the case of neuropeptides. For example, the hormone somatostatin, a 28–amino-acid peptide secreted by the δ cells of the pancreatic islet, acts in paracrine fashion on other islet cells to regulate insulin and glucagon secretion (see p. 1053). However, somatostatin is also made by hypothalamic neurons. Nerve terminals in the hypothalamus release somatostatin into the pituitary portal bloodstream (see pp. 993–994). This specialized segment of the circulatory system then carries the somatostatin from the hypothalamus to the anterior pituitary, where it inhibits the secretion of GH. Somatostatin in the hypothalamus is one of several neuropeptides that bridge the body's two major communication systems.

Hormones may be peptides, metabolites of single amino acids, or metabolites of cholesterol

Although the chemical nature of hormones is diverse, most commonly recognized mammalian hormones can be grouped into one of several classes. Table 47-1 is a list of many of the recognized classic mammalian hormones, which are divided into three groups based on their chemical structure and how they are made in the body.

TABLE 47-1

Chemical Classification of Selected Hormones

Peptide Hormones

Adrenocorticotropic hormone (ACTH)

Atrial natriuretic peptide (ANP)

Arginine vasopressin (AVP), also known as antidiuretic hormone (ADH)


Cholecystokinin (CCK)

Corticotropin-releasing hormone (CRH)

Follicle-stimulating hormone (FSH)


Gonadotropin-releasing hormone (GnRH)

Growth hormone (GH)

Growth hormone–releasing hormone (GHRH)



Insulin-like growth factors 1 and 2 (IGF-1 and IGF-2)

Luteinizing hormone (LH)

Oxytocin (OT)

Parathyroid hormone (PTH)

Prolactin (PRL)



Thyrotropin (TSH)

Thyrotropin-releasing hormone (TRH)

Vasoactive intestinal peptide (VIP)

Amino Acid–Derived Hormones

Dopamine (DA)

Epinephrine (Epi), also known as adrenaline

Norepinephrine (NE), also known as noradrenaline

Serotonin, also known as 5-hydroxytryptamine (5-HT)

Thyroxine (T4)

Triiodothyronine (T3)

Steroid Hormones



Estradiol (E2)



Peptide hormones include a large group of hormones made by a variety of endocrine tissues. Insulin, glucagon, and somatostatin are made in the pancreas. The pituitary gland makes GH; the two gonadotropin hormones, luteinizing hormone (LH) and follicle-stimulating hormone (FSH); adrenocorticotropic hormone (ACTH); thyrotropin (also called thyroid-stimulating hormone or TSH); and prolactin (PRL). The parathyroid glands make parathyroid hormone (PTH), and the thyroid gland make calcitonin.

In addition, other peptide hormones, such as somatostatin and several releasing hormones (e.g., growth hormone–releasing hormone [GHRH]), are made by the hypothalamus. Secretin, cholecystokinin, glucagon-like peptide 1 (GLP-1) and other hormones are made by the gastrointestinal tract, which is not considered a classic endocrine gland.

The synthesis of catecholamines (from tyrosine) and steroid hormones (from cholesterol) requires a number of enzymes present in only very specialized tissues. Synthesis of thyroid hormone is even more complex and is essentially restricted to the thyroid gland.

Several glands make two or more hormones. Examples are the pituitary, the pancreatic islets, and the adrenal glands. However, for the most part, individual cells within these glands are specialized to secrete a single hormone. One exception is the gonadotropin-producing cells of the pituitary, which secrete both FSH and LH.

Hormones can circulate either free or bound to carrier proteins

Once secreted, many hormones circulate freely in the blood until they reach their target tissue. Others form complexes with circulating binding protein; this use of binding proteins is particularly applicable for thyroid hormones (thyroxine [T4] and triiodothyronine [T3]), steroid hormones, insulin-like growth factor types 1 and 2 (IGF-1 and IGF-2), and GH.

Formation of a complex between a hormone and a circulating binding protein serves several functions. First, it provides the blood with a reservoir or pool of the hormone and thus minimizes minute-to-minute fluctuations in hormone concentration. Second, it extends the half-life of the hormone in the circulation. For example, >99.99% of T4 circulates bound to one of three binding proteins (see pp. 1008–1009); the half-life of circulating bound T4 is 7 to 8 days, whereas the half-life of free T4 is only several minutes. The hormones bound to plasma binding proteins appear to be those whose actions are long term—in particular, those involving induction of the synthesis of new protein in target tissues. Hormones that play a major short-term role in the regulation of body metabolism (e.g., catecholamines, many peptide hormones) circulate freely without associated binding proteins.

The presence of plasma binding proteins can affect the total circulating concentration of a hormone without necessarily affecting the concentration of unbound or free hormone in the blood. For example, during pregnancy the liver's synthesis of T4-binding globulin increases. Because this protein avidly binds T4, the free T4 concentration ordinarily would fall. However, the pituitary senses the small decline in free T4 levels and secretes more TSH. As a result, the thyroid makes more T4, so plasma levels of total T4 rise. However, the free T4 level does not rise.

Immunoassays allow measurement of circulating hormones

In the late 1950s, Solomon Berson and Rosalyn Yalow demonstrated that patients who receive insulin form antibodies directed against the insulin molecule. This observation was important in two respects:

1. It advanced the principle that the body's immune system can react to endogenous compounds; therefore, autoimmunity or reaction to self-antigens does occur. This notion is a fundamental tenet of our current understanding of many autoimmune diseases, among which are endocrine diseases such as type 1 diabetes mellitus, autoimmune hypothyroidism, Graves disease (a common form of autoimmune hyperthyroidism), and Addison disease (one form of adrenal insufficiency). Before the description of insulin autoantibodies, it was thought that the immune system simply did not react to self-antigens.

2. Because antibodies with a high affinity for insulin were induced in patients who were treated with insulin, Berson and Yalow reasoned that these antibodies could be used to measure the amount of insulin in serum. Figure 47-1 illustrates the principle of a radioimmunoassay and how it is used to measure the concentration of a hormone (or other chemicals). If we incubate increasing amounts of a radiolabeled hormone with an antibody to that hormone, the quantity of labeled hormone that is bound to the antibody yields a saturation plot (see Fig. 47-1A). If we now add unlabeled hormone to the incubation mixture, less radioactively labeled hormone remains complexed to the antibody as unlabeled hormone takes its place. The more unlabeled hormone we add, the less labeled hormone is bound to the antibody (see Fig. 47-1B). A displacement curve is created by plotting the amount of radioactively labeled hormone complexed to the antibody as a function of the concentration of unlabeled hormone that is added (see Fig. 47-1C). This displacement curve can then be used as a standard curve to estimate the amount of hormone present in unknown samples. This estimate is accurate only if two assumptions hold true: first, that nothing else in the unknown mixture binds with the antibody other than the hormone under study, and second, that nothing in the unknown sample interferes with normal binding of the hormone to the antibody.


FIGURE 47-1 Principles of the radioimmunoassay.

Antibodies that are highly specific for the chemical structure of interest can frequently be obtained. Moreover, these antibodies are of sufficiently high affinity to bind even the often minute amounts of hormone that is circulating in blood. Thus, radioimmunoassays—and recent adaptations that substitute chemiluminescent or enzymatic detection for radioactivity—have emerged as a potent and popular tool. Immunoassays are now used for the measurement of virtually all hormones, as well as many drugs, viruses, and toxins. Much of our understanding of the physiology of hormone secretion and action has been gained by the use of immunoassay methodology. Yalow shared the 1977 Nobel Prize in Medicine or Physiology for the discovery of the radioimmunoassay (Berson died before the honor was bestowed). imageN47-1


Rosalyn Yalow

For more information about Rosalyn Yalow and the work that led to her Nobel Prize, visit (accessed September 2014).

Hormones can have complementary and antagonistic actions

Regulation of many complex physiological functions necessitates the complementary action of several hormones. This principle is true both for minute-to-minute homeostasis and for more long-term processes. For example, epinephrine (adrenaline), cortisol, and glucagon each contribute to the body's response to a short-term bout of exercise (e.g., swimming the 50-m butterfly or running the 100-m dash). If any of these hormones is missing, exercise performance is adversely affected, and even more seriously, severe hypoglycemia and hyperkalemia (elevated plasma [K+]) may develop. On a longer time scale, GH, insulin, IGF-1, thyroid hormone, and sex steroids are all needed for normal growth. Deficiency of GH, IGF-1, or thyroid hormone results in dwarfism. Deficiency of sex steroids, cortisol, or insulin produces less severe disturbances of growth.

Integration of hormone action can also involve hormones that exert antagonistic actions. In this case, the overall effect on an end organ depends on the balance between opposing influences. One example is the counterpoised effects of insulin and glucagon on blood glucose levels. Insulin lowers glucose levels by inhibiting glycogenolysis and gluconeogenesis in the liver and by stimulating glucose uptake into muscle and adipose tissue. Glucagon, in contrast, stimulates hepatic glycogenolysis and gluconeogenesis. Whereas glucagon does not appear to directly antagonize glucose uptake by muscle or fat, epinephrine (which, like glucagon, is released in response to hypoglycemia) does. Balancing of tissue function by opposing humoral effector mechanisms appears to be an important regulatory strategy for refining the control of many cellular functions.

Endocrine regulation occurs through feedback control

The key to any regulatory system is its ability to sense when it should increase or decrease its activity. For the endocrine system, this function is accomplished by feedback control of hormone secretion (Fig. 47-2A). The hormone-secreting cell functions as a “sensor” that continually monitors the circulating concentration of some regulated variable. This variable may be a metabolic factor (e.g., glucose concentration) or the activity of another hormone. When the endocrine gland senses that too much (or too little) of the regulated variable is circulating in blood, it responds by decreasing (or increasing) the rate of hormone secretion. This response in turn affects the metabolic or secretory behavior of the target tissue, which may either directly feed back to the sensing cell or stimulate some other cell that eventually signals the sensor regarding whether the altered function of the endocrine gland has been effective.


FIGURE 47-2 Feedback control of hormone secretion. A, A sensor (e.g., a β cell in a pancreatic islet) detects some regulated variable (e.g., plasma [glucose]) and responds by modulating its secretion of a hormone (e.g., insulin). This hormone, in turn, acts on target 1 (e.g., liver or muscle) to modulate its production of another hormone or a metabolite (e.g., reducing [glucose]), which may affect target 2 (e.g., making less glucose available to the brain). In addition, the other hormone or metabolite feeds back on the original sensor cell. B, Under the influence of the cerebral cortex, the hypothalamus releases CRH, which stimulates the anterior pituitary to release ACTH, which in turn stimulates the adrenal cortex to release cortisol. The cortisol acts on a number of effector organs. In addition, the cortisol feeds back on both the anterior pituitary and the hypothalamus.

A simple example is insulin secretion by the β cells of the pancreas. Increases in plasma [glucose] are sensed by the β cell, which secretes insulin in response. The rise in plasma [insulin] acts on the liver to decrease the synthesis of glucose and on the muscle to promote the storage of glucose. As a result, plasma [glucose] falls, and this decrease is sensed by the β cell, which reduces the rate of insulin secretion. This arrangement represents a very simple feedback system. Other systems can be quite complex; however, even this simple system involves the recognition of two circulating signals. The liver and muscle recognize the increase in plasma [insulin] as one signal, and the pancreatic β cell (the cell responsible for insulin secretion) recognizes the signal of a rise or decline in blood [glucose] as the other signal. In each case, the sensing system within a particular tissue is linked to an effector system that transduces the signal to the appropriate biological response.

Endocrine regulation can involve hierarchic levels of control

Faced with a stress (e.g., a severe infection or extensive blood loss), the cerebral cortex stimulates the hypothalamus to release a neuropeptide called corticotropin-releasing hormone (CRH; see Fig. 47-2B). Carried by the pituitary portal system (blood vessels that connect the hypothalamus to the anterior pituitary), CRH stimulates the anterior pituitary to release another hormone, ACTH, which in turn stimulates the adrenal cortical cells to synthesize cortisol. Cortisol regulates vascular tone as well as metabolic and growth functions in a variety of tissues.

This stress response therefore involves the cerebral cortex, specialized neuroendocrine tissue in the hypothalamus, as well as two glands, the pituitary and the adrenal cortex. This hierarchic control is regulated by feedback, just as in the simple feedback between plasma [glucose] and insulin. Within this CRH-ACTH-cortisol axis, feedback can occur at several levels. Cortisol inhibits the production of CRH by the hypothalamus as well as the sensitivity of the pituitary to a standard dose of CRH, which directly reduces ACTH release.

Feedback in hierarchic endocrine control systems can be quite complex and frequently involves interaction between the CNS and the endocrine system. Other examples are regulation of the female menstrual cycle (see pp.1110–1116) and regulation of GH secretion (see pp. 992–994).

Among the classic endocrine tissues, the pituitary (also known as the hypophysis) plays a special role (Fig. 47-3). Located at the base of the brain, just below the hypothalamus, the pituitary resides within a saddle-shaped cavity called the sella turcica (from the Latin sella [saddle] + turcica [Turkish]), which has bony anterior, posterior, and inferior borders and fibrous tissue that separate it from venous sinuses on either side. The human pituitary is composed of both an anterior lobe and a posterior lobe. Through vascular and neural connections, the pituitary bridges and integrates neural and endocrine mechanisms of homeostasis. The pituitary is a highly vascular tissue. The posterior pituitary receives arterial blood, whereas the anterior pituitary receives only portal venous inflow from the median eminence. The pituitary portal system is particularly important in carrying neuropeptides from the hypothalamus and pituitary stalk to the anterior pituitary.


FIGURE 47-3 Hypothalamic-pituitary axis. The pituitary (or hypophysis) is actually two glands—an anterior pituitary and a posterior pituitary (or neurohypophysis). Although in both cases the hypothalamus controls the secretion of hormones by the pituitary, the mechanisms are very different. Anterior pituitary: Small-bodied neurons in the hypothalamus secrete releasing and inhibitory factors into a rich, funnel-shaped plexus of capillaries that penetrates the median eminence and surrounds the infundibular recess. The cell bodies of these neurons are in several nuclei that surround the third ventricle. These include the arcuate nucleus, the paraventricular and ventromedial nuclei, and the medial preoptic and periventricular regions. The capillaries (primary plexus), which are outside of the blood-brain barrier, coalesce into long portal veins that carry the releasing and inhibitory factors down the pituitary stalk to the anterior pituitary. Other neurons secrete their releasing factors into a capillary plexus that is much further down the pituitary stalk; short portal veins carry these releasing factors to the anterior pituitary. There, the portal veins break up into the secondary capillary plexus of the anterior pituitary and deliver the releasing and inhibitory factors to the “troph” cells that actually secrete the anterior pituitary hormones (GH, TSH, ACTH, LH, FSH, and PRL) that enter the systemic bloodstream and distribute throughout the body. Posterior pituitary: Large neurons in the paraventricular and supraoptic nuclei of the hypothalamus actually synthesize the hormones AVP and oxytocin (OT). These hormones travel down the axons of the hypothalamic neurons to the posterior pituitary, where the nerve terminals release the hormones, like neurotransmitters, into a rich plexus of vessels.

The anterior pituitary regulates reproduction, growth, energy metabolism, and stress responses

Glandular tissue in the anterior lobe of the pituitary synthesizes and secretes six peptide hormones: GH, TSH, ACTH, LH, FSH, and PRL. In each case, secretion of these hormones is under the control of hypothalamic releasing hormones (Table 47-2). The sources of these releasing hormones are small-diameter neurons located mainly in the “periventricular” portion of the hypothalamus that surrounds the third ventricle (see pp. 275–277). These small-diameter neurons synthesize the releasing hormones and discharge them into the median eminence and neural stalk, where they enter leaky capillaries—which are not part of the blood-brain barrier (see pp. 284–287). The releasing hormones then travel via the pituitary portal veins to the anterior pituitary. Once in the anterior pituitary, a releasing factor (e.g., GHRH) stimulates specialized cells to release a particular peptide hormone (e.g., GH) into the systemic bloodstream. The integrative function of the anterior pituitary can be appreciated by realizing that the main target for four of the anterior pituitary hormones (i.e., TSH, ACTH, and LH/FSH) is other endocrine tissue. Thus, these four anterior pituitary hormones are themselves “releasing hormones” that trigger the secretion of specific hormones. For example, TSH causes the follicular cells in the thyroid gland to synthesize and release thyroid hormones. The mechanism by which the pituitary regulates these endocrine glands is discussed in detail in Chapters 48 through 50.

TABLE 47-2

Hypothalamic and Pituitary Hormones






GHRH (inhibited by somatostatin)



Stimulates IGF-1 production by multiple somatic tissues, especially liver




Thyroid follicular cells, stimulated to make thyroid hormone




Fasciculata and reticularis cells of the adrenal cortex, to make corticosteroids




Ovarian follicular cells, to make estrogens and progestins
Sertoli cells, to initiate spermatogenesis




Leydig cells, to make testosterone

(inhibited by dopamine)



Mammary glands, initiates and maintains milk production







Collecting duct, to increase water permeability



Uterus, to contract
Mammary gland, to eject milk

GnRH, gonadotropin-releasing hormone; OT, oxytocin.

GH also acts as a releasing factor in that it regulates the production of another hormone, IGF-1. IGF-1 is made in principally nonendocrine tissues (e.g., liver, kidney, muscle, and cartilage). Nevertheless, IGF-1 in the circulation feeds back on the hypothalamus to decrease GHRH level and on the pituitary to inhibit GH secretion. In this respect, the GH–IGF-1 axis is similar to axes involving classic pituitary pathways, such as the thyrotropin-releasing hormone (TRH)–TSH axis.

Regulation of PRL secretion differs from that of other anterior pituitary hormones in that no endocrine feedback mechanism has yet been identified. In humans, the pituitary secretes PRL at relatively low levels throughout life. However, its major biological action is important only in women during lactation. Although PRL is not part of an identified feedback system, its release is controlled. Left to its own devices, the anterior pituitary would secrete high levels of PRL. However, secretion of PRL is normally inhibited by the release of dopamine (DA) from the hypothalamus (see pp. 993–994). During breast stimulation, neural afferents inhibit hypothalamic DA release, thus inhibiting release of the inhibitor and permitting lactation to proceed. PRL receptors are present on multiple tissues other than the breast. However, other physiological actions beyond lactation have not been well characterized.

The posterior pituitary regulates water balance and uterine contraction

Unlike the anterior pituitary, the posterior lobe of the pituitary is actually part of the brain. The posterior pituitary (or neurohypophysis) contains the nerve endings of large-diameter neurons whose cell bodies are in the supraoptic and paraventricular nuclei of the hypothalamus (see Fig. 47-3). Recall that the hypothalamic neurons that produce releasing factors, which act on “troph” cells in the anterior pituitary, are small-diameter neurons. The large-diameter hypothalamic neurons synthesize arginine vasopressin (AVP) and oxytocin and then transport these hormones along their axons to the site of release in the posterior pituitary. Thus, like the anterior pituitary, the posterior pituitary releases peptide hormones. Also as in the anterior pituitary, release of these hormones is under ultimate control of the hypothalamus. However, the hypothalamic axons traveling to the posterior pituitary replace both the transport of releasing factors by the portal system of the anterior pituitary and the synthesis of hormones by the anterior pituitary “troph” cells. Although the posterior pituitary is part of the brain, it is one of the so-called circumventricular organs (see pp. 284–285) whose vessels breach the blood-brain barrier and allow the secreted AVP and oxytocin to reach the systemic circulation.

AVP (or antidiuretic hormone, ADH) is a neuropeptide hormone that acts on the collecting duct of the kidney to increase water reabsorption (see pp. 817–820). Oxytocin (OT) is the other neuropeptide secreted by the posterior pituitary. However, its principal biological action relates to stimulation of smooth-muscle contraction by the uterus during parturition (see pp. 1145–1146) and by the mammary gland during suckling (see p. 1150).

These two posterior pituitary hormones appear to have a common ancestor—vasotocin—in amphibians and other submammalian species. The two peptide hormones secreted by the posterior pituitary are each made by hypothalamic neurons as a precursor molecule that is transported along the axons of the hypothalamic neurons to the posterior pituitary. For AVP, this precursor protein is proneurophysin II (see p. 845 and Fig. 40-8), whereas for oxytocin it is proneurophysin I. In each case, cleavage of the precursor occurs during transport along the axons from the hypothalamus to the posterior pituitary. At the time that the active neurohormone (e.g., AVP) is secreted, its residual neurophysin is co-secreted stoichiometrically. Defects in the processing of the neurophysin precursor can lead to impaired secretion of active hormone. In the case of AVP, the result is partial or complete diabetes insipidus.




Length (m)



Area of apical plasma membrane (m2)









Crypts or glands






Nutrient absorption



Active Na+ absorption



Active K+ secretion