{hohr'-mohn} Chemical messengers released in minute amounts by ductless \Lgland\ls of human and animal \Lendocrine system\ls are known as hormones. The circulatory system transports these messengers to target tissues, where they produce their effects. Hormones regulate \Thomeostasis\t and the body's responses to external and internal stimuli and also control tissue \Tdevelopment\t, MORPHOGENESIS, and \Treproduction\t. Each hormone is produced at a limited number of sites, and most are released into general circulation. Some hormones, however, produce local (paracrine) effects, such as those associated with the gastrointestinal tract. A hormone is generally characterized by its metabolic effect in specific tissues, such as the action of the \Tsex hormone\t testosterone on male genitals; or by its influence on characteristic physiological phenomena, such as the effect of \Tinsulin\t on blood sugar levels. Scientists are beginning to recognize that individual hormones have a diverse range of activity. Like neural impulses, endocrine secretions may act either to stimulate or to inhibit an organism's function, but unlike neural impulses, hormones often cause longer-lasting effects. Some substances, such as norepinephrine (see \Tnoradrenaline\t), may function as both hormones and \Tneurotransmitter\t agents and are known as neurosecretory hormones. Hormones act as maintenance factors, preserving the structural and functional integrity of various organs; for example, gonadal steroids maintain secondary sex characteristics. As another example, the adrenal cortex atrophies in the absence of ADRENOCORTICOTROPHIC \Thormone\t (\TACTH\t); similarly, without the presence of thyrotropin, or thyroid stimulating hormone (TSH), the \Tthyroid gland\t degenerates. CHEMICAL ORIGIN Most hormones fall into three categories: \Tamine\t, \Tpeptide\t, and \Tsteroid\t. The amines include the thyroid hormones, which are iodinated derivatives of the \Tamino acid\t tyrosine, and the catecholamines epinephrine (see \Tadrenaline\t) and norepinephrine. Thyroid hormones and steroid hormones are water-soluble, whereas epinephrine and norepinephrine resemble the peptide hormones. The latter range in size from thyrotropin-releasing hormone (TRH), with three amino acids, to the \Lgrowth hormone\ls and \Lprolactin\ls, which contain about 200 amino acids. Some hormones, such as TSH and the \Lgonadotrophin\ls, are glycoproteins consisting of carbohydrate and polypeptide subunits. Protein hormones circulate or are stored in the body--often in precursor form--and are reduced to smaller, biologically active forms when utilized, whereas steroid hormones are synthesized as needed. The latter are derivatives of \Tcholesterol\t; they include adrenocorticosteroids, androgens, estrogens, progesterone, and such invertebrate molting hormones as ecdysone. The cyclic fatty acids called \Tprostaglandins\t may also function as hormones. DURATION OF EFFECT Hormones of animals and humans are often bound to blood proteins, which either protect the hormones from premature degradation or, in the case of steroid hormones, make them more soluble in a watery medium. In most cases, the time that an individual hormone molecule circulates in the blood is short, ranging from minutes to hours. The concentration of a circulating hormone is influenced by the uptake, the metabolism, and the inactivation of this substance by target tissues, the liver, and excretory organs. Hormones generally produce short-term effects in target cells by modifying the cells' metabolic activities, and produce long-term effects by activating the cells' genetic capabilities. Changes in membrane permeability, membrane transport processes, and enzyme activity are typical short-term responses. For example, insulin stimulates rapid glucose uptake in skeletal muscle by affecting membrane permeability of muscle cells and by stimulating enzymes that regulate glucose utilization in muscle. Long-term responses of tissues to hormones usually involve the \Lnucleic acid\ls, \TDNA\t and \TRNA\t, as well as protein synthesis; these responses are reflected in varying levels of concentration of membrane receptors for these hormones. Other long-term responses include the amounts of specific enzymes; morphogenic changes, including increased numbers of cells as well as growth; differentiation; maturation of tissues or organs; and alterations of behavior. RECEPTORS Each hormone must bind to specific cellular receptors to initiate psysiological activity. Specificity of hormone action results from the fact that each hormone fits only a specific set of receptors. Receptors are located in the cell plasma membrane for peptide, protein hormones and catecholamines; in the cytoplasm for steroid hormones; and in the nucleus for thyroid hormones. There are between 2,000 and 100,000 peptide hormone receptor molecules per cell, but their number and location in the membrane change in response to tissue needs or hormone concentration. For example, insulin binds to skeletal muscle cells, but as the insulin levels rise the membrane receptors diminish in number--a phenomenon called downregulation. This makes the cells less responsive to high levels of insulin, thereby preventing the adverse effects of hormone excess. (Insulin resistance in type 2 diabetes is due to abnormal downregulation; hence a receptor defect rather than insulin deficiency is the cause of this type of diabetes.) Conversely, the number of receptors increases (upregulation) when hormone levels are low; this makes the tissue more sensitive to the hormone. In addition, some hormones can upregulate receptors belonging to another hormone system, providing for integration of responses by various tissues. SECOND-MESSENGER MOLECULES Many hormonal actions are mediated by "second-messenger" molecules, which are nonhormone chemicals located in the target cells. Earl \TSutherland\t received the 1971 Nobel Prize for medicine or physiology for his work on cyclic adenosine monophosphate (see \Tcyclic AMP\t) and the second-messenger concept, which suggests that hormones bind to cell receptors, which in turn regulate the level of these messengers in the cell. Such nucleotides as cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) are considered second messengers, and many hormonal activities have been correlated with changing concentration levels of these metabolites within body cells. It is known that the hormone epinephrine, as an example, binds to cell receptors in the liver and the heart and induces cAMP to stimulate glycolysis (glucose metabolism). Many hormones interact with receptors to increase the activity of adenyl cyclase, an enzyme that catalyzes the conversion of adenosine triphosphate (\TATP\t) to cAMP. Some hormones inhibit enzymes that degrade cAMP, resulting in increased nucleotide levels in the cell. Protein hormones are believed to bind to receptors located on the surface of a cell membrane; also, they possibly can enter the cell by mechanisms related to pinocytosis (invagination of the cell membrane in order to ingest fluid). Steroids bind to receptors within the cytoplasm, which transfer to the nucleus and attach to specific sites on the chromosomes, the genetic material of the cell. Cytoplasmic and nuclear receptors also bind thyroid hormones. HORMONAL INTERACTION Different types of hormones usually act at the same time on a particular target tissue; the determining factor in how the tissue responds to different hormones generally is the sequence of cell exposure to certain concentration levels of hormones. Also, one type of hormone acting directly on a tissue may exert an indirect influence through another hormone whose secretions affect that tissue. Increased levels of estrogen hormones influence mammary epithelial cells in such a way that the number of estrogen receptors is increased. At the same time, estrogens stimulate secretion of the hormone prolactin, which also stimulates estrogen-receptor production in mammary epithelium. Hormonal interactions range from antagonism, or inhibiting each other's effects, to coordination so as to increase each other's effects (potentiation). As an example of antagonism in frogs, prolactin blocks the effects of thyroid hormone, which normally induces the metamorphosis of tadpoles into frogs. As an example of potentiation, several hormones--such as estrogens, progesterone, adrenal cortical steroids, prolactin, and growth hormone--each have minimal effects on mammary gland development alone. Appropriate combinations of these hormones can interact synergistically (wherein their combined effect is greater than additive) to stimulate mammary development to the point at which milk is produced. In many cases of synergism, the result is attributed to the "permissive" action of one hormone upon the activity of another--a hormone conditions or sensitizes a tissue to the action of another hormone. Most hormones that influence general body metabolism, such as growth hormone, thyroid hormones, and insulin, are synergistic. These hormones may not exert an apparent effect on certain tissues, but they influence the reactions of the tissues to other hormones. EVOLUTION By determining amino-acid sequences of one species' protein and polypeptide hormones and comparing the sequence to those of other species, evolutionary relationships can be traced. Several compounds related to human \Tantidiuretic hormone\t and \Toxytocin\t are found among the vertebrates; many of these compounds vary only by a single amino acid. The similarity of amino-acid sequences in growth hormones, prolactins, and placental lactogens of the same species suggests that all these hormones evolved from an ancestral molecule. Human placental lactogen is structurally similar to human growth hormone, which itself has several effects that resemble those of lactogen; human growth hormone, however, differs immunologically from human prolactin. These hormones have developed unique identities even though their biological activities may overlap. Prolactins of distantly related vertebrates tend to show greater immunologic cross-reactivity with one another than with growth hormones from the same or closely related species. HORMONE CONTROL The function of hormone synthesis and release from endocrine glands is to maintain the body's internal homeostasis despite changes in the external environment. Negative-FEEDBACK regulation is the common mode of control, the simplest form of which is illustrated by parathyroid hormone (PTH). This hormone increases the serum calcium level, which in turn inhibits its PTH synthesis and release. Another example involves the negative-feedback effects of thyroxine. Pituitary TSH stimulates thyroidal secretion of thyroxine, but a high circulating level of thyroxine inhibits pituitary TSH release. Other forms of control involve neural mechanisms that evoke or suppress hormone secretion. The stimulus of a suckling infant, for example, elicits the release of oxytocin, resulting in secretion of milk by the breast. Sexual reproduction requires coordinated endocrine changes controlled by neural inputs to the endocrine system, as well as hormonal modulation of nervous function. Part of this type of neural control is genetically predetermined. HORMONES IN MEDICINE Many hormones or their synthetic analogs are used in medicine. Peptide and protein hormones, such as insulin, must be injected to be effective, because proteins are enzymatically degraded during the digestive process if taken orally. Even some steroid hormones are inactivated by the liver, even though they are absorbed from the intestine in intact form. A hormone molecule can be chemically modified to protect it from enzymatic degradation; thus synthetic steroids are usually more effective than naturally occurring steroids. In some abnormally short individuals, growth failure is the result of pituitary insufficiency. In these cases, growth-hormone-replacement therapy is beneficial. Because growth hormone is species-specific, only human material can be used to treat children. Most human growth hormone is obtained by chemical purification of human pituitary tissue obtained at autopsy, which seriously limits the supply; the association of such extracts with transmission of the rare, fatal brain disease called Creutzfeldt-Jacob disease, in the early 1980s, has also mitigated against use of this source. With the advent of genetic-engineering techniques, however, the monoclonal production of the hormone holds the promise of an unlimited supply in the future. \TAddison's disease\t, or adrenal cortical deficiency, can be treated with adrenocorticosteroids. Such drugs include various glucocorticoid drugs. These drugs, however, are most often used in pharmacological dose levels for the treatment of a variety of other disorders. For example, approximately 7 million people in the United States take glucocorticoid drugs for their antiinflammatory effect, as in the treatment of arthritis, or for their antiallergy effect, as in the treatment of asthma. The drugs have serious side effects, after long-term use, and are usually used as the medication of last choice. Hypothyroidism is a serious problem, particularly for the newborn infant, because thyroid hormones are required for maturation of the central nervous system. Treatment with the hormone thyroxine averts the effects of hypothyroidism, provided the treatment is started during the early neonatal period. Thyroxine has also been advocated by some for the treatment of obesity or for feelings of lethargy, but such use is probably unwarranted, because there is a compensatory reduction in the amount of thyroxine produced by the thyroid gland equal to the amount administered. In addition, at pharmacological doses a patient may suffer from heat intolerance, nervousness, or even more serious consequences of hyperthyroidism. Among the other hormones used in medicine are those of the posterior pituitary gland: ADH and oxytocin. The former is used in the treatment of diabetes insipidus, the latter in some obstetrical cases to aid parturition. The use of insulin in the treatment of insulin-deficiency diabetes mellitus is well known. Normally a combination of long- and short-acting preparations are used; the long-acting form provides a low background level of insulin throughout the day, whereas the short-acting form is injected during periods of greater need, such as after a large meal. Calcitonin is used in the treatment of \TPaget's disease\t, a condition characterized by abnormally rapid turnover of skeletal tissue; the drug acts by inhibiting the rate of skeletal resorption. Calcitonin is also used in the treatment of a form of congenital \Tosteoporosis\t in children called osteogenesis imperfecta. The hormone vitamin D is used in the treatment of deficiency diseases such as rickets in children and osteomalacia in adults; it is also used in the treatment of hypoparathyroidism. A new group of genetically engineered hormones are beginning to play a major role in medicine. For example, hematological growth factors stimulate the bone marrow to make red or white blood cells in any quantity desired. One type, called erythopoietin, stimulates red blood cell production and is being used to treat various forms of anemia. Colony-stimulating factor, which stimulates white blood cells, is used in bone marrow transplants and in patients undergoing chemotherapy for cancer. Estrogen and progesterone have been used in the \Tbirth control\t pill since the 1960s. An antiprogesterone steroid, RU-46B, which interrupts pregnancy at a very early stage, was developed in 1980 and approved for use in France in 1988. The hormone is safer and cheaper than surgical \Tabortion\t and it may also prove useful in treating breast cancer and other illnesses. Because of concern over antiabortionist reaction, however, American drug companies have not applied for approval from the Food and Drug Administration to market the drug. INVERTEBRATE HORMONES Many invertebrates, such as insects and crustaceans, secrete hormones from endocrine glands; they also secrete neurohormones, which are basically polypeptides or proteins secreted by cells of the central nervous system. One type of ergone stimulates larval molting by inducing the corpora allata glands to secrete \Tjuvenile hormone\t. Other insect neurosecretions stimulate metamorphosis by inducing the prothoracic gland to secrete ecdysone. A similar molting process occurs in crustaceans, involving the Y-gland and molting hormone. Reviewed by Seiichi Yasumura Bibliography: Buckle, J. W., Animal Hormones (1983); Dufy-Barbe, Luce, "Hypothalamic Hormones," Endeavor 9, no. 1 (1985); Metz, Robert, and Larson, E. B., Blue Book of Endocrinology (1984); Roth, Jesse, et al., "Evolutionary Origins of Hormones, Neurotransmitters, and Other Extracellular Chemical Messengers," New England Journal of Medicine, Mar. 4, 1982; Villee, C. A., Jr., Human Hormones (1987); Wigglesworth, V. B., Insect Hormones, rev. ed. (1983).