L15: The hypothalamic pituitary axis and growth hormone Flashcards
What is the hypothalamic pituitary axis (HPA)?
Hypothalamus and pituitary gland work together (functional unit)
Major link between the nervous system and endocrine
Modulate wide variety of processes
Where are the hypothalamus and pituitary gland located?
Hypothalamus–> Inferior to thalamus
Pituitary gland–> Inferior to hypothalamus in sella turcica
Just anterior to beginning of brainstem
Describe the anatomy of the pituitary gland?
Anterior –> Adrenohypophysis –> grow upwards from the roof of the mouth (primitive gut tissue)
Hypophyseal portal system
Posterior–> Neurohypophysis–> grows downwards from diencephalon of the brain (primitive brain tissue)
PP Gland–> not technically a gland as it doesn’t synthesis its own hormones
Infundibulum–> (pituitary stalk)–> connects hypothalamus to PP–> axons to PP
Specialised glial cells –> pituicytes
What hormones are released from the posterior pituitary?
Oxytocin
Antidiuretic hormone
Where are the PP hormones synthesised and released?How?
The supraoptic and paraventricular nucleus
Transported down axons
Stored in axon terminal
Released into general circulation to act on distant targets
How does the AP function?
Tropic hormones synthesised in the hypothalamus
Transported down axons
Stored in medial eminence
Released into hypophyseal portal system
Stimulate or inhibit target endocrine cells in AP
Release hormone into blood stream
Act on distant target and neighbouring cells (paracrine and autocrine)
What is the function of oxytocin?
Uterine contraction
- -> Pressure on cervix and uterine wall signal to hypothalamus
- -> Hypothalamus via neuronal input
- -> PP release oxytocin
- -> oxytocin receptors in SMC –> contraction
- -> Ferguson reflex –> positive feedback (oxytocin–> contraction–> increased pressure–> oxytocin)
Let down of milk upon suckling
- -> Baby suckling–> signal to hypotalamus
- -> Oxytocin release
- -> Mammary glands causes milk release by activating oxytocin receptors
How is oxytocin used clinically?
Pitocin
Used after birth to increase uterine tone and control bleeding
What is the function of ADH?
Reduction in urine production
Receptors on distal tubular epithelium of collecting ducts
Activated–> translocation of aquaporin channels–> more reabsorbption
What controls ADH release?
Osmoreceptors in hypothalamus detect changes in osmolarity –> control ADH release
Also ADH can increase vascular resistance by increasing the number of ADH receptors on SMC causing vasoconstriction and ↑ arterial BP–> important for restoring BP in hypovolemic shock
What are tropic hormones?
Hormones released form the hypothalamus
Control release of hormones from AP
What is the difference between tropic and trophic hormones?
Tropic hormones–> control AP secretion
Trophic hormones–> affect growth
How do tropic hormones function?
Released from hypothalamus
Stored in median eminence (just above AP)
Released into hypophyseal portal system
Stimulate/inhibit target endocrine cells by binding to specific GPCR
What are the 6 (7) different tropic hormones?
- Thyrotropin releasing hormone (TRH)
- Corticotopin releasing hormone (CRH)
- Gonadotropin releasing hormone (GnRG)
- Growth hormone releasing hormone (GHRH)
- Growth hormone inhibiting hormone (GHIH)–> somatostatin
- Prolactin release-inhibiting hormone (dopamine) (PIH)
(7) . Prolactin releasing hormone (PIH) –> no research evidence to show it exists
What do each of the tropic hormones control in the anterior pituitary?
TRH–> TSH (thyroid stimulating hormone) –> thyroid gland, thyroid production
CRH–> ACTH (adrenocorticotrophic hormone)–> adrenal cortex, cortisol
GnHR–> LH –> ovaries/testes, sex hormone secretion
GnHR–> FSH–> ovaries/testes, gamete production
GHRH/ GHIH–> GH –> liver (IGF production), other tissues, growth
(TRH)(PRH)/ PIH–> Prolactin –> mammary glands, breast growth and milk secretion
What regulates the secretion of hypothalamic and anterior pituitary hormones?
Feedback loops –> usually negative feedback
Ultrashort feedback–> hypothalamic releasing factor feedback on self
Short loop–> Anterior pituitary on hypothalamus–> inhibits releasing hormone or stimulates inhibitory homrone
Long loop–> target endocrine hormone feedback on anterior pituitary (direct long loop) or on the hypothalamus (indirect long loop)
Define hyperplasia?
Increase in cell number
Define hypertrophy?
Increase in cell size
What is growth influences by?
Genetics
Environment
Nutrition
Hormones (GH and others)
What is growth hormone?
Produced by the AP --> Stimulated GHRH --> Inhibited GHIH (somatostatin) Protein hormone 191 aa long Signal pepetide needs to be cleaved before folding
How does GH exert its effects?
GH binds to receptors on liver and skeletal muscle
Induces secretion of insulin-like growth factors (IGFs)
What is GH needed for?
Normal growth in children and teenagers
Long bones
–> epiphyseal growth plate open–> length and width
–> closed –> width only
Adults–> maintain muscle and bone mass
–> promote healing and tissue repair
–> modulate metabolism and body composition
What controls GH secretion?
Via hypothalamus
GHRH –> ↑ GH
GHIH (somatostatin) –> ↓ GH
Secrete occurs in pulsatile fashion –> circadian rhythms important –> Max release at night
How does GH secretion change?
CNS --> Surge in GH after onset of deep sleep REM sleep ↓ GH Stress ↑ GH Exercise ↑ GH
Metabolism--> Glucose or fatty acids ↓--> ↑ GH Glucose or fatty acids ↑ --> ↓ GH Fasting ↑ GH Obesity ↓ GH
grehlin ↑ GH
How is GH secretion regulated (feedback loops)?
Long and short feedback loops
Long loop–> IGFs (released by target tissue)
–> inhibits GHRH
–> stimulates GHIH (somatostatin)
–> inhibits GH from AP
Short loop–> GH feedback on hypothalamus stimulates somatostatin release
What happens if deficient in GH? How is it diagnosed?
Childhood–> pituitary dwarfism
- -> proportional type
- -> Complete or partial deficiency
- -> Responds to GH therapy
Diagnosed
- -> Height below 3rd percentile
- -> Growth rate slower than expected
- -> Delayed or no sexual development
What happens if GH excess?
Gigantism–> rare 3/10^6
- -> excess GH in childhood
- -> pituitary adenoma
Acromegaly –> large extremities
–> giant hands, feet, lower jaw
How does GH exerts it effects on cells?
Directly –> through own GH receptor
- -> GH receptor is a cytokine receptor coupled to Janus kinase (JAK) intracellular enzymes–> tyrosine kinase family
- -> Binding of GH causes dimerisation of receptor
- -> Intracellular JAK autophosphorylate each other
- -> Activation via phosphorylation–> signalling complex forms around receptor
- -> Activation of signalling pathway
- -> Transcription factor activation and IGF production
Indirectly–> through IGF-1 production
- -> Production of IGFs–> paracrine, autocrine and endocrine activity
- -> Circulate blood bound to specific binding proteins
- -> Bind to IGF receptors to modulate
- Cell growth (hypertrophy)
- Cell number (hyperplasia)
- Increase proteins synthesis
- Increase lipolysis in adipose tissue
What are the different types of IGFs? Where are they produced?
Insulin like growth factors --> similar function/action to insulin IGF-1 and IGF-2 Mainly in liver and skeletal muscle Can be bone, kidney and CNS
What are the IGF receptors like?
Similar (homology) to insulin receptor (tyrosine kinase)
Hybrid receptors–> 1/2 insulin receptor, 1/2 IGF-1 receptor
IGF-2–> no kinase activity–> targets IGF2 for lysosomal degradation
IGF-1–> mitogenic effects
Insulin–> Metabolic effects
IGF-1 can ‘tickle’ Insulin receptor and vice versa
What are some other hormones that can influence growth?
Insulin –> somatic growth, IGF receptors
Thyroid hormones–> CNS developement, GH secretion
Androgens–> Pubertal growth spurt, increase muscle mass, promote closure of epiphyseal growth plates
Estrogens–> decrease somatic growth, promote closure of growth plates
Glucocorticoids–> inhibit somatic growth
