Human Endocrinology Flashcards
1
Q
what is endocrinology?
A
study of hormones
2
Q
where is most (99%) of the total calcium in the body stored?
A
as calcium phosphate salts in bones.
3
Q
why is it important that cytoplasmic Ca2+ is very low? (around 0.1μM)
A
provides steep gradient for calcium entry from organelles or extracellular fluids
4
Q
features of Ca2+ in extracellular fluid
A
only about 0.1% of Ca2+, controlled very precisely (within 10% of 2.4mM)
5
Q
how is Ca2+ present in plasma found ?
A
40% combined with plasma proteins, 10% is combined with smaller anions (e.g. citrate and phosphate) 50% ionised.
6
Q
where does extracellular calcium bind?
A
fixed, negative charges on extracellular surface of plasma membranes, altering profile of potential gradient. across membrane without altering size of membrane potential. (surface charge screening)
7
Q
what is the use of surface charge screening with calcium?
A
stabilises the membranes of excitable cells, more difficult to open ion channels.
8
Q
what is Hypocalcaemia?
A
extracellular calcium levels drop to around 1.5mM, nervous system becomes progressively more excitable.
- tetanic contraction of muscles.
9
Q
what can servere hypocalcaemia lead to?
A
tetany of laryngeal muscles leading to asphyxiation
10
Q
what happens in hypercalcaemia
A
depression of nervous and muscular activity. Calcium salts can begin to precipitate out if levels rise higher than 3mM. e.g. calcium oxalate kidney stones
11
Q
what chemical messengers does calcium homeostasis involve?
A
parathyroid hormone [1,25(OH)2D] and calcitonin
12
Q
where does calcitonin and parathyroid hormone target?
A
- Gut (absorb more or less ca2+)
- Kidney ( modulate our rate of absorption)
- Bone (change balance between erosion and deposition)
13
Q
what can present challenges to calcium homeostasis?
A
pregnancy and lactation, egg-laying, poor absorption (vitamin D3 deficiency) and oxalate poisoning
14
Q
where is parathyroid hormone (PTH) secreted from and where is this located?
A
parathyroid glands, 4 glands located behind the thyroid.
15
Q
pattern of PTH release
A
circadian rhythm, released in pulses.
innervated by autonomic nerves, helps modulate rhythms
16
Q
how many amino acids are in the polypeptides
A
84
17
Q
what is the only significant external stimulus to promote increased PTH release?
A
decrease in plasma free calcium levels. (low internal calcium levels promotes vesicular release)
18
Q
what kind of receptors respond to PTH and where are they located?
A
G(q)-protein linked and located on plasma membrane
19
Q
what is the response to increased free calcium levels in the plasma?
A
increase internal calcium levels.
20
Q
how does PTH work on the bone, kidney and gut to increase Ca2+ levels? (general)
A
negative feedback system to increase plasma calcium levels.
gut via Vitamin D3
21
Q
what do osteoblasts do?
A
lay down organic matrix of bone, if they become trapped inside the bone = osteocytes.
both blasts and cytes connect to separate bone fluid (high in calcium and adjacent to bone surface) from ECF.
BOTH HAVE MEMBRANE BOUND PTH RECEPTORS.
22
Q
What is the matrix of the bone composed of? (and where is calcium involved)
A
collagen and proteoglycans. Calcium phosphate salts precipitate on collagen fibres, forming hydroxyapatite crystals.
23
Q
what are osteoclasts?
A
multinucleate cells that release proteolytic enzymes and acids to help digest and dissolve the bone for bone remodelling.
24
Q
what takes place in bone remodelling?
A
bone reabsorption by osteoCLASTS and deposition by osteoBLASTS.
25
what effects does PTH have on the bone?
```
osteocytic osteolysis (erosion of bone crystals by osteocytes) where Ca2+ released transfered to ECF.
- osteoblasts inhibited from laying down more bone and produce a paracrine signal stimulating osteoclasts to erode bone (and progenitor cells to differentiate into more osteoclasts)
```
26
how does PTH work on the kidney?
increases active reabsorption of calcium by Distal convoluted tubule (DCT)
- inhibits reabsorption of inorganic phosphate ions in PCT, lowering extracellular phosphate levels.
- stimulates synthesis of active vitamin D3 derivative.
27
why does PTH cause net phosphate loss despite phosphate absorption from gut and bone being increased?
overwhelmed by increased loss of phosphate in urine.
28
where is Vitamin D3 (cholecalciferol) sythnesised?
keratinocytes (specialised skin cells) from cholesterol. [requires exposure to UVB light]
29
how can Vitamin D3 be obtained in the diet?
from dairy products and fish liver oils. (or D2 from fungal sterol ergosterol)
30
what are liver stores of D3 used for?
maintain consistant level of 25-OHD in the plasma which circulates blood bound to a binding protein.
31
where is 25-OHD taken up?
proximal tubules of kidney, if. under influence of PTH converted to active form [1,25(OH)2D], otherwise converted into an inert form .
32
what are the roles of active 1,25(OH)2D mediated by and what is its main role? (active Vitamin D)
mediated by nuclear receptor, most important effect is to increase Ca2+ absorption from gastrointestinal tract.
[ also has minor roles in promoting bone dissolution]
33
what can a lack of dietary vitamin D3 cause?
children - rickets
| adults (after growth plates fuse) - osteomalacia.
34
where is calcitonin secreted from
C-cells (clear cells) in thyroid gland
| 32 amino acid polypeptide
35
what are the stimuli for calcitonin secretion?
increased plasma Ca2+ (main) and gastrin (helps with anticipatory response)
36
how does calcitonin reduce plasma ca2+ ?
rapidly inhibits absorption of bone by osteoclasts. (favours deposition)
37
what effect does calcitonin have?
stabilises Ca2+ homeostasis when turnover between plasma and bone is unusually high. e.g. growth or lactation.
38
what is somatotropin ?
Growth hormone (GH)
39
where is GH secreted from?
somatotrophs (make up 40% of anterior pituitary gland)
40
what is GH release stimulated by?
growth hormone releasing hormone (GHRH) form hypothalamus and ghrelin from the stomach.
41
what is GHRH inhibited by?
somatostatin. (GH promotes synthesis and release of ; short loop negative feedback)
42
what dies GHRH inhibit?
ITS OWN RELEASE ! (ultra short loop feedback)
43
how is GH found in plasma ad what is its half life?
bound to binding proteins, HL = 20 mins
44
characteristic of GH release
erratic pulses ( blood test won't tell u much about levels)
45
how do GH levels differ between men and women?
Men - large peak in early hours of sleep
women - more irregular but mean level higher then men.
(exercise and metabolic cues can also promote release)
46
GH levels pattern over a life time
high in childhood, peak at puberty and declining (but not zero) over period of adult life.
47
what receptors does GH activate?
membrane based receptors (pre-existing dimers).
48
what happens once GH activates a receptor?
receptor activates JAK-2 (janus kinase 2) ; enzyme in cytoplasm which phosphorylates tyrosine resides on proteins.
49
how is GH release affected by hypoglycaemia?
related in response to this and low free fatty acids levels (FFA levels) - can be seen in an overnight fast.
50
why is GH released due to hypoglycaemia and low FFA levels?
helps to preserve glucose for brain, switching metabolism of peripheral tissues to use of FFAs.
[EFFECTS ANTAGONISTIC TO INSULIN AND ANALOGUS TO CORTISOL]
51
GH Metabolic actions
- causes adipose to release FFAs
- stimulates hepatic gluconeogenesis and glucose output
- acts directly on insulin-sensitive target cells e.g muscles and adipocytes to inhibit glucose uptake (diabetogenic effect)
52
which amino acid in particular stimulates GH release?
arginine (but is released in response to high amino acid levels)
53
why is GH released in response to high aa?
promotes uptake of aa in muscles cells and chondrocytes (a cell which has secreted the matrix of cartilage and become embedded in it.) INCREASES RATE OF PROTEIN SYNTHESIS
- also promotes cellular growth and differentiation
54
what is the control of growth affected by?
many factors - genetic, environmental, gender.
| many permissive hormones needed (insulin and thyroid) [permissive as don't CAUSE growth but are NEEDED)
55
4 different types of dwarfism (deficiencies in growth)
- pituitary dwarfism
- dwarfism of Sindh
- Laron syndrome
- achondroplasia (most common , nothing to do with GH)
56
what can cause excess GH secretion as a child and what does this lead to?
over secretion from a pituitary tumour, causing gigantism.
57
what causes the extreme hight in gigantism?
overstimulation at growth plates of long bones (due to GH). if GH overstimulation occurs after growth plates fuse, height can not increase further (but periosteal bone growth continues)
58
what is acromegaly?
due to periosteal bone growth in gigantism. Anti-insulin effects may lead to form of diabetes.
59
which bones do growth hormones help control the growth of?
long bones (e.g. limbs)
60
how do growth hormones help growth of limbs
chondrocytes (stimulated by GH) lay down cartilage, which becomes calcified and ultimately ossified - allows bone to elongate in growth plate region.
61
life cycle of chondrocytes in growth plates of bones
proliferate, hypertrophy and die as cartilage around them calcifies.
62
zones of growth plate in long bones
resting zone, proliferative zone, hypertrophic zone and calcifying cartilage.
63
what hypothesis was founded after observing cartilage from rats when incubated with GH alone?
"somatomedin hypothesis"
64
what is the somatomedin hypothesis?
most actions of GH on growth are MEDIATED by INSULIN-LIKE GROWTH FACTOR 1 (IGF-1 = Somatomedin)
which is released by the liver in response to GH.
65
why are IGFs names like this?
structural similarity to proinsulin
66
how does IGF-1 work?
forms part of a negative feedback mechanism - increases somatostatin release by the hypothalamus therefore inhibits GH production by pituitary
67
levels of IGF-1 over a life time in plasma
increase with age, peaking at puberty and reducing during adulthood (same as GH)
68
how does IGF-1 circulate and what is its half life
bound to plasma binding proteins, (IGFBP1 and IGFBP6), half life of 20 hours (compared to 20 mins of GH)
69
what are the levels of IGF-1 binding proteins controlled by?
GH and insulin (hormonal control)
70
what challenges the somatomedin hypothesis?
- if liver derived IGF-1 is knocked out, body growth s normal (Sjogren et al, 1999)
- GH injection into growth plate stimulates growth in that growth plate alone, if repeated with IGF-1 removed, growth in that plate is not stimulated
71
what is "dual effector hypothesis" ? (came after somatomedin hypothesis)
suggests that IGF-1 is produced locally, under the influence of GH.
[GH stimulates chondrocytes from precursors in growth plate and also local formation if IGF-1 which driver further growth]
72
current theory of growth at growth plates in long bones
number of endocrine, paracrine and autocrat factors being implicated as promoting intracellular growth regulatory pathways.
73
what is used to dissociated between catabolic and anabolic effects of GH (fed vs fasting)
insulin - stimulating IGF-1 production by liver, reducing levels of some IGF binding proteins. (increasing free IGF-1)
- Thyroid hormone and fibroblast growth factor 21 (FGF21) also required.
74
what is the role of fibroblast growth factor 21 (FGF21) ?
released from liver when fasting, response to free fatty acid levels, promotes "growth hormone resistance" e.g. by reducing amount of IGF-1 produced in response to GH
75
a combination of which molecules is required to promote growth?
high GH, low FGF21, sufficient levels of insulin and thyroid hormone. (GH also promoted by high amino acid etc )
76
why isn't pituitary growth hormone (GH) required before birth? (in utero)
IGF-1 and IGF-2 regulated by other hormones; sommatomammotropins and insulin .
77
what are the 2 regions of the adrenal glands?
cortex and medulla. (blood flows through the cortex, draining into veins of medulla)
78
adrenal medulla mechanism for hormone release
stimulated by sympathetic preganglonic fibres, chromatin cells release CATECHOLAMINE hormones into circulation.
79
which part of adrenal gland is adrenaline made from and where? (and which enzyme)
made from noradrenaline by enzyme PNMT (in medulla of adrenal glands)
80
what kind of hormones does the adrenal cortex secrete?
corticosteroid hormones, synthesised by cholesterol.
81
in the human fetes , where in the adrenal gland is androgen DHEA synthesised?
fetal zone, once born the outer cortex expands to form 3 zones characteristic of adult gland
82
3 regions of adrenal cortex (from outer to inner)
Zona ; glomerulosa, fasciculata, reticularis (GFR)
| [remember it by GFR - glomerular filtrate rate, but not linked]
83
what does the zona glomerulosa secrete?
aldosterone (=mineralocorticoid due to plasma electrocyte effects)
84
aldosterone effects
acts on distal tubule of kidney (+sweat glands, salivary glands and gut) to promote reabsorption of Na+ and secretion of K+
[ also promotes secretion of type A intercalated cells of kidney]
85
factors increasing aldosterone secretion
increased plasma potassium ion conc and angiotensin II .
| ACTH is also a permissive factor. (deficiency in aldosterone without it)
86
what does the bona fasciculata secrete?
glucocorticoids (increase blood sugar levels) e.g. cortisol
87
what is secreted in place of cortisol in some other animals? (e.g. rats)
Corticosterone.
88
what does the zona reticularis secrete
"weak androgens " e.g. DHEA (dehydroepiandrosterone)
89
how do weak adrogens affect males and females?
- no significance in males as testes secrete large amounts of strong androgen TESTOSTERONE.
- account for ~50% of circulating androgens in women.
90
importance of weak androgens in women
converted into testosterone and 5-alpha-DHT which are responsible for pubic and axillary hair.
- also promote sexual behaviour and libido in women.
91
what is the role of pro-opiomelanocortin (POMC) located in the corticotrophs of the anterior pituitary ?
protein precursor from which polypeptide hormones can be cleaved. e.g. Beta-endorphin and melanocyte stimulating hormone (MSH) [associated with colour change in vertebrates]
92
where is ACTH (adrenocortiocotrophic hormone) derived from? (39 amino acid polypeptide)
POMC (in anterior pituitary)
93
HPA (hypothalamic pituitary adrenal) axis mechanism to stimulate release of ACTH
hypothalamus releases corticotropin-releasing hormone (CRH) stimulating corticotrophs in anterior pituitary to release ACTH
94
what can augment ACTH release during times of stress?
ADH
95
what is the effect of ACTH on adrenal CORTEX?
stimulatory effect, increases size of cortical cells, needed for normal cortical function.
- Stimulates synthesis and secretion of CORTISOL
96
What molecules are used in negative feed back loops for HPA axis?
cortisol and ACTH
97
cortisol release pattern
pulses (follows pulsatile release of ACTH)
| - follows circadian rhythm, large surge in hours just before waking up.
98
how is cortisol transported around the body and what is its half life?
bound to cortisol binding globulin (GBG), half life = 70 mins
99
how does cortisol work? (steroid hormone )
binds to cytoplamsic receptor, moves to nucleus to regulate gene expression. (takes hours/days to have an effect)
100
what is physiological stress?
anticipation, justified or not, that a challenge to homeostasis looms
101
example of a stressor met my a specific endocrine response
hypocalcaemia and PTH
102
stages of "general adaptation syndrome' invoked by stressors
- ALARM REACTION; sympathetic response as well as HPA axis, Glucocorticoids released.
- RESISTANCE STAGE; homeostasis is restored (but can have different set points)
- STAGE OF EXHAUSTION; detrimental effects of chronic stress due to chronically elevated levels of glucocorticoids
103
what is the use of cortisol release in response to hypoglycaemia ?
has a glucocorticoid role, important in long term control
104
actions of cortisol in its glucocorticoid role
- breaks down muscle plasma proteins to be used in gluconeogenesis
- amino acids to glucose stimulated in liver (enzymes)
- inhibits glucose uptake by muscle and adipose tissue (conserving for brain)
- promotes FFA release from adipose tissue (directly and permissive as allows adrenaline and GH to have effect)
105
what can happen in humans with a deficiency in both GH and ACTH during strenuous exercise or starvation?
fatal hypoglycemia. - Cortisol therefore essential
106
how does cortisol affect the inflammatory process?
inhibits many components.
107
how does acute stress affect HPA axis?
early activation of some components of immune system but sustained HPA axis activation results in immunosuppression
108
other effects of cortisol (not glucocorticoid role or stress response)
- secreted by fatal adrenal gland for fatal maturation
- smooth muscle to respond to noradrenaline, adrenaline and angiotensin II
- affecting mood (jet lag circadian rhythm is set out of cortisol)
- suppress reproductive function
- inhibition of bone formation and college synthesis
109
why is it important that distal tubule cells express an enzyme that degrades cortisol? what can this enzyme be inhibited by?
- aldosterone receptor has some affinity for cortisol and cortisol is found in greater concentrations.
- Glycyrrhetinic acid inhibits it - found in liquorice root
(will cause you to reabsorb too much Na+, leading to hypertension.)
