Luteinizing hormone (interstitial-cell-stimulating hormone)
Luteinizing hormone (LH; also called interstitial-cell-stimulating hormone, or ICSH) is another gonadotropin, a glycoprotein with a molecular weight of 26,000 in humans. 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. In the male LH promotes the development of the interstitial tissue (Leydig cells) of the testes and hence promotes 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.
Melanocyte-stimulating hormone (intermedin)
Melanocyte-stimulating hormone (MSH; or intermedin), secreted by the pars intermedia region of the pituitary gland, regulates color changes in animals by promoting the concentration of pigment granules in pigment-containing cells (melanocytes and chromatophores) in the skin of lower vertebrates. MSH acts in conjunction with the nervous system in bony fishes and reptiles. No response involving physiological color 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. MSH is known to influence the behavior of mammals and the total amount of pigment in their skin, which darkens in humans 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 color change, in contrast to the physiological one that occurs in the skin of lower vertebrates.
As noted above, MSH exists in three forms. α-MSH contains 13 amino acids, which are found in the same sequence in all species studied thus far. ß-MSH and γ-MSH vary in length and sequence. All three forms are derived from a protein known as proopiomelanocortin (POMC). A change in biological activity results from the differences in amino acid composition, in which each form is capable of activating a different melanocortin receptor (MCR).
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. 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 fibers from the hypothalamus into the adenohypophysis, so that the hypothalamic factors, when released, are either in immediate contact with the secretory cells or in blood capillaries very closely related to them. This route is characteristic of the pars intermedia region, in which neurosecretory fibers 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 fibers have regenerated.
Direct innervation similar to that of the pars intermedia is also found in the pars distalis of bony fishes. Here neurosecretory fibers 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. The median eminence is a neurohemal organ containing a capillary bed into which hypothalamic neurosecretory fibers 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.
Both hypothalamic neurosecretory routes have the same physiological significance: 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 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.
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In most mammals, the neurohormones are oxytocin and vasopressin (sometimes also called arginine vasopressin, since in many species the hormone contains arginine). 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. 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 while 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 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, vasopressin is also commonly known as antidiuretic hormone (ADH). A lack of this hormone in humans results in a copious flow of urine, a condition called diabetes insipidus, which is readily alleviated by pharmacological preparations containing vasopressin.
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. All show the same molecular structure but differ with respect to individual amino acids. The hormones are thought 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 molecules 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. Hypothalamic polypeptides may also 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. For example, 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
Biosynthesis
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. Evidence suggests that 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. 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 hormone. 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 humans 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.
Effects
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 3,400. 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 about 3,430.
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 remodeling 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, 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 remodeled; 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.
