Endocrine - Pituitary Disease Flashcards
Where does anterior pituitary get its blood supply?
From hypothalamic-pituitary portal plexus via SUPERIOR HYPOPHYSIAL ARTERY
What are the subunits of anterior pituitary hormones?
Alpha subunit: common to TSH, LH, FSH and hCG
Beta subunit: determines specificity
Growth hormone is secreted by which cells in response to what?
By somatotrophs in response to GHRH
When is GH secretion elevated?
Deep sleep
Exercise and physical stress
Trauma
Sepsis
When is GH secretion decreased?
Obesity
What stimulates GH secretion?
Ghrelin
Oestrogen
What inhibits GH secretion?
IGF-1
Chronic glucocorticoids
Somatostatin
What is the INDIRECT action of GH?
GH stimulates IGF-1 release from liver.
IGF-1 in skeletal muscle and cartilate then increases uptake of amino acids and protein synthesis.
What is the DIRECT action of GH?
In epithelium: stimulates mitosis
In adipose: stimulates breakdown of fatty acids and cells use fatty acids rather than glucose
In liver: stimulates glucogenolysis
How is IGF-1 circulated?
IGF-1 is bound to circulating IGFBP the main one is IGFBP3 is GH-dependent
Where is IGF-1 synthesised?
In the liver
What conditions have higher levels of IGF-1?
Higher levels in women and puberty
What conditions have lower levels of IGF-1?
Low in hypocaloric states with GH resistance (ie: cachexia, malnutrition and sepsis)
Function of IGF-1?
Induces hypoglycaemia, low doses improve with insulin sensitivity
Anabolic
Increased bone turnover
Laron’s Syndrome
= partial or incomplete GH insensitivity and growth failure
Diagnose with normal/high GH levels but decreased GHBP and IGF-1 levels
Clinical features of adult growth hormone deficiency?
Body composition changes:
- reduced lean body mass
- increased fat mass
- selective deposition of intra-abdominal fat
- increased waist:hip ratio
Hyperlipidaemia
LV dysfunction
Hypertension
Increased (x3) CVS mortality
Increased fibrinogen levels
Reduced bone mineral density
Increased fracture rates
Depression
Diagnosis of growth hormone deficiency?
Insulin tolerance test GHRH test Arginine-L dopa test Glucoagon-stimulation test Serum-IGF
Causes of Acromegaly from Excess GH Secretion:
Pituitary:
- carcinoma
- McCune Albright
- MEN1
Extra-Pituitary:
- pancreatic islet cell tumour
- lymphoma
Causes of Acromegaly from Excess GHRH secretion?
Central
Peripheral:
- *** medullary thyroid cancer
- bronchial carcinoid
- pancreatic islet cell tumour
- SCLC
- Adrenal adenoma
- pheochromocytoma
Clinical features of acromegaly
Frontal bossing / increased hand or feet / mandibular enlargement / widened incisors
Soft tissue swelling Hyperhidrosis Deep hollow voice Oily skin Acanthosis nigricans
Arthropathy
Kyphosis
Carpal tunnel syndrome
Proximal muscle weakness and fatigue
Visceromegaly Cardiomegaly and diastolic failure Hypertension Obstructive sleep apnoea Diabetes (>10%)
Increased risk colon cancer and thyroid cancers
Risk of which cancers is increased with acromegaly?
Colon cancer and thyroid cancer
Which clinical feature of acromegaly is irreversible?
Arthropathy
Diagnosis of Acromegaly?
Elevated IGF-1 (screen)
75mg oral glucose challenge: GH SHOULD suppress to 1-2 hours post intake
(** 20% get a paradoxical rise **)
Prolactin is elevated in 25%
When should someone with acromegaly get colonoscopies?
From age 40yrs
Role of surgery in acromegaly?
First line for adenomas
Transphenoidal resection:
- microadenoma remission 70%
- macroadenoma remission <50%
- swelling improves immediately
- IGF-1 normalises within 3-4 days
- GH normalises within an hour
Post transphenoidal resection for acromegaly how common is hypopituitarism?
15%
Action of somatostatin analogues?
ie Octreotide
Suppress GH secretion by binding to SSTR2 and SSTR5
How well does octreotide work in acromegaly?
Normalises IGF-1 in 60%
Half life is 2hours
Side effects of octreotide?
- suppression of GI motility and secretion
(–> diarrhoea, flatulance and fat malabsorption) - suppresses postprandial gallbladder contractions and delays gallbladder emptying
- mild glucose intolerance
- bradycardia
- hypothyroxinaemia
Action of GH-Receptor Antagonists in acromegaly?
ie: Pegvisomat
Blocks PERIPHERAL GH binding to receptor
(and suppresses serum IGF-1_
How well does Pegvisomat work in acromegaly?
Normalises IGF-1 in 70%
Does not target adenoma (therefore serum GH will remain high)
Side effects of Pegvisomat?
LFT derangement
Lipodystrophy
Action of dopamine agonists in acromegaly?
ie: Bromocriptine and Cabergoline
Only MODESTLY suppresses GH secretinos SOMETIMES
Role for radiation in acromegaly?
GH levels reduce over time
50% of people require >8 years to suppress, therefore usually need interim medical treaments
What is octreotide?
Somatostatin analogue
What is pegvisomat?
GH-Receptor Antagonist
What is Bromocriptine?
Dopamine Agonist
What is Cabergoline?
Dopamine agonist
Prolactin is secreted by what cells?
Lactotrophs
When does prolactin secretion peak?
Between 4-6AM during REM sleep
What stimulates prolactin secretion?
Prolactin Releasing Hormone (PRLH) Thyrotropin-Releasing Hormone (TRH) Vasoactive Intestinal Peptide (VIP) Oestrogen Oxytocin
What is the predominant central inhibition of prolactin secretion?
Dopamine D2 receptor
Elevated levels of prolactin are seen in…?
Post exercise Meals Surgery General anaesthesia Chest wall injury Acute MI
Decreased levels of prolactin are seen in…?
Thyroid hormone
Steroid use
How does prolactin act?
Signals via JAK –> STAT family
Induces and maintains lactation
Decreases oestrogen function
Decreases oestrogen
- -> blocks folliculogenesis
- -> inhibits granulosa cell aromatase
- -> amenorrhoea
Decreases libido
Causes of Hyperprolactinaemia?
Pregnancy/Lactation
Physiologic (nipple or sexual organism, sleep or stress)
Prolactinoma
Pituitary:
- stalk disruption or macroadenoma
- lymphocytic hypophysitis
- radiation and trauma
Primary hypothyroidism
Renal Failure
Pharamcologic:
- Antipsychotics (risperidone)
- metoclopramide (inhibits D2 receptor)
- Methyldopa (inhibits dopamine synthesis)
- CCBs (verapamil) block dopamine release
- H2 antagonists
- opioids
- amitryptiline
Which drugs can cause high prolactin levels?
- Antipsychotics (risperidone)
- metoclopramide (inhibits D2 receptor)
- Methyldopa (inhibits dopamine synthesis)
- CCBs (verapamil) block dopamine release
- H2 antagonists
- opioids
- amitryptiline
How does hyperprolactinaemia present?
Amenorrhoea
Galactorrhoea
Infertility
Visual loss from compression of optic chiasm (Bitemporal hemianopia)
Long term:
- osteopenia
- decreased libido
- weight gain
Diagnosis of hyperprolactinaemia
Basal fasting prolactin level
Measure TFTs
MRI
Role of dopamine agonists in hyperprolactinaemia?
- suppress prolactin secretion and synthesis
- suppress lactotrope cell proliferation
Once prolactin normal and tumour shrinks
–> Then after two years can withdraw medical treatment if >50% reduction in size and >5mm from vital structures
What is important monitoring when giving dopamine agonists in hyperprolactinaemia?
Need formal visual fields before treatment 6-monthly until mass shrinks annually afterwards
How many patients with hyperprolactinaemia will not respond to dopamine agonists?
20% of patients (especially males) are resistant to dopamine agonists
Which are the two dopamine agonists used in hyperprolactinaemia, and how are they different/similar?
CABERGOLINE (Preferred) (ergot-derived)
- suppress prolactin for >14 days
- success in 80% microadenoma, 70% macroadenoma
- side effects less common than bromo
BROMOCRIPTINE (ergot alkaloid)
- short acting
- ** preferred in pregnancy ***
Side effects of the dopamine agonists used in hyperprolactinaemia?
Cabergoline and Bromocriptine:
- constipation, dry mouth
- nightmares and insomnia
- vertigo
- auditory hallucinations
- cardiac valvulopathy (CABERGOLINE)
Role of surgery in treatment of hyperprolactinaemia?
Surgery if:
- dopamine resistant / intolerant
- compromised vision not improving
30% success for macroadenoma (50% long term recurrence)
70% success for microadenoma
Role of radiation in treatment of hyperprolactinaemia?
Only if aggressive and not responding to other treatments
Management of prolactinaemia in pregnancy
Microadenoma:
- discontinue dopamine agonist
- periodic visual loss
- repeat MRI 6 weeks postpartum
Macroadenoma:
- consider surgery prior to pregnancy
- ensure BROMOCRIPTINE SENSITIVE before getting pregnant
- Give BROMOCRIPTINE as soon as vision is compromised
OR
continue if vision is already affected
- consider high dose steroids or surgery during pregnancy if vision is threatened or adenoma haemorrhage
- MRI postpartum at 6 weeks
Where is ACTH synthesised?
In corticotrophs in anterior pituitary
What protein is ACTH derived from?
POMC precursor protein
What suppresses ACTH synthesis?
Glucocorticoids
What induces ACTH synthesis?
CRH
AVP
IL-6
Leukaemia inhibitory factor
What stimulates the secretion of ACTH? And from where?
Stimulated release by CRH from the paraventricular nucleus