The Endocrine System at a Glance E-Book

Ben Greenstein

• Herausgeber: John Wiley & Sons
• Kategorie: Fachliteratur
• Serie: At a Glance
• Sprache: Englisch

Seitenzahl: 328

Veröffentlichungsjahr: 2011

Beschreibung

The Endocrine System at a Glance provides a highly illustrated and unambiguous introduction to the basic principles and mechanisms of endocrinology and the key endocrine organs, followed by sections on reproductive and metabolic endocrinology. Clinical scenarios contextualise the basic science and illustrate how endocrine conditions present, are diagnosed, and are treated on the wards.

This third edition:

• Includes new material on basic diagnostic tests used in the diagnosis of endocrine disorders
• Features new material on cancer and endocrinology
• Includes MCQs for each chapter

The Endocrine System at a Glance is ideal for all medical students studying endocrinology and revising for final exams, as well as preparing for clinical attachments. The book is also suitable for those training in allied health professions and nurses specialising in endocrinology.

Leseprobe

Contents

Preface to the Third Edition

Preface to the First Edition

Part 1 Fundamentals

1 Introduction

Clinical background

The principal endocrine glands

2 Chemical transmission

Classification of endocrine hormones

Basic principles of neurotransmission

Chemical transport

3 Mechanisms of hormone action: I Membrane receptors

Clinical background

Introduction

Membrane receptors

Second messengers

Receptor antagonists

4 Mechanisms of hormone action: II Intracellular receptors

Clinical background

Intracellular receptors

Nature of the steroid receptor

5 The hypothalamus and pituitary gland

Clinical scenario

The hypothalamus

The pituitary gland

The nuclei

The neurohormones

6 Gonadotrophin-releasing hormone: a peptide hormone

Clinical background

Introduction

Synthesis and release of peptide hormones

Structure-function studies

7 Principles of feedback control

Clinical scenario

Homeostasis

8 Endocrine function tests

Clinical setting

Insulin tolerance test

Water deprivation test

Part 2 Growth

9 Growth: I Cellular growth factors

Clinical background

Cellular growth and proliferation

10 Growth: II Normal growth

Clinical background

Normal growth

11 Growth: III Growth hormone

Clinical background

Growth hormone (GH)

12 Growth: IV Pathophysiology

Clinical scenario

Regulation of growth hormone secretion

Pathophysiology of growth hormone secretion

Part 3 Thyroid

13 Thyroid: I Thyroid gland and thyroid hormones

Clinical scenario

Thyroid gland: anatomy and structure

Thyroid hormones

14 Thyroid: II Thyroid hormone secretion and action

Clinical scenario

Control of thyroid hormone synthesis and secretion

Actions of thyroid hormone (Fig. 14d)

Mechanism of action of thyroid hormone

15 Thyroid: III Thyroid pathophysiology

Clinical scenario

Introduction

Thyroid function tests

Thyroid cancer

Part 4 Adrenals and autoimmunity

16 Adrenal gland: I Adrenal medulla

Clinical scenario

The adrenal glands

Actions of epinephrine

17 Adrenal gland: II Adrenocortical hormones

Clinical background

Adrenocortical hormones

Biosynthesis of glucocorticoids

Synthesis of adrenal androgens

Synthesis of adrenal estrogens

Mechanism of action of cortisol

18 Adrenal gland: III Adrenocorticotropic hormone (ACTH)

Clinical scenario

Adrenocorticotropic hormone

19 Adrenal gland: IV Cortisol and androgens

Clinical background

Physiological actions of Cortisol

20 Adrenal gland: V Aldosterone

Clinical scenario

Aldosterone

21 Adrenal gland: VI Pathophysiology

Clinical scenario

Adrenal hypofunction

22 Endocrine autoimmunity

Clinical scenario

Autoimmunity

Part 5 Sexual differentiation and development

23 Sexual differentiation and development: I Introduction

Clinical scenario

Genetic sex

Gonadal sex

Phenotypic sex: secondary sexual characteristics

24 Sexual differentiation and development: II Puberty

Clinical background

Puberty

Endocrine regulation of puberty

Gonadal development in childhood and puberty

Part 6 Female reproduction

25 Female reproduction: I Menstrual cycle

Clinical background

Female reproductive organs

The menstrual cycle

26 Female reproduction: II Ovarian steroids

Clinical scenario

Physiological actions of estrogens

Mechanism of action of estrogens

Ovarian androgens

27 Female reproduction: III Pregnancy

Fertilization and i mplantation

Steroidogenesis

28 Female reproduction: IV Parturition and lactation

Parturition and lactation

Lactation and the suckling reflex

29 Female reproduction: V Pathophysiology

Clinical scenario

Reproductive pathophysiology

30 Female reproduction: VI Contraception

Clinical background

Oral contraceptives

Other uses of estrogens

Part 7 Male reproduction

31 Male reproduction: I The testis

Clinical background

The testis

32 Male reproduction: II Actions of androgens

Clinical scenario

Actions of testosterone

Peripheral actions of testosterone

33 Male reproduction: III Pathophysiology

Clinical background

Male reproductive pathophysiology

Prostatic pathophysiology

Part 8 Posterior pituitary hormones, salt and water balance and hypertension

34 Oxytocin

Biosynthesis

Secretion

Actions

35 Vasopressin

Clinical scenario

Biosynthesis

Mechanism of action of vasopressin

Physiological actions of vasopressin

36 Renin–angiotensin–aldosterone system

Clinical background

Renin

Angiotensin II

37 Endocrine hypertension

Clinical background

Hormonal causes of hypertension and treatments

Part 9 Metabolic endocrinology: Pancreas and gastrointestinal tract

38 Insulin: I The pancreas and insulin secretion

Clinical scenario

Introduction

Insulin

39 Insulin: II Insulin action

Clinical scenario

Mechanism of action of insulin

Insulin effects

40 Insulin: III Type 1 diabetes mellitus

Clinical scenario

Insulin lack

Type 1 diabetes mellitus (IDDM)

Poor diabetic control – microvascular complications

41 Insulin: IV Type 2 diabetes mellitus

Clinical background

Type 2 diabetes mellitus

Treatment of Type 2 diabetes

The diabetic foot

42 Glucagon

Clinical background

Biosynthesis, storage and secretion

Mechanism of action

Effects of glucagon

Glucagon receptor mutations

43 Gastrointestinal hormones

Clinical background

Introduction

Biosynthesis, chemistry and release

Part 10 Metabolic endocrinology: Energy homoeostasis and obesity

44 Energy homoeostasis: I Summary

Clinical background

Endocrine hormones and energy metabolism

Energy stores

Endocrine control of food intake

45 Energy homoeostasis: II Central control

Clinical scenario

Introduction

Central regulation of feeding behaviour

46 Obesity: I Causes of obesity

Clinical background

Introduction

Possible causes of obesity

47 Obesity: II Cardiovascular and respiratory complications

Clinical background

Cardiovascular complications of obesity

Respiratory complications of obesity

48 Obesity: III Insulin resistance and endocrine complications

Clinical background

Other endocrine causes and implications of obesity

Treatment of obesity

Part 11 Calcium and metabolic bone disease

49 Calcium: I Parathyroid hormone

Clinical scenario

Role of calcium

Regulation of calcium metabolism

Synthesis and secretion of PTH

Physiological actions of PTH

Pathophysiology of PTH

50 Calcium: II Calcitonin

Clinical background

Calcitonin

51 Calcium: III Vitamin D

Clinical scenario

Vitamin D

Synthesis of vitamin D

Regulation of metabolism

Mechanism of action

Physiological actions of vitamin D

52 Bone remodeling

Introduction

Cellular structure of bone

Cell types in bone

Bone remodelling

53 Metabolic bone disease: I Paget’ s disease

Clinical background

Paget’s disease of bone

54 Metabolic bone disease: II Primary osteoporosis

Clinical background

Aetiology

Estrogen and osteoporosis

Imaging studies and laboratory findings

Laboratory parameters

55 Metabolic bone disease: III Secondary osteoporosis

Introduction

Glucocorticoids and osteoporosis

Other endocrine disorders

Heritable disorders

Immobilization and osteoporosis

Prevention and treatment of osteoporosis

Part 12 Self assessment

MCQ s

Chapter 1: Introduction

Chapter 2: Chemical transmission

Chapter 3: Mechanisms of hormone action: I Membrane receptors

Chapter 4: Mechanisms of hormone action: II Intracellular receptors

Chapter 5: The hypothalamus and pituitary gland

Chapter 6: Gonadotrophin - releasing hormone: a peptide hormone

Chapter 7: Principles of feedback control

Chapter 8: Endocrine function tests

Chapter 9: Growth: I Cellular growth factors

Chapter 10: Growth: II Normal growth

Chapter 11: Growth: III Growth hormone

Chapter 12: Growth: IV Pathophysiology

Chapter 13: Thyroid: I Thyroid gland and thyroid hormones

Chapter 14: Thyroid: II Thyroid hormone secretion and action

Chapter 15: Thyroid: III Thyroid pathophysiology

Chapter 16: Adrenal gland: I Adrenal medulla

Chapter 17: Adrenal gland: II Adrenocortical hormones

Chapter 18: Adrenal gland: III Adrenocorticotrophic hormone (ACTH)

Chapter 19: Adrenal gland: IV Cortisol and androgens

Chapter 20: Adrenal gland: V Aldosterone

Chapter 21: Adrenal gland: VI Pathophysiology

Chapter 22: Endocrine autoimmunity

Chapter 23: Sexual differentiation and development: I Introduction

Chapter 24: Sexual differentiation and development: II Puberty

Chapter 25: Female reproduction: I Menstrual cycle

Chapter 26: Female reproduction: II Ovarian steroids

Chapter 27: Female reproduction: III Pregnancy

Chapter 28: Female reproduction: IV Parturition and lactation

Chapter 29: Female reproduction: V Pathophysiology

Chapter 30: Female reproduction: VI Contraception

Chapter 31: Male reproduction: I The testis

Chapter 32: Male reproduction: II Actions of androgens

Chapter 33: Male reproduction: III Pathophysiology

Chapter 34: Oxytocin

Chapter 35: Vasopressin

Chapter 36: Renin - angiotensin - aldosterone system

Chapter 37: Endocrine hypertension

Chapter 38: Insulin: I The pancreas and insulin secretion

Chapter 39: Insulin: II Insulin action

Chapter 40: Insulin: III Type 1 diabetes mellitus

Chapter 41: Insulin: IV Type 2 diabetes mellitus

Chapter 42: Glucagon

Chapter 43: Gastrointestinal hormones

Chapter 44: Energy homeostasis: I Summary

Chapter 45: Energy homeostasis: II Central control

Chapter 46: Obesity: I Causes of obesity

Chapter 47: Obesity: II Cardiovascular and respiratory complications

Chapter 48: Obesity: III Insulin resistance and endocrine complications

Chapter 49: Calcium: I Parathyroid hormone

Chapter 50: Calcium: II Calcitonin

Chapter 51: Calcium: III Vitamin D

Chapter 52: Bone remodelling

Chapter 53: Metabolic bone disease: I Paget’ s disease

Chapter 54: Metabolic bone disease: II Primary osteoporosis

Chapter 55: Metabolic bone disease: III Secondary osteoporosis

Answers

Appendix Normal Values

Glossary

Index

This edition first published 2011 © 2011 by Ben Greenstein and Diana Wood

First edition 1994

Second edition 2006

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Library of Congress Cataloging-in-Publication Data

Greenstein, Ben, 1941-

The endocrine system at a glance/Ben Greenstein, Diana Wood. - 3rd ed.

p.; cm. – (At a glance series)

Includes index.

ISBN-13: 978-1-4443-3215-5 (pbk.: alk. paper)

ISBN-10: 1-4443-3215-5

1. Endocrinology. I. Wood, Diana F. II. Title. III. Series: At a glance series (Oxford, England) [DNLM: 1. Endocrine Glands-physiology. 2. Endocrine Glands- physiopathology. 3. Endocrine System Diseases. 4. Hormones-secretion. WK 100] QP187.G834 2011 612.4–dc22

2011007204

Preface to the Third Edition

The third edition of this book is again co-authored by Ben Greenstein and Diana Wood, a clinical endocrinologist. The book aims to relate basic endocrine sciences to the clinical background and presentations of disease and in keeping with the overall philosophy of the At a Glance series, and strives to present data in a varied way that facilitates rapid assimilation of the information. The book is aimed at undergraduate medical students, primarily in the early part of their course, although as a handy and accessible reference book and revision tool it should also be a useful source of information for clinical medical students and junior doctors. The Endocrine System at a Glance, as the name implies, does not claim to replace comprehensive textbooks; rather it serves as a concise guide and revision aid to this fascinating branch of clinical science and medicine. A new addition to the third edition is the presentation of revision questions relating to each chapter.

The authors have striven to present the data clearly and accurately, and every effort has been made to include information that is up-to-date at the time of going to press. We make no claim to infallibility, however, and if readers spot ambiguities, factual inaccuracies or typographical errors, we should be most grateful for feedback and for suggestions which will improve the book and the presentation of the information.

It remains for us to thank the many students and colleagues who have read and commented on the book while in draft form. It has been a pleasure to work with the staff at Wiley-Blackwell, and in particular Karen Moore and Beth Bishop, whose patience and guidance is much appreciated.

Ben Greenstein

Diana Wood

London and Cambridge

Preface to the First Edition

Endocrinology at a Glance published 1994

Endocrinology at a Glance is intended to be just that. It has been designed and written so that the diagrams and text complement each other, and both are to be consulted. The emphasis has been on the diagrams, and words have been kept to a minimum.

The book has been produced to provide as comprehensive an overview of the subject as any medical or science undergraduate student will need in order to pass and pass well an examination in basic endocrinology. In addition, it is hoped that Endocrinology at a Glance will be useful to students of clinical endocrinology who need to refer rapidly to the mechanisms underlying the subject. The book is not presented as an alternative to the several excellent textbooks of endocrinology, which serve as useful reference texts, and some of which have been used during the writing of this book.

Every attempt has been made to present the data accurately and to provide the most up-to-date and reliable information available. When speculative data are given, their fragility has been indicated. Nevertheless, every writer, especially this one, is human and if the reader spots errors or a lack of clarity, or has any suggestions to improve or add to the presentation, this feedback will be gratefully appreciated and acknowledged.

I should like to thank the many undergraduate, medical, dental and science students who have scrutinized and used the diagrams, or similar ones, over the years, and whose criticisms have helped to make them more useful. I should like to thank Elizabeth Bridges, Kay Chan, Yacoub Dhaher, Munther Khamashta and Adam Greenstein for commentating on some of the work. It has been a pleasure working with the staff of Blackwell Science Ltd, and particularly Dr Stuart Taylor and Emma Lynch, whose friendly encouragement and advice cheered me on.

Ben Greenstein

London 1994

Part 1

Fundamentals

2

Chemical transmission

Classification of endocrine hormones

Hormones are chemical messengers. They may be classified several ways (Fig. 2a):

1 Autocrine: acting on the cells that synthesized them; for example insulin- like growth factor (IGF- 1) which stimulates cell division in the cell which produced it.

2 Paracrine: acting on neighbouring cells. An example is insulin, secreted by pancreatic b cells and affecting secretion of glucagon by pancreatic a cells.

3 Endocrine: acting on cells or organs to which they are carried in the bloodstream or through another aqueous ducting system, such as lymph. Examples include insulin, estradiol and cortisol.

4 Neuroendocrine: this is really paracrine or endocrine, except that the hormones are synthesized in a nerve cell (neurone) which releases the hormone adjacent to the target cell (paracrine), or releases it into the bloodstream, which carries it to the target cell, for example from the hypothalamus to the anterior pituitary gland through the portal system.

5 Neural: this is neurotransmission, when a chemical is released by one neurone and acts on an adjacent neurone (Fig. 2b). These chemicals are termed neurotransmitters. Neurotransmitters produce virtually instantaneous effects, for example acetylcholine, whereas some chemicals have a slower onset but longer lasting effect on the target organ, and are termed neuromodulators, for example certain opioids.

6 Pheromonal transmission is the release of volatile hormones, called pheromones, into the atmosphere, where they are transmitted to another individual and are recognized as an olfactory signal.

Basic principles of neurotransmission

When the nerve impulse arrives at the terminal, it triggers a calcium-dependent fusion of neurotransmitter packets or vesicles with the nerve terminal plasma membrane (Fig. 2b), followed by release of the neurotransmitter into the gap, or synapse, between the nerve cells. The neurotransmitters and neuromodulators bind to specific plasma membrane receptors, which transmit the information that the neurotransmitter has brought to the receiving cell by means of other membrane proteins and intracellular ‘second messengers’. The neurotransmitters are inactivated by enzymes or taken up into the nerve that released them and metabolized. The release of the neurotransmitter may be modulated and limited by: (i) autoreceptors on the nerve terminal from which it was released, so that further release of the neurotransmitter is inhibited; and (ii) by presynaptic inhibition, when another neurone synapses with the nerve terminal.

Chemical transport

The movement of chemicals between cells and organs is usually tightly controlled.

Diffusion is the movement of molecules in a fluid phase, in random thermal (Brownian) motion (Fig. 2c). If two solutions containing the same chemical, one concentrated and the other relatively dilute, are separated by a membrane which is completely permeable and passive, the concentrations of the chemical on either side of the membrane will eventually end up being the same through simple diffusion of solutes. This is because there are many molecules of the chemical on the concentrated side, and therefore a statistically greater probability of movement from the more concentrated side to the more dilute side of the membrane. Eventually, when the concentrations are equal on both sides, the net change on either side becomes zero. Lipophilic molecules such as ethyl alcohol and the steroids, for example estradiol, appear to diffuse freely across all biological membranes.

Facilitated transport is the transport of chemicals across membranes by carrier proteins. The process does not require energy and cannot, therefore, transport chemicals against a concentration gradient. The numbers of transporter proteins may be under hormonal control. Glucose is carried into the cell by transporter proteins (see Chapter 39) whose numbers are increased by insulin.

Active transport uses energy in the form of adenosine triphosphate (ATP) or other metabolic fuels. Therefore chemicals can be transported across the membrane against a concentration gradient, and the transport process can be interrupted by metabolic poisons.

Ion channels mediate active transport, and consist of proteins containing charged amino acids that may form activation and inactivation ‘gates’. Ion channels may be activated by receptors, or by voltage changes through the cell membrane. Channels of the ion Ca2+ can be activated by these two methods.

Osmosis is the passive movement of water through a semipermeable membrane, from a compartment of low solute concentration to one which has a greater concentration of the solute. (‘Solute’ refers to the chemical which is dissolved in the ‘solvent’, usually water in biological tissues.) Cells will shrink or swell depending on the concentrations of the solutes on either side of the membrane.

Phagocytosis and pinocytosis are both examples of endocytosis. Substances can enter the cell without having to pass through the cell membrane. Phagocytosis is the ingestion or ‘swallowing’ of a solid particle by a cell, while pinocytosis is the ingestion of fluid. Receptor-mediated endocytosis is the ingestion of specifically recognized substances by coated pits. These are parts of the membrane which are coated with specific membrane proteins, for example clathrin. Exocytosis is the movement of substances, such as hormones, out of the cell. Chemicals which are stored in the small vesicles or packets are secreted or released from the cell in which they are stored by exocytosis, when the vesicle fuses with the membrane.

Hormone transport in blood. When hormones are secreted into the blood, many are immediately bound to plasma proteins (Fig. 2d). The proteins may recognize the hormone specifically and bind it with high affinity and specificity, for example the binding of sex hormones by sex hormone-binding globulin (SHBG). Other proteins, such as albumin, also bind many hormones, including thyroid hormone and the sex hormones, with much lower affinity. Equilibrium is set up between the free and bound hormone, so that a fixed proportion of the hormone travels free and unbound, while most is carried bound. It is currently believed that only the free fraction of the hormone is physiologically active and available to the tissues and for metabolism. When a hormone is bound to plasma proteins it is physiologically inactive and is also protected from metabolic enzymes in organs such as the liver. Some drugs, such as aspirin, can displace other substances such as anticoagulants from their binding sites, which in the case of anticoagulants may cause haemorrhage.

3

Mechanisms of hormone action: I Membrane receptors

Clinical background

Acromegaly is usually caused by anterior pituitary gland tumours which secrete growth hormone. In 30 to 40% of cases, the tumour is thought to arise due to a somatic mutation affecting transmembrane signalling mechanisms. The stimulatory G-protein Gs is involved in signal transduction at the growth hormone releasing hormone receptor. Mutation of the α-subunit of Gs into the gsp oncogene prolongs the activation phase of the G-protein system, allowing unrestrained hormone synthesis and cell division. The distinctive clinical features of acromegaly and development of the pituitary tumour follow.

Introduction

Hormones interact with target cells through a primary interaction with receptors which recognize the hormones selectively. There are several different receptor systems, which vary in mechanism and timing (Fig. 3a). Charged ions such as peptides and neurotransmitters bind to receptors on the cell membrane. This causes a conformational change in other membrane proteins, which activate enzymes inside the cell, resulting in, for example, the synthesis of ‘second messengers’, which activate phosphorylating enzymes.

Uncharged molecules, such as the steroid hormones diffuse into the cell and bind to intracellular receptors (see Chapter 4). The hormone-receptor complex binds to specific hormone response elements (HRE) on the DNA; the result is that RNA and protein synthesis are altered. The cell will react faster to peptide hormones and neurotransmitters than it will to steroid hormones, which work through relatively slow changes in protein synthesis.Nevertheless, membrane receptors have been discovered for steroid hormones, although the significance of these is not yet clear.

Membrane receptors

Three regions can be distinguished in membrane receptors: the extracellular; the membrane-spanning; and the intracellular domains. The extracellular N-terminal domain has the hormone- binding domain, and also has glycosylation sites. The extracellular domain that binds the receptor is often rich in cysteine residues, which form rigid pockets in which the hormone is bound. The transmembrane region consists of one or more segments, made up of hydrophobic (uncharged) amino acids, arranged helically, whose role may include the anchoring of the receptor in the membrane. Different subunits within the membrane may be held together by means of disulphide linkages (e.g. the insulin receptor, Chapter 39). The intracellular domain is the effector region of the receptor, which may be linked with another membrane protein system, a set of enzymes which are guanosine triphosphatases (GTPases). The β-adrenergic receptor is an example of a G-protein-linked receptor. Another class, which includes the insulin receptor, has the intracellular domain as a tyrosine protein kinase. The intracellular region may also have a regulatory tyrosine or serine/ threonine phosphorylation site.

Second messengers

G protein linked receptors. These are protein receptors in the cell membrane, with an extracellular domain and an intracellular domain. The peptide chain that forms the protein always spans the membrane. When the hormone binds to the extracellular domain, this causes a change in shape of the receptor. This causes the intracellular domain to activate G proteins. G proteins have three main parts: an a subunit, a b subunit and a g subunit. When activated, firstly the a subunit substitutes a GDP molecule for a GTP molecule. This results in the activation of the G proteins. They can be either stimulatory or inhibitory, that is they can cause an increased level of enzyme activity or a decreased level of activity in the second messenger systems. Mutations of G proteins can occur and may result in disease (see Clinical scenario above).

Adenylate cyclase system. The hormone binds to the receptor, which activates a membrane G protein, which moves to the receptor (Fig. 3b). In the inactive state, the G protein binds GDP, which is exchanged for GTP, and a subunit of the G protein activates adenylate cyclase to convert ATP to the second messenger cyclic AMP. Adenylate cyclase is situated on the plasma membrane, but does not itself bind the hormone. Once formed in the cytoplasm, cAMP activates the catalytic subunit of a specific protein kinase (PKA), which forms part of a cascade of intracellular phosphorylations resulting in the cellular response. Since just one molecule of hormone can result in the production of many molecules of cAMP, this is a very efficient means of amplifying the receptor-hormone interaction. Once formed, cAMP is rapidly broken down by the enzyme phosphodieste- rase. An example of a hormone operating through adenylate cyclase is epinephrine, through the adrenergic β-receptor.

Hormones can produce inhibitory effects on a cell, and this may be achieved through the fact that some G proteins, such as GI, may inhibit adenylate cyclase, thus inhibiting the formation of cAMP. An example of this mechanism in action is the inhibition of adenylate cyclase through the binding of norepinephrine to the a-2-receptor on the presynaptic nerve terminal.

Inositol triphosphate system. In this system, the hormone- receptor-G-protein complex interaction triggers the membrane enzyme phospholipase C (PLC), which catalyses the hydrolysis of phosphoinositol (PIP2) to two important metabolites, inositol triphosphate (IP3) and diacylglycerol (DAG; Fig. 3c). IP3 generates, from the endoplasmic endothelium, increased free Ca2+, which together with DAG promotes the activation and migration to the membrane of the enzyme protein kinase C (PKC). PKC may also be mobilized through the entry of Ca2+ into the cell. Examples of hormones and neurotransmitters which activate the system are epinephrine acting on α-1 receptors and acetylcholine on muscarinic cholinergic receptors. These systems are important clinically since they provide substantial numbers of possible targets for drugs.

Receptor antagonists

Receptor antagonism is an important aspect of endocrinology and drug use generally, not only in terms of the study of the hormone-receptor interaction, but also in therapeutic terms, since antagonists play a large part in the treatment of endocrine disease. The molecule which binds to the receptor and elicits the normal cellular response is termed the agonist. The ligand which binds, but elicits no response, is the antagonist. Antagonists act at the membrane in different ways. For example the β-receptor blocker propranolol competes with epinephrine at its binding site. The anticonvulsant phenytoin blocks ion channels.

4

Mechanisms of hormone action: II Intracellular receptors

Clinical background

Estrogen stimulates the proliferation of breast cancer tissue and exposure to estrogens may be important in the pathogenesis of this disease. During the treatment of women with breast cancer it is routine practice to establish the presence (ER +ve) or absence (ER -ve) of estrogen receptors in cancer cells. Women who have ER +ve tumours are more likely to respond to endocrine manipulation following surgery and/or chemotherapy (50-60% response rate in ER +ve cancers, 5-10% in ER -ve tumours). The most commonly used endocrine therapy is the drug tamoxifen which has estrogenantagonist effects in the breast, probably mediated by the recruitment of corepressors for estrogen receptor action. It produces a significant fall in tumour recurrence and death rates for women with ER + ve disease, irrespective of age. The possible use of tamoxifen and the newer, selective estrogen receptor modulator drugs (SERMs, e.g. raloxifene, toremifine) for the prevention of breast cancer are under investigation. Trastuzumab, a humanized IgG1 against human epidermal growth factor receptor-2 (HER-2+), is now used to treat early breast cancer that overexpresses HER-2.

Intracellular receptors

Lipophilic hormones, such as steroids and the thyroid hormones, pass easily through the plasma membrane into the cell, where they combine with specific receptor proteins (Fig. 4a). In the inactive state, for the subfamily of glucocorticoid, progesterone, estrogen and androgen receptors, the receptor is bound to a heat shock protein (HSP 90; Fig. 4b).

When the hormone binds to the receptor, the HSP dissociates from it, the receptors form homodimers and the hormone- receptor complex binds to DNA at specific sites, termed hormone response elements (HREs), which lie upstream from transcription initiation sites. Transcription and subsequent protein synthesis are altered. The thyroid hormone and retinoic acid receptors are not associated with HSPs in their inactive state, and are able to associate with their response elements on the DNA in the absence of the hormones, and act as transcription inhibitors (see also below). Activation of receptors expressing the actions of the hormones appears to be achieved through phosphorylation, although at present this process is poorly understood.

Nature of the steroid receptor

The steroid receptors form part of a larger ‘superfamily ‘ of nuclear DNA-binding receptors, including androgen, estrogen, glucocorticoid, thyroid and vitamin D receptors (Fig. 4c). They all have two main regions, a hydrophobic hormone-binding region and a DNA-binding region, which consists of two ‘zinc fingers’, rich in cysteine and basic amino acids. The structures of the receptors are known. Region 1 is the DNA-binding region, and is the most conserved among the members of the receptor family, in that it has a high sequence homology from receptor to receptor, as shown in Fig. 4c. It is thought that the first zinc finger determines the specificity of the binding of the receptor to DNA, while the second finger stabilizes the receptor to its response element of the DNA. Regions 2 and 3 of the receptors determine the hormone specificity of binding, and are not well conserved among the different receptors.

Estrogen receptors

Two distinct, main receptor forms have been discovered, called ER-α and ER-β respectively. They have different affinities for estradiol and different anatomical distribution. For example only ER-α has been found in the liver, and ER-α is the predominant form in prostate. These differences may account, in part, for the wide diversity of estrogen action in different tissues and under different physiological and pathological states. It has been found, for example, that in healthy ovarian tissue the β form predominates, but in ovarian cancer the a form predominates. It is possible that the β form somehow regulates the activity of the α form. The α and β forms have several nuclear coactivators and repressors, and their activity depends also on their rates of turnover.

Estrogen receptor antagonists have found a powerful use in the prevention and treatment of breast cancer (see Clinical scenario above). These compounds interfere with the processing of the normal intracellular hormone-seceptor interaction. This can occur at one or more of several sites (Fig. 4d). The receptor itself may be blocked or post-receptor-binding events, for example receptor dimerization, receptor turnover or mRNA or protein synthesis, may be inhibited. Examples of estrogen receptor blockers are the SERMS (selective estrogen receptor modulators) such as tamoxifen, raloxifene and toremifene. These are interesting because they appear to act as agonists in some tissues such as bone and liver cells, and may therefore be important preventive measures for reducing the rate of development of osteoporosis and for lowering blood cholesterol. SERMS may act by activating as yet unidentified coactivators or corepressors and may modulate estrogen receptor turnover. Their action may also be dictated by whether they combine with ER - a or ER - b receptors.

Thyroid hormone receptors

Like other members of the nuclear receptor family, thyroid hormone receptors function as hormone-activated transcription factors. In contrast to steroid hormone receptors, however, thyroid hormone receptors bind to DNA in the absence of hormone, leading usually to transcriptional repression. When thyroid hormone binds to the receptor, however, it causes a conformational change in the receptor that changes it to function as a transcriptional activator. As with many other receptors, several isoforms have been discovered. Currently, four different isoforms are recognized, namely: α-1, α-2, β-1 and β-2. These different forms appear to be very important in development; different isoforms are expressed at different stages of development and in different organs and tissues. For example α-1, α-2 and β-1 are expressed in virtually all tissues in which thyroid hormones act, but β-2 is synthesized mainly in the developing ear, and in the anterior pituitary gland and hypothalamus. Receptor α-1 is the first isoform detected in the conceptus, and the β form appears to be essential for normal brain development shortly after birth.

5

The hypothalamus and pituitary gland

Clinical scenario

A 51-year-old man was referred to the Endocrine Clinic as an emergency complaining of loss of vision in both sides of his visual field. He had been increasingly tired over the preceding few months, felt ‘sluggish’ and had lost all motivation for his usual activities. He was shaving less frequently than normal and had lost some body hair. He had also lost interest in sex, although put this down to his exhaustion and ‘getting older’. More recently, he felt dizzy when he got out of bed or stood up from a chair. On examination he had clinical features of pan- hypopituitarism and examination of his visual fields revealed a bitemporal hemianopia. Biochemical investigations confirmed the presence of hyperprolactinaemia (serum prolactin 35 000 mU/L) and suppressed values of cortisol, thyroxine, TSH, LH, FSH, testosterone and IGF-1. An MRI scan showed a large pituitary tumour extending superiorly from the pituitary fossa and compressing the optic chiasm. He was treated with cabergoline, a long-acting dopamine agonist drug which subsequently caused shrinkage of the tumour. Examples of pituitary tumours are shown in Fig. 5a.

The hypothalamus