Category: 6. Endocrine System

The endocrine system arises from all three embryonic germ layers. The endocrine glands that produce the steroid hormones, such as the gonads and adrenal cortex, arise from the mesoderm. In contrast, endocrine glands that arise from the endoderm and ectoderm produce the amine, peptide, and protein hormones. The pituitary gland arises from two distinct areas of the ectoderm: the anterior pituitary gland arises from the oral ectoderm, whereas the posterior pituitary gland arises from the neural ectoderm at the base of the hypothalamus. The pineal gland also arises from the ectoderm. The two structures of the adrenal glands arise from two different germ layers: the adrenal cortex from the mesoderm and the adrenal medulla from ectoderm neural cells. The endoderm gives rise to the thyroid and parathyroid glands, as well as the pancreas and the thymus.

As the body ages, changes occur that affect the endocrine system, sometimes altering the production, secretion, and catabolism of hormones. For example, the structure of the anterior pituitary gland changes as vascularization decreases and the connective tissue content increases with increasing age. This restructuring affects the gland’s hormone production. For example, the amount of human growth hormone that is produced declines with age, resulting in the reduced muscle mass commonly observed in the elderly.

The adrenal glands also undergo changes as the body ages; as fibrous tissue increases, the production of cortisol and aldosterone decreases. Interestingly, the production and secretion of epinephrine and norepinephrine remain normal throughout the aging process.

A well-known example of the aging process affecting an endocrine gland is menopause and the decline of ovarian function. With increasing age, the ovaries decrease in both size and weight and become progressively less sensitive to gonadotropins. This gradually causes a decrease in estrogen and progesterone levels, leading to menopause and the inability to reproduce. Low levels of estrogens and progesterone are also associated with some disease states, such as osteoporosis, atherosclerosis, and hyperlipidemia, or abnormal blood lipid levels.

Testosterone levels also decline with age, a condition called andropause (or viropause); however, this decline is much less dramatic than the decline of estrogens in women, and much more gradual, rarely affecting sperm production until very old age. Although this means that males maintain their ability to father children for decades longer than females, the quantity, quality, and motility of their sperm is often reduced.

As the body ages, the thyroid gland produces less of the thyroid hormones, causing a gradual decrease in the basal metabolic rate. The lower metabolic rate reduces the production of body heat and increases levels of body fat. Parathyroid hormones, on the other hand, increase with age. This may be because of reduced dietary calcium levels, causing a compensatory increase in parathyroid hormone. However, increased parathyroid hormone levels combined with decreased levels of calcitonin (and estrogens in women) can lead to osteoporosis as PTH stimulates demineralization of bones to increase blood calcium levels. Notice that osteoporosis is common in both elderly males and females.

Increasing age also affects glucose metabolism, as blood glucose levels spike more rapidly and take longer to return to normal in the elderly. In addition, increasing glucose intolerance may occur because of a gradual decline in cellular insulin sensitivity. Almost 27 percent of Americans aged 65 and older have diabetes.

In your study of anatomy and physiology, you have already encountered a few of the many organs of the body that have secondary endocrine functions. Here, you will learn about the hormone-producing activities of the heart, gastrointestinal tract, kidneys, skeleton, adipose tissue, skin, and thymus.

Heart:

When the body experiences an increase in blood volume or pressure, the cells of the heart’s atrial wall stretch. In response, specialized cells in the wall of the atria produce and secrete the peptide hormone atrial natriuretic peptide (ANP). ANP signals the kidneys to reduce sodium reabsorption, thereby decreasing the amount of water reabsorbed from the urine filtrate and reducing blood volume. Other actions of ANP include the inhibition of renin secretion, thus inhibition of the renin-angiotensin-aldosterone system (RAAS) and vasodilation. Therefore, ANP aids in decreasing blood pressure, blood volume, and blood sodium levels.

Gastrointestinal Tract:

The endocrine cells of the GI tract are located in the mucosa of the stomach and small intestine. Some of these hormones are secreted in response to eating a meal and aid in digestion. An example of a hormone secreted by the stomach cells is gastrin, a peptide hormone secreted in response to stomach distention that stimulates the release of hydrochloric acid. Secretin is a peptide hormone secreted by the small intestine as acidic chyme (partially digested food and fluid) moves from the stomach. It stimulates the release of bicarbonate from the pancreas, which buffers the acidic chyme, and inhibits the further secretion of hydrochloric acid by the stomach. Cholecystokinin (CCK) is another peptide hormone released from the small intestine. It promotes the secretion of pancreatic enzymes and the release of bile from the gallbladder, both of which facilitate digestion. Other hormones produced by the intestinal cells aid in glucose metabolism, such as by stimulating the pancreatic beta cells to secrete insulin, reducing glucagon secretion from the alpha cells, or enhancing cellular sensitivity to insulin.

Kidneys:

The kidneys participate in several complex endocrine pathways and produce certain hormones. A decline in blood flow to the kidneys stimulates them to release the enzyme renin, triggering the renin-angiotensin-aldosterone (RAAS) system, and stimulating the reabsorption of sodium and water. The reabsorption increases blood flow and blood pressure. The kidneys also play a role in regulating blood calcium levels through the production of calcitriol from vitamin D₃, which is released in response to the secretion of parathyroid hormone (PTH). In addition, the kidneys produce the hormone erythropoietin (EPO) in response to low oxygen levels. EPO stimulates the production of red blood cells (erythrocytes) in the bone marrow, thereby increasing oxygen delivery to tissues. You may have heard of EPO as a performance-enhancing drug (in a synthetic form).

Skeleton:

Although bone has long been recognized as a target for hormones, only recently have researchers recognized that the skeleton itself produces at least two hormones. Fibroblast growth factor 23 (FGF23) is produced by bone cells in response to increased blood levels of vitamin D₃ or phosphate. It triggers the kidneys to inhibit the formation of calcitriol from vitamin D₃ and to increase phosphorus excretion. Osteocalcin, produced by osteoblasts, stimulates the pancreatic beta cells to increase insulin production. It also acts on peripheral tissues to increase their sensitivity to insulin and their utilization of glucose.

Adipose Tissue:

Adipose tissue produces and secretes several hormones involved in lipid metabolism and storage. One important example is leptin, a protein manufactured by adipose cells that circulates in amounts directly proportional to levels of body fat. Leptin is released in response to food consumption and acts by binding to brain neurons involved in energy intake and expenditure. Binding of leptin produces a feeling of satiety after a meal, thereby reducing appetite. It also appears that the binding of leptin to brain receptors triggers the sympathetic nervous system to regulate bone metabolism, increasing deposition of cortical bone. Adiponectin—another hormone synthesized by adipose cells—appears to reduce cellular insulin resistance and to protect blood vessels from inflammation and atherosclerosis. Its levels are lower in people who are obese, and rise following weight loss.

Skin:

The skin functions as an endocrine organ in the production of the inactive form of vitamin D₃, cholecalciferol. When cholesterol present in the epidermis is exposed to ultraviolet radiation, it is converted to cholecalciferol, which then enters the blood. In the liver, cholecalciferol is converted to an intermediate that travels to the kidneys and is further converted to calcitriol, the active form of vitamin D₃. Vitamin D is important in a variety of physiological processes, including intestinal calcium absorption and immune system function. In some studies, low levels of vitamin D have been associated with increased risks of cancer, severe asthma, and multiple sclerosis. Vitamin D deficiency in children causes rickets, and in adults, osteomalacia—both of which are characterized by bone deterioration.

Thymus:

The thymus is an organ of the immune system that is larger and more active during infancy and early childhood, and begins to atrophy as we age. Its endocrine function is the production of a group of hormones called thymosins that contribute to the development and differentiation of T lymphocytes, which are immune cells. Although the role of thymosins is not yet well understood, it is clear that they contribute to the immune response. Thymosins have been found in tissues other than the thymus and have a wide variety of functions, so the thymosins cannot be strictly categorized as thymic hormones.

Liver:

The liver is responsible for secreting at least four important hormones or hormone precursors: insulin-like growth factor (somatomedin), angiotensinogen, thrombopoietin, and hepcidin. Insulin-like growth factor-1 is the immediate stimulus for growth in the body, especially of the bones. Angiotensinogen is the precursor to angiotensin, mentioned earlier, which increases blood pressure. Thrombopoietin stimulates the production of the blood’s platelets. Hepcidins block the release of iron from cells in the body, helping to regulate iron homeostasis in our body fluids. The major hormones of these other organs are summarized in Table 17.8.Organs with Secondary Endocrine Functions and Their Major Hormones

Organ	Major hormones	Effects
Heart	Atrial natriuretic peptide (ANP)	Reduces blood volume, blood pressure, and Na+ concentration
Gastrointestinal tract	Gastrin, secretin, and cholecystokinin	Aid digestion of food and buffering of stomach acids
Gastrointestinal tract	Glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide 1 (GLP-1)	Stimulate beta cells of the pancreas to release insulin
Kidneys	Renin	Stimulates release of aldosterone
Kidneys	Calcitriol	Aids in the absorption of Ca2+
Kidneys	Erythropoietin	Triggers the formation of red blood cells in the bone marrow
Skeleton	FGF23	Inhibits production of calcitriol and increases phosphate excretion
Skeleton	Osteocalcin	Increases insulin production
Adipose tissue	Leptin	Promotes satiety signals in the brain
Adipose tissue	Adiponectin	Reduces insulin resistance
Skin	Cholecalciferol	Modified to form vitamin D
Thymus (and other organs)	Thymosins	Among other things, aids in the development of T lymphocytes of the immune system
Liver	Insulin-like growth factor-1	Stimulates bodily growth
Liver	Angiotensinogen	Raises blood pressure
Liver	Thrombopoietin	Causes increase in platelets
Liver	Hepcidin	Blocks release of iron into body fluids

Table17.8

The pancreas is a long, slender organ, most of which is located posterior to the bottom half of the stomach (Figure 17.18). Although it is primarily an exocrine gland, secreting a variety of digestive enzymes, the pancreas has an endocrine function. Its pancreatic islets—clusters of cells formerly known as the islets of Langerhans—secrete the hormones glucagon, insulin, somatostatin, and pancreatic polypeptide (PP).

Figure 17.18Pancreas The pancreatic exocrine function involves the acinar cells secreting digestive enzymes that are transported into the small intestine by the pancreatic duct. Its endocrine function involves the secretion of insulin (produced by beta cells) and glucagon (produced by alpha cells) within the pancreatic islets. These two hormones regulate the rate of glucose metabolism in the body. The micrograph reveals pancreatic islets. LM × 760. (Micrograph provided by the Regents of University of Michigan Medical School © 2012)

Cells and Secretions of the Pancreatic Islets:

The pancreatic islets each contain four varieties of cells:

• The alpha cell produces the hormone glucagon and makes up approximately 20 percent of each islet. Glucagon plays an important role in blood glucose regulation; low blood glucose levels stimulate its release.
• The beta cell produces the hormone insulin and makes up approximately 75 percent of each islet. Elevated blood glucose levels stimulate the release of insulin.
• The delta cell accounts for four percent of the islet cells and secretes the peptide hormone somatostatin. Recall that somatostatin is also released by the hypothalamus (as GHIH), and the stomach and intestines also secrete it. An inhibiting hormone, pancreatic somatostatin inhibits the release of both glucagon and insulin.
• The PP cell accounts for about one percent of islet cells and secretes the pancreatic polypeptide hormone. It is thought to play a role in appetite, as well as in the regulation of pancreatic exocrine and endocrine secretions. Pancreatic polypeptide released following a meal may reduce further food consumption; however, it is also released in response to fasting.

Regulation of Blood Glucose Levels by Insulin and Glucagon:

Glucose is required for cellular respiration and is the preferred fuel for all body cells. The body derives glucose from the breakdown of the carbohydrate-containing foods and drinks we consume. Glucose not immediately taken up by cells for fuel can be stored by the liver and muscles as glycogen, or converted to triglycerides and stored in the adipose tissue. Hormones regulate both the storage and the utilization of glucose as required. Receptors located in the pancreas sense blood glucose levels, and subsequently the pancreatic cells secrete glucagon or insulin to maintain normal levels.

Glucagon:

Receptors in the pancreas can sense the decline in blood glucose levels, such as during periods of fasting or during prolonged labor or exercise (Figure 17.19). In response, the alpha cells of the pancreas secrete the hormone glucagon, which has several effects:

• It stimulates the liver to convert its stores of glycogen back into glucose. This response is known as glycogenolysis. The glucose is then released into the circulation for use by body cells.
• It stimulates the liver to take up amino acids from the blood and convert them into glucose. This response is known as gluconeogenesis.
• It stimulates lipolysis, the breakdown of stored triglycerides into free fatty acids and glycerol. Some of the free glycerol released into the bloodstream travels to the liver, which converts it into glucose. This is also a form of gluconeogenesis.

Taken together, these actions increase blood glucose levels. The activity of glucagon is regulated through a negative feedback mechanism; rising blood glucose levels inhibit further glucagon production and secretion.

Figure 17.19Homeostatic Regulation of Blood Glucose Levels Blood glucose concentration is tightly maintained between 70 mg/dL and 110 mg/dL. If blood glucose concentration rises above this range, insulin is released, which stimulates body cells to remove glucose from the blood. If blood glucose concentration drops below this range, glucagon is released, which stimulates body cells to release glucose into the blood.

Insulin:

The primary function of insulin is to facilitate the uptake of glucose into body cells. Red blood cells, as well as cells of the brain, liver, kidneys, and the lining of the small intestine, do not have insulin receptors on their cell membranes and do not require insulin for glucose uptake. Although all other body cells do require insulin if they are to take glucose from the bloodstream, skeletal muscle cells and adipose cells are the primary targets of insulin.

The presence of food in the intestine triggers the release of gastrointestinal tract hormones such as glucose-dependent insulinotropic peptide (previously known as gastric inhibitory peptide). This is in turn the initial trigger for insulin production and secretion by the beta cells of the pancreas. Once nutrient absorption occurs, the resulting surge in blood glucose levels further stimulates insulin secretion.

Precisely how insulin facilitates glucose uptake is not entirely clear. However, insulin appears to activate a tyrosine kinase receptor, triggering the phosphorylation of many substrates within the cell. These multiple biochemical reactions converge to support the movement of intracellular vesicles containing facilitative glucose transporters to the cell membrane. In the absence of insulin, these transport proteins are normally recycled slowly between the cell membrane and cell interior. Insulin triggers the rapid movement of a pool of glucose transporter vesicles to the cell membrane, where they fuse and expose the glucose transporters to the extracellular fluid. The transporters then move glucose by facilitated diffusion into the cell interior.

Insulin also reduces blood glucose levels by stimulating glycolysis, the metabolism of glucose for generation of ATP. Moreover, it stimulates the liver to convert excess glucose into glycogen for storage, and it inhibits enzymes involved in glycogenolysis and gluconeogenesis. Finally, insulin promotes triglyceride and protein synthesis. The secretion of insulin is regulated through a negative feedback mechanism. As blood glucose levels decrease, further insulin release is inhibited. The pancreatic hormones are summarized in Table 17.7.Hormones of the Pancreas

Associated hormones	Chemical class	Effect
Insulin (beta cells)	Protein	Reduces blood glucose levels
Glucagon (alpha cells)	Protein	Increases blood glucose levels
Somatostatin (delta cells)	Protein	Inhibits insulin and glucagon release
Pancreatic polypeptide (PP cells)	Protein	Role in appetite

Table17.7

This section briefly discusses the hormonal role of the gonads—the male testes and female ovaries—which produce the sex cells (sperm and ova) and secrete the gonadal hormones. The roles of the gonadotropins released from the anterior pituitary (FSH and LH) were discussed earlier.

The primary hormone produced by the male testes is testosterone, a steroid hormone important in the development of the male reproductive system, the maturation of sperm cells, and the development of male secondary sex characteristics such as a deepened voice, body hair, and increased muscle mass. Interestingly, testosterone is also produced in the female ovaries, but at a much reduced level. In addition, the testes produce the peptide hormone inhibin, which inhibits the secretion of FSH from the anterior pituitary gland. FSH stimulates spermatogenesis.

The primary hormones produced by the ovaries are estrogens, which include estradiol, estriol, and estrone. Estrogens play an important role in a larger number of physiological processes, including the development of the female reproductive system, regulation of the menstrual cycle, the development of female secondary sex characteristics such as increased adipose tissue and the development of breast tissue, and the maintenance of pregnancy. Another significant ovarian hormone is progesterone, which contributes to regulation of the menstrual cycle and is important in preparing the body for pregnancy as well as maintaining pregnancy. In addition, the granulosa cells of the ovarian follicles produce inhibin, which—as in males—inhibits the secretion of FSH.During the initial stages of pregnancy, an organ called the placenta develops within the uterus. The placenta supplies oxygen and nutrients to the fetus, excretes waste products, and produces and secretes estrogens and progesterone. The placenta produces human chorionic gonadotropin (hCG) as well.

The hCG hormone promotes progesterone synthesis and reduces the mother’s immune function to protect the fetus from immune rejection. It also secretes human placental lactogen (hPL), which plays a role in preparing the breasts for lactation, and relaxin, which is thought to help soften and widen the pubic symphysis in preparation for childbirth. The hormones controlling reproduction are summarized in Table 17.6.Reproductive Hormones

Gonad	Associated hormones	Chemical class	Effect
Testes	Testosterone	Steroid	Stimulates development of male secondary sex characteristics and sperm production
Testes	Inhibin	Protein	Inhibits FSH release from pituitary
Ovaries	Estrogens and progesterone	Steroid	Stimulate development of female secondary sex characteristics and prepare the body for childbirth
Placenta	Human chorionic gonadotropin	Protein	Promotes progesterone synthesis during pregnancy and inhibits immune response against fetus

Table17.6

Recall that the hypothalamus, part of the diencephalon of the brain, sits inferior and somewhat anterior to the thalamus. Inferior but somewhat posterior to the thalamus is the pineal gland, a tiny endocrine gland whose functions are not entirely clear. The pinealocyte cells that make up the pineal gland are known to produce and secrete the amine hormone melatonin, which is derived from serotonin.

The secretion of melatonin varies according to the level of light received from the environment. When photons of light stimulate the retinas of the eyes, a nerve impulse is sent to a region of the hypothalamus called the suprachiasmatic nucleus (SCN), which is important in regulating biological rhythms. From the SCN, the nerve signal is carried to the spinal cord and eventually to the pineal gland, where the production of melatonin is inhibited. As a result, blood levels of melatonin fall, promoting wakefulness. In contrast, as light levels decline—such as during the evening—melatonin production increases, boosting blood levels and causing drowsiness.

The secretion of melatonin may influence the body’s circadian rhythms, the dark-light fluctuations that affect not only sleepiness and wakefulness, but also appetite and body temperature. Interestingly, children have higher melatonin levels than adults, which may prevent the release of gonadotropins from the anterior pituitary, thereby inhibiting the onset of puberty. Finally, an antioxidant role of melatonin is the subject of current research.

Jet lag occurs when a person travels across several time zones and feels sleepy during the day or wakeful at night. Traveling across multiple time zones significantly disturbs the light-dark cycle regulated by melatonin. It can take up to several days for melatonin synthesis to adjust to the light-dark patterns in the new environment, resulting in jet lag. Some air travelers take melatonin supplements to induce sleep.

The adrenal glands are wedges of glandular and neuroendocrine tissue adhering to the top of the kidneys by a fibrous capsule (Figure 17.17). The adrenal glands have a rich blood supply and experience one of the highest rates of blood flow in the body. They are served by several arteries branching off the aorta, including the suprarenal and renal arteries. Blood flows to each adrenal gland at the adrenal cortex and then drains into the adrenal medulla. Adrenal hormones are released into the circulation via the left and right suprarenal veins.

Figure 17.17Adrenal Glands Both adrenal glands sit atop the kidneys and are composed of an outer cortex and an inner medulla, all surrounded by a connective tissue capsule. The cortex can be subdivided into additional zones, all of which produce different types of hormones. LM × 204. (Micrograph provided by the Regents of University of Michigan Medical School © 2012)

The adrenal gland consists of an outer cortex of glandular tissue and an inner medulla of nervous tissue. The cortex itself is divided into three zones: the zona glomerulosa, the zona fasciculata, and the zona reticularis. Each region secretes its own set of hormones.

The adrenal cortex, as a component of the hypothalamic-pituitary-adrenal (HPA) axis, secretes steroid hormones important for the regulation of the long-term stress response, blood pressure and blood volume, nutrient uptake and storage, fluid and electrolyte balance, and inflammation. The HPA axis involves the stimulation of hormone release of adrenocorticotropic hormone (ACTH) from the pituitary by the hypothalamus. ACTH then stimulates the adrenal cortex to produce the hormone cortisol. This pathway will be discussed in more detail below.

The adrenal medulla is neuroendocrine tissue composed of postganglionic sympathetic nervous system (SNS) neurons. It is really an extension of the autonomic nervous system, which regulates homeostasis in the body. The sympathomedullary (SAM) pathway involves the stimulation of the medulla by impulses from the hypothalamus via neurons from the thoracic spinal cord. The medulla is stimulated to secrete the amine hormones epinephrine and norepinephrine.

One of the major functions of the adrenal gland is to respond to stress. Stress can be either physical or psychological or both. Physical stresses include exposing the body to injury, walking outside in cold and wet conditions without a coat on, or malnutrition. Psychological stresses include the perception of a physical threat, a fight with a loved one, or just a bad day at school.

The body responds in different ways to short-term stress and long-term stress following a pattern known as the general adaptation syndrome (GAS). Stage one of GAS is called the alarm reaction. This is short-term stress, the fight-or-flight response, mediated by the hormones epinephrine and norepinephrine from the adrenal medulla via the SAM pathway. Their function is to prepare the body for extreme physical exertion. Once this stress is relieved, the body quickly returns to normal. The section on the adrenal medulla covers this response in more detail.

If the stress is not soon relieved, the body adapts to the stress in the second stage called the stage of resistance. If a person is starving for example, the body may send signals to the gastrointestinal tract to maximize the absorption of nutrients from food.

If the stress continues for a longer term however, the body responds with symptoms quite different than the fight-or-flight response. During the stage of exhaustion, individuals may begin to suffer depression, the suppression of their immune response, severe fatigue, or even a fatal heart attack. These symptoms are mediated by the hormones of the adrenal cortex, especially cortisol, released as a result of signals from the HPA axis.

Adrenal hormones also have several non–stress-related functions, including the increase of blood sodium and glucose levels, which will be described in detail below.

Adrenal Cortex:

The adrenal cortex consists of multiple layers of lipid-storing cells that occur in three structurally distinct regions. Each of these regions produces different hormones.

Hormones of the Zona Glomerulosa:

The most superficial region of the adrenal cortex is the zona glomerulosa, which produces a group of hormones collectively referred to as mineralocorticoids because of their effect on body minerals, especially sodium and potassium. These hormones are essential for fluid and electrolyte balance.

Aldosterone is the major mineralocorticoid. It is important in the regulation of the concentration of sodium and potassium ions in urine, sweat, and saliva. For example, it is released in response to elevated blood K⁺, low blood Na⁺, low blood pressure, or low blood volume. In response, aldosterone increases the excretion of K⁺ and the retention of Na⁺, which in turn increases blood volume and blood pressure. Its secretion is prompted when CRH from the hypothalamus triggers ACTH release from the anterior pituitary.

Aldosterone is also a key component of the renin-angiotensin-aldosterone system (RAAS) in which specialized cells of the kidneys secrete the enzyme renin in response to low blood volume or low blood pressure. Renin then catalyzes the conversion of the blood protein angiotensinogen, produced by the liver, to the hormone angiotensin I. Angiotensin I is converted in the lungs to angiotensin II by angiotensin-converting enzyme (ACE). Angiotensin II has three major functions:

1. Initiating vasoconstriction of the arterioles, decreasing blood flow
2. Stimulating kidney tubules to reabsorb NaCl and water, increasing blood volume
3. Signaling the adrenal cortex to secrete aldosterone, the effects of which further contribute to fluid retention, restoring blood pressure and blood volume

For individuals with hypertension, or high blood pressure, drugs are available that block the production of angiotensin II. These drugs, known as ACE inhibitors, block the ACE enzyme from converting angiotensin I to angiotensin II, thus mitigating the latter’s ability to increase blood pressure.

Hormones of the Zona Fasciculata:

The intermediate region of the adrenal cortex is the zona fasciculata, named as such because the cells form small fascicles (bundles) separated by tiny blood vessels. The cells of the zona fasciculata produce hormones called glucocorticoids because of their role in glucose metabolism. The most important of these is cortisol, some of which the liver converts to cortisone. A glucocorticoid produced in much smaller amounts is corticosterone. In response to long-term stressors, the hypothalamus secretes CRH, which in turn triggers the release of ACTH by the anterior pituitary. ACTH triggers the release of the glucocorticoids. Their overall effect is to inhibit tissue building while stimulating the breakdown of stored nutrients to maintain adequate fuel supplies. In conditions of long-term stress, for example, cortisol promotes the catabolism of glycogen to glucose, the catabolism of stored triglycerides into fatty acids and glycerol, and the catabolism of muscle proteins into amino acids. These raw materials can then be used to synthesize additional glucose and ketones for use as body fuels. The hippocampus, which is part of the temporal lobe of the cerebral cortices and important in memory formation, is highly sensitive to stress levels because of its many glucocorticoid receptors.

You are probably familiar with prescription and over-the-counter medications containing glucocorticoids, such as cortisone injections into inflamed joints, prednisone tablets and steroid-based inhalers used to manage severe asthma, and hydrocortisone creams applied to relieve itchy rashes. These drugs reflect another role of cortisol—the downregulation of the immune system, which inhibits the inflammatory response.

Hormones of the Zona Reticularis:

The deepest region of the adrenal cortex is the zona reticularis, which produces small amounts of a class of steroid sex hormones called androgens. During puberty and most of adulthood, androgens are produced in the gonads. The androgens produced in the zona reticularis supplement the gonadal androgens. They are produced in response to ACTH from the anterior pituitary and are converted in the tissues to testosterone or estrogens. In adult women, they may contribute to the sex drive, but their function in adult men is not well understood. In post-menopausal women, as the functions of the ovaries decline, the main source of estrogens becomes the androgens produced by the zona reticularis.

Adrenal Medulla:

As noted earlier, the adrenal cortex releases glucocorticoids in response to long-term stress such as severe illness. In contrast, the adrenal medulla releases its hormones in response to acute, short-term stress mediated by the sympathetic nervous system (SNS).

The medullary tissue is composed of unique postganglionic SNS neurons called chromaffin cells, which are large and irregularly shaped, and produce the neurotransmitters epinephrine (also called adrenaline) and norepinephrine (or noradrenaline). Epinephrine is produced in greater quantities—approximately a 4 to 1 ratio with norepinephrine—and is the more powerful hormone. Because the chromaffin cells release epinephrine and norepinephrine into the systemic circulation, where they travel widely and exert effects on distant cells, they are considered hormones. Derived from the amino acid tyrosine, they are chemically classified as catecholamines.

The secretion of medullary epinephrine and norepinephrine is controlled by a neural pathway that originates from the hypothalamus in response to danger or stress (the SAM pathway). Both epinephrine and norepinephrine signal the liver and skeletal muscle cells to convert glycogen into glucose, resulting in increased blood glucose levels. These hormones increase the heart rate, pulse, and blood pressure to prepare the body to fight the perceived threat or flee from it. In addition, the pathway dilates the airways, raising blood oxygen levels. It also prompts vasodilation, further increasing the oxygenation of important organs such as the lungs, brain, heart, and skeletal muscle. At the same time, it triggers vasoconstriction to blood vessels serving less essential organs such as the gastrointestinal tract, kidneys, and skin, and downregulates some components of the immune system. Other effects include a dry mouth, loss of appetite, pupil dilation, and a loss of peripheral vision. The major hormones of the adrenal glands are summarized in Table 17.5.Hormones of the Adrenal Glands

Adrenal gland	Associated hormones	Chemical class	Effect
Adrenal cortex	Aldosterone	Steroid	Increases blood Na+ levels
Adrenal cortex	Cortisol, corticosterone, cortisone	Steroid	Increase blood glucose levels
Adrenal medulla	Epinephrine, norepinephrine	Amine	Stimulate fight-or-flight response

Table17.5

Disorders Involving the Adrenal Glands:

Several disorders are caused by the dysregulation of the hormones produced by the adrenal glands. For example, Cushing’s disease is a disorder characterized by high blood glucose levels and the accumulation of lipid deposits on the face and neck. It is caused by hypersecretion of cortisol. The most common source of Cushing’s disease is a pituitary tumor that secretes cortisol or ACTH in abnormally high amounts. Other common signs of Cushing’s disease include the development of a moon-shaped face, a buffalo hump on the back of the neck, rapid weight gain, and hair loss. Chronically elevated glucose levels are also associated with an elevated risk of developing type 2 diabetes. In addition to hyperglycemia, chronically elevated glucocorticoids compromise immunity, resistance to infection, and memory, and can result in rapid weight gain and hair loss.

In contrast, the hyposecretion of corticosteroids can result in Addison’s disease, a rare disorder that causes low blood glucose levels and low blood sodium levels. The signs and symptoms of Addison’s disease are vague and are typical of other disorders as well, making diagnosis difficult. They may include general weakness, abdominal pain, weight loss, nausea, vomiting, sweating, and cravings for salty food.

The parathyroid glands are tiny, round structures usually found embedded in the posterior surface of the thyroid gland (Figure 17.15). A thick connective tissue capsule separates the glands from the thyroid tissue. Most people have four parathyroid glands, but occasionally there are more in tissues of the neck or chest. The function of one type of parathyroid cells, the oxyphil cells, is not clear. The primary functional cells of the parathyroid glands are the chief cells. These epithelial cells produce and secrete the parathyroid hormone (PTH), the major hormone involved in the regulation of blood calcium levels.

Figure 17.15Parathyroid Glands The small parathyroid glands are embedded in the posterior surface of the thyroid gland. LM × 760.

The parathyroid glands produce and secrete PTH, a peptide hormone, in response to low blood calcium levels (Figure 17.16). PTH secretion causes the release of calcium from the bones by stimulating osteoclasts, which secrete enzymes that degrade bone and release calcium into the interstitial fluid. PTH also inhibits osteoblasts, the cells involved in bone deposition, thereby sparing blood calcium. PTH causes increased reabsorption of calcium (and magnesium) in the kidney tubules from the urine filtrate. In addition, PTH initiates the production of the steroid hormone calcitriol (also known as 1,25-dihydroxyvitamin D), which is the active form of vitamin D₃, in the kidneys. Calcitriol then stimulates increased absorption of dietary calcium by the intestines. A negative feedback loop regulates the levels of PTH, with rising blood calcium levels inhibiting further release of PTH.

Figure 17.16 Parathyroid Hormone in Maintaining Blood Calcium Homeostasis Parathyroid hormone increases blood calcium levels when they drop too low. Conversely, calcitonin, which is released from the thyroid gland, decreases blood calcium levels when they become too high. These two mechanisms constantly maintain blood calcium concentration at homeostasis.

Abnormally high activity of the parathyroid gland can cause hyperparathyroidism, a disorder caused by an overproduction of PTH that results in excessive calcium reabsorption from bone. Hyperparathyroidism can significantly decrease bone density, leading to spontaneous fractures or deformities. As blood calcium levels rise, cell membrane permeability to sodium is decreased, and the responsiveness of the nervous system is reduced. At the same time, calcium deposits may collect in the body’s tissues and organs, impairing their functioning.

In contrast, abnormally low blood calcium levels may be caused by parathyroid hormone deficiency, called hypoparathyroidism, which may develop following injury or surgery involving the thyroid gland. Low blood calcium increases membrane permeability to sodium, resulting in muscle twitching, cramping, spasms, or convulsions. Severe deficits can paralyze muscles, including those involved in breathing, and can be fatal.

When blood calcium levels are high, calcitonin is produced and secreted by the parafollicular cells of the thyroid gland. As discussed earlier, calcitonin inhibits the activity of osteoclasts, reduces the absorption of dietary calcium in the intestine, and signals the kidneys to reabsorb less calcium, resulting in larger amounts of calcium excreted in the urine.

A butterfly-shaped organ, the thyroid gland is located anterior to the trachea, just inferior to the larynx (Figure 17.12). The medial region, called the isthmus, is flanked by wing-shaped left and right lobes. Each of the thyroid lobes are embedded with parathyroid glands, primarily on their posterior surfaces. The tissue of the thyroid gland is composed mostly of thyroid follicles. The follicles are made up of a central cavity filled with a sticky fluid called colloid. Surrounded by a wall of epithelial follicle cells, the colloid is the center of thyroid hormone production, and that production is dependent on the hormones’ essential and unique component: iodine.

Figure 17.12 Thyroid Gland The thyroid gland is located in the neck where it wraps around the trachea. (a) Anterior view of the thyroid gland. (b) Posterior view of the thyroid gland. (c) The glandular tissue is composed primarily of thyroid follicles. The larger parafollicular cells often appear within the matrix of follicle cells. LM × 1332.

Synthesis and Release of Thyroid Hormones:

Hormones are produced in the colloid when atoms of the mineral iodine attach to a glycoprotein, called thyroglobulin, that is secreted into the colloid by the follicle cells. The following steps outline the hormones’ assembly:

1. Binding of TSH to its receptors in the follicle cells of the thyroid gland causes the cells to actively transport iodide ions (I^–) across their cell membrane, from the bloodstream into the cytosol. As a result, the concentration of iodide ions “trapped” in the follicular cells is many times higher than the concentration in the bloodstream.
2. Iodide ions then move to the lumen of the follicle cells that border the colloid. There, the ions undergo oxidation (their negatively charged electrons are removed). The oxidation of two iodide ions (2 I^–) results in iodine (I₂), which passes through the follicle cell membrane into the colloid.
3. In the colloid, peroxidase enzymes link the iodine to the tyrosine amino acids in thyroglobulin to produce two intermediaries: a tyrosine attached to one iodine and a tyrosine attached to two iodines. When one of each of these intermediaries is linked by covalent bonds, the resulting compound is triiodothyronine (T₃), a thyroid hormone with three iodines. Much more commonly, two copies of the second intermediary bond, forming tetraiodothyronine, also known as thyroxine (T₄), a thyroid hormone with four iodines.

These hormones remain in the colloid center of the thyroid follicles until TSH stimulates endocytosis of colloid back into the follicle cells. There, lysosomal enzymes break apart the thyroglobulin colloid, releasing free T₃ and T₄, which diffuse across the follicle cell membrane and enter the bloodstream.

In the bloodstream, less than one percent of the circulating T₃ and T₄ remains unbound. This free T₃ and T₄ can cross the lipid bilayer of cell membranes and be taken up by cells. The remaining 99 percent of circulating T₃ and T₄ is bound to specialized transport proteins called thyroxine-binding globulins (TBGs), to albumin, or to other plasma proteins. This “packaging” prevents their free diffusion into body cells. When blood levels of T₃ and T₄ begin to decline, bound T₃ and T₄ are released from these plasma proteins and readily cross the membrane of target cells. T₃ is more potent than T₄, and many cells convert T₄ to T₃ through the removal of an iodine atom.

Regulation of TH Synthesis:

The release of T₃ and T₄ from the thyroid gland is regulated by thyroid-stimulating hormone (TSH). As shown in Figure 17.13, low blood levels of T₃ and T₄ stimulate the release of thyrotropin-releasing hormone (TRH) from the hypothalamus, which triggers secretion of TSH from the anterior pituitary. In turn, TSH stimulates the thyroid gland to secrete T₃ and T₄. The levels of TRH, TSH, T₃, and T₄ are regulated by a negative feedback system in which increasing levels of T₃ and T₄ decrease the production and secretion of TSH.

Figure 17.13Classic Negative Feedback Loop A classic negative feedback loop controls the regulation of thyroid hormone levels.

Functions of Thyroid Hormones:

The thyroid hormones, T₃ and T₄, are often referred to as metabolic hormones because their levels influence the body’s basal metabolic rate, the amount of energy used by the body at rest. When T₃ and T₄ bind to intracellular receptors located on the mitochondria, they cause an increase in nutrient breakdown and the use of oxygen to produce ATP. In addition, T₃ and T₄ initiate the transcription of genes involved in glucose oxidation. Although these mechanisms prompt cells to produce more ATP, the process is inefficient, and an abnormally increased level of heat is released as a byproduct of these reactions. This so-called calorigenic effect (calor- = “heat”) raises body temperature.

Adequate levels of thyroid hormones are also required for protein synthesis and for fetal and childhood tissue development and growth. They are especially critical for normal development of the nervous system both in utero and in early childhood, and they continue to support neurological function in adults. As noted earlier, these thyroid hormones have a complex interrelationship with reproductive hormones, and deficiencies can influence libido, fertility, and other aspects of reproductive function. Finally, thyroid hormones increase the body’s sensitivity to catecholamines (epinephrine and norepinephrine) from the adrenal medulla by upregulation of receptors in the blood vessels. When levels of T₃ and T₄ hormones are excessive, this effect accelerates the heart rate, strengthens the heartbeat, and increases blood pressure. Because thyroid hormones regulate metabolism, heat production, protein synthesis, and many other body functions, thyroid disorders can have severe and widespread consequences.

Calcitonin:

The thyroid gland also secretes a hormone called calcitonin that is produced by the parafollicular cells (also called C cells) that stud the tissue between distinct follicles. Calcitonin is released in response to a rise in blood calcium levels. It appears to have a function in decreasing blood calcium concentrations by:

• Inhibiting the activity of osteoclasts, bone cells that release calcium into the circulation by degrading bone matrix
• Increasing osteoblastic activity
• Decreasing calcium absorption in the intestines
• Increasing calcium loss in the urine

However, these functions are usually not significant in maintaining calcium homeostasis, so the importance of calcitonin is not entirely understood. Pharmaceutical preparations of calcitonin are sometimes prescribed to reduce osteoclast activity in people with osteoporosis and to reduce the degradation of cartilage in people with osteoarthritis. The hormones secreted by thyroid are summarized in Table 17.4.Thyroid Hormones

Associated hormones	Chemical class	Effect
Thyroxine (T4), triiodothyronine (T3)	Amine	Stimulate basal metabolic rate
Calcitonin	Peptide	Reduces blood Ca2+ levels

Table17.4

Of course, calcium is critical for many other biological processes. It is a second messenger in many signaling pathways, and is essential for muscle contraction, nerve impulse transmission, and blood clotting. Given these roles, it is not surprising that blood calcium levels are tightly regulated by the endocrine system. The organs involved in the regulation are the parathyroid glands.

The hypothalamus–pituitary complex can be thought of as the “command center” of the endocrine system. This complex secretes several hormones that directly produce responses in target tissues, as well as hormones that regulate the synthesis and secretion of hormones of other glands. In addition, the hypothalamus–pituitary complex coordinates the messages of the endocrine and nervous systems. In many cases, a stimulus received by the nervous system must pass through the hypothalamus–pituitary complex to be translated into hormones that can initiate a response.

The hypothalamus is a structure of the diencephalon of the brain located anterior and inferior to the thalamus (Figure 17.7). It has both neural and endocrine functions, producing and secreting many hormones. In addition, the hypothalamus is anatomically and functionally related to the pituitary gland (or hypophysis), a bean-sized organ suspended from it by a stem called the infundibulum (or pituitary stalk). The pituitary gland is cradled within the sellaturcica of the sphenoid bone of the skull. It consists of two lobes that arise from distinct parts of embryonic tissue: the posterior pituitary (neurohypophysis) is neural tissue, whereas the anterior pituitary (also known as the adenohypophysis) is glandular tissue that develops from the primitive digestive tract. The hormones secreted by the posterior and anterior pituitary, and the intermediate zone between the lobes are summarized in Table 17.3.

Figure 17.7 Hypothalamus–Pituitary Complex The hypothalamus region lies inferior and anterior to the thalamus. It connects to the pituitary gland by the stalk-like infundibulum. The pituitary gland consists of an anterior and posterior lobe, with each lobe secreting different hormones in response to signals from the hypothalamus. Pituitary Hormones

Pituitary lobe	Associated hormones	Chemical class	Effect
Anterior	Growth hormone (GH)	Protein	Promotes growth of body tissues
Anterior	Prolactin (PRL)	Peptide	Promotes milk production from mammary glands
Anterior	Thyroid-stimulating hormone (TSH)	Glycoprotein	Stimulates thyroid hormone release from thyroid
Anterior	Adrenocorticotropic hormone (ACTH)	Peptide	Stimulates hormone release by adrenal cortex
Anterior	Follicle-stimulating hormone (FSH)	Glycoprotein	Stimulates gamete production in gonads
Anterior	Luteinizing hormone (LH)	Glycoprotein	Stimulates androgen production by gonads
Posterior	Antidiuretic hormone (ADH)	Peptide	Stimulates water reabsorption by kidneys
Posterior	Oxytocin	Peptide	Stimulates uterine contractions during childbirth
Intermediate zone	Melanocyte-stimulating hormone	Peptide	Stimulates melanin formation in melanocytes

Table17.3

Posterior Pituitary

The posterior pituitary is actually an extension of the neurons of the paraventricular and supraoptic nuclei of the hypothalamus. The cell bodies of these regions rest in the hypothalamus, but their axons descend as the hypothalamic–hypophyseal tract within the infundibulum, and end in axon terminals that comprise the posterior pituitary (Figure 17.8).

Figure 17.8Posterior Pituitary Neurosecretory cells in the hypothalamus release oxytocin (OT) or ADH into the posterior lobe of the pituitary gland. These hormones are stored or released into the blood via the capillary plexus.

The posterior pituitary gland does not produce hormones, but rather stores and secretes hormones produced by the hypothalamus. The paraventricular nuclei produce the hormone oxytocin, whereas the supraoptic nuclei produce ADH. These hormones travel along the axons into storage sites in the axon terminals of the posterior pituitary. In response to signals from the same hypothalamic neurons, the hormones are released from the axon terminals into the bloodstream.

Oxytocin:

When fetal development is complete, the peptide-derived hormone oxytocin (tocia- = “childbirth”) stimulates uterine contractions and dilation of the cervix. Throughout most of pregnancy, oxytocin hormone receptors are not expressed at high levels in the uterus. Toward the end of pregnancy, the synthesis of oxytocin receptors in the uterus increases, and the smooth muscle cells of the uterus become more sensitive to its effects. Oxytocin is continually released throughout childbirth through a positive feedback mechanism. As noted earlier, oxytocin prompts uterine contractions that push the fetal head toward the cervix. In response, cervical stretching stimulates additional oxytocin to be synthesized by the hypothalamus and released from the pituitary. This increases the intensity and effectiveness of uterine contractions and prompts additional dilation of the cervix. The feedback loop continues until birth.

Although the mother’s high blood levels of oxytocin begin to decrease immediately following birth, oxytocin continues to play a role in maternal and newborn health. First, oxytocin is necessary for the milk ejection reflex (commonly referred to as “let-down”) in breastfeeding women. As the newborn begins suckling, sensory receptors in the nipples transmit signals to the hypothalamus. In response, oxytocin is secreted and released into the bloodstream. Within seconds, cells in the mother’s milk ducts contract, ejecting milk into the infant’s mouth. Secondly, in both males and females, oxytocin is thought to contribute to parent–newborn bonding, known as attachment. Oxytocin is also thought to be involved in feelings of love and closeness, as well as in the sexual response.

Antidiuretic Hormone (ADH):

The solute concentration of the blood, or blood osmolarity, may change in response to the consumption of certain foods and fluids, as well as in response to disease, injury, medications, or other factors. Blood osmolarity is constantly monitored by osmoreceptors—specialized cells within the hypothalamus that are particularly sensitive to the concentration of sodium ions and other solutes.

In response to high blood osmolarity, which can occur during dehydration or following a very salty meal, the osmoreceptors signal the posterior pituitary to release antidiuretic hormone (ADH). The target cells of ADH are located in the tubular cells of the kidneys. Its effect is to increase epithelial permeability to water, allowing increased water reabsorption. The more water reabsorbed from the filtrate, the greater the amount of water that is returned to the blood and the less that is excreted in the urine. A greater concentration of water results in a reduced concentration of solutes. ADH is also known as vasopressin because, in very high concentrations, it causes constriction of blood vessels, which increases blood pressure by increasing peripheral resistance. The release of ADH is controlled by a negative feedback loop. As blood osmolarity decreases, the hypothalamic osmoreceptors sense the change and prompt a corresponding decrease in the secretion of ADH. As a result, less water is reabsorbed from the urine filtrate.

Interestingly, drugs can affect the secretion of ADH. For example, alcohol consumption inhibits the release of ADH, resulting in increased urine production that can eventually lead to dehydration and a hangover. A disease called diabetes insipidus is characterized by chronic underproduction of ADH that causes chronic dehydration. Because little ADH is produced and secreted, not enough water is reabsorbed by the kidneys. Although patients feel thirsty, and increase their fluid consumption, this doesn’t effectively decrease the solute concentration in their blood because ADH levels are not high enough to trigger water reabsorption in the kidneys. Electrolyte imbalances can occur in severe cases of diabetes insipidus.

Anterior Pituitary:

The anterior pituitary originates from the digestive tract in the embryo and migrates toward the brain during fetal development. There are three regions: the pars distalis is the most anterior, the pars intermedia is adjacent to the posterior pituitary, and the pars tuberalis is a slender “tube” that wraps the infundibulum.

Recall that the posterior pituitary does not synthesize hormones, but merely stores them. In contrast, the anterior pituitary does manufacture hormones. However, the secretion of hormones from the anterior pituitary is regulated by two classes of hormones. These hormones—secreted by the hypothalamus—are the releasing hormones that stimulate the secretion of hormones from the anterior pituitary and the inhibiting hormones that inhibit secretion.

Hypothalamic hormones are secreted by neurons, but enter the anterior pituitary through blood vessels (Figure 17.9). Within the infundibulum is a bridge of capillaries that connects the hypothalamus to the anterior pituitary. This network, called the hypophyseal portal system, allows hypothalamic hormones to be transported to the anterior pituitary without first entering the systemic circulation. The system originates from the superior hypophyseal artery, which branches off the carotid arteries and transports blood to the hypothalamus. The branches of the superior hypophyseal artery form the hypophyseal portal system (see Figure 17.9). Hypothalamic releasing and inhibiting hormones travel through a primary capillary plexus to the portal veins, which carry them into the anterior pituitary. Hormones produced by the anterior pituitary (in response to releasing hormones) enter a secondary capillary plexus, and from there drain into the circulation.

Figure 17.9Anterior Pituitary The anterior pituitary manufactures seven hormones. The hypothalamus produces separate hormones that stimulate or inhibit hormone production in the anterior pituitary. Hormones from the hypothalamus reach the anterior pituitary via the hypophyseal portal system.

The anterior pituitary produces seven hormones. These are the growth hormone (GH), thyroid-stimulating hormone (TSH), adrenocorticotropic hormone (ACTH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), beta endorphin, and prolactin. Of the hormones of the anterior pituitary, TSH, ACTH, FSH, and LH are collectively referred to as tropic hormones (trope- = “turning”) because they turn on or off the function of other endocrine glands.

Growth Hormone:

The endocrine system regulates the growth of the human body, protein synthesis, and cellular replication. A major hormone involved in this process is growth hormone (GH), also called somatotropin—a protein hormone produced and secreted by the anterior pituitary gland. Its primary function is anabolic; it promotes protein synthesis and tissue building through direct and indirect mechanisms (Figure 17.10). GH levels are controlled by the release of GHRH and GHIH (also known as somatostatin) from the hypothalamus.

Figure 17.10Hormonal Regulation of Growth Growth hormone (GH) directly accelerates the rate of protein synthesis in skeletal muscle and bones. Insulin-like growth factor 1 (IGF-1) is activated by growth hormone and indirectly supports the formation of new proteins in muscle cells and bone.

A glucose-sparing effect occurs when GH stimulates lipolysis, or the breakdown of adipose tissue, releasing fatty acids into the blood. As a result, many tissues switch from glucose to fatty acids as their main energy source, which means that less glucose is taken up from the bloodstream.

GH also initiates the diabetogenic effect in which GH stimulates the liver to break down glycogen to glucose, which is then deposited into the blood. The name “diabetogenic” is derived from the similarity in elevated blood glucose levels observed between individuals with untreated diabetes mellitus and individuals experiencing GH excess. Blood glucose levels rise as the result of a combination of glucose-sparing and diabetogenic effects.

GH indirectly mediates growth and protein synthesis by triggering the liver and other tissues to produce a group of proteins called insulin-like growth factors (IGFs). These proteins enhance cellular proliferation and inhibit apoptosis, or programmed cell death. IGFs stimulate cells to increase their uptake of amino acids from the blood for protein synthesis. Skeletal muscle and cartilage cells are particularly sensitive to stimulation from IGFs.

Dysfunction of the endocrine system’s control of growth can result in several disorders. For example, gigantism is a disorder in children that is caused by the secretion of abnormally large amounts of GH, resulting in excessive growth. A similar condition in adults is acromegaly, a disorder that results in the growth of bones in the face, hands, and feet in response to excessive levels of GH in individuals who have stopped growing. Abnormally low levels of GH in children can cause growth impairment—a disorder called pituitary dwarfism (also known as growth hormone deficiency).

Thyroid-Stimulating Hormone:

The activity of the thyroid gland is regulated by thyroid-stimulating hormone (TSH), also called thyrotropin. TSH is released from the anterior pituitary in response to thyrotropin-releasing hormone (TRH) from the hypothalamus. As discussed shortly, it triggers the secretion of thyroid hormones by the thyroid gland. In a classic negative feedback loop, elevated levels of thyroid hormones in the bloodstream then trigger a drop in production of TRH and subsequently TSH.

Adrenocorticotropic Hormone:

The adrenocorticotropic hormone (ACTH), also called corticotropin, stimulates the adrenal cortex (the more superficial “bark” of the adrenal glands) to secrete corticosteroid hormones such as cortisol. ACTH come from a precursor molecule known as pro-opiomelanocortin (POMC) which produces several biologically active molecules when cleaved, including ACTH, melanocyte-stimulating hormone, and the brain opioid peptides known as endorphins.

The release of ACTH is regulated by the corticotropin-releasing hormone (CRH) from the hypothalamus in response to normal physiologic rhythms. A variety of stressors can also influence its release, and the role of ACTH in the stress response is discussed later in this chapter.

Follicle-Stimulating Hormone and Luteinizing Hormone:

The endocrine glands secrete a variety of hormones that control the development and regulation of the reproductive system (these glands include the anterior pituitary, the adrenal cortex, and the gonads—the testes in males and the ovaries in females). Much of the development of the reproductive system occurs during puberty and is marked by the development of sex-specific characteristics in both male and female adolescents. Puberty is initiated by gonadotropin-releasing hormone (GnRH), a hormone produced and secreted by the hypothalamus. GnRH stimulates the anterior pituitary to secrete gonadotropins—hormones that regulate the function of the gonads. The levels of GnRH are regulated through a negative feedback loop; high levels of reproductive hormones inhibit the release of GnRH. Throughout life, gonadotropins regulate reproductive function and, in the case of women, the onset and cessation of reproductive capacity.

The gonadotropins include two glycoprotein hormones: follicle-stimulating hormone (FSH) stimulates the production and maturation of sex cells, or gametes, including ova in women and sperm in men. FSH also promotes follicular growth; these follicles then release estrogens in the female ovaries. Luteinizing hormone (LH) triggers ovulation in women, as well as the production of estrogens and progesterone by the ovaries. LH stimulates production of testosterone by the male testes.

Prolactin:

As its name implies, prolactin (PRL) promotes lactation (milk production) in women. During pregnancy, it contributes to development of the mammary glands, and after birth, it stimulates the mammary glands to produce breast milk. However, the effects of prolactin depend heavily upon the permissive effects of estrogens, progesterone, and other hormones. And as noted earlier, the let-down of milk occurs in response to stimulation from oxytocin.

In a non-pregnant woman, prolactin secretion is inhibited by prolactin-inhibiting hormone (PIH), which is actually the neurotransmitter dopamine, and is released from neurons in the hypothalamus. Only during pregnancy do prolactin levels rise in response to prolactin-releasing hormone (PRH) from the hypothalamus.

Intermediate Pituitary: Melanocyte-Stimulating Hormone

The cells in the zone between the pituitary lobes secrete a hormone known as melanocyte-stimulating hormone (MSH) that is formed by cleavage of the pro-opiomelanocortin (POMC) precursor protein. Local production of MSH in the skin is responsible for melanin production in response to UV light exposure. The role of MSH made by the pituitary is more complicated. For instance, people with lighter skin generally have the same amount of MSH as people with darker skin. Nevertheless, this hormone is capable of darkening of the skin by inducing melanin production in the skin’s melanocytes. Women also show increased MSH production during pregnancy; in combination with estrogens, it can lead to darker skin pigmentation, especially the skin of the areolas and labia minora. Figure 17.11 is a summary of the pituitary hormones and their principal effects.

Figure 17.11 Major Pituitary Hormones Major pituitary hormones and their target organs.

Although a given hormone may travel throughout the body in the bloodstream, it will affect the activity only of its target cells; that is, cells with receptors for that particular hormone. Once the hormone binds to the receptor, a chain of events is initiated that leads to the target cell’s response. Hormones play a critical role in the regulation of physiological processes because of the target cell responses they regulate. These responses contribute to human reproduction, growth and development of body tissues, metabolism, fluid, and electrolyte balance, sleep, and many other body functions. The major hormones of the human body and their effects are identified in Table 17.2.Endocrine Glands and Their Major Hormones

Endocrine gland	Associated hormones	Chemical class	Effect
Pituitary (anterior)	Growth hormone (GH)	Protein	Promotes growth of body tissues
Pituitary (anterior)	Prolactin (PRL)	Peptide	Promotes milk production
Pituitary (anterior)	Thyroid-stimulating hormone (TSH)	Glycoprotein	Stimulates thyroid hormone release
Pituitary (anterior)	Adrenocorticotropic hormone (ACTH)	Peptide	Stimulates hormone release by adrenal cortex
Pituitary (anterior)	Follicle-stimulating hormone (FSH)	Glycoprotein	Stimulates gamete production
Pituitary (anterior)	Luteinizing hormone (LH)	Glycoprotein	Stimulates androgen production by gonads
Pituitary (posterior)	Antidiuretic hormone (ADH)	Peptide	Stimulates water reabsorption by kidneys
Pituitary (posterior)	Oxytocin	Peptide	Stimulates uterine contractions during childbirth
Thyroid	Thyroxine (T4), triiodothyronine (T3)	Amine	Stimulate basal metabolic rate
Thyroid	Calcitonin	Peptide	Reduces blood Ca2+ levels
Parathyroid	Parathyroid hormone (PTH)	Peptide	Increases blood Ca2+ levels
Adrenal (cortex)	Aldosterone	Steroid	Increases blood Na+ levels
Adrenal (cortex)	Cortisol, corticosterone, cortisone	Steroid	Increase blood glucose levels
Adrenal (medulla)	Epinephrine, norepinephrine	Amine	Stimulate fight-or-flight response
Pineal	Melatonin	Amine	Regulates sleep cycles
Pancreas	Insulin	Protein	Reduces blood glucose levels
Pancreas	Glucagon	Protein	Increases blood glucose levels
Testes	Testosterone	Steroid	Stimulates development of male secondary sex characteristics and sperm production
Ovaries	Estrogens and progesterone	Steroid	Stimulate development of female secondary sex characteristics and prepare the body for childbirth

Table17.2

Types of Hormones:

The hormones of the human body can be divided into two major groups on the basis of their chemical structure. Hormones derived from amino acids include amines, peptides, and proteins. Those derived from lipids include steroids (Figure 17.3). These chemical groups affect a hormone’s distribution, the type of receptors it binds to, and other aspects of its function.

Figure 17.3Amine, Peptide, Protein, and Steroid Hormone Structure

Amine Hormones:

Hormones derived from the modification of amino acids are referred to as amine hormones. Typically, the original structure of the amino acid is modified such that a –COOH, or carboxyl, group is removed, whereas the −NH+3−NH3+, or amine, group remains.

Amine hormones are synthesized from the amino acids tryptophan or tyrosine. An example of a hormone derived from tryptophan is melatonin, which is secreted by the pineal gland and helps regulate circadian rhythm. Tyrosine derivatives include the metabolism-regulating thyroid hormones, as well as the catecholamines, such as epinephrine, norepinephrine, and dopamine. Epinephrine and norepinephrine are secreted by the adrenal medulla and play a role in the fight-or-flight response, whereas dopamine is secreted by the hypothalamus and inhibits the release of certain anterior pituitary hormones.

Peptide and Protein Hormones:

Whereas the amine hormones are derived from a single amino acid, peptide and protein hormones consist of multiple amino acids that link to form an amino acid chain. Peptide hormones consist of short chains of amino acids, whereas protein hormones are longer polypeptides. Both types are synthesized like other body proteins: DNA is transcribed into mRNA, which is translated into an amino acid chain.

Examples of peptide hormones include antidiuretic hormone (ADH), a pituitary hormone important in fluid balance, and atrial-natriuretic peptide, which is produced by the heart and helps to decrease blood pressure. Some examples of protein hormones include growth hormone, which is produced by the pituitary gland, and follicle-stimulating hormone (FSH), which has an attached carbohydrate group and is thus classified as a glycoprotein. FSH helps stimulate the maturation of eggs in the ovaries and sperm in the testes.

Steroid Hormones:

The primary hormones derived from lipids are steroids. Steroid hormones are derived from the lipid cholesterol. For example, the reproductive hormones testosterone and the estrogens—which are produced by the gonads (testes and ovaries)—are steroid hormones. The adrenal glands produce the steroid hormone aldosterone, which is involved in osmoregulation, and cortisol, which plays a role in metabolism.

Like cholesterol, steroid hormones are not soluble in water (they are hydrophobic). Because blood is water-based, lipid-derived hormones must travel to their target cell bound to a transport protein. This more complex structure extends the half-life of steroid hormones much longer than that of hormones derived from amino acids. A hormone’s half-life is the time required for half the concentration of the hormone to be degraded. For example, the lipid-derived hormone cortisol has a half-life of approximately 60 to 90 minutes. In contrast, the amino acid–derived hormone epinephrine has a half-life of approximately one minute.

Pathways of Hormone Action:

The message a hormone sends is received by a hormone receptor, a protein located either inside the cell or within the cell membrane. The receptor will process the message by initiating other signaling events or cellular mechanisms that result in the target cell’s response. Hormone receptors recognize molecules with specific shapes and side groups, and respond only to those hormones that are recognized. The same type of receptor may be located on cells in different body tissues, and trigger somewhat different responses. Thus, the response triggered by a hormone depends not only on the hormone, but also on the target cell.

Once the target cell receives the hormone signal, it can respond in a variety of ways. The response may include the stimulation of protein synthesis, activation or deactivation of enzymes, alteration in the permeability of the cell membrane, altered rates of mitosis and cell growth, and stimulation of the secretion of products. Moreover, a single hormone may be capable of inducing different responses in a given cell.

Pathways Involving Intracellular Hormone Receptors:

Intracellular hormone receptors are located inside the cell. Hormones that bind to this type of receptor must be able to cross the cell membrane. Steroid hormones are derived from cholesterol and therefore can readily diffuse through the lipid bilayer of the cell membrane to reach the intracellular receptor (Figure 17.4). Thyroid hormones, cross the cell membrane by a specific carrier-mediated mechanism that is energy and Na⁺ dependent.

The location of steroid and thyroid hormone binding differs slightly: a steroid hormone may bind to its receptor within the cytosol or within the nucleus. In either case, this binding generates a hormone-receptor complex that moves toward the chromatin in the cell nucleus and binds to a particular segment of the cell’s DNA. In contrast, thyroid hormones bind to receptors already bound to DNA. For both steroid and thyroid hormones, binding of the hormone-receptor complex with DNA triggers transcription of a target gene to mRNA, which moves to the cytosol and directs protein synthesis by ribosomes.

Figure 17.4Binding of Lipid-Soluble Hormones A steroid hormone directly initiates the production of proteins within a target cell. Steroid hormones easily diffuse through the cell membrane. The hormone binds to its receptor in the cytosol, forming a receptor–hormone complex. The receptor–hormone complex then enters the nucleus and binds to the target gene on the DNA. Transcription of the gene creates a messenger RNA that is translated into the desired protein within the cytoplasm.

Pathways Involving Cell Membrane Hormone Receptors:

Hydrophilic, or water-soluble, hormones are unable to diffuse through the lipid bilayer of the cell membrane and must therefore pass on their message to a receptor located at the surface of the cell. Except for thyroid hormones, which are lipid-soluble, all amino acid–derived hormones bind to cell membrane receptors that are located, at least in part, on the extracellular surface of the cell membrane. Therefore, they do not directly affect the transcription of target genes, but instead initiate a signaling cascade that is carried out by a molecule called a second messenger. In this case, the hormone is called a first messenger.

The second messenger used by most hormones is cyclic adenosine monophosphate (cAMP). In the cAMP second messenger system, a water-soluble hormone binds to its receptor in the cell membrane (Step 1 in Figure 17.5). This receptor is associated with an intracellular component called a G protein, and binding of the hormone activates the G-protein component (Step 2). The activated G protein in turn activates an enzyme called adenylyl cyclase, also known as adenylate cyclase (Step 3), which converts adenosine triphosphate (ATP) to cAMP (Step 4). As the second messenger, cAMP activates a type of enzyme called a protein kinase that is present in the cytosol (Step 5). Activated protein kinases initiate a phosphorylation cascade, in which multiple protein kinases phosphorylate (add a phosphate group to) numerous and various cellular proteins, including other enzymes (Step 6).

Figure 17.5Binding of Water-Soluble Hormones Water-soluble hormones cannot diffuse through the cell membrane. These hormones must bind to a surface cell-membrane receptor. The receptor then initiates a cell-signaling pathway within the cell involving G proteins, adenylyl cyclase, the secondary messenger cyclic AMP (cAMP), and protein kinases. In the final step, these protein kinases phosphorylate proteins in the cytoplasm. This activates proteins in the cell that carry out the changes specified by the hormone.

The phosphorylation of cellular proteins can trigger a wide variety of effects, from nutrient metabolism to the synthesis of different hormones and other products. The effects vary according to the type of target cell, the G proteins and kinases involved, and the phosphorylation of proteins. Examples of hormones that use cAMP as a second messenger include calcitonin, which is important for bone construction and regulating blood calcium levels; glucagon, which plays a role in blood glucose levels; and thyroid-stimulating hormone, which causes the release of T₃ and T₄ from the thyroid gland.

Overall, the phosphorylation cascade significantly increases the efficiency, speed, and specificity of the hormonal response, as thousands of signaling events can be initiated simultaneously in response to a very low concentration of hormone in the bloodstream. However, the duration of the hormone signal is short, as cAMP is quickly deactivated by the enzyme phosphodiesterase (PDE), which is located in the cytosol. The action of PDE helps to ensure that a target cell’s response ceases quickly unless new hormones arrive at the cell membrane.

Importantly, there are also G proteins that decrease the levels of cAMP in the cell in response to hormone binding. For example, when growth hormone–inhibiting hormone (GHIH), also known as somatostatin, binds to its receptors in the pituitary gland, the level of cAMP decreases, thereby inhibiting the secretion of human growth hormone.

Not all water-soluble hormones initiate the cAMP second messenger system. One common alternative system uses calcium ions as a second messenger. In this system, G proteins activate the enzyme phospholipase C (PLC), which functions similarly to adenylyl cyclase. Once activated, PLC cleaves a membrane-bound phospholipid into two molecules: diacylglycerol (DAG) and inositol triphosphate (IP₃). Like cAMP, DAG activates protein kinases that initiate a phosphorylation cascade. At the same time, IP₃ causes calcium ions to be released from storage sites within the cytosol, such as from within the smooth endoplasmic reticulum. The calcium ions then act as second messengers in two ways: they can influence enzymatic and other cellular activities directly, or they can bind to calcium-binding proteins, the most common of which is calmodulin. Upon binding calcium, calmodulin is able to modulate protein kinase within the cell. Examples of hormones that use calcium ions as a second messenger system include angiotensin II, which helps regulate blood pressure through vasoconstriction, and growth hormone–releasing hormone (GHRH), which causes the pituitary gland to release growth hormones.

Factors Affecting Target Cell Response:

You will recall that target cells must have receptors specific to a given hormone if that hormone is to trigger a response. But several other factors influence the target cell response. For example, the presence of a significant level of a hormone circulating in the bloodstream can cause its target cells to decrease their number of receptors for that hormone. This process is called downregulation, and it allows cells to become less reactive to the excessive hormone levels. When the level of a hormone is chronically reduced, target cells engage in upregulation to increase their number of receptors. This process allows cells to be more sensitive to the hormone that is present. Cells can also alter the sensitivity of the receptors themselves to various hormones.

Two or more hormones can interact to affect the response of cells in a variety of ways. The three most common types of interaction are as follows:

• The permissive effect, in which the presence of one hormone enables another hormone to act. For example, thyroid hormones have complex permissive relationships with certain reproductive hormones. A dietary deficiency of iodine, a component of thyroid hormones, can therefore affect reproductive system development and functioning.
• The synergistic effect, in which two hormones with similar effects produce an amplified response. In some cases, two hormones are required for an adequate response. For example, two different reproductive hormones—FSH from the pituitary gland and estrogens from the ovaries—are required for the maturation of female ova (egg cells).
• The antagonistic effect, in which two hormones have opposing effects. A familiar example is the effect of two pancreatic hormones, insulin and glucagon. Insulin increases the liver’s storage of glucose as glycogen, decreasing blood glucose, whereas glucagon stimulates the breakdown of glycogen stores, increasing blood glucose.

Regulation of Hormone Secretion:

To prevent abnormal hormone levels and a potential disease state, hormone levels must be tightly controlled. The body maintains this control by balancing hormone production and degradation. Feedback loops govern the initiation and maintenance of most hormone secretion in response to various stimuli.

Role of Feedback Loops:

The contribution of feedback loops to homeostasis will only be briefly reviewed here. Positive feedback loops are characterized by the release of additional hormone in response to an original hormone release. The release of oxytocin during childbirth is a positive feedback loop. The initial release of oxytocin begins to signal the uterine muscles to contract, which pushes the fetus toward the cervix, causing it to stretch. This, in turn, signals the pituitary gland to release more oxytocin, causing labor contractions to intensify. The release of oxytocin decreases after the birth of the child.

The more common method of hormone regulation is the negative feedback loop. Negative feedback is characterized by the inhibition of further secretion of a hormone in response to adequate levels of that hormone. This allows blood levels of the hormone to be regulated within a narrow range. An example of a negative feedback loop is the release of glucocorticoid hormones from the adrenal glands, as directed by the hypothalamus and pituitary gland. As glucocorticoid concentrations in the blood rise, the hypothalamus and pituitary gland reduce their signaling to the adrenal glands to prevent additional glucocorticoid secretion (Figure 17.6).

Figure 17.6Negative Feedback Loop The release of adrenal glucocorticoids is stimulated by the release of hormones from the hypothalamus and pituitary gland. This signaling is inhibited when glucocorticoid levels become elevated by causing negative signals to the pituitary gland and hypothalamus.

Role of Endocrine Gland Stimuli:

Reflexes triggered by both chemical and neural stimuli control endocrine activity. These reflexes may be simple, involving only one hormone response, or they may be more complex and involve many hormones, as is the case with the hypothalamic control of various anterior pituitary–controlled hormones.

Humoral stimuli are changes in blood levels of non-hormone chemicals, such as nutrients or ions, which cause the release or inhibition of a hormone to, in turn, maintain homeostasis. For example, osmoreceptors in the hypothalamus detect changes in blood osmolarity (the concentration of solutes in the blood plasma). If blood osmolarity is too high, meaning that the blood is not dilute enough, osmoreceptors signal the hypothalamus to release ADH. The hormone causes the kidneys to reabsorb more water and reduce the volume of urine produced. This reabsorption causes a reduction of the osmolarity of the blood, diluting the blood to the appropriate level. The regulation of blood glucose is another example. High blood glucose levels cause the release of insulin from the pancreas, which increases glucose uptake by cells and liver storage of glucose as glycogen.

An endocrine gland may also secrete a hormone in response to the presence of another hormone produced by a different endocrine gland. Such hormonal stimuli often involve the hypothalamus, which produces releasing and inhibiting hormones that control the secretion of a variety of pituitary hormones.

In addition to these chemical signals, hormones can also be released in response to neural stimuli. A common example of neural stimuli is the activation of the fight-or-flight response by the sympathetic nervous system. When an individual perceives danger, sympathetic neurons signal the adrenal glands to secrete norepinephrine and epinephrine. The two hormones dilate blood vessels, increase the heart and respiratory rate, and suppress the digestive and immune systems. These responses boost the body’s transport of oxygen to the brain and muscles, thereby improving the body’s ability to fight or flee.