Physiology Flashcards
(149 cards)
1
Q
Define the endocrine system
A
A system that integrates and controls organ function via secretion of hormones from cells tissues or glands
These are then carried via blood to target organs, distal from site of hormone synthesis where they influence activity of target organ
Cells have receptors specific to the hormone
No receptor = no response
2
Q
Describe paracrine chemicals
A
Act locally to site of synthesis (neighbouring cells), do not travel to distant sites e.g. histamine
3
Q
Describe autocrine chemicals
A
act on/in the same cell that synthesises the hormones e.g. cytokines
4
Q
Describe exocrine chemicals
A
releases from exocrine glands via ducts to external environment including GI tract e.g. saliva, sweat, bile
5
Q
Describe neural communication
A
Neurotransmitters released from pre-synaptic neurons travel across synaptic cleft to post-synaptic cell to influence its activity
Neurotransmitter acts locally within synaptic cleft
6
Q
Define the neuroendocrine system
A
Endocrine and nervous systems combine
Nerves release hormones which enter blood and travel to target cells e.g. hypothalamic - posterior pituitary axis
7
Q
What are the sites of the principal endocrine glands?
A
Hypothalamus, pituitary, thyroid, parathyroid, adrenal glands, both medulla and cortex and kidneys themselves.
Also the GIT, ovary and testis
8
Q
What are the features of an endocrine hormone?
A
- Produced by a cell or group of cells
- Secreted from those cells into blood
- Transported via blood to distant targets
- Exert their effects at v low concentrations (range 10-9, to 10-12M)
- Act by binding receptors on target tissues
- Have their action termination, often via -ve feedback loops
9
Q
What are the classifications of endocrine hormones?
A
- Peptide or protein hormones - composed of AA chains (most common)
- Steroid hormones - all derived from cholesterol
- Amine hormones - all derives from one of two AAs (trytophan or tyrosine)
10
Q
Describe peptide hormones
A
i.e. insulin, TRH, FSH
Synthesised then stored in vesicles until needed
Initial protein ribosomes produce is large & inactive - preprohormones. These contain one/more copies of active hormone in AA sequence
They are cleaved in RER to leave smaller, inactive proteins called prohormones. These are packaged into vesicles in Golgi, along with proteolytic enzymes which break them down into active hormone and other fragments.
Hormones & fragments stored in vesicles in endocrine cells until release triggered, then all vesicle contents released into plasma (co-secretion)
measuring inactive fragments in plasma can be useful clinically i.e. C-peptide in diabetes
11
Q
What is C-peptide?
A
Inactive fragment cleaved from insulin prohormone
Levels of C-peptide in plasma or urine often measured to indicate endogenous insulin production from pancreas (produced in equal amounts)
Levels of C-peptide typically 5x insulin as insulin metabolised faster
12
Q
Describe the mechanism of action of peptide hormones
A
Water soluble so easily dissolve in plasma making transport via blood easy. However means cannot cross cell membrane so bind to membrane bound receptors on target cell.
Once bound receptors generally create relatively fast bio responses (secs to mins)
Most work by modulating either GPCR or tyrosine kinase linked signalling pathways. These phosphorylate existing proteins in cell and modify their function i.e. open or close ion channels
13
Q
Describe peptide hormone signal transduction
A
Hydrophilic/lipophobic signal molecule binds to cell receptor which is either;
- G protein couple receptor; activates 2nd messenger and/or ion channels leading to mod of existing proteins. Rapif response
- Tyrosine kinase linked receptor; alters gene expression, slower longer lasting activity
14
Q
Describe steroid hormones
A
Synthesised as needed, not stored and released. This is bc they are highly lipid soluble so cannot be retained in lipid membranes. Once synthesised, diffuse across membrane into ISF and blood
Poorly soluble in blood so transported bound to carrier proteins i.e. albumin. Stabilises their transport through plasma and protects from enzymatic degradation, increasing their half life
All derived from cholesterol. Which is made depends on which enzyme acting on which cholesterol derivative
15
Q
Where are steroid hormones produced?
A
- Gonads (testes and ovary); sex steroids
- Placenta; hCG, sex steroids
- Kidney; Vit D3
- Adrenal cortex; corticosteroids (cor, cor)
16
Q
Describe the mechanism of action of steroid hormones
A
Cross plasma membrane easily, into and out of cells. Receptors are inside cells (cytoplasmic or nuclear receptors) and trigger either activation or repression of gene function within nucleus = genomic effect
Genes control synthesis of protein so hormones either inc or dec protein synthesis
Relatively slow process so lag time between hormone release and bio effect (hours to days) but effect persists
17
Q
Describe derivation of amine hormones
A
Most derived from tyrosine
There are Catecholamines which have similar mechanism of action to peptide hormones
- dopamine from brain
- NorAd from neurons
- epinephrine from adrenal medulla
There are Thyroid hormones which have similar mechanism of action to steroid hormones
- thyroxine
- trilodothyronine
ONLY amine hormone derived from tryptophan is melatonin (regulates circadian rhythm)
18
Q
Describe presence of lipophilic hormones in blood
A
Small amount unbound free steroid/thyroid hormone in plasma - this is the physiologically important fraction
ONLY free hormone can diffuse across cap wall to target cells
free hormone; hormone-protein complex ratio favours bound (complexed) hormone
Typically only minute quantities of homrone required for function
19
Q
What does the Law of Mass Action dictate?
A
as free hormone leaves the plasma (taken up by cells) more hormone is released from carriers
20
Q
Describe total plasma hormone
A
TPH = free hormone + complexed hormone
21
Q
Describe hormone carrier proteins
A
- specific (corticosteroid-binding globulin)
- non-specific (albumin)
These increase solubility req for blood-mediated transport and protect from degradation (increased half-life)
22
Q
Describe hormone metabolism and excretion
A
Hormone in blood depends on secretion and removal rates
Removal by excretion or metabolic transformation, mainly occurs in liver & kidneys
Generally catecholamine and peptide hormones excreted easily so short half life in plasma (mins to hours)
Steroids and thyroid hormones take hours/days to excrete/metabolise bc protein bound
23
Q
Describe control of hormone secretion
A
- most endocrine pathways respond to -ve feedback reflexes i.e. parathyroid hormone
- some respond to neural feedback loops e.g. adrenaline
- secretion some hormones can be subject to multiple control mechanisms i.e. insulin
Other factors
- hormones can influence ability of target cells to respond by regulating number of hormone receptors
24
Q
How do hormones regulate the number of hormone receptors?
A
- After prolonged exposure to low plasma hormone, there is up-reg so inc of hormone receptors in target tissues (increasing tissue sensitivity to hormone)
- After prolonged exposure to high plasma hormone there is down-reg so dec hormone receptors in target tissues (decreasing tissue sensitivity to hormone)
May affect not only hormone’s own receptors but also receptors for other hormones (permissive or antagonistic effects)
25
Describe permissive effects of hormones
Presence of one hormone enhances effect of another
e.g. epinephrine causes only modest lipolysis in adipose tissue, but when thyroid hormone is also present increased lipolysis occurs
TH causes increased synthesis receptors for epinephrine on adipocytes
TH itself has no effect on lipolysis but is PERMISSIVE to epinephrine
26
Why might 24 hour hormone monitoring be a more accurate representation of hormone levels?
Most hormones released in short burst so levels vary
single values may be misleading so 24 hour monitoring give true picture
27
What connects the hypothalamus and pituitary?
A stalk called the infundibulum
28
Describe hypothalamic communication with pituitary gland
Both neural (to posterior pituitary) and endocrine (to anterior pituitary) hence neuroendocrine function
29
What role do the hypothalamus and pituitary play in the endocrine system?
They are the principal organisers
30
Describe the anatomy of the hypothalamus
Integration centre for endocrine systems
Located at base of brain, below thalamus
Connected to pituitary via infundibulum stalk
31
Describe the anatomy of the pituitary
Bean-shaped and bean-sized endocrine gland (~14mm diameter)
Located in pocket in the sphenoid bone, directly below hypothalamus
Contains 2 distinct types tissue - anterior and posterior pituitary
32
Describe hypothalamic-pituitary hormones
Both hypothalamus and anterior pituitary release tropic and non-tropic hormones (tropic hormones govern release of another hormone)
All hormones released by hypothalamus are neurohormones
All hormones released by posterior pituitary are neurohormones (from hypothalamus)
All hormones released by anterior pituitary are classic endocrine hormones
33
Describe hypothalamic neurohormones
two forms
- tropic; neurohormones secreted into capillaries travelling to ant pituitary, govern release ant pituitary hormones
- non-tropic; neurohormones produced in hypothalamus and travel to post pituitary (via axons of hypothalamic neurons) where they are released into blood
34
Describe hypothalamic hormones to AP
All tropic bind to AP and stimulate AP hormone release
At least 5 hypothalamic releasing hormones
- Thyrotropin Releasing Hormone (TRH)
- Corticotropin Releasing Hormone (CRH)
- Growth Hormone Releasing Hormone (GHRH)
- Prolactin Releasing Hormone (PRH)
- Gonadotropin Releasing Hormone (GnRH)
2 hypothalamic inhibiting hormones
- Growth Hormone Inhibiting Hormone (GHIH) aka somatostatin
- Dopamine aka Prolactin Inhibiting Hormone (PIH)
All are peptides except dopamine
35
Describe the hypothalamo-hypophyseal portal system
Network of tiny vessels which transfer tropic hormones from hypothalamus to AP
Small numbers neurosecretory neurons sufficient for control
Hormones released from neurosecretory neurons at median eminence
Very small amounts required
Short distance - very rapid and dynamic
36
Describe the anterior pituitary gland
- True endocrine tissue
- epithelial origin
- connected to hypothalamus via hypothalamic-hypophyseal portal system (two cap beds conn in series)
- also called adenohypophysis
- makes up 2/3rds of gland
Hypothalamus produces releasing or inhibiting tropic hormones which stim or inhibit hormone production from AP
6 hormones are released from AP, all peptides. 5 of these also tropic hormones
37
Describe the posterior pituitary gland
- neuroendocrine tissue
- neural tissue origin
- neural connection to hypothalamus
- secretes neurohormones made in hypothalamus
- also called neyrohypophysis
- makes up 1/3 of gland
38
What are the AP hormones?
1. Thyroid Stimulating Hormone (TSH) aka thyrotropin
2. Adrenocorticotrophic Hormone (ACTH) aka corticotropin
3. Follicle Stim Hormone (FSH) aka gonadotropin
4. Luteinising Hormone (LH) aka gonadotropin
5. Growth Hormone (GH)
6. Prolactin
1-5 control secretion of other endocrine glands and have direct/indirect effects in promoting growth = tropic hormones
Prolactin directly stimulates milk production during lactation
39
Describe AP feedback control
complex, multi-tiered pathways involving up to 3 integration centres
1) hypothalamus 2) AP 3) target endocrine cell
hormones act as -ve feedback signal - each hormone feeds back to inhibit hormone secretion by integrating centres earlier in the reflex
feedback from endocrine target = long-loop feedback
feedback from AP to hyp = short-loop feedback
40
Describe the PP hormones
Stores and releases 2 peptide neurohormones
- vasopressin aka ADH
- oxytocin
these are synthesised in magnocellular neurons which have cell bodies in specific areas hypothalamus
diff subsets make either vasopressin or oxytocin
axons project down infundibulum to PP
DO NOT synapse with other neurons, terminals end directly on capillaries
hormones synthesised in hyp and transported to nerve terminal in PP for release
activity in these neurons results in vasopressin/oxytocin into bloodstream directly at PP
41
Describe vasopressin
aka ADH
Main function; regulates water balance
Triggered by; inc plasma osmolarity, dec plasma vol/BP
Site/mode of action;
- kidney collecting ducts; inc water reabsorption
- vasc smooth muscle; inc BP
42
Describe oxytocin
Main function; milk ejection and uterine contraction
Triggered by; labour (baby's head against cervix), suckling
Site/mode of action;
- milk duct smooth muscle; contracts muscle ejecting milk
- uterine smooth muscle; child birth
43
What are the classifications of endocrine disorders?
Hyposecretion; too little hormone
Hypersecretion; too much hormone
Hyporesponsiveness; reduced target cell response, relates to altered receptor, disordered post-receptor events or failure metabolic activation hormone
Hyperresponsiveness; increased target cell response, could be due to permissive effects
1º disorders; defect is in cells secreting the hormone
2º disorders; defect is too little or too much trophic hormone from pituitary
3º disorders; relate to hypothalamic defects
44
How is energy intake from food determined?
By activity balance in 2 hypothalamic centres;
- Feeding centre; promotes feelings hunger and drive to eat
- Satiety centre; promotes feelings fullness by suppressing feeding centre
Activity in each controlled by complex balance neural and chemical signs as well as nutrients in plasma. Obesity results from obstruction of these pathways
45
What is glucostatic theory?
food intake is determined by blood glucose;
- as blood glucose increases, drive to eat decreases (-Feeding centre, +satiety centre)
46
What is lipostatic theory?
food intake is determined by fat stores;
- as fat stores increase, drive to eat decreases (-feeding centre, +satiety centre). Leptin is a peptide hormone released by fat stores which represses feeding activity
47
What are the three categories of energy output?
- Cellular work; transporting molecules across membranes, growth and repair, storage of energy e.g. fat, glycogen
- Mechanical work; movement, either large scale with muscles or intracellularly
- Heat loss; assoc with cellular and mechanical work, accounts for half energy output
THE ONLY part of energy output we can regulate voluntarily is mechanical work by skeletal muscle
48
What is metabolism?
integration of all biochemical reactions in the body
49
What are the elements of metabolism?
1. Extracting energy from nutrients in food
2. Storing that energy
3. Utilising that energy fro work
50
What are anabolic pathways?
Build up
Net effect is synthesis of large molecules from smaller ones, usually for storage purposes
51
What are catabolic pathways?
Break down.
Net effect is degradation large molecules to smaller molecules, releasing energy for work
52
Describe the absorptive state
after eating, ingested nutrients supply the energy needs of the body and excess is stored
anabolic phase
53
Describe the post-absorptive state
aka; fasted state
between meals and overnight, pool of plasma nutrients decreases and we rely on body stores to provide energy
catabolic phase
54
The brain in post-absorptive state
Requires glucose for energy
maintain blood glucose by synthesising glucose from glycogen (glucogenolysis) or amino acids (gluconeogenesis)
Failure to do so results in hypoglycaemia --> coma and death
55
Normal blood glucose range
4. 2-6.3 mM (80-120mg/dl)
| * 5 mMoles useful to remember
56
Endocrine pancreas
Only 1% pancreatic function; Islets of Langerhans
4 types islet cells
- alpha produce glucagon
- beta produce insulin
- delta produce somatostatin
- F cells produce pancreatic polypeptide
57
What does blood glucose control depend on?
Insulin/glucagon balance
- in fed state insulin dominates to absorb glucose from plasma
- in fasted state glucagon dominates to produce glucose from stores
58
How is insulin synthesised?
Insulin is peptide hormone produced pancreatic beta cells. Synthesised as preproinsulin, converted to proinsulin in ER.
Proinsulin packaged as granules in secretory vesicles. In the granules, cleaved to give insulin and C-peptide. Stored in this form until B cell activated and secretion occurs.
59
How is excess glucose stored?
As glycogen in liver & TAG in liver and adipose tissue
60
Describe the mechanism of control of insulin secretion by blood glucose concentration
Beta cells have a specific type of K ion channel sensitive to the ATP conc in the cell
When glucose abundance it enters cells via GLUT transporter proteins and metabolism increases. Increase in ATP inside cell causes K ion channel to close. Intracellular K rises, depolarising cell. Voltage-gated Ca channels open and trigger insulin vesicle exocytosis into circulation
61
Describe the primary action of insulin
Binds to tyrosine kinase receptors on cell membrane of insulin-sensitive tissues (muscle and adipose tissue) to increase glucose uptake by these tissues
Insulin stims the mobilisation of specific glucose transporters (GLUT4) which reside in cytoplasm of muscle and adipose cells
When stim by insulin GLUT4 migrates to membrane and transports glucose into cell. When insulin stim stops, GLUT4 returns to cytoplasmic pool
62
What proportion of body do muscle and fat make up?
Muscle ~40% and fat ~20-25% (normally)
Therefore very large proportion of body DEPENDENT on insulin for glucose uptake
63
What glucose transporters are not insulin dependent?
GLUT1; basal glucose uptake in many tissues i.e. brain, kidney, RBCs
GLUT3; similar
GLUT2; beta cells of pancreas and liver
64
Describe liver glucose uptake
NOT insulin dependent
Uptake by GLUT2 transporters. Enters down conc gradient.
Although insulin has no direct effect on liver, glucose transport into hepatocytes is affected by insulin status.
- fed state liver takes up glucose bc insulin activates hexokinase which lowers Glc conc by converting it to glucose-6-phosphate, creating conc gradient favouring entry into hepatocytes
- fasted state liver synthesises glucose increasing Glc conc, creating gradient favouring glucose movement into blood
65
What are the additional actions of glucose?
1. Increases glycogen synthesis in muscle and liver (stimulates glycogen synthase, inhibits glycogen phosphorylase)
2. Increases AA uptake into muscle, promoting protein synthesis
3. Increases protein synthesis and inhibits proteolysis
4. Increases TAG synthesis in adipocytes and liver (stimulates lipogenesis and inhibits lipolysis)
5. Inhibits enxymes of gluconeogenesis in liver
6. Has permissive effect on GH
7. Promotes K ion entry into cells by stim NA/KATPase
66
Where is insulin degraded?
Primarily in liver and kidneys
Half-life ~5mins
67
How are insulin receptors removed?
Once insulin action complete, insulin bound receptors internalised by endocytosis and destroyed by insulin proteas
Some recycled
68
Describe stimuli which increase insulin release
1. Inc blood glucose
2. Increased plasma AAs
3. Glucagon
4. Other (incretin) hormones controlling GI secretion and motiliy i.e. gastrin, CCK
5. Vagal nerve activity (stim GI hormone release, thus also insulin)
69
Describe stimuli which inhibit insulin release
1. Low blood glucose
2. Somatostatin
3. Sympathetic alpha2 effects
4. Stress e.g. hypoxia
70
Describe glucagon
Peptide hormone produced by alpha cells in pancreatic islets
Primary purpose to raise blood glucose
It is a glucose-mobilising hormone, acting mainly on the liver
Plasma half-life ~5-10mins
Degraded mainly by liver
71
Describe actions of Glucagon
Primarily opposes insulin action. Most active in fasted state.
Glucagon receptors are G protein coupled, linked to cAMP system. When activated phosphorylate specific liver enzymes resulting in;
- increased glycogenolysis
- increased gluconeogenesis
- formation ketones from FAs
All processed occur in liver, net result is elevated blood glucose
72
Which hormones are part of the glucose counter-regulatory control system?
glucagon
cortisol
epinephrine
growth hormone
73
Describe glucagon secretion (generally)
relatively constant
increases dramatically when BG< 5.6 mM
ratio to insulin more significant than actual concentration
AAs are potent stimulus for secretion
74
Describe stimuli promoting glucagon release
1. Low BG
2. High AAs
3. Symp innervation and epinephrine, beta2 effect
4. cortisol
5. stress e.g. exercise, infection
75
Describe stimuli inhibiting glucagon release
1. Glucose
2. FFAs and ketones
3. Insulin
4. Somatostatin
76
Describe ANS innervation of islet cells
generally
- inc parasymp vagus leads to inc insulin and lesser extent inc glucagon
- inc symp promotes glucose mobilisation leading to inc glucagon and epinephrine, inhibition of insulin
77
Describe the basic normal Glc metabolism pathway
inc glucose --> inc insulin --> inc glucose uptake by cells --> dec glucose in serum
78
Describe somatostatin (SS)
Peptide hormone, secrete by D-cells of pancreas (and hypothalamus aka GHIH)
Main pancreatic function is to inhibit activity in GI tract
- slow down nutrient absorption to prevent exaggerated peaks in plasma concentration
Is not counter-regulatory in control of blood Glc but does strongly suppress release of both insulin and glucagon in a paracrine fashion
Patients with pancreatic SS secreting tumours develop symptoms diabetes which disappear when tumour removed
Synthetic SS can be used to treat life-threatening diarrhoea assoc w/gut or pancreatic tumours
79
Describe the effect of exercise on blood Glc
Entry Glc into skeletal muscle inc during exercise, even in absence insulin, as GLUT4 can migrate to membrane without insulin being present
Exercise also inc insulin sensitivity of muscle, causes inc in number GLUT4 transporters into muscle membrane
Effect persists several hours after exercise and reg exercise can produce prolonged inc insulin sensitivity
80
What happens in starvation?
Nutrients scarce, body relies on stores
Adipose tissue broken down to FAs. FFAs can be used by most tissues for energy.
Liver converts excess to ketone bodies which provide additional energy source for muscle and brain
*after period starvation, brain adapts to be able to use ketones
This spares protein to avoid extreme weakening and vulnerability to infection. It is the last store to be depleted in starvation
81
Describe ketoacidosis
Build-up of ketones in plasma. As they are acidic plasma pH < 7.1
Death will occur within hours if untreated.
In poorly controlled insulin-dependent diabetes, lack of insulin depresses ketone body uptake which can lead to ketoacidosis
82
Describe assessment tools for growth and pubertal development
- height/length/weight
- growth charts and plotting
- MPH and Target centiles
- growth velocity
bone age
pubertal assessment
83
What are the most important pubertal stages?
- breast budding (tanner stage B2) in girl
| - testicular enlargement (Tanner stage G2, T 3-4ml) in boy
84
Indications for referral for growth disorders
- extreme short or tall stature (off centiles)
- height below target height
- abnormal height velocity (crossing centiles)
- history of chronic disease
- obvious dysmorphic syndrome
- early/late puberty
85
Describe Mid Parental Height
Must remember for a girl to plot the mother, and the father 15cm shorted
For a boy plot the father and the mother 15cm taller
86
What are the Tanner stages of puberty?
- B 1 to 5 (breast development)
- G 1 to 5 (genital development)
- PH 1 to 5 (pubic hair)
- AH 1 to 3 (axillary hair)
- T 2ml to 20ml
87
How is testicular maturation measured?
Prader Orchidometer
Major male growth spurt occurs at testicular volume 10ml
88
What factors influence height?
Age, sex, race, nutrition, parental height, puberty, skeletal maturity, gen health, specific growth disorders, socio-economic stautus, emotional well-being
89
Describe constitutional delay of Growth and Puberty
Boys mainly
FH in dad or brothers
Bone age delay
Need exclude organic disease
90
What are some syndromes that can cause obesity?
Prader Willi syndrome
Laurence-Moon-Biedl Syndrome
Pseudohypoparathyroidism type 1
Down's Syndrome
91
How is growth regulated?
1. Balance of GHRH and GHIH from hypothalamus
2. Thyroid hormones
3. Insulin
4. Sex steroids (esp at puberty)
5. Availability of nutrients
6. Stress
7. Genetics
92
Describe growth hormone
peptide hormone released from AP aka somatotropin
GH release controlled by two hypothalamic neurohormones
- Somatostatin (GHIH)
- GHRH
The balance of these is determined by a myriad of factors which impinge on hypothalamus
Actions;
- Growth and development (indirect)
- regulation of metabolism (direct action)
93
Describe GH and growth & development
Growth first 8-10months largely controlled by nutrition, but after this GH dominant influence
GH req permissive action thyroid hormones and insulin before stim growth
Secretion continue through adult life for maintenance and repair of tissue
GH effect on growth almost entirely indirect, achieved through an intermediate; insulin-like growth factor I (IGF-1) aka somatomedin C
IGF-1 secreted by liver (and others) in response to GH release and controls GH release through -ve feedback
GH and IGF-1 are transported via carrier proteins
94
Describe GH/IGF-1 effects on bone growth
1. GH stim chondrocyte precursor cells (prechondrocytes) in epiphyseal plates to differentiate into chondrocytes
2. During differentiation, cells begin to excrete IGF-1 and become responsive to IGF-1
3. IGF-1 then acts as autocrine/paracrine agent to stim differentiating chondrocytes to undergo cell division and produce cartilage (foundation for bone growth)
95
Describe the direct effects of GH
Regulation of metabolism
1. Inc gluconeogenesis by liver
2. Reduces ability insulin to stim glucose uptake by muscle and adipose tissue
3. Makes adipocytes more sensitive to lipolytic stimuli
(all above are energy releasing - like cortisol)
4. Increases muscle, liver, adipose tissue AA uptake and protein synthesis
(like insulin rather than cortisol)
96
Describe GH release
Large quantities present pituitary both adults & children, highest rate secretion teenage years
Secretion rate rapid spontaneous fluctuations and inc or dec in response to stimuli
Majority GH releases during first 2hrs sleep; 20x GH release in children during this time . Gen energy req low so energy diverted to growth
97
Describe control of GH release
Influenced by nutritional status, mainly mediated via modulation of GHRH/GHIH release from hypothalamus
Stimuli that inc GHRH secretion, inc GH secretion
- Actual or potential dec in energy supplied to cells
- inc AA in plasma
- Stressful stimuli e.g. infection
- Delta sleep
- Oestrogen and androgens
Stimuli that inc GHIH secretion, dec GH secretion
- Glucose
- FFA
- REM sleep
- Cortisol
98
What are the periods of rapid growth in humans?
1. Infancy
- spurts 2.5cm in a few days then nothing
- episodic, mechanism unknown
2. Puberty
- due to androgens and oestrogens
- produce spikes in GH secretion that in IGF-1 so inc growth
- same hormones also terminate growth by causing fusion epiphyses of long bones
99
Describe effects of hypersecretion GH
Endocrine tumours usually the cause
Gigantism; XS GH due to pituitary tumour before epiphyseal plates of long bones close
Acromegaly; XS GH due to pituitary tumour after epiphyseal plates have sealed - no longitudinal growth but characteristic large hands and feet
100
Describe the role of calcium in the body
1. Signalling; exocytosis synaptic vesicles e.g. NTs/hormones
2. Blood clotting; essential component
3. Apoptosis
4. Skeletal strength; 99% wrapped up in bone
5. Membrane excitability; Ca dec Na permeability
* 5 = most critical in ST homeostasis
101
How does Ca affect membrane excitability?
Hypocalcaemia
- inc Na permeability leading to hyperexcitation
- in extreme situations causes tetany
Hypercalcaemia
- dec Na permeability, reducing excitability and depressing neuromuscular activity
- extreme cases trigger cardiac arrythmias
102
Describe calcium distribution in the body
Bones 99%
Intracellular 0.9%; mostly stored in mitochondria and sarcoplasmic reticulum
ECF 0.1%; nearly half bound to protein
only 0.05% calcium in body is free in solution and physiologically active
103
What effect does pH have on Ca binding?
Binding capacity plasma proteins changes with pH
Alkalinity = increased binding so free plasma Ca falls
Acidity = reduced binding so free plasma Ca rises
104
Describe endocrine control of Ca homeostasis
Two key hormones inc plasma Ca
- parathyroid hormone (PTH)
- calcitriol (active form vit d3)
One hormone acts dec plasma Ca
- calcitonin; bind to osteoclasts and inhibit bone resorption and inc renal secretion
105
Describe action of PTH
Released response to red free plasma Ca
1. Stim osteoclasts to inc resorption Ca and phosphate in bone
2. inhibit osteoblasts
3. Increasing reabsorption Ca from kidney tubules, dec excretion in urine
4. Inc renal excretion phosphate, elevates free Ca by preventing deposition back into bone (req phosphate)
5. Stim kidney to synthesis calcitriol from Vit D - promote Ca absorption at gut and kidney
106
Describe action of calcitriol
Complements action of PTH; inc plasma Ca
Steroid hormone produced in two steps from dietary vit d or from cholesterol derivatives as a result UV light on skin
1. Increase Ca absorption from gut
2. Facilitate renal absorption Ca
3. Mobilises Ca stores in bone by stim osteoclast activity
107
Other endocrine hormones affecting Ca balance
1. Cortisol
2. Insulin
3. Oestrogen
4. GH
5. Prolactin
108
Where do the adrenal veins drain?
Left --> left renal vein
| Right --> directly into IVC
109
Describe the anatomy of the adrenal gland
two separate endocrine glands, rolled into one structure
Adrenal medulla (25%);
- modified sympathetic ganglion, derived neural crest tissue
- Secretes catecholamines (mainly epinephrine, also norAd, and dopamine)
Adrenal cortex (75%);
- true endocrine gland derived from mesoderm
- secretes 3 classes steroid hormones; mineralocorticoids e.g. aldosterone, Glucocorticoids e.g. cortisol, androgens e.g. testosterone
110
What are the 3 zones of the cortex and what do they produce?
- Zona glomerulosa; mineralocorticoids e.g. aldosterone
- Zona fasciculata; glucocorticoids e.g. cortisol
- Zona reticularis; androgens e.g. testosterone
111
Describe cortisol
A glucocorticoid hormone (influences glucose metabolism)
95% bound to a carrier protein, cortisol binding globulin
All nucleated cells have cytoplasmic glucocorticoid receptors
Hormone receptor complex migrates to nucleus, binding to DNA via hormone-response element to alter gene expression, transcription and translation
has permissive action on glucagon, vital to protecting brain from hypoglycaemia
112
Describe cortisol release
Characteristic pattern
marked circadian rhythm, preceded by similar pattern release of ACTH
Peak 6-9am, nadir around midnight
113
Action of cortisol on glucose metabolism (glucocorticoid actions)
1. Gluconeogenseis; stim formation gluconeogenic enzymes in liver
2. Proteolysis; stim breakdown muscle protein to provide gluconeogenic substrates for liver
3. Lipolysis; stim lipolysis in adipose tissue increasing plasma FFA, alternative fuel supply
4. Decreases insulin sensitivity of muscles and adipose tissue
* acts to oppose insulin
114
Additional actions of cortisol
1. -ve effect on Ca balance; dec absorption from gut, inc excretion at kidney, inc bone resorption
2. Impairment mood and cognition; depression and impaired cognitive function strongly assoc w/hypercortisolaemia
3. permissive effect on NorAd; esp in vasc smooth muscle
4. Suppression of immune system; reduces circulating lymphocyte count
115
Describe action of aldosterone
Mineralocorticoid - acts on distal tubule of kidney to determine mineral levels absorbed/excreted
Increases reabsorption Na ions, promotes excretion K ions
end effect of its release
- increased aldosterone stim Na (and H2O) retention and K depletion resulting in inc blood vol and inc blood pressure
- decreased aldosterone leads to Na (and H2O) loss and inc plasma K, diminished blood volume and dec blood pressure
116
Describe secretion of aldosterone
Adrenal cortex
| - primarily controlled by complex reflex path originating in kidney (renin-angiotensin-aldosterone system)
117
Describe hypersecretion of cortisol
Cushing's syndrome
- hypersecretion due to a tumour in adrenal cortex; 1° hypercortisolism
Cushing's disease
- hypersecretion due to tumour in pituitary gland 2° hypercortisolism (most common)
118
Describe hyposecretion of cortisol
Much less common than hypersecretion
Addison's disease
- hyposecretion all adrenal steroid hormones
- due to autoimmune destruction adrenal cortex
119
What is the HPA axis?
Hypothalamo-Pituitary-Adrenal axis
120
Describe the adrenal medullla
Modified sympathetic ganglion
- not true endocrine tissue
- similar to PP in having neuroendocrine role
Pre-ganglionic symp fibres terminate on special post-ganglionic cells in adrenal medulla
- do not have axons, insteade release neurohormones (adrenaline) directly into blodo
121
What are the physiologically active forms of thyroid hormones?
- T3; triiodothyronine
| - T4; thyroxine
122
What cell types are present in the thyroid gland?
C cells
- secrete calcitonin (Ca regulating hormone)
Follicular cells
- surround hollow follicles
- manufacture enzymes that make thyroid hormones and also thyroglobulin (protein rich in tyrosine residues)
- enzymes and thyroglobulin packaged into vesicles, exported into colloid
- actively concentrate iodide from plasma, transport to colloid
*in colloid iodide and tyrosine residues combine to form thyroid hormones
123
What are thyroid follicles?
spherical structures
walls made of follicular cells
Centre filled with colloid (stick glycoprotein matrix)
Contain 2-3mnth supply TH
124
What are thyroid hormones made from?
Iodide and tyrosine residues
reaction catalysed by thyroid peroxidase (apical membrane follicular cells)
125
How does iodide enter follicular cells and colloid?
Obtained from diet
enters follicular cells from plasma via Na/I transporter (symport)
Coupling Na enables follicular cells to take up iodide against conc gradient
then enters colloid via pendrin transporter
INHIBITED by thiocyanates, compounds formed from detoxification of cyanide; common origin cigarette smoke
126
Describe the role of thyroid peroxidase
enzyme exocytosed into colloid, catalyses addition of iodide to tyrosine (located on thyroglobulin)
Adding one iodide
- Monoiodotyrosine MIT
Adding a second
- Diiodotyrosine DIT
MIT and DIT undergo reactions to form T3 or T4
127
Describe how TSH affects thyroid
In response to TSH, portions colloid taken back up into follicular cell by endocytosis
Within cells form vesicles contain proteolytic enzymes that cut the thyroglobulin to release thyroid hormones
128
Describe T3 and T4 in the blood
Both lipid soluble so pass across follicular membrane into plasma, bind to plasma proteins (mainly thyroxine-binding globulin)
Circulate in plasma
T4 longer half life due to affinity for binding protein ~6days
T3 half life ~1day
Only free hormone will inhibit TSH and TRH
129
T3 vs T4
Most TH is protein bound T4
50x more total (free+bound) T4 than T3
But 90% TH binding to receptors is T3 as lower affinity for plasma protein
T3 thus more physiologically active
130
Describe deiodination
T3 can be deiodinated to T3 by deiodinase enzymes
Around half T4 deiodinated in plasma, remainder in target cells
Level deiodinase activity can be altered at diff times to suit demand
131
Describe thyroid hormone function
Bind to nuclear receptors in target cells, change transcription
- raises met rate and promotes thermogenesis
- increases hepatic gluconeogenesis
- net inc in proteolysis
- net inc in lipolysis
- critical for growth (anabolic and stim GH receptor expression)
- req for foetal brain development (deficiency = congenital hypothyroidism; can be caused iodine deficiency in mother)
132
Causes of hyperthyroidism
Graves Disease
- common
- antibodies produced that mimic TSH and continuously activate thyroid gland
- inc release TH switches off TSH release from AP so plasma TSH v low
- thyroid 2-3x normal size due to hyperplasia
Thyroid Adenoma
- rare
- hormone-secreting thyroid tumour
133
Symptoms of hyperthyroidism
- inc metabolic rate and ehat production; weight loss/heat intolerance
- inc protein catabolism; muscle weakness, weight loss
- altered NS function; hyperexcitable reflexes and psychological disturbances
- elevated CV function (TH permissive to epinephrine); inc HR/contractile force, high output, cardiac failure
134
Causes of hypothyroidism
Hashimoto's Disease
- autoimmune attack of thyroid gland
Dietary iodine deficiency
Idiopathic
135
Symptoms of hypothyroidism
- dec met rate and heat production; weight gain, cold intolerance
- disrupted protein synthesis; brittle nails, thin skin
- Altered NS function; slow speech/reflexes, fatigue
- reduced CV function; slow HR, weaker pulse
136
Multifactorial aetiology of autoimmune endocrine disorders
```
Genetic factors
Immune regulatory factors
Hormonal factors
Environmental factors
'other factors'
```
137
Multifactorial pathology of autoimmune endocrine disorders
```
Antibody mediated
Cell mediated
Complement mediated
Phagocytes, cytokines, NKCs etc.
Combos of above
```
138
What HLA molecules are aberrant in endocrine autoimmune disorders?
Class II HLA molecules
- HLA-DR
- HLA-DP
- HLA-DQ
expressed on the cells of the organs and raising the possibility that they will present self-antigens to T-helper cells in an abnormal and unregulated fashion
*class II molecules are usually only present on a very specific, restricted range of professional antigen presenting cells i.e. dendritic cells, monocytes, macrophages etc.
139
How does aberrant HLA expression affect autoimmunity?
1. May act as receptors for aetiological agents
2. Influence on defective tolerance induction / +ve selection of autoreactive T cell clones
3. Through structural similarity between HLA molecules and aetiological agents (molecular mimicry)
140
Endocrine cell autoimmune reactions
Thyroid
- TSH (Grave's)
- Anti-thyroid peroxidase antibodies and anti-thyroglobulin antibodies (Hashimoto's, myxoedema)
Pancreas
- IDDM
Steroid cell
- gonadal insufficiency
Gastrin cells
- Type A gastritis most commonly affecting body/fundus
141
Hormone autoimmune reactions
Insulin
- insulin reactions
- insulin resistance
142
Target cell autoimmune reactions
Insulin
- insulin resistance
TSH
- Grave's
- myxoedema
Gastrin
- pernicious anaemia (type A gastritis)
143
How does the level of circulating 1,25(OH)2D3 affect dietary calcium absorption?
In healthy individuals, circulating calcitriol is normal and Ca absorbed is 30%
Vit-D deficient = low calcitriol, Ca absorbed 10-15%
In pregnancy/lactation/growth spurts there is high calcitriol, Ca absorbed 45-55%
144
Describe Vit D deficiency
circulating Vit D <20ng/ml
leads to intestinal malabsorption of Ca, reducing plasma [Ca], increasing PTH
This aggravates loss from bone resulting in weak, brittle bones; rickets in chidren, osteomalacia in adults
Vit D3 deficiency implicated in MS, cancer, arthritis, CVD
145
Describe 21-hydroxylase
Enzyme in pathway for production of aldosterone and cortisol
Defective 21-hydroxylase can is a common cause of congenital adrenal hyperplasia causing deficiency of aldosterone and cortisol, with associated disruption glucose salt balance
Androgen synthesis unaffected so accumulating steroid precursors channelled into making excess adrenal androgens
146
Thelarche
Breast budding
147
Menarche
Onset of periods aka menstruation
148
Adrenarche
Maturation adrenal zona reticulalris which releases androgens
149
Pubarche
Growth of pubic hair
*commonly early due to early onset of adrenarche
