endocrine system, human

endocrine system, human

Introduction
 group of ductless glands (gland) that regulate body processes by secreting chemical substances called hormones (hormone). Hormones act on nearby tissues or are carried in the bloodstream to act on specific target organs and distant tissues. Diseases of the endocrine system can result from the oversecretion or undersecretion of hormones or from the inability of target organs or tissues to respond to hormones effectively.

      It is important to distinguish between an endocrine gland, which discharges hormones into the bloodstream, and an exocrine gland, which secretes substances through a duct opening in a gland onto an external or internal body surface. Salivary glands (salivary gland) and sweat glands (sweat gland) are examples of exocrine glands. Both saliva, secreted by the salivary glands, and sweat, secreted by the sweat glands, act on local tissues near the duct openings. In contrast, the hormones secreted by endocrine glands are carried by the circulation to exert their actions on tissues remote from the site of their secretion.

      As far back as 3000 BCE, the ancient Chinese were able to diagnose and provide effective treatments for some endocrinologic disorders. For example, seaweed, which is rich in iodine, was prescribed for the treatment of goitre (enlargement of the thyroid gland). Perhaps the earliest demonstration of direct endocrinologic intervention in humans was the castration of men who could then be relied upon, more or less, to safeguard the chastity of women living in harems. During the Middle Ages and later, the practice persisting well into the 19th century, prepubertal boys were sometimes castrated to preserve the purity of their treble voices. Castration established the testes (testis) (testicles) as the source of substances responsible for the development and maintenance of “maleness.”

      This knowledge led to an abiding interest in restoring or enhancing male sexual powers. In the 18th century, London-based Scottish surgeon, anatomist, and physiologist John Hunter (Hunter, John) successfully transplanted the testis of a rooster into the abdomen of a hen. In the 19th century, French neurologist and physiologist Charles-Édouard Brown-Séquard (Brown-Séquard, Charles-Édouard) asserted that the testes contained an invigorating, rejuvenating substance. His conclusions were based in part on observations obtained after he had injected himself with an extract of the testicle of a dog or of a guinea pig. These experiments resulted in the widespread use of organ extracts to treat endocrine conditions (organotherapy).

      Modern endocrinology largely originated in the 20th century, however. Its scientific origin is rooted in the studies of French physiologist Claude Bernard (Bernard, Claude) (1813–78), who made the key observation that complex organisms such as humans go to great lengths to preserve the constancy of what he called the “milieu intérieur” (internal environment). Later, American physiologist Walter Bradford Cannon (Cannon, Walter Bradford) (1871–1945) used the term homeostasis to describe this inner constancy.

      The endocrine system, in association with the nervous system (nervous system, human) and the immune system, regulates the body's internal activities and the body's interactions with the external environment to preserve the internal environment. This control system permits the prime functions of living organisms—growth, development, and reproduction—to proceed in an orderly, stable fashion; it is exquisitely self-regulating, so that any disruption of the normal internal environment by internal or external events is resisted by powerful countermeasures. When this resistance is overcome, illness ensues.

Traditional endocrinology
      The body of knowledge of the endocrine system is continually expanding, driven in large part by research that seeks to understand basic cell functions and basic mechanisms of human endocrine diseases and disorders. The traditional core of an endocrine system consists of an endocrine gland, the hormone it secretes, a responding tissue containing a specific receptor to which the hormone binds, and an action that results after the hormone binds to its receptor, termed the postreceptor response.

      Each endocrine gland consists of a group of specialized cells that have a common origin in the developing embryo. Some endocrine glands, such as the thyroid gland and the islets of Langerhans (Langerhans, islets of) in the pancreas, are derived from cells that arise in the embryonic digestive system. Other endocrine glands, such as the parathyroid glands (parathyroid gland) and the adrenal medulla, are derived from cells that arise in the embryonic nervous system. Certain glands, including the ovary, testis, and adrenal cortex, arise from a region of the embryo known as the urogenital ridge. There are also several glands that are derived from cells that originate in multiple regions of the embryo. For example, the pituitary gland is composed of cells from the nervous system and the digestive tract.

      Each endocrine gland also has a rich supply of blood vessels (blood vessel). This is important not only because nutrients are delivered to the gland by the blood vessels but also because the gland cells that line these vessels are able to detect serum levels of specific hormones or other substances that directly effect the synthesis and secretion of the hormone the gland produces. Hormone secretion is sometimes very complex, because many endocrine glands secrete more than one hormone. In addition, some organs function both as exocrine glands and as endocrine glands. The best-known example of such an organ is the pancreas.

 In addition to traditional endocrine cells, specially modified nerve cells (neuron) within the nervous system secrete important hormones into the blood. These special nerve cells are called neurosecretory cells, and their secretions are termed neurohormones (neurohormone) to distinguish them from the hormones produced by traditional endocrine cells. Neurohormones are stored in the terminals of neurosecretory cells and are released into the bloodstream upon stimulation of the cells.

      Most hormones are one of two types: protein hormones (including peptides (peptide) and modified amino acids (amino acid)) or steroid hormones (steroid hormone). The majority of hormones are protein hormones. They are highly soluble in water and can be transported readily through the blood. When initially synthesized within the cell, protein hormones are contained within large biologically inactive molecules called prohormones. An enzyme splits the inactive portion from the active portion of the prohormone, thereby forming the active hormone that is then released from the cell into the blood. There are fewer steroid hormones than protein hormones, and all steroid hormones are synthesized from the precursor molecule cholesterol. These hormones (and a few of the protein hormones) circulate in the blood both as hormone that is free and as hormone that is bound to specific proteins. It is the free unbound hormone that has access to tissues to exert hormonal activity.

      Hormones act on their target tissues by binding to and activating specific molecules called receptors (receptor). Receptors are found on the surface of target cells in the case of protein and peptide hormones, or they are found within the cytoplasm or nuclei (nucleus) of target cells in the case of steroid hormones and thyroid hormones. Each receptor has a strong, highly specific affinity (attraction) for a particular hormone. A hormone can have an effect only on those tissues that contain receptors specific for that hormone. Often, one segment of the hormone molecule has a strong chemical affinity for the receptor while another segment is responsible for initiating the hormone's specific action. Thus, hormonal actions are not general throughout the body but rather are aimed at specific target tissues.

      A hormone-receptor complex activates a chain of specific chemical responses within the cells of the target tissue to complete hormonal action. This action may be the result of the activation of enzymes within the target cell, interaction of the hormone-receptor complex with the deoxyribonucleic acid ( DNA) in the nucleus of the cell (and consequent stimulation of protein synthesis), or a combination of both. It may even result in the secretion of another hormone.

Function of the endocrine system

The nature of endocrine regulation
      Endocrine gland secretion is not a haphazard process; it is subject to precise, intricate control so that its effects may be integrated with those of the nervous system (nervous system, human) and the immune system. The simplest level of control over endocrine gland secretion resides at the endocrine gland itself. The signal for an endocrine gland to secrete more or less of its hormone is related to the concentration of some substance, either a hormone that influences the function of the gland (a tropic hormone), a biochemical product (e.g., glucose), or a biologically important element (e.g., calcium or potassium). Because each endocrine gland has a rich supply of blood, each gland is able to detect small changes in the concentrations of its regulating substances.

      Some endocrine glands are controlled by a simple negative feedback mechanism. For example, negative feedback signaling mechanisms in the parathyroid glands (located in the neck) rely on the binding activity of calcium-sensitive receptors that are located on the surface of parathyroid cells. Decreased serum calcium concentrations result in decreased calcium receptor binding activity that stimulates the secretion of parathyroid hormone from the parathyroid glands. The increased serum concentration of parathyroid hormone stimulates bone resorption (breakdown) to release calcium into the blood and reabsorption of calcium in the kidney to retain calcium in the blood, thereby restoring serum calcium concentrations to normal levels. In contrast, negative feedback mechanisms are activated by increased serum calcium concentrations, which results in increased calcium receptor-binding activity and inhibition of parathyroid hormone secretion by the parathyroid glands. This allows serum calcium concentrations to decrease to normal levels. Therefore, in people with normal parathyroid glands, serum calcium concentrations are maintained within a very narrow range even in the presence of large changes in calcium intake or excessive losses of calcium from the body.

      There are also positive feedback control systems, in which a substance stimulates the secretion of a hormone and the hormone acts to reduce the serum concentrations of the substance. For example, high blood glucose concentrations stimulate insulin secretion from the beta cells of the islets of Langerhans (Langerhans, islets of) in the pancreas. Insulin stimulates glucose uptake by skeletal muscle and adipose (adipose cell) tissue and decreases glucose production by the liver, thereby promoting glucose storage and reducing blood glucose concentrations.

      Control of the hormonal secretions of other endocrine glands is more complex, because the glands themselves are target organs of a regulatory system called the hypothalamic-pituitary-target gland axis. The major mechanisms in this regulatory system consist of complex interconnecting negative feedback loops that involve the hypothalamus (a structure located at the base of the brain and above the pituitary gland), the anterior pituitary gland, and the target gland. The hypothalamus produces specific neurohormones that stimulate the pituitary gland to secrete specific pituitary hormones that affect any of a number of target organs, including the adrenal cortex, the gonads (testes and ovaries), and the thyroid gland. Therefore, the hypothalamic-pituitary-target gland axis allows for both neural and hormonal input into hormone production by the target gland.

      When stimulated by the appropriate pituitary hormone, the target gland secretes its hormone (target gland hormone) that then combines with receptors located on its target tissues. These receptors include receptors located on the pituitary cells that make the particular hormone that governs the target gland. Should the amount of target gland hormone in the blood increase, the hormone's actions on its target organs increases. In the pituitary gland, the target gland hormone acts to decrease the secretion of the appropriate pituitary hormone, which results in less stimulation of the target gland and a decrease in the production of hormone by the target gland. Conversely, if hormone production by a target gland should decrease, the decrease in serum concentrations of the target gland hormone leads to an increase in secretion of the pituitary hormone in an attempt to restore target gland hormone production to normal. The effect of the target gland hormone on its target tissues is quantitative; that is, within limits, the greater (or lesser) the amount of target gland hormone bound to receptors in the target tissues, the greater (or lesser) the response of the target tissues.

      In the hypothalamic-pituitary-target gland axis, a second negative feedback loop is superimposed on the first negative feedback loop. In this second loop, the target gland hormone binds to nerve cells (neuron) in the hypothalamus, thereby inhibiting the secretion of specific hypothalamic-releasing hormones (neurohormones) that stimulate the secretion of pituitary hormones (an important element in the first negative feedback loop). The hypothalamic neurohormones are released within a set of veins (vein) that connects the hypothalamus to the pituitary gland (the hypophyseal-portal circulation), and therefore the neurohormones reach the pituitary gland in high concentrations. Target gland hormones effect the secretion of hypothalamic hormones in the same way that they effect the secretion of pituitary hormones, thereby reinforcing their effect on the production of the pituitary hormone.

      The importance of the second negative feedback loop lies in the fact that the nerve cells of the hypothalamus receive impulses from other regions of the brain, including the cerebral cortex (cerebrum) (the centre for higher mental functions, movement, perceptions, emotion, etc.), thus permitting the endocrine system to respond to physical and emotional stresses. This response mechanism involves the interruption of the primary feedback loop to allow the serum concentrations of hormones to be increased or decreased in response to environmental stresses that activate the nervous system (see below The hypothalamus (endocrine system, human)). The end result of the two negative feedback loops is that, under ordinary circumstances, hormone production by target glands and the serum concentrations of target gland hormone are maintained within very narrow limits but that, under extraordinary circumstances, this tight control can be overridden by stimuli originating outside of the endocrine system.

      There are important supplemental mechanisms that control endocrine function. When more than one cell type is found within a single endocrine gland, the hormones secreted by one cell type may exert a direct modulating effect upon the secretions of the other cell types. This form of control is known as paracrine control. Similarly, the secretions of one endocrine cell may alter the activity of the same cell, an activity known as autocrine control. Thus, endocrine cell activity may be modulated directly from within the endocrine gland itself, without the need for hormones to enter the bloodstream.

      If the requirement that a hormone act at a site remote from the endocrine cells in which the hormone is produced is excluded from the defining characteristics of hormones, additional classes of biologically active materials can be considered as hormones. Neurotransmitters (neurotransmitter), a group of chemical compounds of variable composition, are secreted at all synapses (synapse) (junctions between nerve cells over which nervous impulses must travel). They facilitate or inhibit the transmission of neural impulses and have given rise to the science of neuroendocrinology (the branch of medicine that studies the interaction of the nervous system and the endocrine system). A second group of biologically active substances is called prostaglandins (prostaglandin). Prostaglandins are a complex group of fatty acid derivatives that are produced and secreted by many tissues. Prostaglandins mediate important biological effects in almost every organ system of the body.

      Another group of substances, called growth factors, possess hormonelike activity. Growth factors are substances that stimulate the growth of specific tissues. They are distinct from pituitary growth hormone in that they were identified only after it was noted that target cells grown outside the organism in tissue culture could be stimulated to grow and reproduce by extracts of serum or tissue chemically distinct from growth hormone.

      Still another area of hormonal activity that has come under intensive investigation is the effect of endocrine hormones on behaviour. While simple direct hormonal effects on human behaviour are difficult to document because of the complexities of human motivation, there are many convincing demonstrations of hormone-mediated behaviour in other life-forms. A special case is that of the pheromone, a substance generated by an organism that influences, by its odour, the behaviour of another organism of the same species. An often-quoted example is the musky scent of the females of many species, which provokes sexual excitation in the male. Such mechanisms have adaptive value for species survival.

The endocrine system and the human system
Maintenance of homeostasis
      For an organism to function normally and effectively, it is necessary that the biochemical processes of its tissues operate smoothly and conjointly in a stable setting. The endocrine system provides an essential mechanism called homeostasis that integrates body activities and at the same time ensures that the composition of the body fluids bathing the constituent cells remains constant.

      Scientists have postulated that the concentrations of the various salts present in the fluids of the body closely resemble the concentrations of salts in the primordial seas, which nourished the simple organisms from which increasingly complex species have evolved. Any change in the salt composition of fluids that surround cells, such as the extracellular fluid and the fluid portion of the circulating blood (the serum), necessitates large compensating changes in the salt concentrations within cells. As a result, the constancy of these salts (electrolytes (electrolyte)) inside and outside of cells is closely guarded. Even small changes in the serum concentrations of these electrolytes (e.g., sodium, potassium, chloride, calcium, magnesium, and phosphate) elicit prompt responses from the endocrine system in order to restore normal concentrations. These responses are initiated through negative feedback regulatory mechanisms similar to those described above.

      Not only is the concentration of each individual electrolyte maintained through homeostasis, but the total concentration of all of the electrolytes per unit of fluid (osmolality) is maintained as well. If this were not the case, an increase in extracellular osmolality (an increase in the concentrations of electrolytes outside of cells) would result in the movement of intracellular fluid across the cell membrane into the extracellular fluid. Because the kidneys (kidney) would excrete much of the fluid from the expanded extracellular volume, dehydration would occur. Conversely, decreased serum osmolality (a decrease in the concentrations of electrolytes outside of cells) would lead to a buildup of fluid within the cells.

      Another homeostatic mechanism involves the maintenance of plasma volume. If the total volume of fluid within the circulation increases (overhydration), the pressure against the walls of the blood vessels and the heart increases, stimulating sensitive areas in heart and vessel walls to release hormones. These hormones, called natriuretic hormones, increase the excretion of water and electrolytes by the kidney, thus reducing the plasma volume to normal.

      Hormonal systems also provide for the homeostasis of nutrients and fuels that are needed for body metabolism. For example, the blood glucose concentration is closely regulated by several hormones to ensure that glucose is available when needed and stored when in abundance. After food is ingested, increased blood glucose concentrations stimulate the secretion of insulin. Insulin then stimulates the uptake of glucose by muscle tissue and adipose tissue and inhibits the production of glucose by the liver. In contrast, during fasting, blood glucose concentrations and insulin secretion decrease, thereby increasing glucose production by the liver and decreasing glucose uptake by muscle tissue and adipose tissue and preventing greater reductions in blood glucose concentrations.

Growth and differentiation
      Despite the many mechanisms designed to maintain a constant internal environment, the organism itself is subject to change: it is born, it matures, and it ages. These changes are accompanied by many changes in the composition of body fluids and tissues. For example, the serum phosphate concentration in healthy children ranges from about 4 to 7 mg per 100 ml (1.1 to 2.1 millimole per litre [mmol/l]), whereas the concentration in normal adults ranges from about 3 to 4.5 mg per 100 ml (1 to 1.3 mmol/l). These and other more striking changes are part of a second major function of the endocrine system—namely, the control of growth and development. The mammalian fetus develops in the uterus of the mother in a system known as the fetoplacental unit. In this system the fetus is under the powerful influence of hormones from its own endocrine glands and hormones produced by the mother and the placenta. Maternal endocrine glands assure that a proper mixture of nutrients is transferred by way of the placenta to the growing fetus. Hormones also are present in the mother's milk and are transferred to the suckling young.

      Sexual differentiation of the fetus into a male or a female is also controlled by delicately timed hormonal changes. Following birth and a period of steady growth in infancy and childhood, the changes associated with puberty and adolescence take place. This dramatic transformation of an adolescent into a physically mature adult is also initiated and controlled by the endocrine system. In addition, the process of aging and senescence in adults is associated with endocrine-related changes.

Adaptive responses to stress
      Throughout life the endocrine system and the hormones it secretes enhance the ability of the body to respond to stressful internal and external stimuli. The endocrine system allows not only the individual organism but also the species to survive. Acutely threatened animals and humans respond to stress with multiple physical changes, including endocrine changes, that prepare them to react or retreat. This process is known as the “fight or flight” response. Endocrine changes associated with this response include increased secretion of cortisol by the adrenal cortex, increased secretion of glucagon by the islet cells of the pancreas, and increased secretion of epinephrine and norepinephrine by the adrenal medulla.

      Adaptive responses to more prolonged stresses also occur. For example, in states of starvation or malnutrition, there is reduced production of thyroid hormone, leading to a lower metabolic rate. A low metabolic rate reduces the rate of the consumption of the body's fuel and thus reduces the rate of consumption of the remaining energy stores. This change has obvious survival value since death from starvation is deferred. Malnutrition also causes a decrease in the production of gonadotropins and sex steroids, reducing the need for fuel to support reproductive processes.

Parenting behaviour
      The endocrine system, particularly the hypothalamus, the anterior pituitary, and the gonads (gonad), is intimately involved in reproductive behaviour by providing physical, visual, and olfactory (pheromonal (pheromone)) signals that arouse the sexual interest of males and the sexual receptivity of females. Furthermore, there are powerful endocrine influences on parental behaviour in all species, including humans.

Integrative functions
      The endocrine systems of humans and other animals serve an essential integrative function. Inevitably, humans are beset by a variety of insults, such as trauma, infection, tumour formation, genetic defects (genetic disease, human), and emotional damage. The endocrine glands play a key role in mediating and ameliorating the effects of these insults on the body. Subtle changes in the body's fluids, although less obvious, also have important effects on storage and expenditure of energy and steady and timely growth and development. These subtle changes largely result from the constant monitoring and measured response of the endocrine system.

 The menstrual cycle (menstruation) in women and the reproductive process in men and women are under endocrine control. The endocrine system works in concert with the nervous system (nervous system, human) and the immune system. When functioning properly, these three systems direct the orderly progression of human life and protect and defend against threats to health and survival.

Synthesis and transport of hormones
Hormone synthesis
 Endocrine cells are rather homogeneous in appearance and are usually cuboidal in shape. When viewed under an electron microscope (a microscope of extraordinary magnifying power), the fine, detailed structure of endocrine cells can be seen. Many of the various intracellular structures, called organelles, are involved in the sequence of events that occurs during the synthesis and secretion of hormones. In the case of protein hormone synthesis, the target cell is stimulated when a hormone or other substance binds to a receptor on the surface of the cell. For example, growth hormone-releasing hormone binds to receptors on the surface of anterior pituitary cells to stimulate the synthesis and secretion of growth hormone. In some cases, protein hormone synthesis can be stimulated by the entrance of a metabolite into the cytoplasm or nucleus of a target cell. This type of stimulation occurs when glucose enters insulin-producing beta cells in the islets of Langerhans of the pancreas. There are also hormones and metabolites that lead to the inhibition of specific cellular activities. For example, dopamine is released from neurons and binds to receptors on lactotrophs in the anterior pituitary to inhibit the secretion of prolactin.

      The stimulation of a receptor at the cell surface is followed by a series of complex events within the cell membrane. Events that occur within the cell membrane then stimulate activities within the cell that lead to the activation of specific genes (gene) in the nucleus. Genes contain unique sequences of DNA that code for specific protein hormones or for enzymes that direct the synthesis of other hormones. The transcription of genes results in the formation of messenger ribonucleic acid (m RNA) molecules.

      In the case of hormone stimulation, the mRNA molecules contain the translated code required for synthesis of the target protein hormone (or enzyme). When mRNA leaves the nucleus and associates with the endoplasmic reticulum in the cytoplasm, it directs the synthesis of a relatively inert precursor to the hormone, called a prohormone, from amino acids available within the cytoplasm. The prohormone is then transported to an organelle called the Golgi apparatus, where it is packaged into vesicles known as secretory granules. As the granules migrate to the cell surface the prohormone is cleaved by a special enzyme called a proteolytic enzyme that separates the inactive region from the active region of the hormone. Through a process known as exocytosis, the active hormone is discharged through the cell wall into the extracellular fluid. It should be noted that the same signal that increases the synthesis of a protein hormone usually also increases the immediate release of hormone from already synthesized secretory granules into the extracellular fluid.

      The precursor of all steroid hormones, cholesterol, is produced in nonendocrine tissues (e.g., the liver) or is obtained from the diet. The cholesterol is then taken up by the adrenal gland and the gonads (gonad) and is stored in vesicles within the cytoplasm. Through the actions of several enzymes, cholesterol is converted into steroid hormones.

      The first step in steroid hormone synthesis is the conversion of cholesterol into pregnenolone, which occurs in mitochondria (organelles that produce most of the energy used for cellular processes). This conversion is mediated by a cleavage enzyme, the synthesis of which is stimulated in the adrenal glands by corticotropin (adrenocorticotropin, or ACTH) or angiotensin and in the ovaries and testes by follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Corticotropin, angiotensin, follicle-stimulating hormone, and luteinizing hormone also stimulate the production of enzymes required for later steps in steroid hormone synthesis. Once pregnenolone is formed, it is transported out of the mitochondria and into the endoplasmic reticulum, where it undergoes further enzymatic conversion to progesterone. Progesterone is then converted into specific steroid hormones. For example, in the ovaries and testes, progesterone is converted into androgens (androgen) and estrogens (estrogen), and in the adrenal cortex, progesterone is converted into androgens, mineralocorticoids, which regulate salt and water metabolism, and glucocorticoids, which stimulate the breakdown of fat and muscle to metabolites that can be converted to glucose in the liver.

      The process of thyroid hormone synthesis is mediated by several enzymes. The synthesis of these enzymes is stimulated by the anterior pituitary hormone thyrotropin (thyroid-stimulating hormone, or TSH). Thyroid hormone synthesis is unique in that it requires iodine, which is available only from the diet, and it occurs within an already synthesized protein known as thyroglobulin. Thyroglobulin also serves as a storage protein and must be broken down to release thyroid hormone.

Modes of hormone transport
      Most hormones are secreted into the general circulation to exert their effects on appropriate distant target tissues. There are important exceptions, however, such as self-contained portal circulations in which blood is directed to a specific area. A portal circulation begins in a capillary bed. As the capillaries extend away from the capillary bed, they merge to form a set of veins (vein), which then divide to form a second capillary bed. Thus, blood collected from the first capillary bed is directed solely into the tissues nourished by the second capillary bed.

      Two portal circulations in which hormones are transported are present in the human body. One system, the hypothalamic-hypophyseal portal circulation, collects blood from capillaries originating in the hypothalamus and, through a plexus of veins surrounding the pituitary stalk, directs the blood into the anterior pituitary gland. This allows the neurohormones (neurohormone) secreted by the neuroendocrine cells of the hypothalamus to be transported directly to the cells of the anterior pituitary. These hormones are largely, but not entirely, excluded from the general circulation. In the second system, the hepatic portal circulation, capillaries originating in the gastrointestinal tract and the spleen merge to form the portal vein, which enters the liver and divides to form portal capillaries. This allows hormones from the islets of Langerhans of the pancreas, such as insulin and glucagon, as well as certain nutrients absorbed from the intestine, to be transported into the liver before being distributed through the general circulation.

      In serum, many hormones exist both as free, unbound hormone and as hormone bound to a serum carrier or transport protein. These proteins, which are produced by the liver, bind to specific hormones in the serum. Transport proteins include sex hormone-binding globulin, which binds estrogens and androgens; corticosteroid-binding globulin, which binds cortisol; and growth hormone-binding protein, which binds growth hormone. There are two specific thyroid hormone binding proteins, thyroxine-binding globulin and transthyretin (thyroxine-binding prealbumin), and at least six binding proteins for insulin-like growth factor-1 (IGF-1).

      In serum, protein-bound hormones are in equilibrium with a much smaller concentration of free, unbound hormones. As free hormone leaves the circulation to exert its action on a tissue, bound hormone is immediately freed from its binding protein. Thus, the transport proteins serve as a reservoir within the circulation to maintain a normal concentration of the biologically important free hormone. In addition, transport proteins protect against sudden surges in hormone secretion and facilitate even distribution of a hormone to all of the cells of large organs such as the liver. The production of many transport proteins is hormone-dependent, being increased by estrogens and decreased by androgens; however, the biological importance of this sensitivity to sex steroids is not well understood.

      The affinity (attraction) of hormones for binding proteins is not constant. The thyroid hormone thyroxine, for example, binds much more tightly to thyroxine-binding globulin than does triiodothyronine. Therefore, triiodothyronine is readily released as a free molecule and has easier access to tissues than thyroxine. Similarly, among the sex steroids, testosterone binds more tightly to sex hormone-binding globulin than do other androgens or estrogens.

Biorhythms (biological rhythm)
      Some hormones, such as insulin, are secreted in short pulses every few minutes. Presumably, the time between pulses is a reflection of the lag time necessary for the insulin-secreting cell to sense a change in the blood glucose concentration. Other hormones, particularly those of the pituitary, are secreted in pulses that may occur at one- or two-hour intervals. Pulsatile secretion is a necessary requirement for the action of pituitary gonadotropins. For example, pituitary gonadotropin secretion increases substantially and is maintained at increased levels when gonadotropin-producing cells (gonadotrophs) are stimulated at 90- to 120-minute intervals by the injection of hypothalamic gonadotropin-releasing hormone. If, however, the gonadotrophs are subjected to a continuous injection of gonadotropin-releasing hormone, gonadotropin secretion is inhibited.

 In addition to pulses of secretion, many hormones are secreted at different rates at different times of the day and night. These longer periodic changes are called circadian rhythms (circadian rhythm). One example of a circadian rhythm is that of cortisol, the major steroid hormone produced by the adrenal cortex. Serum cortisol concentrations rapidly increase in the early morning hours, gradually decrease during the day, with small elevations after meals, and remain decreased for much of the night. This particular rhythm is dependent on night-day cycles and persists for some days after airplane travel to different time zones. The transitional period is reflected in the well-known phenomenon of jet lag. Other hormones follow different circadian rhythms. For example, serum concentrations of growth hormone, thyrotropin, and the gonadotropins are highest shortly after the onset of sleep. In the case of gonadotropins, this sleep-related increase is the first biochemical sign of the onset of puberty. In addition, women have monthly biorhythms, which are reflected in their menstrual cycles.

Endocrine dysfunction
Endocrine hypofunction and receptor defects
      In some cases, a decrease in hormone production, known as hypofunction, is required to maintain homeostasis. One example of hypofunction is decreased production of thyroid hormones during starvation and illness. Because the thyroid hormones control energy expenditure, there is survival value in slowing the body's metabolism when food intake is low. Thus, there is a distinction between compensatory endocrine hypofunction and true endocrine hypofunction. Only those forms of hypofunction that result in disease states are discussed in general terms below. Detailed descriptions of specific endocrine deficiency states are provided in later sections devoted to each of the individual endocrine organs.

Acquired and congenital endocrine hypofunction
      Endocrine glands may be destroyed in a variety of ways, but complete destruction is unusual. For most endocrine glands, at least 90 percent of the gland must be destroyed before major signs of hormone deficiency become apparent. There are many acquired causes of endocrine hypofunction. In the case of paired endocrine glands, such as the adrenal glands and the gonads, the removal of one of the pair is followed by a compensatory increase in the activity and the size of the remaining gland, which allows normal hormone levels to be maintained. In the case of physical trauma, including surgical trauma and severe hemorrhage within the gland, gland destruction may occur, which leads to endocrine hypofunction. Other acquired causes of endocrine hypofunction include infiltration by cancer cells or inflammatory (inflammation) cells; accumulation of large amounts of a metal (e.g., iron) or an abnormal protein (e.g., amyloid); bacterial, fungal, and viral infections; and damage from X-rays (X-ray) or radioactive elements.

      Congenital defects (congenital disorder) or deficiencies can also cause endocrine gland hypofunction. Congenital endocrine gland hypofunction may be due to incomplete endocrine gland formation during fetal development or an inherited genetic mutation that causes deficiency of an enzyme needed for hormone synthesis, deficiency of substances needed for hormone production, or deficiency of receptors on target organs that leads to reduced hormonal action. In addition, congenital endocrine gland hypofunction may be caused by drugs or other substances that are absorbed through the placenta, thereby blocking fetal hormone production and maternal hormone signaling. Since these disorders affect the primary source of particular hormones, they result in a set of conditions designated as primary endocrine gland hypofunction.

Autoimmune endocrine hypofunction
      Perhaps the single most common cause of endocrine hypofunction is autoimmunity. In autoimmune disorders, immune cells such as lymphocytes (lymphocyte) function improperly, producing antibodies (antibody) that react with the body's own tissues instead of with foreign substances (see immune system; immune system disorder). In the endocrine system, autoimmune components act on and usually alter an endocrine gland's function. For instance, in the case of the thyroid gland, antibodies may be cytotoxic (cell-killing), damaging and eventually destroying the thyroid cells; inhibitory, blocking the binding of thyrotropin to its receptors on thyroid cells and preventing the action of thyrotropin; or stimulatory, mimicking the action of thyrotropin and causing thyroid hyperfunction. In some situations, cytotoxic lymphocytes will themselves infiltrate and attack the thyroid gland.

Secondary endocrine hypofunction
      Secondary hypofunction is a distinct category of endocrine gland hypofunction in which the gland is basically intact but is dormant because it either is not stimulated or is directly inhibited. This form of hypofunction is reversible in that the gland begins working normally again if the stimulating hormone is supplied or if the inhibiting hormone or agent is removed. An example of secondary endocrine hypofunction is the loss of a stimulating (tropic) hormone that occurs as a result of pituitary gland destruction. In this situation, hormones are lost in a sequential order, beginning with growth hormone, followed by the gonadotropins, and followed by thyrotropin and corticotropin. Ultimately, there is growth failure and hypofunction of the gonads, thyroid gland, and adrenal glands.

Other causes of endocrine hypofunction
      Changes in biochemical environments may lead to endocrine hypofunction. A well-characterized example is the nutritional deficiency state caused by iodine deficiency. Iodine is an integral part of the thyroid hormone molecule, and it must be obtained from the diet. hypothyroidism, a decrease in available thyroid hormone, is common in areas of the world in which iodine levels in the soil are low and therefore the foods that are produced and consumed as the mainstay of the diet in those areas contain very small amounts of iodine. Drugs may also cause endocrine hypofunction. For example, patients with bipolar disorder are often treated with lithium, a drug that blocks thyroid hormone synthesis. Excess of one hormone that leads to the deficiency of another hormone can cause endocrine hypofunction. For example, overproduction of prolactin, a pituitary hormone, results in a secondary suppression of gonadal function, leading to amenorrhea in women and impotence in men. These changes are reversed when the serum concentration of prolactin is reduced to normal.

      Hormone deficiency can also occur as a result of defective hormonal action on target organs. This concept was first proposed in 1942 by American clinical endocrinologist Fuller Albright. Albright and his colleagues studied a young woman who had signs of parathyroid hormone deficiency, but who, unlike other patients with parathyroid hormone deficiency, did not improve after the injection of an extract prepared from parathyroid glands (parathyroid gland). Albright termed this disorder pseudohypoparathyroidism and postulated that “the disturbance is not a lack of parathyroid hormone but an inability to respond to it.” Direct evidence supporting this suggestion emerged decades later, and many other examples of unresponsiveness of target tissues to hormones have been documented since then. For example, an absence of androgen receptors causes people who are genetically male to appear to be female. In another example, some patients with diabetes mellitus do not respond to large quantities of insulin because they lack effective insulin receptors on target cells in the pancreas. In rare instances, a structurally abnormal hormone will not be recognized by its receptors on target cells, resulting in reduced biological activity of the hormone.

      Endocrine hypofunction was once believed to be a cause of aging; however, the only well-documented endocrine hypofunction associated with age is the loss of ovarian hormones leading up to and during menopause. Even in postmenopausal women, however, the ovaries continue to produce small amounts of estrogens. In addition, there is a decline in the production of pituitary growth hormone and adrenal androgen with age in women and men and a decline in testicular function with age in men. For most other endocrine glands there may be no change or only a very small decrease in function. Whether the changes have survival value (or harm) is not clear.

Endocrine hyperfunction
      Endocrine glands that produce increased amounts of hormone are considered hyperfunctional and may undergo hypertrophy (increase in the size of each cell) and hyperplasia (increase in the number of cells). The hyperfunction may be primary, caused by some abnormality within the gland itself, or secondary (compensatory), caused by changes in the serum concentration of a substance that normally regulates the hormone and may in turn be regulated by the hormone. For example, patients diagnosed with primary hyperplasia of the parathyroid glands have increased serum calcium concentrations as a direct result of an abnormality of the parathyroid glands. In contrast, patients diagnosed with secondary parathyroid hyperplasia have decreased serum calcium concentrations, resulting in stimulation of the parathyroid glands to produce more parathyroid hormone in an attempt to restore serum calcium concentrations to normal.

      In some instances, some of the cells of a hyperplastic gland undergo a series of transformations that results in the formation of a tumour. In most instances, however, endocrine tumours arise from normal endocrine tissue. Endocrine tumours are largely autonomous, meaning that they are insensitive to any inhibition of hormone production imposed upon them through negative feedback control mechanisms. The vast majority of endocrine tumours are benign tumours (adenomas), but a few are malignant tumours (carcinomas). Malignant tumours are not only hyperfunctional but are also capable of invading adjacent structures and spreading (metastasizing) to distant organs. Some patients have tumours of several endocrine glands (see below Ectopic hormone and polyglandular disorders (endocrine system, human)), which has been described as a hereditary syndrome called multiple endocrine neoplasia (MEN). While many endocrine tumours are hyperfunctional, others do not produce hormones at all.

      Excess hormone secretion and the resultant symptoms may be caused by intrinsic endocrine gland hyperplasia or tumours or by abnormal stimulation. One example of abnormal stimulation that leads to endocrine hyperfunction is Graves disease, which is characterized by the production of antibodies that bind to and stimulate the receptors (receptor) for thyrotropin in the thyroid gland. This results in the uncontrolled production of thyroid hormone and thyroid hyperplasia. Other syndromes of endocrine hyperfunction may result when a small endocrine tumour, innocuous in itself, secretes excessive amounts of a stimulatory hormone, which then causes secondary hyperplasia of the target gland. A classic example of such a situation is Cushing disease (Cushing syndrome), in which a small pituitary tumour produces excess quantities of corticotropin that cause hyperfunction and hyperplasia of the adrenal glands.

      Some endocrine tumours produce excess quantities of the expected hormone and excess amounts of a hormone that is normally secreted by a different endocrine gland. For example, medullary carcinomas of the thyroid originate from C cells (parafollicular cells) that normally produce calcitonin, a hormone that transiently decreases serum calcium concentrations. These tumours may produce not only calcitonin but also corticotropin, which is normally secreted by cells of the pituitary gland. In addition, tumours arising from tissues that ordinarily have no endocrine function may produce one or more hormones. A typical example is lung cancer, which may produce one or more of an array of hormones, most commonly vasopressin (antidiuretic hormone) and corticotropin. Such tumours are called ectopic hormone-producing tumours.

Glands (gland) and hormones of the human endocrine system

Anatomical considerations of the human endocrine system
       Glands and hormones of the human endocrine system Glands and hormones of the human endocrine systemThe secretory organs that traditionally make up the human endocrine system, such as the anterior pituitary gland, the adrenal glands (adrenal gland), and the pancreas, synthesize and secrete specific hormones. In addition, many glands that were once considered nontraditional endocrine glands, such as the thyroid gland, ovaries, and testes, are discrete, readily recognizable organs with defined borders and endocrine functions. Other glands are embedded within structures; for example, the islets of Langerhans are embedded within the pancreas and may be seen clearly only under the microscope.

      Other body tissues may also function as endocrine organs. Examples include the lungs (lung), the heart, the skeletal muscles (muscle), the kidneys (kidney), the lining of the gastrointestinal tract, and bundles of nerve cells (neuron) called nuclei. While all nerve cells are capable of secreting neurotransmitters (neurotransmitter) into the synapses (synapse) (small gaps) between adjacent nerves, nerve cells that regulate certain endocrine functions—for example, the nerve cells of the posterior pituitary gland (neurohypophysis)—secrete neurohormones (neurohormone) directly into the bloodstream.

      Sometimes, endocrine cells of different embryological origins that secrete different hormones reside side by side within a gland. The most obvious example of this is the existence of the parafollicular cells that reside among the thyroid follicular cells within the thyroid gland. Endocrine glands with mixed cell populations have not evolved by chance. The hormonal secretions of one type of cell may regulate the activity of adjacent cells that have different characteristics. This direct action on contiguous cells, in which a hormone diffuses from its cell of origin directly to target cells without entering the circulation, is known as paracrine function. Excellent examples of the paracrine actions of hormones are provided by the ovaries (ovary) and testes (testis). Estrogens (estrogen) produced in the ovaries are crucial for the maturation of ovarian follicles before ovulation. Similarly, testosterone produced by the Leydig cells of the testes acts on adjacent seminiferous tubules to stimulate spermatogenesis. In these instances, very high local concentrations of hormones stimulate the target organs. A hormone also may act on its own cell, a phenomenon known as autocrine function.

Feedback regulation mechanisms of endocrine signaling
      A constant supply of most hormones is essential for health, and sustained increases or decreases in hormone production often lead to disease. Many hormones are produced at a relatively constant rate, and in healthy individuals the day-to-day serum concentrations of these hormones lie within a rather narrow normal range. However, hormone concentrations in the circulation may change in response to stimulatory or inhibitory influences that act on the hormone-producing cells or to increases or decreases in the degradation or excretion of the hormones.

 Hormone production and serum hormone concentrations are maintained by feedback mechanisms. Target glands, such as the thyroid gland, adrenal glands, and gonads, are under distant feedback regulation by the hypothalamic-pituitary-target gland axis. Other hormonal systems, however, are under direct feedback regulation mechanisms. For example, serum calcium concentrations are detected directly by calcium receptors in the parathyroid glands, and blood glucose concentrations are detected directly by the beta cells of the islets of Langerhans. The metabolism of hormones after their secretion also serves as a mechanism of hormone regulation and may result in either an increase or a decrease in hormone activity. For example, thyroxine (T4) may be converted to triiodothyronine (T3), a change that substantially increases its hormonal potency, or it may be converted to reverse triiodothyronine (reverse T3), a molecule with the same three iodine atoms that has minimal biological activity.

      The hypothalamus is an integral part of the brain. A small cone-shaped structure, the hypothalamus projects downward from the brain, ending in the pituitary (infundibular) stalk, a tubular connection to the pituitary gland. The pituitary gland is contained in a round bony cavity at the base of the brain called the sella turcica. The posterior portion of the hypothalamus, called the median eminence, contains the nerve endings of many neurosecretory cells (neurosecretory cell). Important adjacent structures include the mammillary bodies, the third ventricle, and the optic chiasm (a part of the visual system). The optic chiasm is particularly susceptible to pressure from expanding tumours or inflammatory masses in the hypothalamus or the pituitary gland. Pressure on the optic chiasm can result in visual defects or even blindness. Above the hypothalamus is the thalamus. (For discussion of the function of these surrounding structures, see human nervous system (nervous system, human).)

Regulation of hormone secretion
 The hypothalamus, like the rest of the brain, consists of interconnecting nerve cells (neurons (neuron)) that are nourished by a rich supply of blood. To understand hypothalamic function it is necessary to define the various forms of neurosecretion. First, there is neurotransmission, which occurs throughout the brain and is the process by which one nerve cell communicates with another via a synapse, a small gap between the ends (nerve terminals) of neurons. Nerve terminals are often called presynaptic or postsynaptic in reference to the direction in which an impulse is traveling, with the presynaptic neuron transmitting an impulse to the postsynaptic neuron. Transmission of an electrical impulse requires the secretion of a chemical substance that diffuses across the synapse from the presynaptic membrane of one neuron to the postsynaptic membrane of another neuron. The chemical substance that is secreted is called a neurotransmitter. The process of synthesis and secretion of neurotransmitters is similar to that of protein hormone synthesis, with the exception that the neurotransmitters are contained within neurosecretory granules that are produced in the cell body and migrate through the axon (a projection of the neuron) to the nerve terminal, from which they are discharged into the synaptic space.

      There are four classic neurotransmitters: epinephrine (epinephrine and norepinephrine), norepinephrine, serotonin, and acetylcholine. A large number of additional neurotransmitters have been discovered, of which an important group is the neuropeptides. The neuropeptides function not only as neurotransmitters but also as neuromodulators. As neuromodulators, they do not act directly as neurotransmitters but rather increase or decrease the action of neurotransmitters. Well-known examples are the opioids (e.g., enkephalins), so named because they are endogenous (produced in the human body) peptides (peptide) (short chains of amino acids (amino acid)) with a strong affinity for the receptors that bind opiate drugs, such as morphine and heroin.

      The brain and indeed the entire central nervous system consists of an interconnected network of neurons. The secretion of specific neurotransmitters and neuropeptides lends an organized, directed function to the overall system. The connection of the hypothalamus to many other regions of the brain, including the cerebral cortex, allows intellectual and functional signals, as well as external signals, including physical and emotional stresses, to be funneled into the hypothalamus to the endocrine system. From the endocrine system these signals are able to exert their effects throughout the body.

 The hypothalamus produces and secretes not only neurotransmitters and neuropeptides but also several neurohormones that alter anterior pituitary gland function and two hormones, vasopressin and oxytocin, that act on distant target organs. The neurons that produce and secrete neurohormones are true endocrine cells in that they produce hormones that are incorporated into secretory granules that are then carried through the axons and stored in nerve terminals located in the median eminence or posterior pituitary gland. In response to neural stimuli, the contents of the secretory granules are extruded from the nerve terminals into a capillary network. In the case of hormones that affect pituitary function, the contents of the secretory granules are carried through the hypophyseal-portal circulation and are delivered directly into the anterior pituitary gland.

      These hypothalamic neurohormones are known as releasing hormones because their major function is to stimulate the secretion of hormones originating in the anterior pituitary gland. They consist of simple peptides ranging in size from only three amino acids (thyrotropin-releasing hormone) to 44 amino acids (growth hormone-releasing hormone). One hypothalamic hormone, somatostatin, has an inhibitory action, primarily inhibiting the secretion of growth hormone, although it can also inhibit the secretion of other hormones. The neurotransmitter dopamine, produced in the hypothalamus, also has an inhibitory action, inhibiting the secretion of the anterior pituitary hormone prolactin. The cell bodies of the neurons that produce these neurohormones are not evenly distributed throughout the hypothalamus. Instead, they are grouped together in paired clusters of cell bodies known as nuclei.

      A classic model for neurohormonal activity is the posterior lobe of the pituitary gland (neurohypophysis). Its secretory products, vasopressin and oxytocin, are produced and packaged into neurosecretory granules in specific groups of nerve cells in the hypothalamus (the supraoptic nuclei and the paraventricular nuclei). The granules are carried through the axons that extend through the infundibular stalk and end in and form the posterior lobe of the pituitary gland. In response to nerve signals, the secretory granules are extruded into a capillary network that feeds directly into the general circulation.

Hypothalamic hormones

Corticotropin-releasing hormone
      Corticotropin-releasing hormone is a peptide that consists of a single chain of 41 amino acids. It stimulates both the synthesis and the secretion of corticotropin in the corticotropin-producing cells (corticotrophs) of the anterior pituitary gland. Many factors of neuronal and hormonal origin regulate the secretion of corticotropin-releasing hormone, and it is the final common element that directs the body's response to many forms of stress, including physical and emotional stresses and external and internal stresses. This key role of corticotropin-releasing hormone in the function of the hypothalamic-pituitary-adrenal axis is discussed later in connection with the adrenal gland (see Regulation of adrenal hormone secretion (endocrine system, human)). The secretion of corticotropin-releasing hormone is inhibited by cortisol, the major hormone secreted by the adrenal cortex.

      Excessive secretion of corticotropin-releasing hormone leads to an increase in the size and number of corticotrophs in the pituitary gland. This may result in the formation of a corticotroph tumour that produces excessive amounts of corticotropin, resulting in overstimulation of the adrenal cortex and abnormally high serum concentrations of adrenocortical hormones, including cortisol. Excessive secretion of cortisol causes Cushing syndrome, which is characterized by trunk and facial obesity, high blood pressure ( hypertension), and generalized protein breakdown, causing skin and muscle atrophy and loss of bone. Conversely, a deficiency of corticotropin-releasing hormone can, by decreasing corticotropin secretion, cause adrenocortical deficiency. (These conditions are discussed in relation to the adrenal cortex in the section Diseases and disorders (endocrine system, human).)

Gonadotropin-releasing hormone
      Gonadotropin-releasing hormone, a neurohormone also known as luteinizing hormone-releasing hormone, is a peptide consisting of 10 amino acids and is produced in the arcuate nuclei of the hypothalamus. This hormone stimulates the synthesis and secretion of the two pituitary gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), by the anterior pituitary gland. The effects of gonadotropin-releasing hormone on the secretion of luteinizing hormone and follicle-stimulating hormone are not exactly parallel, and the variations are probably due to other modulating factors such as the serum concentrations of sex steroids.

      Characteristic of all releasing hormones and most striking in the case of gonadotropin-releasing hormone is the phenomenon of pulsatile secretion. Normally, gonadotropin-releasing hormone is released in pulses at intervals of about 90 to 120 minutes. In order to increase serum gonadotropin concentrations in patients with gonadotropin-releasing hormone deficiency, gonadotropin-releasing hormone must be administered in pulses. In contrast, constant administration of gonadotropin-releasing hormone suppresses gonadotropin secretion, which has therapeutic benefits in certain patients, such as children with precocious puberty and men with prostate cancer.

      The neurons that secrete gonadotropin-releasing hormone have connections to an area of the brain known as the limbic system, which is heavily involved in the control of emotions and sexual activity. In rats that are deprived of their pituitary gland and ovaries (ovary) but are given physiological amounts of estrogen, injection of gonadotropin-releasing hormone results in changes in posture characteristic of the receptive female stance for sexual intercourse.

      Hypogonadism, in which the functional activity of the gonads is decreased and sexual development is inhibited, can be caused by a congenital deficiency of gonadotropin-releasing hormone. Patients with this type of hypogonadism typically respond to pulsatile treatment with gonadotropin-releasing hormone. Many of these patients also have deficiencies of other hypothalamic-releasing hormones. A subset of patients with hypogonadism have isolated gonadotropin-releasing hormone deficiency and loss of the sense of smell (anosmia). This disorder is called Kallmann syndrome and is usually caused by a mutation in a gene that directs the formation of the olfactory (sense of smell) system and the formation of parts of the hypothalamus. Abnormalities in the pulsatile secretion of gonadotropin-releasing hormone result in subnormal fertility (infertility) and abnormal or absent menstruation.

Growth hormone-releasing hormone
      Growth hormone-releasing hormone is a large peptide, and it exists in several forms that differ from one another only in the number of amino acids, which can vary from 37 to 44. Unlike other neurohormones, growth hormone-releasing hormone is not widely distributed throughout the brain and is found only in the hypothalamus. The secretion of growth hormone-releasing hormone increases in response to physical and emotional stress, and its secretion is blocked by a powerful hypothalamic neurohormone called somatostatin. The secretion of growth hormone-releasing hormone is also inhibited by insulin-like growth factors, which are generated when tissues are exposed to growth hormone itself (see Insulin-like growth factors (endocrine system, human)).

      Another hypothalamic growth hormone-releasing hormone is ghrelin, a 28-amino acid peptide that acts synergistically with growth hormone-releasing hormone to increase growth hormone secretion. Ghrelin may also stimulate the secretion of growth hormone-releasing hormone and inhibit the secretion of somatostatin. The physiologic role of ghrelin in the regulation of growth hormone secretion is not known. Ghrelin is also found in the stomach, and indeed most of the ghrelin in serum originates in the stomach. The main actions of ghrelin are probably as an appetite-stimulating (orexigenic) hormone and as a regulator of energy homeostasis, particularly with regard to the storage and the metabolism of fat.

      Somatostatin is a polypeptide that exists in two forms, one composed of 14 amino acids and a second composed of 28 amino acids. The name, essentially meaning stagnation of a body, was coined when investigators found that an extract of hypothalamic tissues inhibited the release of growth hormone from the pituitary gland. Somatostatin is widely distributed throughout the central nervous system and is also found in other tissues. In the pancreas, for example, somatostatin serves an important paracrine function in the islets of Langerhans (Langerhans, islets of), where it blocks the secretion of both insulin and glucagon from adjacent cells. Somatostatin also inhibits the secretion of several gastrointestinal hormones, including gastrin, secretin, cholecystokinin (cholecystokinin/pancreozymin) (CCK; or pancreozymin), and vasoactive intestinal peptide (VIP), resulting in the inhibition of many functions of the gastrointestinal tract, including the secretion of acid by the stomach, the secretion of enzymes by the pancreas, and the absorption of nutrients by the intestine.

      Few examples of somatostatin deficiency have been found. Alzheimer disease appears to cause a decrease in somatostatin levels in brain tissue, although it is not clear what role this plays in the course of the disease. In the late 1970s a rare somatostatin-producing tumour called a somatostatinoma was first identified. Since then, somatostatinomas have been well-characterized. The tumours tend to develop in the pancreas, duodenum, or jejunum, and diagnosis is based on plasma levels of a substance called somatostatin-like immunoreactivity (SLI), which may be 50 times greater than normal in individuals with a somatostatinoma. The excess levels of somatostatin may cause abdominal cramps and pain, persistent diarrhea, high blood glucose concentrations, weight loss, and episodic flushing of the skin.

prolactin-inhibiting and prolactin-releasing hormones
      The hypothalamic regulation of prolactin secretion by the anterior pituitary gland is different from the hypothalamic regulation of other pituitary hormones in two respects. First, hypothalamic control of prolactin secretion is primarily inhibitory, whereas the hypothalamic control of the secretion of other anterior pituitary hormones is stimulatory. Thus, if the anterior pituitary is separated from the influence of the hypothalamus, the secretion of prolactin increases, whereas that of the other anterior pituitary hormones decreases. The hypothalamic factor that inhibits prolactin secretion is the neurotransmitter dopamine, which is not a neuropeptide, as are the other hypothalamic hormones that regulate anterior pituitary hormone secretion. Drugs that mimic the action of dopamine are therefore useful in treating patients with high serum prolactin concentrations. Prolactin-stimulating factors also exist, and included among them are thyrotropin-releasing hormone, gonadotropin-releasing hormone, and vasoactive intestinal peptide. However, the physiologic importance of these prolactin-stimulating factors is not well-defined. One example of a prolactin-stimulating factor for which a role has been identified is estrogen, which stimulates prolactin synthesis and secretion in the late stages of pregnancy to prepare the mammary glands (mammary gland) for lactation.

      Thyrotropin-releasing hormone, a neurohormone, is the simplest of the hypothalamic neurohormones. It consists of three amino acids in the sequence glutamic acid– histidine– proline. The structural simplicity of thyrotropin-releasing hormone is deceiving because this hormone actually has many functions. It stimulates the synthesis and secretion of thyrotropin by the anterior pituitary gland. Given in high doses by injection, it stimulates the secretion of prolactin from the pituitary gland, although it does not appear to regulate the secretion of prolactin. Thyrotropin-releasing hormone is also found throughout the brain and spinal cord, where it is thought to serve as a neuromodulator.

      Thyrotropin-releasing hormone appeared very early in the evolution of vertebrates (vertebrate), and, while its concentration is highest in the hypothalamus, the total amount of thyrotropin-releasing hormone in the remainder of the brain far exceeds that in the hypothalamus. The nerve cells that produce thyrotropin-releasing hormone in the hypothalamus are subject to stimulatory and inhibitory influences from higher centres in the brain and from serum thyroid hormone concentrations, with low concentrations stimulating and high concentrations inhibiting the production of thyrotropin-releasing hormone. In this way, thyrotropin-releasing hormone forms the topmost component of the hypothalamic-pituitary-thyroid axis. Deficiency of thyrotropin-releasing hormone is a rare cause of hypothyroidism. For more information about thyroid function, see thyroid gland.

The anterior pituitary
 The pituitary gland lies at the base of the skull and is housed within a bony structure called the sella turcica. Its weight in normal adults is about 500 mg (0.02 ounce). The gland is attached to the hypothalamus by the pituitary stalk, which is composed of the axons (axon) of nerves and the hypophyseal-portal veins. In most species the pituitary gland is divided into three lobes: the anterior lobe, the intermediate lobe, and the posterior lobe. In humans the intermediate lobe does not exist as a distinct anatomic structure, but rather remains only as cells dispersed within the anterior lobe. Despite its proximity to the anterior lobe of the pituitary, the posterior lobe of the pituitary is functionally distinct and is an integral part of a separate neural structure called the neurohypophysis (see below Neurohypophyseal unit (endocrine system, human)).

      The cells comprising the anterior lobe are embryologically derived from an outpouching of the roof of the pharynx, known as Rathke's pouch. While the cells appear to be relatively homogeneous under a light microscope, there are in fact five different types of cells, each of which secretes a different hormone or hormones. The thyrotrophs synthesize and secrete thyrotropin (thyroid-stimulating hormone, or TSH); the gonadotrophs, both luteinizing hormone (LH) and follicle-stimulating hormone (FSH); the corticotrophs, corticotropin (adrenocorticotropin, or ACTH); the somatotrophs, somatotropin ( growth hormone, or GH); and the lactotrophs, prolactin (PRL).

      These hormones are proteins that consist of one or two long polypeptide chains. Furthermore, the gonadotropins and thyrotropin are called glycoproteins because they contain complex carbohydrates known as glycosides (glycoside). Each of these three hormones—luteinizing hormone, follicle-stimulating hormone, and thyrotropin—is composed of two glycopeptide chains, one of which, the alpha chain, is identical in all three hormones. The other chain, the beta chain, differs in structure for each hormone, thereby explaining the different actions of each of these three hormones. As is the case for all protein hormones, the hormones of the anterior pituitary are synthesized in the cytoplasm of the cells as large, inactive molecules called prohormones. These prohormones are stored in granules, within which they are cleaved into active hormones and are secreted into the circulation.

Anterior pituitary hormones

      Corticotropin, also called adrenocorticotropin (adrenocorticotropic hormone) (ACTH), is a segment of a much larger glycoprotein prohormone molecule called proopiomelanocortin (POMC). Proopiomelanocortin is synthesized by the corticotrophs of the anterior pituitary, which constitute about 10 percent of the gland. Proopiomelanocortin is split into several biologically active polypeptides when the secretory granules are discharged from the corticotrophs. Among these polypeptides is corticotropin, whose major action is to stimulate the growth and secretion of the cells of the adrenal cortex. In addition, corticotropin causes an increase in skin pigmentation. Other polypeptides derived from proopiomelanocortin include melanocyte-stimulating hormone (alpha- and beta-melanotropin), which increases skin pigmentation; beta-lipotropin, which stimulates the release of fatty acids (fatty acid) from adipose tissue; a small fragment of corticotropin, which is thought to improve memory; and beta-endorphin (endorphin), which suppresses pain.

      Beta-endorphin and enkephalins (neuromodulators) were discovered when investigators postulated that since exogenous (produced outside of the human body) opiate substances such as morphine bind to cell surface receptors (receptor), there must exist endogenous (produced inside the human body) opiate-like substances that do likewise and therefore have a narcotic action. Therefore, beta-endorphin and enkephalins are known as endogenous opioids. These substances have powerful painkilling properties. The absence of pain in people who have sustained severe trauma is due to the rapid release and action of beta-endorphin in response to the stressful stimulus of the injury. In addition, the release of endorphin or enkephalin may account for the euphoria experienced by long-distance runners (“runner's high”).

      Increased secretion of corticotropin because of a corticotroph tumour or corticotroph hyperplasia causes adrenocortical hyperfunction, which in turn causes the constellation of symptoms and signs called Cushing syndrome (see Hypercorticism (endocrine system, human)). Corticotropin deficiency can occur as part of a multiple pituitary hormone deficiency syndrome (panhypopituitarism) or as an isolated corticotropin deficiency.

Gonadotropins
 Gonadotrophs, which constitute about 10 percent of the pituitary gland, secrete two hormones, luteinizing hormone and follicle-stimulating hormone. However, these hormones are not secreted in equal amounts, and their rate of secretion varies widely at different ages and at different times during the menstrual cycle (menstruation) in women. Secretion of luteinizing hormone and follicle-stimulating hormone is low in both males and females prior to puberty. Following puberty, more luteinizing hormone than follicle-stimulating hormone is secreted. During the menstrual cycle there is a dramatic increase in the serum concentrations of both hormones at the time of ovulation (see The ovary (ovary)), and the secretion of both hormones increases 10- to 15-fold in postmenopausal women.

      In men, follicle-stimulating hormone stimulates the development of spermatozoa, in large part by acting on special cells in the testes called Sertoli cells. Luteinizing hormone stimulates the secretion of androgen (male) hormones by specialized cells in the testes called Leydig cells. In women, follicle-stimulating hormone stimulates the synthesis of estrogens (estrogen) and the maturation of cells lining the spherical egg-containing structures known as Graafian follicles. In menstruating women, there is a preovulatory surge in serum follicle-stimulating hormone and luteinizing hormone concentrations. The preovulatory surge of luteinizing hormone is essential for rupture of the Graafian follicle (ovulation), after which the egg enters the fallopian tube and travels to the uterus. The empty Graafian follicle becomes filled with progesterone-producing cells, transforming it into a corpus luteum. Luteinizing hormone stimulates the production of progesterone by the corpus luteum (see reproductive system, human). Inhibin, a hormone secreted by the Graafian follicles of the ovary and by the Sertoli cells of the testis, inhibits the secretion of follicle-stimulating hormone from the pituitary gonadotrophs.

      Patients with diseases involving the anterior pituitary gland often have gonadotropin deficiency. Thus, the disappearance of menstrual periods may be the first sign of a pituitary tumour or other pituitary disease in women. In men, the most common symptoms of gonadotropin deficiency are loss of libido and erectile dysfunction. Isolated deficiencies of both luteinizing hormone and follicle-stimulating hormone do occur but only rarely. In men, isolated luteinizing hormone deficiency (“fertile eunuch”) is characterized by symptoms and signs of androgen deficiency; however, there is sufficient secretion of follicle-stimulating hormone to permit the maturation of spermatozoa. Some pituitary tumours produce an excess of luteinizing hormone or follicle-stimulating hormone, whereas other pituitary tumours produce the hormonally inactive alpha chain subunit of the glycoprotein hormones.

      Somatotrophs are plentiful in the anterior pituitary gland, constituting about 40 percent of the gland. They are located predominantly in the anterior and the lateral regions of the gland and secrete between one and two milligrams of growth hormone (somatotropin) each day. Growth hormone stimulates the growth of essentially all tissues of the body. In biochemical terms, growth hormone stimulates protein synthesis and increases fat breakdown to provide the energy necessary for tissue growth. Growth hormone also antagonizes the action of insulin and in susceptible people can lead to increased blood glucose concentrations and diabetes mellitus.

      Growth hormone may act directly on tissues, but much of its effect is mediated by stimulation of the liver and other tissues to produce and release insulin-like growth factors, primarily insulin-like growth factor 1 (IGF-1; formerly called somatomedin). The term insulin-like growth factor is derived from the ability of high concentrations of these factors to mimic the action of insulin, although their primary action is to stimulate growth. Serum IGF-1 concentrations increase progressively with age in children, with an accelerated increase at the time of the pubertal growth spurt. After puberty the concentrations of IGF-1 gradually decrease with age, as do the concentrations of growth hormone.

      Growth hormone secretion is stimulated by growth hormone-releasing hormone and is inhibited by somatostatin. In addition, growth hormone secretion is pulsatile, with surges in secretion occurring after the onset of deep sleep that are especially prominent at the time of puberty. In normal subjects, growth hormone secretion increases in response to decreased food intake and to physiological stresses and decreases in response to food ingestion. When damage to the hypothalamus or to the pituitary is mild, growth hormone deficiency may be the only detectable abnormality. When the cells of the pituitary gland are severely damaged or are destroyed, the result is panhypopituitarism, which is characterized by the decreased secretion of all of the anterior pituitary hormones.

Growth hormone deficiency
      Growth hormone deficiency is one of the many causes of short stature and dwarfism (see Growth and development (endocrine system, human)) and primarily results from damage to the hypothalamus or to the pituitary gland during fetal development (congenital growth hormone deficiency) or following birth (acquired growth hormone deficiency). Growth hormone deficiency may also be caused by mutations (mutation) in genes (gene) that regulate the synthesis and secretion of growth hormone. Affected genes include PIT-1 (pituitary-specific transcription factor-1) and POUF-1 (prophet of PIT-1). Mutations in these genes may also cause decreased synthesis and secretion of other pituitary hormones. In some cases, growth hormone deficiency is the result of growth hormone-releasing hormone deficiency, in which case growth hormone secretion may be stimulated by infusion of growth hormone-releasing hormone. In other cases, the somatotrophs themselves are incapable of producing growth hormone, or the growth hormone itself is structurally abnormal and has little growth-promoting activity. In addition, short stature and growth hormone deficiency are often found in children diagnosed with psychosocial dwarfism, which results from severe emotional deprivation. When children with this disorder are removed from the stressing, nonnurturing environment, their endocrine function and growth rate normalize.

      Children with isolated growth hormone deficiency are normal in size at birth, but growth retardation becomes evident within the first two years of life. Radiographs ( X-ray films) of the epiphyses (the growing ends) of bones show growth retardation in relation to the patient's chronological age. While puberty is often delayed, fertility and delivery of normal children is possible in affected women.

      Children with growth hormone deficiency respond well to injections of human growth hormone, which is manufactured by recombinant DNA technology. Affected children treated with growth hormone often achieve near-normal height. However, some children, primarily those with the hereditary inability to synthesize growth hormone, develop antibodies (antibody) in response to growth hormone injections. Children with short stature not associated with growth hormone deficiency may also grow in response to injections of growth hormone, although large doses are often required.

      A rare form of short stature is caused by an inherited insensitivity to the action of growth hormone. This disorder is known as Laron dwarfism and is characterized by abnormal growth hormone receptors, resulting in decreased growth hormone-stimulated production of IGF-1 and poor growth. Serum growth hormone concentrations are high because of the absence of the inhibitory action of IGF-1 on growth hormone secretion. Dwarfism may also be caused by insensitivity of bone tissue and other tissues to IGF-1, resulting from decreased function of IGF-1 receptors.

      Growth hormone deficiency often persists into adulthood, although some people affected in childhood have normal growth hormone secretion in adulthood. Growth hormone deficiency in adults is associated with fatigue, decreased energy, depressed mood, decreased muscle strength, decreased muscle mass, thin and dry skin, increased adipose tissue, and decreased bone density. Treatment with growth hormone reverses some of these abnormalities but can cause fluid retention, diabetes mellitus, and high blood pressure ( hypertension).

Growth hormone excess
      Excess growth hormone production is most often caused by a benign tumour (adenoma) of the somatotroph cells of the pituitary gland. In some cases, a tumour of the lung or of the pancreatic islets of Langerhans (Langerhans, islets of) produces growth hormone-releasing hormone, which stimulates the somatotrophs to produce large amounts of growth hormone. In rare cases, ectopic production of growth hormone by tumour cells that do not ordinarily synthesize growth hormone causes excess growth hormone. Somatotroph tumours in children are very rare and cause excessive growth that may lead to extreme height ( gigantism) and features of acromegaly.

      Acromegaly refers to the enlargement of the distal (acral) parts of the body, including the hands, feet, chin, and nose. The enlargement is due to the overgrowth of cartilage, muscle, subcutaneous tissue, and skin. Thus, patients with acromegaly have a prominent jaw, a large nose, and large hands and feet, as well as enlargement of most other tissues, including the tongue, heart, liver, and kidneys (kidney). In addition to the effects of excess growth hormone, the pituitary tumour itself can cause severe headaches, and pressure of the tumour on the optic chiasm can cause visual defects.

      Because the metabolic actions of growth hormone are antagonistic (opposite) to those of insulin, some patients with acromegaly develop diabetes mellitus. Other problems associated with acromegaly include high blood pressure (hypertension), cardiovascular disease, and arthritis. Patients with acromegaly also have an increased risk of developing malignant tumours of the large intestine. Some somatotroph tumours also produce prolactin, which may cause abnormal lactation (galactorrhea). Patients with acromegaly are usually treated by surgical resection of the pituitary tumour. They can also be treated with radiation therapy or with drugs such as pegvisomant, which blocks the binding of growth hormone to its receptors, and synthetic long-acting analogues of somatostatin, which inhibit the secretion of growth hormone.

      On the evolutionary scale, prolactin is an ancient hormone serving multiple roles in mediating the care of progeny (sometimes called the “parenting” hormone). Prolactin is a large protein molecule that is synthesized in and secreted from the lactotrophs, which comprise about 20 percent of the anterior pituitary gland and are located largely in the lateral regions of the gland. Unlike other anterior pituitary cells whose activity is stimulated by hypothalamic-releasing hormones, prolactin activity is inhibited by the hypothalamic influence of dopamine. Dopamine is a neurotransmitter; however, under these circumstances, dopamine functions as a hypothalamic neurohormone.

      In women the major action of prolactin is to initiate and sustain lactation. In breast-feeding mothers, tactile stimulation of the nipples and the breast by the suckling infant blocks the secretion of hypothalamic dopamine into the hypophyseal-portal circulation. This results in a sharp rise in serum prolactin concentrations, followed by a prompt fall when feeding stops. High serum prolactin concentrations inhibit secretion of gonadotropin-releasing hormone from the hypothalamus, thereby decreasing gonadotropin secretion, and may also inhibit the action of gonadotropins on the gonads. Thus, high serum prolactin concentrations during lactation reduce fertility, protecting lactating women from a premature pregnancy. Prolactin secretion increases progressively during pregnancy, is stimulated by high doses of estrogens, and is also transiently stimulated by stress and exercise.

      Prolactin deficiency occurs as a result of general pituitary hormone deficiency, which is characterized by the deficiency of other pituitary hormones in addition to prolactin. A primary cause of pituitary hormone deficiency is a pituitary tumour. The most striking example of prolactin deficiency is that of Sheehan syndrome (Sheehan's syndrome), in which the anterior pituitary gland of pregnant women is partly or totally destroyed during or shortly after giving birth. This syndrome tends to occur more frequently in women who had excessive bleeding during delivery. Affected women do not produce breast milk and cannot nurse their infants. Prolactin deficiency does not cause abnormalities in women who are not trying to nurse their infants and does not cause abnormalities in men.

      Increased prolactin secretion can be caused by damage to the pituitary stalk, thereby interrupting the flow of dopamine from the hypothalamus through the hypophyseal-portal circulation to the lactotrophs. In addition, increased prolactin secretion may be caused by prolactin-producing pituitary tumours, such as lactotroph adenomas or prolactinomas, and by several systemic diseases, notably thyroid deficiency. Many drugs, particularly those used for the treatment of psychological or psychiatric disorders, high blood pressure, and pain may also increase prolactin secretion. In some patients with high serum prolactin concentrations (hyperprolactinemia), however, no cause is discernible, and they are said to have idiopathic hyperprolactinemia.

      In women of reproductive age, high serum prolactin concentrations result in decreased secretion of gonadotropins and therefore decreased cyclic ovarian function. The frequency of menstrual cycles decreases (oligomenorrhea), and the cycle may even cease (amenorrhea) altogether. Symptoms of estrogen deficiency, such as loss of sexual desire, dryness of the vagina, and infertility, and, less often, abnormal lactation (galactorrhea), also occur. High serum prolactin concentrations are not usually associated with any symptoms in postmenopausal women, although in very rare cases galactorrhea may occur. In men, high serum prolactin concentrations also decrease gonadotropin secretion and therefore testicular function, resulting in low serum testosterone concentrations. The major symptoms are loss of sexual desire, erectile dysfunction, muscle weakness, and infertility.

      Prolactinomas are the most common type of hormone-secreting pituitary tumour. They are four to five times more common in women than men. However, prolactinomas tend to be larger in men at the time of diagnosis. This difference is explained by the fact that menstrual irregularity is a very sensitive indicator of excess prolactin secretion, whereas decreased testicular function in men is not. Prolactinomas often cause headaches, disturbances in vision, and symptoms and signs of other pituitary hormone deficiencies.

      Most patients with a prolactinoma are treated with drugs that mimic the action of dopamine, such as bromocriptine and cabergoline. These drugs result in a prompt decrease in prolactin secretion and a decrease in tumour size. In some cases, however, the drugs are not effective or may cause unacceptable side effects such as nausea, vomiting, and headaches. These patients may be treated by surgery or radiation therapy. Patients with few symptoms—for example, an occasional missed menstrual period—may not require treatment. These patients tend to have tumours that do not grow and tend to have mild hyperprolactinemia that does not increase. Dopamine-like drugs also lower prolactin secretion in patients with hyperprolactinemia from other causes, although it is preferable to remove the offending cause if it can be identified.

      Thyrotropin, also called thyroid-stimulating hormone, is produced by thyrotrophs in the anterior pituitary, which make up about 10 percent of the pituitary gland. Thyrotropin binds to specific receptors on the surface of cells in the thyroid gland. This binding stimulates both secretion of preformed thyroid hormone into the circulation—by stimulating the breakdown of thyroglobulin, a large thyroid hormone-containing protein stored within the follicles of the thyroid gland—and synthesis of additional thyroglobulin and thyroid hormone. Thyrotropin also stimulates the growth of thyroid cells.

      Serum thyrotropin concentrations are high in patients with thyroid deficiency ( hypothyroidism) because there is decreased negative feedback inhibition of thyrotropin release by the low serum thyroid hormone concentrations. Conversely, serum thyrotropin concentrations are low in patients with hyperthyroidism (except in the case of a thyrotropin-secreting tumour of the pituitary gland) because there is increased negative feedback inhibition of thyrotropin secretion by the high serum thyroid hormone concentrations. The changes in serum thyroid hormone concentrations need not be large to produce notable symptoms, and measurement of serum thyrotropin is useful for detecting both hypothyroidism or hyperthyroidism when those disorders are caused by thyroid disease. Hypothalamic or pituitary disease may cause low serum thyrotropin and low serum thyroid hormone concentrations, also known as central hypothyroidism.

The posterior pituitary (neurohypophysis)
Neurohypophyseal system
      The posterior lobe of the pituitary gland consists largely of extensions of processes (axons (axon)) from two pairs of large clusters of nerve cell bodies (nuclei) in the hypothalamus. One of these nuclei, known as the supraoptic nuclei, lies immediately above the optic tract, while the other nuclei, known as the paraventricular nuclei, lies on each side of the third ventricle of the brain. These nuclei, the axons of the cell bodies of nerves that form the nuclei, and the nerve endings in the posterior pituitary gland form the neurohypophyseal system. There are neural connections to the brain and to other centres of the hypothalamus, including a centre that modulates thirst. The two neurohypophyseal hormones, vasopressin (antidiuretic hormone) and oxytocin, are synthesized and incorporated into neurosecretory granules in the cell bodies of the nuclei. These hormones are synthesized as part of a precursor protein that includes one of the hormones and a protein called neurophysin. After synthesis and incorporation into neurosecretory granules the precursor protein is cleaved, forming separate hormone and neurophysin molecules, which remain loosely attached to one another. These granules are carried through the axons and are stored in the posterior lobe of the pituitary gland. Upon stimulation of the nerve cells, the granules fuse with the cell wall of the nerve endings, the hormone and neurophysin dissociate from one another, and both the hormone and the neurophysin are released into the bloodstream.

Vasopressin and oxytocin
      Vasopressin (antidiuretic hormone) and oxytocin evolved from a single primordial neurohypophyseal hormone called vasotocin, which is present in lower vertebrates. Within the secretory granules of nerve cells, each hormone is loosely attached to neurophysin, from which the hormone separates when the granule is discharged into the bloodstream.

      All animals lose water and therefore need water. Vasopressin plays a key role in maintaining osmolality (the concentration of dissolved particles, such as salts and glucose, in the serum) and therefore in maintaining the volume of water in the extracellular fluid (the fluid space that surrounds cells). This is necessary to protect cells from sudden increases or decreases in water content, which are capable of interfering with proper cell function. Normal serum osmolality ranges from about 285 to 300 milliosmoles per kilogram (mOsm/kg) in healthy people.

      Special nerve cells called osmoreceptors in the hypothalamus are very sensitive to changes in serum osmolality. The osmoreceptors are closely associated with the same nerve cells that produce and secrete vasopressin. Serum osmolality that increases or decreases by as little as one percent can cause respective decreases or increases in vasopressin release. The immediate effect of an increase in serum osmolality—for example, if a person becomes dehydrated (i.e., loses water by excessive perspiration)—is to stimulate the osmoreceptors. This stimulation leads to the release of vasopressin from the posterior pituitary gland and the subsequent retention of water by the kidneys. Conversely, the immediate effect of a decrease in serum osmolality—for example, if a person becomes overhydrated (i.e., drinks too much water)—is to inhibit the osmoreceptors. This inhibition leads to a decrease in vasopressin secretion and a subsequent increase in water excretion. The osmoreceptors are also closely linked to the thirst centre, which is stimulated by high serum osmolality and is inhibited by low serum osmolality in the same way as is vasopressin secretion.

      In the kidneys vasopressin acts on the cells of the collecting ducts. These cells contain receptors for vasopressin that are linked to vesicles that contain special water channels (aquaporins). When the cells are stimulated by vasopressin, the aquaporins fuse with the region of the cell membrane that is exposed to urine, allowing water to enter the cells. The water is then returned to the circulation. This causes the volume of urine to decrease, and the urinary content of sodium, chloride, and other substances to increase. When this occurs, the urine is said to be concentrated.

      Vasopressin is also released in response to a decrease in blood volume. Special pressure sensors called baroreceptors can detect arterial blood pressure and are located in the carotid sinus, which is intimately associated with each carotid artery high in the neck, and in a group of specialized cells in the left atrium of the heart. When blood volume increases, the tissues of the carotid sinus and left atrium are stretched and the nerves in the baroreceptors are stimulated. These nerves carry impulses to the vasopressin-producing nerve cells that inhibit the secretion of vasopressin, resulting in increased water excretion. Conversely, if blood volume decreases, the stretch of the carotid sinus and left atrium decreases, vasopressin release increases, and water excretion decreases, thereby helping to restore blood volume to normal. Other stimuli of vasopressin release include pain, stress, and several drugs, including opiate drugs.

      The role of oxytocin is more limited in scope. It stimulates the contractions of the uterus, which are ongoing during the birth process. Injections of oxytocin are sometimes used to stimulate uterine contractions in women in whom labour is flagging. Oxytocin also activates the flow of milk from the breasts (milk letdown) by stimulating the contraction of muscle cells located near the milk-containing glands within seconds after an infant begins to suckle. Emotional influences can increase oxytocin secretion so that the cry of a hungry baby may stimulate milk letdown. There are no known disorders associated with under- or overproduction of oxytocin.

Diabetes insipidus and inappropriate secretion of vasopressin
      The clinical manifestations of diseases of the posterior pituitary may be considered in the context of two extremes in body water content: dehydration and overhydration (water intoxication).

      A person becomes dehydrated when they are deprived of fluids or when they are losing excessive fluids from the body, such as from excessive perspiration, persistent vomiting, or diarrhea. In these circumstances, the volume of fluid in the circulation (plasma volume) is reduced and the serum concentration of solutes (osmolality) is therefore proportionately increased. The decrease in plasma volume and the proportional increase in serum osmolality serve as potent stimuli for the secretion of vasopressin, which then acts on the kidneys to promote retention of water.

      There are two disorders in which this regulatory mechanism is dysfunctional. The first is termed adipsia (hypodipsia) and is a rare disorder in which the brain's thirst centre is damaged. Patients with adipsia have little or no sensation of thirst when they become dehydrated. These patients must be instructed, even forced, to drink fluid at regular intervals.

      The second, far more common disorder is called diabetes insipidus, so named because the large volume of urine that is excreted is tasteless, or “insipid,” rather than sweet as is the case in diabetes mellitus, in which the urine may contain large quantities of glucose. Diabetes insipidus may be caused by a deficiency of vasopressin secretion (central diabetes insipidus) or by a deficiency of vasopressin action in the kidney (nephrogenic diabetes insipidus).

      The causes of central diabetes insipidus include trauma, such as brain or pituitary surgery, and diseases, such as brain tumours, pituitary tumours, or granulomatous infiltration (formation of grainlike lumps that are associated with certain diseases, including tuberculosis or sarcoidosis). In addition, central diabetes insipidus can be caused by mutations in the gene for vasopressin and neurophysin that result in decreased production of vasopressin. Central diabetes insipidus is an uncommon complication of many of these disorders because it only occurs if about 90 percent or more of the neurohypophyseal system is destroyed. In some patients, no cause can be found and the condition is called idiopathic central diabetes insipidus.

      The symptoms of central diabetes insipidus are excessive thirst and excretion of large volumes of urine (usually from three to six litres each day, although up to 20 litres per day has been recorded). Water is the preferred fluid, and, if it or other fluid is freely available, patients remain well except for the inconvenience of frequent drinking and urination day and night. In the absence of a source of fluid, patients become increasingly thirsty and irritable and ultimately stuporous and comatose as a result of hyperosmolality and decreased extracellular fluid volume. Diagnosis is based on the presence of high serum osmolality and low urine osmolality and on the results of a fluid deprivation test, with measurements of serum osmolality and urine output and urine osmolality when fluids are restricted. During a fluid deprivation test, patients with diabetes insipidus continue to excrete large volumes of urine, and administration of vasopressin causes a decrease in urine volume, an increase in urine osmolality, and a decrease in serum osmolality. Central diabetes insipidus can be treated effectively using a chemically modified form of vasopressin called desmopressin, which can be given by nasal spray, tablet, or injection.

      Nephrogenic diabetes insipidus occurs when cells located in the collecting ducts of the kidneys become unresponsive to vasopressin. The symptoms are the same as those of central diabetes insipidus—excessive thirst and excessive urination—but there is no response to administration of vasopressin. The most severe form of this disorder is congenital hereditary nephrogenic diabetes insipidus. This condition is caused by mutations in a gene designated AVPR2 (arginine vasopressin receptor 2) that encodes a specific form of the vasopressin receptor or by mutations in a gene designated AQP2 (aquaporin 2) that encodes a specific form of aquaporin. The vasopressin receptor gene AVPR2 is located on the X chromosome. As a result, affected males have much more severe diabetes insipidus than do females. Acquired nephrogenic diabetes insipidus can occur in patients with electrolyte imbalances, such as high serum calcium concentrations or low serum potassium concentrations, in patients with kidney disease (renal system disease), and in patients taking lithium carbonate. Acquired nephrogenic diabetes insipidus is rarely severe, and patients have normal vasopressin secretion, making treatment with desmopressin ineffective. Adequate fluid must be provided, although the volume needed can be minimized somewhat if salt intake is limited or a diuretic drug is administered.

      Overhydration (water intoxication) occurs when the body's ability to dispose of fluid is overcome by a large fluid intake or the mechanisms for the disposal of excess fluid are defective, as is the case when more vasopressin is secreted than the body needs. Water intoxication from excessive fluid intake is rare but can occur in patients with psychosis, in athletes, and in people who consume large amounts of beer (beer potomania).

      The syndrome of inappropriate vasopressin (antidiuretic hormone) secretion (SIADH) is caused by excessive unregulated secretion of vasopressin. In this situation, vasopressin secretion is inappropriate because it is not stimulated by high serum osmolality or low plasma volume. The excess vasopressin stimulates reabsorption of water by the kidneys, which results in an increase in the volume of extracellular fluid and a decrease in the serum concentrations of sodium, chloride, and other substances. These processes result in the production of concentrated urine and are a reflection of vasopressin activity. The onset of symptoms may be acute or chronic, with sudden or gradual loss of appetite, nausea and vomiting, sleepiness, confusion and disorientation, and ultimately seizures, coma, and death. When the onset is very slow, there may be few or even no symptoms.

      There are no tumours of the neurohypophysis that secrete excess amounts of vasopressin; however, other tumours, particularly those of the lung, may secrete large amounts of vasopressin, causing SIADH. Other causes of excess vasopressin secretion include brain tumours, other central nervous system disorders (nervous system disease), corticotropin deficiency, and several drugs (such as opiates, carbamazepine, and several antitumour drugs). Each of these conditions can result in activation of the neurohypophyseal system and stimulation of vasopressin release independent of the usual regulatory factors.

      Initial treatment for SIADH typically involves restriction of water intake and eradication of the underlying cause, if known. Patients with very low serum sodium concentrations can be treated by intravenous administration of concentrated salt solutions along with a diuretic. This allows the serum concentration of solutes to increase and the plasma volume to decrease.

      All animals must utilize nutrients and consume oxygen to generate the energy needed to maintain body functions at rest as well as to move, grow, and develop. Humans are no exception. Thyroid hormone, by regulating the production of enzymes (enzyme) and other substances, is a major regulator of these processes.

      The thyroid gland is located in the anterior part of the lower neck. It consists of two lobes, one lying on each side of the thyroid cartilage (Adam's apple), that are connected by a band of tissue called the isthmus. It is one of the larger endocrine glands, weighing about 15 g (about 1 oz), with the capacity to grow much larger. Any enlargement of the thyroid, regardless of cause, is called a goitre. The thyroid arises from a downward outpouching of the floor of the pharynx, and a persisting remnant of this migration is known as a thyroglossal duct.

      The thyroid gland consists of many small globular sacs called follicles. The follicles are lined with follicular cells (cell) and filled with a fluid known as colloid that contains the prohormone thyroglobulin. The follicular cells contain the enzymes needed to synthesize thyroglobulin, as well as the enzymes needed to release thyroid hormone from thyroglobulin. When thyroid hormones are needed thyroglobulin is reabsorbed from the colloid in the follicular lumen into the cells, where it is split into its component parts, including the two thyroid hormones thyroxine (T4) and triiodothyronine (T3). The hormones are then released, passing from the cells into the circulation. Nestled in the spaces between the follicles are parafollicular cells, which in essence form a separate endocrine organ. Parafollicular cells have a separate embryological origin from the thyroid follicular cells, and parafollicular cells are not embedded in the substance of the thyroid gland in many species other than humans (see below Calcitonin (endocrine system, human)).

      Thyroxine and triiodothyronine contain iodine and are formed from thyronines, which are composed of two molecules of the amino acid tyrosine. Thyroxine contains four iodine atoms, and triiodothyronine contains three iodine atoms. Because each molecule of tyrosine binds one or two iodine atoms, two tyrosines are used to synthesize both thyroxine and triiodothyronine. These two hormones are the only biologically active substances that contain iodine, and they cannot be produced in the absence of iodine. The process leading to their eventual synthesis begins in the thyroid follicular cells, which concentrate iodine from the serum. The iodine is then oxidized and attached to tyrosine residues (forming compounds called iodotyrosines) within thyroglobulin molecules. The iodinated tyrosine residues are then rearranged to form thyroxine and triiodothyronine. Therefore, thyroglobulin serves as not only the structure within which thyroxine and triiodothyronine are synthesized but also as the storage form of the two hormones.

      Considerably more thyroxine is produced and secreted by the thyroid gland than triiodothyronine. However, thyroxine is converted to triiodothyronine in many tissues by the action of enzymes called deiodinases. After thyroxine enters a cell, deiodinases located in the cytoplasm remove one of its four iodine atoms, converting it into triiodothyronine. The triiodothyronine either enters the nucleus of the cell or is returned to the circulation. As a result, all of the thyroxine and about 20 percent of the triiodothyronine produced each day comes from the thyroid gland. The remaining 80 percent of triiodothyronine comes from deiodination of thyroxine outside of the thyroid. Most, if not all, of the action of thyroid hormone in its target tissues is exerted by triiodothyronine. Therefore, thyroxine may be considered a circulating precursor of triiodothyronine.

      In serum, more than 99 percent of the thyroxine and triiodothyronine is bound to one of three proteins. These binding proteins are known as thyroxine-binding globulin, transthyretin (thyroxine-binding prealbumin), and albumin. The remaining thyroxine and triiodothyronine (less than 1 percent) is free, or unbound. When free hormone enters a cell, it is replenished immediately by hormone attached to the binding proteins. The binding proteins serve as reservoirs of the two hormones to protect the tissues from sudden surges of thyroid hormone production and probably also to facilitate delivery of the hormones to the cells of large, solid organs such as the liver.

      Essentially all cells in the body are target cells of triiodothyronine. Once triiodothyronine is inside a cell, it enters the nucleus, where it binds to proteins (protein) known as nuclear receptors (receptor). The triiodothyronine-receptor complexes then bind to deoxyribonucleic acid ( DNA) molecules. This results in an increase in the rate at which the affected DNA molecules are transcribed to produce messenger ribonucleic acid ( RNA) molecules and an increase in the rate of synthesis of the protein (translation) coded for by the DNA (by way of the messenger RNA). Triiodothyronine increases the transcription of DNA molecules that code for many different proteins; however, it also inhibits the transcription of DNA that codes for certain other proteins. The patterns of activation and inhibition differ in different tissue and cell types.

      The substances produced in increased quantities in response to triiodothyronine include many enzymes, cell constituents, and hormones. Key among them are proteins that regulate the utilization of nutrients and the consumption of oxygen by the mitochondria (cell) of cells. Mitochondria are the sites at which energy is produced in the form of adenosine triphosphate (ATP) or is dissipated in the form of heat. Triiodothyronine activates substances that increase the proportion of energy that is dissipated as heat. It also stimulates lipid production and metabolism, carbohydrate utilization, and central and autonomic nervous system (nervous system, human) activation. During fetal life and in infancy this stimulatory activity of triiodothyronine is critically important for normal neural and skeletal growth and development.

Regulation of hormone secretion
      The thyroid gland is one component of the hypothalamic-pituitary-thyroid axis, which is a prime example of a negative feedback control system. The production and secretion of thyroxine and triiodothyronine by the thyroid gland are stimulated by the hypothalamic hormone thyrotropin-releasing hormone and the anterior pituitary hormone thyrotropin. In turn, the thyroid hormones inhibit the production and secretion of both thyrotropin-releasing hormone and thyrotropin. Decreased production of thyroid hormone results in increased thyrotropin secretion and thus increased thyroid hormone secretion. This restores serum thyroid hormone concentrations to normal levels (if the thyroid gland is not severely damaged). Conversely, increased production of thyroid hormone or administration of high doses of thyroid hormone inhibit the secretion of thyrotropin. As a result of this inhibition, serum thyroid hormone concentrations are able to fall toward normal levels. The complex interactions between thyroid hormone and thyrotropin maintain serum thyroid hormone concentrations within narrow limits. However, if the thyroid gland is severely damaged or if there is excessive thyroid hormone production independent of thyrotropin stimulation, hypothyroidism (thyroid deficiency) or hyperthyroidism (thyroid excess) ensues.

      As noted above, much of the triiodothyronine produced each day is produced by deiodination of thyroxine in extrathyroidal tissues. The conversion of thyroxine to triiodothyronine significantly decreases in response to many adverse conditions, such as malnutrition, injury, or illness (including infections, cancer, and liver, heart, and kidney diseases (renal system disease)). The production of triiodothyronine is also inhibited by starvation and by several drugs, notably amiodarone, a drug used to treat patients with cardiac rhythm disorders (cardiovascular disease). In each of these situations, serum and tissue triiodothyronine concentrations decrease. This decrease in triiodothyronine production may be a beneficial adaptation to starvation and illness because it reduces the breakdown of protein and slows the use of nutrients for generating heat, thereby maintaining tissue integrity and conserving energy resources.

      The fetal thyroid gland begins to function at about 12 weeks of gestation, and its function increases progressively thereafter. Within minutes after birth there is a sudden surge in thyrotropin secretion, followed by a marked increase in serum thyroxine and triiodothyronine concentrations. The concentrations of thyroid hormones then gradually decline, reaching adult values at the time of puberty. Thyroid hormone secretion increases in pregnant women. Therefore, women with thyroid deficiency who become pregnant usually need higher doses of thyroid hormone than when they are not pregnant. There is little change in thyroid secretion in older adults as compared with younger adults.

Diseases and disorders

       hyperthyroidism (thyrotoxicosis) is the constellation of symptoms and signs that result from increased production of thyroid hormone and the effects of excess thyroid hormone on the tissues of the body. The most common cause of hyperthyroidism is Graves disease, named after the Irish physician Robert Graves (Graves, Robert James), who was among the first to describe the disease. Other important causes of hyperthyroidism are a benign thyroid tumour (adenoma), multinodular goitre, thyroid inflammation ( thyroiditis), and high doses of thyroid hormone. In rare cases, hyperthyroidism may be caused by a thyrotropin-secreting tumour of the pituitary gland or a struma ovarii, in which hyperfunctioning thyroid tissue is present in a tumour of the ovary. Hyperthyroidism is 5 to 10 times more common in women than in men.

      Most patients with hyperthyroidism have an enlarged thyroid gland (goitre), but the characteristics of the enlargement vary. For example, patients with Graves disease or thyroiditis have generalized thyroid enlargement, known as diffuse goitre, which may be painless or painful. In contrast, other patients have either a single thyroid nodule, known as uninodular goitre, or multiple thyroid nodules, known as multinodular goitre.

      The onset of hyperthyroidism is usually gradual but can be sudden. The increase in thyroid hormone secretion results in an increase in the function of many organ systems. The cardiovascular and neuromuscular systems are likely to be affected. The cardiovascular symptoms and signs of hyperthyroidism include an increase in heart rate ( tachycardia), atrial fibrillation (rapid irregular heart rhythm), palpitations (pounding in the chest due to forceful contraction of the heart), shortness of breath, and exercise intolerance. Neuromuscular symptoms and signs of hyperthyroidism include nervousness, hyperactivity and restlessness, anxiety and irritability, insomnia, tremor, and muscle weakness. Other common symptoms and signs of hyperthyroidism are weight loss despite a good or even increased appetite, increased perspiration and intolerance of heat, increased frequency of bowel movements, and irregular menstrual cycles and decreased menstrual blood flow in women. Hyperthyroidism also causes an increase in bone resorption and therefore contributes to osteoporosis. The most severe form of hyperthyroidism is thyroid storm. This acute condition is characterized by very rapid heart rate, fever, and severe symptoms and may result in heart failure, low blood pressure ( hypotension), and death.

      Approximately 25 to 35 percent of patients with Graves disease have Graves ophthalmopathy. The defining characteristic of Graves ophthalmopathy is the protrusion of the eyes ( exophthalmos). The eyelids may be retracted upward, making it seem as though the person is constantly staring. The tissues surrounding the eyes may swell, and the eye muscles may not function properly, causing double vision. In rare cases, vision is decreased because of compression or stretching of the optic nerve. These changes are caused by swelling and inflammation of the eye muscles and the adipose (adipose cell) (fat) tissue behind the eyes. Approximately 1 to 2 percent of patients with Graves disease have localized myxedema, which is characterized by circumscribed thickening of the skin and subcutaneous tissue on the lower legs (pretibial myxedema), arms, or trunk. Nearly all patients with localized myxedema have severe ophthalmopathy and have had hyperthyroidism in the past.

      Graves disease is an autoimmune (autoimmunity) disorder in which hyperthyroidism and goitre are caused by thyroid-stimulating antibodies (antibody). These antibodies bind to and activate thyrotropin receptors on the thyroid gland, thereby mimicking the actions of thyrotropin. Risk factors for Graves disease include gender (women are affected more often than men), smoking, and a high intake of iodine. In addition, there is genetic susceptibility to the disease. The immediate events that lead to the production of thyroid-stimulating antibodies that cause hyperthyroidism are not known, although emotional stress has been postulated to be an important factor. Ophthalmopathy and localized myxedema are probably caused by both antibody-mediated and cell-mediated immunologic mechanisms. Whether the antibodies are thyroid-stimulating antibodies or different antibodies is not known. Another feature of Graves disease is spontaneous remission, with disappearance of the thyroid-stimulating antibodies. In these patients, antithyroid drug treatment can be withdrawn without recurrence of hyperthyroidism.

      The second most common cause of hyperthyroidism is toxic multinodular goitre (Plummer disease). This condition begins early in life and is due to iodine deficiency or to other factors that decrease thyroid hormone secretion and result in a persistent increase in thyrotropin secretion and therefore persistent thyroid gland stimulation. This stimulation initially causes generalized thyroid enlargement, but, as time passes, localized regions of the gland grow and function independently of thyrotropin. A less common cause of hyperthyroidism is a benign tumour (toxic adenoma) of the thyroid gland. In many cases these tumours contain a mutation of the thyrotropin receptor gene that results in the synthesis of thyrotropin receptors that are active and therefore lead to excess thyroid hormone production in the absence of thyrotropin.

      Several types of thyroid inflammation ( thyroiditis) can result in the release of stored thyroid hormone in amounts sufficient to cause hyperthyroidism. One type, called silent lymphocytic thyroiditis, is painless and is particularly common in women in the first year after a pregnancy (postpartum thyroiditis). Another type, called subacute granulomatous thyroiditis, is characterized by thyroid pain and tenderness. Hyperthyroidism in patients with thyroiditis is usually mild and self-limiting, lasting only until the stores of hormone in the thyroid gland are exhausted.

      The administration of high doses of thyroid hormone is a common cause of hyperthyroidism. The hormone may have been given by a physician to treat hypothyroidism or to decrease the size of a goitre. In addition, some patients purchase thyroid hormone from health and nutrition stores in the form of a crude thyroid extract or an analogue of thyroid hormone purported to stimulate metabolism and cause weight loss. These preparations may contain variable amounts of thyroid hormone and can have unpredictable effects on the body.

      Hyperthyroidism is diagnosed based on the symptoms and signs described above and on measurements of serum total and free thyroxine and triiodothyronine concentrations and serum thyrotropin concentrations. Most patients with hyperthyroidism have high serum total and free thyroxine and triiodothyronine concentrations and low, usually undetectable, serum thyrotropin concentrations. Patients with a thyrotropin-secreting pituitary tumour, however, have normal or high serum thyrotropin concentrations. Rarely, patients have normal serum thyroxine concentrations but high serum triiodothyronine concentrations. These patients are said to have triiodothyronine thyrotoxicosis. Other patients have low serum thyrotropin concentrations but normal serum thyroxine and triiodothyronine concentrations, with few or no symptoms and signs of hyperthyroidism. These patients are said to have subclinical hyperthyroidism. Thyroid uptake of radioiodine may be measured to distinguish thyroiditis or excess thyroid hormone administration, in which the thyroid uptake is low, from other causes of hyperthyroidism, in which the thyroid uptake is high.

      Hyperthyroidism is a chronic disorder except when caused by thyroiditis. It can be treated with an antithyroid drug, with radioactive iodine, or by thyroidectomy, in which a portion of or all of the thyroid gland is surgically removed. There are three widely used antithyroid drugs—methimazole, carbimazole (which is rapidly converted to methimazole in the body), and propylthiouracil. These drugs block the synthesis of thyroid hormone in the thyroid gland, but have no permanent effect on either the thyroid gland itself or the underlying cause of the hyperthyroidism. Patients with hyperthyroidism caused by Graves disease are often treated with an antithyroid drug for one to two years, with the hope that they will have a remission of the disease and remain well after the drug is stopped. Remission occurs in about 40 percent of patients.

      Radioactive iodine is taken up by thyroid cells in the same way as is nonradioactive iodine, but the radiation destroys the cells, thereby reducing thyroid hormone production. Radioactive iodine therapy is highly effective, but it ultimately results in hypothyroidism in most patients. It is suitable for patients with Graves disease and is the preferred treatment for patients with a nodular goitre since hyperthyroidism is a lifelong condition in these patients. Thyroidectomy is rarely performed except in patients with large goitres. When caused by thyroiditis, hyperthyroidism is mild and transient, lasting only a few weeks or at most one to two months. Most patients need no treatment, but those with marked symptoms may benefit from treatment with a beta-adrenergic antagonist drug ( beta-blocker), which can ameliorate some of the manifestations of hyperthyroidism.

       hypothyroidism is the constellation of symptoms and signs that result from decreased production of thyroid hormone and the effects of this deficiency on the tissues of the body. The most common cause of hypothyroidism is chronic autoimmune thyroiditis. This condition has two forms: Hashimoto thyroiditis ( Hashimoto disease), which is characterized by goitre, and atrophic thyroiditis, which is characterized by shrinkage of the thyroid gland. Hypothyroidism may be caused by treatments for hyperthyroidism, such as radioiodine or surgery. In addition, treatment for certain cancers, such as surgery for thyroid cancer and external-beam radiation therapy directed to the neck to treat patients with tumours of the lymph nodes (lymph node) of the neck ( Hodgkin disease) or of the larynx, may also cause hypothyroidism. Other causes include infiltrative diseases of the thyroid, severe iodine deficiency, certain drugs (e.g., lithium carbonate, iodine, and iodine-containing drugs), developmental defects of the thyroid gland, and hypothalamic or pituitary disease, which result, respectively, in thyrotropin-releasing hormone and thyrotropin deficiency, causing what is known as central hypothyroidism.

      In hypothyroidism the thyroid gland can be affected in different ways and may be large or small in size. For example, Hashimoto disease and other infiltrative disorders usually cause a firm nontender goitre, and iodine deficiency and drug-induced hypothyroidism are likely to cause a small diffuse goitre. In contrast, atrophic thyroiditis and central hypothyroidism cause the thyroid gland to shrink.

      Like other thyroid diseases, hypothyroidism is more common in women than men. The onset is usually gradual, taking several years for notable symptoms and signs to develop, although it may be abrupt, taking only a few months to develop. Abrupt onset of hypothyroidism occurs most commonly after radioiodine treatment for hyperthyroidism. In some cases, hypothyroidism is very mild and is difficult to recognize because it causes few symptoms. In these patients, the condition may be attributed to aging. In other cases, hypothyroidism can be very severe, especially if it is allowed to progress untreated for months or years. In rare cases, it is life-threatening; this is called myxedema coma. The term myxedema refers to thickening of the skin and other organs due to the accumulation of glycoaminoglycans associated with low serum thyroid hormone concentrations. The primary manifestation of myxedema coma is decreased consciousness, ultimately resulting in coma. This condition is commonly precipitated by sedating drugs, cold exposure, or infection and occurs most often in elderly women.

      In contrast to hyperthyroidism, hypothyroidism results in decreased function of many organ systems. Early symptoms include a general slowing of neuromuscular function that results in lethargy, fatigue, sleepiness, muscle weakness, and slow reflexes. Other manifestations of hypothyroidism include dry skin and hair, decreased perspiration, cold intolerance, puffy eyes, a deep or hoarse voice, a decreased appetite but a tendency to gain weight, and constipation. In addition, women tend to have irregular menstrual periods and increased menstrual blood flow. Hypothyroidism also has adverse effects on the heart, leading to decreases in cardiac contractility and heart rate. In later stages of thyroid deficiency, fluid may accumulate around the heart, causing a condition known as pericardial effusion. Hypothyroidism can cause high serum cholesterol concentrations. In infants and young children, hypothyroidism causes mental retardation, and in children of all ages it causes growth retardation. Myxedema coma is characterized by nonresponsiveness, low body temperature ( hypothermia), and respiratory depression.

      Hypothyroidism is diagnosed based on the symptoms and signs described above and on measurements of serum total and free thyroxine and thyrotropin. The usual findings are low serum total and free thyroxine concentrations and high serum thyrotropin concentrations. Some patients have high serum thyrotropin concentrations but normal serum thyroxine and triiodothyronine concentrations. This is known as subclinical hypothyroidism, and these patients have few or no symptoms and signs of hypothyroidism. In patients with hypothyroidism caused by hypothalamic or pituitary disease, serum thyrotropin concentrations may be normal to low, while serum thyroxine concentrations are always low.

      Normal fetal (fetus) development requires both maternally and fetally produced thyroid hormone. In the first 12 weeks of gestation the fetus is dependent on maternal thyroid hormone. At about 12 weeks of gestation the fetal thyroid gland begins to function, although some maternal thyroid hormone crosses the placenta to reach the fetal circulation. The most severe impairment of fetal mental and skeletal development, known as cretinism, occurs when both mother and fetus have thyroid deficiency. This tends to occur more often in regions of the world where severe iodine deficiency is a problem. Cretinism also occurs in infants who have little or no thyroid tissue, especially if the hypothyroidism is not recognized very soon after birth. The ability to prevent cretinism by prompt treatment has led to routine screening for hypothyroidism in newborns. Treatment with thyroxine is initiated based on measurements of thyrotropin and thyroxine in blood that is obtained from the infant a few days after birth.

      Patients with hypothyroidism should be treated with thyroxine in doses sufficient to raise serum thyroxine concentrations and lower serum thyrotropin concentrations. This treatment normalizes serum thyroxine and thyrotropin concentrations and is usually sufficient to reverse the symptoms and signs of hypothyroidism in patients of all ages. Prompt treatment of newborn infants with hypothyroidism results in normal development.

       iodine is essential for normal thyroid hormone production and can be obtained only from the diet. The recommended iodine intake is 150 micrograms daily for adults, 220 micrograms daily for pregnant women, and 290 micrograms daily for lactating women. Worldwide, iodine deficiency is the most common cause of thyroid disease; it is most common in mountainous areas, where the soil and therefore the food and water contain very small amounts of iodine, and is least common in coastal areas, where the soil often contains large amounts of iodine and where iodine-rich seafood is likely to be consumed. It can be prevented by an adequate dietary intake of iodine, which is most often achieved by the addition of iodine to salt.

      When iodine intake is low, thyroid hormone production decreases. This results in an increase in thyrotropin secretion by the pituitary gland. Increased thyrotropin secretion stimulates the thyroid to take up more of the iodine that is available, using it to produce thyroid hormone. While these actions minimize the decrease in thyroid hormone production, they also cause enlargement of the thyroid gland, resulting in goitre. Many people with iodine deficiency have only very mild hypothyroidism, but even this degree of hypothyroidism is sufficient to cause mental retardation in very young infants. Severe iodine deficiency, particularly during gestation and in the first months following birth, can result in cretinism. Children and adolescents with iodine deficiency typically have diffuse goitre, which will decrease in size if iodine intake is increased. However, in adults the goitre becomes nodular and does not regress when iodine intake is increased.

Thyroid nodules and tumours
      Thyroid nodules are very common, with the frequency of occurrence increasing with age. In the United States they can be detected by physical examination in approximately 5 percent of the adult population and by ultrasonography in approximately 40 percent of the adult population. They may be caused by a multinodular goitre, a benign thyroid tumour (adenoma), or thyroid cancer ( carcinoma). The best way to distinguish between benign and malignant thyroid nodules is to aspirate (remove) cells from the nodule using a fine needle so that they can be examined under a microscope. Typically, 95 percent of nodules prove to be benign and 5 percent prove to be malignant. The benign nodules can be left alone; they enlarge only slightly, if at all, with time and can be removed surgically if they become bothersome to the patient. Malignant nodules, along with the entire thyroid gland, should be removed surgically to avoid potential metastasis to other sites of the body.

      There are four types of thyroid cancer (thyroid tumour): papillary carcinoma, which accounts for about 90 percent of cases, and follicular carcinoma, anaplastic carcinoma, and medullary carcinoma, which together account for the remaining 10 percent of cases. Papillary and follicular carcinomas are very slow-growing tumours, and, while they can spread to lymph nodes (lymph node) in the neck, the lungs (lung), or elsewhere, most patients are cured by a combination of surgery, radioactive iodine therapy, and thyroid hormone therapy. The only established risk factors for papillary carcinoma are external-beam radiation to the head and neck region and exposure to radioactive iodine in infants and children. In contrast to papillary and follicular carcinomas, anaplastic carcinomas are highly malignant and rapidly fatal. Medullary carcinomas are tumours of the parafollicular cells of the thyroid gland and are somewhat more malignant than papillary or follicular carcinomas.

The parathyroid glands (parathyroid gland)
       calcium is a key element in the human body. It serves as the major constituent of bone and is essential for many normal cellular functions, including blood clotting and nerve excitability. Because calcium is fundamental to many cellular activities, the serum concentration of calcium is closely regulated to avoid wide fluctuations. Many of the actions of calcium also require adequate supplies of magnesium and phosphate. A healthy person needs a regular, continuous supply of these elements and requires about a gram each day of calcium and phosphate and about one-third of a gram of magnesium.

      Almost all of the calcium contained in the human body is deposited in bone, amounting to about 1.3 kg (2.9 pounds) of calcium in normal adults. This mass provides skeletal support and serves as a reserve from which calcium may be mobilized into body fluids. However, it is the remaining 1 percent, dissolved in these fluids, that is so closely regulated. In serum, calcium exists in equal amounts of two forms: as free calcium ions (ion) (Ca2+) and as reversibly bound calcium, mostly bound to serum albumin but also to other molecules, including other proteins (protein), phosphate, and citrate. The major regulators of serum calcium concentrations are parathyroid hormone and the active metabolites of vitamin D.

      The parathyroid glands (parathyroid gland), usually four in number, are small structures adjacent to or occasionally embedded in the thyroid gland. Each gland weighs about 50 mg (0.002 ounce). Because of their small size and their close association with the thyroid gland, it is not surprising that they were recognized as distinct endocrine organs rather late in the history of endocrinology. At the beginning of the 20th century, symptoms due to deficiency of the parathyroid glands were attributed to the absence of the thyroid gland. At that time, surgeons inadvertently removed the parathyroid glands when they removed the thyroid gland. It was recognized in the early part of the 20th century that parathyroid deficiency could be mitigated by the administration of calcium salts. Soon after, scientists successfully prepared active extracts of the parathyroid glands and characterized the parathyroid glands as endocrine glands that secreted parathyroid hormone. These discoveries were followed by the realization that parathyroid tumours caused high serum calcium concentrations.

      The parathyroid glands arise in the embryo from the third and fourth pairs of branchial pouches, bilateral grooves resembling gill slits in the neck of the embryo and reminders of human evolution from fish.

Hormones

      The parathyroid glands produce only one hormone, parathyroid hormone. Under the microscope the parathyroid hormone-producing cells, called chief cells, occur in sheets interspersed with areas of fatty tissue. Occasionally the cells are arranged in follicles similar to but smaller than those present in the thyroid gland. As with other protein hormones, parathyroid hormone is synthesized as a large, inactive prohormone. At the time of secretion the prohormone is split, and the active hormone (a protein containing 84 amino acids (amino acid)) is released from the inactive precursor.

      The major determinant of parathyroid hormone secretion is the serum concentration of ionized calcium. Serum calcium concentration is monitored by calcium-sensing receptors (receptor) located on the surface of the parathyroid cells. When serum calcium concentrations increase, more calcium binds to the receptors, causing a decrease in parathyroid hormone secretion. Conversely, when serum calcium concentrations decrease, decreased calcium receptor binding causes an increase in parathyroid hormone secretion. Magnesium controls parathyroid hormone secretion in a similar fashion.

      Parathyroid hormone has multiple actions, all of which result in an increase in serum calcium concentration. For example, it activates large bone-dissolving cells called osteoclasts (osteoclast) that mobilize calcium from bone tissue, and it stimulates the kidney tubules to reabsorb calcium from the urine. Parathyroid hormone also stimulates the kidney tubules to produce calcitriol (1,25-dihydroxyvitamin D), the most active form of vitamin D, from calcidiol (25-hydroxyvitamin D), a less active form of vitamin D. Calcitriol helps increase serum calcium concentrations because it stimulates the absorption of calcium from the gastrointestinal tract. Parathyroid hormone also inhibits the reabsorption of phosphate by the kidney tubules, thereby decreasing serum phosphate concentrations. This potentiates the ability of parathyroid hormone to increase serum calcium concentrations because fewer insoluble calcium-phosphate complexes are formed when serum phosphate concentrations are low.

       calcitonin is a protein containing 32 amino acids that is synthesized by and secreted from special cells called parafollicular cells (or C cells), which lie between the thyroid follicular cells in the thyroid gland. During embryonal development, parafollicular cells migrate into the substance of the thyroid gland from a fetal structure called a branchial pouch.

      Calcitonin is secreted when serum calcium concentrations increase. Calcitonin then acts to decrease serum calcium concentrations by inhibiting the activity of the osteoclasts in bone tissue and by increasing calcium excretion in the urine. However, both increased calcitonin secretion and increased calcitonin activity are very short-lived, lasting only a few days. As a result, patients with chronically high serum calcium concentrations (hypercalcemia) do not have high serum calcitonin concentrations. Patients with medullary thyroid carcinoma, a cancer of the parafollicular cells that secretes large quantities of calcitonin, have high serum calcitonin concentrations but normal serum calcium concentrations, further evidence that calcitonin activity is short-lived.

vitamin D and the calciferols
      Vitamin D deficiency was first described more than 300 years ago as a disorder called rickets. However, the chemical transformations that produce the biologically active form of vitamin D and how this active form of vitamin D affects the bones were described only recently. The term vitamin D refers to a family of compounds that are derived from cholesterol. There are two major forms of vitamin D: vitamin D3, found in animal tissues and often referred to as cholecalciferol, and vitamin D2, found in plants and better known as ergocalciferol. Both of these compounds are inactive precursors of potent metabolites and therefore fall into the category of prohormones. This is true not only for cholecalciferol and ergocalciferol obtained from the diet but also for cholecalciferol that is generated from 7-dehydrocholesterol in the skin during exposure to ultraviolet (ultraviolet radiation) light. These precursors are first converted to calcidiol (25-hydroxyvitamin D) in the liver. Calcidiol then binds to special vitamin D binding proteins in the blood and is transported to the kidney tubules, where it is converted to calcitriol (1,25-dihydroxyvitamin D), the most potent derivative of vitamin D.

      The recommended daily intake of vitamin D is 200 IU (international units (International Unit); internationally accepted units defined by specified effects of a substance) for children, adolescents, and adults up to 50 years old. The recommended daily intake of vitamin D is 400 IU for people 51 to 70 years old and 600 IU for people over 70 years old. Because sunlight exposure in temperate zones is limited in winter and because the vitamin D content of many foods is relatively low, food products and milk are supplemented with vitamin D in many countries. Maintaining adequate vitamin D intake can be a problem for very young breast-fed infants because human breast milk contains only small amounts of vitamin D. In addition, older adults tend to consume inadequate amounts of vitamin D-supplemented foods and to avoid sunlight, placing them at a high risk for vitamin D deficiency.

      Vitamin D deficiency may be caused by limited sunlight exposure, dietary deficiency of vitamin D, poor absorption of vitamin D as a result of gastrointestinal disease, abnormalities of vitamin D metabolism (caused by anticonvulsant drugs or kidney disease (renal system disease)), or vitamin D resistance (caused by decreased vitamin D receptors in the intestines). People with vitamin D deficiency cannot absorb calcium and phosphate efficiently and therefore have low serum calcium and phosphate concentrations and high serum parathyroid hormone concentrations. The low serum calcium and phosphate concentrations result in poorly calcified bones. In children this is known as rickets, and in adults it is known as osteomalacia (see below Rickets and osteomalacia (endocrine system, human)).

      Ingestion of high doses (daily doses of 10,000 IU or more) of vitamin D or metabolites of vitamin D can cause hypercalcemia and low serum parathyroid hormone concentrations. This tends to occur most often in patients with hypoparathyroidism who are being treated with vitamin D or calcitriol. However, it may also occur in people who ingest nutritional supplements that contain vitamin D. Occasionally, patients with sarcoidosis (a disease characterized by the formation of nests of inflammatory cells in the lungs (lung), lymph nodes (lymph node), and other tissues) or with malignant tumours have hypercalcemia caused by excess production of calcitriol by the abnormal tissue.

Diseases and disorders

      Hyperparathyroidism, defined as hyperfunction of one or more parathyroid glands, may be primary or secondary. In primary hyperparathyroidism, one or more parathyroid glands produces excessive amounts of parathyroid hormone. This causes an increase in serum calcium concentrations by stimulating the breakdown of bone and by increasing calcium reabsorption by the kidneys. In secondary (compensatory) hyperparathyroidism, the parathyroid glands become overactive in an attempt to compensate for low serum calcium concentrations. Secondary hyperparathyroidism occurs most often in patients with vitamin D deficiency or chronic kidney disease (renal system disease).

      Primary hyperparathyroidism is a relatively common disorder and is usually detected when serum calcium is measured as part of a routine health examination. Most patients have mild hypercalcemia, although there are some patients who have no symptoms at all. There are also other patients who have nonspecific symptoms, such as fatigue, weakness, depression, and loss of appetite. Patients with more severe hypercalcemia may have nausea, vomiting, weight loss, constipation, bone pain, and more marked weakness and depression. About 20 percent of cases are detected because patients develop kidney stones (kidney stone), and about 1 to 2 percent of cases are detected because the patient has symptomatic osteoporosis (loss of bone). In rare cases, patients have a severe form of osteoporosis called osteitis fibrosa cystica, in which there is intense local resorption of bone that results in the formation of cystlike spaces within the bones that are filled with fibrous tissue.

      The diagnosis of primary hyperparathyroidism is based on the findings of high serum calcium concentrations and high serum parathyroid hormone concentrations. Less common findings include low serum phosphate concentrations, increased calcium excretion in the urine, and decreased bone density. Hypercalcemia in combination with low serum parathyroid hormone concentrations can be caused by many types of cancer, such as that of the lung, breast, or kidney. This occurs because tumours may produce substances such as parathyroid hormone-related protein that stimulate the breakdown of bone and release calcium into the bloodstream. In addition, tumours can also invade the bones, causing hypercalcemia. Other causes of hypercalcemia and low serum parathyroid hormone concentrations are hyperthyroidism and vitamin D intoxication. In addition to primary hyperparathyroidism, causes of hypercalcemia and high serum parathyroid hormone concentrations include thiazide diuretic drugs (used to treat hypertension) and lithium carbonate (used to treat depression). In some cases, serum calcium and serum parathyroid hormone concentrations are high as a result of a disorder called familial hypocalciuric hypercalcemia (familial benign hypercalcemia). This disorder is caused by a mutation in the calcium receptor gene that reduces the ability of calcium to inhibit parathyroid hormone secretion. In most patients with this disorder, serum calcium and parathyroid hormone concentrations are only minimally elevated.

      Primary hyperparathyroidism is most often caused by an adenoma (a benign tumour) of one parathyroid gland. The adenoma produces and secretes an excessive amount of parathyroid hormone largely independent of the serum calcium concentration. The cause of parathyroid gland tumours is not known. About 10 percent of patients have primary hyperplasia of all the parathyroid glands. Primary parathyroid hyperplasia can occur as a result of a familial disorder known as multiple endocrine neoplasia type 1 (MEN1; see below Ectopic hormone and polyglandular disorders (endocrine system, human)). In rare cases, the cause of hyperparathyroidism is attributed to parathyroid carcinoma (a malignant tumour).

      Patients with primary hyperparathyroidism with symptoms of hypercalcemia, kidney stones, or bone disease are treated by surgical removal of the tumour (or most of the hyperplastic tissue). The most appropriate treatment of patients with asymptomatic hyperparathyroidism is less clear. Many of these patients remain symptom-free; their serum calcium concentrations do not increase, and their bone density does not decrease. Thus, one alternative is to monitor the patient from year to year, periodically measuring serum calcium and bone density, deciding to treat the patient only when the condition becomes more severe. Another alternative is to treat the patient with a bisphosphonate drug to prevent or to decrease the rate of bone loss.

      In patients who have acute marked symptoms of hypercalcemia, fluids are administered intravenously as a way to rapidly lower serum calcium concentrations. If that is not effective, a bisphosphonate drug, such as pamidronate or zoledronate, is administered intravenously to reduce hypercalcemia.

       hypoparathyroidism can be due to decreased secretion of parathyroid hormone or less often to decreased action of parathyroid hormone (pseudohypoparathyroidism). In either case, hypoparathyroidism results in decreased mobilization of calcium from bone, decreased reabsorption of calcium by kidney tubule cells, decreased absorption of calcium by the gastrointestinal tract, and increased reabsorption of phosphate by kidney tubule cells. This abnormal pattern of calcium and phosphate regulation results in low serum calcium concentrations (hypocalcemia) and high serum phosphate concentrations.

      The symptoms of hypoparathyroidism are the result of low serum calcium concentrations. Most prominent is muscular cramping (cramp) and twitching, exemplified most dramatically by carpopedal (wrist and foot) spasms. These are painful contractions of the muscles of the arms and hands (and feet) in which the four fingers are rigidly extended while the thumb presses against the palm. This neuromuscular excitability can progress to generalized convulsions (convulsion). Other common symptoms are a sensation of numbness and tingling around the mouth and in the hands and feet. Patients with chronic hypocalcemia may develop cataracts (cataract) and calcification in the basal ganglia (ganglion) of the brain, which in turn can cause symptoms of parkinsonism. Patients who have pseudohypoparathyroidism may have skeletal abnormalities, including a short neck and extremities and shortened metacarpal bones, and may have abnormal physical features, characterized primarily by a rounded face.

      Hypoparathyroidism is a rare disorder; indeed, the most common cause is inadvertent removal of the parathyroid glands during thyroid gland surgery. In some cases, hypoparathyroidism will occur spontaneously as the result of an autoimmune (autoimmunity) disorder. In these patients, hypoparathyroidism is often only one component of a multiple endocrine deficiency syndrome (see below Ectopic hormone and polyglandular disorders (endocrine system, human)). Other causes of hypoparathyroidism are iron deposition in the parathyroid glands (in patients with iron storage disorders), magnesium deficiency (usually in alcoholic patients), congenital absence of the parathyroid glands, and a mutation in the calcium receptor of the parathyroid glands that increases the ability of calcium to inhibit parathyroid hormone secretion. Most patients with pseudohypoparathyroidism have a genetic defect in which the action of parathyroid hormone on its target cells in the bones and kidney is defective.

      Other causes of hypocalcemia include vitamin D deficiency, vitamin D resistance, severe inflammation of the pancreas ( pancreatitis), and, most common of all, severe kidney failure. All of these disorders result in secondary (compensatory) hyperparathyroidism.

      Patients with symptomatic hypocalcemia can be treated with intravenous administration of calcium salts. Long-term treatment consists of oral administration of vitamin D or calcitriol and of calcium salts. Serum calcium must be measured periodically to be certain that treatment is effective and that neither hypocalcemia nor hypercalcemia is present.

Hypercalcitoninemia
      Hypercalcitoninemia is a characteristic feature of medullary thyroid carcinomas, which are tumours of the parafollicular cells (C cells) of the thyroid gland. These tumours occur both sporadically and predictably, affecting multiple members of families who carry gene mutations. In some families, medullary thyroid carcinomas are the only tumours that appear, whereas in other families, medullary thyroid carcinomas are one component of multiple endocrine neoplasia type 2 (MEN2). Medullary thyroid carcinomas are moderately malignant tumours that invade nearby tissues in the neck and spread to distant organs, such as the lungs and liver. Despite marked increases in serum calcitonin concentrations, patients with medullary thyroid carcinoma do not have hypocalcemia, because their tissues are resistant to calcitonin.

      Nearly all patients affected by medullary thyroid carcinoma or MEN2 have hereditary mutations in the RET (rearranged during transfection) protooncogene (a gene that can become a cancer-causing gene, or oncogene). Patients with medullary thyroid carcinoma should be tested for mutations in RET; if a mutation is detected, other family members should also be tested. Virtually all people carrying a mutation in RET will develop medullary thyroid carcinoma, and some people will develop it at a young age. Therefore, any individual carrying a RET mutation should undergo thyroidectomy at an early age, before a tumour appears.

Metabolic bone diseases (bone disease)
      The skeleton (skeletal system, human), like many other tissues of the body, undergoes a constant process of breakdown and renewal. This ongoing process of bone resorption and formation permits the skeleton to adjust to the changes required for healthy functioning and subtle remodeling to maintain maximal bone strength and to the changes required for healing fractures. Normal bone provides rigid support and is not brittle. It consists of two major components: a protein matrix called osteoid and mineral complexes. Osteoid consists mostly of a fibrous protein called collagen, while the mineral complexes are made up of crystals of calcium and phosphate, known as hydroxyapatite, that are embedded in the osteoid. Bone also contains nutritive cells called osteocytes (osteocyte). However, the major metabolic activity in bone is carried out by osteoblasts (osteoblast), which generate the protein matrix, and osteoclasts (osteoclast), which are large, multinucleated cells that digest and dissolve the components of bone.

      Metabolic bone diseases (bone disease)—that is, diseases that affect many bones to a lesser or greater extent—include osteoporosis, rickets, osteomalacia, osteogenesis imperfecta, osteopetrosis, Paget disease (Paget disease of bone) of bone, and fibrous dysplasia. In clinical terms, metabolic bone diseases may result in bone pain and loss of height (due to compression of vertebrae), and they predispose patients to fractures (fracture).

      Most of these diseases are defined by the extent to which they reduce bone density. Bone density can be measured in different bones using radiologic techniques. The bones commonly measured are the bones of the lumbar spine, hip, and radius (a bone in the forearm), and the most widely used procedure is dual X-ray absorptiometry. Bone density peaks at about the age of 30 and varies according to sex and genetic background. For example, bone density is higher in men than women and is higher in African Americans than in Europeans or Asians. The results of measurements of bone density (bone densitometry) are usually expressed in terms of the patient's bone density in relation to the mean peak bone density of people of the same sex and genetic background. The result is a measurement known as the T score. Osteopenia is defined as bone density that is more than one standard deviation below peak bone density (T score –1), and osteoporosis (including any disorder in which bone density is reduced) is defined as bone density that is two and a half or more standard deviations below the mean peak bone density (T score –2.5). The results of measurements of bone density can also be expressed as Z scores. A Z score of zero is the mean bone density of people of the same age, sex, and genetic background. Low T or Z scores are associated with an increased risk of bone fracture.

      The most common metabolic bone disease, osteoporosis, literally meaning porous bone, is the result of decreased bone formation or increased bone resorption. In osteoporosis, bone is lost in such a way that the normal balance between osteoid and mineral is retained. However, because there is less bone per unit volume, the decrease in bone density of osteoporosis is great (as noted above, it is defined by a T score of –2.5 or lower). There are many causes of osteoporosis, including normal aging, menopause, hypogonadism in men and in premenopausal women, primary hyperparathyroidism, hyperthyroidism, glucocorticoid excess, nutritional deficiency (e.g., anorexia nervosa), immobilization, several therapeutic agents (e.g., heparin and anticonvulsants), liver disease, and renal disease (renal system disease). Both genetic and lifestyle factors contribute to osteoporosis. Family history, such as the tendency to fracture, is an important factor in osteoporosis. Lifestyle choices also influence the development of osteoporosis, as risk is higher in people who are physically inactive, have low calcium intake, are very thin, or are smokers.

      Osteoporosis occurs most often in women, although the disease occurs in men as well. Of the many causes of osteoporosis, by far the most common is menopause. It is estimated that approximately one-fourth of the world population of women over 60 years of age have some degree of osteoporosis. For these women, fracture is a leading cause of morbidity and mortality.

      Most patients with osteoporosis have no symptoms, whereas other patients have back pain. As the thoracic vertebrae (vertebral column) become compressed, the spine bends forward, producing the typical “dowager's hump,” with an accompanying loss of height. A compression fracture of a vertebra may be signaled by a sudden, sharp pain in the affected area after minimal or no trauma or by a sudden loss of height. It is common, however, for the patient not to recall pain or trauma, and vertebral compression fractures may be detected as incidental X-ray findings. Fractures of the femur after little or no trauma are quite common and are a major cause of morbidity and mortality in postmenopausal women.

      In most cases, osteoporosis can be prevented. The most effective measures for preventing osteoporosis include good nutrition and a liberal calcium and vitamin D intake throughout life, particularly in the early postmenopausal years. Moderate, regular physical activity, especially weight-bearing exercise such as walking, running, and weightlifting, also protects against bone loss. There are several therapeutic agents that play different roles in preventing bone loss, reducing fracture risk, and rebuilding bone. estrogen, raloxifene (an estrogen-like drug), bisphosphonate drugs, and calcitonin decrease bone resorption. Calcium and vitamin D supplements decrease bone resorption and stimulate bone formation. In addition, parathyroid hormone, when given intermittently, increases bone formation.

Rickets and osteomalacia
      The softening of bones in children, known as rickets, and in adults, known as osteomalacia, is caused primarily by vitamin D deficiency. Vitamin D deficiency was a worldwide problem, particularly in temperate zones, until the 1920s, when scientists found that vitamin D deficiency could be prevented and cured by exposure to sunlight and by administration of cod liver oil, a substance rich in vitamin D. While the production of osteoid, the protein matrix on which calcium is deposited, is normal or increased in vitamin D deficiency, it is poorly calcified. This causes soft bones, the literal meaning of the term osteomalacia. In children there is an overgrowth of cartilage, resulting in the enlargement of the ends of long bones and in the junction of the ribs (rib) with the rib cage in the chest (rachitic rosary). The bones become distorted, and children who have vitamin D deficiency often have bow legs, a bulging forehead, and short stature. Healing is prompt when high doses of vitamin D and calcium are administered. Consuming products to which vitamin D has been added, such as vitamin D-enriched milk and cereals, is a simple way to prevent rickets and osteomalacia.

      Rickets and osteomalacia can also occur as a result of low serum phosphate concentrations ( hypophosphatemia). Examples of disorders that cause low serum phosphate concentrations include inherited defects in the ability of the kidneys to reabsorb phosphate (familial hypophosphatemia) and production of substances by tumours that inhibit the reabsorption of phosphate by the kidneys (oncogenic osteomalacia). Tumours that cause hypophosphatemia are often hard to locate because they are small and occur in fibrous or mesenchymal tissue, including bone.

      Osteogenesis imperfecta, also known as brittle bone disease, is a rare inherited disease that occurs in several forms. In one form, multiple fractures, particularly of the bones of the extremities, occur near the time of birth, resulting in a high death rate in affected infants. Another, far less severe form is characterized by fractures of long bones that occur in adolescence and young adulthood. Associated abnormalities include a blue tint to the whites of the eyes (blue sclerae) and an abnormal dentition (the teeth and their position in the jaw). Osteogenesis imperfecta is caused by mutations in the gene for collagen, the protein most abundant in the organic matrix of bone tissue. Treatment with bisphosphonate drugs has proved effective in some patients.

      Osteopetrosis (marble bone disease) is characterized by an increase in bone density, but the bone tends to be brittle and fractures are common. The overgrowth of bone may result in anemia because increased bone mass crowds the bone marrow, resulting in a reduced amount of marrow and therefore a reduced capacity to produce red blood cells. There are both congenital and acquired forms of osteopetrosis. The congenital forms are associated with a decreased number of osteoclasts or decreased osteoclast function. Affected patients are often treated successfully with bone marrow transplantation (transplant), which provides cells that can be converted to osteoclasts. Acquired osteopetrosis is usually caused by fluoride deposition in bone tissue ( fluorosis), which results in the growth of dense but brittle bone. The excess fluoride is usually ingested when drinking well water. Localized osteopetrosis can occur in patients with cancer, usually in patients with breast cancer or prostate cancer, whose tumours have metastasized into bone tissue.

Paget disease (Paget disease of bone)
      Paget disease (Paget disease of bone), also called osteitis deformans, is not a generalized metabolic bone disease but rather a localized disease that may be unifocal, affecting a single bone, or multifocal, affecting many bones. For this reason, it is included among the metabolic disorders of bone.

      The disease is characterized by excessive bone resorption and excessive bone formation. When osteoclasts isolated from patients with Paget disease are viewed through an electron microscope, structures that very closely resemble viruses can be seen. The osteoclasts are extraordinarily active, resorbing bone rapidly and at the same time activating a “coupling factor” that leads to an increase in bone formation by local osteoblasts. This increase may be both excessive and disorganized. The result is a “chaotic” bone structure, with areas of bone resorption and areas of excessive bone formation, which leads to bone weakening and bone deformities.

      Paget disease affects older women and men in approximately equal proportions, but men tend to have more advanced disease. Many patients are asymptomatic, and the bony abnormalities are detected by X-rays or by radionuclide bone scans that are done for other purposes. Some patients are found to have high serum concentrations of alkaline phosphatase, an enzyme involved in bone formation. Some patients have pain in the affected bone or pain associated with the overgrown bone. Overgrowth of a bone of the skull or vertebrae may impinge on the spinal cord or nerves, causing a significant amount of pain. In some patients the disease involves only a single bone, whereas in others it involves nearly the entire skeleton. The most common sites of the disease are the femur, pelvis, skull, and spine, but almost any bone may be involved. Patients with classic, advanced Paget disease have a large skull, a shortened spine, and bowed thighs and legs, and pathological fractures are common. In rare cases the disease is complicated by bone cancer. There is no known cure, but the disease can be treated effectively with a bisphosphonate drug.

       fibrous dysplasia also is a disseminated rather than generalized bone disease, and its cause is unknown. It may be monostotic, localized to one bone, or polyostotic, affecting more than one bone. Monostotic fibrous dysplasia is characterized by an expanding mass composed of osteoblasts and fibroblasts (fibroblast) that originates from bone tissue. Polyostotic fibrous dysplasia is characterized by masses of fibroblasts and woven bone. It is a component of McCune-Albright syndrome, which includes patches of tan pigmentation (“café au lait” spots), premature puberty, and occasionally hyperthyroidism or acromegaly. Patients with this syndrome have somatic mutations (mutations in body cells as opposed to germ cells) of an intracellular hormone-signaling pathway that cause the pathway to remain constantly active.

Robert D. Utiger

      The discovery of insulin in 1921 was one of the most important events in modern medicine. It saved the lives of innumerable patients with diabetes mellitus, and it ushered in the present-day understanding of the function of the endocrine pancreas. The importance of the endocrine pancreas lies in the fact that its principal hormone, insulin, plays a central role in the regulation of energy metabolism. A relative or absolute deficiency of insulin leads to diabetes mellitus, a major cause of disease and death throughout the world.

 In humans the pancreas weighs approximately 80 grams (about 3 ounces) and is shaped like a pear. It is located in the upper abdomen, with the head lying immediately adjacent to the duodenum and the body and tail extending across the midline nearly to the spleen. In adults, most of the pancreatic tissue is devoted to exocrine function, in which digestive enzymes are secreted via the pancreatic ducts into the duodenum. Only 1 to 2 percent of pancreatic tissue has endocrine function.

      The endocrine pancreas consists of the islets of Langerhans (Langerhans, islets of). There are approximately one million islets that weigh about one gram in total and are scattered throughout the pancreas. The cells that make up the islets arise from both endodermal (endoderm) and neuroectodermal precursor cells. Approximately 75 percent of the cells in each islet are insulin-producing beta cells, which are clustered centrally in the islet. The remainder of each islet consists of alpha, delta, and F (or PP) cells, which secrete glucagon, somatostatin, and pancreatic polypeptide, respectively, and are located at the periphery of the islet. Each islet is supplied by one or two very small arteries (artery) (arterioles) that branch into numerous capillaries (capillary). These capillaries emerge and coalesce into small veins (vein) outside of the islet. The islets also contain many nerve endings (predominantly involuntary, or autonomic, nerves that monitor and control internal organs). The principal function of the endocrine pancreas is the secretion of insulin and other polypeptide hormones necessary for the cellular storage or mobilization of glucose, amino acids (amino acid), and triglycerides (triglyceride). Islet function may be regulated by signals initiated by autonomic nerves, circulating metabolites (e.g., glucose, amino acids, ketone bodies), circulating hormones, or local (paracrine) hormones.

Hormones

       insulin, produced by the beta cells of the islets of Langerhans, is a protein composed of two chains, an A chain (with 21 amino acids) and a B chain (with 30 amino acids), which are linked together by sulfur atoms. Insulin is derived from a 74-amino acid prohormone molecule called proinsulin. Proinsulin is relatively inactive, and under normal conditions only a small amount of it is secreted. In the endoplasmic reticulum of beta cells the proinsulin molecule is cleaved in two places, yielding the A and B chains of insulin and an intervening, biologically inactive C peptide. The A and B chains become linked together by two sulfur-sulfur (disulfide) bonds. Proinsulin, insulin, and C peptide are stored in granules in the beta cells, from which they are released into the capillaries of the islets in response to appropriate stimuli. These capillaries empty into the portal vein, which carries blood from the stomach, intestines, and pancreas to the liver. The pancreas of a normal adult contains approximately 200 units of insulin, and the average daily secretion of insulin into the circulation in healthy individuals ranges from 30 to 50 units.

      Several factors stimulate insulin secretion, but by far the most important is the concentration of glucose in the arterial (oxygenated) blood that perfuses the islets. When blood glucose concentrations increase (i.e., following a meal), large amounts of glucose are taken up and metabolized by the beta cells, and the secretion of insulin increases. Conversely, as blood glucose concentrations decrease, the secretion of insulin decreases; however, even during fasting, small amounts of insulin are secreted. The secretion of insulin may also be stimulated by certain amino acids, fatty acids (fatty acid), keto acids (products of fatty acid oxidation), and several hormones secreted by the gastrointestinal tract. The secretion of insulin is inhibited by somatostatin and by activation of the sympathetic nervous system (the branch of the autonomic nervous system responsible for the “fight or flight” response).

      Insulin acts primarily to stimulate glucose uptake by three tissues—adipose (adipose cell) (fat), muscle, and liver—that are important in the metabolism and storage of nutrients. Like other protein hormones, insulin binds to specific receptors (receptor) on the outer membrane of its target cells, thereby activating metabolic processes within the cells. A key action of insulin in these cells is to stimulate the translocation of glucose transporters, molecules that mediate cell uptake of glucose, from within the cell to the cell membrane.

      In adipose tissue, insulin stimulates glucose uptake and utilization. The presence of glucose in adipose cells, in turn, leads to increased uptake of fatty acids from the circulation, increased synthesis of fatty acids in the cells, and increased esterification (when an acid molecule binds to an alcohol) of fatty acids with glycerol to form triglycerides (triglyceride), the storage form of fat. In addition, insulin is a potent inhibitor of the breakdown of triglycerides (lipolysis). This prevents the release of fatty acids and glycerol from fat cells, saving them for when they are needed by the body (e.g., when exercising or fasting). As serum insulin concentrations decrease, lipolysis and fatty acid release increase.

      In muscle tissue, insulin stimulates the transport of glucose and amino acids into muscle cells. The glucose is stored as glycogen, a storage molecule that can be broken down to supply energy for muscle contraction during exercise and to supply energy during fasting. The amino acids transported into muscle cells in response to insulin stimulation are utilized for the synthesis of protein. In contrast, in the absence of insulin the protein of muscle cells is broken down to supply amino acids to the liver for transformation into glucose.

      Insulin is not required for the transport of glucose into liver cells, but it has profound effects on glucose metabolism in these cells. It stimulates the formation of glycogen (a storage form of glucose), and it inhibits the breakdown of glycogen (glycogenolysis) and the synthesis of glucose from amino acids and glycerol (gluconeogenesis). Therefore, the overall effect of insulin is to increase glucose storage and to decrease glucose production and release by the liver.

      Glucagon is a 29-amino acid protein produced by the alpha cells of the islets of Langerhans. It has a high degree of similarity with several glucagon-like peptides that are secreted by cells scattered throughout the gastrointestinal tract. Glucagon secretion is stimulated by the ingestion of protein, by low blood glucose concentrations ( hypoglycemia), and by exercise. In contrast, it is inhibited by the ingestion of carbohydrates, an effect that may be mediated by the resultant increase in blood glucose concentrations and insulin secretion. The major actions of glucagon are to stimulate the breakdown of liver glycogen into glucose (glycogenolysis) and to stimulate the production of glucose from amino acids and glycerol (gluconeogenesis) in the liver. The glucose is then released into the bloodstream. Through this action, glucagon plays a critical role in maintaining blood glucose concentrations during fasting and exercise.

      Somatostatin, a peptide that was initially discovered in the hypothalamus (see above Somatostatin (endocrine system, human)), contains 14 amino acids and is produced by the delta cells of the islets of Langerhans. It inhibits both insulin and glucagon secretion. It also inhibits the secretion of several gastrointestinal hormones and nutrient absorption and motility in the gastrointestinal tract.

      In summary, insulin, glucagon, and somatostatin act in concert to control the flow of nutrients into and out of the circulation. The relative concentrations of these hormones regulate the rates of absorption, utilization, and storage of glucose, amino acids, and fatty acids. The anatomic proximity of the beta, alpha, and delta cells in the islets of Langerhans is important. Somatostatin and glucagon appear to have a paracrine relationship, each influencing the secretion of the other, with both affecting the rate of insulin release.

Pancreatic polypeptide
      Pancreatic polypeptide, secreted by the F (or PP) cells of the islets of Langerhans, contains 36 amino acids. Its secretion is stimulated by eating, exercising, and fasting. It can inhibit gallbladder contraction and pancreatic exocrine secretion, but its role in the metabolism of nutrients is uncertain.

Hormonal control of energy metabolism
      The pancreatic hormones, particularly insulin and glucagon, play key roles in maintaining glucose homeostasis and regulating nutrient storage. An adequate supply of glucose is required for optimal body growth and development and for the function of the central nervous system (nervous system, human), for which glucose is the major source of energy. Therefore, elaborate mechanisms have evolved to ensure that blood glucose concentrations are maintained within narrow limits during both feast and famine. Excess nutrients that are consumed can be stored in the body and made available later—for example, when nutrients are in short supply, as during fasting, or when the body is using energy, as during physical activity. adipose tissue is the principal site of nutrient storage, nearly all in the form of fat. A single gram of fat contains twice as many calories (calorie) as a single gram of carbohydrate or protein. In addition, the content of water is very low (10 percent) in adipose tissue. Thus, a kilogram of adipose tissue has 10 times the caloric value as the same weight of muscle tissue.

      After food is ingested, molecules of carbohydrate are digested and absorbed as glucose. The resulting increase in blood glucose concentrations is followed by a 5- to 10-fold increase in serum insulin concentrations, which stimulate glucose uptake by liver, adipose, and muscle tissues and inhibits glucose release from liver tissue. Fatty acids and amino acids derived from the digestion of fat and protein are also taken up by and stored in the liver and peripheral tissues, especially adipose tissue. Insulin also inhibits lipolysis (the breakdown of fat), preventing the mobilization of fat. Thus, during the “fed,” or anabolic, state, ingested nutrients that are not immediately utilized are stored, a process largely dependent on the food-associated increase in insulin secretion.

      A few hours after a meal, when intestinal absorption of nutrients is complete and blood glucose concentrations decrease toward premeal values, insulin secretion decreases and glucose production by the liver resumes in order to sustain the needs of the brain. Similarly, lipolysis increases, providing fatty acids that can be used as fuel by muscle tissue and glycerol that can be converted into glucose in the liver. As the period of fasting lengthens (e.g., 12 to 14 hours), blood glucose concentrations and insulin secretion continue to decrease and glucagon secretion increases. The increase in glucagon secretion and concomitant decrease in insulin secretion stimulates the breakdown of glycogen to form glucose (glycogenolysis) and the production of glucose from amino acids and glycerol (gluconeogenesis) in the liver. After liver glycogen is depleted, blood glucose concentrations are maintained by gluconeogenesis. Thus, the fasting, or catabolic (catabolism), state is characterized by decreased insulin secretion, increased glucagon secretion, and nutrient mobilization from stores in the liver, muscle, and adipose tissue.

      With further fasting, the rate of lipolysis continues to increase for several days and then plateaus. A large proportion of the fatty acids released from adipose tissue is converted to keto acids (beta-hydroxybutyric acid and acetoacetic acid, also known as ketone bodies) in the liver, a process that is stimulated by glucagon. These keto acids are small molecules that contain two carbon atoms. The brain, which generally utilizes glucose for energy, begins to use keto acids in addition to glucose. Eventually, more than half of the brain's daily metabolic energy needs are met by the keto acids, substantially diminishing the need for glucose production by the liver and the need for gluconeogenesis in general. This reduces the need for amino acids produced by muscle breakdown, thus sparing muscle tissue. Starvation is characterized by low serum insulin concentrations, high serum glucagon concentrations, and high serum free fatty acid and keto acid concentrations.

      In summary, in the fed state insulin stimulates the transport of glucose into tissues (to be consumed as fuel or stored as glycogen), the transport of amino acids into tissues (to build or replace protein), and the transport of fatty acids into tissues (to provide a depot of fat for future energy needs). In the fasting state, insulin secretion decreases and glucagon secretion increases. Liver glycogen stores, followed later by protein and fat stores, are mobilized to produce glucose. Ultimately, most nutrient needs are provided by fatty acids mobilized from fat stores.

Diseases and disorders

      An absolute or relative deficiency of insulin results in high blood glucose concentrations ( hyperglycemia), which define diabetes mellitus, by far the most common disorder of the endocrine system. The number of patients with diabetes has increased substantially, and it has become a major cause of morbidity and mortality. Morbidity and mortality are not due to the immediate effects of diabetes. They are instead related to the diseases that develop as a result of chronic diabetes mellitus. These include diseases of large blood vessels (blood vessel) (macrovascular disease, including coronary heart disease and peripheral arterial disease) and small blood vessels (microvascular disease, including retinal and renal vascular disease), as well as disease of the nerves.

      There are two major types of diabetes mellitus, known as type 1 and type 2. Type 1 diabetes is characterized by absolute insulin deficiency, whereas type 2 diabetes is characterized by resistance to insulin action and by a decrease in insulin secretion. Diabetes can be caused by specific genetic defects that impair insulin secretion or insulin action. Diabetes may also be caused by diseases of the pancreas or diseases of the endocrine system, including Cushing syndrome, acromegaly, and glucagon-secreting tumours (tumour). In addition, drugs, such as thiazide diuretics (diuretic) and nicotinic acid, and certain conditions, such as congenital rubella or cytomegalovirus infection, can cause diabetes. Some of these causes result in type 1 diabetes, whereas others result in type 2 diabetes. Gestational diabetes is a transient form of type 2 diabetes, occurring only during pregnancy and disappearing after delivery. In all types of diabetes, regardless of insulin secretion, the cells of many tissues in the body are starved of glucose.

Diagnosis of diabetes mellitus
      The diagnosis of diabetes is based on the presence of blood glucose concentrations equal to or greater than 126 mg per 100 ml (7.0 mmol/l) after an overnight fast or on the presence of blood glucose concentrations greater than 200 mg per 100 ml (11.1 mmol/l) in general. People with fasting blood glucose values between 110 and 125 mg per 100 ml (6.1 to 6.9 mmol/l) are diagnosed with a condition called impaired fasting glucose. Normal fasting blood glucose concentrations are less than 110 mg per 100 ml (6.1 mmol/l). While the blood glucose concentrations used to define diabetes and impaired fasting glucose are somewhat arbitrary, they do correlate with the risk of macrovascular and microvascular disease. Patients with impaired fasting glucose are likely to have diabetes later in life. Glucose tolerance tests (glucose tolerance test), in which blood glucose is measured hourly for several hours after ingestion of a large quantity of glucose (usually 75 or 100 grams), are used in pregnant women to test for gestational diabetes. The criteria for diagnosing gestational diabetes are more stringent than the criteria for diagnosing other types of diabetes, which is a reflection of the presence of decreased blood glucose concentrations in healthy pregnant women as compared to nonpregnant women and men.

      A consequence of hyperglycemia is a gradual increase in irreversible binding of glucose to various proteins (glycosylation), including hemoglobin, the oxygen-carrying molecule in red blood cells (erythrocyte). Red blood cells live for 120 days and are subject to glycosylation as soon as they are produced and enter the circulation. Proteins that undergo glycosylation remain so until they are cleared from the body. They are called advanced glycosylation end products (AGEs) and are probably responsible for many of the vascular complications of diabetes. Because the amount of glycosylation is an accurate indicator of glucose concentrations in the blood, measurements of glycosylated hemoglobin, specifically hemoglobin subtype A1c (HbA1c), can be used to estimate the duration and the severity of hyperglycemia.

Type 1 diabetes mellitus
      Type 1 diabetes accounts for about 5 to 10 percent of cases of diabetes. Most patients with type 1 diabetes are children or adolescents, but about 20 percent are adults. The frequency of type 1 diabetes varies widely in different countries, from less than 5 cases per 100,000 people per year in several Asian countries to more than 30 cases per 100,000 people per year in Finland. Most patients present with symptoms of hyperglycemia, but some patients present with diabetic ketoacidosis, a clear indication that insulin secretion has significantly deteriorated.

      Type 1 diabetes is usually caused by autoimmune (autoimmunity) destruction of the islets of Langerhans of the pancreas. Patients with type 1 diabetes have serum antibodies (antibody) to several components of the islets of Langerhans, including antibodies to insulin itself. The antibodies are often present for several years before the onset of diabetes, and their presence may be associated with a decrease in insulin secretion. Some patients with type 1 diabetes have genetic variations associated with the human leukocyte antigen (HLA) complex, which is involved in presenting antigens to immune cells and initiating the production of antibodies that attack the body's own cells (autoantibodies). However, the actual destruction of the islets of Langerhans is thought to be caused by immune cells sensitized in some way to components of islet tissue rather than to the production of autoantibodies. In general, 2 to 5 percent of children whose mother or father has type 1 diabetes will also develop type 1 diabetes.

Type 2 diabetes mellitus
      Type 2 diabetes is far more common than type 1 diabetes. The frequency of type 2 diabetes varies greatly within and between countries and is increasing throughout the world. Most patients with type 2 diabetes are adults, often older adults, but it can also occur in children and adolescents. There is a stronger genetic component to type 2 diabetes than to type 1 diabetes. For example, identical twins are much more likely to both develop type 2 diabetes than to both develop type 1 diabetes, and 7 to 14 percent of people whose mother or father has type 2 diabetes will also develop type 2 diabetes; this estimate increases to 45 percent if both parents are affected. In addition, it is estimated that about 40 percent of the Pima Indian population in Arizona has type 2 diabetes, whereas in the entire United States it is estimated that more than 10 percent of the population has type 2 diabetes.

      Many patients with type 2 diabetes are asymptomatic, and they are often diagnosed with type 2 diabetes when routine measurements reveal high blood glucose concentrations. In some patients, the presence of one or more symptoms associated with the long-term complications of diabetes lead to a diagnosis of type 2 diabetes. Other patients present with symptoms of hyperglycemia that have been present for months or with the sudden onset of symptoms of very severe hyperglycemia and vascular collapse.

      Type 2 diabetes is strongly associated with obesity and is a result of both insulin resistance and insulin deficiency. While insulin resistance is a very common characteristic of type 2 diabetes in patients who are obese, many obese patients are able to increase insulin secretion to maintain normal blood glucose concentrations. However, if the compensatory increase in insulin secretion is inadequate, hyperglycemia ensues. Patients with type 2 diabetes often have serum insulin concentrations that are higher than normal. If blood glucose concentration is increased to a similar level in a healthy subject and in an obese subject, the healthy subject will secrete more insulin than the obese subject. The cellular mechanisms that result in insulin resistance and in defects in insulin secretion in patients with type 2 diabetes are not understood.

Gestational diabetes mellitus
      A healthy pregnancy is characterized by increased nutrient utilization, increased insulin resistance, and increased insulin secretion. Blood glucose concentrations tend to be lower in pregnant women than in nonpregnant women because the mother is supplying glucose to the growing fetus. All pregnant women have some degree of insulin resistance as a result of the normal secretion of several placental hormones, including placental growth hormone, placental lactogen, progesterone, and corticotropin-releasing hormone, which stimulates the production of adrenocorticotropin in the pituitary and cortisol in the adrenal glands. In some cases, insulin resistance is increased by excessive weight gain during pregnancy. If insulin secretion does not increase sufficiently to counter the insulin resistance imposed by these changes, gestational diabetes occurs.

      The frequency worldwide of gestational diabetes varies from about 1 to 15 percent of pregnant women. The large variability in frequency is due in part to the fact that there is no widely agreed upon definition of gestational diabetes. However, no matter how it is defined, it is more common among obese women and among African American or Asian women than among women of European descent. The outcomes of gestational diabetes also vary widely, ranging from large babies (fetal macrosomia), birth trauma, and neonatal hypoglycemia to maternal preeclampsia (preeclampsia and eclampsia) and increased perinatal morbidity. Risk factors for gestational diabetes include older age, obesity, a previous large baby, and a family history of diabetes. Some physicians believe that all pregnant women should be tested for gestational diabetes at 24 to 28 weeks of gestation, whereas other physicians limit testing to women who have risk factors for gestational diabetes. While gestational diabetes is by definition transient, affected women have an increased risk of developing type 2 diabetes later in life.

Acute clinical manifestation of diabetes mellitus
       hyperglycemia itself can cause symptoms, but usually only when blood glucose concentrations are approximately 180 mg per 100 ml (10 mmol/l) or higher. When blood glucose concentrations increase, more glucose is filtered by the glomeruli of the kidneys (kidney) than can be reabsorbed by the kidney tubules, resulting in glucose excretion in the urine. High glucose concentrations in the urine create an osmotic effect that reduces the reabsorption of water by the kidneys, causing polyuria (excretion of large volumes of urine). The loss of water from the circulation stimulates thirst. Therefore, patients with moderate or severe hyperglycemia typically have polyuria and polydipsia (excessive thirst). The loss of glucose in the urine results in weakness, fatigue, weight loss, and increased appetite (polyphagia). Patients with hyperglycemia are prone to infections, particularly vaginal and urinary tract infections, and an infection may be the presenting manifestation of diabetes.

      There are two acute life-threatening complications of diabetes, hyperglycemia and acidosis (increased acidity of the blood), either of which may be the presenting manifestation of diabetes. In patients with type 1 diabetes, insulin deficiency, if not recognized and treated properly, leads to severe hyperglycemia and to a marked increase in lipolysis, with a greatly increased rate of release of fatty acids from adipose tissue. In the liver, much of the excess fatty acid is converted to the keto acids beta-hydroxybutyric acid and acetoacetic acid. The increased release of fatty acids and keto acids from adipose, liver, and muscle tissues raises the acid content of the blood, thereby lowering the pH of the blood. The combination of hyperglycemia and acidosis is called diabetic ketoacidosis and leads to hyperventilation and to impaired central nervous system function, culminating in coma and death. Patients with diabetic ketoacidosis must be treated immediately with insulin and intravenous fluids.

      In patients with type 2 diabetes, high blood glucose concentrations can lead to very severe and prolonged hyperglycemia and to marked polyuria, with the loss of a large volume of fluid and a very high serum osmolality. These factors place patients with type 2 diabetes at a high risk of developing central nervous system dysfunction and vascular collapse (hyperglycemia coma). Ketoacidosis is usually not a problem in patients with type 2 diabetes because they secrete enough insulin to restrain lipolysis. Patients with hyperglycemic coma should be treated aggressively with intravenous fluids and insulin.

Treatment of diabetes mellitus
      Treatment for diabetes mellitus is aimed at reducing blood glucose concentrations to normal levels. Achieving this is important in promoting well-being and an acceptable lifestyle and in minimizing the development and progression of the long-term complications of diabetes. Measurements of glycosylated hemoglobin (HbA1c) can be used to assess whether an individual's treatment for diabetes is effective. Target values of HbA1c levels should be close to normal.

      All patients with diabetes should follow a diet that is relatively low in fat and contains adequate amounts of protein. In practice about 30 percent of calories should come from fat, 20 percent from protein, and the remainder from carbohydrates, preferably from complex carbohydrates rather than simple sugars (sugar). The total caloric content should be based on the patient's nutritional requirements for growth or weight loss if the patient is obese. Patients taking insulin may need to vary food intake from meal to meal, according to their level of activity. As exercise frequency and intensity increase, less insulin and more food intake may be needed. In overweight or obese patients with type 2 diabetes, caloric restriction for even just a few days may result in considerable improvement in hyperglycemia. In addition, weight loss, preferably combined with exercise, can lead to improved insulin sensitivity and even restoration of normal glucose metabolism.

      Virtually all patients with type 1 diabetes and many of those with type 2 diabetes are treated with insulin, given either by intermittent subcutaneous injections or by continuous subcutaneous infusion using an insulin pump. In addition, there are many insulin products, and decisions on which type of insulin to use and on how it should be administered are based largely on a patient's blood glucose concentrations and lifestyle.

      Synthetic forms of human insulin are manufactured using recombinant DNA technology. Insulin may be given as a form that is identical to the natural form of insulin found in the body, which acts quickly but transiently, or as a form that has been biochemically modified so as to prolong its action for up to 24 hours. The optimal regimen is one that most closely mimics the normal pattern of insulin secretion, which is a constant low level of insulin secretion plus a pulse of secretion after each meal. This can be achieved by administration of a long-acting insulin preparation once daily plus administration of a rapid-acting insulin preparation with or just before each meal. Patients also have the option of using an insulin pump, which allows them to control variations in the rate of insulin administration. A satisfactory compromise for some patients is twice-daily administration of mixtures of intermediate-acting and short-acting insulin.

      Patients with type 1 diabetes have been treated by transplantation of the pancreas or of the islets of Langerhans. However, limited quantities of pancreatic tissue are available for transplantation, prolonged immunosuppressive therapy is needed, and there is a high likelihood that the transplanted tissue will be rejected even when the patient is receiving immunosuppressive therapy. Attempts to improve the outcome of transplantation and to develop mechanical islets are ongoing.

      Several types of drugs other than insulin may be used to treat patients with type 2 diabetes. One type, the sulfonylurea drugs, acts by increasing insulin secretion. Another type, the thiazolidinedione drugs, acts primarily by increasing insulin sensitivity in muscle and adipose tissues. Other drugs include metformin, which acts by decreasing glucose production by the liver and to a lesser extent by increasing insulin sensitivity in muscle and adipose tissues, and drugs that inhibit the intestinal enzymes that break down complex carbohydrates, thereby making less glucose available for absorption. In general, drugs (other than insulin) lower mean blood glucose concentrations by only about 50 to 80 mg per 100 ml (2.8 to 4.4 mmol/l), and sensitivity to these drugs tends to decrease with time.

      A major side effect of insulin and the sulfonylurea drugs is hypoglycemia. In contrast, the thiazolidinedione drugs and other types of diabetes drugs, when used alone, tend to be antihyperglycemic, meaning that they sensitize tissues to insulin and increase glucose uptake without stimulating insulin secretion or causing hypoglycemia. Thiazolidinedione drugs, however, may cause severe side effects, such as leg and ankle edema (swelling), muscle pain, and liver toxicity. All patients with diabetes mellitus, particularly those taking insulin, should measure blood glucose concentrations periodically at home, especially when they have symptoms of hypoglycemia. This is done by pricking a finger, obtaining a drop of blood, and using an instrument called a glucometer to measure the blood glucose concentration. Using this technology, many patients become skilled at evaluating their diabetes and making appropriate adjustments in therapy on their own initiative.

Long-term complications of diabetes mellitus
      The prolonged survival of patients with diabetes mellitus has led to an increasing incidence of long-term complications. The most common complications are vascular complications, which may involve large arteries, small arteries, or capillaries. Large-vessel disease generally presents as atherosclerotic vascular disease ( atherosclerosis). Atherosclerosis in diabetic patients does not differ from that which occurs in nondiabetic patients, although it may occur sooner and progress more rapidly in diabetic than nondiabetic patients. It involves the coronary arteries (coronary artery), the cerebral arteries, and the large arteries (iliac and femoral arteries) that supply blood to the legs. Thus, nonfatal and fatal myocardial infarction, stroke, and ulceration and gangrene of the feet, often necessitating amputation, are common in patients with diabetes. Small-artery disease (microangiopathy) consists of thickening of the walls of small arteries and capillaries, which initially renders them permeable (leaky) to fluids and subsequently renders them prone to obstruction (thrombosis or embolism). These changes occur primarily in the retina (diabetic retinopathy) and kidneys (diabetic nephropathy), and as a result diabetes is the most common cause of blindness and end-stage kidney disease (renal system disease). Vascular complications are aggravated by hypertension and hyperlipidemia (high serum levels of lipids (lipid)), both of which are common in patients with diabetes.

      There are other, nonvascular complications of diabetes, including cataract formation and neuropathy (diabetic neuropathy). The most common type of neuropathy is symmetric polyneuropathy. This causes abnormal sensation (numbness or tingling) or loss of sensation, loss of position sense and vibratory sense, and weakness of the muscles of the feet, lower legs, and hands. Other patients have single- neuropathy, such as loss of function of a nerve to the muscles of one eye, causing visual disturbances, or of a nerve to the muscles of the forearm, causing wrist drop. They may also have autonomic neuropathy, which may result in postural hypotension (fainting upon sitting up or standing), gastric retention, erectile dysfunction, or urinary bladder dysfunction. These complications may be caused by glycosylation of ocular tissue or nervous tissue, accumulation of osmotically active glucose metabolites in these tissues, or disease of the small vessels in these tissues.

      The development or progression of the small-vessel complications of diabetes, such as diabetic retinopathy, diabetic nephropathy, and diabetic neuropathy, can be slowed or prevented by control of hyperglycemia. It is less clear whether the control of hyperglycemia has a similar effect in controlling large-vessel complications. The onset and progression of the vascular complications of diabetes can be delayed by controlling high blood pressure ( hypertension). Many antihypertensive treatments are aimed specifically at preventing the actions of angiotensin II, a peptide that stimulates blood vessel constriction to increase blood pressure. The increase in blood pressure can be prevented by drugs that inhibit angiotensin-converting enzyme (drugs known as ACE inhibitors), which converts inactive angiotensin I to active angiotensin II, or by drugs that block the angiotensin receptor, which prevents angiotensin II from stimulating blood vessels to constrict. Cessation of smoking and lowering serum lipid concentrations are also helpful in slowing progression of vascular disease in patients with diabetes.

Prevention of diabetes mellitus
      Attempts to prevent type 1 diabetes have been unsuccessful. On the other hand, in people with impaired fasting glucose, progression to type 2 diabetes can be prevented by weight loss and exercise and by treatment with metformin, a thiazolidinedione drug, an ACE inhibitor, or a statin (a type of cholesterol-lowering drug).

      Hypoglycemia is best defined as blood (serum) glucose concentrations that are sufficiently low to cause symptoms that are relieved by the administration of glucose. The most common cause of hypoglycemia is insulin treatment in patients with diabetes, but it can occur spontaneously. Regardless of the underlying cause, the manifestations of hypoglycemia evolve in a characteristic pattern. Mild hypoglycemia—for example, blood glucose concentrations less than 55 mg per 100 ml (3.0 mmol/l)—causes hunger, fatigue, tremour, rapid pulse rate, and anxiety. These symptoms are known as sympathoadrenal symptoms because they are caused by activation of the sympathetic nervous system, including the adrenal medulla. Activation of the sympathetic nervous system increases blood glucose concentrations by mobilizing liver glycogen. More severe hypoglycemia—for example, blood glucose concentrations less than 45 mg per 100 ml (2.5 mmol/l)—causes blurred vision, impaired thinking and consciousness, confusion, seizures, and coma. These symptoms are known as neuroglycopenic symptoms because they are indicative of glucose deprivation of the brain. Sympathoadrenal symptoms and neuroglycopenic symptoms are nonspecific and should be attributed to hypoglycemia only when relieved by either oral or intravenous administration of glucose.

      The principal causes of hypoglycemia can be grouped into two categories: insulin-dependent and insulin-independent. Insulin-dependent hypoglycemia is caused by too much insulin (hyperinsulinemia), usually attributed to a sulfonylurea drug or excess insulin in a patient with diabetes. Other, much less common causes of insulin-dependent hypoglycemia may include an insulin-secreting tumour of the islets of Langerhans or an IGF-2-secreting tumour, usually of fibrous tissue, that activates insulin receptors. Insulin-independent hypoglycemia is caused by disorders that result in impaired glucose mobilization during fasting (defects in gluconeogenesis or glycogenolysis). Impaired glucose mobilization may be caused by adrenal insufficiency, severe liver disease, glycogen storage disease, severe infections, and starvation. Insulin-dependent hypoglycemia is diagnosed by an inappropriately high serum insulin concentration when symptoms of hypoglycemia are present. Conversely, insulin-independent hypoglycemia is diagnosed by an inappropriately low serum insulin concentration when symptoms of hypoglycemia are present.

      Many people have hypoglycemia-like symptoms three to five hours after a meal. However, few of these people have hypoglycemia when symptomatic, and their symptoms may not improve with the administration of glucose. Symptoms can often be controlled by eating small snacks every few hours, exercising regularly, and managing weight. A known cause of post-meal hypoglycemia is gastrectomy (removal of the stomach) or gastric bypass surgery for obesity, which results in rapid absorption of glucose into the blood, thereby triggering excessive insulin secretion and hypoglycemia.

Islet cell tumours (tumour) of the pancreas
      Most pancreatic tumours arise from the exocrine tissues of the gland. Tumours of the endocrine pancreas, which occur in the cells of the islets of Langerhans, are rare and are often classified as functional or nonfunctional tumours. Functional tumours are characterized by excess hormone secretion, whereas nonfunctional tumours, which are more common, do not secrete hormones. The most common functional tumour of the endocrine pancreas is an insulin-secreting tumour called an insulinoma, which is benign in about 90 percent of affected patients. In some cases, hypersecretion of insulin may be caused by diffuse hyperplasia of the islet cells or by a carcinoma (malignant tumour) of the islet cells. A small number of patients with hypersecretion of insulin have islet cell hyperplasia or single or multiple insulin-secreting tumours (insulinomas) as part of a syndrome known as multiple endocrine neoplasia type 1 (MEN1, characterized primarily by islet, parathyroid, and pituitary tumours). In addition, diffuse hyperplasia of beta cells, called nesidioblastosis, can cause hypoglycemia in infants.

      A type of malignant tumour of the endocrine pancreas is a gastrin-secreting tumour called a gastrinoma. These tumours secrete gastrin, which stimulates the stomach to produce acid, and therefore ulcers of the stomach and duodenum are common. This disorder is known as Zollinger-Ellison syndrome. Gastrinomas may also originate in the stomach and duodenum. Gastrinomas are associated with MEN1 in some patients. A very rare type of tumour of the endocrine pancreas is a glucagon-secreting tumour called a glucagonoma. Glucagonomas cause a “diabetes-dermatitis syndrome” that is characterized by mild diabetes, anemia, and a red blistering rash that appears in one area of the body and then fades only to reappear at a different site. These patients have very high serum glucagon concentrations but only mild type 2 diabetes. Other rare tumours of the islet cells include somatostatin-secreting tumours (somatostatinomas) and pancreatic polypeptide-secreting tumours. Tumours of the endocrine pancreas are difficult to diagnose because findings are nonspecific and may include diabetes, gallstones (gallstone), excessive fat in the stool, indigestion, and diminished secretion of gastric acid. In addition, islet cell tumours may also produce “ectopic” hormones, meaning that the tumour secretes a hormone that is not normally secreted by the tissue in which the tumour occurs.

The adrenal cortex
      The adrenal glands (adrenal gland) are small triangular glands, one lying just above each kidney. Each adrenal gland weighs about 5 g (0.2 oz) and consists of two parts, the adrenal medulla and the adrenal cortex, that are anatomically, embryologically, and functionally distinct. The adrenal cortex forms the outer covering of the adrenal gland and is derived from the fetal mesodermal ridge, a structure that also gives rise to the kidneys. Within the adrenal cortex are three zones known as the zona glomerulosa (the outer zone), the zona fasciculata (the middle zone), and the zona reticularis (the inner zone). Under the microscope the cells are rather typical endocrine cells, and the cells in the different zones are distinguished on the basis of differing histological (histology) characteristics.

Hormones
      Adrenocortical cells synthesize and secrete chemical derivatives (steroids) of cholesterol. While cholesterol can be synthesized in many body tissues, further modification into steroid hormones (steroid hormone) takes place only in the adrenal cortex and its embryological cousins, the ovaries (ovary) and the testes (testis).

      The adrenal cortex is capable of synthesizing all of the steroid hormones produced by the body, including progesterone, estrogens (estrogen), androgens (androgen), mineralocorticoids (secreted from the zona glomerulosa), and glucocorticoids (synthesized and released from the zona fasciculata and zona reticularis). Many steroids are produced in the adrenal cortex, but only a few members of these major categories have physiological importance.

      The biological action of aldosterone, the principal mineralocorticoid (salt-retaining steroid) produced by the zona glomerulosa, is to increase the retention of sodium and water and to increase the excretion of potassium by the kidneys (and to a lesser extent the skin and intestines (intestine)). It acts by binding to and activating a receptor in the cytoplasm of renal tubular cells. The activated receptor then stimulates the production of ion channels in the renal tubular cells, thereby increasing sodium reabsorption into the blood and increasing potassium excretion into the urine.

       cortisol (hydrocortisone) is the major glucocorticoid in humans. It has two primary actions: it stimulates gluconeogenesis—the breakdown of protein and fat to provide metabolites that can be converted to glucose in the liver—and it activates antistress and anti-inflammatory pathways. It also has weak mineralocorticoid activity. Cortisol plays a major role in the body's response to stress. It helps to maintain blood glucose concentrations by increasing gluconeogenesis and by blocking the uptake of glucose into tissues other than the central nervous system (nervous system, human). It also contributes to the maintenance of blood pressure by augmenting the constrictive effects of catecholamines (catecholamine) on blood vessels.

      Cortisol, along with more potent and longer-acting synthetic derivatives such as prednisone, methylprednisolone, and dexamethasone, has powerful anti-inflammatory and antiallergy actions. At a cellular level, glucocorticoids inhibit the production and action of inflammatory cytokines (cytokine). In high doses, glucocorticoids can impair the function of the immune system, thereby reducing cell-mediated immune reactions and reducing the production and action of antibodies. Reducing immune system function with glucocorticoids is useful for preventing transplant rejection and for treating allergic or autoimmune diseases, such as rheumatoid arthritis and disseminated lupus erythematosus. However, these beneficial effects are offset by the serious side effects of high doses of glucocorticoids, especially when administered over a long period of time. The manifestations of chronic exposure of the body to excess levels of glucocorticoids can be seen in patients with Cushing syndrome. In addition, glucocorticoids are generally not used in patients with infectious diseases because immunosuppressive and anti-inflammatory actions may allow the infection to spread.

      Cortisol exists in serum in two forms. The majority of cortisol is in the bound form, attached to cortisol-binding globulin (transcortin), while the remaining amount of cortisol is in the free, or unbound, form. As the free cortisol leaves the serum to enter cells, the pool of free cortisol in the serum is replenished cortisol that is released from transcortin or new cortisol that is secreted from the adrenal cortex. In the cytoplasm of a target cell, cortisol binds to a specific receptor. The cortisol-receptor complex then enters the nucleus of the cell. In the nucleus, the complex activates or inhibits the transcription of specific genes (gene), thereby altering the production of messenger ribonucleic acid ( RNA) molecules that direct the synthesis of many proteins, including enzymes (enzyme) and structural proteins.

      In contrast to cortisol, aldosterone and adrenal androgens do not bind as readily to serum proteins. While small amounts of cortisol and other steroid hormones are excreted in the urine, the majority of these hormones are inactivated in the liver or other tissues.

Adrenal androgens (androgen)
      The adrenal glands produce very small amounts of estrogen; however, it is not enough to contribute in any important way to overall estrogen production. In contrast, the adrenal production of androgens is of importance to several physiological processes, although adrenal androgens are not as potent as testosterone, the major androgenic steroid secreted by the testes. Several of the adrenal androgens, including androstenedione, dehydroepiandrosterone (DHEA), and dehydroepiandrosterone sulfate (DHEA sulfate), can be converted to testosterone in other tissues. Only a very small amount of androgen is secreted before puberty. In both girls and boys puberty is associated with an increase in adrenal androgen production. This “adrenarche” contributes to pubertal maturation, particularly growth of axillary and pubic hair.

Regulation of adrenal hormone secretion
 The secretion of cortisol and aldosterone is regulated by different mechanisms. The secretion of cortisol is regulated by the classical hypothalamic-pituitary-adrenal feedback system. The major determinant that controls the secretion of cortisol is corticotropin (adrenocorticotropic hormone) (adrenocorticotropin, ACTH). In normal subjects, there is both pulsatile and diurnal (referred to as a circadian rhythm) secretion of corticotropin, which causes pulsatile and diurnal secretion of cortisol. Variations in the secretion of corticotropin are caused by variations in the secretion of corticotropin-releasing hormone by the hypothalamus and by variations in serum cortisol concentrations. An increase in serum cortisol concentrations inhibits the secretion of both corticotropin-releasing hormone and corticotropin. Conversely, a decrease in serum cortisol concentration results in an increase in the secretion of corticotropin-releasing hormone and corticotropin, thereby restoring the secretion of cortisol to normal concentrations. However, if the adrenal glands are unable to respond to stimulation by corticotropin, decreased serum cortisol concentrations will persist. Severe physical or emotional stresses stimulate the secretion of corticotropin-releasing hormone and corticotropin, resulting in large increases in serum cortisol concentrations. However, under these circumstances, increased serum cortisol concentrations do not inhibit the secretion of corticotropin-releasing hormone or corticotropin and thereby allow large amounts of cortisol to be secreted until the stress subsides. Corticotropin also stimulates the secretion of adrenal androgens from the adrenal cortex, but the androgens do not inhibit corticotropin secretion.

      Aldosterone secretion is regulated primarily by the renin-angiotensin system. renin is an enzyme secreted into the blood from specialized cells that encircle the arterioles at the entrance to the glomeruli of the kidneys (the renal capillary networks that are the filtration units of the kidney). The renin-secreting cells, which compose the juxtaglomerular apparatus, are sensitive to changes in blood flow and blood pressure, and the primary stimulus for increased renin secretion is decreased blood flow to the kidneys. A decrease in blood flow to the kidneys may be caused by loss of sodium and water (as a result of diarrhea, persistent vomiting, or excessive perspiration) or by narrowing of a renal artery. Renin catalyzes the conversion of a plasma protein called angiotensinogen into a decapeptide (consisting of 10 amino acids) called angiotensin I. An enzyme in the serum called angiotensin-converting enzyme (ACE) then converts angiotensin I into an octapeptide (consisting of eight amino acids) called angiotensin II. Angiotensin II acts via specific receptors in the adrenal glands to stimulate the secretion of aldosterone, which stimulates salt and water reabsorption by the kidneys, and the constriction of small arteries (arterioles), which causes an increase in blood pressure. Aldosterone secretion is also stimulated by high serum potassium concentrations (hyperkalemia) and to a lesser extent by corticotropin.

      Excessive aldosterone production or excessive renin secretion, which leads to excessive angiotensin and aldosterone production, can cause high blood pressure (see hyperaldosteronism).

Diseases and disorders

Adrenal insufficiency ( Addison disease)
      Adrenal insufficiency ( Addison disease) is a rare disease because it only occurs when at least 90 percent of the adrenal cortex is destroyed. In the past the most common cause of adrenal insufficiency was destruction of both adrenal glands by tuberculosis. Today the most common cause of adrenal insufficiency is autoimmune destruction of the adrenal glands, which is sometimes inherited as part of a multiple endocrine deficiency syndrome (see below Ectopic hormones and polyglandular disorders (endocrine system, human)). Other causes of adrenal insufficiency are infectious diseases, including fungal infections (e.g., histoplasmosis) and viral infections (e.g., cytomegalovirus). Tuberculosis and fungal infections typically result in the calcification of the adrenal glands. Noninfectious causes of adrenal insufficiency include adrenal hemorrhage or infarction, metastatic cancer, congenital adrenal hyperplasia, bilateral adrenalectomy (surgical removal of both adrenal glands), and drugs such as ketoconazole (an antifungal drug that inhibits steroid synthesis) and mitotane (a derivative of the insecticide DDT that causes adrenocortical suppression). Adrenal insufficiency may also occur as a result of diseases of the pituitary gland, which cause corticotropin deficiency, or diseases of the hypothalamus, which cause corticotropin-releasing hormone deficiency.

      Adrenal insufficiency, if undiagnosed, is fatal. The onset is often gradual and the symptoms may be nonspecific. The most common symptoms and signs of chronic adrenal insufficiency are gradually increasing weakness and fatigue, loss of appetite, loss of weight, vomiting, diarrhea, salt craving, and hypoglycemia. Pigmentation is increased in exposed areas of the skin and also in the nails, skin creases, and mouth in patients with adrenal insufficiency. In contrast, pigmentation does not increase in patients with diseases of the hypothalamus or the pituitary gland that cause corticotropin deficiency. Adrenal insufficiency is also characterized by a decrease in blood pressure, thereby increasing the risk for episodes of postural hypotension (orthostatic hypotension; characterized as fainting upon sitting up or standing). Most patients with adrenal insufficiency have deficiencies in aldosterone and cortisol and therefore have decreased serum sodium concentrations (hyponatremia) and increased serum potassium concentrations (hyperkalemia). In contrast, deficiencies in aldosterone are not found in patients with diseases of the hypothalamus or the pituitary gland.

      The symptoms of adrenal insufficiency increase in intensity over time and eventually (after several months) lead to acute adrenal insufficiency, known as adrenal crisis. Adrenal crisis is characterized by fever, vomiting, diarrhea, and a precipitous fall in blood pressure. The patient may go into shock and die unless he or she is treated vigorously with an intravenous saline solution and with cortisol or other glucocorticoid. Adrenal crisis may occur in individuals with no previous evidence of adrenal disease and may be provoked by physical stress, such as trauma or illness. The most common cause of adrenal crisis is bilateral adrenal hemorrhage, which can occur in newborn infants and in adults, especially in those who are treated with anticoagulant drugs (e.g., heparin or warfarin).

      Patients with chronic adrenal deficiency are treated with replacement doses of cortisol and with supplemental doses of a synthetic mineralocorticoid such as fluorohydrocortisone (fludrocortisone). In some patients, salt tablets can be given in place of a mineralocorticoid. Because aldosterone is poorly absorbed from the intestine, it is not used to treat adrenal deficiency. In addition, patients with adrenal insufficiency must learn to take additional doses of cortisol during periods of acute illness or injury. Patients who receive adequate treatment can live normal lives.

Hypercorticism ( Cushing syndrome)
      Hypercorticism, an illness that results from overactivity of the adrenal cortex, is a constellation of symptoms and signs that together make up a specific and distinct clinical entity. In 1932 American neurosurgeon Harvey Cushing (Cushing, Harvey Williams) described the clinical findings that provided the link between specific physical characteristics (e.g., abnormal obesity of the face and trunk) and a specific type of pituitary tumour. This pituitary disorder became known as Cushing syndrome. It later became clear that many patients with similar symptoms and signs did not have a pituitary tumour. Thus, the term Cushing syndrome has been modified to refer to all patients with the classic symptoms and signs of the condition, regardless of the cause, while the term Cushing disease is restricted to patients in whom the symptoms and signs are caused by a corticotropin-secreting pituitary tumour.

      Among patients with spontaneously occurring Cushing syndrome, about 70 percent have Cushing disease, which is caused by a benign and usually small corticotropin-secreting tumour of the anterior pituitary gland. Other causes of Cushing syndrome include benign and malignant tumours of the adrenal cortex (adenomas and carcinomas), which occur in about 10 percent of patients, corticotropin-producing tumours of nonendocrine tissues that do not normally produce corticotropin (ectopic corticotropin syndrome), which occur in about 20 percent of patients, and, rarely, tumours of the hypothalamus or tumours of other tissues that produce corticotropin-releasing hormone. Iatrogenic Cushing syndrome is far more common than any of the disorders described above and is caused by the therapeutic administration of high doses of glucocorticoids, usually in the form of prednisone, prednisolone, or dexamethasone. Glucocorticoid drugs are commonly used for the treatment of chronic inflammatory and allergic disorders and for immunosuppression.

      For the most part, the symptoms and signs of Cushing syndrome are caused by excess cortisol. However, depending on the cause, there may also be symptoms and signs of excess mineralocorticoids, androgens, or corticotropin. The most common symptoms and signs of excess levels of cortisol in the body are obesity, facial plethora (facial redness), violaceous abdominal striae (purple or bluish stripes on the abdomen), thinning of the skin that leads to spontaneous bruising, muscle weakness and wasting, back pain, osteopenia and osteoporosis, depression and other psychological symptoms, hypertension, and menstrual disturbances ( oligomenorrhea and amenorrhea) in women. Weight gain associated with excess cortisol occurs in a peculiar distribution, with fat accumulation confined to the central body areas, such as the abdomen, back, and buttocks. In contrast, the extremities, such as the arms and legs, are thin as a result of a loss of muscle mass. Excess fat deposits also occur in the cheeks, giving rise to a “moon face,” as well as in the anterior neck, producing a “dewlap,” or in the upper back, producing a “buffalo hump.” Excess levels of cortisol also cause increased gluconeogenesis and decreased insulin sensitivity, which may give rise to diabetes mellitus. Patients with adrenal cancer may have increased production of adrenal androgens that cause excess hair growth (hirsutism), virilization (characterized by frontal balding and deepening of the voice), and menstrual abnormalities in women. Patients with ectopic corticotropin syndrome may have hyperpigmentation and mineralocorticoid excess.

      A diagnosis of Cushing syndrome is often confirmed by high levels of cortisol in the serum, saliva, or urine. The different causes of Cushing syndrome are distinguished from one another by measurements of serum corticotropin and serum cortisol concentrations before and after the administration of dexamethasone. If the production of excess cortisol is caused by Cushing disease (a pituitary tumour), cortisol production decreases after the administration of dexamethasone, whereas cortisol production will not decrease if the cause is an adrenal tumour. In addition, imaging studies directed toward identification of a pituitary or adrenal tumour or a tumour of nonendocrine tissue are used to distinguish the underlying cause of excess cortisol production.

      Treatment of Cushing syndrome depends upon the specific cause. Pituitary tumours can be surgically removed in about 80 percent of patients with Cushing disease, and radiation therapy can be used to destroy the tumour if surgery is not an option or if the tumour cannot be removed completely. Adrenal tumours can be surgically removed, and patients with benign tumours are usually cured in this way. Complete surgical removal of an adrenal cancer is often impossible, and even when possible the patients are rarely cured. While these patients can be treated with drugs, such as ketoconazole and mitotane, to reduce cortisol secretion and slow tumour growth, most die within one to four years after diagnosis. Patients with ectopic corticotropin-producing tumours are treated by either surgery, radiation, or chemotherapy. Occasionally, if the pituitary or nonendocrine tumour cannot be controlled, both adrenal glands may have to be removed. The ensuing adrenal insufficiency is treated in the same way as spontaneously occurring adrenal insufficiency. In patients with Cushing disease, bilateral adrenalectomy is sometimes followed by pituitary tumour growth and intense skin pigmentation, a combination known as Nelson syndrome.

Hypoaldosteronism
      Hypoaldosteronism nearly always arises as a result of disorders in which the adrenal glands are destroyed. There exists, however, a disease in which defective aldosterone synthesis and secretion from the zona glomerulosa occur in the presence of otherwise normal adrenocortical function.

      Isolated aldosterone deficiency results in low serum sodium concentrations (hyponatremia), decreased extracellular (including plasma) volume, and high serum potassium concentrations (hyperkalemia). These biochemical changes cause weakness, postural hypotension (a decrease in blood pressure upon standing), salt craving, and heart block, which may be fatal. Hypoaldosteronism is often associated with mild to moderate kidney disease (renal system disease), especially in patients with diabetes mellitus. In patients with diabetes mellitus, hypoaldosteronism is caused by deficient production of renin by the kidneys that leads to decreased production of angiotensin II and therefore decreased secretion of aldosterone. Other causes of hypoaldosteronism are rare and are primarily the result of enzymatic defects in the synthesis of aldosterone and resistance of the kidneys to the actions of aldosterone. In patients with hypoaldosteronism from these causes, renin production by the kidneys is increased. Treatment of hypoaldosteronism consists of the administration of salt or a potent synthetic mineralocorticoid such as fluorohydrocortisone (fludrocortisone). Orally administered aldosterone is ineffective because it is poorly absorbed by the body.

      In 1955 American internist Jerome Conn described a form of high blood pressure ( hypertension) associated with low serum potassium concentrations (hypokalemia) in patients who had a benign tumour (adenoma) of the cells of the zona glomerulosa of the adrenal cortex. These patients had high serum aldosterone concentrations and increased urinary aldosterone excretion. In most patients, hypertension and hypokalemia disappeared when the tumour was removed. This disorder is called primary hyperaldosteronism, or primary aldosteronism, to distinguish it from secondary hyperaldosteronism. While most patients have an adrenal adenoma, other patients have hyperplasia of both adrenal glands, the cause of which is not known. Primary hyperaldosteronism is a rare cause of hypertension, accounting for 1 to 5 percent of cases.

      In addition to hypertension, patients with primary hyperaldosteronism may have headaches, muscle weakness, muscle aches, muscle cramps, numbness and tingling of the hands and feet, increased thirst and urination, and disturbances in cardiac rhythm (cardiovascular disease), including ventricular tachycardia. The key biochemical findings are hypokalemia, alkalosis (reduced acidity of the blood), high serum aldosterone concentrations, and low plasma renin activity. Hormonal and radiological studies can be used to distinguish primary hyperaldosteronism caused by an adrenal tumour from that caused by adrenal hyperplasia. The former is treated by surgery, whereas the latter is treated by antihypertensive drugs and by spironolactone, a drug that blocks the action of aldosterone on the kidney tubules.

      Secondary hyperaldosteronism occurs as a consequence of activation of the normal physiological mechanisms that maintain salt and water balance, blood volume, and blood flow to the kidneys. When salt and water are lost—for example, as a result of diarrhea, persistent vomiting, or excessive perspiration—the production of renin is increased, and therefore the production of angiotensin II and aldosterone is increased. As aldosterone production increases, the kidneys are stimulated to reabsorb salt and water from the urine to correct deficits in serum electrolyte concentrations and in blood volume. Some diseases stimulate this same sequence of events. For example, congestive heart failure or cirrhosis of the liver can cause an effective decrease in blood pressure, and narrowing of a renal artery can cause a reduction in the flow of blood to a kidney. In these situations, successful treatment of the primary disease leads to a restoration of normal production of renin, angiotensin II, and aldosterone. While the development of hypertension or hypokalemia can occur in patients with secondary hyperaldosteronism, most patients, with the exception of patients with underlying renal artery disease, do not develop these conditions.

      Another cause of hyperaldosteronism is Bartter syndrome (potassium wasting syndrome), named after American endocrinologist Frederic Bartter, who initially described the primary characteristics of the disorder, including hyperplasia of the juxtaglomerular apparatus of the kidneys, hypokalemia, and high serum renin concentrations, with resultant increases in angiotensin and aldosterone production. Later it was discovered that patients with Bartter syndrome also have increased production and urinary excretion of prostaglandins (prostaglandin). The increased potassium excretion that occurs as a result of increased production of aldosterone causes loss of acid from the body, which leads to alkalosis. The onset of Bartter syndrome is usually in late infancy or in childhood, and patients may have short stature and mental retardation. The cause of Bartter syndrome is not well understood, but several genetic defects (genetic disease, human), primarily affecting potassium and chloride transport in the renal tubules, have been associated with Bartter syndrome. The discovery of these mutations, occurring in different genes, has led to the stratification of Bartter syndrome into three main categories that include neonatal Bartter syndrome, appearing in infancy, classic Bartter syndrome, appearing in infancy or early childhood, and Gitelman syndrome, appearing in late childhood or in adulthood. Hypokalemia may be treated with potassium supplements, while other symptoms may be reversed by drugs that inhibit the formation of prostaglandins, such as the anti-inflammatory drug indomethacin.

       congenital adrenal hyperplasia is a group of inherited disorders in which deficiency or absence of a single enzyme has far-reaching consequences. The enzymes involved are those that catalyze the synthesis of cortisol and sometimes aldosterone. As a result, cortisol production is decreased. In order to restore cortisol production, corticotropin secretion from the adrenal cortex is increased. Because cortisol production is significantly decreased or nonexistent, adrenal production of the precursors of cortisol—namely, androgens and sometimes mineralocorticoids—is increased. The exact pattern and clinical manifestations of the disorder depend on the particular enzyme deficiency. Congenital adrenal hyperplasia is inherited as an autosomal recessive trait, and the mutations in the genes (gene) for the enzymes vary from a single change in one of the nucleotide bases that constitute the gene to the deletion of the entire gene.

      In the most common form of congenital adrenal hyperplasia, there is deficiency of an enzyme called 21-hydroxylase that catalyzes the next to last step in the synthesis of cortisol. In infants with partial 21-hydroxylase deficiency, the production of cortisol is near normal but there is excess production of adrenal androgens. Excess production of androgens begins in utero so that the infants are virilized at birth. If 21-hydroxylase deficiency is severe, infants are not only virilized but also have mineralocorticoid deficiency and salt wasting. Severe 21-hydroxylase deficiency becomes evident soon after birth and may be fatal if not recognized and treated promptly.

      The clinical manifestations of excess androgen production in utero that affect newborn genetic females include an enlarged clitoris, which may be mistaken for a penis; an enlarged vulva, which resembles a bilobed scrotum; and partial or complete fusion of the labia majora, with the opening of the urethra at the base of the clitoris. If not diagnosed early in life, girls with severe congenital hyperplasia, known as female pseudohermaphrodites, may be raised as boys and live thereafter as short, muscular men. These individuals are infertile and have only vestigial ovaries. There has been much debate as to whether genetic females who have been raised as boys can then, when diagnosed late in childhood or in adolescence, assume the sexual identity of women. It appears that, at least in some instances, this is possible. Affected genetic males are more normal in appearance but may have penile enlargement. Continued excess androgen production in both girls and boys leads to rapid growth in the first years of life. However, the androgens also stimulate maturation and closure of the epiphyseal centres of bones so that linear growth ceases well before the usual age of puberty. The frequency of 21-hydroxylase deficiency varies widely in different regions of the world, from as high as 1 in 300 births to less than 1 in 20,000 births. Because the postnatal consequences are so severe, 21-hydroxylase deficiency is sometimes tested for as part of newborn screening programs.

      Deficiency of 11-hydroxylase, an enzyme that catalyzes the last step in the synthesis of cortisol, leads to virilization and hypertension, the latter of which is caused by excess production of deoxycorticosterone, a mineralocorticoid similar to aldosterone. Deficiency of 17-hydroxylase leads to deficiency of estrogens and androgens and to excess deoxycorticosterone, causing sexual infantilism and hypertension. Congenital lipoid adrenal hyperplasia is caused by a defect in a very early step in the steroid synthetic pathway that results in glucocorticoid and mineralocorticoid deficiency and failure of development of secondary sex characteristics. Another genetic defect, 18-hydroxylase deficiency, results in aldosterone deficiency.

      Infants with congenital adrenal hyperplasia are treated with cortisol or a synthetic glucocorticoid, such as prednisone or dexamethasone, and a mineralocorticoid if necessary. Glucocorticoids inhibit corticotropin secretion, resulting in decreased production of adrenal androgens. However, it can be difficult to control the excess production of adrenal androgens without causing symptoms and signs of cortisol excess (iatrogenic or physician-induced Cushing syndrome). Girls may need surgery to correct labial fusion and to reduce the size of the clitoris. Infants treated appropriately soon after birth have a normal growth rate, undergo normal puberty, and are fertile.

      Congenital adrenal hyperplasia also occurs in adolescents and adults in a disorder known as late-onset congenital adrenal hyperplasia. In women it results primarily in excess facial hair growth (hirsutism), decreased frequency or cessation of menstrual periods, and infertility. In contrast, men experience minimal effects, because the production of androgens by the testes far exceeds the production of androgens by the adrenal cortex, even when the latter is excessive. Patients with late-onset congenital adrenal hyperplasia should also be treated with a glucocorticoid, but a mineralocorticoid is not needed.

The adrenal medulla
      The adrenal medulla is embedded in the centre of the cortex of each adrenal gland. It is small, making up only about 10 percent of the total adrenal weight. The adrenal medulla is composed of chromaffin cells that are named for the granules within the cells that darken after exposure to chromium salts. These cells migrate to the adrenal medulla from the embryonic neural crest and represent specialized neural tissue. Indeed, the adrenal medulla is an integral part of the sympathetic nervous system, a major subdivision of the autonomic nervous system (see human nervous system (nervous system, human)). The sympathetic nervous system and the adrenal medulla are collectively known as the sympathoadrenal system. The chromaffin granules contain the hormones of the adrenal medulla, which include dopamine, norepinephrine, and epinephrine (epinephrine and norepinephrine). When stimulated by sympathetic nerve impulses, the chromaffin granules are released from the cells and the hormones enter the circulation, a process known as exocytosis. Thus, the adrenal medulla is a neurohemal organ.

Catecholamines (catecholamine)
      The hormones (hormone) and neurotransmitters (neurotransmitter) of the sympathetic nervous system are known as catecholamines (catecholamine). They are synthesized from the amino acid l-tyrosine according to the following sequence: tyrosine → dopa (dihydroxyphenylalanine) → dopamine → norepinephrine (noradrenaline) → epinephrine (epinephrine and norepinephrine) (adrenaline). The close proximity of the adrenal cortex to the adrenal medulla is not accidental. The enzyme that catalyzes the transformation of norepinephrine to epinephrine is formed only in the presence of high local concentrations of glucocorticoids from the adjacent cortex; chromaffin cells in tissues outside the adrenal medulla are incapable of synthesizing epinephrine.

      -Dopa is well known for its role in the treatment of parkinsonism, but its biological importance lies in the fact that it is a precursor of dopamine, a neurotransmitter widely distributed in the central nervous system, including the basal ganglia of the brain (groups of nuclei within the cerebral hemispheres that collectively control muscle tone, inhibit movement, and control tremour). A deficiency of dopamine in these ganglia leads to parkinsonism, and this deficiency is at least partially alleviated by the administration of l-dopa.

      Under ordinary circumstances, more epinephrine than norepinephrine is released from the adrenal medulla. In contrast, more norepinephrine is released from the sympathetic nervous system elsewhere in the body. In physiological terms, a major action of the hormones of the adrenal medulla and the sympathetic nervous system is to initiate a rapid, generalized “fight or flight” response. This response, which may be triggered by a fall in blood pressure or by pain, physical injury, abrupt emotional upset, or hypoglycemia, is characterized by an increased heart rate ( tachycardia), anxiety, increased perspiration, tremour, and increased blood glucose concentrations (due to glycogenolysis, or breakdown of liver glycogen). These actions of catecholamines occur in concert with other neural or hormonal responses to stress, such as increases in corticotropin and cortisol secretion. Furthermore, the tissue responses to different catecholamines depend on the fact that there are two major types of adrenergic receptors (adrenoceptors) on the surface of target organs and tissues. The receptors are known as alpha-adrenergic and beta-adrenergic receptors, or alpha receptors and beta receptors, respectively (see human nervous system: Anatomy of the human nervous system (nervous system, human)). In general, activation of alpha-adrenergic receptors results in the constriction of blood vessels, contraction of uterine muscles, relaxation of intestinal muscles, and dilation of the pupils (pupil). Activation of beta-receptors increases heart rate and stimulates cardiac contraction (thereby increasing cardiac output), dilates the bronchi (thereby increasing air flow into and out of the lungs), dilates the blood vessels, and relaxes the uterus. Drugs such as propranolol that block the activation of beta receptors (beta blockers (beta-blocker)) are often given to patients with tachycardia (rapid heart beat), high blood pressure, or chest pain ( angina pectoris). These drugs are contraindicated in patients with asthma because they worsen bronchial constriction.

      Catecholamines play a key role in nutrient metabolism and the generation of body heat (thermogenesis). They stimulate not only oxygen consumption but also consumption of fuels, such as glucose and free fatty acids (fatty acid), thereby generating heat. They stimulate the breakdown of glycogen to form glucose (glycogenolysis) and the breakdown of triglycerides (triglyceride), the stored form of fat, to free fatty acids (lipolysis). They also have a role in the regulation of secretion of multiple hormones. For example, dopamine inhibits prolactin secretion, norepinephrine stimulates gonadotropin-releasing hormone secretion, and epinephrine inhibits insulin secretion by the beta cells of the islets of Langerhans (Langerhans, islets of) of the pancreas.

Adrenomedullary dysfunction
      Isolated loss of the medulla of both adrenal glands does not occur; such loss is always accompanied by loss of the function of the adrenocortical tissue that surrounds the medulla. Any effects that can be attributed to the loss of the medulla are overshadowed by the effects of glucocorticoid and mineralocorticoid deficiency.

      Tumours of the adrenomedullary chromaffin cells, called pheochromocytomas (pheochromocytoma), do occur, and they can cause striking symptoms and signs that are exaggerations of the physiologic actions of the catecholamines. Most pheochromocytomas are benign, but a few are malignant. In addition, most pheochromocytomas are sporadic, but they also occur in patients with several hereditary tumour syndromes, including multiple endocrine neoplasia type 2 (MEN2; see Multiple endocrine neoplasia (endocrine system, human)) and von Hippel-Lindau syndrome. In some patients, a pheochromocytoma arises from extra-adrenal chromaffin tissue, which may be located in the sympathetic nervous system adjacent to the vertebral column anywhere from the neck to the pelvis or even in the urinary bladder. Most pheochromocytomas secrete norepinephrine.

      High blood pressure ( hypertension) is an invariable finding in patients with a pheochromocytoma. It may be constant, mimicking the common forms of hypertension, or episodic and associated with headache, excessive perspiration, heart palpitation, pallor, tremour, and anxiety. Episodic attacks may end abruptly and the patient may appear normal afterward. The attacks may last a few minutes to several hours, and they may occur at intervals that range from once a month to several per day. In persons with tumours that secrete an appreciable amount of epinephrine, anxiety may be increased, and the patient may experience weight loss and fever and have diabetes mellitus. The presence of a pheochromocytoma can be confirmed by measurements of catecholamines or by measurements of degradation products of catecholamines in serum or urine. The tumour itself can also be identified by imaging procedures.

      Patients with a pheochromocytoma are treated surgically and should receive preoperative treatment with both an alpha-adrenergic drug and a beta-adrenergic antagonist drug to ameliorate hypertension and to prevent marked fluctuations of epinephrine and norepinephrine during the operation. Patients with a malignant pheochromocytoma are treated with antagonist drugs indefinitely.

The ovary
 The ovaries (ovary) nurture and prepare oocytes (eggs) for the process of ovulation (rupture and release of the mature egg from the ovary). Once an egg is released, it migrates down a fallopian tube to the uterus. While in the fallopian tube, an egg may be penetrated and fertilized by a sperm. If an egg becomes fertilized, it will implant in the wall of the uterus. The processes of ovulation and fertilization are controlled largely by cells in the ovaries that produce and secrete hormones. Hormones secreted by the ovaries are essential for female sexual development and the menstrual cycle (menstruation) (periodic shedding of the uterine lining), and they are necessary to sustain a pregnancy.

      In healthy women the two ovaries are roughly bean-shaped structures, each weighing about 4 to 8 grams (about 0.15 to 0.3 ounce), that are located in the pelvis and are attached to a structure called the broad ligament (see human reproductive system (reproductive system, human)). Each ovary consists of an outer cortex, which contains the follicles, oocytes, and some interstitial cells, and an inner medulla, which contains additional interstitial cells, fibrous tissue, blood vessels, and nerves.

      At birth the ovaries contain no more than 2,000,000 immature follicles, and it is not uncommon for them to contain as few as 150,000 to 500,000 of these follicles. By the beginning of a woman's reproductive life, the number of immature follicles has fallen to about 34,000, and this number continues to fall thereafter. At the beginning of each menstrual cycle, known as the early follicular phase, several follicles enlarge and migrate from the cortex toward the outer surface of the ovary. The cells lining the follicle multiply to form a layer known as the zona granulosa, and a cavity forms within this zone. The stromal and interstitial cells that surround the follicle arrange themselves concentrically to form a theca (an enclosing sheath) around the zona granulosa. One or sometimes more of the follicles are selected for further growth and maturation. The mature follicles, known as Graafian follicles, may reach 30 mm in diameter before they rupture.

      The interstitial cells, especially those in the theca, produce mainly androgens (androgen). Within the granulosa cells these androgens are converted to estrogens (estrogen) (estradiol and estrone), the major ovarian hormones. The fluid in the cavity bathing the oocyte contains high concentrations of estrogens and other steroid hormones (steroid hormone) ( progesterone and androgens), as well as enzymes and bioactive proteins. This phase of the menstrual cycle, during which follicular development occurs, lasts about two weeks.

      At the end of the follicular phase of the menstrual cycle, one or occasionally two (or even more) mature follicles at the surface of the ovary rupture and release the egg. The egg then enters a fallopian tube to be carried to the uterus. After the follicle ruptures, the granulosa and theca cells fill the lumen of the follicle, forming the corpus luteum. The corpus luteum produces large amounts of progesterone for about two weeks, after which it involutes (becomes smaller) and menstruation occurs. If a woman becomes pregnant, the corpus luteum continues to produce large amounts of progesterone for several months. The processes of follicular development, ovulation, and formation and function of the corpus luteum are controlled by gonadotropins known as follicle-stimulating hormone (FSH) (follicle-stimulating hormone) and luteinizing hormone (LH) (luteinizing hormone), both of which are secreted from the pituitary gland.

Regulation of ovarian function
      Before the onset of puberty the ovaries are quiescent, and the cortex of each ovary contains only immature follicles. Puberty begins with pulsatile nocturnal secretion of gonadotropin-releasing hormone from the hypothalamus. Nocturnal pulses are initiated at least in part by increasing body size, which may cause an increase in the secretion of leptin (from the Greek leptos, meaning “thin”; protein hormone important for regulation of reproduction, metabolism, and body weight), which in turn stimulates the secretion of gonadotropin-releasing hormone. Pulsatile secretion of gonadotropin-releasing hormone activates the gonadotroph cells of the anterior pituitary, resulting in pulses of secretion of moderate quantities of follicle-stimulating hormone and of significant quantities of luteinizing hormone. In time, pulsatile secretion of gonadotropin-releasing hormone and pulsatile secretion of the gonadotropins occur continuously. Increasing secretion of gonadotropins leads to increasing production of estrogens by the ovaries. Estrogens stimulate the development of secondary sex characteristics and the maturation of ovarian follicles. Increased secretion of estrogens normally occurs between the ages of 8 and 14 in girls.

 With continued maturation of the hypothalamus, pituitary, and ovaries, the cyclic hypothalamic-pituitary-ovarian activity characteristic of adult women begins. During the first days of the menstrual cycle, secretion of follicle-stimulating hormone increases, causing the maturation of follicles as described above. As follicles mature, they secrete more estradiol (the most potent of the estrogens), which is paralleled by an increase in the secretion of luteinizing hormone. Increased secretion of luteinizing hormone stimulates the secretion of more estradiol and a small amount of progesterone that then trigger a transient surge in the secretion of luteinizing hormone and to a lesser extent the secretion of follicle-stimulating hormone, causing rupture of the mature Graafian follicle. The surge in secretion of luteinizing hormone can be readily detected in the urine, providing a means whereby women can determine if they have ovulated and therefore are potentially fertile.

      The follicular phase of the cycle ends at the time of ovulation. Serum luteinizing hormone, follicle-stimulating hormone, and estradiol concentrations then decrease considerably, and the corpus luteum begins to produce some estrogen and large quantities of progesterone. This is known as the luteal phase of the menstrual cycle, which lasts until the corpus luteum degenerates (luteolysis) and estradiol and progesterone production decreases. The decreasing serum estrogen and progesterone concentrations result in constriction of uterine arteries, thus interrupting the delivery of oxygen and nutrients to the endometrium. The endometrium is then sloughed off, causing the vaginal bleeding characteristic of menstruation. A new menstrual cycle then begins.

      The normal menstrual cycle is typically divided into a follicular phase of about 14 days and a luteal phase of about 14 days, the two phases being separated by ovulation on the one hand and by menstruation on the other hand. The phases vary in length by several days in different women and sometimes in the same woman. Variations in cycle length are most common in the first years after menarche (the first menstrual cycle) and just before menopause (when menstruation ceases). During the follicular phase the endometrium proliferates, and during the luteal phase it changes to a secretory state and is sloughed off, causing menstruation. (The structural and functional changes that occur in the endometrium and the other tissues of the reproductive tract in women that accompany these hormonal fluctuations are discussed in more detail in the section on the human reproductive system (reproductive system, human). The extension and accentuation of these changes that occur in the event of pregnancy are also discussed there.)

      The changing serum estrogen and progesterone concentrations during the menstrual cycle have several other effects. Basal body temperature fluctuates little during the follicular phase of the menstrual cycle but increases abruptly after ovulation. This increase parallels the post-ovulatory increase in serum progesterone concentrations and is caused by an effect of progesterone on the temperature-regulating centres in the brain. The decrease in serum estradiol and progesterone concentrations near the end of the cycle may be accompanied by changes in mood and activity and by an increase in fluid retention. The changes initiated by the decrease in secretion of estradiol and progesterone comprise the symptoms of premenstrual syndrome, although the relationship between hormonal changes and these symptoms is unclear.

Ovarian hormones
      Similar to the adrenal cortex, cholesterol is the parent molecule from which all ovarian steroid hormones are formed. Cholesterol is converted to pregnenolone, and pregnenolone is converted to progesterone. The steps in the conversion of progesterone to the main estrogens (estrogen)—estradiol and estrone—include the intermediate formation of several androgens (male sex hormones)—dehydroepiandrosterone, androstenedione, and testosterone. In short, androgens are precursors of estrogens; they are converted to estrogens through the action of an enzyme known as aromatase. The ovaries are the richest source of aromatase, although some aromatase is present in adipose tissue. Adipose tissue is an important source of estrogen in postmenopausal women.

      Estradiol, the most potent estrogen, is synthesized from testosterone. Estrone can be formed from estradiol, but its major precursor is androstenedione. Estriol, the weakest of the estrogens, is formed from both estrone and estradiol.

      Once secreted into the blood, estrogens bind reversibly to a protein known as sex hormone-binding globulin. Thus, some of the hormone in serum is bound and some is free, or unbound. At its target tissues, the free hormone penetrates the cell surface and then binds to a protein known as an estrogen receptor in the cytoplasm of the cells. The estrogen-receptor complexes enter the cell nucleus, where they modulate protein synthesis by influencing the rate at which particular genes (gene) are transcribed. Gene transcription is the process by which deoxyribonucleic acid (DNA) (DNA) codes for certain proteins by producing specific molecules of messenger ribonucleic acid ( RNA) that direct the synthesis of those proteins (protein). In the case of estrogens, there are two types of cytoplasmic receptors, estrogen receptor-alpha and estrogen receptor-beta, that have a different tissue distribution but similar capacities to activate DNA synthesis.

      Estrogens have multiple physiological actions. The actions of estrogen on the female reproductive system at the time of puberty include the stimulation of the development of the breasts (thelarche), the growth of pubic and axillary hair, the growth of the vaginal mucosa, the secretion of vaginal substances, and an increase in libido. During the follicular phase of the menstrual cycle, estrogens stimulate the proliferation of the endometrium. Actions of estrogens that are related to bone development and bone maintenance include the stimulation of bone formation and the closure of bone epiphyses, which causes linear growth to cease at the end of puberty, and the maintenance of bone throughout the reproductive years, which limits bone resorption and preserves bone strength. Estrogens tend to decrease serum cholesterol concentrations and increase serum triglyceride concentrations. The overall effect of these changes, perhaps in conjunction with direct effects of estrogens on blood vessels (blood vessel), is to protect against atherosclerosis before menopause. Estrogens also increase the serum concentrations of binding proteins that transport other substances, including the binding proteins for cortisol, thyroxine, and iron, as well as sex hormone-binding globulin.

       progesterone is synthesized in maturing follicles and especially in the corpus luteum after ovulation. It is also synthesized in the adrenal cortex, but adrenal production contributes only small amounts of progesterone to serum progesterone concentrations, and the increase in serum progesterone concentrations during the luteal phase of the menstrual cycle is entirely of ovarian origin. Progesterone acts mainly to stimulate the conversion of the endometrium from a state of proliferation to a state of secretion that makes it receptive to implantation of a fertilized oocyte. The term progestin is used to describe progesterone and synthetic steroids with progesterone-like properties.

      Other ovarian products include inhibin, which is secreted by the granulosa cells (and by Sertoli cells in men), and relaxin, which is produced by the corpus luteum. The primary action of inhibin is to inhibit the secretion of follicle-stimulating hormone by the anterior pituitary gland. Since the major action of follicle-stimulating hormone is to stimulate the formation and function of granulosa cells, the relationship between inhibin and follicle-stimulating hormone represents a typical negative feedback servomechanism. Relaxin induces relaxation of the pubic ligaments that connect the two halves of the pelvis, an action that may ease infant delivery at the end of pregnancy.

Diseases and disorders

Precocious puberty and delayed puberty

Precocious puberty
      Given the complexity of hypothalamic-pituitary-ovarian function during puberty and thereafter, it is not surprising that abnormalities occur. Precocious puberty is defined as the onset of menstruation before the age of eight years. True precocious puberty is characterized by normal pubertal development at an abnormally early age, sometimes as early as two years of age. Early onset of puberty is then followed by adult cyclic hypothalamic-pituitary-ovarian function, including ovulation, and the child must be protected from the possibility of pregnancy. The rise in estrogen production also stimulates skeletal growth, followed by premature closure of the epiphyses, with eventual short stature. In most girls the cause of this disorder is unknown (idiopathic), and affected girls are otherwise normal. Occasionally it is caused by a tumour or other abnormality of the hypothalamus that secretes gonadotropin-releasing hormone or that activates the secretion of gonadotropin-releasing hormone by the hypothalamus.

      Treatment of these girls is important for proper psychological and social development and to prevent short stature. In the past, affected girls were often treated with a progestin to inhibit the secretion of gonadotropins from the pituitary, which resulted in some regression of breast development and cessation of menstruation but often did not prevent short stature. This form of treatment has been superseded by long-acting derivatives of gonadotropin-releasing hormone that down-regulate the gonadotropin-releasing hormone receptors on the gonadotropin-secreting cells of the pituitary. Thus, gonadotropin secretion decreases, ovarian function ceases, and in most girls pubertal development gradually declines and growth rate slows.

      Precocious pseudopuberty is partial pubertal development that results from autonomous (gonadotropin-independent) production of estrogen in prepubertal girls. Affected girls have premature development of their breasts and pubic hair, experience rapid growth, and may have irregular vaginal bleeding (due to the stimulatory effects of estrogen alone on the endometrium). However, these girls do not have true menstrual cycles and are not fertile. Precocious pseudopuberty is usually caused by an ovarian tumour, a chorionic gonadotropin-secreting tumour (tumours that secrete a hormone normally produced by the placenta that stimulates the ovaries), or exogenous estrogen. Affected girls must be evaluated carefully to find the cause of the disorder, and they must be treated accordingly—for example, by removal of the tumour.

Delayed puberty
      In girls, puberty is considered to be delayed if no pubertal development has occurred by 13 or 14 years of age, and girls who have not menstruated by 16 years of age are considered to have primary amenorrhea. Delayed puberty and primary amenorrhea may be subdivided according to associated changes in stature. If the affected girl is short, the likely causes are gonadal dysgenesis (Turner syndrome (Turner's syndrome)) or hypopituitarism (with both gonadotropin and growth hormone deficiency). Gonadal dysgenesis results from the absence of a sex chromosome or other abnormality of a sex chromosome. In affected girls the gonads are streaks of fibrous tissue and contain no follicles, and these girls may have a variety of congenital anomalies, including a webbed neck, a shieldlike chest, or a small jaw. If the affected girl's stature is normal, the likely causes are gonadotropin-releasing hormone deficiency (sometimes with absence of the sense of smell, called Kallman syndrome), gonadotropin deficiency, chronic illness, or excessive exercise. In many cases, however, there is no cause to be found (idiopathic or constitutional delay in puberty). Very rarely, the cause is decreased estrogen synthesis, which may be due to the absence of the aromatase enzyme that converts androgens to estrogens or due to the presence of defective estrogen receptors. In the latter disorder, estrogen is produced, but the receptors to which it must bind in order to act are missing or abnormal.

      Some girls with normal stature have normal pubertal development but primary amenorrhea. Affected girls may have anomalous development of the uterus or vagina so that menstrual bleeding cannot occur. This may be due to testicular feminization in genetic males. Testicular feminization is caused by a mutation in the gene for the androgen receptor that prevents testosterone from acting on its target tissues. Affected patients have female external genitalia, a short vagina (but no uterus), breast development, and other features of estrogen action.

      Many types of menstrual disorders occur in adult women who have normal sexual maturation. Many of these disorders lead to infertility. The most common disorders are characterized as dysfunctional uterine bleeding and include oligomenorrhea, defined as a decreased frequency of menstrual periods, and amenorrhea, often defined as an absence of menstrual periods for at least six months. Dysfunctional uterine bleeding occurs most often during adolescence or during the perimenopausal period (a transitional period occurring for several years before the cessation of the menstrual cycle in menopause) and is characterized by anovulatory cycles and irregular heavy bleeding. Estrogen production is normal or subnormal, but there is no surge of luteinizing hormone secretion and therefore no increase in progesterone secretion. The continued estrogen production stimulates continued proliferation of the endometrium, which sloughs off irregularly in the absence of progesterone stimulation. Women with dysfunctional uterine bleeding need to be evaluated for a uterine tumour or other uterine disorder. If no tumour is found, they can be treated with periodic courses of a progestin or with a combination of estrogen and progestin such as can be found in an oral contraceptive (contraception).

       oligomenorrhea and amenorrhea have similar causes, excluding pregnancy and normal lactation, which are associated only with amenorrhea. Both oligomenorrhea and amenorrhea result in infertility, and either disorder may be accompanied by symptoms of estrogen deficiency, such as loss of libido, breast atrophy, vaginal dryness, and hot flashes. The causes of oligomenorrhea and amenorrhea include hypothalamic, pituitary, or ovarian dysfunction. Hypothalamic amenorrhea is a term used to describe women who have oligomenorrhea or amenorrhea as a result of decreased pulsatile secretion of gonadotropin-releasing hormone. This may be caused by psychological or emotional disorders (e.g., anorexia nervosa), chronic illnesses of nonendocrine organs (e.g., chronic liver, kidney, lung, or heart disease), starvation, or excessive exercise. Pituitary causes of oligomenorrhea and amenorrhea include hyperprolactinemia (high serum prolactin concentrations), without or with galactorrhea (inappropriate lactation), and gonadotropin deficiency, such as that caused by a nonsecreting pituitary tumour or other disorder that results in decreased pituitary function. Ovarian causes include autoimmune premature ovarian failure, surgical removal of the ovaries, and radiation of the ovaries with X-rays (X-ray). In addition, numerous drugs and hormones can inhibit the secretion of gonadotropin-releasing hormone or gonadotropin or cause a decrease in ovarian function. For example, some psychoactive drugs cause hyperprolactinemia; glucocorticoids and androgens, whether taken for some therapeutic purpose or secreted in excess, inhibit gonadotropin secretion; and cyclophosphamide, an anticancer drug, causes ovarian deficiency.

      The cause of oligomenorrhea or amenorrhea can often be determined from the woman's history and a physical examination. Information about the cause of oligomenorrhea or amenorrhea may be revealed by measurements of serum concentrations of follicle-stimulating hormone, luteinizing hormone, prolactin, and testosterone. Images of the hypothalamus and pituitary or the ovaries may provide additional information about the underlying cause of oligomenorrhea or amenorrhea. High serum follicle-stimulating hormone and luteinizing hormone concentrations indicate the presence of ovarian dysfunction (primary hypogonadism), whereas low concentrations indicate the presence of hypothalamic or pituitary dysfunction (secondary or central hypogonadism). Treatment depends on the cause; if a specific cause cannot be corrected or if no cause is identified, then treatment will depend on the woman's desire for fertility (infertility). Treatment may consist of administration of a progestin for 7 to 10 days. If vaginal bleeding occurs after the progestin is stopped, repeated courses of progestin may be administered and spontaneous menstrual cycles and ovulatory cycles may resume. If fertility is not desired, a combination of estrogen and progestin or an oral contraceptive may be given. If fertility is desired, clomiphene, which stimulates a surge in luteinizing hormone secretion, may successfully induce ovulation. Fertility may also be restored by gonadotropin injections to stimulate follicle maturation and ovulation.

androgen excess in women
      Women produce about one-twelfth as much androgen as men. Androgens are essential precursors of estrogens, and no estrogens can be produced without them. Whether androgens have physiological actions in women is less clear. Some evidence suggests that androgens contribute to bone growth and libido. Mild androgen excess in women results in excess hair growth (hirsutism) that occurs all over the body but is most often noted on the face. With increasing androgen excess, menstrual periods become irregular (oligomenorrhea) and eventually cease (amenorrhea), and women are virilized. The manifestations of virilism include frontal balding, deepening of the voice, acne, clitoral enlargement, and increased muscle mass.

      In women, about half of the daily production of androgen comes from the ovaries in the form of testosterone and the less active androstenedione. The remainder comes from the adrenal glands (adrenal gland), mostly as dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEA sulfate), which are converted to androstenedione and testosterone in other tissues. The tissues capable of these conversions include the skin, fat, muscle, and brain. Some of these tissues are also capable of converting androstenedione to the more potent testosterone. Some of the testosterone produced in this way returns to the circulation to act at distant sites, but high concentrations may accumulate in key local areas such as hair follicles.

      In women excess production of androgen can occur as a result of adrenal disorders, ovarian disorders, ingestion or injection of androgens, and perhaps disorders of fat or other nonendocrine tissues. The adrenal causes of excess production of androgens are Cushing syndrome, congenital adrenal hyperplasia, and adrenal tumours. Tumours (including cancers (cancer)) of the interstitial cells and other cells of the ovary are a rare cause of androgen excess in women. While these disorders are rare, it is important to rule them out in women who have signs of androgen excess.

      A far more common cause of excess production of androgens in women is polycystic ovary syndrome (PCOS; also called Stein-Leventhal syndrome). This syndrome is characterized by excess androgens and the presence of a menstrual disorder. Androgen excess often manifests as hirsutism, with or without increased serum concentrations of one or more androgens. Other women have increased serum androgen concentrations and no hirsutism. A variety of menstrual disorders have been associated with PCOS, including oligomenorrhea, amenorrhea, anovulation, and infertility. Many women with this syndrome are obese (obesity). Ultrasonography (ultrasound) may reveal multiple ovarian cysts; however, many women with normal reproductive function also have polycystic ovaries. Another characteristic feature of PCOS is tissue resistance to the action of insulin. This is expected in obese women, but it is also present in nonobese women with this syndrome. As a consequence of insulin resistance, the frequency of diabetes mellitus is increased in women with PCOS. In addition, insulin resistance leads to an increase in insulin secretion (hyperinsulinemia), which is thought to stimulate ovarian androgen production. Hyperinsulinemia also decreases the production of sex hormone-binding globulin so that more of the testosterone in serum is free and accessible to the tissues. In addition, the conversion of androgens to estrogens in adipose tissue is increased (particularly in obese women), which leads to a small sustained increase in the secretion of luteinizing hormone and to the suppression of ovulation.

      There are several options for treatment of PCOS. Weight loss and the administration of drugs such as metformin that increase tissue sensitivity to insulin and result in a decrease in the secretion of insulin may reverse all of the abnormalities of PCOS, thereby restoring fertility. Treatment with clomiphene also may restore fertility. Hair growth may be slowed and regular menstrual cycles restored by administration of an oral contraceptive. Hirsutism alone may be ameliorated by the administration of drugs, such as spironolactone or cyproterone, that block the actions of androgens.

       menopause is the permanent cessation of menstruation that results from the loss of ovarian function. At the time of menopause the ovaries contain very few follicles; they have decreased in size, and they consist mostly of atretic (shrunken) follicles, some interstitial cells, and fibrous tissue. estrogen production decreases by 80 percent or more, and this along with the loss of follicles results in marked increases in the secretion of luteinizing hormone and follicle-stimulating hormone. Menopause occurs in most women between 45 and 55 years of age and is considered to be premature when it occurs before 40 years of age. Menstrual periods may cease abruptly or may be irregular for a year or so before ceasing. In a similar fashion, menopausal symptoms may occur abruptly or gradually. While menopausal symptoms may begin when the woman is still menstruating, they are more likely to begin after menstruation ceases.

      As a result of estrogen deficiency, during menopause and in general, the uterus and breasts decrease in size, the vaginal mucosa becomes atrophic and dry, and sexual intercourse often becomes painful ( dyspareunia). The most common symptom of declining estrogen production during menopause is “hot flashes,” which are characterized by a sensation of warmth of the face and upper body, flushing of the skin, sweating, tachycardia (accelerated heart rate), irritability, and headache. A hot flash typically lasts for a few minutes and may be followed by a sensation of cold and even shivering. About 75 percent of women have hot flashes at the time of menopause and about 30 percent may still have hot flashes five years later. The frequency of hot flashes varies from one or two per day to one per hour. Hot flashes may be a source of embarrassment during the day and may interfere with sleep at night. They seem to be caused by sudden autonomic nerve (autonomic nervous system) activation that stimulates the dilation of blood vessels that supply the skin, leading to an increase in skin temperature. Many menopausal women have psychological symptoms, such as changes in mood, depression, or feeling as though they lack well-being. Other symptoms associated with menopause include decreased libido and dryness and atrophy of the skin. Although hot flashes and psychological symptoms subside with time, they may be rapidly relieved by estrogen therapy.

      Important consequences of menopause are osteopenia and osteoporosis (see Metabolic bone disease (endocrine system, human)). In women (and men) bone density is maximal at about 30 years of age, after which it gradually decreases, except for a period of accelerated bone loss that occurs at the time of and for several years after menopause. Another important consequence of menopause is an increase in atherosclerotic cardiovascular disease. Increased risk of atherosclerosis and cardiovascular disease in menopausal women is attributed to decreased levels of estrogen that lead to increased serum cholesterol and triglyceride concentrations and to changes in vascular function and the production of blood clotting factors. (See also cardiovascular disease: Diseases of the arteries (cardiovascular disease).)

      The administration of estrogen is effective for treating many problems associated with menopause, including hot flashes, breast atrophy, vaginal dryness, and psychological symptoms. Estrogen is also effective for increasing libido. In addition, estrogen increases bone density, thereby decreasing the risk of fracture. Although estrogen therapy causes a decrease in serum cholesterol concentrations, it does not appear to reduce the frequency of cardiovascular disease, and it may actually increase the risk of developing cardiovascular disease. Estrogen therapy increases the risk of uterine cancer, which can be avoided if estrogen is given in conjunction with a progestin, and it slightly increases the risk of breast cancer.

      There are important practical aspects of estrogen therapy in menopausal women. It can be given orally or applied to the skin (transdermal estrogen) or to the vagina. Estrogen that is applied to the skin is absorbed into the circulation and has effects throughout the body, although it is less active in the liver than oral estrogen and therefore has fewer effects on serum lipids, hormone-binding proteins, and blood clotting factors that are produced in the liver. Estrogen that is applied to the vagina is not well absorbed and acts mostly on local tissues. Because of the risks of irregular vaginal bleeding and uterine cancer, any woman who has not had a hysterectomy (removal of the uterus) who is given estrogen should also be given a progestin. The two hormones are usually given together continuously, which results in uterine atrophy. They also can be given cyclically, with estrogen administered most of the time and progestin administered for 7 to 10 days each month, in which case there often will be vaginal bleeding after the progestin is stopped.

      There is no reason to treat menopausal women who have no symptoms. Bone loss can be minimized or prevented by exercise, good general nutrition, vitamin D and calcium supplementation, avoiding smoking, and by drugs such as bisphosphonates that block the resorption of bone.

The testes (testis)
      The testes (testis), or testicles, are the male gonads (gonad). They contain germ cells that differentiate into mature spermatozoa, supporting cells called Sertoli cells, and testosterone-producing cells called Leydig cells. The germ cells migrate to the fetal testes from the embryonic yolk sac. The Sertoli cells are analogous to the granulosa cells in the ovary, and the Leydig (interstitial) cells are analogous to the hormone-secreting interstitial cells of the ovary.

      The embryonic differentiation of the primitive, indifferent gonad into either the testes or the ovaries is determined by the presence or absence of genes carried on the Y chromosome (see Growth and development (endocrine system, human)). Testosterone and its potent derivative, dihydrotestosterone, play key roles in the formation of male genitalia in the fetus during the first trimester of gestation, but do not play a role in the actual formation of the testes. The testes are formed in the abdominal cavity and descend into the scrotum during the seventh month of gestation when they are stimulated by androgens. About 2 percent of newborn boys have an undescended testis at birth, but this condition often corrects itself by the age of three months.

      The adult testis consists of a series of seminiferous tubules, each with a central lumen, or cavity, connected to the epididymis and spermatic duct (vas deferens). sperm cells originate as spermatogonia along the walls of the seminiferous tubules. The spermatogonia mature into spermatocytes, which mature into spermatids that mature into spermatozoa as they move into the central lumen of the seminiferous tubule. The spermatozoa then move through the epididymis and the spermatic duct to be stored in the seminal vesicles for eventual ejaculation with the seminal fluid. Normal men produce about one million spermatozoa daily. The Sertoli cells are interspersed between the germinal epithelial cells within the seminiferous tubules, and the testosterone-producing Leydig cells are located between the tubules.

Regulation of testicular function
      The principal androgen produced by the testes is testosterone. The production of testosterone by the testes is stimulated by luteinizing hormone, which is produced by the anterior pituitary and acts via receptors (receptor) on the surface of the Leydig cells. The secretion of luteinizing hormone is stimulated by gonadotropin-releasing hormone, which is released from the hypothalamus, and is inhibited by testosterone, which also inhibits the secretion of gonadotropin-releasing hormone. These hormones constitute the hypothalamic-pituitary-testes axis. When serum testosterone concentrations decrease, the secretion of gonadotropin-releasing hormone and luteinizing hormone increase. In contrast, when serum testosterone concentrations increase, the secretion of gonadotropin-releasing hormone and luteinizing hormone decrease. These mechanisms maintain serum testosterone concentrations within a narrow range. In addition, the secretion of gonadotropin-releasing hormone and the secretion of luteinizing hormone must be pulsatile to maintain normal testosterone production. Continuous administration of gonadotropin-releasing hormone results in a decrease in the secretion of luteinizing hormone and therefore a decrease in the secretion of testosterone.

      In boys, as in girls, puberty begins with the onset of nocturnal pulses of gonadotropin-releasing hormone, which stimulate pulses of follicle-stimulating hormone and luteinizing hormone. The testes enlarge and begin to secrete testosterone, which then stimulates the development of male secondary sex characteristics, including facial, axillary, pubic, and truncal hair growth; scrotal pigmentation; prostatic enlargement; increased muscle mass and strength; increased libido; and increased linear growth. Many boys also have transient breast enlargement ( gynecomastia) during puberty. This process starts at 10 or 11 years of age and is complete at 16 to 18 years of age.

      Testosterone produced locally in the testes and follicle-stimulating hormone produced distally in the pituitary gland stimulate the process of spermatogenesis. Testosterone inhibits the secretion of follicle-stimulating hormone, which is also inhibited by inhibin, a polypeptide hormone produced by the Sertoli cells of the testes. Testosterone production and spermatogenesis decrease very slowly in older men, in contrast to women, in whom ovarian function ceases abruptly at the time of menopause.

Testicular hormones
      A healthy man produces about 5 mg of testosterone daily. Testosterone serves as a circulating prohormone for a more active androgen called dihydrotestosterone. Testosterone is converted to dihydrotestosterone in most tissues that are sensitive to androgens, including the testes, prostate gland, hair follicles, and muscles. Although testosterone itself has androgenic actions, its conversion to dihydrotestosterone is critical to the development of external genitalia in boys. Testosterone is also converted to estradiol in adipose tissue (and to a lesser extent in some other tissues), which is the most important source of estrogen in men. Furthermore, testosterone is interconvertible with androstenedione, which can be converted into estrogens. When androstenedione is formed in adipose tissue, it may be converted to a form of estrogen called estrone.

      Similar to other steroid hormones, testosterone exists in serum in two forms. Most testosterone in the serum is bound to sex hormone-binding globulin and to albumin, while the remaining amount (about 1 percent) is free, or unbound. Free testosterone is in equilibrium with bound testosterone so that when free testosterone enters cells some bound testosterone is immediately freed. In the cytoplasm of target cells, testosterone or dihydrotestosterone binds to specific androgen receptors, and the hormone-receptor complexes enter the cell nucleus, where they modulate protein synthesis by influencing the rate at which particular genes are transcribed.

      Testosterone has several major actions. It provides negative feedback inhibition on the secretion of gonadotropin-releasing hormone from the hypothalamus and the secretion of luteinizing hormone from the pituitary. It also directs the development of the embryonic Wolffian ducts (Wolffian duct) into the vas deferens and seminal vesicles and stimulates the formation of muscle and bone. Dihydrotestosterone is responsible for sperm maturation during spermatogenesis, for the formation of the prostate gland and external genitalia, and for sexual maturation at puberty.

Diseases and disorders

Precocious and delayed puberty

Precocious puberty
      Boys, like girls, can undergo true precocious puberty or various forms of precocious pseudopuberty. Precocious puberty in boys is defined as sexual development before the age of nine. In true precocious puberty there is premature activation of the hypothalamic-pituitary-testes axis, with spermatogenesis, virilization, and growth acceleration, which paradoxically causes premature closure of the epiphyseal disks and short stature. The causes of precocious puberty in boys include hypothalamic tumours and other brain tumours, traumatic brain injuries, and other brain disorders. However, in some boys no cause can be found (idiopathic precocious puberty). Because damage to the brain or disorders of the brain are the primary causes of true precocious puberty in boys, neurosurgical intervention may be needed. If neurosurgical intervention is unsuccessful or if no cause is found, affected boys can be treated with long-acting derivatives of gonadotropin-releasing hormone that down-regulate gonadotropin-releasing hormone receptors on the gonadotropin-secreting cells of the anterior pituitary. Thus, gonadotropin secretion decreases, testicular function ceases, and in most boys growth rate slows.

      Precocious pseudopuberty is partial pubertal development that results from autonomous (gonadotropin-independent) production of testosterone in a prepubertal boy. Affected boys have premature virilization and rapid growth, and they do not produce sperm. Precocious pseudopuberty may be caused by a liver tumour or other tumour that secretes chorionic gonadotropin (a hormone normally produced by the placenta), an adrenal or testicular tumour, congenital adrenal hyperplasia, a mutation that results in activation of the luteinizing hormone receptor (testotoxicosis), or exogenous androgen (e.g., steroid drugs). Affected boys must be evaluated carefully to find the cause of precocious pseudopuberty, and they must be treated accordingly—for example, by removal of the tumour.

Delayed puberty
      In boys, puberty is considered to be delayed if no pubertal development has occurred by 14 years of age. If the boy's stature is short, the likely cause is hypopituitarism (with both gonadotropin and growth hormone deficiency). If the boy's stature is normal, the likely causes are deficiency of gonadotropin-releasing hormone (sometimes with absence of the sense of smell, called Kallman syndrome), deficiency of gonadotropin, chronic illness, and primary gonadal disorders; however, in many cases no cause is found (idiopathic or constitutional delay in puberty). Primary gonadal disorders include absence of the testes, cryptorchidism, Klinefelter syndrome (Klinefelter's syndrome), enzymatic defects in testosterone biosynthesis, and testicular resistance to the action of luteinizing hormone. Klinefelter syndrome is a chromosomal disorder in which there is one or occasionally more than one X chromosome, and it is characterized by small testes, breast enlargement, decreased testosterone production, and increased serum gonadotropin concentrations. If diagnosis and treatment are delayed in patients with any disorder of delayed puberty, the epiphyseal centres remain open and linear growth continues. The patients often become tall with long legs and long arms, a body type referred to as eunuchoid habitus. Disorders of delayed puberty are treated with testosterone, which causes the development of secondary sex characteristics and a growth spurt, followed by epiphyseal closure.

      In men, decreased testicular function (hypogonadism) may result in testosterone deficiency and infertility. Hypogonadism is caused by hypothalamic, pituitary, and testicular diseases. Hypothalamic and pituitary diseases that may cause hypogonadism include tumours and cysts of the hypothalamus, nonsecreting and prolactin-secreting pituitary tumours (pituitary tumour), trauma, hemochromatosis (excess iron storage), infections, and nonendocrine disorders, such as chronic illness and malnutrition. The primary testicular disorders that result in hypogonadism in postpubertal men include Klinefelter syndrome and related chromosomal disorders, although these disorders usually manifest at the time of puberty. Other causes of hypogonadism in men include testicular inflammation ( orchitis) caused by mumps; exposure to gonadal toxins, including alcohol, marijuana, and several anticancer drugs (chemotherapy) (e.g., cyclophosphamide, procarbazine, and platinum); and radiation with X-rays (X-ray). Many of the disorders that cause delayed puberty are sufficiently mild that affected men do not seek care until well into adult life. This particularly applies to those disorders that decrease spermatogenesis and therefore fertility but spare Leydig-cell function.

      The clinical manifestations of hypogonadism in adult men include decreased libido, erectile dysfunction (inability to have or maintain an erection or to ejaculate), slowing of facial and pubic hair growth and thinning of hair in those regions, drying and thinning of the skin, weakness and loss of muscle mass, hot flashes, breast enlargement, infertility, small testes, and osteoporosis. The evaluation of men suspected to have hypogonadism should include measurements of serum testosterone, luteinizing hormone, follicle-stimulating hormone, and prolactin, in addition to the analysis of semen. Men with hypogonadism who have decreased or normal serum gonadotropin concentrations are said to have hypogonadotropic hypogonadism and may need to be evaluated for hypothalamic or pituitary disease with computed tomography (computerized axial tomography) (CT) or magnetic resonance imaging (nuclear magnetic resonance) (MRI) of the head (see diagnosis: Physical examination (diagnosis)). Men with hypogonadism who have increased serum gonadotropin concentrations are said to have hypergonadotropic hypogonadism, and their evaluation should be focused on the causes of testicular disease, including chromosomal disorders.

      Men with hypogonadism caused by a hypothalamic disorder, pituitary disorder, or testicular disorder are treated with testosterone. Testosterone can be given by intramuscular injection or by patches or gels applied to the skin. Testosterone treatment reverses many of the symptoms and signs of hypogonadism but will not increase sperm count. Sperm count cannot be increased in men with testicular disease, although it is sometimes possible to increase sperm count in men with hypothalamic or pituitary disease by prolonged administration of gonadotropin-releasing hormone or gonadotropins. In men with testicular disease, viable sperm can sometimes be obtained by aspiration from the testes for in vitro fertilization.

      Testicular tumours, most of which do not secrete hormones, occur in both boys and men. The most common testicular tumours are seminomas, which are derived from immature germ cells in the tissues of the seminiferous tubules. Men who have undescended testes (cryptorchidism) are at an increased risk of developing a seminoma. Other types of testicular tumours, often referred to as nonseminomas, are derived from mature germ cells and tend to be malignant and to metastasize, as opposed to seminomas, which are slow growing and can be effectively treated. Nonseminomas include embryonal-cell carcinomas, teratomas (tumours derived from multiple cell types from multiple layers of germ tissue), and choriocarcinomas. Many of these tumours secrete alpha-fetoprotein or chorionic gonadotropin (a hormone with properties similar to luteinizing hormone). Chorionic gonadotropin, if secreted in sufficient quantities, stimulates the Leydig cells to produce increased quantities of testosterone and estradiol. Excess testosterone has little effect in adult men, but estradiol may cause breast enlargement. Germ cell tumours, especially seminomas, are very sensitive to radiation therapy and anticancer drugs, so the prognosis for men with these tumours has become very good.

      Tumours of the Leydig cells are very rare and are almost always benign. They secrete large quantities of testosterone, thereby causing pseudopuberty in prepubertal boys. In adult men the only consistent clinical abnormality associated with a tumour of the Leydig cells is breast enlargement.

      The pineal gland, the most enigmatic of endocrine organs, has long been of interest to anatomists. Several millennia ago it was thought to control the flow of memories into consciousness. The 17th-century French philosopher-mathematician René Descartes (Descartes, René) concluded that the pineal gland was the seat of the soul. A corollary notion was that calcification of the pineal caused psychiatric disease, but modern imaging techniques have revealed that the pineal gland becomes more or less calcified in most people.

      The pineal gland is small, weighing little more than 0.1 gram (0.004 ounce). It lies deep within the brain, between the two cerebral hemispheres and above and behind the third ventricle. It has a rich supply of adrenergic nerves (adrenergic nerve fibre) that greatly influence its function. Microscopically, the gland is composed of pinealocytes (rather typical endocrine cells except for extensions that mingle with those of adjacent cells) and supporting cells that are similar to the astrocytes of the brain.

Hormones
      The pineal gland contains several neuropeptides and neurotransmitters (neurotransmitter), such as somatostatin, norepinephrine (epinephrine and norepinephrine), and serotonin. The major pineal hormone, however, is melatonin, a derivative of the amino acid tryptophan. Melatonin was first discovered because it lightens amphibian skin, an effect opposite to that of corticotropin and melanocyte-stimulating hormone of the anterior pituitary gland. The secretion of melatonin is increased by sympathetic nervous system stimulation. Of greater interest, however, is the fact that secretion increases soon after a person is placed in the dark and decreases soon after exposure to light. A major action of melatonin, well-documented in animals, is to block the secretion of gonadotropin-releasing hormone by the hypothalamus and therefore of gonadotropins by the pituitary gland. However, melatonin has no well-defined action in humans. It has been used to treat such conditions as depression, insomnia, and jet lag, but its efficacy for these purposes is controversial.

Pineal tumours (tumour)
      Pineal tumours are rare, occurring most often in children and young adults. The most common of these are germ cell tumours (germinomas and teratomas), which arise from embryonic remnants of germ cells. Germ cell tumours are malignant and invasive and may be life-threatening. Tumours of the pinealocytes also occur and vary in their potential for malignant change.

      Pineal tumours may cause headache, vomiting, and seizures because of the increase in intracranial pressure that results from the enlarging tumour mass. Some patients may become hypogonadal with regression of secondary sex characteristics, whereas others may undergo precocious puberty because of secretion of chorionic gonadotropin (a placental hormone that stimulates ovarian theca cells and testicular Leydig cells to secrete sex steroids). diabetes insipidus is frequently present and is usually due to tumour invasion of the hypothalamus. Invasion of the pituitary stalk may interfere with the inhibition of prolactin secretion by dopamine from the hypothalamus, resulting in high serum prolactin concentrations. Treatment consists of surgery and radiation therapy.

growth and development (biological development)
      The processes of growth and development are governed by many factors, including the inherent capacity of tissues for growth and differentiation, the hormonal influence of the endocrine system, and the stimulatory signals from the nervous system. In the amount of time from the 10th to the 20th week of pregnancy, the fetus grows 12.7 cm (5 inches) in length. This phenomenal growth rate slows dramatically as birth approaches. Birth weight is an important marker of nutrition during gestation and an important predictor of growth following birth. Low birth weight is common among infants of mothers whose family histories include low birth weight, and it may also be an indication of premature birth or of poor intrauterine nourishment. Rapid growth occurs during infancy and then slows until the onset of puberty, when it increases strikingly for several years. The pubertal growth spurt lasts 2 to 3 years, and it is accompanied by the appearance of secondary sexual characteristics. The pubertal growth spurt is associated with both an increase in nocturnal secretion of growth hormone and an increase in serum concentrations of sex steroids. The growth potential of a child can be estimated with moderate accuracy from measurements of the child's height and the heights of the parents and from measurements of the child's skeletal, or bone, age.

Endocrine influences
      Accurate estimates of bone age in children can be made from X-rays (X-ray) of the hands and wrists. These X-rays reveal the extent of maturation of the epiphyses (growth centres) of bones, which allows the bone age of the child being examined to be compared with the bone age of healthy children of the same chronological age. In children with endocrine disorders, bone age may not correlate closely with chronological age. For example, bone age is delayed in children with growth hormone deficiency and accelerated in children with growth hormone-producing tumours (tumour). hyperthyroidism, even when it occurs in the developing embryo, is associated with an increase in bone age, whereas hypothyroidism is associated with a decrease in bone age. Children with Cushing syndrome not only have osteoporosis but also have delayed growth and bone age. Excess production of androgens (androgen) or estrogens (estrogen) in childhood is associated with an increase in growth rate and acceleration of epiphyseal maturation so that bone age is advanced. The excess production of androgens and estrogens ultimately causes premature closure of the epiphyses and short stature. Deficiency of androgens and estrogens during crucial periods of growth in childhood leads to a delay in epiphyseal maturation (retarded bone age), and consequently, in adulthood, affected individuals have long arms and long legs and a normal trunk (eunuchoid habitus, or height that is equal to or less than arm span).

Growth factors: insulin-like growth factors
      When investigators began studying the effects of biological substances on cells (cell) and tissues outside of the body, they discovered a group of peptide hormones that were distinct from any previously known hormones and were active in stimulating the growth of these cells and tissues. This group of peptides includes insulin-like growth factors (somatomedins), epidermal growth factor, platelet-derived growth factor, and nerve growth factor. Among them, only the insulin-like growth factors have well-described endocrine actions in humans, and only they will be considered here.

      There are two insulin-like growth factors, insulin-like growth factor 1 (IGF-1) and insulin-like growth factor 2 (IGF-2). The name reflects the fact that they have insulin-like actions in some tissues, but in fact they are far less potent than insulin in decreasing blood glucose concentrations, and their fundamental action is to stimulate growth. These two factors, despite the similarity of their names, are distinguishable in terms of specific actions on tissues because they bind to and activate different receptors (receptor).

      The major action of the insulin-like growth factors is on cell growth. Indeed, most of the actions of pituitary (pituitary gland) growth hormone are mediated by the insulin-like growth factors, primarily IGF-1. Growth hormone stimulates many tissues, particularly the liver, to synthesize and secrete IGF-1, which in turn stimulates both hypertrophy and hyperplasia of most tissues, including bone. Serum IGF-1 concentrations progressively increase during childhood and peak at the time of puberty, and they progressively decrease thereafter (as does growth hormone secretion). Children and adults with deficiency of growth hormone have low serum IGF-1 concentrations compared to healthy individuals of the same age. In contrast, patients with high levels of growth hormone (e.g., acromegaly) have increased serum IGF-1 concentrations. The production of IGF-2 is less dependent on the secretion of growth hormone than is the production of IGF-1, and IGF-2 is much less important in stimulating linear growth. While serum insulin-like growth factor concentrations seem to be determined by production by the liver, these substances are produced by many tissues, and many of the same tissues also have receptors for them. In addition, there are multiple serum binding proteins for insulin-like growth factors that may stimulate or inhibit the biological actions of the factors. It is likely that the growth-promoting actions of the insulin-like growth factors occur at or very near the site of their formation; in effect, they probably exert their major actions by way of paracrine and autocrine effects.

Disorders of growth

Sexual differentiation
      The embryological and anatomical aspects of the gonads (gonad) and genitalia are detailed in the article reproductive system, human; and descriptions of chromosomes (chromosome) and the genes (gene) that they carry can be found in genetics, human, so only a brief review is presented here. In humans, each egg contains 23 chromosomes, of which 22 are autosomes and 1 is a female sex chromosome (the X chromosome). Each sperm also contains 23 chromosomes: 22 autosomes and either one female sex chromosome or one male sex chromosome (the Y chromosome). An egg that has been fertilized has a full complement of 46 chromosomes, of which two are sex chromosomes. Therefore, genetic sex of the individual is determined at the time of fertilization; fertilized eggs containing an XY sex chromosome complement are genetic males, whereas those containing an XX sex chromosome complement are genetic females.

      Regardless of the complement of sex chromosomes, all developing embryos become feminized unless masculinizing influences come into play at key times during gestation. In males, several testis-determining genes on the Y chromosome direct the sexually undifferentiated (indeterminate) embryonic gonads to develop as testes. The X chromosome also participates in the differentiating process, because two X chromosomes are necessary for the development of normal ovaries (ovary). Every fetus contains structures that are capable of developing into either male or female genitalia.

      During the third month of fetal development, the Sertoli cells of the testes of XY fetuses begin to secrete a substance called Müllerian inhibiting hormone. This causes the set of ducts known as the Müllerian ducts to atrophy instead of developing into the oviducts (fallopian tubes (fallopian tube)) and uterus. A separate set of ducts called the Wolffian ducts (Wolffian duct) are stimulated by testosterone to develop eventually into the spermatic ducts (vas deferens), ejaculatory ducts, and seminal vesicles (seminal vesicle). If the fetal gonads do not secrete testosterone at the proper time, the genitalia develop in the female direction regardless of whether testes or ovaries are present. In normal female fetuses, no androgenic effects occur; the ovaries develop along with the Müllerian ducts, while the Wolffian duct system deteriorates. Sexual differentiation is completed at puberty, at which time the reproductive system in both women and men is mature.

      In such a complex system there are many opportunities for aberrant development. The causes of disorders of sexual differentiation, while not fully understood, have been greatly elucidated by advances in chromosomal analysis, the identification of isolated genetic defects in steroid hormone synthesis, and the understanding of abnormalities in steroid hormone receptors.

Klinefelter syndrome (Klinefelter's syndrome)
      Klinefelter syndrome (Klinefelter's syndrome) (47,XXY seminiferous tubule dysgenesis) is the most frequent chromosomal disorder in males, occurring in approximately 1 in every 1,000 males. Men with this syndrome have small, firm testes, and they often have breast enlargement ( gynecomastia) and inordinately long legs and arms (eunuchoidism) and are infertile. Affected men have decreased serum testosterone concentrations and increased serum follicle stimulating hormone (follicle-stimulating hormone) (FSH) and luteinizing hormone (LH) concentrations. While normal in intelligence, some affected men have difficulties making social adjustments. Klinefelter syndrome results from an unequal sharing of sex chromosomes very soon after fertilization, with one cell of a dividing pair receiving two X chromosomes and a Y chromosome and the other cell of the pair receiving only a Y chromosome and usually dying.

      The mosaic form of Klinefelter syndrome (normal male chromosome number and sex chromosome composition is 46,XY; males with mosaic Klinefelter syndrome have an extra X chromosome, resulting in a chromosome composition of 47,XXY) is the second most common type of chromosomal disorder in males, and affected men usually have fewer symptoms than do men with the complete Klinefelter syndrome. Other, rare chromosome complements associated with mosaic Klinefelter syndrome include 48,XXYY, 48,XXXY, 49,XXXYY, and 49,XXXXY. Men with these chromosome complements suffer from a variety of additional abnormalities, and, unlike men with classic Klinefelter syndrome, they are often mentally retarded. Another chromosome variant is the XX male syndrome in which Y chromosome material is transferred to an X chromosome or a nonsex chromosome (autosome). Men with XX syndrome have a male phenotype (physical appearance), but they have changes typical of Klinefelter syndrome. Treatment with androgens reduces gynecomastia and evidence of male hypogonadism and increases strength and libido in patients with all variants of Klinefelter syndrome. In a few of these individuals, sperm obtained from the testes have successfully fertilized oocytes in vitro.

Turner syndrome (Turner's syndrome)
      Turner syndrome (Turner's syndrome) (gonadal dysgenesis) occurs when one sex chromosome is deleted so that the chromosomal complement is 45,X. In genetic terms, these patients are neither male nor female since the second, sex-determining chromosome is absent. However, phenotypically, affected individuals develop as females because there is no Y chromosome to direct the fetal gonads to the male configuration. Clinically, patients with Turner syndrome are short, and they have a small chin, prominent folds of skin at the inner corners of the eyes (epicanthal folds), low-set ears, a webbed neck, and a shieldlike chest. Individuals with Turner syndrome also have an increased incidence of anomalies of the heart and large blood vessels (blood vessel). Both the internal and the external genitalia are infantile, and the ovaries are only “streaks” of connective tissue. The diagnosis may be made during infancy or childhood on the basis of these anomalies or at puberty when the patients fail to develop secondary sex characteristics or have no menses. In genetic terms, Turner syndrome is common; one-tenth of all spontaneously aborted fetuses have a 45,X chromosome constitution, and only 3 percent of affected fetuses survive to term.

      Patients with Turner syndrome can be treated with growth hormone during childhood to increase linear growth. Affected individuals should also be treated with estrogen and progestin (similar to progesterone) at the time of puberty to stimulate the appearance of secondary sexual characteristics and monthly vaginal bleeding that simulates a menstrual cycle. Estrogen and progestin also prevent osteoporosis, which will occur if ovarian deficiency is not treated.

      As with Klinefelter syndrome, there are multiple variants of Turner syndrome. There are mixtures of chromosomes (mosaics), such as a 45,X and 46,XX chromosomal complement or a 45,X and 47,XXX chromosomal complement, and chromosomal translocations, in which a portion of one chromosome is transferred to another chromosome. Another variant is the 45,X/46,XY mosaic, in which a person may be reared as either a male or a female because the genitalia are “ambiguous,” meaning that it is difficult to determine whether the phallus is an enlarged clitoris or a small penis. Patients with this variant of Turner syndrome have streak gonads, and the presence of the Y chromosome is associated with an increased risk of development of a malignant tumour of the streak gonad.

       hermaphroditism is, in strict medical terms, very rare. A true hermaphrodite is an individual who has both ovarian and testicular tissue. The ovarian and testicular tissue may be separate, or the two may be combined in an ovotestis. Most often, but not always, the chromosome complement is 46,XX, and in every such patient there also exists evidence of Y chromosomal material on one of the autosomes. Patients with a 46,XX chromosome complement usually have ambiguous external genitalia with a sizable phallus and are therefore often reared as males. They develop breasts during puberty and menstruate and in only rare cases actually produce sperm.

      Treatment depends upon the age at which the diagnosis is made. If it is decided that a male identity is deeply embedded and therefore a male role is preferable, all female tissues, including the oviducts and ovaries, are removed. In those persons to be reared as females, the male sexual tissues are removed. In older patients, the accepted gender should be reinforced by the appropriate surgical procedures and hormonal therapy.

      If, during the first trimester of pregnancy, a woman carrying a female fetus is given an androgen, an anabolic steroid, or a progestin, her fetus may be masculinized. Androgen-producing tumours of either adrenal or ovarian origin may also lead to masculinization of a female fetus. congenital adrenal hyperplasia due to defects in adrenal enzymes (enzyme) is a far more common cause of female pseudohermaphroditism (see above The adrenal cortex (endocrine system, human)).

Male pseudohermaphroditism
      Male pseudohermaphrodites are genetic males (45,XY) who develop female configurations and identities. Affected individuals have testes, but their genital ducts and external genitalia are female. Secondary sex characteristics may never appear in some patients, whereas others may achieve a fully feminized appearance. Male pseudohermaphroditism is rare and almost always results from autosomal recessive genetic defects (genetic disease, human). Several specific defects lead to feminization in genetic males. Each of these defects, by one mechanism or another, results in a loss of androgenic effects on body tissues. In rare instances, Leydig cells are absent or greatly reduced in number, presumably because the receptors for luteinizing hormone are defective. Without Leydig cells, only small amounts of testosterone are produced. In other patients there are enzyme deficiencies analogous to those that occur in female pseudohermaphrodites, although the enzyme deficiencies in males result in fetal androgen deficiency.

      In some patients, tissue receptors for androgens are absent or reduced, forming a spectrum of syndromes of partial to complete resistance to androgens. The most striking example of resistance to androgens is complete testicular feminization. Affected patients are born with female genitalia and a vagina that ends blindly (no cervix or uterus is present). Despite having testes located either in the labia or within the abdomen, these patients grow into well-proportioned females with normal breasts and scant or absent axillary and pubic hair. They have a strong female orientation, but they do not menstruate. The hormonal aberrations in these patients are dramatic and predictable. With a loss of hypothalamic and pituitary androgen receptors, there is no inhibition of gonadotropin secretion. Serum luteinizing hormone concentrations are high, leading to stimulation of the Leydig cells and high serum testosterone concentrations. The conversion of the increased amounts of testosterone to estrogen in peripheral tissues increases serum estrogen concentrations in males.

      In another extraordinary variant, the lesion lies not in the loss of androgen receptors but rather in the loss of 5-alpha-reductase, an enzyme necessary for the conversion of testosterone to the more potent hormone dihydrotestosterone. In this syndrome, because of a lack of testosterone directing fetal development toward a normal male configuration, genetic males are born with what appears to be female genitalia with an enlarged clitoris. These persons are often raised as females, but at puberty an increase in testosterone secretion leads to masculinization. There then ensues a transition from the psychosocial behaviour of a prepubertal female to that of an adult male. This change in gender identity seems to occur without undue emotional turmoil.

      In some fetuses there occurs, for unknown reasons, regression and disappearance of the testes, known as the “vanishing testes syndrome.” When this occurs early in pregnancy, before androgen-induced differentiation toward male genitalia, the child is born with female genitalia. If the testes disappear during the crucial period between 8 and 10 weeks of gestation, the child is born with ambiguous genitalia, whereas if the disappearance occurs after this key period, the individual is a male but without any testes (anorchia).

      Treatment of these patients must be highly individualized. In many instances, gender identity has been established by the age of 18 to 24 months, and changes in sexual identity thereafter should be attempted only after careful consideration. Intraabdominal testes should be removed because of an increased risk of tumour formation. The patient can be treated at the appropriate time with sex hormones.

Hormones of the intestinal mucosa
      In 1902 two English physiologists, Sir William M. Bayliss (Bayliss, Sir William Maddock) and Ernest H. Starling (Starling, Ernest Henry), placed dilute hydrochloric acid into a segment of a dog's bowel from which the nerve supply had been severed. They then collected an extract of the bowel lining and injected it into another dog. The result was an increase in the secretion of pancreatic juice in the dog that received the injection. They named the material in the extract “ secretin.” With this discovery emerged the concept that chemical messages could act at distant sites to regulate bodily functions. Interest in secretin soon waned, however, because of discoveries in what became the mainstream of endocrinology, the study of discrete endocrine glands, such as the pituitary gland and thyroid gland. With the advent of modern techniques for isolating, characterizing, and measuring protein hormones, interest in the endocrinology of the gastrointestinal tract revived. Today it is clear that the gastrointestinal tract not only is a complex system for the digestion and absorption of nutrients but also is an endocrine organ that secretes many hormones. The hormones of the gastrointestinal tract have many effects on gastrointestinal function when given in large doses, but their physiological actions are undoubtedly more limited; indeed, in many instances their actions are not precisely known. To complicate matters further, many of these hormones exist in several forms that have different actions.

      Secretin, a polypeptide that comprises 27 amino acids (amino acid), is produced in the cells that line the upper small intestine. When hydrochloric acid passes from the stomach into the duodenum, secretin is released into the bloodstream and stimulates the acinar cells of the pancreas to secrete water and bicarbonate into the pancreatic ducts that drain into the duodenum. By this mechanism, hydrochloric acid secreted by the stomach, which can be damaging to the intestinal lining, is promptly diluted and neutralized. Secretin also inhibits the secretion of gastrin and delays gastric emptying.

      Cholecystokinin (cholecystokinin/pancreozymin) (CCK) is secreted by cells of the upper small intestine. Its secretion is stimulated by the introduction of hydrochloric acid or fatty acids (fatty acid) into the stomach or the duodenum. Cholecystokinin stimulates the gallbladder to contract and release stored bile into the intestine. It also stimulates the secretion of pancreatic juice and may induce satiety. There are several hypotheses regarding cholecystokinin's ability to induce satiety. One hypothesis is that meal-induced secretion of cholecystokinin activates the satiety centre of the hypothalamus so that the person feels full and stops eating. A second hypothesis is that, because cholecystokinin inhibits emptying of the stomach, the sensation of satiety may be the result of distension of the stomach.

       gastrin is a 17-amino-acid polypeptide that is secreted into the bloodstream by the cells that line the stomach. Gastrin stimulates the secretion of hydrochloric acid and a digestive enzyme called pepsin into the stomach while simultaneously increasing the contractility of the distal part of the stomach. The medical importance of gastrin lies in the fact that there are pancreatic islet-cell tumours called gastrinomas that secrete large quantities of gastrin (hypergastrinemia). Hypergastrinemia stimulates the production of gastric acid, which causes severe peptic ulcer disease and diarrhea. Gastrinomas are one component of the syndrome of multiple endocrine neoplasia type 1 (MEN1) and are also the defining tumour type of a rare disorder known as Zollinger-Ellison syndrome, which may occur sporadically or as a part of MEN1. Treatment consists of surgically removing the tumour or treating the patient with a drug that inhibits gastric acid secretion (a proton pump inhibitor).

Gastric inhibitory polypeptide
      Gastric inhibitory polypeptide (GIP) is a hormone secreted by cells of the intestinal mucosa that blocks the secretion of hydrochloric acid into the stomach. It also increases insulin secretion from the beta cells of the islets of Langerhans (Langerhans, islets of), causing an increase in serum insulin concentrations that is significantly larger after glucose feeding than after intravenous administration of the same amount of glucose.

Ghrelin
      Ghrelin is a 28-amino-acid peptide produced primarily in the stomach, but it is also produced in the upper small intestine and hypothalamus. Ghrelin secretion increases before meals and decreases after food is eaten, indicating that it stimulates appetite. The pattern of ghrelin secretion is similar when caloric intake is restricted, but the level of secretion is increased. Surgical removal of the stomach and operations for obesity that bypass the stomach result in marked decreases in serum ghrelin concentrations. In addition to its appetite-stimulating (orexigenic) activity, ghrelin contributes to the regulation of energy homeostasis. It may also participate in regulating the secretion of growth hormone by the anterior pituitary gland.

Vasoactive intestinal polypeptide
      Vasoactive intestinal polypeptide (VIP), a 28-amino-acid polypeptide, is secreted by cells throughout the intestinal tract. It stimulates the secretion of electrolytes (electrolyte) and water by the intestinal mucosa. Some pancreatic islet-cell tumours secrete excessive amounts of vasoactive intestinal polypeptide (Verner-Morrison syndrome, or pancreatic cholera). Vasoactive intestinal polypeptide-secreting tumours cause severe, intractable, debilitating watery diarrhea and an associated loss of large quantities of potassium. The resulting dehydration may be life-threatening.

      Some gastrointestinal hormones may also serve as neurotransmitters in the brain, but they have not been found to cause disease. These hormones include motilin, neuropeptide Y (which interacts with ghrelin to regulate appetite), gastrin-releasing peptide (bombesin-like peptide), glucagon (see above The pancreas (endocrine system, human)), and somatostatin (see above The hypothalamus (endocrine system, human); The pancreas (endocrine system, human)).

Prostaglandins (prostaglandin)
      The prostaglandins (prostaglandin) are a group of modified fatty acids (fatty acid) that have many different actions that are generally paracrine or autocrine in nature. These substances were first identified in extracts of seminal vesicles and semen and were given the name prostaglandins because they were thought to be produced in the prostate gland.

      The prostaglandins are made up of unsaturated fatty acids that contain a cyclopentane (5-carbon) ring and are derived from the 20-carbon, straight-chain, polyunsaturated fatty acid precursor arachidonic acid. Each prostaglandin differs slightly from the others in chemical structure; these differences are responsible for their different biological activities.

      Arachidonic acid is a key component of phospholipids (phospholipid), which are themselves integral components of cell membranes (membrane). In response to many different stimuli, including various hormonal, chemical, or physical agents, a chain of events is set in motion that results in prostaglandin formation and release. These stimuli, either directly or indirectly, result in the activation of an enzyme called phospholipase A2. This enzyme catalyzes the release of arachidonic acid from phospholipid molecules. Depending on the type of stimulus and the enzymes present, arachidonic acid may diverge down one of several possible pathways. One enzyme, lipoxygenase, catalyzes the conversion of arachidonic acid to one of several possible leukotrienes, which are important mediators of the inflammatory process (inflammation). Another enzyme, cyclooxygenase, catalyzes the conversion of arachidonic acid to one of several possible endoperoxides. The endoperoxides undergo further modifications to form prostaglandins, prostacyclin, and thromboxanes. The thromboxanes and prostacyclin have important functions in the process of blood coagulation.

      The actions of the prostaglandins are multiple and varied and are in part determined by the type of receptor to which they bind. This contributes to the ability of the same prostaglandin to stimulate a reaction in one tissue and inhibit the same reaction in another tissue. Prostaglandins usually act locally, near the site of their synthesis. For instance, they are powerful locally acting vasodilators. Vasodilation occurs when the muscles in the walls of blood vessels relax so that the vessels dilate. This creates less resistance to blood flow and allows blood flow to increase and blood pressure to decrease. An important example of the vasodilatory action of prostaglandins is found in the kidneys (kidney), in which widespread vasodilation leads to an increase in the flow of blood to the kidneys and an increase in the excretion of sodium in the urine. Thromboxanes on the other hand are powerful vasoconstrictors that cause a decrease in blood flow and an increase in blood pressure.

      Although prostaglandins were first detected in semen, no clear role in reproduction has been established for them in males. This is not true, however, in women. Prostaglandins play a role in ovulation, and they stimulate uterine muscle contraction—a discovery that led to the successful treatment of menstrual cramps ( dysmenorrhea) with inhibitors of prostaglandin synthesis, such as ibuprofen. Prostaglandins also play a role in inducing labour in pregnant women at term, and they are given to induce therapeutic abortions.

      Thromboxanes and prostacyclins play an important role in the formation of blood clots (coagulation). The process of clot formation begins with an aggregation of blood platelets (platelet). This process is strongly stimulated by thromboxanes and inhibited by prostacyclin. Prostacyclin is synthesized in the walls of blood vessels and serves the physiological function of preventing needless clot formation. In contrast, thromboxanes are synthesized within platelets, and in response to vessel injury, which causes platelets to adhere to one another and to the walls of blood vessels, thromboxanes are released to promote clot formation. Platelet adherence is increased in arteries that are affected by the process of atherosclerosis. In affected vessels, the platelets aggregate into a plaque called a thrombus along the interior surface of the vessel wall. A thrombus may partially or completely block (occlude) blood flow through a vessel or may break off from the vessel wall and travel through the bloodstream, at which point it is called an embolus. When an embolus becomes lodged in another vessel where it completely occludes blood flow, it causes an embolism. Thrombi and emboli are the most common causes of heart attack (myocardial infarction). Therapy with daily low doses of aspirin (an inhibitor of cyclooxygenase) has had some success as a preventive measure for people who are at a high risk of heart attack.

      Prostaglandins also play a pivotal role in inflammation, a process characterized by redness (rubor), heat (calor), pain (dolor), and swelling (tumor). The changes associated with inflammation are due to dilation of local blood vessels that permits increased blood flow to the affected area. The blood vessels also become more permeable, leading to the escape of white blood cells from the blood into the inflamed tissues. Thus, drugs such as aspirin or ibuprofen that inhibit prostaglandin synthesis are effective in suppressing inflammation in patients with inflammatory but noninfectious diseases, such as rheumatoid arthritis.

      The function of the digestive tract is also affected by prostaglandins, with prostaglandins either stimulating or inhibiting contraction of the smooth muscles of the intestinal walls. In addition, prostaglandins inhibit the secretion of gastric acid, and therefore it is not surprising that drugs such as aspirin that inhibit prostaglandin synthesis may lead to peptic ulcers (peptic ulcer). Prostaglandin action on the digestive tract may also cause severe watery diarrhea and may mediate the effects of vasoactive intestinal polypeptide in Verner-Morrison syndrome (see above Vasoactive intestinal polypeptide (endocrine system, human)), as well as the effects of cholera toxin.

Ectopic hormone and polyglandular disorders
      There are several syndromes of hormone hypersecretion that are caused by the unregulated production of hormones, usually by tumours. The unregulated secretion of a hormone often occurs in a tissue that does not ordinarily produce the hormone at all (ectopic hormone production). There also are several genetic disorders characterized by hormone-producing tumours of several endocrine glands. In these disorders, known as multiple endocrine neoplasia (MEN), affected patients have germ line mutations (mutation) (heritable mutations that are incorporated into all of the cells of the body) in genes that predispose them to endocrine gland hyperplasia and tumour development. The tumours may occur in more than one endocrine gland and may appear simultaneously or at varying times in the course of the disease. The embryonic origin of the cells of the endocrine glands that are involved may also be different. In addition, there exist multiple endocrine deficiency syndromes (polyglandular autoimmune disorders), in which affected persons have deficiencies of multiple endocrine glands caused by autoimmune destruction of the glands. Multiple endocrine deficiency syndromes result in multiple hormonal deficiencies and are suspected to be caused by underlying heritable genetic mutations.

Ectopic hormone production
      Ectopic hormone production is the synthesis and secretion of peptide or protein hormones by benign or malignant tumours of tissues that do not normally synthesize and secrete the particular hormone. The hormone that is most commonly produced ectopically is corticotropin (adrenocorticotropic hormone), resulting in ectopic Cushing syndrome. This syndrome occurs most often in patients with small-cell carcinomas of the lung (lung cancer) (SCLC), but it can occur in patients with carcinoid tumours (benign or malignant tumours that secrete hormonelike substances such as serotonin), islet-cell tumours of the pancreas, and carcinomas of many other organs. Many patients with ectopic corticotropin production have the symptoms and signs of Cushing syndrome, as well as intense pigmentation, caused by hypersecretion of corticotropin, and severe depletion of potassium (hypokalemia), caused by the mineralocorticoid action of high serum cortisol concentrations. Treatment ordinarily involves surgical removal or drug-induced destruction of the tumour. However, in cases in which the tumour cannot be removed or its function reduced, adrenalectomy (removal of the adrenal glands) or treatment with a drug such as ketoconazole, an antifungal drug that inhibits adrenal steroid synthesis, may be more effective.

      Ectopic hormone production can result in numerous abnormal hormone-related physiological conditions, including hypercalcemia (increased serum calcium concentrations), hyponatremia (decreased serum sodium concentrations), hypoglycemia (decreased blood sugar concentrations), and acromegaly (excess production of growth hormone). Tumour-induced hormone production (or production of hormonelike substances) can cause many of these conditions. For example, hypercalcemia can be caused by tumour production of parathyroid-hormone-related protein (structurally similar to parathyroid hormone) or, rarely, by tumour production of parathyroid hormone, 1,25-dihydroxyvitamin D3 (the active form of vitamin D in animal tissues; sometimes called calcitriol, or 1,25-dihydroxycholecalciferol), or interleukins (interleukin) (mediators of immune response). Hypercalcemia can also be caused by the invasion and destruction of bone tissue by a tumour. Hyponatremia can occur as a result of vasopressin secretion, usually by small-cell carcinomas of the lung, and hypoglycemia may be caused by tumour production of insulin-like growth factors or, very rarely, insulin. Acromegaly is caused by tumour production of growth hormone or, very rarely, tumour production of growth hormone-releasing hormone (GHRH). As discussed above, treatment is aimed at removing the offending tumour, reducing the size or activity of the tumour, or mitigating the effects of the hormone that is produced in excess.

      Production of thyrotropin, luteinizing hormone, and follicle-stimulating hormone by nonpituitary tumours does not occur. Similarly, the production of steroid or thyroid hormones by tumours of tissues that do not normally produce these hormones does not occur. This may be because these hormones have a high degree of structural complexity, with multiple rings, chains of amino acids, and carbohydrate molecules, and the production of these hormones is dependent upon genes expressed by the tumour that are required to produce the multiple enzymes involved in hormone synthesis. The placental hormone chorionic gonadotropin, which is structurally similar to luteinizing hormone and has similar biological properties, is produced by tumours of cells of embryonic origin, such as hepatoblastomas and chorionic tumours (e.g., hydatidiform moles (hydatidiform mole) and choriocarcinomas), and is occasionally produced by other tumours. The clinical effects of excess chorionic gonadotropin production include precocious pubertal development in children, ovarian hyperstimulation in women, and estrogen excess in men. Chorionic tumours that produce very large amounts of chorionic gonadotropin can cause hyperthyroidism, since this hormone also has weak thyroid-stimulating activity.

Multiple endocrine neoplasia
      The syndromes of multiple endocrine neoplasia (MEN) are hereditary disorders that are transmitted in an autosomal dominant (dominance) fashion, meaning that the defect can occur in males and females, and, statistically, one-half of the children of an affected person will also be affected. Multiple endocrine neoplasia is often difficult to recognize in its early stages because the pattern of endocrine gland hyperplasia and tumour development varies, and the tumours that characterize the syndromes of MEN do not appear simultaneously. Thus, a patient may have incomplete expression of one of these inherited syndromes when first examined; however, many of these individuals will later develop other tumours or conditions that are characteristic of a particular type of MEN syndrome.

      The first described and the most frequently occurring of these rare disorders is multiple endocrine neoplasia type 1 (MEN1). The principal glands involved in this syndrome are the parathyroid glands (parathyroid gland), the pancreatic islets of Langerhans (Langerhans, islets of), and the anterior pituitary gland. Patients with tumours of two of these three glands are considered to have MEN1. If one family member has been diagnosed with the disorder and a first-degree relative has a tumour of one of the three glands, the condition is defined as familial MEN1. The most common disorder associated with MEN1 is primary hyperparathyroidism (characterized by the presence of parathyroid adenomas or hyperplasia), which occurs in about 90 percent of patients. Coinciding disorders may include pancreatic islet-cell tumours, such as gastric acid-secreting tumours (gastrinomas), pancreatic polypeptide-secreting tumours, insulin-secreting tumours (insulinomas), and, less commonly, glucagon-secreting, vasoactive intestinal polypeptide-secreting, or somatostatin-secreting tumours. About 20 percent of cases present as nonsecreting pituitary adenomas or as pituitary adenomas that secrete prolactin or growth hormone (see The anterior pituitary (endocrine system, human)). Carcinoid tumours and tumours of the adrenal cortex may occur, but they may be coincidental rather than an integral part of the disorder. Treatment usually consists of surgery for patients with hyperparathyroidism, insulinomas, or growth hormone-secreting and nonsecreting pituitary tumours. A dopamine agonist (a drug that increases dopamine activity) may be used for patients with prolactin-secreting pituitary tumours because dopamine is an effective prolactin-inhibiting factor, and surgery or a proton pump inhibitor (a drug that blocks gastric acid secretion) may be used for patients with gastrinomas to decrease levels of gastric acid and the occurrence of peptic ulcers.

      Most patients with MEN1, as well as people with a familial risk of developing MEN1, have germ line mutations (mutations that affect all cells in the body) in a tumour suppressor gene designated MEN1. This gene codes for a protein called menin that normally helps prevent neoplastic proliferation (uncontrolled new growth) of cells. Mutations in MEN1 lead to the synthesis of a form of menin that is less active in preventing neoplastic proliferation. The MEN1 gene is expressed in many tissues, including nonendocrine tissues, and it is not understood why mutations in MEN1 result in tumours only in endocrine glands. Mutation testing in affected patients confirms diagnosis of MEN1, and testing in asymptomatic family members identifies whether they are at risk of developing MEN1. People who carry mutations in MEN1 should be evaluated periodically by history and physical examination and measurements of serum concentrations of calcium, gastrin, and prolactin. Detecting the development of MEN1 in its early stages is important because early treatment is more effective and safer than treatment of more advanced disease.

      Multiple endocrine neoplasia type 2 (MEN2) is characterized by a different constellation of endocrine abnormalities than MEN1 and is associated with some nonendocrine abnormalities. Conditions associated with MEN2 include medullary carcinoma of the thyroid, pheochromocytomas (pheochromocytoma) (tumours characterized by high blood pressure), hyperparathyroidism, ganglioneuromas (tumours derived from cells originating in the neural crest during embryological development), and a tall, lean body with long extremities (similar to the physical appearance of individuals affected by Marfan syndrome). If one family member has been diagnosed with medullary thyroid carcinoma and a first-degree relative is diagnosed with any manifestation of the disorder, the condition is defined as familial MEN2. There are three forms of the disorder: MEN2A (accounting for about 75 percent of affected families), familial medullary thyroid carcinoma (FMTC-only; accounting for 5 to 20 percent of affected families), and MEN2B (accounting for less than 5 percent of affected families). The primary tumour type found in patients with MEN2A is medullary thyroid carcinoma, which occurs in at least 90 percent of affected patients. This is followed by pheochromocytoma, often bilateral (meaning that it occurs in both adrenal glands; see The adrenal medulla (endocrine system, human)), in about 50 percent of patients and primary hyperparathyroidism in about 20 percent of patients. The least common form of MEN2, MEN2B, is characterized by medullary thyroid carcinoma in 95 percent of patients, bilateral pheochromocytoma in about 50 percent of patients, intestinal or mucosal ganglioneuromas (benign tumours of the lips, tongue, and lining of the mouth, throat, and intestine) in about 95 percent of patients (but not primary hyperparathyroidism), and a tall, lean physical appearance in roughly 50 percent of patients. Patients and families with FMTC-only should be studied very carefully to be sure affected family members do not have other features of MEN2A or 2B.

      Medullary carcinomas of the thyroid gland arise from the parafollicular, or C cells, of the thyroid gland (see above The thyroid gland (endocrine system, human)), which secrete calcitonin (see above The parathyroid glands (endocrine system, human)). Medullary thyroid carcinoma is nearly always the first manifestation of MEN2, and it can occur in very young children. It is preceded by hyperplasia of the C cells. Nearly all patients who have only C-cell hyperplasia are cured by total thyroidectomy (removal of the thyroid gland), whereas patients that have hyperplasia that has progressed to carcinoma may not be cured by this operation. Patients with pheochromocytomas should be treated surgically as well. Unlike MEN1, in which several drugs are available to control hormone overproduction by some glands, there is no effective treatment for the other components of MEN2.

      Nearly all patients with MEN2 and FMTC-only have germ line mutations in the RET (rearranged during transfection) proto-oncogene (a gene susceptible to mutations that transform it into an oncogene, or cancer-inducing gene). The RET gene codes for a transmembrane protein receptor that contains an intracellular signaling region called a tyrosine kinase domain. The kinase domain is fundamental in activating cell signaling cascades. Kinase activity causes the transfer of high-energy phosphate molecules to tyrosine residues on nearby proteins, resulting in protein activation and initiation of downstream signaling events. These signaling events culminate in specific cellular functions, such as promoting cell survival and differentiation. Mutations in RET that are associated with MEN2 cause the kinase domain to be constantly active (gain-of-function mutations), which predisposes the cells to tumour formation because cell death signaling pathways are inhibited and proliferation pathways are stimulated. The RET gene is expressed in multiple types of tissues, including nonendocrine tissues, and it is not clear why the mutations in this gene that are associated with MEN2 primarily affect only the C cells of the thyroid and the cells of the adrenal medulla.

      Because medullary thyroid carcinoma occurs in nearly all individuals that carry a mutation in RET and because it appears at an early age, it is important that all patients with medullary thyroid carcinoma be tested for mutations in RET. If a mutation is found, all family members should be tested for that specific mutation, and prophylactic total thyroidectomy should be done in all family members who carry the mutation. The timing of the operation depends on the mutation. Patients carrying some mutations should undergo thyroidectomy within the first year of life, before medullary thyroid carcinoma has appeared. In other patients, operations can be delayed until adolescence. Given the lower likelihood of pheochromocytoma and hyperparathyroidism, prophylactic adrenalectomy or parathyroidectomy is not recommended. Family members who do not have the mutation do not need to undergo screening for tumours or prophylactic surgery.

Multiple endocrine deficiency syndromes
      There are two familial syndromes, known as polyglandular autoimmune (autoimmunity) syndromes, in which affected patients have multiple endocrine gland deficiencies. Some patients produce serum antibodies (antibody) that react with, and presumably damage, multiple endocrine glands and other tissues, and other patients produce lymphocytes (lymphocyte) that migrate into and damage endocrine glands. Type 1 polyglandular autoimmune syndrome occurs in children or adolescents and is characterized primarily by hypoparathyroidism, infection with the fungal organism Candida albicans, which causes candidiasis of the skin or the mucous membrane of the mouth, and adrenal insufficiency (see Adrenal insufficiency (endocrine system, human)). Affected patients may also have diabetes mellitus, hypogonadism, hypothyroidism, or intestinal malabsorption. Type 1 polyglandular autoimmune syndrome is inherited as an autosomal recessive trait and is caused by a mutation in the AIRE (autoimmune regulator) gene, although the gene product and its function are not known. Type 2 polyglandular autoimmune syndrome occurs in adults and is characterized by adrenal insufficiency, type 1 diabetes mellitus, hypothyroidism or Graves disease, hypogonadism, and pernicious anemia. Type 2 polyglandular autoimmune syndrome may affect multiple members of a family, but the pattern of inheritance is not known.

Endocrine changes with aging
      Because the endocrine glands play pivotal roles both in reproduction and in development, it seems plausible to extend the role of the endocrine system to account for the progressive changes in body structure and function that occur with aging (human aging) (senescence). Indeed, years ago an “endocrine theory of aging” enjoyed wide popularity, but it is now clear that—with some exceptions—endocrine function does not significantly change with age. The greatest change is in ovarian function, which decreases abruptly following menopause. There are gradual age-related decreases in the production of melatonin, growth hormone and insulin-like growth factor 1 (IGF-1), and dehydroepiandrosterone (DHEA). The recognition of these decreases has led to the view that administration of these hormones might somehow slow the process of aging. However, there is no scientific evidence that administration of these or any other hormones mitigates, much less reverses, any of the biological changes of aging. (See aging.)

      The most striking age-related change in endocrine function is menopause (see above The ovary (endocrine system, human)). Estrogens (estrogen) are produced by granulosa and interstitial cells, which line the egg-containing ovarian follicles. The depletion of ovarian follicles with age makes a reduction in estrogen secretion inevitable, and this decrease defines the onset of menopause. In postmenopausal women, serum estrogen concentrations decrease by at least 80 percent. This decrease leads to increases in the secretion and serum concentrations of follicle-stimulating hormone and luteinizing hormone. Increases in the secretion and serum concentrations of these hormones provide evidence that the pituitary gland remains functional in normal postmenopausal women, even though ovarian function declines markedly.

The testis
      Serum testosterone concentrations decrease very gradually in men over 70 years of age. This is due to a decrease in the number of androgen-secreting Leydig cells and is accompanied by a gradual decrease in spermatogenesis, although men often remain fertile for many years. In addition, there is a small compensatory increase in gonadotropin secretion. The small decrease in testicular function in older men has been called the “andropause,” but there are no symptoms that can be closely related to the decreases in serum testosterone concentrations. Nor is there evidence that testosterone therapy ameliorates any symptoms in older men in the way that estrogen ameliorates symptoms in postmenopausal women.

Thyroid (thyroid gland) and adrenal (adrenal gland) function
      Thyroid function does not significantly change with age. The clearance of thyroxine and triiodothyronine decreases somewhat and is matched by a decrease in their production. Therefore, serum thyroxine and triiodothyronine concentrations do not change, nor do serum thyrotropin concentrations. As many as 10 to 12 percent of people aged 60 years and older have slightly increased serum thyrotropin concentrations because of mild chronic autoimmune thyroiditis. Similarly, corticotropin and cortisol secretion do not significantly change with age, but serum dehydroepiandrosterone (DHEA) concentrations decrease progressively beginning at about 30 years of age. The cause of the decrease in dehydroepiandrosterone is not known. The secretion of aldosterone also decreases slightly, as does plasma renin activity, but healthy elderly people are able to maintain normal fluid and electrolyte balance. (See above The adrenal cortex (endocrine system, human).)

      Growth hormone secretion and serum insulin-like growth factor 1 (IGF-1) concentrations decrease gradually with age. As compared with young adults, older people have mild deficiency of growth hormone and IGF-1. Deficiency of IGF-1 could help to explain the decrease of muscle mass and the increase in fat mass that occurs in many older people. Whether growth hormone treatment reverses these changes is controversial, and the treatment has important side effects, including increased blood pressure and fluid retention.

Parathyroid hormone and bone
      Parathyroid hormone secretion tends to increase slightly with age, but serum calcium concentrations do not significantly change. The possible reasons for increased secretion of parathyroid hormone include decreased calcium and vitamin D intake (and possibly decreased sun exposure) and decreased kidney function that causes a reduction in the amount of vitamin D that an older individual can absorb.

      Peak bone mass and density occur at about 30 years of age. Thereafter, bone mass declines gradually with age; the decline accelerates during the first years after menopause in women, after which the rate of loss slows but nonetheless continues indefinitely. This loss of bone contributes to the well-known increase in fractures (fracture) that occur in elderly people, especially in women. A very important contributing factor to an increased risk of fracture is an increased likelihood of falls, caused by decreases in muscle strength and coordination. The risk factors for loss of bone in older people include genetic susceptibility, smoking, lean body build, inactivity, calcium and vitamin D deficiency, and estrogen deficiency in women and testosterone deficiency in men.

      Older people tend to have decreased thirst in response to water deprivation and increased basal serum vasopressin (antidiuretic hormone) concentrations. In addition, their kidneys tend to respond less well to vasopressin when compared with younger people. These changes increase the risk of dehydration. On the other hand, if water is available, increased vasopressin secretion may result in an increase in water retention and decreased serum sodium concentrations, leading to hyponatremia.

The pancreatic islets
      Blood glucose concentrations, while usually normal in the fasting state, increase after the ingestion of glucose in increments proportional to the age of the subject. That is, the older the subject, the higher the increase in blood glucose after glucose ingestion. The accompanying increase in insulin secretion, although appreciable, is not sufficient to maintain blood glucose concentrations in the range found in healthy young adults. Whether these changes should be viewed as abnormal or whether they merely reflect modifications appropriate to the aging process remains a matter of debate.

      In summary, endocrine changes in healthy aging people generally do not account for the aging process. The case of the failing ovary excepted, the endocrine glands appear to be able to sustain their major function of supporting a state of health in the face of declining tissue and organ function.

Robert D. Utiger

Additional Reading

Endocrinology
Victor Cornelius, A History of Endocrinology (1982); David G. Gardner and Dolores Shoback, Greenspan's Basic and Clinical Endocrinology, 8th ed. (2007); Jill B. Becker, et al. (eds.), Behavioral Endocrinology, 2nd ed. (2002); Gerald M. Doherty and Britt Skogseid (eds.), Surgical Endocrinology (2001); George H. Greeley, Jr. (ed.), Gastrointestinal Endocrinology (1999); and Jerome F. Strauss and Robert L. Barbieri (eds.), Yen and Jaffe's Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management, 5th ed. (2004).

Endocrine glands
Shlomo Melmed (ed.), The Pituitary, 2nd ed. (2002); Lewis E. Braverman and Robert D. Utiger (eds.), Werner's The Thyroid: A Fundamental and Clinical Text, 9th ed. (2005); and John P. Bilezikian, et al. (eds.), The Parathyroids: Basic and Clinical Concepts, 2nd ed. (2001).

Diabetes and associated conditions
American Diabetes Association Complete Guide to Diabetes, 4th ed. (2005); O. Paul van Bijsterveld (ed.), Diabetic Retinopathy (2000); Aubie Angel, et al. (eds.), Diabetes and Cardiovascular Disease: Etiology, Treatment, and Outcomes (2001); Aristidis Veves (ed.), Clinical Management of Diabetic Neuropathy (1998); and Ronald G. Gill, et al. (eds.), Immunologically Mediated Endocrine Diseases (2002).Robert D. Utiger

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