hormone

hormone
—hormonal, hormonic /hawr mon"ik, -moh"nik/, adj.
/hawr"mohn/, n.
1. Biochem. any of various internally secreted compounds, as insulin or thyroxine, formed in endocrine glands, that affect the functions of specifically receptive organs or tissues when transported to them by the body fluids.
2. Pharm. a synthetic substance used in medicine to act like such a compound when introduced into the body.
3. Bot. Also called phytohormone. any of various plant compounds, as auxin or gibberellin, that control growth and differentiation of plant tissue.
[1900-05; < Gk hormôn (prp. of hormân to set in motion, excite, stimulate), equiv. to horm(é) HORME + -on prp. suffix, with ending assimilated to -ONE]

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Organic compound (often a steroid or peptide) that is produced in one part of a multicellular organism and travels to another part to exert its action.

Hormones regulate physiological activities including growth, reproduction, and homeostasis in vertebrates; molting and maintenance of the larval state (see larva) in insects; and growth, bud dormancy, and leaf shedding in plants. Most vertebrate hormones originate in specialized tissues (see endocrine system; gland) and are carried to their targets through the circulation. Among the many mammalian hormones are ACTH, sex hormones, thyroxine, insulin, and epinephrine. Insect hormones include ecdysone, thoracotropic hormone, and juvenile hormone. Plant hormones include ethylene, abscisin, auxins, gibberellins, and cytokinins.

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Introduction

      organic substance secreted by plants and animals that functions in the regulation of physiological activities and in maintaining homeostasis. Hormones carry out their functions by evoking responses from specific organs or tissues that are adapted to react to minute quantities of them. The classical view of hormones is that they are transmitted to their targets in the bloodstream after discharge from the glands that secrete them. This mode of discharge (directly into the bloodstream) is called endocrine (endocrine system) secretion. The meaning of the term hormone has been extended beyond the original definition of a blood-borne secretion, however, to include similar regulatory substances that are distributed by diffusion across cell membranes instead of by a blood system.

General features

Relationships between endocrine and neural regulation
      Hormonal regulation is closely related to that exerted by the nervous system, and the two processes have generally been distinguished by the rate at which each causes effects, the duration of these effects, and their extent; i.e., the effects of endocrine regulation may be slow to develop but prolonged in influence and widely distributed through the body, whereas nervous regulation is typically concerned with quick responses that are of brief duration and localized in their effects. Advances in knowledge, however, have modified these distinctions.

 Nerve cells (neuron) are secretory, for responses to the nerve impulses that they propagate depend upon the production of chemical transmitter substances, or neurohumors, such as acetylcholine and noradrenaline (norepinephrine), which are liberated at nerve endings in minute amounts and have only a momentary action. It now has been established, however, that certain specialized nerve cells, called neurosecretory cells (neurosecretory cell), can translate neural signals into chemical stimuli by producing secretions called neurohormones (neurohormone). These secretions, which are often polypeptides (compounds similar to proteins but composed of fewer amino acids), pass along nerve-cell extensions, or axons, and are typically released into the bloodstream at special regions called neurohemal organs, where the axon endings are in close contact with blood capillaries (Figure 1A—>). Once released in this way, neurohormones function in principle similar to hormones that are transmitted in the bloodstream and are synthesized in the endocrine glands.

 The distinctions between neural and endocrine regulation, no longer as clear-cut as they once seemed to be, are further weakened by the fact that neurosecretory nerve endings are sometimes so close to their target cells that vascular transmission is not necessary (Figure 1B—>). There is good evidence that hormonal regulation occurs by diffusion in plants and (although here the evidence is largely indirect) in lower animals (e.g., coelenterates), which lack a vascular system.

The evolution of hormones
      Hormones have a long evolutionary history, knowledge of which is important if their properties and functions are to be understood. Many important features of the vertebrate endocrine system, for example, are present in the lampreys and hagfishes, modern representatives of the primitively jawless vertebrates (Agnatha (agnathan)), and these features were presumably present in fossil ancestors that lived more than 500,000,000 years ago. The evolution of the endocrine system in the more advanced vertebrates with jaws (Gnathostomata) has involved both the appearance of new hormones and the further evolution of some of those already present in agnathans; in addition, extensive specialization of target organs has occurred to permit new patterns of response.

      The factors involved in the first appearance of the various hormones is largely a matter for conjecture, although hormones clearly are only one mechanism for chemical regulation, diverse forms of which are found in living things at all stages of development. Other mechanisms for chemical regulation include chemical substances (so-called organizer substances) that regulate early embryonic development and the pheromones that are released by social insects as sex attractants and regulators of the social organization. Perhaps, in some instances, chemical regulators including hormones appeared first as metabolic by-products. A few such substances are known in physiological regulation: carbon dioxide, for example, is involved in the regulation of the respiratory activity of which it is a product, in insects as well as in vertebrates. Substances such as carbon dioxide are called parahormones to distinguish them from true hormones, which are specialized secretions.

The hormones of vertebrates

Hormones of the pituitary gland
 The pituitary gland, or hypophysis (Figure 2—>), which dominates the vertebrate endocrine system, is formed of two distinct components. One is the neurohypophysis, which forms as a downgrowth of the floor of the brain and gives rise to the median eminence and the neural lobe; these structures are neurohemal organs. The other is the adenohypophysis, which develops as an upgrowth from the buccal cavity (mouth region) and usually includes two glandular portions, the pars distalis and the pars intermedia, which secrete a number of hormones. The hormones secreted by the adenohypophysis are protein or polypeptide in nature and vary in complexity; as a result, their chemical constitution has not always been as fully characterized as has that of structurally simpler molecules of some other endocrine secretions. Functional analysis of these hormones also is difficult, for the targets of certain hormones of the adenohypophysis, called tropic, or trophic, hormones, are other endocrine glands. The action of such tropic hormones can be understood only in the light of the mode of function of the endocrine glands they regulate.

      Growth hormone is a protein, the primary structure of which has been fully established for the human and bovine forms of the hormone. It is probably universally distributed in gnathostomes (vertebrates with jaws), in which it is essential for the maintenance of growth, but its presence in agnathans (jawless vertebrates) has not yet been established with certainty. The physical and chemical properties of growth hormone ( Table 1), which differ from species to species, are associated with marked differences in biological activity. Only part of the molecule, however, is actually responsible for its biological activity, for up to 25 percent of it can be lost without causing any decline in potency. Man responds to growth hormones obtained from other primates, but the rat responds to those from a wide range of species. Even more striking, growth of teleost (bony) fishes, which stops if the pituitary gland is removed, can be restarted by treatment with mammalian growth hormone; on the other hand, preparations of pituitary glands from these fishes have no effect on the growth of mammals. The growth hormones of lungfishes, which are closely related to the terrestrial vertebrates, and of sturgeons, which are primitive members of the evolutionary line that led to bony fishes, affect mammalian growth, perhaps because these hormones have a more generalized molecular structure.

      Growth is such a complex process that definition of the growth hormone's mode of action is difficult. One of its known effects is an increase in the rate of protein synthesis, which is to be expected, since growth involves the deposition of new protein material. In addition, growth hormone affects the metabolism of certain ions (including sodium, potassium, and calcium), promotes the release of fats from fat stores, and influences carbohydrate metabolism in ways that tend to cause an increase in the level of glucose in the bloodstream. The last action creates a demand for an increased output of insulin (a hormone secreted by the pancreas), which acts to return the blood-glucose level to normal. Prolonged treatment of dogs with growth hormone can overstrain the pancreatic tissue in which insulin is synthesized and bring about a diabetic (diabetes mellitus) condition, in which insulin is formed in inadequate quantities. It is unlikely, however, that this is a factor in establishing diabetes mellitus in man. Excess secretion of growth hormone does, however, have damaging effects in man, for it produces overgrowth of the skeleton. If this occurs in youth, before the closure of the epiphyses (ends) of the long bones, it results in gigantism. If it occurs afterward, it causes acromegaly, in which the disturbance is more serious, with enlargement of the bones and soft tissues, and consequent distortion of the skull.

      Prolactin is a protein hormone that in sheep has a molecular weight of about 23,000 (based on a molecular weight for hydrogen of one). It is doubtful that it is present in agnathans, but it is widely distributed in jawed vertebrates. In female mammals, prolactin initiates and maintains the secretion of milk, the mammary glands having been previously prepared for this function by the action of other hormones. In the female rat prolactin also maintains the secretion of the hormone progesterone, which is formed by the corpus luteum, an endocrine gland of the ovary; i.e., prolactin, termed luteotropin in the rat, is a gonadotropin (see below Hormones of the reproductive system (hormone)) in this animal, because its target is an endocrine gland. Evidence is accumulating that the molecular structures of prolactin and growth hormone are similar. This explains why they show some overlap in biological properties; in particular, administration of prolactin promotes some growth in many terrestrial vertebrates. Human growth hormone has prolactin-like luteotropic properties, and it is not yet certain that man actually has a distinct prolactin hormone.

      Prolactin itself shows remarkable variety in biological action from one vertebrate group to another. It promotes the production of so-called crop-milk with which pigeons feed their young, and the associated changes in structure and arrangement of the wall of the crop provide a convenient means to assay the hormone. In certain newts (Triturus species) prolactin induces the change of behaviour that drives young animals into the water (water-drive action). In bony fishes, prolactin is concerned with the regulation of the level of sodium in blood plasma; it therefore is essential in some teleost species (e.g., Poecilia lattipinna) for the maintenance of life in fresh water. Although other teleosts (e.g., eels) can survive in fresh water after hypophysectomy, this means only that prolactin is but one factor in a complex regulatory mechanism involving several factors. Mammalian prolactin can regulate sodium metabolism when given to eels and can maintain the life of hypophysectomized Poecilia. Yet, although other convincing evidence suggests that the hormone must be present in the pituitaries of these teleosts, preparations of their glands tested on pigeons do not have a typical crop-stimulating action. This evidence is best accounted for by supposing that the prolactin molecule has undergone evolutionary changes in its molecular structure and biological properties with respect to particular species and has also established specific adaptive relationships with target organs such as the crop and mammary glands.

      ACTH is present in all jawed vertebrates but has not yet been decisively demonstrated in agnathans. It regulates the activity of part of the outer region (cortex) of the adrenal glands (considered below under Hormones of the adrenal glands). In mammals its action on the adrenal cortex is limited to areas called the zona reticularis and zona fasciculata, in which important steroid hormones (e.g., cortisol and corticosterone, known as glucocorticoids) are formed; ACTH does not affect the synthesis of the mineralocorticoid hormone aldosterone, which takes place chiefly in the outer cortical region (zona glomerulosa). Evidence strongly suggests that the action of ACTH is mediated by a substance known as CAMP (cyclic 3′,5′-adenosine monophosphate), the rate of synthesis of which increases in adrenal tissue in the presence of ACTH; CAMP in turn promotes synthesis of enzymes necessary for the formation of cortisol and corticosterone. The relationship between ACTH and the adrenal cortex is an example of the negative feedback characteristic of endocrine systems; i.e., a decrease in the level of glucocorticoids circulating in the bloodstream evokes an increase in the secretion of ACTH, which, by stimulating the secretory activity of its target gland (the adrenal cortex), tends to restore to normal the level of glucocorticoids in the bloodstream. The release of ACTH can also be influenced by the level of circulating adrenaline, which is not surprising in view of the close functional relationship between the hormones of the adrenal cortex and medulla.

      The ACTH of mammals is a polypeptide molecule consisting of 39 amino acids, only the first 20 of which are required for full activity. This region, often referred to as the active centre, is constant in composition in all mammals studied thus far; the remainder of the molecule varies slightly in amino-acid composition among different species. Since, however, the mammalian hormone is active in all vertebrates, ACTH structure probably varies little from one class to another. The concept that biological activity is localized in an active centre of a complex molecule is applicable to other polypeptide and protein hormones, including growth hormone, whose structure, as noted previously, can be partly lost without causing loss of activity. The concept of an active centre, however, raises the question of the function of the rest of the molecule. It may serve as the site of antigenic properties or of structural features important in establishing relations with specialized receptors in target cells.

      Thyrotropin regulates the thyroid gland through a feedback relationship similar to that for ACTH; thyrotropin increases the secretion of the hormones from the thyroid gland and, if its action is prolonged, evokes increase in cell number (hyperplasia) and increase in size of the gland. One consequence of an overactive thyroid in man is a bulging of the eyes ( exophthalmos). The cause of this is obscure, although it has been thought to result from the action of a distinct exophthalmos-producing substance that, while closely associated with thyrotropin, can be chemically separated from it. Thyrotropin, which is probably absent from agnathans, is a glycoprotein; i.e., a protein combined with carbohydrate. Its molecular weight is estimated to be about 26,000 to 30,000 in mammals. Some variability occurs in the degree of response obtained when a hormonal preparation from one species is tested on other species. This suggests, as with prolactin, that it has undergone molecular evolution.

      FSH is termed a gonadotropin because it is concerned with the regulation of the activity of the gonads, or sex organs, which are endocrine glands as well as the sources of eggs and sperm. FSH stimulates development of the graafian follicle, a small vesicle containing an egg, in the ovary of the female mammal; in the male, it promotes the development of the tubules of the testes and the differentiation of sperm. FSH, like thyrotropin, is a glycoprotein, with an estimated molecular weight (in man) of 41,000 to 43,000. The effects of FSH are discussed further in Hormones of the reproductive system (hormone), below.

luteinizing hormone (LH; interstitial-cell-stimulating hormone; ICSH)
      Luteinizing hormone is another gonadotropin, a glycoprotein with a molecular weight of 26,000 in man. In the female mammal it promotes the transformation, following release of the egg (ovulation), of the graafian follicle into the corpus luteum, an endocrine gland; its complex functional interrelationship with FSH is dealt with below in Hormones of the reproductive system (hormone). In the male, luteinizing hormone promotes the development of the interstitial tissue (Leydig cells) of the testes and hence promotes the secretion of the male sex hormone, testosterone. It may be associated with FSH in this function. The interrelationship of LH and FSH has made it difficult to establish with certainty that two separate hormones exist, particularly since both are glycoproteins. Although the existence of two hormones has been established in mammals, the situation in lower vertebrates is not yet certain. All vertebrates undoubtedly have gonadotropic activity in their pituitary glands; but, although FSH-like and LH-like effects are detectable, it is not yet clear that two distinct hormones always exist.

      An unexpected property of mammalian FSH and LH is that both have a thyrotropic action (i.e., stimulate secretion of thyroid hormones) in lower vertebrates. This so-called heterothyrotropic effect has led to the supposition that FSH, LH, and thyrotropin may have evolved by modification of a common ancestral glycoprotein molecule, resulting in an overlap of properties. Similar examples are pointed out in later sections.

      This hormone, secreted by the pars intermedia region of the pituitary gland, regulates colour changes in animals by promoting the concentration of pigment granules in pigment-containing cells (melanocytes, chromatophores (chromatophore)) in the skin of lower vertebrates; MSH acts in conjunction with the nervous system in bony fishes and reptiles. No response involving physiological colour change is found in birds and mammals, although the hormone is secreted by them, even in species in which a pars intermedia region is no longer distinguishable in the adenohypophysis. The reason for the presence of MSH in birds and mammals is not clear since the function of the hormone in these animals has not yet been established. MSH is known to influence the behaviour of mammals and the total amount of pigment in their skin, which darkens in man after administration of large doses of the hormone. This type of change, however, which results from a change in the total amount of pigment present, is called a morphological colour change, in contrast to the physiological one that occurs in the skin of lower vertebrates.

      As noted above, MSH exists in two forms. α-MSH contains 13 amino acids, which are found in the same sequence in all species studied thus far; β-MSH has 18 amino acids, in sequences that differ in different species. Remarkable are the facts that the 13 amino acids of α-MSH are identical with the first 13 amino acids of ACTH and that both α and β forms of MSH have a heptapeptide (seven-amino-acid) sequence that has some melanocyte-stimulating activity, and that is identical with an amino-acid sequence of ACTH. This close correspondence in sequence can hardly be coincidental and suggests, as has been postulated above for FSH, LH, and thyrotropin, that ACTH and α- and β-MSH may have differentiated within the adenohypophysis by evolutionary modification of a common ancestral molecule. A change in biological activity results from modifications in the amino-acid composition; β-MSH preparations from the pig and the horse, for example, are five times more effective than those of the ox in evoking pigment dispersion in frogs. MSH molecules do not show ACTH activity, which is dependent on the presence of amino acids that occur in the region of the molecule not found in MSH. On the other hand, ACTH does have a slight effect on pigment dispersion, presumably because its structure contains the heptapeptide sequence mentioned above.

      Evidence shows that each of the adenohypophysial hormones is secreted by a specific cell type. The cell types can be differentiated by staining sections of the pituitary gland, and known changes in the output of an individual hormone, induced experimentally or correlated with phases in the life cycle, can be shown to correspond with changes in the appearance of the corresponding cell type.

      The regulation of the activity of the secretory cells of the adenohypophysis depends upon its association with the floor of the brain and results from the existence of a neurosecretory system located mainly, perhaps entirely, in the hypothalamic region there. Much remains to be learned about this system, which involves the passage into the adenohypophysis of neurosecretions from the hypothalamus called hypothalamic releasing factors. Chemical characterization of these factors shows them to be simple polypeptides, in which respect they resemble the hypothalamic polypeptide hormones (discussed in the next section). This neurosecretory system is best understood in mammals, in which good evidence has been found for the existence of a separate releasing factor for each hormone secreted by the pars distalis region of the adenohypophysis; a similar arrangement probably exists in other gnathostomes. The situation in agnathans is obscure, but the anatomical organization of the pituitary glands of these animals implies at least some form of chemical communication between the hypothalamus and the pituitary gland.

 Chemical communication is achieved by two routes. One route is by the entry of neurosecretory-cell fibres from the hypothalamus into the adenohypophysis, so that the hypothalamic factors, when released, are either in immediate contact with the secretory cells (Figure 1B—>) or in blood capillaries very closely related to them. This route is characteristic of the pars intermedia region, in which neurosecretory fibres from the hypothalamus control the functioning of the secretory cells. If the pars intermedia is separated from its direct connection with the floor of the brain, for example, MSH secretion in amphibians increases, and prolonged darkening of the skin results. Secretory activity of the pars intermedia cannot then be regulated again until the nerve fibres have regenerated.

  Direct innervation similar to that of the pars intermedia is also found in the pars distalis of bony fishes. Here neurosecretory fibres arise from a localized region of the hypothalamus, called the nucleus lateralis tuberis, and end in contact either with the various types of secretory cells or with blood capillaries related to them. The other route of chemical communication to the pars distalis is found in many fishes and in all terrestrial vertebrates; it is a vascular route that depends upon the median eminence, which lies at the front end of the neurohypophysis (see Figure 2—>). The median eminence is a neurohemal organ containing a capillary bed into which hypothalamic neurosecretory fibres discharge their releasing factors. These are then transmitted through blood vessels known as the hypophysial portal system, into the capillaries of the pars distalis, where each factor influences its specific target cells (compare Figure 1A—>).

      Both hypothalamic neurosecretory routes have the same physiological significance; i.e., they provide chemical communication between the adenohypophysis and the central nervous system, thus making it possible for the latter to regulate the activity of the gland (and also of the endocrine glands its tropic hormones influence) in response to the demands of both the internal and external environments. The hypothalamic neurosecretory system is also involved in the function of the negative-feedback mechanisms that regulate the secretion of the tropic hormones. As already mentioned for ACTH, the secretions of tropic hormones from the adenohypophysis are controlled by bloodstream levels of the hormones secreted by their target glands; the hormones of the target glands may act directly on specific adenohypophysial cells or indirectly by influencing the output of releasing factors from the hypothalamus.

Neurohypophysis and the polypeptide hormones of the hypothalamus
 Another neurosecretory system, which involves the hypothalamic region of the brain and the neurohypophysis of the pituitary gland, originates in groups of neurosecretory cells in the hypothalamus called, in mammals, the nucleus supraopticus and the nucleus paraventricularis and, in lower vertebrates, the nucleus preopticus. Neurohormones from these regions pass along the axons of the neurosecretory cells to the neural lobe (see Figure 2—>) bound to a protein called neurophysin (molecular weight of 20,000 to 25,000). In the neural lobe, which is the neurohemal organ of this neurosecretory system, the hormones separate from neurophysin and are released into the bloodstream.

 In most mammals, the neurohormones are oxytocin and arginine vasopressin. Both have relatively simple and very similar molecular structures; each is composed of nine amino acids arranged as a ring, which is formed by the linkage of two molecules of the amino acid cysteine (a disulfide linkage −S−S−), and a short side chain (Table 2—>). The two hormones differ in structure only at amino acids numbered 3 and 8. In some species of the family Suidae (pig, peccary, hippopotamus) arginine vasopressin is replaced by lysine vasopressin; in others, both may be present. The difference between the two vasopressin hormones is that one has the amino acid lysine (Lys) at position 8; the other has arginine (Arg). Both the vasopressins and oxytocin show some overlap of activity, which is a consequence of the similarities in their molecular structures. Preparations of the three hormones evoke responses from the mammalian kidney, from the epithelial-cell layer of the frog bladder, and from the smooth muscle in blood vessels, uterus, and milk glands. The slight variation in amino-acid composition, however, affects the levels of the responses; i.e., the vasopressins differ slightly from each other in response, and oxytocin differs markedly from both. Each, therefore, is said to have a characteristic pharmacological spectrum, and all have some medical use.

      The primary actions of oxytocin are the promotion of uterine contraction (of value in obstetrical medicine) and the release of milk during suckling. The stimulation exerted upon the nipples during suckling leads to the transmission of nerve impulses to the hypothalamus. These bring about the discharge of oxytocin, which causes contraction of the smooth muscle of the small ducts of the mammary glands (mammary gland) and the release of milk. Although the vasopressins cause an increase in blood pressure in mammals through vasoconstriction (i.e., contraction of blood vessels), this action requires a high concentration of hormone and is probably not a normal physiological effect. The primary action of the vasopressins is on the kidneys; it brings about a reduction in the output of urine. As a result arginine vasopressin is commonly called the antidiuretic hormone (ADH). A lack of this hormone in man results in a copious flow of urine, a condition called diabetes insipidus, which is readily alleviated by preparations containing arginine vasopressin from bovine sources.

      The antidiuretic action of vasopressin is thought to depend upon its binding to the outer surface of the kidney tubule, resulting in an increase in the uptake of sodium from the urine into the tubule cells and, concurrently, an increase in the uptake of water. The amount of water, however, is greater than can be accounted for merely by increased diffusion of sodium into tubule cells, suggesting that ADH increases either the number of or the size of pores on the surfaces of the cells. One stimulus that increases the release of vasopressin is a rise in the concentration of certain substances—chloride, for example—in blood plasma. These substances act directly upon the neurosecretory cells, although other receptors may also be involved. Another stimulus is a lowering of plasma volume, which probably acts chiefly through receptors in the vascular system, particularly in the heart and in the carotid blood sinuses. Both conditions necessitate increased retention of fluid; as soon as normal conditions are restored in the bloodstream, the secretion of ADH is reduced by negative feedback.

 Oxytocin and the vasopressins are members of a series of hormones of which seven members have thus far been fully characterized. The existence of others is suspected (see Table 2—>). All show the same molecular structure but differ with respect to individual amino acids. The hormones are believed to have been derived from each other by mutations that resulted in one amino-acid substitution at a time; the starting point in the series is arginine vasotocin, which is the only one of the series found in agnathans. Two types of molecule are found in gnathostomes—a result, presumably, of a genetic duplication that established two lines of evolution. One line (basic vasopressor principles) is constituted mainly of arginine vasotocin, which is present in all gnathostomes except mammals; amino-acid substitution in the molecule gave rise to the vasopressins of mammals. The second line (neutral oxytocin-like principles) is represented by oxytocin, isotocin, glumitocin, and mesotocin. Each evolutionary line tends to have characteristic molecules, but the molecular history in the second line is not clear. Oxytocin is thought to exist in some lower gnathostomes, and it is not yet certain whether it or mesotocin is phylogenetically the older molecule.

      The functions of the hypothalamic polypeptide hormones in lower vertebrates are not yet clear, except to some extent in amphibians, in which arginine vasotocin evokes the so-called Brunn (water-balance) response; that is, water accumulates within the body as a result of a combination of increased water uptake through the skin and the wall of the bladder and decreased urinary output. This response, which also involves the uptake of sodium by the skin, is found only in the more terrestrial members of the Amphibia, in which it is an adaptation that enables them to conserve water. It is not yet known whether or not comparable adaptive specializations are associated with the molecules characteristic of the other groups of lower vertebrates. There is some evidence that hypothalamic polypeptides may be involved in the movements of water and ions (charged particles) in fishes. Changes in the functions of the polypeptide hypothalamic hormones during vertebrate evolution have occurred, partly as a result of evolution of their targets; e.g., water balance in amphibians is mediated by a hormonal molecule that was already present in agnathans and was thus a part of the earliest hormonal endowment of vertebrates.

Hormones of the thyroid gland
      The two thyroid hormones, thyroxine (3,5,3′,5′-tetraiodothyronine) and 3,5,3′-triiodothyronine, are formed by the addition of iodine to an amino-acid (tyrosine) component of a glycoprotein called thyroglobulin. Thyroglobulin is stored within the gland in follicles as the main component of a substance called the thyroid colloid. This arrangement, which provides a reserve of thyroid hormones, perhaps reflects the frequent scarcity of environmental iodine, particularly on land and in fresh water. Iodine is most abundant in the sea, where thyroidal biosynthesis probably first evolved. Although the possibility that the thyroid hormones originated as metabolic by-products is suggested by the widespread occurrence in animals of the binding of iodine to tyrosine, the binding commonly results only in the formation of iodotyrosines, not the thyroid hormones. On present evidence, only the vertebrates and the closely related protochordates have a mechanism to synthesize significant amounts of biologically active thyroid hormones.

      The synthesis of thyroid hormones in vertebrates begins with the active uptake by thyroid-gland cells of inorganic iodide circulating in the bloodstream; the inorganic iodide is oxidized (combined with oxygen) during a reaction catalyzed by an enzyme (iodide peroxidase). The product of this reaction (active iodine) combines with tyrosine components of the thyroglobulin molecule to form two compounds (3-monoiodotyrosine and 3,5-diiodotyrosine), which then join to form the active hormones. The synthesis of the thyroid hormones is inhibited by certain chemical agents called goitrogens, which reduce the output of thyroid hormones, thereby causing, through negative feedback, an increased output of thyrotropin and hence an enlargement of the thyroid gland (see below). Some goitrogens (e.g., thiocyanates) reduce or inhibit the uptake of iodide; others (e.g., thiourea, thiouracil) inhibit the peroxidase system and thus prevent the binding of iodine to thyroglobulin.

      Release of the thyroid hormones into the bloodstream begins when the thyroid cells take up droplets of the stored thyroid colloid. The thyroglobulin in these droplets is then hydrolyzed (broken down in a reaction involving the elements of water) by an enzyme to form both iodotyrosines and the hormones. Normally, only the latter pass out of the cells in significant quantities. The iodine is removed from the iodotyrosines, which are not hormonally active, by an enzyme (deiodinase), and the iodine thus is conserved and used again. The hormones, usually bound to proteins (globulin and albumin) in the bloodstream, where they constitute the protein-bound iodine of the plasma, must be unbound from the proteins before they can function. The iodine is removed from the hormones largely in the liver and in the kidneys, and most of it returns to the thyroid gland, an economy that again emphasizes the need for conservation; some iodine, however, is lost in the alimentary tract.

      Synthesis of the thyroid hormones is regulated by the level of circulating hormones (i.e., a negative-feedback mechanism) operating, as indicated earlier, partly by direct action on the thyrotropin-secreting cells of the pituitary gland and partly by indirect action on the hypothalamus and its thyrotropin-releasing factor. Thyrotropin attaches to the cells of the thyroid gland and may exert its effect by stimulating CAMP synthesis. It causes resorption of thyroid colloid and increases the rates of both glucose metabolism and protein synthesis as secretion of thyroid hormones increases in response to it. After the thyroid gland of the rat has been under thyrotropin stimulation for two or three hours, an increase in the size of the cells of the gland occurs, along with an increase in iodide uptake into them; prolonged thyrotropin action causes a marked enlargement of the gland ( goitre), which in man may become externally apparent as a swelling. Goitres, which are of various types, result from a negative-feedback reaction that attempts to maintain output from the thyroid gland.

      One established effect of the thyroid hormones in mammals is an increase in metabolic rate and in oxygen consumption, but the effects of the hormones undoubtedly are more wide-ranging than this. On the one hand, impairment of the thyroid function in mammals results in disturbances in the processes of growth and maturation. Both growth and maturation disturbances occur in the cretinous dwarfism resulting from thyroid deficiency in newborn infants; on the other hand, the metabolic effect is not apparent in lower vertebrates (e.g., fish), even though treatment of these animals with thyroid hormones promotes an increase in the growth rate, provided pituitary growth hormone is also secreted. In addition, evidence suggests that, in lower vertebrates, the thyroid hormones are active during moments of stress in the life cycle (e.g., migration and reproduction) and affect the activity of the central nervous system. Disturbance of thyroid output also affects reproduction in mammals, impairing the functioning of the ovary, for example, and causing irregularities of the ovarian cycle.

      The complex effects of thyroid hormones are well documented in the metamorphosis, or change in body form, of the amphibian tadpole into a frog. Metamorphosis, which involves a diversity of integrated morphological and biochemical changes, requires the presence of the thyroid gland and depends upon a delicate balance between the changing output of its hormones and changing sensitivities of the target tissues. Studies involving the tail of the frog tadpole show that the thyroid hormones directly promote the formation of the enzymes needed for reduction of the tail and suggest that the diverse effects produced in vertebrates by the thyroid hormones might depend upon their capacity to regulate protein metabolism, in which case the target cells would have to be adapted to respond by appropriate patterns of enzyme synthesis.

Ultimobranchial tissue and calcitonin
      The discovery of calcitonin (thyrocalcitonin) in 1961 demonstrated the importance of comparative studies in endocrinology. It originally had been thought that this hormone, which is present in preparations made from mammalian thyroid glands, was secreted by the parathyroid glands, which in some species are combined with the thyroid gland. Later, the hormone was concluded to be a secretion of the thyroid gland itself. In fact, calcitonin is not a product of either of them. Its actual source is the ultimobranchial tissue, represented in vertebrates from fishes upward by the ultimobranchial gland, which develops from the hinder part of the pharynx. Ultimobranchial tissue is the source of distinctive cells (called light, C, or parafollicular cells), which are found in the thyroid gland of mammals; in birds, however, the ultimobranchial gland is separate, thus making it possible to remove the gland and to show that it is the source of the hormone. The molecular structure of hog calcitonin is that of a polypeptide, containing 32 amino acids and having a molecular weight of about 3,600. The calcitonin of the salmon, which is more potent than that of the pig, has the same number (but some different types) of amino acids, and the molecular weight is 3,427.

      Calcitonin lowers the level of calcium in the blood (hypocalcemic action) when it rises above the normal level. Its secretion probably is regulated by a negative-feedback relationship between the gland and the blood plasma. The hormone affects bone, which is an active tissue. It undergoes not only growth but also remodelling as it adapts to the changing patterns of stress to which it is subjected; its calcium exchanges continuously with that of the plasma. The effect of calcitonin is to decrease the mobilization (resorption) of calcium from the skeleton into the blood plasma. In this respect, as is discussed in the next section, it is opposite in direction to the effect of parathormone of the parathyroid glands. Little is known of the action of calcitonin in the lower vertebrates, but its presence in fish raises interesting functional problems. Elasmobranch fishes (e.g., sharks) lack bone, and many bony fishes have a type of bone that cannot be remodelled; the hormone, therefore, cannot act in these vertebrates as it does in higher ones. It is possible that in these fishes the hormone may control the level of plasma calcium by regulating its movement across cell membranes.

Parathormone of the parathyroid gland
      The parathyroid glands, which are found only in terrestrial vertebrates (amphibians, birds, reptiles, and mammals), develop from certain pharyngeal pouches, which are embryonic remnants of the gill slits of fish. The parathyroid glands secrete a hormone called parathormone (PTH), which is a polypeptide of variable amino-acid composition. PTH, which consists of 83 to 85 amino acids in the human, regulates calcium metabolism in conjunction with calcitonin; its evolution in terrestrial vertebrates may have been an adaptation to the increased demand for continuous skeletal adjustments imposed by the evolution of terrestrial locomotion. Skeletal adjustments must be made without disturbing the delicate calcium balance of the rest of the body, for calcium is involved in maintaining the transport of substances through cell membranes; hence, it has an important role in muscle contractility, excitability of motor end plates in the nervous system, and coagulation of blood.

      Removal of the parathyroid glands in mammals causes a fall in the level of calcium in the blood plasma, which, if sufficiently severe, is accompanied by convulsions and other symptoms resulting from increased excitability of the motor nerves. These symptoms can be corrected by injection of appropriate preparations of parathyroid glands. The activity of the glands, like that of the ultimobranchial tissue, is regulated by negative feedback; i.e., lowering of the plasma calcium level increases the output of parathormone (but decreases the output of calcitonin). The hypercalcemic effect (i.e., increase in level of blood calcium) of the hormone depends largely upon its action on bone, since it promotes the transfer of calcium from this tissue into the plasma, probably by a direct action on the active bone-forming cells (osteocytes). In addition, however, parathormone promotes the formation of new bone tissue, and thus also increases its metabolic activity and the turnover of its structural material. Other effects of parathormone, at least in part, contribute to the elevation of plasma calcium; i.e., PTH increases both the absorption of calcium by the intestine and its resorption by the kidney tubule. Since, however, the hypercalcemia induced by the hormone results in more of it passing into the kidney tubule, the net result may be increased excretion of calcium despite the increased resorption. Other actions of the hormone, less easy to relate to its well-defined influence upon calcium metabolism, include a regulatory influence upon the level of magnesium in blood plasma and upon the rate of removal of phosphate from urine.

      In general, therefore, the action of parathormone is opposite in direction to that of calcitonin. Parathormone keeps the level of blood calcium up to its normal value; on the other hand, calcitonin ensures, through its hypocalcemic action, that the level does not rise far above this critical point. The combined actions of the two hormones serve to illustrate the importance of endocrine regulation in homeostasis. vitamin D is a third factor in calcium regulation; its absence in young children results in skeletal malformations ( rickets). Parathormone is unable to regulate the absorption and mobilization of calcium in the absence of vitamin D, which is also associated with the hormone in promoting mobilization of magnesium from bone and perhaps in the movement of phosphate within the kidney tubule.

Hormones of the pancreas
      The vertebrate pancreas contains, in addition to the zymogen cells that secrete digestive enzymes, groups of endocrine cells called the islets of Langerhans (Langerhans, islets of). Certain of these cells (the B, or beta, cells) secrete the hormone insulin, inadequate production of which is responsible for the condition called diabetes mellitus. Insulin and the characteristic B cells are present in gnathostomes and in agnathans; in the latter, however, the islet cells are not associated with zymogen cells to form a typical pancreas. Insulin is, as mentioned earlier, a polypeptide molecule composed of two chains of amino acids, an A chain of 21 amino acids containing an intrachain disulfide linkage (−S−S−) and a B chain of 30 amino acids. The two chains are linked by two other disulfide linkages, the destruction of which destroys the activity of the molecule. It is thought that the molecule first appears in the B cell as the single-chain compound proinsulin, which is disrupted by an enzyme-catalyzed reaction to form the two chains of the active hormone. As with other polypeptide hormones, extensive variation in amino-acid composition of the molecule occurs among different species, with the differences tending to be greater between the more widely separated species—e.g., between fish and mammal. The variations in amino-acid composition have little effect on the biological activity of the molecules, but certainly influence their immunological reactions; this suggests that the two properties depend on the amino-acid sequences at different parts of the molecule.

      Injection of insulin lowers blood-sugar (glucose) levels, but this so-called hypoglycemic effect is only one expression of the wide-ranging influence of insulin on storage and mobilization of energy, in which the target tissues of primary importance are muscle, adipose (fat) tissue, and liver. The actions of insulin on these tissues are varied. First, it promotes the use of the sugar glucose as an energy source; at the same time, it encourages the storage of excess carbohydrate as glycogen, the storage carbohydrate of animals. Second, insulin reduces the use of fat as an energy source and promotes its storage. Third, it reduces the use of protein as an energy source and promotes the formation of proteins from amino acids.

      Insulin probably acts on carbohydrate metabolism in muscle by increasing the ability of glucose to pass through the muscle-cell membranes. This effect depends on a specific interaction between the cell membrane and the hormone; although the same effect occurs in adipose (fat) tissue, it does not occur either in the liver or in the central nervous system, despite the latter's complete dependence upon glucose for its energy supply. After the entry of glucose into a muscle cell, phosphate is added to the molecule, and two compounds form in succession, first glucose-6-phosphate, then glucose-1-phosphate; after these reactions, the metabolism of glucose is probably aided by two secondary actions of insulin (see also metabolism: The catabolism of glucose (metabolism)). The hormone stimulates the synthesis of an enzyme (glycogen synthetase), thus promoting the transformation of glucose-1-phosphate into glycogen; it also aids in the breakdown of glucose, thus providing energy to the cell. All of these effects contribute to the hypoglycemic (blood-glucose-lowering) action of the hormone. Insulin has other effects on muscle cells—it slows the breakdown of fat and increases the formation of proteins from amino acids. Insulin affects carbohydrate and protein metabolism in adipose tissue much as it does in muscle and also promotes storage of fat.

      The action of insulin in liver differs from that in muscle in that it has no direct influence upon the transport of glucose into liver cells; probably, however, insulin promotes the metabolism of glucose within liver cells in much the same way that it does in those of muscle, resulting in increased uptake of glucose from the bloodstream. In addition, insulin decreases gluconeogenesis (the formation of glucose in the liver from amino acids and other noncarbohydrate sources). These various effects cause a decrease in the level of blood glucose. Other actions of the hormone upon the liver include, as in adipose tissue, increases in fat deposition and protein synthesis.

      The diverse effects of insulin apparently are adaptively linked to regulating the storage and release of energy, but it is difficult to judge whether or not all of the effects result from a single mode of action of the hormone. The interaction of insulin with the muscle-cell membrane suggests that all of its effects might be produced by similar interactions between it and membranes within cells. The mechanism, however, has not yet been established with certainty.

      The B cells of the islets of Langerhans respond directly through negative feedback to the level of glucose in the blood that reaches them; i.e., an increase in blood glucose above the normal level (80 to 100 milligrams per 100 millilitres in man) brings about increased synthesis and release of insulin with the result that the level of blood glucose falls. As a consequence, the rate of insulin output then decreases. This, however, is only part of the complex hormonal mechanism that regulates carbohydrate metabolism. Another factor is the hormone glucagon, which is secreted in the islets of Langerhans by a second cell type, the A (alpha, or A2) cells. (The function of a third type, the D (gamma, or A1) cells, has not yet been established.)

      Glucagon, which is present in gnathostomes but absent from agnathans, is a polypeptide molecule consisting of 29 amino acids. It strongly opposes the action of insulin, primarily through a hyperglycemic (blood-glucose-raising) effect that results from its promotion of the breakdown of glycogen (glycogenolysis) in the liver, a process that results in the formation of glucose. Glucagon exerts its action by increasing the availability of the enzyme required for the reaction by which glucose units are released from the glycogen molecule. It also reduces the rate of synthesis of glycogen, promotes the breakdown of protein, promotes the use of fat as an energy source, and evokes increased glucose uptake by muscle cells. The last effect, however, may be a consequence of hyperglycemia induced by the increased secretion of insulin.

      Another form of glucagon, called gastrointestinal glucagon, is secreted into the blood when glucose is ingested. Its only action appears to be to stimulate insulin secretion, an effect that may provide information to the islet cells of the pancreas about the entry of glucose into the bloodstream. It is also possible that pancreatic glucagon, which is secreted in the islets by the A cells, may directly stimulate the release of insulin from the adjacent B cells without actually entering the bloodstream.

      A number of other hormones also influence the release of insulin, mainly through their own actions upon blood-sugar levels. Growth hormone, thyroxine, adrenaline, and cortisol, e.g., may increase insulin release because they can promote a rise in blood sugar through effects upon carbohydrate metabolism. Growth hormone and cortisol can also probably act directly upon the B cells.

      The complexity and delicacy of the control of metabolism by insulin and other hormones in mammals illustrate again the importance of homeostasis, the control of which may not be as well organized in the lower vertebrates. Some of the responses in mammals, however, do occur in lower forms; for example, removal of pancreatic islet tissue from fishes produces hyperglycemia. Thyroxine induces hyperglycemia in amphibians, and corticosteroids promote gluconeogenesis in them. Far more information is needed, however, before the evolution of these remarkable regulating mechanisms can be determined.

Hormones of the adrenal glands (adrenal gland)
Chromaffin tissue of the medulla
      The adrenal gland of mammals is composed of an outer region, the cortex, which consists of adrenocortical tissue that secretes steroid hormones (steroids are fat-soluble organic compounds), and an inner region, the medulla, which is composed of chromaffin tissue, so called because its cells contain granules that can be characteristically coloured by certain reagents. Chromaffin tissue secretes two hormones, adrenaline (epinephrine (epinephrine and norepinephrine)) and noradrenaline (norepinephrine), which are members of a class of compounds called catecholamines. Both chromaffin and adrenocortical tissues are present in gnathostomes and probably in agnathans (although the evidence on the latter point is not yet decisive), but the tissues vary in the degree to which they are associated, being completely separated in elasmobranch fishes.

 Noradrenaline and adrenaline are each composed of a benzene ring containing two hydroxyl (−OH) groups and an amine (NH2-containing) side chain as shown in Figure 3—>.

      During the synthesis of these hormones, a sequence of enzyme-catalyzed reactions in the chromaffin granules of the secretory tissue transforms tyrosine into a compound commonly called dopa (dihydroxyphenylalanine), which then forms dopamine; dopamine then is hydroxylated (i.e., an −OH group is added) to form noradrenaline. Adrenaline is formed from noradrenaline by methylation (the addition of a methyl, or −CH3, group), a reaction that occurs outside the granules of the chromaffin cells. Noradrenaline (but not adrenaline) is also formed in certain neurons (nerve cells), where it functions as one of the chemical transmitter substances.

      After their release, both hormones are so rapidly metabolized that they probably remain in the bloodstream only for a few seconds. The first step in the breakdown, which usually occurs in the liver and kidneys, is methylation of one of the hydroxyl groups of the benzene ring; the products (metanephrine or normetanephrine), or compounds derived from them, are excreted in the urine. Small quantities (about 2 to 5 percent of the daily secretion of the gland in man) of nonmetabolized hormones are also found in the urine.

       Effects of adrenaline and noradrenaline in humansAdrenaline and noradrenaline evoke diverse and widespread responses but differ from each other in certain of their effects (see Table 3 (Effects of adrenaline and noradrenaline in humans) for their effects on man). Both influence the heart and blood vessels in ways which, although opposed to each other in a few respects, generally result in an increase in blood pressure and in output of blood from the heart. Both hormones also have metabolic actions. Adrenaline, for example, like glucagon, stimulates glycogenolysis (breakdown of glycogen to glucose) in the liver, which results in the raising of the level of blood sugar; in addition, it increases oxygen consumption and the output of blood from the heart, probably contributing thereby to the regulation of body temperature in mammals. Adrenaline has effects upon the nervous system, which are recognizable subjectively in man by feelings of anxiety and of increased mental alertness.

      The chromaffin tissue is closely related to the sympathetic nerves of the autonomic nervous system, which innervates the components of circulation and digestion and controls their involuntary functions; in fact, the two may be said to form a sympatheticochromaffin complex. It is generally assumed that this complex acts to increase the capacity of the animal for effective action in emergencies. At such times, cardiac output increases, blood is distributed with maximum effectiveness, respiration is enhanced, and the nervous system is stimulated. The sympathetic nerves initiate these reactions and directly promote the release of adrenaline and noradrenaline because these nerves directly innervate the chromaffin cells. The hormones are thus able to develop and prolong an integrated set of responses; noradrenaline functions both as a neurohumor chemical transmitter of the sympathetic nervous system and also as a hormone of the chromaffin tissue.

 The fact that adrenaline and noradrenaline, which have very similar molecular structures (Figure 3—>), can exert different actions is probably in part a consequence of the specialization of their target tissues. It has been suggested by some researchers that the target tissues possess two different kinds of receptors, the alpha type, which responds to noradrenaline, and the beta type, which responds to adrenaline. Evidence for this theory is that adrenaline has a vasodilator effect (i.e., it expands blood vessels), which can be blocked by certain drugs, and noradrenaline has an opposing vasoconstrictor effect, which can be blocked by other drugs. The actions of both hormones are thought to be mediated by CAMP; alpha responses are associated with reduced synthesis of this mediator and beta ones with increased synthesis.

      The interpretation of the function of these hormones in mammals has not yet been established as applicable to lower vertebrates in which the hormones are present, but they are known to influence metabolism and heartbeat in some genera. It is possible that in early stages of vertebrate evolution, the sympatheticochromaffin complex evoked more generalized physiological responses than it now does and that more precise action developed in mammals as part of their high level of homeostatic organization. Laboratory studies show that even in mammals the complex is not essential for life; animals from which it has been removed, however, are much less able to resist environmental stresses (stress) than are those whose complex is functional.

Adrenocortical tissue of the cortex
 The adrenocortical tissue develops from coelomic epithelium (a cell layer surrounding the body cavity, or coelom). In this respect it resembles the endocrine tissue of the gonads, a resemblance emphasized by the fact that both the adrenocortical hormones (corticoids (corticoid)) and the sex hormones are steroids produced by similar metabolic pathways (the structures of some steroid hormones are illustrated in Figure 4—>).

 Many steroids have been isolated from the adrenal cortex, but in most vertebrate groups only three of them are active as hormones; they are cortisol (hydrocortisone; compound F), corticosterone (compound B), and aldosterone. Their biosynthesis is outlined in Figure 5—>.

 The principal sterol of animals is cholesterol, which is formed by a complex series of reactions from a two-carbon compound (acetate). progesterone, which is derived from cholesterol, can be used to form either corticosterone and aldosterone or cortisol (Figure 4—>). All three corticoids are bound to proteins during transfer in the bloodstream to their targets; cortisol, for example, is bound to a glycoprotein called transcortin. Some inactivation of the corticoids takes place in the kidney and in the alimentary tract, but most of it occurs in the liver. The metabolic products, which eventually appear in the urine, provide a basis for determination of the output of adrenocortical hormones in man.

      The normal secretion of the hormones is best determined by direct measurement of the contents of the venous blood leaving the adrenal gland. In man, the daily secretion rates of the hormones, as determined by this procedure, are cortisol, 20 milligrams; corticosterone, two to five milligrams; aldosterone, 75 to 150 micrograms (one microgram = 1,000,000th of a gram). Very small amounts of aldosterone are secreted, because the molecule has a high level of activity. Animal tissues maintained in culture fluid together with compounds from which the hormones are formed (e.g., acetate, cholesterol, or progesterone containing radioactive isotopes of carbon or hydrogen) show that cortisol and corticosterone are produced in all vertebrates, including the agnathans, although the proportion of each is species-dependent; elasmobranch fishes are unique, however, in having 1-α-hydroxycorticosterone as the principal hormone. Aldosterone is produced by all terrestrial vertebrates. It has also been found in bony fishes, although its function in them has not yet been established as a hormonal one. The presence of aldosterone has not yet been established in elasmobranchs and agnathans, but whether or not this particular molecule occurs in them, the ability to synthesize corticoids must have evolved very early in vertebrate history.

      In contrast to the chromaffin tissue of the adrenal medulla, the adrenocortical tissue is essential for life. Two primary functions of the corticosteroids are distinguishable in mammals. One, which contributes to the regulation of carbohydrate metabolism, is an action of cortisol and corticosterone, which are therefore called glucocorticoids. These hormones promote gluconeogenesis (formation of glucose) in the liver and are thus important in maintaining normal blood-sugar levels, particularly during glucose shortage; lack of them results in low levels of blood sugar and an increase in the sensitivity of the liver to insulin (whose effect there is to decrease gluconeogenesis). In addition, lack of the glucocorticoids is associated with a decrease in the entry of amino acids into muscles and an increase in their uptake by the liver, where enzymes required to convert amino acids to glucose must be synthesized.

      In contrast to glucocorticoid action is the so-called mineralocorticoid action of aldosterone, which is manifested in mammals in the regulation of sodium metabolism. In the absence of aldosterone, sodium is lost from the body by excretion in urine; secondary consequences include a decrease in blood volume and in the filtration rate of substances through kidney structures called glomeruli. Cortisol and corticosterone also play a minor part in mineral regulation, so that slight overlap in function occurs between the two corticoid types.

      The action of aldosterone is exerted mainly upon the distal segment of the nephron (kidney tubule), where it promotes an increase in the permeability of the tubule membrane to the passage of sodium, and also an increase in the quantity of sodium removed into the blood from the fluid passing through the kidney tubule. At the same time, potassium and hydrogen pass into the fluid from the blood. Aldosterone also exerts other effects. It promotes sodium retention in salivary glands, in sweat glands, and in the colon of the large intestine; it also promotes the excretion of magnesium in the urine. The effects of aldosterone result in an increase in the rate of synthesis of enzymes required to transport these substances through membranes.

      Other actions of the corticoids are apparent in patients suffering from Addison's disease (Addison disease), which is caused by a general deficiency in corticoid production. A deficiency of corticoids causes disturbances in urinary output and fat metabolism, diminished resistance to stress, muscular weakness, and nervous disturbances manifested by depression and a general lack of mental alertness. The adrenocortical hormones, then, like the hormones of the chromaffin tissue of the medulla, are involved in resistance to stress. It has been postulated that the response to alarm stimuli initially involves both the sympatheticochromaffin complex and the adrenocortical secretion; then a stage of full resistance occurs that may be followed by mental exhaustion if the alarm stimuli are prolonged. Although a close functional relationship is known to exist between the adrenocortical and chromaffin tissues in mammals, the function of the corticoids in the lower vertebrates has not yet been established. Indications are, however, that the general pattern of action may be similar; for example, the cortisol type of corticoid promotes gluconeogenesis in fish and removal of adrenocortical tissue impairs the metabolism of water and ions in the eel. Any interpretation of corticoid action in teleost, or bony, fishes has to incorporate prolactin, for, as has been noted previously, this hormone also influences the movement of ions.

      In contrast to the chromaffin cells, the adrenocortical cells are not innervated. Both cortisol and corticosterone production are regulated by the action of ACTH from the pituitary gland on the zona reticularis and the zona fasciculata. The regulation of aldosterone secretion in the zona glomerulosa, however, is associated with the so-called renin–angiotensin system (renin-angiotensin system), which is best characterized in mammals. renin, an enzyme with a molecular weight of about 40,000, is formed in the kidney and is released into the bloodstream, where it catalyzes the formation of angiotensin, a polypeptide molecule. Angiotensin acts upon smooth muscle and raises blood pressure. In man it reduces sodium excretion, probably by a direct action on kidney filtration, and may, in fact, be a true hormone, acting to aid sodium retention. In addition, however, angiotensin contributes to sodium retention by increasing aldosterone secretion. The exact physiological significance of the renin–angiotensin system is not yet known. In one form or another the system is probably widely distributed in vertebrates.

Hormones of the reproductive system
      The hormones of the reproductive system of vertebrates (sex hormones (sex hormone)) are steroids that are secreted, like those of the adrenal cortex, by tissues derived from the coelomic epithelium. Both types of secretory tissues also share biosynthetic pathways (see above Adrenocortical tissue of the cortex (hormone)).

Female hormones
      The sex hormones, together with the hypothalamic region of the forebrain and the pituitary gland, form a regulatory system, which is most complex in the female mammal. It is common for sexual activity of vertebrates to be cyclical and for the cycles to be coordinated with the seasons of the year; this ensures that the young are born at the most favourable time. In mammals, however, reproduction is complicated by the need to provide for the intrauterine life of the developing fetus and to ensure that interference by another generation of embryos cannot occur.

Estrogens (estrogen)
 Two types of gonadal hormone, estrogens and progestins (Figure 4—>) are secreted in the female mammal. Estrogens are substances that evoke the cyclical onset of heat, or estrus, during which the animal is sexually active and receptive to the male. Estrus in this sense is not found in human females, but estrogens contribute to the events of the menstrual cycle (menstruation), bringing about cyclical changes in the reproductive system that are comparable with those accompanying estrus in other mammals.

      Hormones are secreted from the mammalian ovary by the ovarian follicle, or vesicle, including the granulosa cells immediately surrounding the ovum, or egg, and the cells of the theca, which forms a supporting outer wall for the follicle. The main estrogen secreted is called β-estradiol. The close relationship between the female and the male sex hormones is revealed by the fact that testosterone (the main male hormone) is an intermediate compound in the pathway that leads to the synthesis of estradiol, although another route, which avoids the formation of testosterone, is possible. Other estrogens are also known; the most familiar ones in man and other mammals, estrone and estriol, are much less active than estradiol, estriol being the weakest. Estrone can be converted to estradiol and vice versa in the ovary and in other tissues; e.g., estradiol is converted, particularly in the liver, to estriol, which is an excretory product. The metabolism of these compounds is complex; they may be combined in part with other substances, or they may pass through the bile into the intestine for reabsorption and circulation through the body before excretion in the urine occurs. Their urinary concentrations provide an important clinical index of reproductive function.

      Estrogens are concerned not only with reproductive behaviour but also with the general maintenance of the sexual organization of the female. When estradiol is administered to a mammal, the hormone becomes bound to uterine tissue, where it increases the rates of protein synthesis, of uptake of water and glucose, and, eventually, of growth of the lining epithelium and underlying muscular tissue (endometrium) of the uterus. Estradiol also evokes changes in the vagina, including hardening of the epithelium, a phenomenon that, in the laboratory rat, is used to determine its sexual condition. Estradiol and other estrogens have also been found in fishes and in other lower vertebrates. As with the corticosteroids, the sex hormones evolved very early in vertebrate history. Indeed, they have even been identified in invertebrates—in the eggs of the lobster, for example, and in the ovaries of starfishes, where, however, they may be no more than by-products of the metabolism of other steroids. Estrogenic activity is not necessarily restricted to steroids; for example, the estrogen mirestrol from a Thailand plant is not a steroid, nor is the very potent synthetic estrogen, stilbestrol, which is widely used in medicine.

Progestins
      Progestins, of which the most important is progesterone, are concerned with the maintenance of pregnancy. Progesterone, therefore, evolved in viviparous mammals; i.e., those that produce living young. Its chemical origin is demonstrable, since it is also an important intermediate compound in the biosynthetic pathways leading to corticoid and estrogen production. Mammals thus converted to hormonal use a substance that was synthesized by vertebrates long before the evolution of terrestrial vertebrates.

      Some progesterone is probably formed in the ovarian follicle, but the main site of production is the corpus luteum, which is formed by a transformation of the follicle after ovulation; the secretory cells are formed from granulosa cells. The functions of the two important follicular phases, preceding and following ovulation, therefore, are continuous. The hormone is metabolized in several ways, but one important product is pregnanediol; formed mainly in the liver, it appears in part in the urine, where it can be measured to determine the degree of ovarian function.

      The transformation of the follicle into the corpus luteum is an important turning point in the diphasic menstrual cycle of women and in the ovarian cycles of other mammals, from which the human cycle evolved. Progesterone prepares the uterus for the implantation of fertilized eggs, and it is also needed for the maintenance of pregnancy once implantation has taken place. It evokes a reduction in the ability of the uterine walls to contract, a proliferation of the glands of the endometrium, and the formation of glycogen. In addition, through its feedback action upon pituitary secretion, progesterone inhibits further ovulation (see below), thus ensuring undisturbed fetal development. Ovulation in women occurs at about the middle of the monthly cycle, and the follicular phase is succeeded by the luteal phase. The vaginal bleeding at the end of the cycle is an indication that ovulation has not been followed by implantation of a fertilized egg and is immediately followed by the inception of a new cycle. If implantation does take place, the uterus provides metabolic support for the fetus until birth (see also menstruation).

      The vertebrate reproductive cycle depends upon delicate interrelationships between the sex hormones and the pituitary gonadotropic hormones (FSH and LH). As mentioned, it is uncertain whether or not there are two distinct gonadotropins in lower forms, but their separate action is well defined in mammals. Broadly speaking, FSH (follicle-stimulating hormone), with some support from LH (luteinizing hormone), promotes growth and secretory activity of the follicle. The increasing output of estrogen from the ovary eventually tends, by feedback to the pituitary gland, to reduce FSH output and to stimulate the secretion of LH; it is a sudden peak release of the latter hormone that evokes ovulation in many mammals. In others, such as the cat and rabbit, however, ovulation occurs as a response to the stimulus of copulation. Although some progesterone may be secreted by the granulosa cells of the follicle, the development of the corpus luteum greatly increases its secretion. Luteotropic activity in one form or another (the action of prolactin, for example, in the rat) is important in the early stage of this phase. Progesterone, in conjunction with the estrogen that is also being secreted (in part, probably, by the corpus luteum), suppresses further ovulation. This interaction of the two hormones is the basis of the design of contraceptive pills.

      The corpus luteum continues to function during pregnancy, supplemented (in eutherian, or placental (placenta), mammals but not in marsupials) by endocrine secretions of the placenta (the organ through which contact between mother and fetus is maintained). The hormonal activity of the placenta varies with the species; in man, for example, the placenta secretes two gonadotropins called human chorionic gonadotropin (HCG) and human placental lactogen (HPL). HCG, like the pituitary gonadotropins, is a glycoprotein, with a molecular weight of 25,000 to 30,000. HPL is a protein, with a molecular weight variously estimated at about 19,000 or 30,000. One or perhaps both of these hormones, which become detectable during the early weeks of human pregnancy, probably stimulate luteal secretion. After two months the human placenta begins to manufacture estrogen and progestin; as a consequence, the corpus luteum is no longer needed for the maintenance of pregnancy. Much of the estrogen, although synthesized in the placenta, is derived from a compound (dehydroepiandrosterone) formed in the adrenal glands of the fetus. The placenta and the fetus thus form an integrated endocrine complex, a striking index of the high level of specialization found in the regulation of mammalian reproduction. (See also pregnancy.)

      The placenta probably secretes a luteotropin in all mammalian species, thereby contributing to prolongation of the life of the corpus luteum. In the mare and the monkey the placenta also secretes estrogen and progesterone, as in man, but in the mouse and rabbit it secretes only estrogen, and in the hamster and rat it secretes neither. In these last four species and in others like them, in which the placenta cannot substitute completely for the corpus luteum, ovariectomy (removal of the ovaries) of a pregnant female leads to the termination of pregnancy unless progesterone is administered to the female.

      The interrelationships between the ovarian and the pituitary hormones are based upon negative feedback involving both the cells of the pituitary and those of the hypothalamus, which contains centres that are excited or inhibited by gonadotropin released from the pituitary gland. It is the hypothalamic involvement that enables vertebrate reproductive cycles to be adjusted by the central nervous system relative to external stimuli, particularly the seasonal fluctuations of daylight and other environmental factors that determine the onset of reproduction in many vertebrate species.

Male hormones
      The sex hormones of the male follow a much simpler pattern than do those of the female, although the same principle of interaction exists between the pituitary gland and the gonads. The latter organs, the testes, secrete steriods called androgens (androgen), which are responsible for the maintenance of male characteristics and behaviour. FSH (follicle-stimulating hormone) from the pituitary gland stimulates the growth of the seminiferous tubules that constitute much of the structure of the testes and promotes within them the cell divisions that result in the production of mature sperm. LH (luteinizing hormone) from the pituitary gland promotes the development within the testes of endocrine tissue, which is composed of groups of cells (interstitial tissue) between the seminiferous tubules. The interstitial tissue of certain bony fishes, however, is represented by cells, called lobule boundary cells, situated within the tubule tissue.

      Under the influence of LH (often called ICSH, or interstitial-cell-stimulating hormone, in males), the interstitial tissue secretes the steroid hormone testosterone, which is the most important vertebrate androgen. The fact that it is an intermediate compound in the metabolic pathway of estrogen synthesis accounts for the origin of some forms of abnormal sexual organization in man; for example, the testes may secrete predominantly estrogen instead of androgen, resulting in markedly female appearance and behaviour in a male. Although testosterone may be secreted by the adrenal cortex, occasionally producing sexual disturbances, the amount of secretion is not normally significant. Testosterone, which is bound to a protein as it circulates in human blood, can be converted to the compound (androstenedione) from which it is formed, especially in the liver and in muscle; both compounds are metabolized, mainly in the liver, to substances that are excreted in urine. Very small quantities of testosterone can also be excreted in urine, and the quantities of testosterone and compounds derived from it frequently are measured to provide an index of testicular condition.

      In addition to promoting male characteristics, male behaviour, and the maintenance of the spermatic tubules, testosterone, in the presence of normal amounts of growth hormone, also promotes growth of the bony skeleton. The reason for rapid growth at puberty is that the secretion of androgen markedly increases. The hormone brings about the closure of the epiphyses (ends) of the long bones, which completes the process of growth (estrogens have a similar action in the female). Thus, as often occurs among animals, growth ceases before full reproductive activity is attained, and competition between two processes, both of which make heavy demands upon the resources of the body, is avoided.

Hormones of the digestive system
      In vertebrates, the muscular and secretory activities (digestion) of the alimentary canal and its associated glands are regulated by nervous and hormonal mechanisms. The hormones comprise a self-contained complex that functions at a relatively primitive level of organization and is distinguished by peculiar features; for example, specialized glandular tissues that secrete the hormones cannot be identified, although certain cells that can be seen in the wall of the alimentary canal are thought to be involved in their production. In addition, the digestive hormones regulate the systemthat produces them and are largely independent of the rest of the endocrine system, although certain relationships may not yet have been discovered.

      The functions of digestive hormones are best understood in mammals, in whom at least three are well characterized; the existence of others has been postulated. The three hormones— gastrin, secretin, and cholecystokinin/pancreozymin (CCK-PZ)—are polypeptide molecules whose amino-acid sequences are known. When food enters the stomach, the wall of its pyloric end (the area at which the stomach joins the small intestine) releases a hormone called gastrin, which promotes the flow of acid from the gastric glands in the stomach. These glands also release pepsinogen, which is the inactive form of the protein-digesting enzyme pepsin, but this process is primarily under nervous control. The entry of the acidified stomach contents into the first part of the small intestine (duodenum) releases secretin and cholecystokinin/pancreozymin. Secretin evokes the discharge of fluid and bicarbonate ions from the pancreas (hydrelatic action) and promotes the secretion of bile from the liver (chloretic action). Cholecystokinin/pancreozymin, so-called because its two main actions were formerly attributed to two separate hormones, evokes the release of enzymes from the pancreas (ecbolic action) and causes contraction of the gallbladder (cystokinetic action), thereby promoting the entry of bile into the duodenum.

      Little is known regarding hormonal control of alimentary activities in lower vertebrates; however, hydrelatic, ecbolic, and cystokinetic activities are present in preparations of the alimentary tracts of both agnathans (agnathan) and gnathostomes, indicating that substances able to regulate digestive activity appeared very early in the evolution of the vertebrate alimentary tract. Evidence suggests that the appearance of these hormones may have resulted in molecular diversification similar to examples previously discussed. The structure of the glucagon molecule from the pancreas, for example, is similar to that of secretin in that each molecule includes the same 15 amino acids located in the same positions. It has therefore been suggested that the two hormones may have evolved from a common ancestral molecule.

Endocrine-like glands and secretions
      In addition to the well-defined hormones, other substances, which are found in blood and in tissues and are of uncertain function, may be concerned in various ways with physiological regulation in vertebrates, although their hormonal status has not yet been established.

      Blood contains kinins, which are polypeptides that originate in the blood and perhaps elsewhere; bradykinin, for example, causes contraction of most smooth muscles and has a very potent action in dilating certain blood vessels. Its function, which is not yet established, may be to regulate the rate of blood flow or to participate in the inflammatory response of an animal to injury.

      Some endocrine-like glands are associated with organs. One example in mammals is the carotid bodies, which are found on the carotid arteries that supply blood to the head. The carotid glands are stimulated by a decrease in the oxygen content of the blood and are considered to be the source of a substance, the nature of which has not yet been established with certainty, that promotes the process of red-blood-cell formation (erythropoiesis).

      The pineal organ (pineal gland) is an endocrine-like body found in the brain of all vertebrates. In lower vertebrates, it contains sensory and supporting cells and functions as a light-sensitive organ; in higher vertebrates, beginning with amphibians, the pineal gland has secretory functions, and in mammals, it is exclusively a secretory organ, producing from an amino acid (tryptophan) the compound serotonin (5-hydroxytryptamine, or 5HT) and a derivative of serotonin called melatonin. Preparations of melatonin, when given to amphibians, stimulate the concentration of pigment granules in chromatophores, an effect comparable with that of intermedin (MSH) but much more powerful. The normal physiological function of melatonin in higher vertebrates has not yet been established, although involvement in the regulation of reproduction is suspected. Serotonin is widely distributed in animals, especially in the brain and alimentary tract of vertebrates; it may function as a neurohumor in the invertebrate mollusks, but its significance in other animals is not yet certain.

      The thymus is essential for the normal development in mammals of the system responsible for immunological responses. Its removal in newborn mice results in a deficiency of one type of white blood cells (lymphocytes) and a consequent likelihood of early death from infection. Preparations of thymus glands from various species contain a protein component, called thymosin, that promotes the development of lymphocytes. Although thymosin is sometimes regarded as a possible thymus hormone, the evidence is not yet complete.

      The urohypophysis, an organ found only in elasmobranch and bony fishes, probably developed independently in each group. The neurosecretory cells comprising the urohypophysis are concentrated at the hind end of the spinal cord, where they are associated with a vascular plexus to form a neurohemal organ. The urohypophysis resembles the neurosecretory system of the hypothalamus and the neural lobe (see above Neurohypophysis and the polypeptide hormones of the hypothalamus (hormone)), but its functions have not yet been established.

      The corpuscles of Stannius, found only in bony fishes (teleost), are sac-like bodies in the kidney. Although they were once thought to be a form of adrenocortical tissue, they differ from it in embryological origin as well as in cytological characteristics; moreover, although the corpuscles of Stannius are capable of limited steroid biosynthesis, they cannot convert cholesterol into corticoids, a process that occurs in adrenocortical tissue. Evidence suggests that these corpuscles secrete some substance, as yet uncharacterized, which plays a part in maintaining ionic homeostasis, perhaps in conjunction with the corticoid hormones.

The hormones of invertebrates
      Some form of endocrine regulation probably occurs in all invertebrates; in arthropods (as exemplified in insects (insect) and crustaceans) it attains a level of complexity similar to that of vertebrates.

Hormones of insects
      Insects secrete hormones from neurosecretory cells and also from endocrine glands. Important neurosecretory centres occur in the pars intercerebralis region of the brain. The several cell types found in these centres indicate that more than one hormone is produced there.

Neurohormones
      One of the brain hormones is thoracotropic hormone. This is released from nerve endings located in a neurohemal organ called the corpus cardiacum; the relationship between the corpus cardiacum and the brain closely parallels that between the neural lobe of the pituitary gland and the hypothalamic region of the brain of vertebrates. The thoractropic hormone is transferred in the blood to the thoracic glands in the body region called the thorax. It stimulates the production and release from the glands of ecdysone, a hormone that initiates molting, which is the periodic shedding of the outer skeleton that typically occurs in insects and other arthropods. The thoracotropic hormone is probably a polypeptide molecule.

      A neurosecretion of the insect brain distinct from the thoracotropic hormone and called bursicon acts directly on the adult cuticle (skin) of arthropods to stimulate darkening and hardening processes. Bursicon is almost certainly a polypeptide, with a molecular weight of about 40,000. The brain of insects also produces a third neurohormone, which has a hyperglycemic (increase in level of blood glucose) effect in a tissue mass called the fat body, and a fourth neurohormone, which acts on the malpighian tubules (excretory organs) and rectum to facilitate the removal of excess fluid taken in with food; these two hormones, which may actually be one hormone with two effects, are also probably polypeptides. Another more active hyperglycemic hormone is formed within the corpora cardiaca, perhaps under the control of cerebral neurosecretion.

Molting hormones
      Ecdysone is a steroid compound derived from cholesterol. Two forms are found in insects—α-ecdysone and β-ecdysone; ecdysones of unknown biological significance are also present in plants. Unlike vertebrates, insects cannot synthesize cholesterol, and they thus must obtain it from their food. Evidence concerning the mode of action of ecdysone indicates that it has a direct action upon the synthesis of the ribonucleic acid (RNA) that controls protein synthesis in the cell.

      The distinction in insects between molts that occur within the larval stage of development and those that result in the transformation of larvae to other stages (pupae, adults) in the life cycle is controlled by another hormone, called juvenile hormone, which is secreted in epithelial glands, called the corpora allata, near the brain. The hormone controls the appearance of juvenile characters in larval stages, presumably by suppressing the activity of genes concerned with the expression of adult characters; reduction in the amount of or absence of the hormone at later molts results in the appearance of mature characters. The hormone nevertheless may continue to function in adults and often is necessary for normal egg production in females. Juvenile hormone is a lipoidal (fatlike) compound of similar structure from all sources. Many synthetic compounds mimic its effect, as do certain natural products—e.g., substances in the balsam fir tree (Abies). Substances that mimic the action of juvenile hormone sometimes are used as insecticides, for if they are present in abnormal amounts in the later stages of the life cycle, they kill the insects.

Pheromones
      Pheromones are important as insect sex attractants and as regulators of the social organization of social insects; e.g., bees. The sex attractant of the female silk moth (Bombyx mori) is called bombykol. A related compound, gyptol, is the sex attractant of the female gypsy moth (Porthetria dispar), and gyplure is a synthetic compound that acts as an even more powerful attractant. The use of these compounds in the chemical control of insect pests is probably more promising than is the use of juvenile hormone.

      The odour of the sex attractant of the honeybee (Apis mellifera), 9-oxodecenoic acid, stimulates the olfactory receptors of the drones (males). Secreted by the queen bee in the hive, the pheromone inhibits the development of the ovaries of the worker bees (sterile females) but is entirely effective only when it acts in conjunction with another inhibitory pheromone, 9-hydroxydecenoic acid. Removal of the queen from the hive results in the building of new queen cells by the workers and the development of functional ovaries in the drones. The mechanism by which these inhibitory substances function is not yet understood; some effect upon the nervous system presumably is involved.

Hormones of crustaceans (crustacean)
      The endocrine systems of crustaceans resemble those of insects; important differences occur, however, implying extensive independent evolution in the two groups. The main sources of neurohormones are groups of cells (the X-organs) located in the optic ganglia of the eyestalks; the most important neurohemal organ is the sinus gland beside the eyestalks. Less important neurosecretory centres and neurohemal organs also occur. Decapods, for example, have a special organ located in the walls of the pericardium, enclosing the heart; the pericardial organ secretes a substance, perhaps a polypeptide neurohormone, that accelerates the heartbeat.

      Neurosecretions control many crustacean functions, including the movement of pigment in the chromatophores, which determine body colour, and in the retina of the compound eye. They also regulate molting and the associated metabolic functions by actions exerted upon the so-called Y-organ in the head; this organ so closely resembles the thoracic gland of insects that the two may share a common ancestry. In crustaceans, however, the neurosecretion inhibits secretions from the Y-organ, and the molt is initiated by the withdrawal of the inhibitory hormone (in insects, the thoracotropic hormone from the corpus cardiacum stimulates the secretion of the molting hormone, ecdysone, from the thoracic gland). Neurosecretory hormones of crustaceans have diverse chemical and biological characteristics but apparently are polypeptides, as are the neurosecretory hormones of vertebrates.

      Unlike insects, crustaceans have an androgenic gland, which typically is located on the genital duct (vas deferens) of the male. The androgenic gland secretes a hormone, possibly steroid in nature, that controls both the differentiation of the gonad of the male into a testis and the male characteristics of its limbs. The absence of the androgenic gland in the female results in the formation of an ovary, which subsequently synthesizes one or more hormones that, in female amphipods, promote the development of brood chambers (in which the young are hatched) and other structures associated with reproduction.

Other invertebrate hormones
      The characterization of the hormones of other invertebrates awaits further study. Evidence indicates that the brain of polychaete worms produces neurosecretions that regulate growth and reproduction; in Nereis and Nephtys the neurosecretory fibres apparently have a close and presumably functional relationship with an epithelial gland (infracerebral organ), which is formed from coelomic epithelium and is situated on the wall of the brain.

      Neurosecretory cells probably are present in mollusks such as gastropods and lamellibranchs. Experimental studies indicate an endocrine relationship in gastropods between the gonad (ovotestis) and possible neurosecretory cells in the tentacles and the brain; one ganglion of the gastropod Lymnaea may secrete a neurohormone with a diuretic (urine producing) action. Epithelial glands in mollusks are important; in the cephalopods, which are the most advanced invertebrates in some respects, optic glands on the optic stalks (eyestalks) secrete a hormone that promotes development and maturation of the gonads. In immature cephalopods the activity of the glands is inhibited by the central nervous system, apparently by a chemical mediator that diffuses from nerve fibres.

      The nerve net, which constitutes the very primitive nervous system of the coelenterates, probably the most primitive multicellular animals, apparently contains neurosecretory cells; indirect but convincing evidence suggests that the cells release a secretion that promotes growth and inhibits sexual reproduction.

The hormones of plants (plant)
      Growth in plants is regulated by a variety of plant hormones, including auxins, gibberellins, cytokinins, and growth inhibitors, primarily abscisic acid and ethylene.

Growth promoters
Auxins (auxin)
 The distribution of auxins, which promote the lengthwise growth of plants, is correlated with the distribution of the growth regions of the plant. The most important auxin, whose structure is represented in Figure 6—>, is β-indolylacetic acid (IAA), which is formed either from the amino acid tryptophan or from the breakdown of carbohydrates known as glycosides. The hormone affects plants by its action on chemical bonds of carbohydrates comprising plant cell walls. The process permits the cells to be irreversibly deformed and is accompanied by the entry of water and the synthesis of new cell-wall material. Many animal hormones may exert their effects by influencing protein synthesis, and evidence suggests that auxins may act in a similar way.

      Many other naturally occurring and synthetic compounds called auxins also have growth-promoting properties, but they are not always as active as IAA. Some of these compounds, however, resist the enzymatic destruction that is the normal fate of IAA within the plant; this feature is of great value in research and in horticulture, because auxin action can be prolonged. Other auxin-like compounds are used as selective weed killers (e.g., to disturb the leaf growth of dicotyledonous plants either in fields containing monocotyledonous cereal crops or on lawns) and as agents that remove leaves from dicotyledonous plants (defoliating agents).

      The hormonal characteristics of IAA are readily demonstrated in grass seedlings, in which the hormone is synthesized at the tip of the coleoptile (the protective sheath of the emerging plumule, or embryonic bud) and passes downward to its point of action in the growing region, where it evokes elongation of the coleoptile cells; growth stops if the tip is removed. The movement of the hormone downward from the tip of the coleoptile depends upon an interaction between the hormone and the cells through which the movement normally takes place.

      In addition to promoting normal growth in plant length, auxins influence the growth of stems toward the light (phototropism) and against the force of gravity (geotropism). The phototropic response occurs because greater quantities of auxin are distributed to the side away from the light than to the side toward it; the geotropic response occurs because more auxin accumulates along the lower side of the coleoptile than along the upper side. The downward growth of roots is also associated with a greater quantity of auxin in their lower halves. This effect, which is the opposite to that found in coleoptiles, is attributed to an inhibitory action of auxins on root growth, but this aspect of auxin action is not yet fully understood. Auxins have actions other than those associated with promoting growth; e.g., they play a role in cell division, in cell differentiation, in fruit development, in the formation of roots from cuttings, and in leaf fall (abscission). In experimental conditions, auxins tend to inhibit the progress of plant aging, perhaps because of their stimulating effect upon protein synthesis.

Gibberellins (gibberellin)
      Gibberellins are named after the fungus Gibberella fujikuroi, which produces excessive growth and poor yield in rice plants. One gibberellin is gibberellic acid (GA3), which is present in higher plants as well as in fungi; many related compounds have structural variations that correlate with marked differences in effectiveness.

      Gibberellins, abundant in seeds, are also formed in young leaves and in roots; they move upward from the roots in the xylem (woody tissue) and thus do not show the movement characteristic of auxins. Evidence suggests that gibberellins promote the growth of main stems, especially when applied to the whole plant. Unlike the auxins, gibberellins have little effect upon pieces of coleoptile in tissue culture. Gibberellins promote the growth of dwarf peas and are involved in the bolting (elongation) of rosette plants such as the carrot. Elongation of rosette plants occurs after exposure to certain environmental stimulation (e.g., cold, or long periods of daylight), which is accompanied by an increase in the gibberellin content of the affected plant. In experimental conditions gibberellins tend, like auxins, to retard senescence.

Cytokinins (cytokinin)
      Cytokinins are compounds derived from a nitrogen-containing compound (adenine). One cytokinin is 6-furfurylaminopurine (kinetin); other compounds derived from adenine with effects similar to those of kinetin, and certain compounds derived from another nitrogen-containing compound, urea, are conveniently referred to as cytokinins, although not all are natural products. Cytokinins are synthesized in roots, from which, like the gibberellins, they move upward in the xylem and pass into the leaves and the fruit. Required for normal growth and differentiation, cytokinins act, in conjunction with auxins, to promote cell division and to retard senescence (aging), which, at least in its early stages, is an organized phase of metabolism and not just a breakdown of tissue. An example of senescence is the yellowing of isolated leaves, which occurs as proteins are broken down and chlorophyll is destroyed. Cytokinins, which prevent yellowing by stabilizing the content of protein and chlorophyll in the leaf and the structure of chloroplasts, are used commercially in the storage of green vegetables.

Growth inhibitors
      Growth inhibitors of various types have been identified in plants. The best characterized one is abscisic acid, which is chemically related to the cytokinins. It is probably universally distributed in higher plants and has a variety of actions; for example, it promotes abscission (leaf fall), the development of dormancy in buds, and the formation of potato tubers. The mode of action of abscisic acid has not yet been clarified but is thought to involve the direct inhibition of the synthesis of RNA and protein.

      Another growth inhibitor is ethylene, which is a natural product of plants, formed possibly from linolenic acid (a fatty acid) or from methionine (an amino acid). Ethylene promotes abscission in senescent leaves, perhaps by facilitating the struction of auxin. Its effects extend beyond that of inhibiting growth; in fruit, for example, ethylene is regarded as a ripening hormone. Involved in its action in fruit is another factor, perhaps auxin or another growth-regulating hormone, which influences the ethylene sensitivity of the tissues.

      The hormonal interaction conspicuous in animals is found also in plants; one example is the control of abscission, which requires the synthesis of enzymes at an abscission zone, at the base of the structure concerned, to catalyze reactions involving breakdown of cell walls. Auxin reaching the abscission zone from the tip of the structure promotes abscission; if auxin reaches the structure from the opposite direction, however, it tends to inhibit the process, probably by its influence on metabolism. Other hormones are also involved in abscission; ethylene stimulates the synthesis of the enzymes, and abscisic acid accelerates the associated senescence. Gibberellin tends to inhibit abscission by promoting growth.

      Another example of hormonal interaction occurs during the germination of cereal seeds. The embryo (germ) is first activated by uptake of water, which enables it to produce gibberellin. Gibberellin acts on the living cells (aleurone layer) surrounding the food reserves (endosperm). This action induces the aleurone cells to produce enzymes that break down starch to sugars and release tryptophan from the protein of the endosperm. The tryptophan migrates to the coleoptile tip and is transformed into indolylacetic acid, which in turn moves to the growth zone and weakens the cell walls, thus permitting water uptake.

      The target tissues probably play a role in such sequential actions, and it is likely that changes in their responsiveness to hormonal action, perhaps correlated with environmental stimuli, contribute to adaptive integration. The similarities in the hormonal mechanisms of plants and animals, two groups that are so profoundly different in their structure and mode of life, effectively illustrate the fundamental uniformity of biological organization.

Ernest J.W. Barrington

Additional Reading
Comprehensive works are Henry R. Mahler and Eugene H. Cordes, Basic Biological Chemistry (1968); Abraham White et al., Principles of Biochemistry, 6th ed. (1978); Albert L. Lehninger, David L. Nelson, and Michael L. Cox, Principles of Biochemistry, 2nd ed. (1993); Thomas Briggs and Albert M. Chandler (eds.), Biochemistry, 2nd ed. (1992); John W. Hill, Dorothy M. Feigl, and Stuart J. Baum, Chemistry and Life, 4th ed. (1993); Lubert Stryer, Biochemistry, 3rd ed. (1988); Donald Voet and Judith G. Voet, Biochemistry (1990); Geoffrey Zubay, Biochemistry, 3rd ed. (1993); and Laurence A. Moran et al., Biochemistry, 2nd ed. (1994). David J. Holme and Hazel Peck, Analytical Biochemistry, 2nd ed. (1993), covers newer methods of analysis. Ed.More specific references on hormones include E.J.W. Barrington (ed.), Hormones and Evolution, 2nd ed., 2 vol. (1979), for students and general readers, concerned with the molecular structure and mode of action of hormones in relation to evolutionary theory; G.K. Benson and J.G. Phillips (eds.), Hormones and the Environment (1970), a wide-ranging review and research symposium; Max Hamburgh and E.J.W. Barrington (eds.), Hormones in Development (1971); W.R. Butt, Hormone Chemistry, 2nd rev. ed., 2 vol. (1975–76), a correlation of research on the major mammalian hormones, requiring some knowledge of chemistry; Sheldon Aaronson, Chemical Communication at the Microbial Level, 2 vol. (1981); Rex E. Coupland, The Natural History of the Chromaffin Cell (1965), an integrated treatment of research on structure and function, considered at all levels of analysis, from the gross anatomical to the molecular; John Ebling and Kenneth C. Highnam, Chemical Communication (1969), a concise elementary introduction for high school and first-year university students; G.V. Hoad et al. (eds.), Hormone Action in Plant Development (1987); B.E. Frye, Hormonal Control in Vertebrates (1967), an elementary introduction, with emphasis on general principles and physiological adaptation; John W. Buckle, Animal Hormones (1983); Claude A. Villee, Jr., Human Hormones (1987); M. Gabe, Neurosecretion (1966), an authoritative and comprehensive treatment; G.W. Harris, Neural Control of the Pituitary Gland (1955), an authoritative monograph for students and research workers; Mary Pickford, The Central Role of Hormones (1969), an elementary treatment for students and general readers with some knowledge of vertebrate biology; Clark T. Sawin, The Hormones: Endocrine Physiology (1969), a lucid treatment of hormone action for university students; Charles B. Nemeroff (ed.), Neuroendocrinology (1992); Barry D. Bercu (ed.), Basic and Clinical Aspects of Growth Hormone (1988); and Roman J. Kutsky, Handbook of Vitamins, Minerals, and Hormones, 2nd ed. (1981).Ernest J.W. Barrington Ed.

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