Hormones and growth factors
This chapter discusses hormones and growth factors. Cells are highly sensitive to a variety of chemical signals, and the overall activities of tissues in different metabolic states are to a large extent controlled by hormones. Hormones are involved in both short- and long-term control. Hormones may be defined as substances that are produced in very small amounts and are carried in the blood from the site of their production to a specific target tissue or tissues where they bring about a response that is appropriate to the functioning of the body as a whole. Hormones are essential for normal development and activity, and most of them are produced continuously at a slow rate. Under certain conditions, however, much larger amounts are released and the factors that trigger their release are more or less specific for each endocrine gland. The effects of hormones are individual and striking. Hormones produced by specialized cells but not by clearly defined endocrine glands include gastrin, secretin, pancreozymin, and enterogastrone, which are produced in the alimentary canal, and renin and erythropoietin, which are produced by the kidney. Several other substances that have hormone-like activity are widely distributed and exert their effects in the area in which they are produced. Histamine, serotonin, and various plasma kinins are considered to be local hormones.
Cells are highly sensitive to a variety of chemical signals and the overall activities of tissues in different metabolic states are to a large extent controlled by hormones. Hormones are involved in both short- and long-term control.
Hormones may be defined as substances that are produced in very small amounts and are carried in the blood from the site of their production to a specific target tissue or tissues where they bring about a response that is appropriate to the functioning of the body as a whole. Hormones are essential for normal development and activity and most of them are produced continuously at a slow rate. Under certain conditions, however, much larger amounts are released and the factors that trigger their release are more or less specific for each endocrine gland.
The effects of hormones are individual and striking. Hormones produced by specialized cells but not by clearly defined endocrine glands include gastrin, secretin, pancreozymin and enterogastrone, which are produced in the alimentary canal, and renin and erythropoietin, which are produced by the kidney.
Several other substances which have hormone-like activity are widely distributed and exert their effects in the area in which they are produced. Histamine, serotonin and various plasma kinins may be considered to be local hormones.
Chemically speaking there are three types of hormone, steroids, amino acid derivatives and polypeptides. The steroid hormones include the adrenal cortical hormones and the sex hormones. The amino acid derivatives are adrenaline, noradrenaline and thyroxine which are all derived from tyrosine. The remainder, which constitute the largest group, are oligo- and polypeptides with chain lengths varying from three amino acid residues in thyrotropin-releasing hormone to nearly 200 residues in growth hormone and prolactin. Sometimes a hormone has completely different effects in different species. For example prolactin, which stimulates the development of the mammary glands in pregnant mammals, acts as a general growth stimulant in amphibians and reptiles, and plays a part in the regulation of salt and water balance in certain fishes. On the other hand, human, pig, rabbit and beef insulins show small structurual differences but have similar activities. This is fortunate for diabetics who have been able to lead normal lives with the help of insulin derived from other species. With growth hormone the situation is different since humans only respond to growth hormone from humans or other primates. Consequently only a very few of the people who suffer from lack of growth hormone can be given replacement therapy although recombinant DNA techniques give hope for the future.
The factors that trigger hormonal release are many and varied, their nature depending on the hormone in question; for example, adrenaline and noradrenaline are secreted in response to stimulation of the sympathetic system. Insulin is secreted in response to an increase in the blood sugar level, while glucagon is secreted when the level falls. A dual control system also operates with respect to the regulation of the level of Ca2+ ions in blood. When this is lowered parathormone is secreted, while calcitonin is secreted when the level is raised. These systems both appear to operate on a simple negative feedback basis, and when the level of glucose or Ca2+ ions in the blood has been restored to normal, the hormone levels are also restored.
In many instances the regulation of hormone output is more complex. The gonadotropins and several other hormones are under the control of the anterior pituitary which secretes a whole range of peptide hormones, including growth hormone, adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH) and luteinizing hormone (LH) which exert their effects on other endocrine glands.
Since hormones are needed in particular circumstances, means for their destruction or removal are required. This usually involves enzymic modification which either inactivates the hormone or converts it into a form suitable for excretion in the urine.
Hormones such as insulin occur in the plasma at concentrations in the range 10−9–10−10 M, which is a million times lower than the concentration of metabolites in cells. For measurement of the latter very sensitive spectrophotometric techniques are required while the understanding of hormone function has largely depended on the development of the radioimmunoassay technique for estimating peptide hormones.
In order to assay insulin by this method, a specific insulin-binding antibody must be produced. A sample of insulin is then radioactively labelled by incorporation of 125I into some of its tyrosine residues. When the radiolabelled hormone is mixed with the antibody, a complex is formed which can be separated by centrifugation, and the radioactivity that has been bound measured. The assay is calibrated by mixing a constant amount of radiolabelled insulin with known amounts of a standard solution of unlabelled insulin, adding an exact amount of antibody and measuring the radioactivity bound. Since the antibody will bind native insulin and iodinated insulin with the same affinity, there will be competition between labelled and unlabelled insulin for the available binding sites. The more unlabelled insulin there is present, the less labelled insulin will be bound and vice versa. A typical calibration curve for such an assay is shown in Figure 24.1. The concentration of insulin in an unknown solution may then be measured by mixing the solution with radioactive insulin and antibody as before, measuring the radioactivity bound and reading the insulin concentration from the calibration curve.
Similar principles may be used for the assay of many other hormones. The radioimmunoassay technique is widely used in research into the mechanism of hormone synthesis and secretion, and is also used to determine the concentration of hormones in plasma in normal and pathogenic conditions.
The actions of hormones are very diverse. Some, e.g. glucagon, have specific and clearly defined effects on the metabolism of particular tissues. Others such as growth hormone and the sex hormones have more general effects on growth and development while the tropic hormones stimulate their target tissues to secrete further hormones. For example the adrenocorticotropic hormone (ACTH), which is produced in the anterior pituitary, promotes the synthesis and release of glucocorticoids by the adrenal cortex. A list of some of the hormones and their effects on metabolism is given in Table 24.1.
|Hormone||Type||Site of production||target||Effect|
|Insulin||Polypeptide||β-Cells of pancreatic islets||Most tissues||Regulation of carbohydrate, fat and protein metabolism. Lowers blood glucose|
|Glucagon||Polypeptide||α-Cells of pancreatic islets||Liver||Increase in glycogenolysis. Hyperglycaemia. Increased gluconeogenesis. Mobilization of fat|
|Tyrosine derivatives||Thyroid||Most tissues||Increase in metabolic rate. General role in growth and development|
|Calcitonin||Polypeptide||Thyroid||Bones and kidney||Decrease in blood calcium concentration. Inhibition of calcium release from bones. Increased excretion of calcium and phosphorus|
|Parathormone||Polypeptide||Parathyroid||Bones and kidney||Elevation of blood calcium concentration. Mobilization of calcium from bones and decreased excretion by kidney|
|Adrenaline||Tyrosine derivative||Adrenal medulla||Most cells||Numerous vascular effects. Increased glycolysis and lipolysis. Hyperglycaemia|
|Steroids||Adrenal cortex||Most cells||Hyperglycaemia. Increased gluconeogenesis. Balancing carbohydrate, fat and protein metabolism. Anti-inflammatory effects|
|Aldosterone||Steroid||Adrenal cortex||Kidney||Promotes reabsorption of Na+ in the kidney|
|Growth hormone (somatotropin)||Polypeptide||Anterior pituitary||All tissues||Growth of tissues. Promotes nitrogen retention|
|Adrenocorticotropin (ACTH)||Polypeptide||Anterior pituitary||Adrenal cortex||Promotion of synthesis and release of glucocorticoids|
|Thyrotropin (TSH)||Polypeptide||Anterior pituitary||Thyroid||Promotion of synthesis and release of thyroid hormones|
|Oxytocin||Polypeptide||Posterior pituitary||Uterus and mammary glands||Contraction of smooth muscle. Milk ejection|
|Vasopressin||Polypeptide||Posterior pituitary||Kidneys and blood vessels||Reabsorption of water. Contraction of smooth muscle|
Since hormones regulate pre-existing processes within the cell, before they can act they must either enter the cell themselves or they must use a messenger molecule which the hormone causes to enter or to be produced within the target cell. The ability of the target cell to respond to any particular extracellular signalling molecule depends on it posssessing a specific receptor protein which binds the signalling molecule with high affinity. The receptor protein may either be built into the cell membrane or may be located inside the cell.
Each different type of cell possesses a distinctive set of protein hormone receptors which determines the signals to which it will respond but the actual response of the target cells to a particular signal is characteristic of the tissue in question.
Most hormones are water-soluble, the main exceptions being the steroid and thyroid hormones. These are more or less insoluble in water and are carried in the bloodstream bound to special carrier proteins. Being hydrophobic, once they have been released from their carrier, they are able to pass through the plasma membrane and bind to specific receptor proteins inside the cell. Whereas water-soluble hormones are usually removed from the bloodstream or broken down within a few minutes, the steroid hormones may remain in the blood for hours and the thyroid hormones for days, so that their effects are usually of relatively long duration.
Not only do steroid hormones persist for a relatively long time in blood but they are also responsible for relatively long-term alterations in the metabolism of their target cells. A typical target cell possesses about 10000 steroid receptors and the effect of their activation is usually to change the amounts of particular enzymes within the cell. Cortisol is a typical steroid hormone which operates in this way but much of the work on the mechanism of action of the steroid hormones has been carried out using the female sex hormone oestradiol and it is thought likely that the mechanism of its action may be common to all steroid hormones.
After entering the target cell, each type of steroid hormone binds with high affinity to a specific type of receptor in the cytoplasm. The hormone-receptor complex then undergoes some sort of transformation, as shown by an increase in its sedimentation rate, after which it migrates to the nucleus and binds to the DNA at specific sites (Figure 24.2). After binding to the chromatin the hormone-receptor complex seems to stimulate the transcripton of specific genes with the production of the corresponding mRNA molecules. The response to a steroid hormone may take place in two stages. In the primary response there is a direct induction of transcription of certain genes while, in the secondary response, further genes are activated by the products of the primary response. The actual nature of the response is determined by the nature of the target cell. For example, oestradiol causes epithelial development in the uterus and mammary glands while it decreases the resorption of bone.
Most of the non-steroid hormones are unable to enter their target cells directly and instead they bind to high-affinity receptors on the cell surface. Some of them, e.g. insulin and thyroid-stimulating hormone (TSH), are taken into the cell by receptor-mediated endocytosis but it is uncertain whether, once inside the cell, they have a direct effect on cell processes or use an intermediary.
The majority of hormones that bind to cell surface receptors do not enter the cell at all but instead they generate an intracellular signal or second messenger and it is this which is responsible for altering the behaviour of the cell. They may do this by changing the activity of an enzyme bound to the plasma membrane or by opening or closing gated ion channels (page 197) within the plasma membrane. The most important membrane-bound enzyme with respect to such hormones is adenylate cyclase which catalyses the synthesis of cAMP from ATP in the cytoplasm.
cAMP acts as an intracellular regulator in both eukaryotes and prokaryotes and all its known effects result from the activation of cAMP-dependent protein kinases which use ATP to phosphorylate proteins. Other enzymes or phosphodiesterases which are present in the cytosol break down cAMP to 5’-AMP.