1 - Pituitary Gland Flashcards
How does the hypothalamus communicate with the anterior pituitary gland?
Neurohormones
Through a specialised portal vascular system.
Do direct neural connections exist between the hypothalamus and the anterior pituitary gland?
No.
How does the hypothalamus communicate with the posterior pituitary gland?
Through axons that originate within hypothalamic neuronal cell bodies.
What are the two inhibitory neurohormones produced by the hypothalamus?
Dopamine
Somatostatin
What anterior pituitary hormones does dopamine inhibit?
FSH
LH
Prolactin
TSH
What anterior pituitary hormones does somatostatin inhibit?
Growth Hormone
TSH
What hormone does POMC (pro-opiomelanocortin) give rise to?
ACTH
POMC and MSH (melanocyte-stimulating hormone) result in what change? And occur in what disease?
Hyperpigmentation
Addison’s disease
Nelson syndrome
Where does vasopressin (ADH) act and how does it work?
Distal tubule
Increases permeability to water
At high concentrations, what can ADH cause?
Vasoconstriction
What are the two main stimuli of ADH secretion?
Sensed by which receptors?
Increased osmotic pressure + volume depletion.
Osmoreceptors (within hypothalamus) and baroreceptors.
What 4 locations are baroreceptors located?
Carotid sinus
Aortic arch
Left atrium
Pulmonary veins
A lack of ADH results in what condition?
Central diabetes insipidus
What pathology occurs in nephrogenic diabetes insipidus?
Inability of kidney to respond to ADH.
What are the two target areas of oxytocin?
1) Uterine smooth muscle
2) Myoepithelial cells within the breast
What stimulates oxytocin release?
1) Suckling
2) Increases gradually throughout pregnancy
What 6 hormones are produced by the anterior pituitary gland?
ACTH GH TSH LH FSH Prolactin
What 2 hormones are produced by the posterior pituitary gland?
Oxytocin
ADH (vasopressin)
What are the two possible effects arising from pituitary tumours?
1) Mass effect (headache, visual loss)
2) Hormonal effects (hormone overproduction)
What is a clonal tumour?
A tumour made up of all the same cells.
What pathology arises as as a result of a clonal tumour of somatotrophs?
Acromegaly (GH excess)
What features are present in acromegaly?
Tall stature
Enlarged hands, feed
Metabolic effects: HTN + diabetes
Sweating (gland proliferation)
What is a clonal tumour of lactotrophs called?
Prolactinoma
What symptoms occurs as a result of a prolactinoma?
Lactation
Amenorrhoea
What pathology arises as as a result of a clonal tumour of corticotrophs?
Cushing’s disease
ACTH-secreting pituitary tumour from POMC
What are the characteristic features of Cushing’s disease?
Moon face (fat deposition) Striae Recession of hair Hirsutism Bruising
Which two clonal tumours are termed ‘non-functioning’ adenomas?
And why?
Gonadotroph adenomas
Thyrotroph adenomas
Both very rare
What are craniopharyngiomas?
Rare, benign tumours
Form as solid tissue, cysts or calcified nodules.
Name 3 destructive lesions which result in hypopituitarism
Rathke’s cleft cyst
Meningiomas
Gliomas
Hypopituitarism lesions results in which 3 hormones insufficiencies?
Hypoadrenalism
Hypothyroidism
Hypogonadism
Polyclonal tumours arise from what pathology?
Hormone dysregulation resulting in hyperplasia
e. g. high-dose estrogen = PRLoma
(e. g. Transgenic GH-RH excess = GHoma)
What are the 4 candidates for protein mutation in polyclonal tumours?
Receptors
G-protein subunits
Kinases
Nuclear proteins
(cell signalling capital)
What two receptors result in a prolactinoma if mutated?
Dopamine D2 receptor
(K/o studies get them because Dopamine is an important inhibitor of prolactin secretion)
FGF4-Receptor
(splice variant may be associated, but not causative)
What are the 5 diseases involving adenomas?
1) McCune-Albright Syndrome
2) Multiple Endocrine Neoplasia (MEN) 1
3) Familial isolated pituitary adenoma
4) X-linked acromegaly
5) Carney complex
What is the underlying pathophysiology of McCune-Albright Syndrome?
G-protein activating mutation in the protein GSP, resulting in excess GH.
How does a GSP mutation result in excess GH?
GalphaS mutation (GSP)
1) Inhibition of GTP-ase activity
2) Constitutive activation of adenylate cyclase
3) LOTS OF cAMP
4) Protein kinase A activation
5) CREB phosphorylation
6) Excess gene expression
In what % of GHomas is a GSP mutation found?
40%
What inheritance trait is the GSP mutation?
Dominant
As a result of its effect, what type of gene is GSP?
Oncogene
MEN-1 is what kind of gene?
Tumour suppressor gene
For MEN-1 to manifest, however, given its TSG trait, what has to occur?
Two-hit hypothesis
What is the difference in protein expression between the 1st and 2nd hit?
1st = reduced protein expression
2nd = NO Protein expressed (phenotype)
MEN-1 results in tumours forming in which 3 glandular organs?
Pituitary
Parathyroid
Pancreas
What NUCLEAR protein does MEN-1 gene code for?
Menin
What inheritance pattern does MEN-1 have?
Autosomal dominant trait (occurs even in heterozygous)
**High-penetrance
On what chromosome is MEN-1 mutation found?
Chromosome 11
11q33
Describe what happens in the process of ubiquination?
Protein targeting for degradation.
What kind of protein is USP8?
A de-ubiquitinase
A mutation in USP8 results in what condition?
Cushing’s disease
How does Cushing’s disease arise from a USP8 mutation?
Increases de-ubiquitination of EGFR.
Rescues EGFR from lysosomal degradation.
Increase in EGFR signalling.
Increase in ERK
Increased ATH production.
Explain the combined model of pathogenesis in regards to pituitary adenomas.
Hormonal / environmental induced proliferation occurring.
More divisions = more likely for mutation.
Incidental mutation (e.g. GSP / USP8) results in monoclonal tumour forming.
What are the 3 main modalities to treat pituitary tumours?
1) Surgery
2) Radiotherapy
3) Drug therapy
What type of surgery is used to remove pituitary tumours?
Transsphenoidal adonectomy
Name two important structures that need to be avoided in Transsphenoidal surgery
Optic nerve
Internal carotid artery
Possible complications from pituitary surgery?
Visual field defects
Various endocrine complications
CSF leak
Radiotherapy is often an adjuvant. What consequence will occur after therapy?
Hypopituitarism
What 3 consequences occur from a prolactinoma?
Anovulation
Amenorrhoea
Galactorrhoea
Name 3 drugs that can cause prolactinaemia
Dopamine antagonists (metoclopramide)
SSRI (e.g. fluoxetine)
Tricyclic anti-depressants
What pharmaceutical therapy can be used to treat prolactinomas / hyperprolactinaemia?
Dopamine agonists (e.g. bromocriptine)
Name a few side effects of bromocriptine
12% get them
Nausea
Postural hypotension
Abdo pain
Name one novel dopamine agonist
And why is it better?
Quinagolide (similar to bromocriptine)
Less common SE
What pharmaceutical therapy can be used to treat acromegaly?
Somatostain receptor agonists
OR
GH antagonists
Name a GH antagonist
Pegvisomant
What is the mechanism of action of Pegvisomant?
Binds to one half of the GH-receptor, inhibiting the binding of GH and subsequent dimerisation.
Reduces levels of IGF-1 and GH production.
Pegvisomant is a modified GH molecule. It is also pegylated for two reasons - what are they?
Decrease immunogenicity
Increase half-life
