Endocrinology Flashcards
Describe the affects of hypo and hypercalcaemia:
Hypocalcaemia: nervous system becomes more excitable as intracellular stores of Ca2+ are released in an attempt to increases blood Ca2+ levels. Muscles may also become tetanic.
Hypercalcaemia: leads to depression of nervous system and muscular activity. Ca2+ may precipitate out of blood as calcium oxalate kidney stones
Suggest when there may be a change to Ca2+ homeostasis?
- During pregnancy and lactation: huge loss of Ca2+ into milk (can lead to eclampsia)
- Egg-laying: Ca2+ deposited in spongy medullary bone to allow fast calcium mobilisation
- Poor absorption: due to low D3 or foods high in phylates which bind Ca2+ and prevent its absorption.
- Oxalate poisoning: Ca2+/oxalate compounds are excreted or crystallise to form kidney stones.
How is parathyroid release controlled?
- Low extracellular Ca2+ around chief cells in the PT gland leads to a reduction in binding of Ca2+ to Gq receptors
- Causes decreased intracellular calcium (opposite to normal)
- Increased PTH vesicle release (due to specialised SNARE proteins which are calcium inhibited)
- Also innervated by autonomic nerves so has a slight circadian rhythm.
How are Ca2+ bone stores controlled by PTH?
Balance between growth (by osteoblasts) and destruction (by osteoclasts)
- PTH promotes osteocytic osteolysis (erosion) of bone and inhibits osteoblasts from laying down new bone.
- Progenitor cells differentiate into osteoclasts.
- Positive feedback of osteoblasts on osteoclasts to cause further erosion.
Detail the effects of PTH on the kidneys
Fast response:
- Causes increased active reabsorption in the DCT of the kidney (insertion of TRVP5 and calbindin).
- Powerfully inhibits reabsorption of Pi ions in PCT to lower extracellular concentration.
- Loss of Pi from kidneys offsets increase from bone dissolution
Slower response:
- Activates vit D3 for intestinal absorption of Ca2+ (from 25-OHD to calcitriol)
How is vitamin D3 obtained and what are its roles?
- Obtained via synthesis from cholesterol in keratinocytes (when exposed to UVB) or in diet and stored in liver.
- Increases calcium absorption in gut: 25-OHD (calcitriol) acts as a nuclear receptor to upregulate the expression of apical Ca2+ channels; upregulate calbindin protein and upregulate Ca2+/ATPase and Ca2+/Na+ exchange pumps
What is calcitonin and what are its functions?
- Produced by C-cells in thyroid
- Works antagonistically against PTH (less powerful) to inhibit the absorption of bone
- Better to reduce PTH levels than increase calcitonin massively.
What are the consequences of low vitamin D levels?
- Poor Ca2+ absorption, leading to
weakened bones - Rickets results in children, osteomalacia (distorted bones) in adults. Osteoporosis also common.
Describe the general structure of the pituitary gland and how each section is controlled.
Anterior pituitary (adenohypophysis) = hormonally controlled:
- Hypothalamus (median eminence) secretes into the hypothalamic-hypophyseal portal vein to pituitary.
- Tertiary organ often involved to create axis of control (e.g. hypothalamus-pituitary-thyroid axis)
Posterior pituitary (neurohypophysis) = nervous control:
- Nervous control from hypothalamus
What are sommatomamotropins?
Body-breast-change
- Secreted by somatotrophs and inhibited by somatostatins (produced by δ-cells in pancreas)
- Mainly for metabolic control in pregnancy
What controls growth hormone release?
Primary control:
- Growth hormone releasing hormone (GHRH) from hypothalamus
- Ghrelin from stomach
Feedback Loops:
- Short-loop: GH promotes somatostatin release
- Ultra-short loop: GHRH inhibits its own release
Other factors:
- Sex: males release spike in early sleep; females more erratic
- Metabolism: fasting causes GH resistance as fibroblast growth factor (FGF21) levels high
How is growth hormone (GH) transported? How does it cause a response?
- Bound to binding protein with a 20min half life (even though water soluble)
- Binds to membrane based receptors. Tyrosine kinase linked and activated Janus kinase (JAK-2) enzymes to phosphorylate proteins.
- E.g. responsive cells produce insulin-like growth factors (IGFs)
What are some permissive factors required for growth hormone effect?
- High amino acid levels (particularly arginine)
- High insulin levels (hypoglycemic even)
- Low fibroblast growth factor (FGF-21)
- High thyroid hormone
What effects does growth hormone have on a) muscle growth b) bone growth?
Muscle growth:
- Promotes amino acid uptake into muscle cells
- Increases protein synthesis rate
- Results in insulin-like growth factor release (IGF-1)
Bone growth:
- Promotes amino acid uptake into chondrocytes (cartilage cells): opposes closing of growth plate.
Describe the zones of a growing bone:
- Resting zone (chondrocyte stem cells present)
- Proliferative zone (division)
- Hypertrophy zone (increase in size)
- Calcifying zone (cells die and calcify into crystalline structure)
What role do oestrogen and testosterone have in bone growth?
- Oestrogen induces closure of growth plate
- Testosterone locally converted to oestrogen for same purpose.
What role does GH have in metabolic control?
Preserves glucose for brain. When FFA and glucose levels low:
- Stimulates adipose tissue to release free fatty acids
- Stimulates hepatic gluconeogenesis and glucose release
- Diabetogenic effect: inhibits glucose uptake by muscles and adipocytes (insulin sensitive target cells)
What are IGFs and what are their roles?
IGF = insulin-like growth factor
- GH stimulates IGF production and differentiation of chondrocytes (diabetogenic effect and increased FFA to allow for growth - shifts body from storage to release state)
- IGF stimulates growth of chondrocytes (growth, proliferation and hypertrophy).
- In utero IGF-1 and 2 control growth (not GH)
What is the evidence for the GH/IGF system and its control of growth?
Theory: GH stimulates differentiation of chondrocytes and IGF production (must be present to prepare the growth plate).
- Original theory was that hepatic GH receptors lead to IGF production (evenly distributed in blood)
- However; GH injection into growth plate stimulated growth only in that area –> liver not directly involved.
- Further: if IGF-1 gene in liver knocked out, growth is normal.
What is dwarfism and how can it caused?
Small size but normal proportions (not the same as acondroplasia which is IGF-1 deficiency and results in stunted (non-proportional) growth).
- Pituitary dwarfism: failure to produce functional GH
- Dwarfism of Sindh: defection of GHRH receptor (GH not stimulated)
- Laron syndrome: GH receptor mutations (failure of IGF-1 production and preparation of growth plate)
How can gigantism occur?
Child: overstimulation of growth plates in long bones from high GH levels
Adult: acromegaly (after fusion of long bones) results in large extremities/brow-bone.
Describe the structure of the adrenal gland and which hormones are produced.
Medulla: catecholamine production (e.g. adrenaline)
Cortex: corticosteroid production (travels bound to bp causing longer-lasting effects)
- Outer = zona glomerulosa: aldosterone production
- Middle = zona fasciculata: corticosteroids like cortisol
- Inner = zona reticularis: androgens such as DHEA
Blood flows from cortex to medulla
What is DHEA? What does it control?
- DHEA is an androgen
- Controls pubic hair and libido in females (overwhelmed by testosterone in males)
How is ACTH released? What does it stimulate?
ACTH = adrenocorticotropic hormone
- Hypothalamus releases corticotropin releasing hormone (CRH)
- CRH stimulates corticotrophs (20% of anterior pituitary cells) to cleave POMC into ACTH and release it
(- MSH and β-endorphin also released this way). - General stimulating effect on kidneys including cortisol production
How is ACTH release controlled?
- Long-loop -ve feedback: ACTH stimulates adrenal glands to produce cortisol which inhibits ACTH production – shown by injection of exogenous cortisol causing atrophy of adrenal cortex (ACTH not produced)
- Simulated by corticotropin releasing hormone (CRH)
- Circadian rhythm evident (surge before waking). The increase in cortisol resulting protects glycogen stores for later use.
How is adrenaline release stimulated?
- Sympathetic pre-ganglionic fibres release ACh
- Acts on nicotinic receptors on chromaffin cells (Cr stain affinity) in the medulla of adrenal gland
- Stimulates PNMT enzyme to convert noradrenaline to adrenaline
- Adrenaline released into bloodstream
What stimulates aldosterone production?
- Angiotensin II binds to angiotensin type I receptors in the cortex promoting aldosterone release.
- High [K+]
- ACTH does not directly stimulate aldosterone but is a permissive factor.
Give three examples of hormones released by the adrenal gland and their primary stimulus:
Adrenaline: nervous stimulation causing ACh release to chromaffin cells in medulla
Aldosterone: high [K+] and angiotensin II causes zona glomerulosa to produce aldosterone
Cortisol: released in response to hypoglycaemia and ACTH stimulation
What was Hans Selye’s 3 stage theory of stress?
‘Alarm reaction’ : sympathetic nervous response and glucocorticoid release (minutes)
‘Stage of resistance’ : a new dynamic homeostasis reached with new set points
‘Stage of exhaustion’ : detrimental effects of long-term elevated glucocorticoids due to chronic stress
Why do steroids take longer to be released?
- Cannot be contained in vesicles since lipid soluble
- Therefore must be synthesised on command
- Takes more time
What effects does cortisol have on metabolism?
Released in response to hypoglycemia:
- Promotes muscle and plasma protein breakdown for gluconeogenesis
- Stimulates liver enzymes to perform gluconeogenesis
- Inhibits glucose uptake by muscle and adipose tissue (diabetogenic effect)
- Promotes FFA release from adipose tissue (both direct effect and permissive factor for GH and adrenaline)
How does cortisol travel through the body?
- Steroid hormone so travels in blood, diffuses into cells and alters gene expression.
- Travels bound to transcortin with long half-life (> 60mins)
What effects does cortisol have on the immune system and brain?
Immune system effects: brings immune system back under control after alarm response
- Normal cortisol levels result in early activation of immune system
- Inhibits many components of inflammatory response (inhibits NO, cyclooxygenase (like aspirin), leukotrienes, TNF-α).
Can cross BBB so affects mood/sensory acuity.
What effects does cortisol have on the kidneys?
- Can bind to aldosterone receptor (lower affinity but higher quantities) therefore can cause Na+ reabsorption
- Locally broken down to avoid this (and hypertension). This enzyme is inhibited by glycyrrhetinic acid in liquorice.
- Also allows smooth muscle to respond to noradrenaline and angiotensin II (BP control).
