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ЗмістDirect metabolic effects of growth hormone
Indirect actions of GH on skeletal growth
12.4 The thyroid gland
12.4 The thyroid gland
12.4 The thyroid gland
What causes the increase in oxygen consumption in response to thyroid hormone?
The thyroid hormones modify the metabolism of fats and carbohydrates to provide substrates for oxidation
Thyroid hormones stimulate both protein synthesis and degradation
Whole-body actions of thyroid hormones
The clinical features of thyroid hormone excess
The clinical features of hypothyroidism
12.5 The adrenal glands
12.5 The adrenal glands
Synthesis, storage, and secretion of adrenal cortical hormones
220 12 The hormonol regulation of the body
Principal actions of the adrenocorticosteroids
Effects of Cortisol
The hormonal regulation of the body
Complex, multicellular organisms require coordinating systems that can regulate and integrate the functions of different cell types. The two coordinating systems that have evolved are the nervous system and the endocrine system. The former uses elec-
trical signals to transmit information very rapidly between cells while the endocrine system uses chemical signaling. Chemical agents, hormones, are produced by a particular type of cell and travel in the bloodstream to other cells, upon which they exert a regulatory effect. A hormone is, therefore, a bloodborne chemical messenger (see also Chapter 5) and endocrinology is the study of
Fig. 12.1 The anatomical localization of the principal endocrine glands and the hormones they secrere.
tion of the principal endocrine glands is shown in Fig. 12.1. The figure also indicates the principal hormones secreted by each gland.
if -,11 the
physiological systems of the body. They are of particular importance in the regulation of growth, development, metabolism, the maintenance of a stable internal environment, and the reproductive processes of both men and women.
Originally, hormones were considered to be chemicals secreted by a specific endocrine gland into the bloodstream for transport to its target cells. Although many hormones and glands do fit this classical definition, it is now clear that such a description needs to be widened to include a variety of tissues which, while having other crucial roles within the body, also synthesize and secrete substances that exert effects on other cells. Examples of such organs include the heart, which secretes atrial natriuretic peptide (ANP), the liver, which secretes a number of growth factors, and the brain, which secretes specific hormones from the hypothalamus. Recently it has been shown that adipose tissue secretes a hormone (leptin) that travels to the brain where it acts to regulate food intake. A number of tumor cells are also known to be capable of secreting polypeptide hormones which may result in specific disease processes. An example of a hormone-secreting tumor is the small cell carcinoma of the lung
Table 12.1 The secretion of hormones by nonclassical endocrine tissues
corticotropic hormone), vasopressin (antidiuretic hormone or ADH), and a parathyroid hormone-like agent. A list of the
mainr 'non-classical' endocrine organs is shown in Table 12.1. Not all hormones travel in the general circulation. Some, like
the hypothalamic releasing hormones, do not enter the systemic circulation in appreciable quantities. Others exert their effects at a still more local level, in some cases acting only on contiguous cells (a so-called paracrine action) or even performing an autocrine function in modifying the secretory action of the cells that produce them (Chapter 5). One such example is estradiol which, in addition to its normal endocrine role, also modifies the activity of the follicular granulosa cells that secrete it (Chapter 19).
While clearly differing in several respects, the nervous and endocrine systems are closely linked. Many neurons are capable of secreting hormones. This is known as neurosecretion and is seen, for example, in the hypothalamus, where releasing hormones are secreted into specialized portal blood vessels, which carry them to the anterior pituitary gland where they alter the rate of secretion of other hormones. The hormones of the posterior pituitary gland are also synthesized and secreted by neurons. Certain agents which were originally believed to act only as bloodborne hormones, have since been shown to act as neurotransmitters within the central nervous system. Examples are the gastrointestinal hormones gastrin and cholecystokinin.
The chemical nature of hormones, their
carriage in the blood, and their modes of
Hormones fall into three broad categories according to their chemical properties:
The chemical nature of hormones influences the manner in which they are transported in the bloodstream. While the catecholamines and peptide hormones generally travel in free solution in the plasma, the steroids and thyroid hormones are very hydrophobic and are carried in the blood bound to a variery of plasma proteins, including albumin. The specific binding
12.1 introduction 201
proteins have a high affinity for one, or sometimes several, hormones. Examples of these include testosterone-binding globulin, cortisol-binding globulin, and thyroid hormone-binding globulin.
Hormones that are bound to carrier proteins in the plasma are cleared from the circulation much more slowly than those traveling in free solution. This means that their half-lives in the blood are much longer and helps to explain why the effects of steroids and thyroid hormones are more long-lasting than those of peptide hormones. This ensures a regulated endocrine response and a constant rate of tissue delivery.
All hormones act by binding to specific receptors on their target cells. These may be situated on the plasma membrane itself, within the cytoplasm, or in the nucleus. The details of the mechanisms of hormone action are discussed in Chapter 5. Briefly, steroid and thyroid hormones are thought to diffuse into cells before binding to intracellular receptors, primarily within the cytoplasm, and the receptor—hormone complex then migrates to the nucleus to alter gene expression. Water-soluble protein hormones, catecholamines, and neurotransmitters bind to receptors on the plasma membrane where they exert their effects either through second messengers such as calcium, cyclic AMP, and inositol trisphosphate (IP3) or by activating membrane-bound kinases which act to alter gene expression.
Measurement of hormone levels in body fluids
Most hormones are present in the plasma and other body fluids in very low concentrations. Modern assay techniques have, nevertheless, made it possible to detect and quantify these hormone levels to give information concerning their rates of secretion, half-lives, and rates of clearance from the blood. Such information is valuable in the assessment of endocrine function.
The earliest hormone assays were mostly based on the biological response of a tissue or whole animal to a hormone, the bioassay. Most of these lacked precision, specificity, and sensitivity. Although chemical analysis of body fluids has been used to measure the plasma levels of the catecholamines, it has been of limited value in the measurement of plasma levels of other hormones. The whole field of endocrinology was revolutionized by the development of competitive binding assays and radioimmunoassays. While these assays measure immunological rather than biological activity, they are relatively quick, sensitive, and specific. Radioimmunoassays are now available for all the polypeptide, thyroid, and steroid hormones, and are the most widely used form of hormone assay.
Patterns of hormone secretion—circadian rhythms and feedback control
Many bodily activities show periodic or rhythmic changes that are controlled by the brain. Some of these patterns follow
environmental cues such as the light/dark cycle or the sleep/ wakefulness cycle, while some appear to be independent of the environment and are driven by an internal biological clock. Such 24-hour rhythms are called circadian rhythms (Chapter 11). The secretion of several hormones, including pituitary ACTH, Cortisol, growth hormone, and prolactin, follows circadian rhythms. Knowledge of such patterns of hormone secretion is important when interpreting the results of assays performed on blood samples obtained at different times of the day.
Many biological systems, including the secretion of hormones, are regulated by negative feedback so that the response to a particular signal feeds back on the signal generator to inhibit the signal (Chapter 1). In the case of endocrine systems, such feedback regulation may be seen when the target tissue itself secretes a hormone. Many of the anterior pituitary hormones show negative feedback control of this kind. Thus, for example, thyroid-stimulating hormone (TSH) stimulates the output of thyroid hormones from the thyroid gland. Once released into the bloodstream, thyroid hormones (T5 and T4) exert negative feedback on the anterior pituitary gland to inhibit the release of TSH. In this way the secretion of TSH is kept within narrow limits.
Although negative feedback is the most widespread form of endocrine regulation, positive feedback is also seen under some conditions. During the ovarian cycle, for example, the preovulatory gonadotropin surge is brought about by the positive feedback actions of estrogens on the anterior pituitary (Chapter 19). Positive feedback is also seen during parturition when oxytocin, a powerful spasmogenic agent, is secreted in response to stretch of the uterus and vagina.
12 The hormonal regulation of the body
12.2 The pituitary gland and the hypothalamus
The pituitary gland is situated in a depression of the sphenoid bone at the base of the skull called the sella turcica. It consists of two anatomically and functionally distinct regions, the posterior lobe and the anterior lobe. Between these two lies a small sliver of tissue called the intermediate lobe. The anterior lobe is derived from embryonic ectoderm as an upgrowth from the pharynx. The posterior lobe is neural in origin.
Figure 12.2 illustrates the way in which the pituitary gland is formed during the first trimester of gestation. In the early embryo, the roof of the mouth lies adjacent to the third ventricle of the brain and both sheets of tissue bulge towards each other, the buccal cavity bulging upwards to form Rathke's pouch, and the neural ectoderm downwards to form the infundibulum. Eventually, Rathke's pouch pinches off from the rest of the
Fig. 12.2 The embryonic development of the pituitary gland. (a)—(c) Outgrowths of neural and ectodermal tissue, with separation of Rathke's pouch, (d) The structure of an adult gland.
pharyngeal ectoderm and folds around the infundibulum. Embryogenesis is complete at around 11 or 12 weeks of gestation in humans. The neural tissue, which remains as part of the brain, forms the posterior pituitary and the non-neural tissue forms the anterior pituitary.
The neurohypophysis consists strictly of three parts: the median eminence, which is the neural tissue of the hypothalamus from which the pituitary protrudes; the posterior pituitary itself; and the infundibular stem which connects the two.
The adenohypophysis consists of two portions, the anterior pituitary itself (also called the pars distalis) and the much smaller pars tuberalis, which is wrapped around the infundibular stem to form the pituitary stalk. The principal features of the hypothalamo-pituitary system are shown in Fig. 12.3.
The anterior pituitary gland lies at the core of the endocrine system. It secretes at least seven different hormones, many of which regulate the secretions of other endocrine organs. Nevertheless, the anterior pituitary is itself under the control of hormones secreted by neurons in the hypothalamic region of the brain. The hypothalamus, pituitary, and the products of its target tissues form a complex functional unit.
Although the anterior pituitary receives relatively little direct neural input from the median eminence, it is now understood that the hypothalamus plays a key role in regulating pituitary function. Between the hypothalamus and the anterior pituitary there is a system of blood vessels known as the hypothalamic-hypophyseal portal system. This system originates in capillary loops in the median eminence—the primary plexus. Blood then flows in parallel veins, the long portal vessels, down the pituitary stalk to the anterior lobe. Here the portal veins break up into sinusoids which form its main blood supply. The blood supply of the anterior pituitary is shown in Fig. 12.3. It is now clear that the role of this system is to transport specific hormones secreted by the neurons of the median eminence to the anterior pituitary, where they regulate the output of the pituitary hormones (see below).
The hormones of the anterior pituitary
The hormones of the anterior pituitary are listed in Table 12.2. They are all protein or polypeptide agents. The major hormones are:
All of these hormones will be discussed fully in the relevant sections dealing with their target glands. For a detailed dis-
12.2 The pituitary gland and the hypothalamus
Fig. 12.3 The relationship between the hypothalamus and the pituitary gland. Note the prominent portal system that links the hypothalamus to the anterior pituitary gland. The anterior pituitary has no direct neural connection with the hypothalamus. In contrast, nerve fibers from the paraventricular and supraoptic nuclei pass directly to the posterior pituitary where they secrete the hormones they contain into the bloodstream.
Table 12.2 The anterior pituitary hormones
204 12 The hormonal regulation of the body
cussion of the actions of the gonadotropins and prolactin see chapters 19 and 22.
The various pituitary cell types which secrete the anterior pituitary hormones line the blood sinusoids and, on the basis of electron microscopic examination of granule size and number, the cells secreting certain pituitary hormones can be identified. At least five different endocrine cell types may be distinguished. Although many of the cells secrete only one type of hormone (e.g. lactotrophs secrete prolactin and somatotrophs secrete growth hormone), it is now known that some of the pituitary cells are able to produce more than one hormone. The best example of this is provided by the gonadotrophs, many of which secrete both FSH (follicle-stimulating hormone) and LH (luteinizing hormone). Furthermore the corticotrophs, although chiefly secreting ACTH (adrenocorticotropic hormone), also secrete jS-lipotropin and a- and /3-melanocyte-stimulating hormones.
Growth hormone and prolactin
These hormones bear considerable structural similarities with one another. They are both single peptide chains, prolactin having 198 amino acid residues and growth hormone (GH) 191. GH is synthesized and stored in somatotrophs, which are the most abundant pituitary cell type. It acts upon every tissue of the body, exerting powerful effects on growth and metabolism. The effects of growth hormone will be discussed in detail in Section 12.3.
Prolactin is also weakly somatotropic (reflecting its structural closeness to GH) but its predominant action is to promote
growth and maturation of the mammary gland during pregnancy in order to prepare it for milk secretion (for more details
see Chapter 22).
Adrenocorticotropic hormone (ACTH)
ACTH is a small polypeptide hormone consisting of a chain of 39 amino acid residues which is derived from a much larger precursor molecule, pre-pro-opiomelanocortin, which also gives rise to jS-lipotropin, /3-endorphin—an endogenous opioid, part of which may further split off to form met-enkephalin, a-MSH, and CLIP (a corticotropin-like peptide), as well as a variety of other peptides with unknown physiological properties. The relationships between these peptides derived from the common precursor are illustrated in Fig. 12 A.
ACTH regulates the function of the adrenal cortex, playing a crucial role in the stimulation of glucocorticoid secretion in response to stress. Its pattern of secretion varies during the day, showing a typical circadian rhythm. ACTH secretion is also markedly inhibited by glucocorticoids (steroid hormones secreted from the adrenal cortex, see Section 12.5). This inhibition provides a classic example of the negative feedback regulation of hormone secretion.
Melanocyte-stimulating hormone (MSH)
The chemical structure of MSH is related to that of ACTH but although ACTH has some MSH-like activity MSH does not appear to share any of the actions of ACTH. In certain species it
Fig. 12.4 The relationship between the amino acid sequences of the various hormones derived from pre-pro-opiomelanocortin. ACTH, β-lipoprotein, /S-endorphin and a 76-amino-acid peptide are the end products that are secreted by the anterior lobe of the pituitary gland. The number of amino acids in each peptide is given in brackets after the peptide name, a, /3 refer to the sequences of a and /3 MSH.
12.2 The pituitary gland and the hypothalamus
plays a role in skin pigmentation and the control of sodium excretion but the physiological significance of these effects in humans is unclear.
Pituitary glycoprotein hormones—
thyroid-stimulating hormone (TSH),
follicle-stimulating hormone (FSH), and
luteinizing hormone (LH)
The pituitary glycoprotein hormones consist of two interconnected amino-acid chains (a- and /3-subunits) containing a carbohydrate moiety. The α-subunits of all three hormones are identical while the /3-subunits confer biological specificity (another example of a 'family' of related hormones). They are all tropic hormones which means that they not only regulate the secretions of their target glands but are also responsible for the maintenance and integrity of the target tissue itself. TSH controls the function of the thyroid gland, and the output of the thyroid hormones thyroxine and triiodothyronine (see Section 12.4 for further details). The secretion of TSH is under strong negative feedback control.
The gonadotropins, FSH and LH, control the cyclical activity of the ovaries. They play an important role in spermatogenesis by the testes and in the production of the sex steroids in both sexes. Both negative and positive feedback control mechanisms may operate to control their release (Chapter 19).
The secretion of the anterior pituitary
hormones is controlled by hormones
released by the hypothalamus into the
hypophyseal portal blood
The hypothalamus controls the anterior pituitary gland. Specific hormones are synthesized in the cell bodies of neurons lying
within discrete areas of the median eminence. They move along the axons by axonal transport, and are then released from the nerve terminals into the hypophyseal portal blood in response to neural activity. The hypothalamic hormones are then carried down the pituitary stalk to the anterior lobe where they act on specific pituitary cells to modify the secretion of one, or sometimes several, of the anterior pituitary hormones.
The rates of secretion of TSH, FSH, LH, ACTH, MSH, and the other peptides related to ACTH are all stimulated by hypothalamic hormones (known as releasing hormones) while prolactin secretion is mainly regulated by the inhibitory effect of dopamine. The release of GH (growth hormone) is under dual control by the hypothalamus. Its secretion is stimulated by growth hormone-releasing hormone (GHRH) and suppressed by another peptide which is also found in locations other than the hypothalamus, called somatostatin or growth hormone-inhibiting hormone (GHIH). All the major hypothalamic releasing and inhibiting hormones, along with their target hormones and alternative names, are listed in Table 12.3.
The hypothalamic releasing hormones are
localized to specific groups of neurons in
the median eminence
The neurons that synthesize and store the various hypothalamic releasing hormones have been identified by immunocytochem-istry (a specific staining technique that identifies substances by their immunological reactivity). Most of the releasing hormones seem to be produced by relatively discrete groups of neurons in the median eminence. Corticotropin-releasing hormone (CRH), for example, is located mainly in the paraventricular nucleus, along with vasopressin which also stimulates ACTH secretion. Gonadotropin-releasing hormone (GnRH) is found mainly in
Table 12.3 The hypothalamic releasing and inhibitory hormones with their alternative names
12 The hormonal regulation of the body
Fig. 12.5 Location of the principal nuclei of the hypothalamus that are associated with the production and secretion of releasing hormones.
neurons of the medial preoptic area and in the arcuate nucleus. Dopamine is also present in neurons of the arcuate region, while thyrotropin-releasing hormone (TRH) is located in both the preoptic and paraventricular nuclei. A simple diagram showing the positions of these nuclei is shown in Fig. 12.5.
A further point to note is that some of the hypothalamic hormones may be found in parts of the body other than the hypothalamus, acting in different ways. Somatostatin, for example, is found acting as a neurotransmitter in other parts of the brain, as a hormone throughout the gut, and in the pancreas as an inhibitor of the release of insulin and glucagon.
Feedback mechanisms operate -within the
hypothalamo-pituitary—target tissue axes
to ensure fine control of endocrine
The introduction to this chapter includes a brief discussion of the regulatory role played by both negative and positive feedback mechanisms throughout the endocrine systems of the body. Such processes are of the utmost importance in determining the responsiveness of the anterior pituitary to the hypothalamic releasing hormones and thereby in the overall control of the secretion not only of the anterior pituitary hormones but also of its target glands.
In many cases, the output of a pituitary hormone is increased by the removal of its target gland. For example, removal of the thyroid gland, with the subsequent loss of the thyroid hormones, stimulates an increase in the output of thyroid-stimulating hormone (TSH) from the anterior pituitary. It is believed that
the responsiveness of the TSH-secreting pituitary cells to hypothalamic thyrotropin-releasing hormone (TRH) is enhanced in the absence of thyroid hormones. Similarly, administration of exogenous thyroxine depresses the output of TSH by reducing pituitary sensitivity to TRH. There may also be a direct effect of thyroid hormones on the output of TRH itself. Other feedback loops are thought to operate in a similar fashion to modulate pituitary function. ACTH secretion, for example, is depressed by the adrenal steroids as a result of both a direct inhibition of CRH release and a reduction in the responsiveness of the ACTH-secreting cells of the anterior pituitary.
Although the secretion of prolactin is largely controlled by the inhibitory action of dopamine, its release is stimulated by TRH. Like the other hormones discussed above, prolactin secretion is still subject to negative feedback control. In this case, however, prolactin inhibits its own release by stimulating further output of dopamine.
The role of the posterior pituitary gland (neurohypophysis)
As described above, the posterior lobe of the pituitary gland develops as a downgrowth from the hypothalamus but, unlike the anterior pituitary, it remains connected to the hypothalamus via a nerve tract (the hypothalamo-hypophysial nerve tract). For this reason it is also known as the neurohypophysis or neural lobe.
The posterior pituitary secretes two hormones. These are oxytocin and vasopressin (or ADH). The hormones are synthesized within the cell bodies of large (magnocellular) neurons lying in the supraoptic and paraventricular nuclei of the hypothalamus. They are transported in association with specific proteins, the neurophysins, along the axons of these neurons to end in nerve terminals which lie within the posterior lobe. Prior to secretion they are stored in secretory granules, or vesicles, either in the ter-
Fig. 12.6 The relationship between the supraoptic and paraventricular nuclei and the posterior pituitary gland (the neurohypophysis). The neurosecretory fibers originate in these nuclei and terminate in the posterior pituitary gland itself.
12.2 The pituitary gland and the hypothalamus
Fig. 12.7 The amino-acid sequences of arginine vasopressin and oxytocin. The small differences in structure result in molecules that have very different physiological effects.
minals themselves, or in varicosities (Hering bodies) along the length of the axons (Fig. 12.6). The hormones are secreted into the capillaries that perfuse the neural lobe in response to nerve impulses originating in the supraoptic and paraventricular nuclei. Both oxytocin and vasopressin are secreted by calcium-dependent exocytosis, similar to the secretion of neurotransmitters at other nerve terminals (Chapter 5).
Oxytocin and vasopressin (ADH) are
closely related structurally but have
Oxytocin and vasopressin are both nonapeptides and differ in only two of their amino-acid residues, as shown in Fig. 12.7. Although they are secreted along with the neurophysin molecules to which they are bound in the neurons, once released they circulate in the blood largely as free hormones. The kidneys, liver, and brain are the main sites of clearance of these peptides, which have a half-life in the bloodstream of around a minute.
Both oxytocin and vasopressin acr on their target cells via G-protein-linked cell-surface receptors (Chapter 5). Interaction of oxytocin with its receptors stimulates phosphoinositide turnover and thereby raises the level of intracellular calcium in the myoepithelial cells of the mammary gland. In turn, the increased intracellular calcium activates the contractile machinery to cause milk ejection. There are two main classes of vasopressin receptors, V, and V2. Interaction with V\ receptors increases phosphoinositide turnover and elevates intracellular calcium. V1 receptors mediate the effects of vasopressin on vascular smooth muscle. The renal actions of the hormone are mediated by V2 receptors with cAMP as the second messenger (Chapter 17).
Actions of vasopressin (ADH)
The principal physiological action of vasopressin is as an antidiuretic hormone. This role is discussed in more detail in Chapter 17. Briefly, it facilitates the reabsorption of water from the distal tubule and collecting ducts of the kidney by increasing the permeability of the cells to water. The net result of its
actions is an inctease in urine osmolality and a dectease in urine flow. Additional renal effects of vasopressin include stimulation of sodium reabsorption and urea transport from lumen to intetstitial fluid in the medullary collecting duct. By this action vasopressin helps to maintain the osmotic gradient from cortex to papilla which is crucial for the elaboration of a concentrated urine.
Vasopressin, as irs name suggests, is also a potent vasoconstrictor, acting particularly on the arteriolar smooth muscle of the skin and splanchnic circulation. In spite of this, the increase in blood pressure brought about by vasopressin is small under normal circumstances because the hormone also causes bradycardia and a decrease in cardiac output, both actions that tend to offset the increase in total peripheral resistance. The vasoconstrictor effect of vasopressin is important during severe hemorrhage or dehydration (Chapter 28). Vasopressin has a CRH-like activity whereby it stimulates the release of ACTH from the anterior pituitary. It may also play a role in the control of drinking behavior.
The circumstances under which vasopressin (ADH) is secreted are discussed in Chapters 17 and 28. A brief resume will be given here. Figure 12.8 illustrates the changes in plasma osmolality and volume that control vasopressin release. The principal physiological stimulus for its release is an increase in the osmolality of the circulating blood. Osmoreceptors located in the hypothalamus sense this increase and activate neurons in the supraoptic and paraventricular neurons. As a result of the increased rate of action potential discharge of these neutons vasopressin secretion into the circulation is increased.
Vasopressin is secreted in response to a fall in the effective circulating volume (ECV), during hemorrhage for example (Chapter 28), and in response to other factors, including pain, stress, and other traumas. The amount of vasopressin secreted when there is a fall in the ECV increases proportionately as the central venous pressure and arterial pressure fall. Central venous pressure is sensed by the low-pressure receprors (volume receptors) of the atria and great veins, while the arterial blood pressure is sensed by the arterial baroreceptors which are located in the carotid sinuses and aortic arch (see Chapter 15 for further details).
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