Organization of Endocrine Control

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

As shown in Figure 3-1 A , 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. 3-1 B ). 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. 3-1 C ). 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.

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.

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 [T ₄ ] and triiodothyronine [T ₃ ]), 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 T ₄ circulates bound to one of three binding proteins (see pp. 1008–1009 ); the half-life of circulating bound T ₄ is 7 to 8 days, whereas the half-life of free T ₄ 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 T ₄ -binding globulin increases. Because this protein avidly binds T ₄ , the free T ₄ concentration ordinarily would fall. However, the pituitary senses the small decline in free T ₄ levels and secretes more TSH. As a result, the thyroid makes more T ₄ , so plasma levels of total T ₄ rise. However, the free T ₄ 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. 47-1 A ). 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. 47-1 B ). 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. 47-1 C ). 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.

  

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). N47-1

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. 47-2 A ). 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.

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. 47-2 B ). 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.