OPTION 5: ENDOCRINOLOGY 2013-14
1. PRINCIPLES OF HORMONE ACTION
For any particular hormone, you will be expected to know:
its chemical class & broad structure; site and mechanism of production & release;
stimuli that cause or inhibit its release; pattern of secretion into the blood/extracellular fluid;
mechanism of transport in the blood/extracellular fluid (general principles of half-life, distribution and
clearance)
distant action: endocrine (or local action: paracrine and autocrine);
principal target tissue(s) & receptors; mechanism of action in target tissue(s)
principal effects of normal hormone levels, excess and deficiency, and hormone resistance in target
Main regulatory roles of hormones:
in homeostasis, including anticipatory responses; stress responses
in control of reproduction
in development, growth and differentiation
CHARACTERISTICS OF MAIN CLASSES OF HORMONE
Hormones synthesized and stored in endocrine glands:
protein, peptide, bioactive amine, steroid, thyroid
Structure of cells that synthesize and store these hormones
Order of normal concentration in plasma: protein and polypeptide hormones,
typically nanomolar; steroids, typically sub-micromolar
Secretion may be in pulses, rhythms (diurnal, reproductive)
Methods of assay: distinction between free and total (including protein bound) hormone
Hormones produced enzymatically as they are needed: prostaglandins, nitric oxide, angiotensin II
2. PITUITARY
COMPONENTS OF PITUITARY
Development of pituitary gland
Gross and microscopic structure of pituitary and component parts: adenohypophysis, neurohypophysis
Adenohypophysis: anterior part
endocrine cells: thyrotrophs, corticotrophs, gonadotrophs, lactotrophs, and somatotrophs
control of adenohypophysis:
(a) by CNS: neurosecretion of specific releasing factors from hypothalamus via hypothalamo-hypophysial
portal vessels;
(b) by negative feedback of target hormones at pituitary and hypothalamic levels.
Folliculo-stellate cells
Tumours of the adenohypophysis: local and systemic effects
Neurohypophysis: nerve endings of hypothalamic neurosecretory neurons Concept of neurosecretion
HORMONES OF THE ADENOHYPOPHYSIS
Symptoms of excess or insufficiency mostly resemble those of over- or under-activity of the target
endocrine organs
TSH = thyroid stimulating hormone (thyrotrophin) (from thyrotroph cells)
Glycoprotein , Two subunits: α common to TSH, LH, FSH; β specific
Promotes thyroid gland growth and synthesis and secretion of thyroid hormones
Negative feedback by T3 and T4; hypothalamic control
Released in pulses: diurnal rhythm
ACTH = corticotrophin (from corticotroph cells)
Polypeptide
Promotes adrenal cortical steroid secretion and growth
increases mostly glucocorticoid production (some increase in adrenal sex steroids)
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Produced by cleavage from a protein precursor (pro-opiomelanocortin 'POMC')
Acts by raising cAMP in adrenal cortex
Negative feedback by glucocorticoids; hypothalamic control (hypoclycaemia, stress); released in pulses:
diurnal rhythm
LH = luteinising hormone; FSH = follicle-stimulating hormone (gonadotrophins from gonadotroph cells)
Both are glycoproteins
Actions on ovary in female:
FSH stimulates follicle development and ovulation
LH stimulates progesterone production . Both act by raising cAMP
Actions on testis in male:
FSH acts to initiate and maintain spermatogenesis
LH stimulates secretion of testosterone
Released in pulses: hypothalamic control and feedback from gonadal hormones
Cyclical variation in LH and FSH in menstrual cycle
Infertility, precocious puberty as examples of abnormal secretion
Prolactin (from lactotroph cells)
Protein Receptor - tyrosine kinase
Promotes growth and development of breast and milk production
Control: only pituitary hormone whose principal control is inhibition by the hypothalamus
Inhibitory to gonads; lactational amenorrhoea
Inhibition of release is by DA, Prolactinomas. Dopamine agonists (e.g. bromocryptine) suppress lactation
Growth hormone ( from somatotroph cells)
Protein Receptor - tyrosine kinase
Actions on growth: direct and indirect via IGFs; metabolic actions Wide-ranging metabolic effects promotes protein synthesis, but raises blood glucose
Release (pulsatile) controlled via hypothalamus by metabolites; stress, sleep, exercise
Short or excess stature resulting from abnormal juvenile secretion.
Acromegaly resulting from increased adult secretion
HORMONES OF THE NEUROHYPOPHYSIS
Antidiuretic hormone (ADH) = vasopressin
Affects body fluid volume and osmolarity by regulating water reabsortion in the kidney
Diabetes insipidus: (hypothalamic and nephrogenic types)
Oxytocin- Role in parturition, milk-ejection
3. THYROID GLAND AND IODOTHYRONINES, CALCITONIN
Development, gross and microscopic structure of thyroid; vasculature; colloid
Structure of thyroid hormones
Synthesis and storage of thyroglobulin, secretion of thyroid hormones;
iodine economy of the thyroid; action of TSH
Plasma transport, long half lives of T4, T3
Peripheral metabolism of T4 to T3 and rT3 by liver, kidney; clearance of iodothyronines
Different deiodinases; interactions with autonomic nervous system; euthyroid sick syndrome
T3 as the metabolically active hormone; T3 receptors
Action on gene transcription by intracellular receptor
Actions of T3 on basal metabolic rate (protein, carbohydrate & lipid metabolism), development and growth
Catabolic versus anabolic effects; negative feedback of T3, T4 on pituitary and hypothalamus
Control: via TSH, iodide
Excess – thyrotoxicosis; deficiency - cretinism, myxoedema
Thyroid resistance
Thyroid enlargement (goitre), range of causes and effects on thyroid status
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Calcitonin production by parafollicular C cells Lack of endocrine effect of calcitonin secreting tumours
4. ADRENAL GLAND
Development of cortex and medulla; foetal zone of cortex
Gross and microscopic structure of adrenal cortex and medulla; vasculature, innervation
ADRENAL MEDULLA
Catecholamine receptors and their distribution in tissues
Actions on cardiovascular system, respiratory system, gastrointestinal tract,
metabolism. Mediation of effects: cAMP, or IP3/calcium
Control by autonomic nervous system
Phaeochromocytoma
Catecholamine receptors and their distribution in tissues
ADRENAL CORTEX
General principles
Synthesis of glucocorticoids and mineralocorticoids from cholesterol (details not needed)
Steroid action: intracellular receptor controls gene transcription
Inherited disorders of steroid synthesis (general principles)
Congenital adrenal hyperplasia
Plasma transport of corticosteroids; clearance by liver
Cortisol
Widespread action on many tissues: induces enzymes, favours fat
mobilisation, protein catabolism, gluconeogenesis (i.e. opposes insulin)
Adrenal insufficiency (Addison’s) and excess (Cushing’s)
Immunosuppresion (at therapeutic doses)
Some mineralocorticoid effect of cortisol (adverse effects of therapy)
Aldosterone, Juxtaglomerular apparatus , Renin-angiotensin-aldosterone system
Consequences of hyper- and hypoaldosteronism on renal tubular transport and body electrolyte balance
Action of aldosterone on Na+ re-absorption and K+ and H+ secretion;
Sympathetic control
Adrenal androgens
At most times a very minor component of secretion Route for synthesis of sex steroids: action of adrenal
androgens in fetus and at puberty
Adrenal sex steroid production in inherited disorder
5. ENDOCRINE PANCREAS
Development and microscopic structure of islets of Langerhans Blood and nerve supply of islets
INSULIN
Metabolic effects of insulin and diabetes mellitus
A protein synthesized in β-cells Synthesis as proinsulin with C-peptide
Receptor: tyrosine-kinase
Secretion stimulated by: raised blood glucose, amino acids, hormones e.g.
GLP (glucagon-like peptide - sensitises β-cells to glucose), nervous inputs
Mechanism of stimulus-secretion coupling: role of ATP-inhibited K+ channels; action of sulphonylureas
GIP: Glucose-dependent insulinotrophic peptide
hormone secreted by cells in small intestine in response to glucose - sensitises β-cells to glucose
Widespread actions to promote anabolism; lowers raised plasma glucose + other type II diabetic drugs
Diabetes mellitus: type I and type II.
Treatment of type I and type II diabetes: diet; insulin; sulphonylureas
Islet transplantation; thiazolidinediones (’glitazones’)
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GLUCAGON
Metabolic effects of glucagon
Polypeptide hormone synthesized in α-cells
Released in response to hypoglycaemia
Acts on liver via cAMP to promote glycogenolysis and gluconeogenesis; promotes lipolysis in adipose tissue
Synergism of actions with catecholamines, glucocorticoids, growth hormone
SOMATOSTATIN
Paracrine peptide produced in δ-cells; inhibits insulin release
Also a negative paracrine modulator in the gut, salivary glands and pituitary
ENDOCRINE TUMOURS OF PANCREAS
Effects of insulinoma (rare)
Multiple endocrine neoplasia
Gastrinoma ectopic gastrin production - no feedback from stomach acid to limit gastrin secretion: ZollingerEllison syndrome
6. GASTROINTESTINAL HORMONES
Endocrine cells scattered in gut epithelium sense contents of lumen
Peptide hormones released by exocytosis
Origin of gut endocrine cells from endoderm
Integrated role of gut endocrine and nervous systems to control motor,
digestive, vascular activity of gut
Concept of two families of gut hormones:
gastrin-like (includes CCK) act via intracellular calcium
secretin-like (includes glucagon) act via cAMP
GASTRIN
Produced in gastric antrum
Stimuli for gastrin secretion; H+ negative feedback
Actions: pepsin secretion; gastric acid secretion
Gastrinomas (pancreatic gastrinoma free from H+ feedback much more common than gastric gastrinoma )
HISTAMINE
Secreted by ECL cells of stomach in response to stretch or vagal stimulation
Paracrine action to stimulate gastric acid via H2 receptors on oxyntic cells
CCK (CHOLECYSTOKININ = PANCREOZYMIN)
Produced in duodenum and jejunum
Stimuli for secretion: protein and fat products in duodenum
Actions: stimulation pancreatic enzyme secretion and gall bladder contraction
SECRETIN
Produced from duodenum to ileum
Stimuli for secretion: acid in duodenum
Actions: stimulation of HCO3- secretion from pancreas and liver Action of secretin via cAMP and CFTR on Clconductance stimulates
Cl-/HCO3 exchange
OTHER GASTROINTESTINAL HORMONES
Somatostatin. Pancreatic polypeptide
Ghrelin – produced by stomach – released in fasting to stimulate appetite
PYY (peptide YY) released by small bowel when food is present to inhibit feeding
Motilin, vasoactive intestinal peptide, neurotensin
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7. HORMONES INFLUENCING CALCIUM, PHOSPHATE, BONE
NORMAL DISTRIBUTION AND ROLES OF CALCIUM
Distribution and total body content of Ca2+: plasma Ca2+ level; cell Ca2+
Functions of Ca2+: consequences of hypo/hypercalcaemia
Whole body Ca2+-fluxes, intestine, kidney, bone- role osteoblasts and osteoclasts: dietary intake vs
requirements
Special considerations: development, pregnancy, lactation
Mechanisms of absorption in gut
Mechanisms of excretion/reabsorption in kidney
Formation and reabsorption of bone, osteoblasts, osteocytes and osteoclasts
The calcium receptor; syndromes in calcium receptor mutations
PARATHYROID HORMONE 'PTH' - PRINCIPAL CONTROL OF PLASMA CALCIUM
Protein hormone. Stimulus for secretion: decreased plasma calcium
Acts to normalize low plasma Ca2+: via kidney; acute/chronic actions in bone; indirect in gut.
Acts via cAMP
Interactions with 1,25 D3; effects on phosphate
VITAMIN-D3 AND ITS METABOLITES — CONTROL OF WHOLE BODY CALCIUM & PHOSPHATE; PERMISSIVE
EFFECTS IN BONE
Steroid hormone: acts primarily via changes in gene expression
Formation of 1,25-D3: role of UV light; liver; kidney 1α-hydroxylase (induced by PTH)
Actions to increase whole body calcium via gut, kidney, bone
24,25-D3 reciprocity with 1,25-D3
Actions on phosphate homeostasis
CALCITONIN — PROTECTION AGAINST HYPERCALCAEMIA
Polypeptide hormone produced in thyroid C cells (neural crest derivative)
Stimulus for secretion: increased plasma calcium
Actions in bone (and gut) to normalize raised plasma calcium
Lack of major effect of calcitonin-secreting tumours , “escape” from the prolonged action of calcitonin
OTHER ENDOCRINE AND PARACRINE EFFECTS ON CALCIUM AND BONE
Actions of glucocorticoids and sex steroids
Effects of thyroid hormone, growth hormone (STH) & IGFs, local growth factor
ABNORMALITIES OF CALCIUM REGULATION
Main effects of hyper- and hypoparathyroidism
Effects of PTH secreting tumour – hypercalcaemia, urinary stones
Effects of removal/non-function of parathyroids – tetany
Vitamin-D3-related abnormalities: rickets, osteomalacia.
Dietary deficiency
Dysfunction: congenital, renal, Vit-D-resistant rickets
Bone resorption in malignancy, PTH-RP
Effect of HRT at menopause in reducing osteoporosis
Vitamin-D poisoning
Glucocorticoids — as cause of osteoporosis
Sex steroids — post-menopausal osteoporosis
8. INTEGRATIVE ROLE OF THE HYPOTHALAMUS, FUNCTIONS OF THE HYPOTHALAMUS
Roles in homeostasis, rhythms, development (e.g. puberty), metabolism,
control of autonomic nervous system, and endocrine system control
Monitoring of plasma levels of hormones, metabolites, plasma osmolality
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Coordination of regulation of blood pressure and volume
Body temperature regulation
Control of the anterior pituitary by secretion of:
releasing hormones: GnRH, GHRH, TRH, CRH
release-inhibiting factors DA, somatostatin
Negative and positive feedback by peripheral hormones and by metabolic signals
Secretion of oxytocin and ADH/vasopressin from posterior pituitary
Control of autonomic nervous system:
neural outputs to brain stem and spinal cord centres
effects of hypothalamus/hypothalamic lesions on autonomic functions in eye (pupil, lacrimation); osmotic
regulation and cardiovascular system; thermoregulation; alimentary system (salivation, peristalsis); genital
system (erection, emission); urinary system; sleep-wake; aggressive behaviour (sham rage)
Autonomic and endocrine components of the stress response
Hypothalamo-pituitary-gonadal system
Local and systemic effects of pituitary tumours
Sexual dimorphism of some hypothalamic nuclei
Role of hypothalamus in sexual behaviour and orientation
Relate effects on autonomic function of stimulation and lesion in anterior and posterior hypothalamus
9. PHYSIOLOGICAL RESPONSE TO STRESS
Stresses: how they influence the hypothalamus; inputs from brainstem, amygdala, hippocampus
Acute stress response: role of the sympathetic nervous system
Prolonged stress response: role of the hypothalamo-pituitary-adrenal axis
Effects of various stresses on the hypothalamic control of: ADH/vasopressin; prolactin; GH; gonadotrophins;
the thyroid
Adverse effects of chronically raised corticosteroids
Autonomic failure
10. CONTROL OF APPETITE
Ventromedial nucleus ‘satiety centre’, - lateral hypothalamus ‘feeding centre’
Arcuate nucleus as an integrative centre for peripheral signals
Signals from alimentary tract hormones: ghrelin, insulin, pancreatic polypeptide
Signals from adipose tissue: leptin
Fröhlich’s syndrome;
Role of melanocortin 4 (MC4) receptor; orexins; AgRP
Other GI hormones affecting feeding behaviour: CCK via vagal inputs; PYY
Stimulus-specific satiety; ‘Cafeteria effect’
MC4 receptor mutation; other mutations associated with obesity
Central signals: NPY, αMSH mesolimbic reward system; social cues
Leptin and leptin receptor deficiency as a rare cause of major obesity
11. ENDOCRINOLOGICAL ASPECTS OF GROWTH
Determinants of prenatal growth, maternal substrate provision, insulin-like
growth factors 1 and 2, fetal insulin
Intra-uterine growth retardation and its consequences – endocrine “programming”
Maternal diabetes and its consequences
Determinants of postnatal growth, genetic, endocrine and nutritional factors
Growth hormone . Inherited defects of fetal growth: Beckwith-Wiedemann syndrome,
Leprechaunism
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