Endocrine

Front 1

Role of the endocrine system

Back 1

One of the major control systems that use chemical messengers

Front 2

What are hormones?

Back 2

Chemical messengers released from a cell to influence the activity of another/the same cell via a receptor.

Front 3

Normal concentrations of hormones in the blood/extracellular fluid

Back 3

Very low - 10^-12 to 10^-7M

Front 4

What are endocrine glands made up of?

Back 4

A well defined collection of endocrine cells

Front 5

What are diffuse endocrine systems?

Back 5

Hormone-producing cells that are not aggregated in glands but instead dispersed e.g. in the gut

Front 6

Neuroendocrine systems

Back 6

Some neurones release hormones into both the bloodstream and into the CNS

Front 7

What is 'classical' endocrine action?
Flaws?

Back 7

When a chemical messenger (the hormone), released by a cell, is transported via the bloodstream to its target cell.
Too narrow a concept - hormones are now known to act via various routes.

Front 8

3 routes via which hormones act

Back 8

Neuroendocrine - the hormone is released from a neurone into the bloodstream
Paracrine - the hormone acts on local cells via the extracellular fluid
Autocrine - the hormone acts on the cell producing the hormone

Front 9

How does the endocrine system promote survival of the species? (2)

Back 9

- Promotes the survival of the individual
- Control of the processes involved in reproduction

Front 10

How does the endocrine system promote the survival of the individual? (3)

Back 10

- Effects development, growth and differentiation
- Helps in preservation of a stable internal environment - homeostasis (often disturbed in the short-term for long-term gain)
- Responds to an altered external environment - especially emergency 'stress responses'

Front 11

How are hormones produced?

Back 11

- Proteins/peptides/glycopeptides (hydrophilic) are translated on the rER and secreted by either the regulated pathway (e.g. insulin, prolactin) or the constitutive pathway (e.g. cytokines, growth factors).
- The original translation product (the pro hormone) is usually processed proteolytically to yield the active hormone

Front 12

Does an endocrine cell specifically produce one hormone?

Back 12

Some endocrine cells produce more than one active peptide hormone, in varying amounts

Front 13

How are hormones stored?
Are all stored?

Back 13

- In large amount in intracellular granules
- Some peptides (e.g. growth factors and cytokines) are not stored

Front 14

How are steroids (e.g. testosterone) synthesised?
Are they hydrophilic or hydrophobic?
Storage?

Back 14

- Hydrophobic
- Synthesised rapidly on demand (i.e. not stored) from cholesterol, via enzymes in the mitochondria and sER

Front 15

How are bioactive amines (e.g. adrenaline, dopamine) synthesised?
Are they hydrophilic or hydrophobic?
Storage?

Back 15

- Hydrophilic
- Produced from tyrosine via intracellular enzymes
- Stored in large amount in intracellular granules

Front 16

How are thyroid hormones ( e.g. thyroxine) produced?
Are they hydrophilic or hydrophobic?
Storage?

Back 16

- Hydrophilic
- Thyroid hormones are iodothyronines produces by iodination and coupling by tyrosyl residues in a protein (thyroglobulin) which are then released by proteolysis.
- Large amounts of iodinated thyroglobulin (the precursor for thyroid hormone synthesis), but not the free hormone, are stored in the thyroid.
- The blood contains a large reservoir of protein-bound thyroid hormone

Front 17

Where is the pituitary gland located?

Back 17

Situated just below the hypothalamus of the brain in a depression of the skull (the pituitary fossa or sella turcica).

Front 18

Pituitary gland (hypophysis) development

Back 18

Anterior - Rathke's pouch grows up from oropharyngeal ectoderm (roof of mouth)
Posterior - infundibular process grows down from forebrain vesicle
Intermediate lobe is formed by the portion of Rathke's pouch in contact with posterior pituitary - in humans its cells become interspersed with the anterior lobe.

Front 19

Pituitary vasculature

Back 19

Hypothalamus - branches from internal carotid artery, form a capillary plexus as base of hypothalamus that gives rise to hypothalamo-hypophysial portal veins which run down the pituitary stalk
Anterior - from the hypothalamo-hypophysial portal veins
Posterior - direct from internal carotid artery

Front 20

Pituitary gland structure?

Back 20

Two lobes - anterior (adenohypophysis) and posterior (neurohypophysis)

Front 21

Cell type of the anterior lobe
How can these types be identified and their structural appearance examined?

Back 21

- Consist of distinct endocrine cell types which produce and secrete the various hormones:
- Thyrotrophs, corticotrophs, gonadotrophs, lactotrophs and somatotrophs
- Folliculostellate cells (type of glial cell) surround and support the endocrine cells.
- Cell types identified by immunocytochemistry
- Structural appearance under an electron microscope

Front 22

Control of adenohypophysis (3)

Back 22

- By CNS - neurohormones from the hypothalamus, secreted via hypothalamo-hypohysial portal vessels.
This control is stimulatory for all anterior pituitary hormones except PRL (inhibitory). The pulsatile release of hypothalamic releasing factors stimulates pulses of anterior pituitary hormones.
- Systemic hormones - 'feedback control', mainly negative, by target hormones
- Paracrine interactions in the adenohypophysis

Front 23

Define paracrine

Back 23

A hormone that has effect only in the vicinity of the gland secreting it

Front 24

Structure of the neurohypophysis?

Back 24

Formed by the axons and terminals of magnocellular neurosecretory neurones originating in the hypothalamus.
Pituicytes (a type of glial cell) surround and support the terminals.

Front 25

Where are the posterior pituitary hormones synthesised?
How are they transported to the PP?

Back 25

Synthesised in the hypothalamus, packed into granules, transported down the axons (of the magnocellular neurosecretory neurones) and released, by exocytosis, into the systemic veins.

Front 26

Hormones secreted by the anterior pituitary

Back 26

Thyroid stimulating hormone (TSH) - secreted by thyrotroph cells
Adreno corticotrophic hormone (ACTH) - secreted by corticotroph cells
Gonadotrophins (LH and FSH) - secreted by gonadotroph cells
Prolactin - secreted by lactotroph cells
Growth hormone - secreted by somatotroph cells

Front 27

TSH chemical nature

Back 27

Glycoprotein hormone made of an alpha subunit (shared with LH and FSH) and a beta subunit specific to TSH

Front 28

TSH receptors

Back 28

G-protein coupled to cAMP, on thyroid gland follicular cells

Front 29

TSH actions

Back 29

Acts in the thyroid:
-Stimulates thyroid hormone (T3 and T4) production
- Increases iodine uptake by the thyroid (required for thyroid hormone production)
- Stimulates thyroid growth

Front 30

TSH control

Back 30

Release is stimulated by thyrotrophin releasing hormone (TRH) from the hypothalamus - TRH secretion is stimulated by cold and stress via the CNS.
TSH is released in pulses with a diurnal rhythm
Release is inhibited by T3 and T4 negative feedback

Front 31

ACTH chemical nature

Back 31

Polypeptide hormone cleaved from the prohormone POMC (ProOpioMelanoCortin)

Front 32

ACTH receptors

Back 32

G-protein coupled to cAMP, in adrenal cortex

Front 33

ACTH actions

Back 33

Stimulates the production and so secretion of cortisol (glucocorticoid steroid hormone) from the cortex of the adrenal gland.
Produces some rise in adrenal sex steroids
Stimulates growth of the adrenal cortex

Front 34

ACTH control

Back 34

Secretion increased by stress and corticotrophin releasing hormone (CRH) from the hypothalamus
Release is pulsatile with a diurnal rhythm - high 7.00AM, low midnight
Inhibited by glucocorticoid negative feedback (systemic control)

Front 35

ACTH dysfunction

Back 35

Cushing's disease - excess ACTH from corticotrophinoma pituitary tumours causing excess glucocorticoid secretion
Addison's disease - ACTH deficiency causes glucorticoid deficiency

Front 36

What are gonadotrophins?
Name 2

Back 36

Hormones secreted by the gonadotroph cells
Luteinizing hormone (LH)
Follicle-stimulating hormone (FSH)

Front 37

Gonadotrophin chemical nature

Back 37

Glycoprotein hormones made up of an alpha subunit (common to TSH) and beta subunit (specific to LH and FSH)

Front 38

Gonadotrophin receptors

Back 38

G-protein coupled to cAMP, in the ovary and testes

Front 39

Gonadotrophin actions in female

Back 39

FSH stimulates...
Growth and development of follicles
Ovulation
LH stimulates...
Secretion of progesterone by the corpus luteum

Front 40

Gonadotrophin actions in male

Back 40

LH stimulates testosterone production and secretion by the Leydig cells
FSH stimulates the Sertoli cells and so spermatogenesis

Front 41

Gonadotrophin control

Back 41

LH and FSH release simulated by hourly pulses of gonadotrophin releasing hormone (GnRH) during reproductive life
Inhibited by oestrogen (sex steroid) through negative feedback - switches to positive feedback during ovulation triggering LH surge
Females - cyclic variations in LH and FSH in menstrual cycle, ovaria peptides (inhibin and follistatin) inhibit FSH
Males - LH release is inhibited by negative feedback from testosterone

Front 42

Gonadotrophin dysfunction

Back 42

Deficiencies of LH and FSH or receptor dysfunction due to genetic mutations causes infertility in adults and lack of sexual maturation in children

Front 43

Prolactin (PRL, mammotrophin) chemical nature

Back 43

Protein, secreted by lactotroph cells in breast

Front 44

PRL receptor

Back 44

Single-transmembrane tyrosine kinase, in breast

Front 45

PRL actions

Back 45

Promotes growth and development of secretory alveoli in the breast and milk production - marked increase in the number of lactotroph cells in pregnancy in preparation for lactation.
Inhibits the reproductive system at gonads and pituitary - causes lactational amenorrhoea

Front 46

PRL control

Back 46

Increased by suckling
Only hormone whose principle control is inhibition by the hypothalamus - inhibited by dopamine.
PRL synthesis stimulated by circulating oestrogen

Front 47

Growth hormone (GH or somatotrophin) chemical nature

Back 47

Protein secreted by somatotroph cells

Front 48

GH receptor

Back 48

Single-transmembrane tyrosine kinase

Front 49

GH actions

Back 49

Stimulates long bone and soft tissue growth - both via stimulating the release of IGFs (insulin-like growth factors) from the liver and by direct actions.
Essential for growth after 2 years but only promotes growth if sufficient nutrition is available
Also has actions on metabolism (amino acid, fatty acid, glucose) - has insulin-like effects to promote amino acid uptake by the liver and muscle, therefore promoting protein synthesis. Switches metabolism away from glucose toward increased oxidation of fat (e.g. in starvation).
If GH is chronically increased it has anti-insulin effects.

Front 50

GH control

Back 50

Secreted in pulses around every 4hr and on entering deep sleep
Secretion increased via the hypothalamus by hypoglycaemia, stress and exercise
Hypothalamic factors that regulate GH release - Stimulates - growth hormone releasing hormones (GHRH)
Inhibits - somatostatin
Also inhibited via negative feedback by GH at the hypothalamus

Front 51

GH dysfunction

Back 51

Insufficiency causes short stature (dwarfism)
Excess causes gigantism (children), acromegaly (adults)

Front 52

Hormones secreted by the posterior pituitary

Back 52

Antidiuretic hormone (vasopressin/ADH)
Oxytocin

Front 53

ADH chemical nature

Back 53

peptide of 9 amino acids

Front 54

ADH receptors

Back 54

Acts on V2 receptors in the kidney, G-protein coupled to cAMP and V1 receptors in vasculature (PLC-coupled - phospholipase C (PIP2 and DAG))

Front 55

ADH actions

Back 55

Increases water reabsorption by acting in the collecting ducts of the kidney (via V2) and alters blood pressure by contricting peripheral arterioles and veins (via V1)

Front 56

ADH control

Back 56

Sensitive to 1% increase from normal plasma OP (oncotic pressure - the pressure exerted by plasma proteins on the capillary wall) - sensed by hypothalamic osmoreceptors.
Also sense decreases in blood volume or pressure

Front 57

ADH dysfunction

Back 57

Diabetes insipidus (hypothalamic and nephrogenic types) - due to a lack of ADH production and action

Front 58

Oxytocin chemical nature

Back 58

Peptide of 9 amino acids

Front 59

Oxytocin receptors

Back 59

Acts on membrane G-protein coupled receptors coupled to PLC in breast and uterine muscle

Front 60

Oxytocin action

Back 60

Causes contraction of urterine myometrium in childbirth and causes contraction of breast myometrium to eject milk.
Also has roles in social behaviour

Front 61

Oxytocin control

Back 61

The Ferguson reflex - stretch the cervix/vagina during parturition
The milk ejection reflex - triggered by stimulation of the nipple through suckling

Front 62

Oxytocin dysfunction

Back 62

Deficit may cause prolonged labour - in knockout mice, labour normal but no milk-ejection.

Front 63

Pituitary tumour effects (2)

Back 63

Hormonal effects - hormone-secreting and non-secreting tumours, effects depend on cell type
Mechanical effects - effects on vision via pressing on optic chasm

Front 64

Development of the thyroid gland

Back 64

- A thyroid diverticulum forms in the midline of the floor of the mouth, between the 1st and 3rd brachial arch components of the developing tongue. Grows caudally over the developing larynx to the anterior aspect of the trachea.
- As it descends, associates the the superior/inferior parathyroids (develop from the 3rd/4th pharyngeal pouches) and neural crest cells, with which it will form the parafollicular C (calcitonin) cells
- Two lateral lobes and a central isthmus form

Front 65

Location and anatomy of the thyroid gland

Back 65

- The isthmus (central part) lies anterior to the 2nd and 4th rings of the trachea and the lateral lobes extend up on either side of the trachea and the larynx.
- Gland is enclosed in pre-tracheal fascia which anchors it to the airway - it therefore moves on swallowing.
- Has a profuse blood supply and venous drainage

Front 66

Control of thyroid hormone secretion

Back 66

- Hypothalamus releases TRH (thyrotrophin releasing hormone) - controls TSH secretion from the anterior pituitary.
- TRH released in response to changes in plasma glucose and core temperature - hyperglycaemia stimulates, hypoglycaemia inhibits, cold stimulates.
- TSH produced in pituitary in thryotroph cells - controls T3 (try-iodothyronine) and T4 (thyroxine) release by thyroid follicle cells.
- T3 and T4 negative feedback on TSH production

Front 67

Production of T3 and T4

Back 67

Stimulated by TSH from the anterior pituitary and requires iodide.
Thyroid stores large amounts of the thyroid hormone precursor extracellularly (unlike any other endocrine gland)

Front 68

Epithelial cells of the thyroid
Distinction between active and inactive

Back 68

Follicular cells - cuboidal arranged into follicles around a lumen filled with colloid
Synthesise thyroglobulin which is released into the colloid
Active thyroids - epithelial cells are tall and colloid is reduced in size
Inactive glands - cells are low cuboidal and follicles are filled with colloid

Front 69

Thyroglobulin storage

Back 69

Stored in colloid - 100x more than normal daily output

Front 70

Parafollicular (C) cells of the thyroid
Action of hormone released

Back 70

Release the peptide hormone calcitonin - located at the base of the follicle epithelium
Calcitonin acts to lower raised plasma calcium

Front 71

TSH action (T3, T4 detailed)

Back 71

Stimulates endocytosis of colloid and its digestion by lysosomes to free T3 and T4
Acts via cAMP - response takes 30 min from addition of TSH to T3 and 4 output

Front 72

Conversion of T4 to T3:
Why?
Where?
Enzymes?

Back 72

- T4 is not metabolically active - T3 is the active form and is produced from metabolism of T4
- Primarily in the liver
- T4 converted to T3 by Type I (5')-deiodinase - produces 80% of total plasma T3
- Also converted to inactive rT3 by Type I (5')-deiodinase in liver
- Converted to T3 in the pituitary by Type II-deiodinase - important for negative feedback of T4

Front 73

Control of conversion of T4 to T3

Back 73

Deiodination to active T3 or inactive rT3 is controlled by the need for metabolism - reduced during starvation due to raised cortisol and by propranolol.

Front 74

Thyroid hormone plasma transport
Binding protein examples (3)

Back 74

T3 and 4 circulate bound to plasma proteins - therefore have a long half life.
Thyronin-binding globulin (TBG) - produced by the liver, a glycoprotein with higher affinity for T4 than T3
Transthyretin - higher affinity for T3 than T4
Albumin - low affinity but high capacity

Front 75

Mechanism of action of T3 - receptors

Back 75

T3 is transported into cells and acts on nuclear receptors (TRs) which act on response elements (TREs) in gene promoters
Interaction results in stimulation or inhibition of the production of many different mRNAs and therefore proteins
(action on gene transcription by intracellular receptor)
Sensitivity to T3 is regulated via the number of TRs

Front 76

Effects of T3 (11)

Back 76

Acts on almost every tissue of the body but has little metabolic effect in the brain, spleen or testis.
T3 acts to increase the basal metabolic rate which increases O2 use and heat production
- Stimulates production of Na+/K+ ATPase (uses 20-45% of all ATP)
- Stimulates RNA polymerase I and II activity and thereby the production of many proteins
- Stimulates protein degradation - when T3 is excessive degradation>production
- Increases β adrenocetor effects increasing glycogenesis and glucose usage
- Increases production of β adrenergic receptors and TRH receptors
- Increases insulin effects increasing glycogenesis and glucose usage
- Stimulates cholesterol breakdown and synthesis - increases number of LDL receptors on cell surface and enhances lipolysis
- Affects cardiovascular system to increase cardiac output, rate, force and systolic BP, but diastolic BP falls due to vasodilation
- Stimulates gut motility
- Stimulates bone turnover (breakdown>synthesis)
- Increase speed of muscle contraction

Front 77

Iodothyronine breakdown

Back 77

Finally deiodinated to thyroinine - iodine is salvaged by the kidney and reused.

Front 78

Action of thyroperoxidase enzyme

Back 78

On apical membrane of the plasmalemma:
- Oxidises the iodide to iodine
- Iodinates tyrosyl residues in the thyroglobulin
- Couples tyrosyl residues to produce inactive (still bound in the thyroglobulin) T3 (try-iodothyronine) and T4 (thyroxine)

Front 79

Iodine excess and deficit

Back 79

Excess - inhibits thyroid activity
Deficiency - can prevent formation of T3 and 4

Front 80

Developmental effects of T3

Back 80

Lungs - stimulates surfactant production and lung maturation (with glucocorticoids)
CNS - essential for postnatal growth of the CNS, stimulates production myelin, neurotransmitters, axonal growth
Bone - stimulates linear growth by effects on chondrocytes
Stimulates normal development, maturation and eruption of teeth, hair and epidermis.

Front 81

Goitre - causes

Back 81

Swelling of the thyroid, may be due to -
- Iodine deficiency - subjects with a goitre may have normal plasma T3 and T4 if the enlarged gland traps enough iodine
- Graves' disease - gland enlarged due to overactivation of the TSH receptor
- A tumour - may be functioning (i.e. secreting T4 and T3) or non-functioning

Front 82

Hyperthyroidism (high T3) causes

Back 82

- Graves' disease - most common cause of hyperthyroidism, auto-antibody with stimulatory activity when it binds to the TSH receptor on thyroid cells
- Pituitary adenoma producing thyroid stimulating hormones
- Tumours of thyroid follicular cells can produce large amounts of T4 and T3
- Lactrogenic - overadministration of thyroxine

Front 83

Hyperthyroidism (high T3) effects

Back 83

- Increased basal metabolism rate - weight loss (despite increased appetite), increased resting heart rate and 'bounding' pulse, heat intolerance, increased sympathetic drive, eye protrusion
- Atrial fibrillation

Front 84

Hypothyroidism (low T3) causes

Back 84

- Deficiency of iodine in diet - rare since introduction of iodinized table salt and greater distribution of seafood
- Sheehan's syndrome - non-functioning pituitary adenoma causing pituitary hypofunction with lack of production of TSH
- Latrogenic - surgical removal of thyroid, damage of thyroid by radioactive iodine, antithyroid drugs
- Thyroid hormone resistance - a number of genetic defects in the thyroid hormone receptor reduce hormone binding.

Front 85

Hypothyroidism (low T3) effects

Back 85

In the neonate: cretinism leads to gross deficits in CNS myelination and stunting of postnatal growth
In the adult: myxoedema - decreased basal metabolic rate (tiredness, lethargy, weight gain), slow mentation, hypothermia, constipation

Front 86

What do parathyroid glands secrete?

Back 86

PTH (parathyroid hormone) - a peptide hormone, secreted from the parathyroid glands in response to falling plasma Ca2+.
PTH is the principle control of plasma Ca2+ and is essential for life
PTH restores low plasma Ca2+ to normal

Front 87

Parathyroid hormone secreting tumours cause...

Back 87

Raised plasma Ca2+, bone destruction, urinary stones

Front 88

Adrenal gland anatomy and location

Back 88

Comprises:
- An inner medulla that secretes the catecholamines, noradrenaline and adrenaline
- An outer cortex that secretes steroid hormones
- Glands located just medial to the upper pole of each kidney

Front 89

Adrenal gland structure (cells)

Back 89

Made up of chromaffin cells packed with granules which store large amounts of adrenaline and noradrenaline
Adrenal cortex is made up of sheets of cells surrounded by capillaries and arranged into three zones:
The outer zona glomerulosa - makes aldosterone
Middle zona fasiculata - makes cortisol
Inner zona reticularis - makes small amounts of androgens

Front 90

Adrenal gland development

Back 90

Medulla develops from neural crest tissue
Cortex from intermediate mesoderm close to the mesonephros under the influence of genes including Wilms' tumour (WT1) and steroidogenic factor 1 (ST1)
Identifiable as a separate organ after 2 months gestation - comprise a fetal zone and a definitive zone.
Fetal zone of the cortex is very prominent in the fetus but regresses after birth.

Front 91

Adrenal blood supply

Back 91

Richly vascularised with arteries directly from the aorta and from its renal and phrenic branches.
These form an arterial plexus beneath the capsule surrounding the adrenal gland - then enters a system of sinusoids (capillary with fenestrated endothelium) that penetrates the cortex and medulla, draining into a single central adrenal vein in each gland.
Adrenal veins drain to the IVC (R) or left renal vein (L)
Blood supply to adrenals dilates in stress

Front 92

Adrenal innervation

Back 92

Chromaffin cells of the medulla - innervated by thoracic preganglionic sympathetic nerves which release ACh acting on nicotinic N2 receptors to cause rapid release of stored catecholamines

Front 93

Catecholamine (hormones produced by the adrenal glands) synthesis - where in cell? Conversions and enzymes

Back 93

- Occurs in the cytoplasm of chromaffin cells
- Tyrosine from plasma is converted to DOPA by tyrosine hydroxylase
- DOPA to dopamine by DOPA decarboxylase
- Dopamine then pumped into vesicles and converted to noradrenaline by dopamine β hydroxylase
- Noradrenaline stored and/or diffuses out of the vesicles for conversion to adrenaline (80% of total) by phenylethanolamine-N-methyl transferase (PNMT) in the cytoplasm of adrenaline secreting cells
- After conversion, adrenaline is pumped back into vesicles for storage and release

Front 94

Adrenal medulla actions

Back 94

Preparation for emergency physical activity - adrenal medulla contributes 10% of the total sympathetic nervous system response to stress, therefore not vital.

Front 95

Define stress

Back 95

Any change that disturbs or threatens to disturb homeostatis
A stressor is any stimulus which activates the sympathetic nervous system e.g. low bp, pain, exercise, low blood glucose

Front 96

Adrenal medulla stimuli

Back 96

Any stressful stimuli that activates the sympathetic nervous system

Front 97

Adrenal medulla receptors

Back 97

Adrenaline and noradrenaline act at adrenergic receptors -
α receptors (PLC-coupled):
α1 – Gq, all blood vessels (vasoconstrictor), gut sphincters
α2 – Gi, presynaptic terminals
β receptors (cAMP-coupled - Gs):
β1- heart, fat
β2 - bronchi, blood vessels (vasodilator skeletal muscle)

Front 98

Relative potency of adrenaline and noradrenaline at receptors

Back 98

α1 - NA>A>>Iso
α2 – NA>A>>Iso
β1 – Iso>A=NA
β2 – Iso>A>>NA

Front 99

Actions of adrenaline on cardiovascular system

Back 99

- Increase heart rate and force of contraction (β1)
- Vasocontriction in skin and splanchnic tissues (α1)
- Potentiate vasodilation in skeletal muscle (β2)
- Noradrenaline increases mean arterial pressure

Front 100

Actions of adrenaline on respiratory system

Back 100

Increases dilation of the bronchi and bronchioles (β2)
Increases respiratory rate by effects in the CNS

Front 101

Actions of adrenaline on GI tract

Back 101

Inhibits peristalsis - relaxes smooth gut muscle (β2)
Contract gut sphincters (α1 and NANC (non-adrenergic, non-cholinergic))
Vasoconstrict (α1) gut vasculature (vasodilation in adrenal - β2)

Front 102

Actions of adrenaline on metabolic substrate metabolism

Back 102

Increases metabolite activity
In liver - promotes glycogenolysis, gluconeogenesis, release of glucose into circulation (β2)
In skeletal muscle - promotes glucogenolysis and lactic acid formation (β2)
In adipose tissue - stimulates lipolysis to release free fatty acids and glycerol (β1)

Front 103

Actions of adrenaline on CNS

Back 103

Causes arousal via actions in the brainstem - causes coarse tremor

Front 104

Phaeochromocytoma

Back 104

Tumors of the adrenal medulla - secrete catecholamines in an unregulated way causing hypertension, tremor, anxiety and forceful heartbeat

Front 105

Function of adrenal cortex

Back 105

Maintenance of essential processes when stress is prolongued

Front 106

Hormones of the adrenal cortex

Back 106

Predominantly produces glucocorticoid and mineralocorticoid (cortisol and aldosterone) hormones
Also, small amounts of androgens
All are produced from cholesterol

Front 107

Synthesis of adrenal hormones

Back 107

- Cholesterol is stored in lipid droplets as cholesterol ester in adrenal cortex cells, mobilised by ACTH stimulation and transported into specialised mitochondria by steroid acute regulatory (STAR) protein
- Here, the side chain of cholesterol is the cleaved by cytochrome P450 side chain cleavage enzyme to yield progenolone - rate-limiting step of synthesis
- Conversion of progenolone to gluco and mineralocorticoids is catalysed by enzymes in the mitochondria and sER (hence why these organelles are prominent in adrenal cortex cells)

Front 108

Hormone production specificity to cortex regions
What determines this pattern?

Back 108

- Zona glomerulosa produces aldosterone
- Zona fasiculata - cortisol
- Zona reticularis - androgens
- Hormone produced depends on the enzymes expressed by the cells

Front 109

Transport of adrenal steroid hormones

Back 109

Bind in plasma -
Cortisol:
Binds to cortisol-binding globulin - high affinity
Albumin - low affinity
Aldosterone:
No affinity binding protein present in plasma so binds weakly to albumin - therefore has a shorter half-life than cortisol

Front 110

Adrenal steroid metabolism

Back 110

Kidney filters free steroid hormone but reabsorbs ~90%
Liver converts steroid hormones to hydrophilic metabolites by hydroxylation and conjugation reactions
Liver damage e.g. cirrhosis, causes cortisol build up

Front 111

Cortisol receptors

Back 111

Glucocorticoid receptors (GR) are present in almost all cells
GR are located in the cytoplasm of cells and migrate to the nucleus to regulate gene transcription when cortisol binds

Front 112

Cortisol metabolism

Back 112

Converted in the liver to cortisone (relatively inactive metabolite) by an inactivating 11β-hydroxysteroid dehydrogenase

Front 113

Control of glucocorticoid secretion

Back 113

Hypothalamus releases corticotrophin-releasing factor (CRF) in response to stress - inhibited by cortisol negative feedback
CRF acts on anterior pituitary corticotrophs to stimulate ACTH production and release
Cortisol is secreted within seconds but takes hours for most actions

Front 114

Cortisol overall action

Back 114

Provides protection of the body in prolonged stress - primarily to preserve glucose for the brain, but also exerts widespread protective actions on many tissues

Front 115

Cortisol effect on metabolic substrate metabolism

Back 115

Stimulates metabolism of:
Carbohydrates - stimulates gluconeogenesis, opposes insulin actions
Lipids - stimulates lipolysis (fat metabolism) and ketogenesis
Proteins - stimulates protein breakdown and gluconeogenesis

Front 116

Cortisol effect on cardiovascular system

Back 116

Maintains circulation via increased myocardial contraction - increases vascular tone
Maintains plasma volume by preventing increased capillary permeability

Front 117

Cortisol effect on haemopoiesis

Back 117

Increases red blood cell production so enhances oxygen carrying capacity of blood

Front 118

Cortisol effect on inflammatory response

Back 118

Immunosuppressive actions:
Inhibits leukocyte translocation from blood to sites of tissue damage or infection
Stimulates lymphocyte destruction

Front 119

Abnormal glucocorticoid function

Back 119

Cushing's - excess cortisol
Addison's - insufficiency

Front 120

Aldosterone overall function

Back 120

Mineralocorticoid regulation of body sodium and fluid volume

Front 121

Aldosterone receptors

Back 121

Mineralocorticoid receptors (MR)
Present in the nuclei of only a few cell types - kidney collecting tubule epithelia, salivary and sweat glands, colon and some brain neurones.
Cortisol also binds to MR - is deactivated by 11β-hydroxysteroid dehydrogenase in aldosterone targets to protect MRs from cortisol at normal plasma levels

Front 122

Aldosterone actions

Back 122

Kidney - aldosterone regulates ion transport in the collecting tubules in order to stimulate reabsorption of Na+ in exchange for secretion of K+, H+ and NH3+. 2hr lag in main response to aldosterone as MRs act by stimulating transcription of Na+/K+-ATPase
Salivary and sweat glands and colon - here also regulates ion transport to retain sodium (additional more acute action to stimulate Na+ channel activity)

Front 123

Control of aldosterone output

Back 123

The renin-angiotensin system:
Aldosterone secretion stimulated by this system which is is in turn stimulated by low plasma Na+ or low renal b.p.
Low plasma Na+/low renal b.p./sympathetic (β1) action - stimulate the juxtaglomerular apparatus (distal tubule) to release renin from the afferent arterioles.
Renin breaks down plasma angiotensinogen to form angiotensin I which is then converted by angiotensin-converting enzyme (ACE) to angiotensin II in the lungs - stimulates output of aldosterone from the adrenal cortex
Sympathetic activation also stimulates secretion of renin from the distal tubule

Front 124

Hypoaldosteronism

Back 124

Too little aldosterone secretion - results in excessive sodium loss, low blood volume and low b.p.

Front 125

Hyperaldosteronism

Back 125

Conn's syndrome - excess aldosterone, results in excessive Na+ retention and therefore water retention, raising b.p.
ACE inhibitors can be used to reduce b.p. as inhibit angiotensin II and so reduce aldosterone output

Front 126

Adrenal androgens - Define, example, action, control

Back 126

Androgens are steroid hormones that control the development and maintenance of male characteristics
DHEA (dehydroepiandrosterone) - weak androgen produced/released by the adrenal cortex zona reticularis
Stimulates development of pubic hair and libido
Release stimulated by ACTH
DHEA is normally a very minor component of adrenal secretions

Front 127

Function of the endocrine pancreas

Back 127

Regulates the availability of metabolic substances

Front 128

Development of the pancreas
Abnormal developments?

Back 128

Formed from endodermal dorsal and ventral pancreatic primodia
Cells bud off the exocrine ducts to form islets
Activin and FGF-2 from the notochord suppress Shh from the endoderm to allow pancreatic buds to form - other specific factors control differentiation of endocrine cells
Nesidioblastosis (abnormal proliferation of insulin cells) causes hypoglycaemia in babies

Front 129

Structure of the pancreas

Back 129

Islets of Langerhans make up 1-2% of the pancreas (1 million) - diffusely distributed throughout the pancreas
β (insulin) cells - 60%, lie centrally
α (glucagon) cells - 15%, lie peripherally
δ (somatostatin) cells - 10%, scattered between them
Pancreatic polypeptide (PP) cells - prominent only in the ventral pancreas

Front 130

Blood supply to islets of Langerhans

Back 130

Rich arterial supply (coeliac and SMA) enters the islets centrally, pancreatic veins drain to the liver via the hepatic portal vein

Front 131

Innervation of the islets of Langerhans

Back 131

Rich autonomic nerve supply from sympathetic and parasympathetic (vagus) nerves

Front 132

Plasma glucose concentrations
Morning fasting blood glucose
Hypoglycaemia
Hyperglycaemia

Back 132

4-5mM rises to 8mM after a meal
<3mM causes - dizziness, confusion, hunger, convulsions, coma: sympathetic arousal
>8mM causes - osmotic effects (if >10mM glucose is lost in urine with water), thirst, abnormal glycation (addition of sugar group) of proteins

Front 133

Sensing blood glucose

Back 133

By cells of islets, hypothalamus and some gut endocrine cells

Front 134

Insulin function

Back 134

Controls metabolic substrate usage, promotes anabolism

Front 135

Insulin chemical nature

Back 135

Protein hormone

Front 136

Insulin synthesis

Back 136

From the prohormone proinsulin, cleaved to insulin +C peptide in secretory granules.
Insulin comprises two chains linked by two S-S bonds, stored with zinc in dense-cored vesicles

Front 137

Mechanism of insulin secretion

Back 137

Glucose enters β cell (diffusion is facilitated by GLUT 2)
Metabolism of glucose in the β cell produces ATP
ATP closes ATP-dependent K+ channels present in the β cell membrane which in turn depolarises the β cell
Depolarisation causes Ca2+ entry - this in turn stimulates exocytosis of insulin

Front 138

What do sulphonylurea drugs do?

Back 138

Inhibits ATP-dependent K+ channels and promotes insulin release

Front 139

Insulin receptors

Back 139

Expressed very widely - liver, muscle, adipose tissue, neural tissue
Single transmembrane tyrosine kinase-linked receptor -two subunits (A and B chains), activation phosphorylates tyrosine of the B chain intracellularly
Two receptors must couple for action
Phosphorylation of insulin receptor substrate (IRS) proteins occurs - activates intracellular signalling cascades
Insulin receptor activity increases amount of GLUT transporters in plasma membrane and therefore increases glucose uptake

Front 140

General insulin actions

Back 140

- Acts to lower elevated plasma glucose (if secreted in uncontrolled excess may cause plasma glucose to fall below normal)
- Controls transport of glucose and amino acids into cells
- Directs their use by cells and augments their oxidation to ATP
- Increases protein synthesis and inhibits proteolysis
- Supports growth and proliferation of many cell types

Front 141

Insulin actions in...
Liver
Muscle
Adipose tissue

Back 141

- Promotes anabolism and inhibits catabolism
- Promotes protein synthesis, promotes glycogen synthesis
- Promotes triglyceride synthesis, inhibits lipolysis

Front 142

Insulin actions in liver on carbohydrate metabolism

Back 142

Stimulates: glycogenesis, glucokinase, glycogen synthase, glycolysis (indirectly), increases glucose oxidation by the pentose phosphate pathway secondary to increased fatty acid synthesis
Inhibits: glucose-6-phosphatase, glycogenolysis, gluconeogenesis,

Front 143

Insulin actions in liver on lipid metabolism

Back 143

Inhibits ketone body synthesis, increases fatty acid/triglyceride synthesis
Increases cholesterol synthesis from AcCoA

Front 144

nsulin action in liver on protein metabolism

Back 144

Increases amino acid transport into hepatocytes, increases protein synthesis

Front 145

Insulin action in muscle on carbohydrate

Back 145

Increases glucose transport into cells (via GLUT 4 transporters)
Increases glycogen synthase
Directly increases glycolysis

Front 146

Insulin action in muscle on protein

Back 146

Increases amino acid transport into cells
Increases protein synthesis
Decreases protein degradation

Front 147

Insulin actions in adipose tissue on lipid

Back 147

Increases fatty acid and trigyceride production
Inhibits lipolysis by inhibiting cAMP production

Front 148

Insulin actions in adipose tissue on protein

Back 148

Increases amino acid transport
Increases protein synthesis

Front 149

Diabetes type I - cause and treatment

Back 149

Insulin dependent diabetes - no insulin secretion due to autoimmune destruction of β cells
Treat with insulin - can have short, intermediate or long lasting types, insulin pump

Front 150

Diabetes type II - cause and treatment

Back 150

Non-insulin dependent, obesity associated
Early stages - peripheral resistance to insulin due to down-regulation of insulin receptors, disordered insulin secretion
Treatment - Regulation of diet (reduced sugar), stimulation of insulin release by sulphonylurea and meglitinide drugs (bind to K+-ATP channel subunit, biguanide decreases gluconeogenesis
Later stages - pancreatic amyloid formation and islet destruction occurs
Treatment - insulin treatment may be necessary

Front 151

Insulinoma

Back 151

Unregulated hypersecretion of insulin by tumour of β cells

Front 152

Glucagon function

Back 152

Protects against lack of metabolic substrates

Front 153

Glucagon chemical nature

Back 153

Peptide hormone

Front 154

Glucagon synthesis

Back 154

Produced as pro hormone proglucagon (family which includes GLP-1)

Front 155

Glucagon secretion

Back 155

Produced by α cells of the pancreatic islets

Front 156

Glucagon release - when?

Back 156

Increased in response to low plasma glucose, mechanism poorly understood
Secreted when plasma glucose is low
When high amounts of protein are ingested/high demand for glucose

Front 157

Glucagon actions

Back 157

Protects against hypoglycaemia - virtually all in the liver via Gs, cAMP
Depends on [glucagon] in plasma:
Low - stimulates glucogenolysis
Medium - stimulates gluconeogenesis
High - Stimulates lipolysis, fatty acid oxidation and ketogenesis

Front 158

Glucagonoma

Back 158

Glucagon-secreting tumour

Front 159

Somatostatin function

Back 159

Local (acts on pancreas) inhibitor

Front 160

Somatostatin chemical nature

Back 160

Peptide hormone made in δ cells of the pancreas

Front 161

Somatostatin receptor

Back 161

7-transmembrane Gi-coupled receptor

Front 162

Somatostatin actions

Back 162

Inhibits secretion of both insulin and glucagons (paracrine action)

Front 163

Somatostatinoma

Back 163

Gives symptoms of diabetes through inhibition of insulin secretion

Front 164

Pancreatic polypeptide function

Back 164

Role in digestion, appetite

Front 165

Pancreatic polypeptide chemical nature

Back 165

Peptide hormone made in islets and exocrine tissue

Front 166

PP release

Back 166

Stimulated by ingestion of a mean by both neuronal (vagus) and hormonal control

Front 167

PP actions

Back 167

Inhibits the secretion of enzymes by the exocrine pancreas
Blocks contraction of gall bladder
No obvious effect on carbohydrate or lipid metabolism
Effect on appetite