Option 5: endocrinology 2013-14



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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)

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

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’)
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: Zollinger-Ellison 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 Cl- conductance 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


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

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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