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Flashcards in Endocrinology Deck (420):

Define: Endocrine gland

Cells which secrete 'messenger' molecules directly into blood


Define: Endocrinology

Study of endocrine glands and their secretions


Define: Hormone

Bioactive 'messenger' molecule secreted by an endocrine gland into blood


Define: Endocrine

Relates to hormone's action of target cells source


Define: Paracrine

Hormone acts within immediate area around source


Define: Autocrine

Hormone has effect on cell that secreted it


Define: Cryptocrine

Hormone can have an effect within its own cell of production


What is the difference between the endocrine and nervous system?

Endocrine= involves release of chemical hormone, effect on many targets, spread throughout body, will take place over long time

Nervous= involves release of chemical NT, effect restricted to target cells, within milliseconds


List examples of protein/polypeptide hormones by size

Complex polypeptides e.g. LH (200 AA)
Intermediate polypeptides e.g. insulin
Small peptides e.g. TRH (3 AA)
Dipeptides e.g. T4 (derived from 2 iodinated tyrosine residues)
Derived from single AA e.g. catecholamines


How are protein hormones synthesised?

AA sequence determined by specific mRNA synthesised in nucleus
Ribosomal synthesis of pre-prohormone (larger than active hormone)


What is a prohormone?

Precursor of a hormone
Shortened (processed by proteolytic enzymes) to become mature, active hormone


Where are protein hormones stored?

In secretory granules
(For release in exocytosis)


Describe ACTH production within a corticotroph cell

Specific mRNA synthesised from DNA within cell nucleus

Translation of specific mRNA to prohormone POMC in RER
POMC -> Golgi apparatus for POMC processing
Mature ACTH stored in secretory granules within cytoplasm


What are steroid hormones derived from?



What 2 groups are steroid hormones divided into?

Intact steroid nucleus (adrenal/gonadal steroids)
Broken steroid nucleus (Vit D and metabolites)


How are precursors of steroid hormones transported?

Passive diffusion across cell membrane from blood stream


How does the precursor molecule produce the steroid hormone?

Action of several enzymes


Describe Cortisol production in an adrenal cortical cell

LDL rich cholesterol transferred into cell by endocytosis (from blood capillary to cytoplasm)
Cholesterol splits from lipoprotein and is esterified and stored in cytoplasmic vacuoles
ACTH stimulation activates cholesterol esterase -> cholesterol release from cholesterol ester depots
StAR protein (steroidogenic acute regulatory protein) mediates transfer of cholesterol from outer to inner mitochondrial membrane


What is the difference between mature steroid hormone and mature protein hormone (regarding cell membrane crossing)?

Steroid hormone can freely cross cell membrane without being packed into secretory granules and actively exocytosed


Where are most hormones secreted?

Systemic circulation
EXCEPT hypothalamus releases into hypophyseal portal system (a rich network of blood vessels that 'bathe' the anterior pituitary)


What hormones are water soluble?

Protein/polypeptide (circulate freely within the bloodstream- QUICK, MINS)


What hormones are more insoluble?

Steroid and thyroid hormones (bound to plasma proteins or transport proteins- SLOWER)


How does the bound hormone remain in dynamic equilibrium with a small amount of free hormone?

The transport protein acts as a reservoir
Changes in plasma protein or free hormone are followed by adjustments of secretion rates of the hormone (so free hormone available to tissues remains constant)


How do free hormones function?

Biologically active
Buffer hormones and protect against rapid hormone concentration changes


What is albumin?

A general transport molecule (plasma protein)
Non-selectively transports a variety of low molecular weight hormones


What are TBG, CBG and SHBG?

TBG- thyroxine-binding globulin (Thyroid hormones)
CBG- corticosteroid-binding globulin (Cortisol)
SHBG- sex hormone-binding globulin (Testosterone/Oestradiol)


How is clearance rate (from circulation) affected by binding of proteins?

Greater binding capacity-> slower clearance rate of the hormone


If hormone levels fall, is the forward or backward reaction favoured?

Hormone + plasma protein Protein bound hormone

Endocrine cell increases hormone synthesis and release


If plasma levels increase, is the forward or backward reaction favoured?

Hormone + plasma protein Protein bound hormone

Endocrine cell increases hormone synthesis and release


Biological response of a hormone target is determined by 3 main factors, these are...

Concentration of hormone in circulation
Concentration of number of receptors
Affinity of hormone-receptor interaction


What concentration of hormones are usually present in circulation?

Very low
10(-9) to 10(-12)M
So need high affinity and high specificity


What is the amount of hormone binding dependent on?

Number of specific receptors on target cell
Because binding of a hormone to receptor is a saturable process


How do peptide/protein and catecholamine hormones act?

Via receptors on cell surface
Binding-> activates effectors system-> IC signal and 2nd messengers
Changes membrane transport, DNA and RNA synthesis, protein synthesis and hormone release


Describe how ACTH acts on an adrenal cortical cell

ACTH binds to the GsPCR
Leads to dissociation of alpha subunit from by subunits
Activated adenylate cyclase (ATP->cAMP)
Need PKA to activate cholesterol esterase (provides free cholesterol from cholesterol esters)
Free cholesterol acted on by steroid synthetase-> StAR protein function (cholesterol from outer to inner mitochondrial membrane)


How do steroid hormones act?

Act via intra-nuclear receptors
Enter most cells by passive diffusion
Hormone binds to specific IC protein receptors within cytoplasm and nucleus

Steroid receptor complex binds to DNA binding sites and response elements (RE) to alter gene transcription and protein synthesis
Leads to stimulation of cell growth, differentiation and regulation of specific proteins

When receptor-hormone complex has interacted with the gene, re-establishment of the unoccupied receptor occurs with elimination of hormone from the cell


Describe how cortisol acts on its target cell

Free cortisol enters cell by passive diffusion
Binds to specific glucocorticoid receptors in cell cytoplasm

Hormone-receptor complex travels to nucleus and binds to DNA binding sites/RE
Leads to changes in transcription rates of specific genes and production of mRNA
Translation of MRNA to protein within endoplasmic reticulum


How is any individual hormone system controlled?

Negative and positive feedback (necessary for normal endocrine homeostasis)

Mostly negative closed loop feedback

E.g. hypothalamus and pituitary with target organs (thyroid, adrenals and gonads)


What is a closed loop feedback system?

Feedback of a substance regulated by its own production
Protect against excessive hormone action


Why is assessment of both stimulatory and peripheral hormones analysis necessary?

Feedback relationship
Need to assess endocrine status


What is another name for the pituitary gland?
Anterior lobe?
Posterior lobe?

Anterior- adenohypophysis
Posterior- neurohypophysis


Where is the hypophysis?

Lies at base of brain in sella turcica directly under the hypothalamus


Where is the hypothalamus?

Around the 3rd ventricle in the brain
Anterior: optic chiasma lies at front of hypothalamus
Posterior: mammillary body at back of hypothalamus is important in the development of the NS


How does the pituitary gland develop?

Anterior lobe (adenohypophysis)- "grows up" and attach to the base of the brain
Posterior lobe (neurohypophysis)- nervous tissue "grows down" and attaches to anterior lobe, consists mainly of nerve axons and nerve terminals


What is in the hypothalamo-adenohypophysial axis?

Hypothalamic nuclei
Neurons to median eminence
Adenohypophysial hormones



What happens in the hypothalamo-adenohypophysial axis to allow adenohypophysial hormons to be released?

Hypothalamic neurone from hypothalamic nucleus-> activation

1. Hypothalamic neurosecretion released into hypothalamo-hypophysial portal system
2. Hypothalamic neurosecretion acts on anterior pituitary target cells
3. Release of adenohypophysial hormone into general circulation


What are the 6 chief adenohypophyseal hormones?

Somatotrophin (growth hormone)


Thyrotrophin (thyroid stimulating hormone TSH)

LF and FSH (luteinizing hormone, follicle stimulating hormone)

Corticotrophin (adrenocorticotrophic hormone, ACTH)


What hypothalamic hormones control the adenohypophyseal cells?

Somatotrophs produce somatotrophin

Lactotrophs produce prolactin

Thyrotrophs produce thyrotrophin (TSH)

Gonadotrophs produce LF and FSH

Corticotrophs produce corticotrophin (ACTH)


Where are adenohypophyseal hormones stored?

In secretory granules (released by exocytosis)


Give an example of an adenohypophyseal precursor pro-hormone

POMC (ProOpioMelanoCorticotrophin)

POMC-> Corticotrophin +Pro-yMSH + BLPH


Group adenohypophyseal hormones into proteins, glycoproteins and polypeptides

- Somatotrophin (191 AA)
- Prolactin (199 AA)

GLYCOPROTEINS consisting of a and B sub-units (92AA alpha subunit common to all)
- Thyrotrophin (TSH) (B-subunit 110 AA)
- LH (B-subunit 115 AA)
- FSH (B-subunit 115 AA)

- Corticotrophin (ACTH) (39AA)


How is the hypothalamus involved in adenohypophyseal hormones?

Hypothalamic hormones have a direct influence on the release of adenohypophyseal hormones


Which hypothalamic hormones affect which adenohypophyseal hormones?

Somatotrophin releasing hormone (SRH or GHRH)- STIM
Somatostatin (SS)- INHIB

Thyrotrophin releasing factor (TRH)- STIM
Dopamine (DA)- INHIB

Thyrotrophin stimulating hormone (TSH)- STIM

Gonadotrophin releasing hormone (GnRH)- STIM

Corticotrophin releasing hormone- STIM


What are the main target cells of the adenohypophyseal hormones?

Somatotrophin-> general body tissue, especially the liver

Prolactin-> breasts (lactating women)

Thyrotrophin-> thyroid

Gonadotrophins-> testes (men), ovaries (women)

Corticotrophin-> adrenal cortex


What are the principle physiological actions of ACTH?

Targets adrenals
Stimulates the adrenal gland to produce a hormone called cortisol


What are the principle physiological actions of TSH?

Targets thyroid
Stimulates the thyroid gland to secrete thyroxine


What are the principle physiological actions of LH and FSH?

Controls reproductive functioning and sexual characteristics

Stimulates ovaries to produce oestrogen and progesterone and stimulates ovulation
Stimulates final maturation of the oocyte
In follicular stage of menstrual cycle: stimulates production of androgens (androstenedione)

Stimulates testes to produce testosterone and sperm (spermatogenesis)
LH is also referred to as interstitial cell stimulating hormone (ICSH) in males


Describe the hypothalamo-adenohypophyseal-thyroidal axis?
(Consider direct, indirect and short negative feedback loops)

Hypothalamus secretes TRH-> stimulates TSH in adenohypophysis-> stimulates thyroid to release T3 (triiodothyronine) or T4 (thyroxine)

High T3 or T4-> stimulates own inhibition (inhibits secretion of TSH in adenohypophysis)

High T3 or T4-> stimulates own inhibition (inhibits secretion of TRH in hypothalamus-> less tSH in adenohypophysis)

TSH inhibits production of TRH in hypothalamus
(Adenhypophysial hormones influence their own release by influencing secretion of release-stimulating or release-inhibiting hypothalamic hormones)


Explain the growth promoting and metabolic actions of somatotrophin (growth hormone)

Direct and indirect (via IGFI) effects

Stimulation of AA transport into cells (e.g. muscle)
Stimulation of protein synthesis (genomic)
Increased cartilaginous growth
Stimulation of lipid metabolism leading to increased fatty acid production
Increased blood glucose concentration [decreased glucose utilization (due to increased insulin resistance) and increased gluconeogenesis]


Outline the direct and indirect pathways of somatotrophin leading to growth and development

Adenohypophysis-> somatotrophin-> body tissues (metabolic actions)-> growth and development

Adenohypophysis-> somatotrophin-> liver-> somatotmedins (IGF I and IGF II)-> body tissues-> growth and development


What stimulates somatotrophin production?

Amino acids
Fasting (hypoglycaemia)
Sleep (stages III and IV)


What negative feedback takes places in somatotrophin release?

Somatotrophin and somatomedin release in itself inhibits further somatotrophin production via negative feedback loops

Somatostatin (SS) -> inhibits release


What positive feedback takes places in somatotrophin release?

Somatotrophin releasing hormone (SRH/GHRH)-> stimulates release


List the effects of prolactin

Breast= lactogenesis in post-partum women (secretes large amounts during pregnancy and breast feeding)
Pituitary= decreased LH release
Hypothalamus= decreased sexual behaviour
Testes/ovaries= increased LH receptors
Immune system= stimulates T cells

Renal Na/water reabsorption?


Outline how prolactin release is controlled

Neuroendocrine arc

1. Suckling of breast (stimulus)
2. Tactile receptors around nipple
3. Afferent nerve pathway
4. Higher centres
5. Hypothalamus (TRH (+) and DA (-))
6. Adenohypophysis
7. Prolactin
8. Milk production in post-partum breast

Neural afferent limb (1, 2, 3 4)
Endocrine efferent limb (5, 6, 7, 8)


Why is hyperprolactinaemia associated with a contraceptive effect?

Excessive prolactin production interferes with hypothalamo-pituitary-gonadal axis

Inhibits reproductive axis because of increased DA (inhibits PL due to short-loop fb)

Men become impotent, lose libido, and become infertile
Women develop amenorrhoea or oligomenorrhoea and may not ovulate


Why are growth charts more useful than signal measurements?

Important to take multiple height measurements over a period of time in order to establish a basis for comparison
A single height measurement is not sufficient
Growth chart must be specific to population individual belongs to


What are various causes of short stature?

Genetic causes: e.g. Down syndrome, osteochondroplasia, Turner’s syndrome; PraderWilli syndrome
Low levels of somatotrophin (GH)
Low levels of SRH/GHRH
High levels of somatostatin (SS)
High levels of somatomedins (IGF1 and IGF2)
Somatotrophin resistance due to a lack of receptors or dysfunctional receptors
Cushing syndrome: excess glucocorticosteroids


How can you test if the GH axis is functioning correctly?

GH released in large pulses during the day
Patient vigorously exercises (or fasts)
Blood sample before and after
Should see marked rise in hormone

Also, can give insulin-> reduce blood glucose-> patient should release GH
Blood sample before and after


What is the posterior pituitary?


Outgrowth of the hypothalamus and is neural tissue


How are neurones that are associated with the neurohypophysis grouped together?

In the supraoptic and paraventricular nuclei in the hypothalamus


Where do unmyelinated axons of paraventricular and supraoptic nuclei pass through and end?

Pass through infundibulum
End within the posterior pituitary (close to capillaries)


Where do magnocellular neurones pass through and terminate? What are they?

Pass through the median eminence and terminate near capillaries of the neurohypophysis

They are neuroendocrine neurones whose cell bodies are mainly in the supraoptic nucleus and paraventricular nucleus of the hypothalamus.


Where do parvocellular neurones release their neurosecretions and send their axons? What are they?

Release their neurosecretions into the primary capillary plexus in the median eminence
Or send their axons to other parts of the brain

They are small neurones within paraventricular nucleus (PVN) of the hypothalamus.


Where do most posterior pituitary capillaries drain into?

The main bloodstream
Via jugular veins
Carries hormones to heart


What are supraoptic neurones and where do they travel from/through?

Leave hypothalamic supraoptic nuclei
Pass through median eminence
Terminate in neurohypophysis
Either vasopressinergic or oxytocinergic

(NB. Have herring bodies along axon)


What are paraventricular neurones and where do they travel from/through?

Originate in paraventricular nuclei
Some parvocellular neurones pass to other parts of the brain
Majority of neurones are magnocellular (pass to other parts of brain)
Some parvocellular (terminate in median eminence)
Either vasopressinergic or oxytocinergic


What are the 2 principal secretory produces of magnocellular neurones?

Vasopressin (ADH)


Where are pro-hormones of neurohypophyseal hormones?

Synthesised as pro-hormones in the supraoptic and paraventricular nuclei
Then transported to posterior pituitary


How are pro-hormones converted to hormones?

Cleaved to form hormones and neurophysin proteins (released together)


What are the similarities and differences between the structure of arginine (vasopressin) and oxytocin

Both are nonapeptides (9 AAs) with a 6 AA ring (has 2 cysteines linked by disulphide bonds at positions 1 and 6)
Also have a 3 AA chain

They differ by two AAs
AVP= phenylaline at position 3, arginine at position 8
OXY= isoleucine at position 3, leucine at position 8


How are neurohypophyseal hormones synthesised, stored and released?

1. Synthesis occurs in cell bodies of magnocellular neurons in supraoptic and paraventricular nuclei in the hypothalamus

2. Initially synthesized as prohormones (pro-vasopressin and pro-oxytocin)
[Exons have vasopressin/ oxytocin sequences, then neurophysins, then glycopeptide (only AVP)]

3. Molecular complexes incorporated into granules which migrate down nerve axons as a result of axon transport

4. During migration= pro-hormone cleaved by basic endopeptidases into the mature hormone and the associated neurophysin

5. Granules collect at nerve terminals and in Herring bodies along nerve axons

6. Nerve endings lie close to capillaries in posterior lobe of pituitary

7. Release associated with APs at nerve endings which depolarise terminal membranes

8. Granule contents released into bloodstream by exocytosis (neurophysins released with hormones, but not bound to each other)


What is found in Herring bodies?

Granules containing molecular complexes of pro-hormones


Describe pre-provasopressin-> prohormone-> hormone of vasopressin

Pre-> pro: glycosylation, disulphide bridging, folding
Pro-> hormone: cleavage and exocytosis

Vasopressin + neurophysin + glycopeptide


Describe pre-oxytocin-> prohormone-> hormone of oxytocin

Pre-> pro: glycosylation, disulphide bridging, folding
Pro-> hormone: cleavage and exocytosis

Oxytocin + neurophysin (diff from AVP)
*NB. no glycopeptide


What are the receptors for vasopressin and what IC pathways do they activate?

V1a (IP3 and DAG)
Linked via G proteins to PLC
Which acts on membrane phospholipids to produce inositol triphosphate IP3 (and diacyl glycerol, DAG)
IP3-> increase cytoplasmic [Ca2+] and other IC mediators (PKC)
Produce cellular response

V2 (cAMP)
Linked via G proteins to adenyl cyclase
Which acts on ATP to form cyclic AMP
Which activates PKA
Which in turn activates other IC mediators
Which produce cellular response (aquaporins, AQP2)


Where are vasopressin receptors found?

Arterial (vasoconstriction)
Hepatocytes (glycogenolysis)
CNS neurones (behaviour and other effects)

V1b (V3)
Adenohypophyseal corticotrophs (corticotrophin production)

Collecting duct cells (water reabsorption)
Probably other unidentified sites
Factor VII and von Willbrandt factor


What are the main physiological actions of vasopressin?

In principal cells (renal collecting duct)= stimulates water reabsorption and has antidiuretic effect
Corticotrophin release (together with CRH)
CNS effects
Acting as NT (or hormone) e.g. on aspects of behaviour
Synthesis of blood clotting factors (VIII and Von Willbrandt)
Hepatic glycogenolysis


What are the main physiological actions of oxytocin?

Stimulates contraction of smooth muscle of myometrium during parturition
Stimulates contraction of myoepithelial cells surrounding ducts of lactating mammary glands during lactation


How does vasopressin cause renal water reabsorption?

1. Vasopressin binds to V2 receptors on BL membrane of epithelial principal cells and activates the associated G protein

2. G protein is exchanges GDP for GTP -> alpha subunit moves from the body of the G protein

3. This activates adenylate cyclase, which causes GTP to give up a phosphate to make cAMP from ATP

4. cAMP activates PKA

5. This causes water channels (aquaporins) (contained in vesicles called aggrephores) to move to apical/luminal membrane
Specifically aquaporin-2

6. This causes the water to move through the epithelial cells and into plasma
Water leaves epithelial cells via aq-3 and aq-4 on BL membrane


What stimulates production of vasopressin?

Decreased water amount in blood causes increased plasma osmolality
Decreased blood volume as a result of haemorrhage
Emotional/surgical stress may-> massive vasopressin release


What stimulates production of oxytocin?

Suckling a lactating mother
Stretch receptors in the vagina/uterus
Emotional stress may-> inhibition of lactation


How does increased plasma osmolality increase vasopressin production?

Detected by osmoreceptors in hypothalamus
Sends axons to the cell bodies of supraoptic and paraventricular nuclei in the hypothalamus
Causes release of AVP from neurohypophysis
Causes increased uptake of water from collecting duct
Decreases plasma osmolality


How does decreased blood volume increase vasopressin production?

Decreased circulating volumes activate:
-Low pressure mechanoreceptors in L atria and central veins
- High pressure baroreceptors in carotid sinus and aortic arch

Decreased arterial blood volume -> decreased frequency of APs from these various stretch receptors
Stimulates release of vasopressin by decreasing inhibitory effect normally operated by this baroreceptor reflex pathway

Increased vasopressin causes vasoconstriction
Causes an increase in arterial blood pressure


How does suckling increase oxytocin production?

Tactile receptors in breasts, especially around nipples, initiate APs
APs propagate along afferent nerve fibres through SC and midbrain to the hypothalamus

Oxytocinergic cell bodies in the paraventricular and supraoptic nuclei are stimulated and cause the release of oxytocin

Oxytocin causes myoepithelial cells to contract (in breast) -> milk ejection


How do stretch receptors in the vagina/uterus increase oxytocin production?

Stimulate APs in afferent pathways
Leads to oxytocin release
Causes smooth-muscle cells of myometrium to contract

E.g. in uterus at parturition-> contraction-> deliver baby


What clinical conditions are associated with vasopressin?

Central DI (no VP)
Nephrogenic DI (tissue insensitivity)

Syndrome of inappropriate ADH


List common symptoms caused by lack of vasopressin

Unquenchable thirst (wakes up at night)
Urinates frequently
Fasting serum glucose level normal
No glucose detected in urine


What can cause lack of vasopressin?

Genetic disorder
Cranial diabetes insipidus
Hypothalamic disorder affecting vasopressinergic neurons e.g. due to trauma or a tumour


What is DDVAP why is it used (not AVP) for measurements to study neurohypophyseal disorders?

DDAVP stimulates water reabsorption in the principle cells of the renal collecting ducts
Increased water absorption in the renal collecting ducts-> urine osmolality rises

DDAVP is synthetic and lasts longer than AVP (nonapeptide broken down too quickly)


How would a 'normal' person's osmolarity of urine respond during a water deprivation test?

Urine osmolality would increase as high blood glucose level exerts an osmotic pressure
This draws water out of plasma and into renal filtrate

Polyuria: increased urine volume
Polydipsia: excessive thirst


How does water reabsorption increase when dehydrated?

1. Become dehydrated
2. Osmolality increases and detected by osmoreceptors
3. Signal sent to vasopressinergic cells (in paraventirular and supraoptic nuclei) to increase vasopressin
4. Vasopressin released by magnocellular neurons
5. Bind to receptor-> stimulates aquaporin to apical membrane
6. Increased water reabsorption
7. Plasma osmolality decreases


What happens to osmolarity after administering DDAVP?

Osmolality of urine rises

(DDAVP functions like AVP)


Why is blood glucose concentration closely regulated?

Glucose is a vital energy substrate

Low glucose (hypoglycaemia (impairs brain function)
Lower glucose (unconsciousness, coma, death)

High glucose can -> diabetic coma which can -> death


What are normal blood glucose levels?



What hormones control glucose level?

Decrease levels= insulin
Increase levels= glucagon, catecholamines (e.g. adrenaline), cortisol and somatotrophin


Which type of diabetes is more common?

Type 2 (85-95%, NB. T1=11%)
Considerable health burden
Defined in terms of glucose but also related to hypertension and dyslipidaemia


How much of the pancreas is associated with exocrine secretions (via duct to small intestine)?



What percentage of pancreatic tissues are small clusters of endocrine cells and what are they called?

Islets of Langerhans


What are the main types of islet cells and what do they secrete?

Alpha= secrete glucagon
Beta 60%= secrete insulin
Delta= secrete somatostatin
F= secretes pancreatic polypeptide (unknown function)


What junctions are present between typical islets of Langerhans?

Gap junctions (allow small molecules to pass directly between cells)
Tight junctions (form small intracellular spaces and involve fusion of outer cell membranes)


Describe Islet of Langerhans cell structures (and how a, b, d, f cell differ)

Alpha cells= more numerous and denser concentrations of granules in their cytoplasm than beta cells
Beta cells are generally smaller
Delta cells contain numerous, more uniform granules which are less dense than those of either alpha or beta cells
Type F cells also found on periphery, secrete pancreatic polypeptides

Gap and tight junctions important


Describe blood flow around/in the pancreas?

Blood flows from the periphery to the core of the islets

Portal blood supply allows blood from beta cells to bathe the alpha and delta cells for rapid communication

Arterial blood supply is from the splenic hepatic and superior mesenteric arteries

Venous blood drains directly into portal vein reaching the liver directly


Describe how insulin is synthesised?

1. On beta cells within islets of Langerhans
2. Initially synthesised as preproinsulin via mRNA translation
3. Removal of its signal peptide during insertion into the endoplasmic reticulum generates proinsulin (a single chain polypeptide)
4. Proinsulin folds spontaneously upon itself -> forms 2 disulphide bridges
5. Proinsulin is incorporated into granules at the Golgi body and the C-peptide is cleaved by proteolysis within the granules
6. This forms the mature insulin molecule and the C peptide


Describe how insulin is stored?

Stored within granules
Partly as polymers and partly complexed with zinc


Describe how insulin is released?

Insulin secretion is triggered by rising blood glucose levels (detected by glucokinase)

GLUT2 transporter takes glucose up
Glucose phosphorylated by glucokinase (rate limiting)
Glycolytic phosphorylation of glucose -> rise in ATP:ADP ratio

Rise inactivates the K channel that depolarizes the membrane-> Ca channels open up allowing Ca ions to flow inward

Increased Ca channels-> exocytotic release of insulin from storage granule


How much insulin is degraded in the liver and kidneys?



What are 3 of insulin's main functions?

Decreases blood glucose concentration (carb metabolism)
Decreases blood AA concentration (protein metabolism)
Decreases blood fatty acid and ketone concentrations (fat metabolism)


How does insulin decrease blood glucose concentration?

Increases uptake of glucose by target cells by directing the insertion of GLUT-4 glucose transporters into cell membranes (as glucose enters cells, blood glucose conc decreases)

Increased glycogenosis and glycolysis (promotes glucose-> glycogen in muscle and liver via enhanced glycogen synthase activity)

Also inhibits glycogenolysis (inhibits glycogen phosphorylase)

Decreases gluconeogenesis by increasing the production of fructose 2,6-biphosphate, so substrate is directed away from formation of glucose



How does insulin decrease blood amino acid concentration?

Stimulates active transport of AAs into peripheral cells

Stimulates protein synthesis directly

Decreases protein catabolism (proteolysis) (because of increased glucose utilisation, stimulated by protein cortisol)


How does insulin decrease fatty acid and ketone concentrations?

Stimulates cellular uptake and oxidation of glucose by adipose tissue

Stimulates lipogenesis in hepatic and adipose tissues and fat storage

Inhibits lipolysis

Activates lipoprotein lipase of endothelial cells which catalyses hydrolysis of triglycerides bound to lipoproteins and stimulates movement of fatty acids into adipocytes

NB. Low prevalence of ketonuria in T2DM


Which factors regulate the release of insulin to decrease blood glucose?

Certain AAs
Certain GI hormones
Alpha cells-> glucagon
Parasympathetic activity (B-receptors)

Delta cells-> somatostatin
Sympathetic activity (a-receptors)
Stress (associated with sympathetic mediators)


Which factors regulate the release of glucagon to decrease blood glucose?

Certain AAs
Certain GI hormones
Sympathetic activity
Parasympathetic activity

Beta cells-> insulin
Delta cells-> somatostatin


What does glucagon raise?

Blood glucose concentration
Blood fatty acid concentration
Urea production


How does glucagon increase blood glucose?

Increased AA transport into liver-> increased gluconeogenesis-> increased blood glucose

Increased hepatic glycogenolysis-> increased blood glucose

Increased lipolysis-> increased gluconeogenesis-> increased blood glucose


What is glucokinase?

Glucose sensory, hexokinase IV
Acts as a glucose receptor on pancreatic B cells


How does glucokinase affect insulin synthesis and release?

Glucokinase acts as a glucose receptor on pancreatic beta cells

1. When glucose levels rise, glucose enters cell via GLUT2 transporters

2. Glucokinase mediates phosphorylation of glucose to glucose-6-phosphate (for glycogen syntehsis and glycolysis)

3. Phosphorylation of glucose causes ATP:ADP ratio to rise-> K channels close-> depolarises membrane

4. Calcium channels open, Ca influx-> exocytotic release of insulin from its secretory granules


What is GLP-1?

Glucagon like peptide-1
Gut hormone secreted in resonse to nutrients in gut
Transcription product of proglucagon gene (mostly from L cell)


What does GLP-1 do?

Stimulates insulin
Suppresses glucagon
Increase satiety


What is GLP-1 degraded by?

Enzyme= Dipeptidyl peptidase-4 (DPPG-4 inhibitor)

Rapid degeneration, so GLP-1 has a short half life


Describe the structure of the insulin receptor

Tetramer with 2 alpha subunits and 2 beta subunits

a= EC subunits, contain insulin binding sites
B= span the membrane, have tyrosine kinase activity


How does insulin binding to the receptor lead to glucose being transported into the cell?

Insulin binds to receptor
TK autophosphorylates the B subunits
Phosphorylated receptor then phosphorylates IC proteins
This initiates a signal transduction cascade which stimulates and actives GLUT4 to tranport glucose into the cell


What colour is urine when it has:
No ketones
Lots of ketones?

No ketones= yellow
Ketones= green
Lots of ketones= very green


What is likely to be the diagnosis of a young patient who has rapidly lost weight, drinks up to 3.5L a day (and passes nearly all of it) and very green urine with lots of glucose?
She also has polydipsia and polyuria

Type 1 diabetes mellitus


Will ketones be in urine in Type 1 diabetes, Type 2, neither or both?

(Ketones won't be in urine unless fasting in T2DM as ketone body formation is surpressed by insulin, fat not broken down)


Why is glucose in the urine of a patient with T1DM?

Lack of insulin-> glucose uptake (via Glut 2 and glut 4) stopped glycogenesis does not occur (glucose -> glycogen)
This means glucose remains in the plasma (doesn't enter cells) and is passed out in the urine

In ABSENCE OF INSULIN, glycogen-> glucose by liver

Protein broken down-> AAs towards gluconeogenesis

Fat broken down-> products go towards making more glucose


Why is so much water passed by a patient with T1DM?

Increased glucose concentration in the urine exerts an increased osmotic pressure
So more water drawn out into the urine (due to increased osmolarity)
Therefore urine volume increases


Why is C peptide a good marker for endogenous insulin?

Longer half life (30 mins not 4) and more stable


In T1DM, what is the concentration of plasma glucose and plasma insulin?

Plasma glucose high
Plasma insulin conc= 0mmol/l

(T1DM- beta islets wiped out by GAD antibodies so no insulin synthesised or secreted0


What is the normal fasting plasma glucose?


Is the fasting plasma glucose for higher or lower in T2DM patients?



What are common characteristics of a patient with T2DM?

Cardiovascular symptoms


What causes T2DM?

Unresponsiveness to insulin
Plasma insulin concentration normal/high
Can't reduce blood glucose levels (high HGO)
Body tries to compensate increasing insulin secretion, but no effect


What do T2DM diets recommend?

Overall calorie control
Reduce fat calories
Reduce refined carb calories

Reduce sodium intake Increase soluble fibre Increase complex carb calories


What does energy restriction in T2DM ensure?

Energy restriction will ensure that glucose is taken up into cells as a necessary energy source
Prevents hyperglycaemia


What's the difference between diabetes insipidus and diabetes mellitus?

Diabetes mellitus is characterized by high levels of sugar in the blood e.g. T1DM, T2DM, gestational.
Involves insulin

Diabetes insipidus (rare) is a disease where kidneys are unable to conserve water
Involves vasopressin


List effects of insulin (across intermediary metabolism, not just relating to diabetes)

Glucose (decreases HGO- hepatic glucose output, increases muscle uptake)

Protein (decreases proteolysis)

Lipid (decreases lipolysis and ketogenesis)


Vascular effects

Ovarian function

Clotting (Pai-1)

Energy expenditure (relation to Leptin)


Where is GLUT-4 expressed?

Muscle and adipose tissues
Lies in vesicles until recruited and enhanced by insulin


What effect does GLUT-4 have on glucose uptake into cells?

7x increase in glucose uptake into cells


What is the structure of GLUT-4?

Hydrophobic outer layer and hydrophilic inside (where glucose goes through)


What are GLUT-2 and GLUT-4?

Glucose transporters

GLUT-2 glucose-stimulated (leads to glucose entry into cell, glucokinase aids this)

GLUT-4 insulin-stimulated transported (recruited and enhanced by insulin)


What stimulates protein synthesis (from AAs)?

Growth hormone


Relating to proteins, what does insulin inhibit?

Conversion of oxygen to carbon dioxide


What are the effects of insulin and glucagon on glucose?

Stimulates glycogenesis (glucose->glycogen)
Inhibits gluconeogenesis (glycogen-> glucose)
Decreases hepatic glucose output

Increases uptake of gluconeogeneic AAs into cells
Stimulates glycogenolysis and gluconeogenesis
Increases hepatic glucose output


What is the difference between carbohydrates, proteins and fat as fuel stores?

Liver and muscle cells: glycogen ->glucose (especially in brain)
Short term source: 16 hrs

Longer term: 15 days

Long term source: 30-40 days
Highest energy released per gram


What do insulin and lipoprotein lipase do in fat metabolism?

Insulin and lipoprotein lipase stimulates the breakdown of triglycerides into glycerol and non-esterified fatty acids

Insulin also stimulates uptake of glucose into adipose tissue (via Glut 4 transporter)


What does insulin do within adipose tissue?

Stimulates formation of triglycerides for glycerol-3-phosphate non-esterified fatty acids

Inhibits the breakdown of triglycerides into glycerol and non-esterified fatty acids


What stimulates the breakdown of triglycerides into glycerol and non-esterified fatty acids?

Catecholamines, cortisol and growth hormone

(Insulin inhibits this)


Describe omental circulation

Via hepatic portal vein:
Heart-> GI tract-> liver-> heart

Adipocytes in GI tract are highly metabolically active


Why is waist circumference a good indicator of heart disease?

Increased circumference means more adipocytes in GI tract
This means increased risk of ischaemic heart disease and death


What is hepatic gluconeogenesis?

Occurs in the liver (hepatocytes)

Glycerol (in blood) taken up into the hepatocytes to form glycerol-3-phosphate

G3P is readily interconverted to triglycerides and to glucose (gluconeogenesis)

Glucose released from the hepatocyte via HGO (into blood)

NB. Ketone bodies and glucose can be used for brain (not fatty acid metabolism)


What % of glucose output (after a 10 hour fast) is released from hepatocytes via HGO?



What happens to fatty acids in the liver?

Non-esterified fatty acids taken up into hepatocytes

NEFAs converted to fatty acyl CoA

Fatty acyl CoA converted to acetyl CoA-> acetoacetate -> acetone and 3 hydroxybutarate

These are then released as ketone bodies (an alternative source of fuel for brain if hypoglycaemia occurs)


What inhibits/stimulates the conversion of fatty acyl CoA (in fatty acid metabolism)

Insulin inhibits
Glycogen stimulates


What do ketones in the urine indicate?

Ketones in urine indicate fasting which has lead to fatty acid metabolism

Elevated glucose and ketones present in urine is abnormal and indicates insulin deficiency


What is hepatic glycogenolysis?

After glucose is taken up into hepatocytes and converted to glucose-6-phosphate-> stored as glycogen

Stimulated by insulin
Inhibited by glucagon and catecholamines (which stimulate the revers)

G6P can also be re-converted to glucose (which can be released from cell via HGO to increase blood glucose levels)


Where are fatty acids taken up into?

Muscle cells


What happens to fatty acids and glucose in muscle cells?

FAs are taken up into muscle cells where they are converted to acetyl CoA (which then enters the Krebs cycle)

Glucose uptake via glut-4
Stimulated by insulin
Inhibited by growth hormones, catecholamines and cortisol
Glucose is then stored as glycogen or converted to acetyl-CoA


Describe the fasted state (and prolonged fasting)

Low insulin to glucagon ratio
Blood glucose conc 3.0-5.5 mM
Increased in non-esterified fatty acids within the blood
Decreased in AAs within the blood when prolonged

Increase in proteolysis (AAs released from muscles)
Increased lipolysis (adipocytes release glycerol and fatty acids)
Increased HGO from glycogenolysis and gluconeogenesis

Muscles use lipid metabolism as energy store
Brain uses glucose metabolism, followed by ketone bodies
Increased ketogenesis


Describe the fed state

1. Stored insulin released
2. Synthesised insulin released slowly

High insulin to glucagon ratio
HGO stopped
Increased glycogenesis
Reduced gluconeogenesis and glycogenolysis
Increased protein synthesis
Decreased proteolysis
Increased lipogenesis (glycerol and fatty acids taken up by adipocytes -> triglycerides)


What is Diabetes Mellitus?

DM= metabolic disorder due to insulin deficiency of hyporesponsiveness
Characterised by hyperglycaemia and other distinct symptoms


What are the main signs of DM?

Weight loss and polyphagia
Diabetic keotacidosis


What causes glycosuria (in DM)?

Glycosuria= Loss of glucose in urine

In relative/total absence of insulin-> blood glucose rises

Renal proximal tubes normally reabsorb glucose unless blood glucose is above renal threshold (180mg/dl)

Hyperglycaemia in DM-> exceeds threshold so glucose not reabsorbed


What causes polyuria (in DM)?

Polyuria= Increased amount of urine produced

Loss of glucose in urine causes osmotic diuresis (because osmotic effect of glucose in tubules greatly decreases the tubular reabsorption of fluid)

Diuresis may be partly due to inhibition of vasopressin release from neurohypophysis


What causes polydipsia (in DM)?

Polydipsia= Thirst and increased fluid intake

Excessive water loss causes dehydration and thirst-> large fluid intake

Elevated glucose-> dehydration of tissue cells (due to increased osmotic pressure in ECF-> osmotic transfer of water out of cells)


What causes weight loss and polyphagia (in DM)?

Weight loss despite polyphagia (excessive eating)

Net increase in protein catabolism and lipolysis

Also caused by decreased glucose and protein utilisation of the body


What causes diabetic ketoacidosis (in DM)?

When body depends almost entirely on fat for energy, keto acid level increases

Acetyl CoA excess accumulates in liver (not for Krebs)

Converted to acetoacetic acid
reduced to B-hydroxybutyric acid OR decarboxylated to acetone

Increases concentration of hydrogen ions

Characterised by heavy and deep (Kussmaul) breathing and acetone breath


What is the difference between T1DM and T2DM?

DEFINE: Type 1 Diabetes (Insulin-Dependent)= hormone completely/almost completely absent from islets of Langerhans and plasma
Insulin therapy essential

DEFINE: Type 2 Diabetes (Non-insulin-Dependent)= hormone is often present in plasma at relatively low levels whilst there is a decreased sensitivity of body tissues to insulin


Describe what happens to ..... in T1DM and T2DM


T1= total failure to secrete
T2= inadequate relative to blood-glucose levels

T1= hyperglycaemia
T2= hyperglycaemia

T1= frequent urinating
T2= less frequent but osmotic symptoms

T1= ketonuria
T2= dyslipidaemia

Weight loss
T1= yes
T2= no (60% are obese)


What is the aetiology of T1DM?

Body's own immune system mistakenly develops autoimmune antibodies against own B cells

Tendency to develop antibodies may be hereditary or in response to certain viral toxins (mumps/Cocksackie virus) or environmental toxins

B cells are destroyed/damaged so inhibit insulin production


What percentage of diabetes cases is T1DM? In under 35s?

25-30% of all cases
90% of all under 35 cases


What is insulin resistance?

Diminished ability of cells to respond to insulin adequately in fat, muscle and liver cells

Normal levels of insulin don't trigger glucose absorption


What happens in insulin resistance in adipose tissue?

Causes increased lipolysis of triglycerides -> elevated fatty acid levels


What happens in insulin resistance in liver cells?

Increases gluconeogenesis and glycogenolysis which -> rise in overall blood glucose level


What happens in insulin resistance in muscle cells?

Reduces glucose uptake and utilisation


Why is obesity a factor in insulin resistance?

Excess adipose tissue may downregulate the production of insulin-sensitive glucose transporters


What is dyslipidaemia?

Abnormal levels of lipid in blood


Why is dyslipidaemia sometimes a result of diabetes?

In diabetes, lack of insulin promotes lipolysis in adipose tissue and increases delivery of free FAs to the liver

The reduced lipoprotein lipase activity reduces VLDL clearance


How does insulin cause hypertension?

Hypertension BP >135/80

Insulin-> increased Na retention-> increased blood pressure


Why does insulin contribute to ischaemic heart disease?

Insulin resistance has a negative effect on lipid production

Can lead to elevated VLDL and LDL levels and low HDL levels
HDLs protect the body against atherosclerosis

Without insulin, plaque deposits build up increasing risk of ischaemic HD

Also, narrowed arteries contribute to the hypertension


What is Syndrome X?

Metabolic syndrome with combo of dyslipidaemia, hypertension and ischaemic heart disease -> increased risk for CV disease and diabetes


What is the concentration of triglycerides and HDL in insulin resistance?

High [TG]
Low [HDL]


What waist circumference indicates a high risk of diabetes?

Men >102
Women >88


How is reduced insulin action related to T2DM?

Mitogenic on growth= hyperinsulinaemic effect
Smooth muscle hypertrophy
Ovarian function
Energy expenditure

Metabolic= Insulin resistance effect


Define obesity

Excess of body fat that frequently results in health impairment
It defined in terms of many factors including weight, waist to hip ratio
(Some definitions include mortality and morbidity)


What BMI is classified as overweight?

26-30 BMI


What does central adiposity show?

Waist to hip ratio reveals central obesity or visceral fat (apple type)
Stronger correlation with CV disease than BMI alone


What are risk factors of obesity?

Heart disease
Sleep apnea


What is leptin and what does it do?

Leptin= important protein hormone released by adipocytes

Essential in the control of food intake and is released proportionally to the amount of fat in adipose cells

Acts on hypothalamus to cause reduction in food intake by inhibiting release of neuropeptide Y (a hypothalamic NT that stimulates eating)


What is the pathophysiology of T2DM?

Majority of all diabetics seen in most populations
Defect in insulin resistance (or insulin sensitivity) and insulin secretion (as disease progresses)
Insulin is often present in plasma at normal or even above-normal levels
Lipolysis and ketogenesis remain inhibited -> low prevalence of ketonaemia and ketonuria
Central obesity predisposes individuals for insulin resistance
Possibly due to its secretion of adipokines (a group of hormones) that impair glucose tolerance
Pancreas histology may show normal islets, sometimes enlarged and more numerous


What are the metabolic changes associated with insulin-induced hypoglycaemia?

High insulin
Lipolysis increased
Increased catecholamines
Increased cortisol
Increased growth hormone
Glucose does enter muscle
Increased HGO later with glycogenolysis and gluconeogenesis


How much does the thyroid gland weigh?

4 lobes x 2.5


How does the thyroid develop?

Originates at back of tongue
Starts in uterus after 7 week

From a midline out-pouching at the base of the pharynx
Out-pouching forms a duct (thyroglossal duct) and elongates down
Duct migrates down the neck and divides into 2 lobes
Reaches final position by week 7 (duct disappears leaving dimple in tongue known as foramen caecum)
Thyroid gland then develops


What do thyroid and parathyroid gland secrete?

Parathyroid hormone (PTH)


Describe the structure and location of the thyroid gland?

Bi-lobed (connected by thin isthmus tissue band) (R>L)
Shield shaped
Embedded within are 4 parathyroid glands (R and L superior, R and L inferior)
Also pyramidal lobe at top sometimes (remnant of thyroglossal duct)

Below larynx
On either side of and anterior to the trachea


What does the thyroid gland consist of?

Circle of follicular cells around colloid (antral mass of proteinaceous yellow jelly-like fluid)
Parafollicular cells lie outside the follicle and secrete calcitonin


What are the main hormones produced by the follicular and parafollicular cells of the thyroid?

Follicular cells= T4 (thyroxine) and T3 (tri-iodothyronine)

Parafollicular cells= calcitonin


What does calcitonin do?

Prevents calcium mobilization from bone and reduced calcium level in blood


How is iodothyronine synthesised?

The follicular cells concentrate iodide using an active pump mechanism in the basal membrane
(IC iodide conc is usually 25-30x greater than the plasma conc)
This process is called IODIDE TRAPPING

Once in the cell, iodide is rapidly oxidised to active iodine by hydrogen peroxide in the presence of thyroid peroxidase (near apical membrane)
-Secreted into colloid very close to apical membrane

Most of the reactive iodine is ‘organified’ by incorporating them into the tyrosine residues within thyroglobulin molecules

An internal coupling reaction between the iodinated tyrosyls (still contained within the thyroglobulin) occurs
-The coupling of two di-iodotyrosine groups (T2) produces tetra-iodothyronine or thyroxine (T4)
-The combination of di-iodotyrosine (T2) with mono-iodotyrosine (T1) produces tri-iodothyronine (T3)

The thyroglobulin containing the iodothyronines is secreted into the colloid


What is incorporated into TG?

Tyrosyl residues are incorporated into TG (thyroglobulin)


What is thyroglobulin?

Thyroglobulin is a large glycoprotein synthesised in the follicular cells containing approx. 140 tyrosine residues

Each thyroglobulin molecule contains around 3 thyroxine molecules and 1 tri-iodothyronine molecule


How is thyroglobulin iodinated?

Thyroglobulin iodinated by one iodine is called mono-iodotyrosine (T1)

When two iodines react with thyroglobulin, di-iodotyrosine (T2) is formed


How is iodothyronine stored?

The thyroid hormones are stored as thyroglobulin in this form within the colloid


How is iodothyronine released?

When stimulated by thyrotrophin, follicular cells absorb colloid molecules via endocytosis at the apical surface
Colloid contains thyroglobulin molecules with the iodothyronines

Lysosomes containing hydrolytic protease enzyme bind with colloid-rich endosomes

The protease liberates the tri-iodothyronine and thyroxine from the thyroglobulin molecules

The free thyroid hormone then diffuses out the lysosome and through the basal membrane of cell into general circulation

Then it binds to carrier proteins for transport to target cells

It is then excreted


What proportion of the hormone excreted is T3 and T4?

Around 90% of the hormone excreted is thyroxine (T4), and 10% tri-iodothyronine (T3)

However most of the thyroxine is eventually converted to T3 in the liver and kidney


Is T3 or T4 more potent?

T3 is about four times as potent as thyroxine


How are iodothyronines (T3 and T4) transported?

Transported in blood mostly bound to plasma proteins

-Thyroxine/thyroid-binding globulin, TBG (70% T4, 80% T3)
-Albumin (10% T4, 15% T3)
-Prealbumin (transthyretin) (15% T4, 2% T3)

Only 0.05% T4 and 0.5% T3 unbound (bioactive components)


What are the latent periods of T3 and T4?

T3= 12h
T4= 72h


What are the biological half-lives?

T3= 2 days
T4= 7-9 days


How is thyroxine deiodinated?

T4 is the main hormone product of the thyroid gland

Largely deiodinated to the more bioactive T3 molecule in target tissues

Can be deiodinated in a different position to produce the biologically inactive molecule known as reverse T3 (rT3)


What are the actions of iodothyronine?

Increased BMR of almost all tissues in the body

Essential for skeletal growth and development

Increases carbohydrate metabolism

Increased fat metabolism

Increased protein metabolism

Increased vitamin A synthesis from carotene (in hypothyroidism makes skin appear yellow)

Potentiates the action of catecholamines on the heart (due to upregulation of β-receptors) e.g. tachycardia

Interact with other endocrine systems e.g. oestrogens

Have effects on CNS


Why is BMR increased by iodothyronine?

Increased O2 consumption and production of heat (calorigenesis)

Except the brain


Why is thyroid hormone and TSH levels measured in newborn infant's heel prick test?

Lack of iodothyronines during fetal development and after birth-> cretinism if untreated within first few months
Because iodothyronine is important for skeletal growth and development
Thyroxine very important (T4)


How does iodothyronine increase carbohydrate metabolism?

Increases rate of absorption of glucose by GI tract
Enhances glycolysis, gluconeogenesis and glycogenolysis


How does iodothyronine increase fat metabolism?

Lipolysis in adipose tissue mobilises lipids
Results in increased free fatty acid in the blood
However, oxidation of fatty acids also enhanced


How does iodothyronine increase protein metabolism?

Catabolism and anabolism
But excess induces degradation


Explain the mechanism of action of the iodothyronines?

To modulate gene expression by stimulating/inhibiting transcription of certain genes

To stimulate mitochondria directly


How does iodothyronines modulate gene expression by stimulating/inhibiting transcription of certain genes?

Thyroid hormones are lipid soluble
Penetrate plasma membranes of target cells with relative ease

TR (thyroid receptors) have 10-fold greater affinity for T3 than T4
Almost all thyroxine deidonated by 1 iodide ion
-> Forms tri-iodothyronine (T3)

TRs are in nucleus (attached to/near DNA genetic strands)
Upon hormone binding-> activation-> initiate transcription

T3-R complex first dimerizes with another R
Forms a homodimer
Interacts with specific base sequences of DNA called hormone response elements

Alters rate of transcription of these genes into mRNA and subsequent new protein synthesis


How does iodothyronines stimulate mitochondria directly?

In most tissues (not brain, spleen or testes), thyroid hormone-> more/bigger mitochondria

Stimulates respiratory chain enzyme activity-> increases ATP formation

Increased Na-K-ATPase

Increased rate of transport of K and Na through membranes (K in, Na out)

Thyroid hormone also causes cell membranes of most cells to become permeable to Na ions therefore further activating Na pump


How does the hypothalamo-pituitary-thyroidal axis control the mechanisms of iodothyronine?

Thyrotrophin (TSH) regulates most aspects of iodothyronine synthesis and release from the thyroid

Stimulates iodide uptake by increasing activity of iodide pump or increasing number of pumps on basal membrane of follicular cells

Stimulates iodination of tyrosine groups in thyroglobulin and increases coupling to form thyroid hormones

Increases peroxidase activity (when iodide is oxidised to iodine)

Increases proteolysis of thyroglobulin molecules already stored in follicles, thus liberating thyroxine and tri-iodothyronine

Stimulates synthesis of thyroglobulin itself

Increases number of follicular cells


What mediates thyrotrophin?

Thyrotrophin’s actions are mediated by activation of membrane-bound adenyl cyclase and subsequent cAMP generation

Thyrotrophin release is controlled by the hypothalamic hormone TRH (thyrotrophin-releasing hormone) which reaches the adenohypophysial thyrotrophe cells via the local portal blood system

Somatostatin has an inhibitory effect on thyrotrophic cells

Circulating T3 and T4 levels have a controlling influence on TRH levels by exerting direct –ve fb at the adenohypophysial level and indirect –ve fb at the hypothalamic level

Oestrogens increase TSH secretion as they stimulate synthesis of TRH receptors in adenohypophysis

Environmental temperature affects T3 and T4 production

Exposure to cold environments increases levels of T4 in plasma


What is thyrostimulin?

2-unit glycoprotein
Found in anterior pituitary (and other tissues e.g. heart, adipose, testis, ovary)
Binds to TSH receptors
Functions unknown- maybe paracrine?


Why is there a risk of voice quality damage during a thyroidectomy?

Left recurrent laryngeal nerve runs close to the gland
Damage can -> changes in voice quality or difficulty talking
Mention when obtaining consent


Describe the hypothalamo-pituitary-thyroid axis

TRH released from hypothalamus
TSH released for pituitary
Acts on thyroid
T4 and T3 -vely fb to pituitary and hypothalamus


List developmental problems of thyroid

Agenesis= complete absence
Incomplete descent= from base of tongue to trachea
Lingual thyroid= complete failure to descend from base of tongue
Thyroglossal cyst= segment of duct persists and presents as lump years later


What is the role of thyroxine (T4)?

Essential for normal brain development
Controls cellular activity
Neonates with deficiency in utero have irreversible damage-> cretin


What is cretinism?

Caused by thyroxine (T4) deficiency
Cretin= individual with irreversible brain damage caused by lack of thyroxine

Mentally sub-normal
Short stature


What tests are used to prevent Cretinism?

Heel-prick test 5-10 days after birth
Thyroid function (measures TSH)- high TSH requires immediate thryoxine

NB. Guthrie test for phenylketonuria


Where is thryoxine synthesised?

Thyroid follicular cell (thyrocyte)


What does thyroxine control?



What percentage of thyroxine does thyroxine binding globulin bind in the circulation?

NOT THYROGLOBULIN (this is present in thyroid gland)


What is the thyroid gland principally responsible for?

Synthesis, storage and secretion of thyroid hormones (which regulate growth, development and BMR)


What percentage of the population are affected by thyroid disease? (F/M? Overactive/Underactive?)

Affects 5% of the population
Female: male=4:1
Overactive: underactive =1:1


What is myxoedema?

Primary hypothyroidism


What causes primary hypothyroidism/myxoedema?

Caused by autoimmune damage to the thyroid, or surgical removal (thyroidectomy)
Underactive thyroid gland
Iodine deficiency
Resistance to TSH


What results from primary thyroid failure?

Primary thyroid failure-> decline in thyroxine secretion by thyroid gland

Anterior pituitary gland detects this fall and secretes TSH (thyroid stimulating hormone)

This leads to thyroxine release which exerts a negative feedback on the hypothalamus and anterior pituitary


What symptoms does primary hypothyroidism/myxoedema cause?

Decrease BMR
Deepening voice – larynx vibrates more slowly
Depression and tiredness
Cold intolerance
Weight gain with reduced appetite
Bradycardia (Heart rate


How is primary hypothyroidism/myxoedema treated?

Treatment essential
If not treated, cholesterol increases causing death from MI/stroke

Thyroxine replacement (usually one 100microgram tablet daily)
Also monitor TSH levels and adjust thyroxine dose until TSH is normal


What is thyrotoxicosis?

Primary hyperthyroidism


What causes primary hyperthyroidism/thyrotoxicosis?

Overactive thyroid gland makes too much thyroxine
TSH levels fall to 0
Thyroid hormones cause sensitisation to catecholamines-> tachycardia and sweating


What symptoms does primary hyperthyroidism/thyrotoxicosis cause?

Increases BMR
Increases body temperature
Weight loss due to increased calorie burning
Tachycardia (heart rate >100 bpm)
Increase metabolic rate of all cells

Mood swings- irritable, short-tempered
Sleep difficulties
Feeling hot in all weather
Increased appetite but weight loss
Tremor of hands
Tiredness and myopathy
Sore eyes- trouble focussing, irritation, sensitivity
Enlarged thyroid- goitre


What are possible causes of hyperthyroidism/thyrotoxicosis?

Cancer (TRH producing tumour in hypothalamus or TSH producing tumour in hypophysis)
Grave’s Disease (autoimmune, see below)

Whole gland is smoothly enlarged and whole gland is overactive
Systemic disease of the whole gland

Autoimmune- antibodies bind to and stimulate the TSH receptors in the thyroid, stimulating thyroxine release
Leads to goitre and hyperthyroidism

Other antibodies bind to muscles behind eye, causing muscle hypertrophy and exophthalmos (swollen eye)

Other antibodies stimulate the growth of the shins and cause pretibial myxoedema

Non-pitting swelling that occurs on the shins (hypertrophy; growth of soft tissue)


How is hyperthyroidism/thyrotoxicosis treated?

PTU: stops thyroxine production
Radiolabelled iodine (131-I): destroys part of the thyroid gland
Carbimazole: treatment of symptoms of hyperthyroidism


What causes secondary hypothyroidism?

Caused by TSH (thyrotrophin) deficiency


What anatomical structures are likely to be affected by an enlarged thryoid gland?

Left recurrent pharyngeal nerve= innervates larynx so may be change in quality of voice or difficulty in speaking

Trachea= may be difficulty in

Oesophagus= may difficulty in swallowing


Describe the anatomy of the adrenal gland?

Adrenal gland sits on kidney
Medulla= core
Cortex= outer layers


What are the 3 cortical zones of the adrenals?

Outer= zona glomerulosa
Middle= zona fasciculata
Inner= zona reticularis

ZF= recognisable, lines of cells running towards ZR
ZG and ZR= no distinguishable form of cells


What is the main difference between the hormonal products from the adrenal medulla and the adrenal cortex?

Medulla= catecholamines (sympathetic)
Cortex= corticosteroids


Describe the main hormonal products from the adrenal medulla

Made up of chromaffin cells
Cells synthesis and release catcholamines

Adrenaline (80%)
Noradrenaline (20%)


What are catecholamines?

Catecholamines are polypeptide hormones synthesised from a tyrosine precursor


Describe the main hormonal products from the adrenal cortex

Mineralocorticoids= aldosterone (ZG)
Glucocorticoids= cortisol (ZF and ZR)
Sex steroids= androgens, oestrogens (ZF and ZR)



How is blood transported through the different cortical zones to the medulla?

Arterial blood supply flows below the capsule surrounding the gland

There 2 ways that blood is transported through cortical zones to the medulla:
1. Blood perfuses through cells until it reaches the tributary of central vein in centre of the medulla
2. Clearly defined arterioles flow from outer capsule to the medulla


What are the main intermediates in the synthesis of the adrenal steroids?

Cholesterol -> pregnenolone-> progesterone-> deoxycorticosterone-> corticosterone-> aldosterone MINERALOCORTICOID

Cholesterol -> pregnenolone-> 17a-hydroxypregnenolone-> 17a-hydroxypregesterone-> 11b deoxycortisol-> cortisol GLUCOCORTICOID

Cholesterol -> pregnenolone-> 17a-hydroxypregnenolone-> dehydroepiandrosterone -> androstenedione -> ANDROGENS/OESTROGENS


What are the steroid hormones from the adrenals?

Mineralocorticoids (C21)
Glucocorticoids (C21)


What are the steroid hormones from the gonads?

Progestogens (C21)
Androgens (C19)
Oestrogens (C18)


Why can't corticosteroids be stored?

Corticosteroids are lipophilic
Easily cross cell membranes
Bind with IC or nuclear membrane receptors

Therefore, if stored would-> excessing binding with Rs-> overstimulation

So hormones produced on demand or bound to plasma proteins in the blood to prevent their action


What do plasma proteins do when bound to corticosteroids?

Plasma proteins act as a store and transport mechanism

Transport hormone where unbound-bound hormone equilibrium is unbalanced, i.e. where hormone needs to be released


What are cortisol and aldosterone bound to?

75% bound to CBG
15% bound to the non-specific protein albumin
10% of the hormone is unbound and bioactive

60% bound to CBG
40% unbound and bioactive

CBG= cortisol binding globulin, AKA transcortin


What is the circulating concentration of cortisol?

Cortisol – controlled by the hypothalamo-pituitary axis, and is released in PULSES

Pulses vary by time of day (circadian rhythm)

8am 140 – 690 nmol/l
4pm 80 – 330 nmol/l


What is the circulating concentration of aldosterones?

Released in PULSES

Pulses vary depending on body position

Upright 140 – 560 pmol/l

PICOMOLES (1000x smaller than nanomoles)


What is the main mineralocorticoid in humans?



What does aldosterone do?

Stimulates Na+ reabsorption in distal convoluted tubule and cortical collecting duct (and in sweat glands, gastric glands, colon)

Stimulates K+ and H+ secretion, also in distal convoluted tubule and cortical collecting duct


How do mineralocorticoids act in the distal convoluted tubule?

Aldosterone diffuses into the distal convoluted tubule from the blood

Binds with an IC mineralocorticoid R (MR)

Receptor-hormone complex is then transported into the nucleus, where it binds to specific DNA

This activates transcription, translation and synthesis of specific proteins

The proteins then act as:
1. Ion channels – in apical membrane, allowing Na+ to be reabsorbed into DCT to form the tubular fluid
2. Ion pumps – on the BL membrane, pumping Na+ into the blood from the DCT, completing reabsorption


What is the overall structure of a kidney nephron?

Proximal convoluted tubule
Loop of Henle (descending – ascending)
Distal convoluted tubule Collecting duct


How is blood supplied to the nephron?

Afferent arteriole brings blood to glomerulus (adjacent to where ascending LoH meets DCT)
Efferent arteriole brings blood to general circulation


Where are secretory juxtaglomerular cells?

Smooth muscle in the wall of the renal afferent arteriole


What do secretory juxtaglomerular cells contain?

Secretory granules which contain renin (enzyme)


What are macula densa cells?

Specialised Na sensors
Part of the ascending loop of Henle
Adjacent to juxtaglomerular cells


What is in the juxtaglomerular apparatus?

Combination of juxtaglomerular and macula densa cells


When is renin released?

Decreased renal perfusion pressure (normally associated with decreased ABP)

Increased renal sympathetic activity (due to trying to increase BP-> direct activation of JGA cells-> renin release)

Decreased Na+ load to top of loop of Henle (recognised by macula densa cells-> renin release)


Describe the Renin-Angiotensin-Aldosterone system?

JGA cells secrete renin

Breaks off peptide from angiotensinogen (plasma protein) -> angiotensin I

Angiotensin I converted by ACE -> angiotensin II


What is the source of angiotensinogen?



What does ACE stand for? (RAAS)

Angiotensin converter enzyme


What are the effects of angiotensin II?


Stimulates the zona glomerulus of the adrenal cortex to synthesise and release aldosterone

Leads to increased Na reabsorption in DCT-> increased water reabsorption-> increased blood ECF-> increased BP, hypertension


Why are ACE inhibitors used as antihypertensives?

Prevents angiotensin II being formed


What stimulates aldosterone release?

Corticotrophin (released from the anterior pituitary gland)
Increased K+ and decreased Na+


What is the main glucocorticoid in humans?



What are the main physiological actions of cortisol (glucocorticoid)?

METABOLIC EFFECTS Peripheral protein catabolism
Hepatic gluconeogenesis
Increased blood glucose concentration
Lypolysis in adipose tissue
Enhanced effects of glucagon and catecholamines

Some, not major

Excretion of water load
Increased vascular permeability

Bone growth
CNS effects


Why is cortisol important in the endocrine response to stress?

Physiological actions-> normal stress response


What are the pharmacological effects of large amounts of cortisol?

Anti-inflammatory action
Immunosuppressive action
Anti-allergic action

These are associated with decreased production of molecules e.g. prostaglandins, leukotrienes, histamine, etc.
Also associated with the movement and function of leukocytes and the production of interleukins


What are the cortisol receptors?

Glucocorticoid receptors
Aldosterone (mineralocorticoid) receptors (aldosterone also binds)

These 2 receptors bind to cortisol with equal affinity


How do you prevent excess mineralocorticoid receptor activation in the kidney?

Bioactive cortisol is converted to biologically inactive cortisone
Involves 11b-hydroxysteroid dehydrogenase 2


What is cortisol's mechanism of action?

Similar to aldosterone

Cortisol binds to IC receptor and the complex is transported to the nucleus where it binds to DNA stimulating protein synthesis

E.g. annexin 1 and annexin 1 receptor are synthesised

The annexin 1 then exhibits autocrine action, preventing prostaglandin synthesis via arachidonic acid


How is cortisol controlled?

Principally via corticotrophin (ACTH)
Released from anterior pituitary gland
Precursor is POMC

Corticotrophin-releasing hormone (CRH) and Vasopressin are control hormones (released by hypothalamus, control the release of corticotrophin)


How is cortisol release stimulated?

Stressors via brain nerve pathway and circadium rhythm (biological clock) stimulate the release of CRH and vasopressin from the hypothalamus, therefore increasing cortisol (and small amounts of androgen) release


How is cortisol release inhibited?

The release of corticotrophin from the anterior pituitary gland has a short autonegative feedback loop with the hypothalamus, inhibiting CRH and vasopressin release

The release of cortisol has two negative feedback loops:
1. Direct negative feedback to the anterior pituitary, inhibiting cortiocotrophin release
2. Indirect negative feedback to the hypothalamus inhibiting CRH and vasopressin release


What is DHEA?


Precursor for androgens and oestrogens
Converted to active hormones within target cells (with enzymes)

Peak serum levels 20-30y, decrease steadily with age

Particularly important in postmenopausal women as precursor for oestrogen (and androgen) synthesis by target tissues in the absence of ovarian steroids


What are the most common adrenal disorders?

Syndromes of excess/deficiency of hormone messengers

Adrenal failure= Addison's
Excess cortisol= Cushing's


Describe the adrenals anatomy?

Adrenals above kidneys
Both adrenals have many arteries/arterioles but only one vein

Left adrenal vein drains into left renal vein
Right adrenal vein drains into the IVC (inferior vena cava)

Spleen is at risk with a left adrenalectomy (so immunise with HIV and penumovax before elective adrenalectomy)


Describe cholesterol

27 carbon compound
Basic cyclic structure 17C
Side chain 8C


Describe pregnenolone

Most basic steroid hormone, just involves removal of part of the cholesterol side chain

Pregnenolone can then be oxidised, hydroxylated etc to form mineralocorticoids (e.g. aldosterone) and glucocorticoids (e.g. cortisol)

Difference between aldosterone and cortisol is just position of OH group

Side chain can be removed completely and then changed to form testosterone


What is POMC?


Large precursor protein that is cleaved to form number of smaller peptides including ACTH, MSH and endorphins

An increasing in MSN leads to darkened skin

Some people with pathologically high levels of ACTH may become tanned


List the causes of primary adrenal failure

Addison's Disease
Autoimmune disease where the immune system wiped out the adrenal cortex
e.g. Autoimmune vitiligo (antibodies vs skin-> depigmented patches)

Most common cause is TB of the adrenal glands


What does Addison's Disease cause?

No cortisol or aldosterone-> increased POMC-> increased ACTH and MSH-> increased pigmentation of the skin

Atrophy of adrenal cortex

No cortisol or aldosterone-> salt loss, reduced blood pressure-> death from hypotension may occur


How is an Addisonian crisis treated?

Rehydrate with normal saline

Give dextrose to prevent hypoglycaemia which could be due to the glucocorticoid deficiency

Give cortisol replacement- hydrocortisone or other glucocorticoid


What are the causes of Cushing's Syndrome?

Excess cortisol or other glucocorticoid

Taking steroids by mouth (common)
Pituitary dependent Cushing’s disease (pituitary adenoma)
Ectopic ACTH (lung cancer – glucocorticoid released from wrong location in body, i.e. the lungs) adrenal adenoma or carcinoma


List the symptoms of Cushing's Syndrome

Impaired glucose tolerance (diabetes)
Weight gain (increase fat, lose protein), with fat redistribution – centripetal obesity
Thin skin and easy bruising, poor wound healing
Hirsutism (facial hair) and acne
Striae (stretch marks)
Proximal myopathy (muscle weakness)
Mental changes (depression)
Moon face– fat deposition in cheeks
Buffalo hump (interscapular fat pad)
Immunosuppression (reactivation of TB)


What is the difference between Cushing's Syndrome and Cushing's Disease?

Cushing’s syndrome= cause unknown, clinical features observes

Cushing’s disease= cause determines to be pituitary adenoma


What are the side effects of steroids?

Easy bruising
Poor wound healing, thin skin


What is Conn's syndrome?

Aldosterone producing adenoma

Low potassium


What is postural hypotension?

Low blood pressure, will feel dizzy -> collapse/faint

Can result from destruction of zona glomerulus (increased water and salt-> affects BP)


Why is there increased pigmentation with Addison's Syndrome?

Autoimmune vitiligo

MSH-> increased pigmentation of skin-> tanned appearance


What is progressive weakness e.g. affecting thighs-> difficulty climbing stairs?

Proximal myopathy
Due to stimulation of proteolysis and suppression of protein synthesis due to excess cortisol


What is gametogenesis?

Production of gametes for reproduction
Derived from germ cells, multiply and increase in number before birth

Spermatogenesis= production of mature spermatozoa
Oogenesis= production of ripe ova


What is steroidogenesis?

Production of steroid hormones

Males- androgens (oestrogens, progestogens)
Females- oestrogens, progestogens (androgens)


Regarding male germ cells, what number are they present at around birth and puberty?

In males, spermatogonia levels remain relatively constant through life (6-7million)


What is the normal spermatogenesis rate for males? When does this start?

Males normally produce 300-600 sperm/gm testis/second

Spermatogenesis begins at puberty


Describe the number of germ cells (oogonia) from gestation to menopause

In females, oogonia reach 5-6million by 24 weeks of gestation, but then no more are produced

These enter the first stage of meiosis where development is halted (primordial follicles 'arrested') until puberty

Rapid atresia of oogonia occurs before birth, therefore at birth numbers have reduced to 2million

By puberty,


Outline the process from germ cell-> spermatozoa (spematogenesis)

1. Germ cell (44+XY= diploid)

2. Spermatogonia (44+XY= diploid)


3. Primary spermatocytes (44+XY= diploid)


4. Secondary spermatocytes (22X or 22Y= haploid)


5. Spermatids (22X or 22Y= haploid)

6. Spermatozoa (22X or 22Y= haploid)


Outline the process from germ cell-> ovum (oogenesis)

1. Germ cell (44+XY= diploid)

2. Oogonia (44+XY= diploid)


3. Primary oocytes (44+XY= diploid)


4. Secondary oocytes and first polar body (both 22X= haploid)


5. Ovum and second polar body (both 22X= haploid)

Polar body eventually disintegrates (doesn't keep cytoplasm)


What is the initial number of oogonia in primordial follicles (in fetus)?

6 million


What do spermatogonia undergo?

Differentiation or self-renewal

So a pool of spermatogonia remains available for subsequent spermatogenic cycles throughout life


Where do the testes develop?

In abdomen
Descend into scrotum


Where does spermatogenesis occur?

In the coiled seminiferous tubules


Where are spermatozoa....?


Spermatozoa are eventually released into lumen of tubules

Migrate (drain) to the rete testis via collecting ducts

Then drained from the rete testis via the vasa efferentia into the epididymis

Mature in the epididymis, and are propelled to the urethra by the vas deferens which is surrounded by smooth muscle


What is the lumen of coiled seminiferous tubules surrounded by?

Sertoli cells connected by tight junctions in periphery


What are sertoli cells?

Form the seminiferous tubules in testes

Spermatogonia engulfed into the sertoli cell, develop in cytoplasm/lumen into the primary and secondary spermatocytes
(Then released into the lumen of the tubule as spermatozoa)

Synthesise FSH and androgen receptors
Produce various molecules including inhibin in response to FSH

Are intimately associated with developing spermatocytes, etc.


What are Leydig cells?

Lie outside seminiferous tubules in clusters

Synthesise LH receptors

In response to LH are the principal source of testicular androgens (mainly testosterone)

'Site of testosterone production'


What does the ovarian stroma consist of?

Primordial follicles undergoing atresia

Graffian follicle (just before ovulation)

Remnants of corpus luteum (after ovulation)


What does a graffian follicle consist of?

Ovum surrounded by follicular fluid

Granulosa cells followed by a layer of thecal cells surround the fluid at the periphery of the follicle


Explain steroidogenesis in gonad synthesis

From precursor cholesterol

Products depend on enzymes (i.e. only adrenals have correct enzymes for aldosterone and cortisol synthesis)

Gonad synthesis:
Progestogens (C21)
Oestrogens (C18)


Outline the synthesis of progesterone, 17b oestradiol and testosterne

Cholesterol-> pregnenolone-> progesterone-> 17 OH progesterone-> androstenedione.....

-> oestrone-> 17b-oestradiol


-> testosterone-> dihydro-testosterone


-> testosterone-> oestrone-> 17b- oestradiol


How long does the menstrual cycle last?

28 days (20-35)
Begins on first day of menstruation


What is menstruation?

Loss of blood and cellular debris from necrotic uterine epithelium


When is a ripe ovum released?

Around day 14


What are the ovarian and endometrial cycles?

Ovarian (ovary)
Follicular phase-> ovulation-> luteal phase

Endometrial (uterus)
Proliferative phase-> secretory phase


What stimulates the proliferative phase of the endometrial cycle?

17b-oestrodiol production in the follicular phase of the ovarian cycle


What stimulates the secretory phase of the endometrial cycle?

Progesterone and 17b-oestrodiol production in the luteal phase of the ovarian cycle


The pre-antral follicle (2 facts)...

Developed in the absence of hormones

Ovum is surrounded by layer of cells


The early antral follicle (2 facts)...

Ovum surrounded by granulosa cells and then thecal cells

Follicle present- antral space filled


The late antral follicle (2 facts)...

Same as early antral follicle

Follicle increases in size therefore more antral filled space around ovum


What happens to cells of graffian follicle post ovulation?

Form the corpus luteum


Describe the hormone production during the ovarian cycle

1. Follicle influenced by FSH and LH
2. Thecal cells produce androgens
3. Androgens stimulate the granulosa cells (which contain aromatase) to produce 17β- oestradiol
4. After ovulation, the corpus luteum converts androgens -> 17β- Oestradiol


What happens in the endometrial cycle: day 6-14 (proliferative phase)?


Early= thin endometrium
Late= thickens and moistens

Early= straight glands
Late= glands enlarge, coil and have increased blood supply


What happens in the endometrial cycle: day 14-15/



What happens in the endometrial cycle: day 15-28 (secretory phase)?

Progesterone (plus oestrogen)

Becomes secretory

Secrete glycogen, mucopolysaccharides etc
Mucosa become engorged with blood


What happens in the endometrial cycle: day 1-5 (menstruation)?

Becomes necrotic and is shed


When do LH and FSH peak?

At ovulation


When does oestrogen peak and trough?

Peaks just before ovulation
Then troughs
Then increases again because produced by corpus luteum

Falls dramatically before menstruation


When is progesterone limited to?

The luteal phase


How do oestrogen and progesterone control gonadotrophin release?

Exert negative feedback at the hypothalamus and anterior pituitary gland for gonadotrophin release


What happens to basal body temperature when ovulation occurs?

Increases (due to action of progesterone)


What happens to oestrogen if fertilisation does not occur?

Menstruation occurs


What androgen is produced first and then converted to testosterone?



Testosterone binds to the androgen receptor and is the precursor to what?

Dihydroxytestosterone (DHT)
More powerful androgen


How is dihydroxytestosterone reduced?

Reduction involving 5-alpha-reductase


What happens when testosterone undergoes aromatization by aromatase enzyme?

Forms oestrone and then 17b-oestradiol (which is the main circulating oestrogen)


Where is oestrogen produced in men?

Sertoli cells


Where are testosterone and DHT produced in men?

Seminiferous tubules (in testis)
Seminal vesicles
Anterior pituitary gland (adenohypophysis)


Where is 17b-oestradiol produced in men?

Sertoli cells (testis)


How are testosterone and DHT transported?

Bound to plasma proteins as the androgens are lipophilic therefore need to be bound to prevent excess effects

Sex hormone binding globulin (SHBG)= 60% bound

Specific for androgens and oestrogens
Albumin= 38% bound
Free bioactive component- 2%

Bound to androgen binding globulin


Define oestrogens

Any substance (natural or synthetic) which induces mitosis in the endometrium

E.g. 17β-oestradiol (main one during menstrual cycle; most potent), oestrone, oestriol (main estrogen of pregnancy)


Define progestogens

Any substance (natural or synthetic) which induces secretory changes in the endometrium

E.g. progesterone, 17a-hydroxyprogesterone


What are the actions of androgens in the fetus?

Development of male internal and external genitalia

General growth (acting with other hormones)

Behavioural effects (development)


What are the actions of androgens in adults?


Growth and development of:
-Male genitalia
-Secondary (accessory) sex glands
-Secondary sex characteristics

Protein anabolism

Pubertal growth spurt (with GH)

Behavioural (CNS) effects

Feedback regulation


What are the actions of oestrogens?

Final maturation of follicle during menstrual cycle

Induces LH surge resulting in ovulation

Stimulates proliferation (mitosis) of the endometrium

Effects on vagina, cervix

Stimulates growth of ductile system of breast

Decreases sebacious gland secretion

Increases renal salt (and water) reabsorption

Increases plasma protein synthesis (hepatic effect

Metabolic actions (e.g. on lipids)

Stimulates osteoblasts

Influences release of other hormones (e.g. prolactin, thyrotrophin)

Feedback regulation (-ve and +ve)

Behavioural influences

Important to note protective effects on cardiovascular system and against osteoporosis

Final maturation of follicle during menstrual cycle

Induces LH surge resulting in ovulation

Stimulates proliferation (mitosis) of the endometrium

Effects on vagina, cervix

Stimulates growth of ductile system of breast

Decreases sebacious gland secretion

Increases renal salt (and water) reabsorption

Increases plasma protein synthesis (hepatic effect

Metabolic actions (e.g. on lipids)

Stimulates osteoblasts

Influences release of other hormones (e.g. prolactin, thyrotrophin)

Feedback regulation (-ve and +ve)

Behavioural influences

Important to note protective effects on cardiovascular system and against osteoporosis


What are the actions of progestogens?

Stimulates secretory activity in the endometrium and cervix

Stimulates growth of alveolar system of breast

Decreases renal NaCl reabsorption (competitive inhibition of the aldosterone)

Associated with increases in basal body temperature (0.1-0.2 degree increase)


Describe the endocrine control of androgen production (hypothalamo-pituitary-gonadal axis)

1. Stimulated by GnRH/LH system (feedforward)
2. Reduced by testosterone
-Direct -ve FB to reduce LH release from anterior pituitary gland
-Indirect –ve FB to slow hypothalamic GnRH pulse generator


Describe the endocrine control of spermatogenesis (hypothalamo-pituitary-gonadal axis)

Stimulated by GnRH/FSH system
Also requires GnRH/LH/testosterone system for complete spermatogenesis
Limited by inhibin negative feedback (direct and indirect)


Describe the endocrine control of ovarian function (hypothalamo-pituitary-gonadal axis)

During the follicular phase of the cycle, rising estradiol levels are dependent on the co-ordinated action of LH and FSH in the thecal and granulosa cells respectively

Involves a local positive feedback loop to enhance estradiol production

Emergence of the Graafian follicle involves a selective –ve FB loop by estradiol and inhibin on the GnRH-FSH system

So all follicles which are still FSH-dependent regress (atresia).

Ovulation is triggered by a positive feedback loop exerted by estradiol to increase the frequency and pulsatility of GnRH release and enhance the selectivity of the anterior pituitary

In the non-pregnant state, during the luteal phase the high levels of progesterone, along with estradiol and inhibin, exert a powerful –ve FB on lH and FSH release
-> Luteolysis and menstruation


Describe the hypothalamus-pituitary-testicular axis

GnRH (gonadotrophin releasing hormone) released from hypothalamus in pulsatile patterns

Gonadotrophs in anterior pituitary gland release gonadotrophins: LH and FSH (enters general circulation)

From the testis:
LH (Leydigg cell)- stimulates testosterone production (stimulates virilisation and spermatogenesis)
FSH (in Sertoli cell) stimulates inhibin production

Testosterone is insufficient on its own to start cycle- but in conjunction with FSH to maintain spermatogenesis cycle


Describe the feedback of testosterone and inhibin

Direct inhibition of FSH and LH release from the ant. pit. gland

Indirect inhibition of the pulse generator releasing GnRH from the hypothalamus, which in turn also reduced gonadotrophin (FSH & LH) release

(Inhibin same effects as testosterone)


Describe the differences between the hypothalamo-pituitary-ovarian axis and the testicular axis

FSH and LH act on ovaries


What are the effects of LH and FSH on the early follicular phase?

At the end of the previous menstrual cycle, there is a decreasing oestrogen and progesterone production, but the steroid hormones still result in an inhibition of FSH and LH

This is due to direct negative feedback on the anterior pituitary gland o Indirect negative feedback on the hypothalamus


What are the effects of LH and FSH on the early-mid follicular phase?

The decrease in steroid hormones (oestrogen and progesterone) from the previous cycle reduces inhibition of gonadotrophins from the anterior pituitary-> LH and FSH are released

LH acts on thecal cells within the ovaries (binding to the LH receptor), inducing androgen synthesis
-> Androgens are then released into the general circulation, follicular fluid, or taken up by granulosa cells within the ovary

FSH binds to FSH receptor on granulosa cells, inducing the aromatisation of androgens to
-> This is a local positive feedback loop which enhances oestradiol production in developing follicles – crypotcrine effect


What are the effects of LH and FSH on the mid-follicular phase?

Steps of the early-mid follicular phase continues, leading to an exponential increase of oestradiol-> negative feedback effect -> decreased FSH and LH production

Also a production of inhibin from the follicle

Selective negative feedback loop by oestrogen and inhibin on the GnRH-FSH system results in atresia (regression) of all follicles that are still FSH dependent

Graffian follicle
-Largest follicle no longer requires FSH to develop and proliferate
-It keeps growing and producing large amounts of 17b-oestradiol


What are the effects of LH and FSH on the late follicular phase?

Rising concentration of 17b-oestradiol (in absence of progesterone) for a minimum of 36h-> a certain level where the positive feedback switch on the hypothalamo-adenohypophysial system

This triggers the LH surge (and lesser FSH surge) which stimulates the final development of ovum and ovulation

Also a surge in 17-alpha-hydroxy-progestrone just before this surge, which could be responsible for the final oestrogen concentration increase


What are the effects of LH and FSH on the luteal phase?

After the gonadotrophin surges-> increase in the production of steroids 17-beta-oestradiol and proesterone

If fertilization doesn't occur, progesterone, oestradiol and inhibin exert a negative feedback on LH and FSH release -> luteolysis and menstruation

The steroid concentrations then start to decrease towards the end of cycle


Define amernorrhoea

Absence of menstrual cycles

Primary= if they've never happened
Secondary= if they did happen but have stopped (can be physiological e.g. pregnancy)


Define oligomenorrhoea

Infrequent cycles


What causes oligomenorrhoea?


Can be absence of LH surge (e.g. due to insufficent oestrogenic effect at end of follicular phase)

Ovulation doesn't take place-> don't get corpus luteum-> don't get progesterone-> no menstruation


What is infertility?

Unable to get pregnant (or men to impregnate)


What are the main causes of infertility?

Various causes e.g. physical, pyschological, emotional, endocrine

Excess prolatin (e.g. from prolactinoma) can be cause of infertility


What is a prolactinoma?

Tumour-> releasing lots of prolactin
High levels of prolactin acts on hypothalamo-pituitary-ovarian axis
Can inhibit effects at hypothalamus, pituitary and ovaries

Low LH, FSH, oestradiol and progesterone


What is galactorrhoea?

Discharge of milk-like substance from the breast that is not associated with breastfeeding after pregnancy
Due to high prolactin


Why would a tumour e.g. prolactinoma lead to headaches and loss of peripheral vision?

Headaches= increased cranial pressure

Loss of peripheral vision= tumour growing upwards is suprasellar, above pituitary is optic chiasma


What is a common visual condition due to a suprasellar tumour?

Bitemporal hemianopia


What is most calcium in the body present as?

Calcium salts
Mainly in bone (99%) as complex hydrated calcium salt (hydroxyapatite) crystals

In blood= some present as ionized calcium, some bound to protein and very small bit as soluble salts


What are the main roles of calcium in the body?

Neuromuscular excitability
Muscle contraction
Strength in bones
IC 2nd messenger
IC co-enzyme
Hormone/neurotransmitter stimulus-secretion coupling
Blood coagulation (factor IV)


Describe how calcium is found in the blood

Controlled very precisely, as many metabolic processes in body are Ca-mediated

50% of calcium remained unbound – this is the ionized component which is biologically active

45% is bound to plasma proteins (approx 1.13Mm)

5% remain as diffusible salts (approx 0.13 Mm) – these include citrate and lactate are can readily diffuse through cell membranes


What is the total concentration of calcium in the blood?



How is calcium regulated?

Parathyroid hormone (PTH) – a polypeptide hormone
1, 25 (OH)2 vitamin D3 metabolite – dihydroxycholecalciferol, or calcitrol – a steroid hormone

Calcitonin (released by parafollicular cells)– a polypeptide hormone that is relatively short lasting and increases in levels during pregnancy
PTH is released by parathyroid glands


What are the effects of PTH on blood?

Increased Ca2+ reabsorption and increased PO43- excretion from the kidneys leads to increased Ca2+ concentration in blood

Increased Ca2+ and PO43- absorption from the small intestine leads to increased blood Ca2+

Increased Ca2+ mobilization due to increased osteoclast activity -> increased blood Ca2+


How is PTH synthesised?

Initially synthesised as protein pre-proPTH

84 amino acids long

Binds to transmembrane G-protein linked receptors

Activated adenyl cyclase, but also probably phospholipase C as a 2nd messenger


How is 1,25 (OH)2D3 synthesised?

Diet OR 7-dehydrocholesterol + UV

-> Cholecalciferol (form of D3)

-> 25 Hydroxy-cholecalciferol (25, (OH) D33)= synthesised and stored in liver, released when needed

[1 alpha-hydroxylase stimulated by PTH)

-> 1,25 di-hydroxy-cholecalciferol (1,25 (OH)2D3)= synthesized in kidneys from 25 (OH) D3 to form main bioactive form


What is 1,25 di-hydroxy-cholecalciferol (1,25 (OH)2D3) also known as



How is calcitonin synthesised?

Synthesized as pre-procalcitonin

Calcitonin is 32 AA polypeptide

Binds to transmembrane G-protein linked receptor

Activation of adenyl cyclase or PLC as second messenger systems


What are the principal actions of PTH on the kidneys, bone and small intestine?

Increased Ca reabsorption
Increased PO43- excretion
Stimulates 1a hydroxylase activity-> increased calcitonin synthesis (-> small intestine)

Increased Ca absorption
Increased PO43- absorption

Stimulate osteoclasts (breakdown)
Inhibit osteoblasts (rebuilding)
Increased bone resorption


Describe how PTH acts in bones

PTH leads to the inhibition of new bone formation

It binds with the PTH receptor on osteoblasts, which stimulate osteoclast stimulating factor (OAFs, e.g. cytokines)

OAFS stimulate osteoclasts to increase bone matrix breakdown and release Ca2++ and PO43--> increased bone reabsorption

NB: PTH does not have a direct effect on osteoclasts as there are no receptors present


What are the actions of 1,25 (OH)2D3 on the kidneys, bone and small intestine?

Increased Ca2+ and PO43- reabsorption in the proximal tubule

Increased Ca2+ absorption
Increased PO43- absorption

Increased osteoblast activity
Therefore increased storage of Ca2+ in bones


What are the actions of calcitonin?

Increased plasma calcium concentration
-> Gastrin
-> Calcitonin

Increased urinary excretion of Ca (Na, PO43-)
-> Decreased plasma calcium (limited effect)

Inhibition of osteoclast activity
-> Decreased plasma calcium (limited effect)


How is PTH regulated?

-> Increased PTH production in parathyroid glands
-> Increased Ca2+
-> Increased Ca2+ then exhibits negative feedback on the parathyroid glands

Synthesis of 1,25 (OH)2D3
-> +ve influence increasing plasma Ca2+
-> -ve influence on the parathyroid glands to reduce PTH production, which then has a secondary effect reducing Ca2+

Catecholamines have a positive effect on the parathyroid glands via beta receptors


How is calcitonin regulated?

Stimulus: increased plasma Ca2+ concentration stimulates the parafollicular cells of the thyroid to produce calcitonin

Gastrin also stimulates this


How is phosphate reabsorbed?

Na/Po43-= cotransporter
Inhibited by PTH
Inhibited by FGF23 (inhibits calcitriol which stimulates it)

FGF23= fibroblast growth factor 23 from osteocytes


What happens to plasma Ca, plasma PO4 and PTH in hypoparathyroidism, pseudo-hypoparathyroidism and vitamin D deficiency?

Plasma Ca= decreased
Plasma PO4= increased
PTH= decreased

Plasma Ca= decreased
Plasma PO4= increased
PTH= increased

Plasma Ca= decreased
Plasma PO4= decreased
PTH= increased


What is tetany?

Where smooth muscle goes into auto-contraction
Can be used to observe where decreases in calcium have occurred


What is Trousseau's sign?

Tetany in the hands can be induced by decreased calcium


What is Chvostek's sign?

The facial nerve can be 'tapped' to induce a twitch


What causes hypoparathyroidism?

Consequence of thyroid surgery
Idiopathic – cause unknown
Hypomagnesaemia (very rare)
Suppression by raised plasma calcium concentration (chronic raised Ca2+ levels inhibit the parafollicular cells)


What is pseudo-hypoparathyroidism?

Also known as Allbright hereditary osteodystrophy
Due to target organ resistance to PTH (multiple underlying causes, believed to be due to defective G protein)


What are common features of pseudo-hypoparathyroidism?

Particular physical appearance (short stature, round face)
Low IQ
Subcutaneous calcification and various bone abnormalities (e.g. shortening of metacarpals)
Associated endocrine disorders (e.g. hypothyroidism, hypogonadism)
Vitamin D deficiency


What does vitamin D deficiency cause?

Rickets in children
Osteomalacia in adults


What is a common clinical feature of pseudo-hypoparathyroidism?

Decreased calcification of bone matrix resulting in softening of bone-> bowing of bones in children and fractures in adults


What are the 3 main causes of hypercalcaemia?

Primary hyperparathryoidism
Tertiary hyperparathyroidism
Vitamin D toxicosis


What causes primary hyperparathryoidism?


Disrupts pathway which should be:
Increased calcium -> inhibits parathryoids (so prevents -> PTH increase-> increased calcium etc.)


What causes tertiary hyperparathyroidism?

Low plasma calcium concentration concentration e.g. renal failure
Affects parathyroids (so increased PTH decreases or equalised calcium)


What causes Vitamin D toxicosis?

Initial chronic low plasma calcium concentration

Disrupts pathway which should be:
Increased calcium -> inhibits parathryoids AUTONOMOUS (so prevents -> PTH increase-> increased calcium etc.


What happens when there is an excess of parathyroid hormone?

Ca reabsorption
PO4 excretion
Renal stones
1,25 (OH)2 D2 synthesis

Gastric acid
Duodenal ulcers

Bone lesions
Bone rarefaction


What is primary hyperparathyroidism?

Hyperfunction of the parathyroid glands themselves

Oversecretion of OTH due to parathyroid adenoma, parathyroid hyperplasia or, rarely, a parathyroid carcinoma


What is secondary hyperparathyroidism?

Due to physiological secretion of PTH by the parathyroid glands in response to hypocalcaemia


What is tertiary hyperparathyroidism?

Seen in patients with long-term secondary hyperparathyroidism

Leads to hyperplasia of the parathyroid glands and a loss of response to serum calcium levels