The endocrine and metabolic systems of the body consist of glands with organs that secrete hormones into the circulation. Thus secreted hormones modulate tissue function elsewhere in the body, and these effects will be relatively slow compared to other communication processes (e.g. neurons). Glands include the hypothalamus, pituitary, thyroid, adrenals, gonads, pancreatic islets of Langerhans and parathyroids. Seven major physiological functions are regulated, and these are control of blood sugar levels, growth and development (growth hormone-insulin growth factor, IGF axis), metabolic rate (thyroid hormone), ion (calcium ion, Ca 2+ ) homeostasis, reproduction function (sex steroids), adaption to physiologic stress (glucocorticosteroids), and circulatory volume ( Table 17.1 ). This chapter discusses the function and pharmacology of the thyroid, the adrenal cortex, the pancreas and blood sugar and the reproductive systems. Ca 2+ homeostasis is discussed in Chapter 20 (Drugs and the musculoskeletal system), and circulatory volume in Chapter 18 (Drugs and the renal system) and Chapter 14 (Drugs and the cardiovascular system). Additional discussion on disorders of the genitourinary system is found in Chapter 22 (Drugs and the genitourinary system).
| Endocrine function | Regulatory factors | Endocrine organ/hormone | Target tissues |
|---|---|---|---|
| Availability of metabolic energy (fuel) | Serum glucose, amino acids, enteric hormones (somatostatin, cholecystokinin, gastrin, secretin), vagal reflex, sympathetic nervous system | Pancreatic islets of Langerhans/insulin, glucagon | All tissues, especially liver, skeletal muscle, adipose tissue, indirect effects on brain and red blood cells |
| Metabolic rate | Hypothalamic thyrotropin-releasing hormone (TRH), pituitary thyrotropin (TSH) | Thyroid gland/triiodothyronine (T 3 ) | All tissues |
| Circulatory volume | Renin, angiotensin II, hypothalamic osmoreceptor | Adrenals/aldosterone Pituitary/vasopressin | Kidney, blood vessels, central nervous system (CNS) |
| Somatic growth | Hypothalamic growth hormone-releasing hormone (GHRH), somatostatin, sleep, exercise, stress, hypoglycemia | Pituitary/growth hormone Liver/insulin-like growth factors (IGFs) | All tissues |
| Calcium homeostasis | Serum calcium ion (Ca 2+ ) and magnesium ion (Mg 2+ ) concentration | Parathyroid glands/parathyroid hormone, calcitonin, vitamin D | Kidney, intestines, bone |
| Reproductive function | Hypothalamic gonadotropin-releasing hormone (GnRH), pituitary follicle-stimulating hormone (FSH) and luteinizing hormone (LH) inhibins | Gonads/sex steroids Adrenals/androgens | Reproductive organs, CNS, various tissues |
| Adaptation to stress | Hypothalamic corticotropin-releasing hormone (CRH), pituitary adrenocorticotropic hormone (ACTH), hypoglycemia, stress | Adrenals/glucocorticosteroids, epinephrine | Many tissues: CNS, liver, skeletal muscle, adipose tissue, lymphocytes, fibroblasts, cardiovascular system |
The Hypothalamic-Pituitary Axis
The hypothalamus and pituitary glands integrate physiological signals and release hormones that then regulate the production of hormones affecting the function of other glands, for example adrenocorticotropin (ACTH) acting on the adrenal cortex, thyroid stimulating hormone (TSH) acting on the thyroid, growth hormone (GH) acting on the liver, and prolactin, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) acting on the female reproductive system ( Fig. 17.1 ).
The Adrenal Cortex
The adrenal cortex produces steroids. Principal adrenal steroids are the glucocorticoids (GC) (e.g. hydrocortisone and cortisone) and the mineralocorticoids (MC) (e.g. aldosterone). Some sex steroids (mainly androgens) are also secreted. Synthetic steroids have been developed in which the GC and the MC actions have been separated. Examples are prednisolone (GC > MC), fludrocortisone (MC > GC).
Glucocorticoids
GCs are not stored pre-formed but are released when needed. The controlling factors are shown in Fig. 17.2 . The starting substrate for synthesis is cholesterol.
Pharmacological actions of the glucocorticoids
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Regulatory : Negative feedback effects on anterior pituitary and hypothalamus (prolonged therapy can cause atrophy of adrenal cortex).
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Metabolic :
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carbohydrates: decreased uptake and utilization of glucose, increased gluconeogenesis (thus tendency to hyperglycaemia);
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protein: increased catabolism and decreased synthesis; and
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fat: permissive effect on the lipolytic hormones.
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(These actions are only made use of therapeutically in replacement therapy.)
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Anti-inflammatory and immunosuppressive: A physiological role, and important pharmacological interest is the use of glucocorticoids in the treatment of inflammatory diseases (see Chapter 16 ).
Mechanism of action
The interaction of GCs with intracellular receptors belonging to a superfamily that control transcription is discussed elsewhere (see Chapter 16 ).
For metabolic actions, most of the mediator proteins induced are enzymes, e.g. cyclic adenosine monophosphate (cAMP)-dependent kinase.
Mineralocorticoids
The synthesis and release of the MCs is shown in Fig. 17.3 .
Pharmacological actions
The MCs are critically important for water and electrolyte balance. Aldosterone acts on the distal renal tubules to cause increased sodium ion (Na + ) reabsorption, with concomitant increased excretion of potassium ion (K + ) and hydrogen ion (H + ).
Mechanism of action
The mechanism of action is the same as that of the GCs (see Chapter 16 ) but aldosterone receptors occur virtually only in the kidney. (Spironolactone is a competitive antagonist of aldosterone at these receptors, see Chapter 18 .) GCs enter renal cells but are inactivated by an enzyme (11-β-hydroxysteroid dehydrogenase) and thus have little or no action on these receptors (see Chapter 18 ). The effect of the mediator(s) produced by interaction of the steroid-receptor complex with the DNA is initially to increase the number of Na + channels in the apical membrane of the renal cell and later to increase the number of Na + pumps in the basolateral membrane.
Pathophysiology of the Adrenal Corticosteroids
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Excess production of endogenous GCs results in Cushing’s disease. (Prolonged therapy with exogenous GCs can give a similar picture, Cushing’s syndrome , see Chapter 16 , unwanted effects of glucocorticoids.)
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Decreased GC production results in Addison’s disease (muscular weakness, low blood pressure, depression, anorexia, loss of weight, hypoglycaemia).
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Excess production of MCs, termed hyperaldosteronism , causes marked Na + and water retention, with resultant increase in the volume of extracellular fluid, hypokalaemia, alkalosis and hypertension.
Glucocorticoids
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Anti-inflammatory/immunosuppressive therapy:
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in asthma (by inhalation or, in severe cases, systemically) in hypersensitivity states, e.g. severe allergic reactions to drugs or insect venom;
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in miscellaneous diseases with autoimmune and inflammatory components, e.g. rheumatoid arthritis and other connective tissue diseases;
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in various inflammatory conditions of skin, eye, ear or nose (given topically);
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to prevent graft-versus-host disease following organ or bone marrow transplantation; and
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in various neoplastic diseases, often in combination with cytotoxic drugs.
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Replacement therapy for patients with adrenal failure, e.g. Addison’s disease (a mineralocorticoid (MC) will also be necessary).
Mineralocorticoids
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Replacement therapy in adrenal insufficiency ( fludrocortisone orally with a glucocorticoid (GC)).
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Spironolactone is a competitive antagonist of aldosterone used as an antihypertensive drug (see Chapter 22 ). Eplerenone has fewer side effects as it has lower affinity for sex hormone receptors.
The Thyroid
The main thyroid hormones are thyroxine (T 4 ) and triiodothyronine (T 3 ). They are critically important for normal growth and development and for energy metabolism (see Fig. 17.4 for their regulation). The functional unit of the thyroid is the follicle. Each follicle consists of a single layer of epithelial cells around a cavity, the follicle lumen, which is filled with a thick colloid containing thyroglobulin (TG). The sequence of events in the thyroid is shown in Fig. 17.5 . Unlike other endocrine secretions, the thyroid retains a store of precursors. More T 4 is released than T 3 .
The action of the thyroid hormones
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On metabolism:
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increased oxygen consumption and increased heat production leading to increase in basal metabolic rate (not in brain and gonads); and
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increase in metabolism of carbohydrates, fats and proteins by modulation of the action of glucocorticoids, catecholamines, insulin and glucagon.
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On growth and development:
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essential for normal growth by direct action on cells and potentiation of growth hormone, and
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essential for maturation of the central nervous system (CNS) and for skeletal development.
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Cellular action : T 4 is converted to T 3 , which binds to specific receptors on DNA. These receptors, when unbound, repress basal transcription. T 3 binding activates transcription, resulting in mRNA generation and protein synthesis.
Synthesis and secretion of the thyroid hormones and sites of drug action
The sequence of events leading to the production and release of T 4 and T 3 is shown in Fig. 17.5 . There is a large pool of T 4 in the body; it has a low turnover rate and is found mainly in the circulation where it is bound to thyroxine-binding globulin. There is a small pool of T 3 in the body; it has a fast turnover rate and is found mainly intracellularly in the target organs.
Pathophysiology
Hyperthyroidism
Hyperthyroidism ( thyrotoxicosis ) results from overactivity of the thyroid. There is a high metabolic rate and an increase in temperature, sweating, nervousness, tremor, tachycardia, fatigability and increased appetite, but loss of weight occurs. The main types are the following:
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Diffuse toxic goitre (Graves’ disease or exophthalmic goitre): Caused by an immunological action against the thyrotrophin receptor; patients have protrusion of the eyeballs (exophthalmos) and there is increased sensitivity to catecholamines.
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Toxic nodular goitre: Caused by a benign tumour; there is no exophthalmos.
Hypothyroidism
Hypothyroidism is a condition that results from decreased activity of the thyroid; it has several causes. The main types are the following:
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Myxoedema , which is immunological in origin; its manifestations include low basal metabolic rate (BMR), slow speech, deep hoarse voice, lethargy, bradycardia, sensitivity to cold, mental impairment and a thickening of the skin.
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Cretinism (hypothyroidism in childhood); manifestations are retardation of growth and mental deficiency.
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Hashimoto’s thyroiditis , an autoimmune disease in which there is an immune reaction against TG, can lead to hypothyroidism.
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Radioiodine therapy induced hypothyroidism.
Simple, non-toxic goitre
Simple goitre is caused by dietary deficiency of iodine, which causes a rise in plasma thyrotrophic hormone and eventually an increase in the size of the gland. Normal amounts of thyroid hormone are produced, but eventually hypothyroidism may occur.
Drugs used in hyperthyroidism
The main drugs are the thioureylenes (e.g. carbimazole , propylthiouracil) and radioiodine . Iodide/iodine is also used.
The thioureylenes
Mechanism of action
Thioureylenes act on the thyroid to decrease hormone output ( Fig. 17.5 ).
Actions and pharmacokinetic aspects
The drugs gradually decrease the thyroid hormone output and reduce the signs of thyrotoxicosis over 3–4 weeks.
All are given by mouth. Carbimazole is converted to methimazole (the active compound), which has a half-life of 16 h and causes 90% inhibition of the oxidation of iodine (organification of iodine) within 12 h. The clinical action is delayed until the store of hormones in the follicle lumen has been depleted, which may take several weeks. Propylthiouracil acts a little more quickly because it also inhibits the conversion of T 4 to T 3 . The thioureylenes have no effect on the exophthalmos.
Unwanted effects
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Granulocytopenia (rare but serious)
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Rashes (more common)
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Headache, nausea, jaundice and joint pain (occasionally)
Radioiodine
Given orally, iodine-131 ( 131 I) is taken up by the thyroid and processed in the same way as I – , becoming incorporated into TG. It emits both β-particles and X-rays. The X-rays pass through the tissue, but the short range β-radiation causes significant destruction of nearby thyroid cells. Radioiodine has a radioactive half-life of 8 days. It is used in one single dose; its effect on the gland is delayed for 1–2 months and reaches maximum after 4 months.
Hypothyroidism occurs eventually and will need replacement therapy with levothyroxine (synthetic T 4 ).
Iodide/iodine
Iodide/iodine given orally in high doses temporarily reduces thyroid hormone secretion (mechanism not clear) and decreases the vascularity of the gland.
Other miscellaneous drugs
The β-adrenoceptor antagonists decrease signs and symptoms such as tachycardia, dysrhythmias, tremor and agitation.
Drugs used in hypothyroidism
The main drugs are levothyroxine (T 4 ) and liothyronine (T 3 ).
The actions and mechanism of action are the same as the natural hormones.
Unwanted effects
The thyroid hormones increase heart rate and output, cause dysrhythmias and the signs and symptoms of hyperthyroidism.
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