Acromegaly

Acromegaly Dr Thomas fox SpR Diabetes and Endocrinology Derriford Hospital

Learning outcomes
Incidence and presentation
The roles of IGF-1 and GH
An approach to management 2009
Prognosis
Novel therapies

Definition
Disproportionate skeletal tissue and soft tissue overgrowth
Results from hyperplasia of pituitary somatotroph cells and excessive growth hormone production
First described by Verga in 1864

Incidence and presentation
5 cases per million
In a study of 600 cases commonest presenting symptoms
Acral and facial changes
Hyperhydrosis
Headaches
Paraesthesia
Hypertension
Goitre
Rarely visual field defects
Frontal skull bossing

Diagnosis
Historically variable reliability of GH assays
Acronegaly results in
Excessive GH throughout the day
Loss of bursts
High random GH not useful
Low random GH <0.04µg/l makes diagnosis unlikely
IGF-I vs OGTT

Loss of pulsatility of GH in acromegaly (umIU/L)

GH physiology
Produced in anterior pituitary gland
Stimulated by
GHRH from hypothalamus
Ghrelin (gut)
Inhibited by
somatostatin via SSTR 2 and 5 receptor subtypes
SS regulates the timing and amplitude of GH release
GH receptors widely expressed in liver, fat and muscle

GH production

OGTT
75g oral glucose load is neuroendocrine stimulus that should suppress GH secretion
GH should drop to <1.0µg/l during 2 hours following glucose load (sample at 0, 30, 60 and 120mins)
False positives
Obesity
Renal failure
Oestrogen replacement
Diabetes mellitus

IGF-I
Polypeptide target of GH
Synthesised
Liver (80%)
Bone
Muscle
Kidney
Endocrine and paracrine hormone
Mediates growth actions of GH
IGF-I receptor found ubiquitously

IGF-I
Relatively stable (unlike GH)
Positively correlated with GH
Age-matched controlled levels required (levels fall 14% per decade)
Falsely low levels in
Renal failure
Hepatic failure
Oestrogen replacement

Mr IG
Referred in 2007 by ENT surgeons
10 year history of snoring
Recent onset facial pain
Acromegalic features
CT scan arranged by ENT showed a 1cm pituitary adenoma
On systems review he also had sweating but had not noticed increased size in his hands or feet.
No headaches/visual disturbances
BP 185/65mm/Hg
On clinical examination features of acromegaly

Initial investigations
IGF-I 85.5
OGTTT (GH 0-10mIU/L old units)
12.4 0mins
9.8 30
8.5 60
8.1 90
10.9 120

Other endocrine parameters
TSH 0.7
FT4 18.3
FSH 6.3
Lh 3.1
Testosterone 8.7
PRL 279
ITT cortisol peak 668

Pre-treatment MRI (pre and post-contrast)

Treatment
Acromegaly with macroadenoma
Enrolled in Medical Therapy For Acromegaly Trial (MTAT)
Dose titrated up to 120mg monthly of lantreotide Autogel
Disappointing response after 6 months treatment
IGF-I remained elevated at 94
OGTT
Basal 10.7 mIU/L (reduced from 12.4)
Nadir 8.1 mIU/L
On balance decided to continue in the trial

Interval MRI (pre and post-contrast)

At trial end
No significant reduction in tumour size
He underwent transphenoidal hypophysectomy
3 month following surgery MRI demonstrated tumour size reduction

Post TSH MRI (pre and post-contrast)

Post TSH
IGF-I 42.4
ITT (hypoglycaemia to glucose of 0.6 – seizure)
Peak cortisol 745
Basal GH 0.33 µg/L
Peak GH 19.9 µg/L
OGTT low basal level and supressed
TSH 0.85
FT4 21.1
FSH 3.1
LH 2.5
PRL 73

Follow-up
MR IG continued to feel unwell
Repeat MRI – no change
Repeat OGTT
Basal 0.19 µg/L
Nadir 0.1 µg/L
Repeat IGF-I 45-48
Discordant results
what to do next?

IGF-I and GH discordance
Belgian registry
229 patients
65% concordance in GH and IGF=I results
Mostly IGF-I was not suppressed
General feeling that IGF-I gives a better idea of cure and also determines clinical prognosis

The role of surgery
Transphenoidal hypopyhsectomy gold standard in dedicated centre
`75-95% cure rate in intrasellar microadeomas
40-65% cure for macroadenomas
Complications on 1% of patients
Transient occulomotor palsies
Deterioration of vision
Carotid artery injury
Epistaxis/CSF leak
DI (transient or permanent)

Primary medical therapy?
Only indicated in treatment of macroadenomas
ie invasion into the cavernous sinus
May increase the cure rate with tumour shrinkage prior to surgery

Medical therapy
3 drug classes
Somatostatin receptor ligands
Dopamine agonists
GHRH antagonists

SRLs
Target the somatostatin 2 and 5 receptor subtypes in pituitary and directly on the liver to inhibit IGF-I synthesis
Octreotide LAR and lanreotide Autogel no head-to-head stduies
Indications
Those who refuse surgery/are too unfit
Failure of surgical cure
Primary therapy if surgical cure unlikely
Whilst waiting for radiotherapy to take effect
75% will see a 25% tumour shrinkage
Biochemical control in 34-45% of patients
SE – abdominal bloating, gallstones/sludge
NB may interfere with GH response to OGTT

GHR antagonist
Pegvisomant
Binds to peripheral GH receptors blocking function
GH levels increase ?due to impairment of IGF-I negative feedback on somatotroph secretion
Daily injection 1030mg (£50-100 daily!)
Indicated
No biochemical control despite surgical and medical therapy
Risks
Tumour growth
Abnormal LFTs (25%)
lipohypertrophy
?GHR antagonist in combination with SRL

Radiotherapy
Fractionated or gamma-knife
50% biochemical cure at 10 years
Usually second or third line
Indicated in those
Not cured by surgery to remove need for lifelong medical Rx
After debulking surgery
In those who have failed SRL therapy and are at risk of tumour growth from GHR antagonist Rx

Risks of radiotherapy
Hypopituitism in 50%
TSH 27%
LH/FSH 18%
ACTH 15%
Visual defects 5%
Secondary tumours?
Radiation vasculopathy
Neurocognitive defects

Prognosis
Life expectancy reduced by 10%
Mortality determined by
Random GH<2.5µg/L or suppressed <1µg/L
Normalisation of IGF-1
Age
HTN
Diabetes
Cardiac disease
Duration of disease
GH <2.5µg/L RR 1.1
GH > 2.5µg/L RR 1.9
IGF-I>95% confidence interval – SMR 3.4 fold increase
IGF-I <2SD below the mean had only 1.2 fold increase in SMR
Effects on tumour mass

Follow-up
IGF-I and OGTT at 3 months
Continued follow-up biochemically
(GH is not measured in GHR antagonist therapy)
OGTT not helpful in SRL therapy
MRI
3-6 months post-op
May not need to be regular if biochemically “cured”6 months after commencing GHR antagonist
Pituitary function 3 months post-surgery
ITT

Summary
Diagnosis and natural history of acromegaly
IGF-I and GH measurements and relevance as prognostic indicators
Surgical, medical and radiotherapy options
A management and follow-up strategy for acromegaly

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Acromegaly

by PeninsulaEndocrine on Aug 12, 2011

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Acromegaly — Presentation Transcript