Acromegaly - The Annual Endocrine Society of Australia Seminar ...

Acromegaly
Endocrine Society of Australia
April, 2012
Laurence Katznelson, M.D.
Stanford Univ. Medical Center

Hypertension and
Sleep
apnea
heart disease
Cerebrovascular events
and headache
Acromegaly
Co-morbidities
Insulin-resistant
diabetes
Arthritis

Case 1
45 yo male sent to PCP because dentist
noted teeth spacing.
Further history of headaches for 3 years
Carpal tunnel syndrome surgery last year
Referred to Endocrinologist
Further history: wedding band resized prior
year.

Case 1
Exam: acral features
BP 150/95 mm
Lab testing:
OGTT (75gm glucola) nadir GH 0.9 ng/ml
Insulin-like growth factor-1 (IGF-1) 780 ng/ml
(normal < 380 ng/ml)
Prolactin 56 ng/ml
Fasting glucose 134 mg/dl

MRI scan: microadenoma

Limitations of Guideline Development
The biochemical diagnosis of acromegaly and the biochemical monitoring of
therapy is controversial
Interpretation of biochemical results
• Variability between and within assays
• Assays are of variable sensitivity
Correlation of GH and IGF-1 values and morbidity
outcomes unclear
What are appropriate biochemical goals?
• Epidemiologic studies provide the best evidence for GH and
IGF-1 endpoints
• No clear consensus on how biochemical goals impact on
morbidity endpoints
Limited prospective, controlled studies comparing therapeutic
interventions

Biochemical Diagnostic Testing
Random GH
A “high” value is consistent with acromegaly, but a discrete cutoff is not
available
AACE guidelines:
Serum IGF-1
OGTT (75g) with nadir GH < 1 ng/ml considered normal
There is consideration of lowering the nadir GH to < 0.4 ng/ml
• Based on studies involving highly sensitive assays

Goals of Therapy
Normalize biochemical parameters
Reduce tumor burden and prevent local mass effects
Reduce signs and symptoms of disease
Prevent/control premature morbidities
Prevent premature mortality

Therapy
Surgery is primary therapeutic option
Surgical experience is key
Endonasal , microscopic transsphenoidal surgery
Endoscopic approach may improve exposure and
patient experience

MRI scan: microadenoma
For a microadenoma, surgery is clearly
indicated as cure >80%

Post-Surgical Assessment (A)
Immediate postoperative fasting GH
If < 2 ng/ml, correlates with surgical remission
may have more limited prognostic value as the stress of surgery
may stimulate the remaining normal gland to elevate GH levels
Oral glucose tolerance test
May be performed as early as one week after surgery
A nadir < 1 may define surgical success, assuming the OGTT was
abnormal preoperatively
A nadir < 0.4 ng/ml is suggested in this setting.

Post-Surgical Assessment (B)
12 week assessment is more valid determination
of surgical efficacy
Serum IGF-1
OGTT
A nadir < 1 may define surgical success, assuming the OGTT
was abnormal preoperatively
A nadir < 0.4 ng/ml is suggested in this setting.
MRI scan
Test for hypopituitarism i.e. free T4, TSH, cortrosyn stimulation
testing, LH, sex steroids, prolactin

Case 1, contd.
12 week serum IGF-1 normal, and nadir GH
following OGTT 0.3 ng/ml
Surgical cure!

7-ft and 8-in tall, shakes hands with President
Barack Obama after a rally. Recognized by
Guinness World Records on May 24, 2010, as
the tallest man in the United States.

Case 2
48 yo female with joint pain and fatigue. Also
with blurred vision. Has severe sleep apnea
syndrome, oligomenorrhea. PCP notices large
hands and refers to endocrinologist.
Physical exam suggestive. Ophthalmology
exam shows bitemporal hemianopsia
IGF-1: 1,260 ng/ml.
Nadir GH 8.3 ng/ml after OGTT
Prolactin 92 ng/ml

Macroadenoma
CS involvement
Chiasmal compression
Needs Surgery!

Pre-operative Medical Therapy?
Improve surgical outcomes?
There are supportive data
The panel did not support routine use in this regard
Improve medical co-morbidities?
May be used to improve intubation if tongue or mouth tissues
are thickened
Case by case basis

Does pretreatment improve biochemical
cure in macroadenomas?
Randomized
studies
N Drug/Mo IGF-1 nl
(%)
% ↑
IGF-1
nl
IGF-1
and GH

Peri-operative risk with acromegaly
Cardiovascular disease, with reduced ejection
fraction and arrhythmia
Sleep apnea
Traumatic intubation
Will medical therapy improve these
morbidities and be of value in preparation
for surgery?

Back to Case 2, Postoperative
assessment
Patient underwent surgery
No preoperative therapy
At 12 weeks, IGF-1 remained elevated at 530
ng/ml
Headaches persist

Therapy of Residual Disease after
Surgery
Re-operation?
Medical Therapy
Radiation Therapy

Medical Therapy
Dopamine Agonists
Bromocriptine
Cabergoline
Somatostatin Analogs
Octreotide
Subcutaneous or LAR
Lanreotide
Autogel depot
Growth Hormone Receptor Antagonist
Pegvisomant

Biochemical Monitoring on
Medical Therapy
Serum IGF-1
Important to utilize same assay throughout
To be assessed at least four weeks after dose change
Does not need to be fasting
GH assessment (not to be performed with use of
pegvisomant!)
Glucose suppressed often used
Recent study questions utility of this test during somatastatin analogue therapy

Medical Therapy
Dopamine Agonists
Bromocriptine
Cabergoline
Oral, relatively inexpensive
Side effect profiles similar (mostly GI, orthostasis)
although cabergoline often tolerated better
Risk of cardiac valve disease with cabergoline of unclear
significance
Try to maintain a cabergoline less than or equal to 3 mg/week

Medical Therapy
Somatostatin Analogs
Octreotide
Subcutaneous or LAR (nurse injects IM)
Lanreotide
Autogel depot (patient can inject subcutaneous)
Similar efficacy, differences in administration
Somatostatin analog biochemical efficacy
Normal IGF-1 in 67%
Controlled GH in 57%
a function of GH levels, tumor size
– Freda, Katznelson, van der Lely, et al, JCEM (2005)
Monthly, sometimes q6 week, injections

Medical Therapy
Side effects include gallstones, GI upset,
hyperglycemia, hair loss
Subcutaneous octreotide tid or qid particularly
useful if cost or headache control are issues

Growth Hormone Receptor
Antagonist (Pegvisomant)
Serum IGF-I
(ng/mL)
2500
2000
1500
1000
500
van der Lely et al Lancet 2001:358;1754
• up to 40 mg/day
• 97% normalized IGF-I
16-24 25-39 40-54
Age (years)
90 patients, 12 mo
55+

Medical Therapy: Pegvisomant
Utilized usually as secondary medical therapy
May be particularly useful in setting of hyperglycemia
Side effects:
ACRO study, 1288 subject data: approximately 2.5% of subjects
with LFTs > 3 x ULN
– Van der Lely et al, JCEM (2012)
Tumor growth uncommon: in a prospective study in Germany,
3/61 (4.9%), all during first year
Rebound following SSA withdrawal?
Lipohypertrophy
– Buhk et al, JCEM (2010) 95:552

Case 2, contd
Because of residual disease after surgery,
Octreotide LAR is initiated at 20 mg monthly,
and increased to 30 mg monthly with a modest
reduction in IGF-1, but still elevated
What are options?

Somatostatin analog resistance
Consider higher dose SSA

SSA resistant acromegaly: Increase the Dose?
Giustina et al, Eur J Endocrinol (2009), 61:331-338
24-week randomized trial SSA resistant acromegaly despite ≥6
month conventional SSA therapy.
high-dose (60 mg/28 days) or high-frequency (30 mg/21 days)
octreotide i.m. injection
Normal IGF-1 in 4 out of 11 (36%) HD and none of the HF
Mazziotti G et al. Eur J Endocrinol
2011;164:341-347
Posthoc analysis
Glucose status worsened in 25%
Worsening glucose associated
with inadequate GH/IGF-1
reduction

Somatostatin analog resistance
Consider higher dose SSA
Tumor debulking?
How about other agents?
Addition of Pegvisomant
Or substitution, if there is no IGF-1
response
Addition of dopamine agonist,
cabergoline
Radiotherapy

van der Lely, Eur J Endo
2011;164:325
• 57 pts uncontrolled with Lanreotide autogel 120 mg/mo received
pegvisomant (adapted every 8 weeks based on IGF1 levels to
40–80 mg once weekly or 40 or 60 mg twice weekly).
IGF1 normalized in 58% after 7 mos
results suggest a pegvisomant-sparing
effect versus daily pegvisomant
monotherapy
“It can…be presumed that combination
therapy will result in a cost benefit”

Radiation Therapy
Goal of disease cure
May take many years
No data that clearly show benefit of stereotactic radiotherapy
versus conventional radiotherapy
Primary Indications
Failed surgery
Inability of medical therapy to control disease

Radiation Therapy: Types
Conventional
Stereotactic Radiosurgery (high energy photons)
Gamma Knife
CyberKnife
Linear accelerator (LINAC)
Particle therapy with Proton beam

Radiation Therapy:
Consequences
Hypopituitarism
Serial pituitary function monitoring, at least annually
Secondary Malignancy
Accelerated cerebrovascular disease

Back to case…
Macroadenoma
CS involvement
Chiasmal compression

AACE 2011 Guidelines, Katznelson et al
Residual disease after TSS
SSA usually first line medical
therapy
d , consider a DA in the
setting of modest disease
e , consider RT in patients with
residual tumor following TSS
GH antagonist utilized as next
line therapy

Case 3
Macroadenoma
CS involvement
No chiasmal compression
Surgery unlikely to be curative
Surgery?
Primary Medical Therapy?

AACE 2011 Guidelines, Katznelson et al
b , consider primary medical
therapy if no VF deficit and no
chance of surgical cure given
cavernous sinus involvement
c , re-consider surgery to
debulk tumor to improve
medical tx response, to
reduce medical comorbidities,
or due to patient
preference
e , consider RT in patients with
residual tumor following TSS

Additional Monitoring:
Comorbidities
Skeletal
Prognathism: maxillofacial correction of dental malocclusion once
GH and IGF-1 levels are controlled
Degenerative joint disease pain may persist and is a common
source of persistent limitation in quality of life
Need aggressive anti-inflammatory management
Physical therapy
May require joint replacement surgery
Carpal Tunnel Syndrome
May require physical therapy or corrective surgery

Additional Monitoring:
Comorbidities
Respiratory
Presence of sleep apnea syndrome should be considered and evaluated
as warranted
Sleep apnea parameters may improve following successful biochemical
management, though may persist
Cardiovascular
Acromegaly is associated with a hypertrophic cardiomyopathy
May improve following successful treatment
Echocardiogram not generally indicated
• Suggest performance if clinically suspicious
Diabetes mellitus
Hypertension
Hyperlipidemia

Additional Monitoring:
Comorbidities
Neoplasia
Risk of cancer, particularly, colon, has been associated, but controversial
whether connected
Risk of death from cancer, especially colon, premenopausal breast, and
prostate maybe heightened in acromegaly
• Orme et al, JCEM (1998) 83:2730
Screening colonoscopy and breast exams/mammogram
recommended for subjects of all ages
Hypopituitarism
Especially from radiotherapy
GH deficiency may occur following successful therapy, particularly with
radiation
Controversy: GH replacement therapy in such patients
• A recent study suggests that may be beneficial

Case 4
32 yo female with acromegaly controlled with
a SSA.
Wishes to conceive
MRI scan shows modest cavernous sinus
disease, residual sellar mass without
suprasellar component

Pregnancy and Acromegaly
Limited data
An MRI and GH/IGF-I hormonal status should be performed just prior
to pregnancy.
medical therapy with a long-acting SSA should be discontinued two to
three months before a planned pregnancy , depending on clinical
condition
Once patient conceives:
If worsening symptoms, medical therapy can be re-initiated to ameliorate
specific concerns and reduce IGF-1 to pregnancy levels
Most experience during pregnancy with SSA, limited with DA, and
minimal with pegvisomant

Chen et al, Clin Endo
(2012) 76:264
•N=106
•81% pregnancies
uncomplicated, 3 with
GDM, 7 preeclampsia,
and 9 nine with
exacerbation of
acromegaly symptoms
mainly headaches.
•The development of
these complications was
not significantly modified
by the different
treatments
•78% newborns normal
weight

Pregnancy and Acromegaly
Once patient conceives:
Concern is tumor growth in response to estrogen stimulation
Close follow-up with serial visual field tests during pregnancy,
particularly in the setting of a macroadenoma is indicated
Acromegaly signs may not worsen during pregnancy
Estrogen protection?
Measurement of IGF-1 not useful