Endocrinology Flashcards
1
Q
Define: Endocrine gland
A
Cells which secrete ‘messenger’ molecules directly into blood
2
Q
Define: Endocrinology
A
Study of endocrine glands and their secretions
3
Q
Define: Hormone
A
Bioactive ‘messenger’ molecule secreted by an endocrine gland into blood
4
Q
Define: Endocrine
A
Relates to hormone’s action of target cells source
5
Q
Define: Paracrine
A
Hormone acts within immediate area around source
6
Q
Define: Autocrine
A
Hormone has effect on cell that secreted it
7
Q
Define: Cryptocrine
A
Hormone can have an effect within its own cell of production
8
Q
What is the difference between the endocrine and nervous system?
A
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
9
Q
List examples of protein/polypeptide hormones by size
A
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
10
Q
How are protein hormones synthesised?
A
In RER
AA sequence determined by specific mRNA synthesised in nucleus
Ribosomal synthesis of pre-prohormone (larger than active hormone)
11
Q
What is a prohormone?
A
Precursor of a hormone
Shortened (processed by proteolytic enzymes) to become mature, active hormone
12
Q
Where are protein hormones stored?
A
In secretory granules
For release in exocytosis
13
Q
Describe ACTH production within a corticotroph cell
A
NUCLEUS
Specific mRNA synthesised from DNA within cell nucleus
CYTOPLASM
Translation of specific mRNA to prohormone POMC in RER
POMC -> Golgi apparatus for POMC processing
Mature ACTH stored in secretory granules within cytoplasm
14
Q
What are steroid hormones derived from?
A
Cholesterol
15
Q
What 2 groups are steroid hormones divided into?
A
Intact steroid nucleus (adrenal/gonadal steroids)
Broken steroid nucleus (Vit D and metabolites)
16
Q
How are precursors of steroid hormones transported?
A
Passive diffusion across cell membrane from blood stream
17
Q
How does the precursor molecule produce the steroid hormone?
A
Action of several enzymes
18
Q
Describe Cortisol production in an adrenal cortical cell
A
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
19
Q
What is the difference between mature steroid hormone and mature protein hormone (regarding cell membrane crossing)?
A
Steroid hormone can freely cross cell membrane without being packed into secretory granules and actively exocytosed
20
Q
Where are most hormones secreted?
A
Systemic circulation
EXCEPT hypothalamus releases into hypophyseal portal system (a rich network of blood vessels that ‘bathe’ the anterior pituitary)
21
Q
What hormones are water soluble?
A
Protein/polypeptide (circulate freely within the bloodstream- QUICK, MINS)
22
Q
What hormones are more insoluble?
A
Steroid and thyroid hormones (bound to plasma proteins or transport proteins- SLOWER)
23
Q
How does the bound hormone remain in dynamic equilibrium with a small amount of free hormone?
A
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)
24
Q
How do free hormones function?
A
Biologically active
Buffer hormones and protect against rapid hormone concentration changes
25
What is albumin?
A general transport molecule (plasma protein)
| Non-selectively transports a variety of low molecular weight hormones
26
What are TBG, CBG and SHBG?
TBG- thyroxine-binding globulin (Thyroid hormones)
CBG- corticosteroid-binding globulin (Cortisol)
SHBG- sex hormone-binding globulin (Testosterone/Oestradiol)
27
How is clearance rate (from circulation) affected by binding of proteins?
Greater binding capacity-> slower clearance rate of the hormone
28
If hormone levels fall, is the forward or backward reaction favoured?
Hormone + plasma protein Protein bound hormone
Back
| Endocrine cell increases hormone synthesis and release
29
If plasma levels increase, is the forward or backward reaction favoured?
Hormone + plasma protein Protein bound hormone
Forward
| Endocrine cell increases hormone synthesis and release
30
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
31
What concentration of hormones are usually present in circulation?
Very low
10(-9) to 10(-12)M
So need high affinity and high specificity
32
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
33
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
34
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)
35
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
36
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
37
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)
38
What is a closed loop feedback system?
Feedback of a substance regulated by its own production
| Protect against excessive hormone action
39
Why is assessment of both stimulatory and peripheral hormones analysis necessary?
Feedback relationship
| Need to assess endocrine status
40
What is another name for the pituitary gland?
Anterior lobe?
Posterior lobe?
Hypophysis
Anterior- adenohypophysis
Posterior- neurohypophysis
41
Where is the hypophysis?
Lies at base of brain in sella turcica directly under the hypothalamus
42
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
43
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
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44
What is in the hypothalamo-adenohypophysial axis?
```
Hypothalamic nuclei
Neurons to median eminence
Neurosecretions
Adenohypophysis
Adenohypophysial hormones
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SEE DIAGRAMS OF HYPOTHALAMIC NUCLEI/ MEDIAN EMINENCE
45
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
46
What are the 6 chief adenohypophyseal hormones?
Somatotrophin (growth hormone)
Prolactin
Thyrotrophin (thyroid stimulating hormone TSH)
LF and FSH (luteinizing hormone, follicle stimulating hormone)
Corticotrophin (adrenocorticotrophic hormone, ACTH)
47
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)
48
Where are adenohypophyseal hormones stored?
In secretory granules (released by exocytosis)
49
Give an example of an adenohypophyseal precursor pro-hormone
POMC (ProOpioMelanoCorticotrophin)
POMC-> Corticotrophin +Pro-yMSH + BLPH
50
Group adenohypophyseal hormones into proteins, glycoproteins and polypeptides
PROTEINS
- 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)
POLYPEPTIDE
- Corticotrophin (ACTH) (39AA)
51
How is the hypothalamus involved in adenohypophyseal hormones?
Hypothalamic hormones have a direct influence on the release of adenohypophyseal hormones
52
Which hypothalamic hormones affect which adenohypophyseal hormones?
-> STOMATOTROPHIN
Somatotrophin releasing hormone (SRH or GHRH)- STIM
Somatostatin (SS)- INHIB
-> PROLACTIN
Thyrotrophin releasing factor (TRH)- STIM
Dopamine (DA)- INHIB
-> THYROTROPHIN (TRH)
Thyrotrophin stimulating hormone (TSH)- STIM
-> FSH AND LH
Gonadotrophin releasing hormone (GnRH)- STIM
-> ACTH
Corticotrophin releasing hormone- STIM
*Vasopressin
53
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
54
What are the principle physiological actions of ACTH?
Targets adrenals
| Stimulates the adrenal gland to produce a hormone called cortisol
55
What are the principle physiological actions of TSH?
Targets thyroid
| Stimulates the thyroid gland to secrete thyroxine
56
What are the principle physiological actions of LH and FSH?
Controls reproductive functioning and sexual characteristics
FEMALES
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)
MALES
Stimulates testes to produce testosterone and sperm (spermatogenesis)
LH is also referred to as interstitial cell stimulating hormone (ICSH) in males
57
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)
DIRECT NEGATIVE FEEDBACK
High T3 or T4-> stimulates own inhibition (inhibits secretion of TSH in adenohypophysis)
INDIRECT NEGATIVE FEEDBACK
High T3 or T4-> stimulates own inhibition (inhibits secretion of TRH in hypothalamus-> less tSH in adenohypophysis)
AUTO (SHORT-LOOP) NEGATIVE FEEDBACK
TSH inhibits production of TRH in hypothalamus
(Adenhypophysial hormones influence their own release by influencing secretion of release-stimulating or release-inhibiting hypothalamic hormones)
58
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]
59
Outline the direct and indirect pathways of somatotrophin leading to growth and development
DIRECT
Adenohypophysis-> somatotrophin-> body tissues (metabolic actions)-> growth and development
INDIRECT
Adenohypophysis-> somatotrophin-> liver-> somatotmedins (IGF I and IGF II)-> body tissues-> growth and development
60
What stimulates somatotrophin production?
```
Amino acids
Fasting (hypoglycaemia)
Exercise
Oestrogens
Sleep (stages III and IV)
Stress
```
61
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
62
What positive feedback takes places in somatotrophin release?
Somatotrophin releasing hormone (SRH/GHRH)-> stimulates release
63
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
```
Steroidogenesis?
Renal Na/water reabsorption?
64
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)
65
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
66
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
67
What are various causes of short stature?
Malnutrition
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
Hypothyroidism
Cushing syndrome: excess glucocorticosteroids
68
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
69
What is the posterior pituitary?
Neurohypophysis
Outgrowth of the hypothalamus and is neural tissue
70
How are neurones that are associated with the neurohypophysis grouped together?
In the supraoptic and paraventricular nuclei in the hypothalamus
71
Where do unmyelinated axons of paraventricular and supraoptic nuclei pass through and end?
Pass through infundibulum
| End within the posterior pituitary (close to capillaries)
72
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.
73
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.
74
Where do most posterior pituitary capillaries drain into?
The main bloodstream
Via jugular veins
Carries hormones to heart
75
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)
76
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
77
What are the 2 principal secretory produces of magnocellular neurones?
Vasopressin (ADH)
| Oxytocin
78
Where are pro-hormones of neurohypophyseal hormones?
Synthesised as pro-hormones in the supraoptic and paraventricular nuclei
Then transported to posterior pituitary
79
How are pro-hormones converted to hormones?
Cleaved to form hormones and neurophysin proteins (released together)
80
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
81
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)
82
What is found in Herring bodies?
Granules containing molecular complexes of pro-hormones
83
Describe pre-provasopressin-> prohormone-> hormone of vasopressin
Pre-> pro: glycosylation, disulphide bridging, folding
Pro-> hormone: cleavage and exocytosis
Vasopressin + neurophysin + glycopeptide
84
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
85
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)
86
Where are vasopressin receptors found?
V1a
Arterial (vasoconstriction)
Hepatocytes (glycogenolysis)
CNS neurones (behaviour and other effects)
```
V1b (V3)
Adenohypophyseal corticotrophs (corticotrophin production)
```
V2
Collecting duct cells (water reabsorption)
Probably other unidentified sites
Factor VII and von Willbrandt factor
87
What are the main physiological actions of vasopressin?
In principal cells (renal collecting duct)= stimulates water reabsorption and has antidiuretic effect
Vasoconstriction
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
88
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
89
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
90
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
91
What stimulates production of oxytocin?
Suckling a lactating mother
Stretch receptors in the vagina/uterus
Emotional stress may-> inhibition of lactation
92
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
93
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
94
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
95
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
96
What clinical conditions are associated with vasopressin?
```
DIABETES INSIPIDUS
Central DI (no VP)
Nephrogenic DI (tissue insensitivity)
```
SIADH
Syndrome of inappropriate ADH
97
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
98
What can cause lack of vasopressin?
Genetic disorder
Cranial diabetes insipidus
Hypothalamic disorder affecting vasopressinergic neurons e.g. due to trauma or a tumour
99
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)
100
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
101
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
102
What happens to osmolarity after administering DDAVP?
Osmolality of urine rises
| DDAVP functions like AVP
103
Why is blood glucose concentration closely regulated?
Glucose is a vital energy substrate
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Low glucose (hypoglycaemia (impairs brain function)
Lower glucose (unconsciousness, coma, death)
```
High glucose can -> diabetic coma which can -> death
104
What are normal blood glucose levels?
4-5mMol
105
What hormones control glucose level?
Decrease levels= insulin
| Increase levels= glucagon, catecholamines (e.g. adrenaline), cortisol and somatotrophin
106
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
107
How much of the pancreas is associated with exocrine secretions (via duct to small intestine)?
98%
108
What percentage of pancreatic tissues are small clusters of endocrine cells and what are they called?
2%
| Islets of Langerhans
109
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)
110
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)
```
111
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
112
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
113
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
114
Describe how insulin is stored?
Stored within granules
| Partly as polymers and partly complexed with zinc
115
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
116
How much insulin is degraded in the liver and kidneys?
80%
117
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)
118
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
LOW INSULIN TO GLUCAGON RATIO
119
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)
120
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
121
Which factors regulate the release of insulin to decrease blood glucose?
```
STIMULATE BETA CELLS
Certain AAs
Certain GI hormones
Alpha cells-> glucagon
Parasympathetic activity (B-receptors)
```
INHIBIT BETA CELLS
Delta cells-> somatostatin
Sympathetic activity (a-receptors)
Stress (associated with sympathetic mediators)
122
Which factors regulate the release of glucagon to decrease blood glucose?
```
STIMULATE ALPHA CELLS
Certain AAs
Certain GI hormones
Sympathetic activity
Parasympathetic activity
```
INHIBIT ALPHA CELLS
Beta cells-> insulin
Delta cells-> somatostatin
123
What does glucagon raise?
Blood glucose concentration
Blood fatty acid concentration
Urea production
124
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
125
What is glucokinase?
Glucose sensory, hexokinase IV
| Acts as a glucose receptor on pancreatic B cells
126
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
127
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)
128
What does GLP-1 do?
Stimulates insulin
Suppresses glucagon
Increase satiety
129
What is GLP-1 degraded by?
Enzyme= Dipeptidyl peptidase-4 (DPPG-4 inhibitor)
Rapid degeneration, so GLP-1 has a short half life
130
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
```
131
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
132
What colour is urine when it has:
No ketones
Ketones
Lots of ketones?
No ketones= yellow
Ketones= green
Lots of ketones= very green
133
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
134
Will ketones be in urine in Type 1 diabetes, Type 2, neither or both?
T1DM
(Ketones won't be in urine unless fasting in T2DM as ketone body formation is surpressed by insulin, fat not broken down)
135
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
136
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
137
Why is C peptide a good marker for endogenous insulin?
Longer half life (30 mins not 4) and more stable
138
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
139
What is the normal fasting plasma glucose?
140
Is the fasting plasma glucose for higher or lower in T2DM patients?
Higher
141
What are common characteristics of a patient with T2DM?
Older
Overweight
Cardiovascular symptoms
142
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
143
What do T2DM diets recommend?
Overall calorie control
Including:
Reduce fat calories
Reduce refined carb calories
Reduce sodium intake Increase soluble fibre Increase complex carb calories
144
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
145
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
```
146
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)
Growth
Vascular effects
Ovarian function
Clotting (Pai-1)
Energy expenditure (relation to Leptin)
147
Where is GLUT-4 expressed?
Muscle and adipose tissues
| Lies in vesicles until recruited and enhanced by insulin
148
What effect does GLUT-4 have on glucose uptake into cells?
7x increase in glucose uptake into cells
149
What is the structure of GLUT-4?
Hydrophobic outer layer and hydrophilic inside (where glucose goes through)
150
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)
151
What stimulates protein synthesis (from AAs)?
Insulin
Growth hormone
IGF1
152
Relating to proteins, what does insulin inhibit?
Proteolysis
| Conversion of oxygen to carbon dioxide
153
What are the effects of insulin and glucagon on glucose?
INSULIN
Stimulates glycogenesis (glucose->glycogen)
Inhibits gluconeogenesis (glycogen-> glucose)
Decreases hepatic glucose output
GLUCAGON
Increases uptake of gluconeogeneic AAs into cells
Stimulates glycogenolysis and gluconeogenesis
Increases hepatic glucose output
154
What is the difference between carbohydrates, proteins and fat as fuel stores?
CARBS
Liver and muscle cells: glycogen ->glucose (especially in brain)
Short term source: 16 hrs
PROTEIN
Longer term: 15 days
FAT
Long term source: 30-40 days
Highest energy released per gram
155
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)
156
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
157
What stimulates the breakdown of triglycerides into glycerol and non-esterified fatty acids?
Catecholamines, cortisol and growth hormone
| Insulin inhibits this
158
Describe omental circulation
Via hepatic portal vein:
Heart-> GI tract-> liver-> heart
Adipocytes in GI tract are highly metabolically active
159
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
160
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)
161
What % of glucose output (after a 10 hour fast) is released from hepatocytes via HGO?
25%
162
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)
163
What inhibits/stimulates the conversion of fatty acyl CoA (in fatty acid metabolism)
Insulin inhibits
| Glycogen stimulates
164
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
165
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)
166
Where are fatty acids taken up into?
Muscle cells
167
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
168
Describe the fasted state (and prolonged fasting)
FASTED STATE
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
PROLONGED FASTING
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
169
Describe the fed state
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)
170
What is Diabetes Mellitus?
DM= metabolic disorder due to insulin deficiency of hyporesponsiveness
Characterised by hyperglycaemia and other distinct symptoms
171
What are the main signs of DM?
```
Glycosuria
Polyuria
Polydisia
Weight loss and polyphagia
Diabetic keotacidosis
```
172
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
173
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
174
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)
175
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
176
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
177
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
178
Describe what happens to ..... in T1DM and T2DM
```
Insulin
Glucose
Glycosuria
Ketones
Weight
```
Insulin
T1= total failure to secrete
T2= inadequate relative to blood-glucose levels
Glucose
T1= hyperglycaemia
T2= hyperglycaemia
Glycosuria
T1= frequent urinating
T2= less frequent but osmotic symptoms
Ketones
T1= ketonuria
T2= dyslipidaemia
Weight loss
T1= yes
T2= no (60% are obese)
179
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
180
What percentage of diabetes cases is T1DM? In under 35s?
25-30% of all cases
| 90% of all under 35 cases
181
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
182
What happens in insulin resistance in adipose tissue?
Causes increased lipolysis of triglycerides -> elevated fatty acid levels
183
What happens in insulin resistance in liver cells?
Increases gluconeogenesis and glycogenolysis which -> rise in overall blood glucose level
184
What happens in insulin resistance in muscle cells?
Reduces glucose uptake and utilisation
185
Why is obesity a factor in insulin resistance?
Excess adipose tissue may downregulate the production of insulin-sensitive glucose transporters
186
What is dyslipidaemia?
Abnormal levels of lipid in blood
187
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
188
How does insulin cause hypertension?
Hypertension BP >135/80
Insulin-> increased Na retention-> increased blood pressure
189
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
190
What is Syndrome X?
Metabolic syndrome with combo of dyslipidaemia, hypertension and ischaemic heart disease -> increased risk for CV disease and diabetes
191
What is the concentration of triglycerides and HDL in insulin resistance?
High [TG]
| Low [HDL]
192
What waist circumference indicates a high risk of diabetes?
Men >102
| Women >88
193
How is reduced insulin action related to T2DM?
```
Mitogenic on growth= hyperinsulinaemic effect
Lipoproteins
Smooth muscle hypertrophy
Ovarian function
Clotting
Energy expenditure
```
Metabolic= Insulin resistance effect
Glucose
Protein
Lipid
194
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)
195
What BMI is classified as overweight?
26-30 BMI
196
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
197
What are risk factors of obesity?
```
T2DM
Hypertension
Heart disease
Stroke
Sleep apnea
```
198
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)
199
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
200
What are the metabolic changes associated with insulin-induced hypoglycaemia?
```
High insulin
Glucagon
Lipolysis increased
Increased catecholamines
Increased cortisol
Increased growth hormone
Glucose does enter muscle
Increased HGO later with glycogenolysis and gluconeogenesis
```
201
How much does the thyroid gland weigh?
20g
| 4 lobes x 2.5
202
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
203
What do thyroid and parathyroid gland secrete?
Parathyroid hormone (PTH)
204
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
205
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
206
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
207
What does calcitonin do?
Prevents calcium mobilization from bone and reduced calcium level in blood
208
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
209
What is incorporated into TG?
Tyrosyl residues are incorporated into TG (thyroglobulin)
210
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
211
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
212
How is iodothyronine stored?
The thyroid hormones are stored as thyroglobulin in this form within the colloid
213
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
214
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
215
Is T3 or T4 more potent?
T3 is about four times as potent as thyroxine
216
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)
217
What are the latent periods of T3 and T4?
```
T3= 12h
T4= 72h
```
218
What are the biological half-lives?
```
T3= 2 days
T4= 7-9 days
```
219
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)
220
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
221
Why is BMR increased by iodothyronine?
Increased O2 consumption and production of heat (calorigenesis)
Except the brain
222
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)
223
How does iodothyronine increase carbohydrate metabolism?
Increases rate of absorption of glucose by GI tract
| Enhances glycolysis, gluconeogenesis and glycogenolysis
224
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
225
How does iodothyronine increase protein metabolism?
Catabolism and anabolism
| But excess induces degradation
226
Explain the mechanism of action of the iodothyronines?
To modulate gene expression by stimulating/inhibiting transcription of certain genes
To stimulate mitochondria directly
227
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
228
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
229
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
230
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
231
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?
232
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
233
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
234
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
235
What is the role of thyroxine (T4)?
Essential for normal brain development
Controls cellular activity
Neonates with deficiency in utero have irreversible damage-> cretin
236
What is cretinism?
Caused by thyroxine (T4) deficiency
Cretin= individual with irreversible brain damage caused by lack of thyroxine
Mentally sub-normal
Short stature
237
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
238
Where is thryoxine synthesised?
Thyroid follicular cell (thyrocyte)
239
What does thyroxine control?
BMR
240
What percentage of thyroxine does thyroxine binding globulin bind in the circulation?
```
75%
NOT THYROGLOBULIN (this is present in thyroid gland)
```
241
What is the thyroid gland principally responsible for?
Synthesis, storage and secretion of thyroid hormones (which regulate growth, development and BMR)
242
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
243
What is myxoedema?
Primary hypothyroidism
244
What causes primary hypothyroidism/myxoedema?
Caused by autoimmune damage to the thyroid, or surgical removal (thyroidectomy)
Underactive thyroid gland
Iodine deficiency
Resistance to TSH
245
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
246
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
Constipation
Bradycardia (Heart rate
```
247
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
```
248
What is thyrotoxicosis?
Primary hyperthyroidism
249
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
250
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
Restless
Sleep difficulties
Feeling hot in all weather
Diarrhoea
Increased appetite but weight loss
Tremor of hands
Tiredness and myopathy
Palpitations
Sore eyes- trouble focussing, irritation, sensitivity
Enlarged thyroid- goitre
```
251
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)
252
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
253
What causes secondary hypothyroidism?
Caused by TSH (thyrotrophin) deficiency
254
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
255
Describe the anatomy of the adrenal gland?
Adrenal gland sits on kidney
Medulla= core
Cortex= outer layers
256
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
257
What is the main difference between the hormonal products from the adrenal medulla and the adrenal cortex?
```
Medulla= catecholamines (sympathetic)
Cortex= corticosteroids
```
258
Describe the main hormonal products from the adrenal medulla
Made up of chromaffin cells
Cells synthesis and release catcholamines
Adrenaline (80%)
Noradrenaline (20%)
(Dopamine)
259
What are catecholamines?
Catecholamines are polypeptide hormones synthesised from a tyrosine precursor
260
Describe the main hormonal products from the adrenal cortex
Mineralocorticoids= aldosterone (ZG)
Glucocorticoids= cortisol (ZF and ZR)
Sex steroids= androgens, oestrogens (ZF and ZR)
SALT, SUGAR, SEX
261
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
262
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
263
What are the steroid hormones from the adrenals?
Mineralocorticoids (C21)
Glucocorticoids (C21)
(Androgens)
264
What are the steroid hormones from the gonads?
Progestogens (C21)
Androgens (C19)
Oestrogens (C18)
265
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
266
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
267
What are cortisol and aldosterone bound to?
CORTISOL
75% bound to CBG
15% bound to the non-specific protein albumin
10% of the hormone is unbound and bioactive
ALDOSTERONE
60% bound to CBG
40% unbound and bioactive
CBG= cortisol binding globulin, AKA transcortin
268
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
269
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)
270
What is the main mineralocorticoid in humans?
Aldosterone
271
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
272
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
273
What is the overall structure of a kidney nephron?
Glomerulus
Proximal convoluted tubule
Loop of Henle (descending – ascending)
Distal convoluted tubule Collecting duct
274
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
275
Where are secretory juxtaglomerular cells?
Smooth muscle in the wall of the renal afferent arteriole
276
What do secretory juxtaglomerular cells contain?
Secretory granules which contain renin (enzyme)
277
What are macula densa cells?
Specialised Na sensors
Part of the ascending loop of Henle
Adjacent to juxtaglomerular cells
278
What is in the juxtaglomerular apparatus?
Combination of juxtaglomerular and macula densa cells
279
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)
280
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
281
What is the source of angiotensinogen?
Liver
282
What does ACE stand for? (RAAS)
Angiotensin converter enzyme
283
What are the effects of angiotensin II?
Vasoconstriction
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
284
Why are ACE inhibitors used as antihypertensives?
Prevents angiotensin II being formed
285
What stimulates aldosterone release?
RAAS
Corticotrophin (released from the anterior pituitary gland)
Increased K+ and decreased Na+
286
What is the main glucocorticoid in humans?
Cortisol
287
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
MINERALOCORTICOID EFFECTS
Some, not major
RENAL AND CARDIOVASCULAR EFFECTS
Excretion of water load
Increased vascular permeability
OTHER EFFECTS
Bone growth
CNS effects
288
Why is cortisol important in the endocrine response to stress?
Physiological actions-> normal stress response
289
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
290
What are the cortisol receptors?
Glucocorticoid receptors
Aldosterone (mineralocorticoid) receptors (aldosterone also binds)
These 2 receptors bind to cortisol with equal affinity
291
How do you prevent excess mineralocorticoid receptor activation in the kidney?
Bioactive cortisol is converted to biologically inactive cortisone
Involves 11b-hydroxysteroid dehydrogenase 2
292
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
293
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)
294
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
295
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
296
What is DHEA?
De-hydro-epi-androsterone
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
297
What are the most common adrenal disorders?
Syndromes of excess/deficiency of hormone messengers
Adrenal failure= Addison's
Excess cortisol= Cushing's
298
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)
299
Describe cholesterol
27 carbon compound
Basic cyclic structure 17C
Side chain 8C
300
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
301
What is POMC?
Pro-opio-melanocortin
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
302
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
303
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
304
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
305
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
306
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)
Osteoporosis
Hypertension
Moon face– fat deposition in cheeks
Buffalo hump (interscapular fat pad)
Immunosuppression (reactivation of TB)
```
307
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
308
What are the side effects of steroids?
```
Hypertension
Diabetes
Osteoporosis
Immunosuppression
Easy bruising
Poor wound healing, thin skin
```
309
What is Conn's syndrome?
Aldosterone producing adenoma
Hypertension
Oedema
Low potassium
310
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)
311
Why is there increased pigmentation with Addison's Syndrome?
Autoimmune vitiligo
MSH-> increased pigmentation of skin-> tanned appearance
312
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
313
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
```
314
What is steroidogenesis?
Production of steroid hormones
Males- androgens (oestrogens, progestogens)
Females- oestrogens, progestogens (androgens)
315
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)
316
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
317
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,
318
Outline the process from germ cell-> spermatozoa (spematogenesis)
1. Germ cell (44+XY= diploid)
2. Spermatogonia (44+XY= diploid)
MITOTIC DIVISION
3. Primary spermatocytes (44+XY= diploid)
FIRST MEIOTIC DIVISION
4. Secondary spermatocytes (22X or 22Y= haploid)
SECOND MEIOTIC DIVISION
5. Spermatids (22X or 22Y= haploid)
6. Spermatozoa (22X or 22Y= haploid)
319
Outline the process from germ cell-> ovum (oogenesis)
1. Germ cell (44+XY= diploid)
2. Oogonia (44+XY= diploid)
MITOTIC DIVISION
3. Primary oocytes (44+XY= diploid)
FIRST MEIOTIC DIVISION
4. Secondary oocytes and first polar body (both 22X= haploid)
SECOND MEIOTIC DIVISION
5. Ovum and second polar body (both 22X= haploid)
Polar body eventually disintegrates (doesn't keep cytoplasm)
320
What is the initial number of oogonia in primordial follicles (in fetus)?
6 million
321
What do spermatogonia undergo?
Differentiation or self-renewal
So a pool of spermatogonia remains available for subsequent spermatogenic cycles throughout life
322
Where do the testes develop?
In abdomen
| Descend into scrotum
323
Where does spermatogenesis occur?
In the coiled seminiferous tubules
324
Where are spermatozoa....?
Released
Drained
Matured
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
325
What is the lumen of coiled seminiferous tubules surrounded by?
Sertoli cells connected by tight junctions in periphery
326
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.
327
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'
328
What does the ovarian stroma consist of?
Primordial follicles undergoing atresia
Graffian follicle (just before ovulation)
Remnants of corpus luteum (after ovulation)
329
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
330
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)
(C19)
Oestrogens (C18)
331
Outline the synthesis of progesterone, 17b oestradiol and testosterne
Cholesterol-> pregnenolone-> progesterone-> 17 OH progesterone-> androstenedione.....
-> oestrone-> 17b-oestradiol
OR
-> testosterone-> dihydro-testosterone
OR
-> testosterone-> oestrone-> 17b- oestradiol
332
How long does the menstrual cycle last?
```
28 days (20-35)
Begins on first day of menstruation
```
333
What is menstruation?
Loss of blood and cellular debris from necrotic uterine epithelium
334
When is a ripe ovum released?
Around day 14
335
What are the ovarian and endometrial cycles?
Ovarian (ovary)
Follicular phase-> ovulation-> luteal phase
Endometrial (uterus)
Proliferative phase-> secretory phase
336
What stimulates the proliferative phase of the endometrial cycle?
17b-oestrodiol production in the follicular phase of the ovarian cycle
337
What stimulates the secretory phase of the endometrial cycle?
Progesterone and 17b-oestrodiol production in the luteal phase of the ovarian cycle
338
The pre-antral follicle (2 facts)...
Developed in the absence of hormones
Ovum is surrounded by layer of cells
339
The early antral follicle (2 facts)...
Ovum surrounded by granulosa cells and then thecal cells
Follicle present- antral space filled
340
The late antral follicle (2 facts)...
Same as early antral follicle
Follicle increases in size therefore more antral filled space around ovum
341
What happens to cells of graffian follicle post ovulation?
Form the corpus luteum
342
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
343
What happens in the endometrial cycle: day 6-14 (proliferative phase)?
DOMINANT HORMONE
Oestrogen
ENDOMETRIUM
Early= thin endometrium
Late= thickens and moistens
GLAND CHANGES
Early= straight glands
Late= glands enlarge, coil and have increased blood supply
344
What happens in the endometrial cycle: day 14-15/
Ovulation
345
What happens in the endometrial cycle: day 15-28 (secretory phase)?
DOMINANT HORMONE
Progesterone (plus oestrogen)
ENDOMETRIUM
Becomes secretory
GLAND CHANGES
Secrete glycogen, mucopolysaccharides etc
Mucosa become engorged with blood
346
What happens in the endometrial cycle: day 1-5 (menstruation)?
ENDOMETRIUM
| Becomes necrotic and is shed
347
When do LH and FSH peak?
At ovulation
348
When does oestrogen peak and trough?
Peaks just before ovulation
Then troughs
Then increases again because produced by corpus luteum
Falls dramatically before menstruation
349
When is progesterone limited to?
The luteal phase
350
How do oestrogen and progesterone control gonadotrophin release?
Exert negative feedback at the hypothalamus and anterior pituitary gland for gonadotrophin release
351
What happens to basal body temperature when ovulation occurs?
Increases (due to action of progesterone)
352
What happens to oestrogen if fertilisation does not occur?
Falls
| Menstruation occurs
353
What androgen is produced first and then converted to testosterone?
Androstenedione
354
Testosterone binds to the androgen receptor and is the precursor to what?
Dihydroxytestosterone (DHT)
| More powerful androgen
355
How is dihydroxytestosterone reduced?
Reduction involving 5-alpha-reductase
356
What happens when testosterone undergoes aromatization by aromatase enzyme?
Forms oestrone and then 17b-oestradiol (which is the main circulating oestrogen)
357
Where is oestrogen produced in men?
Sertoli cells
358
Where are testosterone and DHT produced in men?
```
Prostate
Seminiferous tubules (in testis)
Seminal vesicles
Skin
Brain
Anterior pituitary gland (adenohypophysis)
```
359
Where is 17b-oestradiol produced in men?
```
Adrenals
Sertoli cells (testis)
Liver
Skin
Brain
```
360
How are testosterone and DHT transported?
IN BLOOD
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%
IN SEMINIFEROUS FLUID
Bound to androgen binding globulin
361
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)
362
Define progestogens
Any substance (natural or synthetic) which induces secretory changes in the endometrium
E.g. progesterone, 17a-hydroxyprogesterone
363
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)
364
What are the actions of androgens in adults?
Spermatogenesis
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
365
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
366
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)
367
Describe the endocrine control of androgen production (hypothalamo-pituitary-gonadal axis)
ANDROGEN PRODUCTION (Leydig cells)
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
368
Describe the endocrine control of spermatogenesis (hypothalamo-pituitary-gonadal axis)
SPERMATOGENESIS (Sertoli cells)
Stimulated by GnRH/FSH system
Also requires GnRH/LH/testosterone system for complete spermatogenesis
Limited by inhibin negative feedback (direct and indirect)
369
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
370
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
371
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)
372
Describe the differences between the hypothalamo-pituitary-ovarian axis and the testicular axis
FSH and LH act on ovaries
373
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
374
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
375
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
376
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
377
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
378
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)
```
379
Define oligomenorrhoea
Infrequent cycles
380
What causes oligomenorrhoea?
Various
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
381
What is infertility?
Unable to get pregnant (or men to impregnate)
382
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
383
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
384
What is galactorrhoea?
Discharge of milk-like substance from the breast that is not associated with breastfeeding after pregnancy
Due to high prolactin
385
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
386
What is a common visual condition due to a suprasellar tumour?
Bitemporal hemianopia
387
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
388
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)
```
389
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
390
What is the total concentration of calcium in the blood?
2.5mM
391
How is calcium regulated?
CONC INCREASED BY:
Parathyroid hormone (PTH) – a polypeptide hormone
1, 25 (OH)2 vitamin D3 metabolite – dihydroxycholecalciferol, or calcitrol – a steroid hormone
CONC DECREASED BY:
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
392
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+
393
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
394
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
395
What is 1,25 di-hydroxy-cholecalciferol (1,25 (OH)2D3) also known as
Calcitriol
396
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
397
What are the principal actions of PTH on the kidneys, bone and small intestine?
KIDNEYS
Increased Ca reabsorption
Increased PO43- excretion
Stimulates 1a hydroxylase activity-> increased calcitonin synthesis (-> small intestine)
SMALL INTESTINE
Increased Ca absorption
Increased PO43- absorption
BONE
Stimulate osteoclasts (breakdown)
Inhibit osteoblasts (rebuilding)
Increased bone resorption
398
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
399
What are the actions of 1,25 (OH)2D3 on the kidneys, bone and small intestine?
KIDNEY
Increased Ca2+ and PO43- reabsorption in the proximal tubule
SMALL INTESTINE
Increased Ca2+ absorption
Increased PO43- absorption
BONES
Increased osteoblast activity
Therefore increased storage of Ca2+ in bones
400
What are the actions of calcitonin?
Increased plasma calcium concentration
- > Gastrin
- > Calcitonin
KIDNEYS
Increased urinary excretion of Ca (Na, PO43-)
-> Decreased plasma calcium (limited effect)
BONES
Inhibition of osteoclast activity
-> Decreased plasma calcium (limited effect)
401
How is PTH regulated?
DECREASED PLASMA CALCIUM
- > Increased PTH production in parathyroid glands
- > Increased Ca2+
- > Increased Ca2+ then exhibits negative feedback on the parathyroid glands
```
INCREASED PTH
Synthesis of 1,25 (OH)2D3
-> +ve influence increasing plasma Ca2+
BUT
-> -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
402
How is calcitonin regulated?
Stimulus: increased plasma Ca2+ concentration stimulates the parafollicular cells of the thyroid to produce calcitonin
Gastrin also stimulates this
403
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
404
What happens to plasma Ca, plasma PO4 and PTH in hypoparathyroidism, pseudo-hypoparathyroidism and vitamin D deficiency?
HYPOPARATHYROIDISM
Plasma Ca= decreased
Plasma PO4= increased
PTH= decreased
PSEUDO-HYPOPARATHYROIDISM
Plasma Ca= decreased
Plasma PO4= increased
PTH= increased
VITAMIN D DEFICIENCY
Plasma Ca= decreased
Plasma PO4= decreased
PTH= increased
405
What is tetany?
Where smooth muscle goes into auto-contraction
| Can be used to observe where decreases in calcium have occurred
406
What is Trousseau's sign?
Tetany in the hands can be induced by decreased calcium
407
What is Chvostek's sign?
The facial nerve can be 'tapped' to induce a twitch
408
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)
409
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)
410
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
411
What does vitamin D deficiency cause?
Rickets in children
| Osteomalacia in adults
412
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
413
What are the 3 main causes of hypercalcaemia?
Primary hyperparathryoidism
Tertiary hyperparathyroidism
Vitamin D toxicosis
414
What causes primary hyperparathryoidism?
Adenoma
Disrupts pathway which should be:
Increased calcium -> inhibits parathryoids (so prevents -> PTH increase-> increased calcium etc.)
415
What causes tertiary hyperparathyroidism?
```
Low plasma calcium concentration concentration e.g. renal failure
Affects parathyroids (so increased PTH decreases or equalised calcium)
```
416
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.
417
What happens when there is an excess of parathyroid hormone?
```
KIDNEYS
Ca reabsorption
PO4 excretion
Polyuria
Renal stones
Nephrocalcinosis
1,25 (OH)2 D2 synthesis
```
GI TRACT
Gastric acid
Duodenal ulcers
BONE
Bone lesions
Bone rarefaction
Fractures
418
What is primary hyperparathyroidism?
Hyperfunction of the parathyroid glands themselves
Oversecretion of OTH due to parathyroid adenoma, parathyroid hyperplasia or, rarely, a parathyroid carcinoma
419
What is secondary hyperparathyroidism?
Due to physiological secretion of PTH by the parathyroid glands in response to hypocalcaemia
420
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
