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Medical options in the
treatment of acromegaly
I M Holdaway
June 29 2013
Medical treatments for acromegaly
(non-surgical and non-radiotherapy)
• Older treatments
- medroxyprogesterone
- oestrogen (tablets or patches or look-alike preparations)
• Dopamine – like agents:
- bromocryptine
- cabergoline (special authority)
• Somatostatin analogues:
- aqueous octreotide (subcut injection) (special authority)
- depot octreotide (sandostatin LAR) (special authority)
- Lanreotide (not marketed in NZ)
- Oral octreotide (under trial in USA)
- Pasireotide (not available in NZ)
• Pegvisomant (Named Patient Pharmaceutical Assessment)
Brain (hypothalamus)
Pituitary
gland
A few direct
effects of
growth
hormone e.g.
on fat cells
Action of growth
hormone and insulinlike growth factor-I
(IGF-I)
Growth
hormone
liver
IGF-I (insulin-like growth factor-I)
Growth and metabolic effects
Older studies of the medical
treatment of acromegaly
• Medroxyprogesterone (depot-provera & Megace)
• Oestrogen
- oral oestrogen tablets
- oestrogen patches
- oestrogen – like agents, anti-oestrogens
(Note – later
studies could not
replicate these
results)
Remission level of GH
JCEM 1970
Pituitary, 2012
Published series using oestrogen to
treat acromegaly
45% cure level
of IGF-I
Dopamine – like agents
• Bromocryptine
• Cabergoline (longer duration of action, very low rate
of side-effects compared with bromocryptine)
Labelled dopamine
binding to its
receptor in the
pituitary
Cabergoline treatment in acromegalics with
elevated IGF-I
A meta-analysis of 10 studies
20% given as initial
treatment, 70%
had received
previous surgical
treatment
51% developed
normal IGF-I
48% GH <2.5
Individuals with elevated serum IGF-I during
treatment with LAR octreotide, then treated
with addition of cabergoline
52% achieved
normal IGF-I
levels
45% GH <2.5ug/l
But you have to take tablets correctly……..
Somatostatin look-alike agents
• Octreotide – a potent somatostatin-like
agent
- aqueous octreotide injection (short duration of action)
- depot octreotide injection (long duration of action)
- aqueous and depot lanreotide similar
• Pasireotide – a somatostatin-like agent
with a broader range of action than
octreotide
• Orally active octreotide
Somatostatin action on growth hormone –
producing pituitary cells
Main receptor
for octreotide
and lanreotide
SR 2
SR = somatostatin
receptor
SR 3
SR 4
SR 1
Cell wall
Signal to interior of
pituitary cell to stop
making growth
hormone
SR 5
Effect of 1 and 5yrs LAR octreotide therapy on GH and IGF-I
levels in acromegalic men
Safe level
Pretreatment
1 year
5 years
Safe level
Colao 2009
Serum GH with LAR therapy
serum GH (ug/l)
(mean  SD)
Auckland patients
65
60
55
50
45
40
35
30
25
20
15
10
5
0
P = 0.002
Basal GH
On LAR
Serum IGF-I with LAR therapy
(Z-score, expressed as mean  SD)
Auckland patients
Serum IGF-I (Z-score)
7
6
5
P = <0.001
4
3
2
1
0
Basal IGF-I
IGF-I on LAR
Shinkage of acromegaly
adenoma with LAR
octreotide
Large
adenoma
baseline
6 months LAR
octreotide
smaller
Almost
gone
18 months LAR
octreotide treatment
Effect of LAR octreotide on adenoma size
Meta-analysis
53% of individuals with
acromegaly show more
than 20% shrinkage of
their adenoma with LAR
octreotide (average
volume reduction 50%)
53%
Giustina et al, 2012
Remission of acromegaly with initial surgery
or with LAR octreotide
Mean ± SEM proportion of acromegalic
patients achieving safe hormone levels
with LAR octreotide
17 surgical series 1987-2011
0.6
0.4
0.2
0.0
FI
microadenomas
0.8
IG
all tumours
1.0
G
90
80
70
60
50
40
30
20
10
0
H
Proportion with target levels
Percent remission
Remission rate
with surgery
Meta-analysis by Freda et al, 2005, n= 612
Pasireotide
A somatostatin-like agent with a broad
range of action
Pasireotide
SR 2
SR = somatostatin
receptor
SR 3
SR 4
SR 1
Cell wall
Signal to pituitary cell
to stop making growth
hormone
SR 5
Pituitary tissue – microscopic view, stained for
various somatostatin receptors
Type 1
Type 2
Type 3
Type 4
Type 5
Use of the somatostatin receptor analogue, Pasireotide
in the treatment of acromegaly
Bronstein M US Endo Soc meeting 2012
Serum IGF-I and GH levels in an acromegalic subject
given a single injection of pasireotide
P
0.8
0.6
400
0.4
200
0.2
IGF-I
20
11
O
ct
20
11
N
ov
20
11
D
ec
20
11
Se
pt
A
ug
20
1
Ju
ly
20
1
Ju
ne
20
11
0.0
11
0
Growth hormone
Serum GH (ug/l)
Serum IGF-I (ug/l)
600
Oral octreotide - the way of the future?
TPE absorption system for small peptides such as
octreotide
.
Barrier to absorbing large molecules from the
intestine
Intestinal contents
Tight junctions
between cells
(impermeable)
Tight junctions opened up by
oily film (allows entry of larger
molecules into circulation)
Cells lining
the intestine
Blood
flow
Effect of oral octreotide (Chiasma)
on growth hormone secretion
stimulated by GHRH
Stimulated
GH
Stimulated
GH after oral
octreotide
Tuvia, 2012
Pegvisomant
A drug designed to block the growth
hormone receptor and prevent the adverse
effects of high growth hormone levels in
acromegaly
Brain (hypothalamus)
Pituitary
gland
A few direct
effects of
growth
hormone e.g.
on fat cells
Action of growth
hormone and insulinlike growth factor-I
(IGF-I)
Growth
hormone
liver
IGF-I (insulin-like growth factor-I)
Growth and metabolic effects
pituitary
Blockade of growth
hormone action by
Pegvisomant
Growth
hormone
Direct
actions of
GH e.g. on
fat cells
Pegvisomant
liver
↓ IGF-I (insulin-like growth factor-I)
↓ Growth and metabolic effects
Design of Pegvisomant
Serial IGF-I measurements during pegvisomant
treatment in the German observational study
76%
normalised
n = 229
Schreiber et al, 2007
What of the future?
• Effective oral octreotide
• By-passing surgery and using medical
treatment as first option
• Treatment with a drug linked to either a
chemotherapy agent such as tozolamide,
or linked to a radioactive agent to kill the
tumour cells
• A combined dopamine/octreotide agent
THE END!
Australian acromegaly awareness campaign
•
•
•
•
•
While there was minimal mainstream print, radio and television consumer
media coverage the more targeted media ran the story. Targeting
magazines was effective.
The medical media release hit all the targets and more with the smaller
groups keen to run the story for their local newsletters.
An increase in the Australian Pituitary Foundation website hits saw June
(????), July (907 hits), August (982 hits), September (583 hits) (Notemedical media release issued mid July and consumer media release
issued 1 August)
A key learning is that mainstream media may not always be the best
approach when it comes to disease awareness campaigns of this type.
This a good example of widespread medical and patient/consumer
coverage via non-mainstream mediums.
Pretreatment with SSAs prior to pituitary surgery
in acromegaly
concept
57
90
32
pr
et
re
at
ed
co
nt
pr
et
re
at
ed
POTA study
(Norway)
ro
l
30
ro
l
90
80
70
60
50
40
30
20
10
0
co
nt
Percent cured at surgery
Abe et al, 2001
Abe & Ludecke
(Hamburg)
Symptomatic response to
octreotide LAR (n=10)
Symptom
after
n before
Headache
OSA - like
Arthralgia
Sweating
CTS
Hypertension
Diabetes
4
7
5
6
4
3
2
n
0
1
2
1
0
2
2
Effect of cabergoline on GH secretion in acromegaly
Cabergoline + LAR
octreotide therapy
52% had
normal
IGF-I
Sandret et al, 2011
Individual patients