1) Acromegaly is caused by excess growth hormone production, usually from a pituitary tumor. The goals of treatment are to control symptoms, suppress hormone levels, decrease tumor size, and preserve normal pituitary function. 2) Surgical removal of the tumor via transsphenoidal surgery often results in remission, with higher rates for microadenomas versus macroadenomas. Pre-operative factors like tumor size and invasiveness affect outcomes. 3) Medical therapies like somatostatin analogs and GH receptor antagonists can help control hormone levels and symptoms in cases where surgery is not effective or possible. These medications provide alternatives or adjuncts to surgery in treating acromegaly.

1. ACROMEGALY
Ilan Shimon, MD
Rabin Medical Center,
Petach-Tiqva

2. Objectives of Treatment for Acromegaly
• Control and reverse symptoms and signs
• Suppress GH and IGF-1 to control morbidity and
mortality
• Decrease pituitary tumor size
• Control tumor mass effects
• Preserve normal pituitary hormone secretion

3. Surgical Outcome in Acromegaly
• Experience of the neurosurgeon
• Adenoma size
• Invasiveness into adjacent structures
• Pre-operative GH level

4. Remission of Acromegaly After
Transsphenoidal Surgery
Microadenomas – 70-90 %
Macroadenomas – 40-60 %
100
90
80
Remission Rate (%)
70
60
50
40
30
20
10
0
Microadenoma (n=44) Macroadenoma (n=44)
Shimon I. Neurosurgery. 2001;48:1239

5. Remission of Acromegaly After
Transsphenoidal Surgery
GH Criteria Micro- Macro-
Study Patients IGF-1
ng/mL adenomas adenomas
Ahmed Mean GH
139 91% 46%
1990 <2.5
Fahlbusch
224 OGTT <2 72% 50%
1992
Davis Basal/OGTT
175 60% 35%
1993 <2.5
Osman OGTT
79 84%
1994 <2.5
Sheaves Mean GH
100 61% 23%
1996 <2.5

6. Remission of Acromegaly After
Transsphenoidal Surgery (cont’d)
GH Criteria Micro- Macro-
Study Patients IGF-1
ng/mL adenomas adenomas
Swearingen Normal-
162 OGTT <2 91% 48%
1998 82%
Basal/OGTT Normal-
Freda 1998 115 88% 53%
<2 87%
OGTT
Lissett 1998 73 59% 14%
<2.5
Shimon Basal/OGTT Normal-
98 84% 64%
2001 <2 72%
Mean GH
Normal-
De P 2003 90 <2.5 79% 56%
68%
OGTT <1

7. Remission of Acromegaly After
Transsphenoidal Surgery According
to Adenoma Size
100
90
80
Remission Rate (%)
70
60
50
40
30
20
10
0
3-6 (n=16) 7-10 (n=26) 11-20 (n=26) >20 (n=10)
Adenoma Size (mm)
Shimon I. Neurosurg. 2001;48:1239

8. Acromegaly
• Definition of surgical cure
• Pre-operative medical treatment
• Primary medical treatment
• Improved remission by medical therapy after
surgical debulking
• Multi-recepotor SRIF analogs
• GH receptor antagonist
• Combination therapy

9. Current Clinical Practice?
Nadir GH Nadir GH
<1 µg/L >1 µg/L
IGF-1 Normal No Treatment ?
IGF-1 Elevated “Treat” Treat

10. Association Between
Serum IGF-I and Nadir GH
Concentrations Across an OGTT
Nadir GH Nadir GH
<1 µg/L >1 µg/L
IGF-1 Normal 52 (58%) 37 (42%)
IGF-1 Elevated 34 (13%) 226 (87%)
108 treated patients P<0.0001
Ayuk, et al (unpublished data).

11. Mortality in Acromegaly
1.0
GH <1 µg/L
0.8
NZ Population
0.6 GH <2 µg/L
Probability
GH <5 µg/L
0.4
GH >5 µg/L
0.2
0
0 5 10 15 20 25 30
Time (Years)
Holdaway IM,JCEM; 2004, 89:667

12. Factors Influencing Mortality
in Acromegaly
1.0
IGF SD Score <2
0.8
Proportion Surviving
NZ Population
0.6
IGF SD Score >2
0.4
0.2
0
0 5 10 15 20 25 30
Time (Years)
Holdaway IM,JCEM; 2004, 89:667

13. ng-term Mortality After Transsphenoidal Surgery
1.0
Normal IGF-I
0.8 Elevated IGF-I
Cox model 0.6
predicted
survival
0.4
Patient in remission
0.2 Patient not in remission
0.0
0 5 10 15 20
Years after surgery
Swearingen, B. et al. J Clin Endocrinol Metab 1998;83:3419

14. Nadir GH levels after OGTT in postoperative
patients with normal IGF-I
Freda PU, et al. 2004, JCEM; 89:495

15. Post-operative Follow-Up With
Normal IGF-1 Values
• 110 post-operative patients with acromegaly
– 76 remission (normal IGF-1)
• 50 normal GH nadir (<0.14 µg/L; group 1)
• 26 abnormal GH nadir (0.3+0.05 µg/L;group 2)
• Longitudinal follow-up 1-6.5 years
– IGF-1 Group 1 normal in all
– IGF-1 Group 2 elevated in 5
• Conclusion: persistent abnormal GH
suppression is associated with
increased risk of recurrence
Freda PU, et al. 2004, JCEM; 89:495

16. Conclusions
• Evaluate normal ranges of GH and IGF-1 assays
(“know your assay”)
• Patients with evidence of hypersecretion of GH
should be considered for treatment irrespective of
IGF-1 value
• Patients with elevated IGF-1 should be
considered for treatment irrespective of GH value
• Treatment of co-morbidities may be even more
important and may influence the decision to treat

17. Pre-operative Treatment With
Somatostatin Analogs—
Clinical Studies
• Only few studies with small number of patients
• No randomized placebo-controlled studies
• Most studies with short-acting analogs
• No consistency in pre-operative dosage and
treatment interval

18. Pre-operative Treatment With
Somatostatin Analogs
• Six studies with treated/untreated patients
before pituitary surgery
• Five studies used subcutaneous OCT
• OCT dose was usually started at 300 µg/day,
and individually increased
• Pre-operative medical therapy was maintained
for 1-39 months before surgery, usually for
3-6 months
• The criteria for post-operative remission not
similar

19. Available Comparative Studies
Study OCT Untreated
Stevenaert—Metabolism 1996 64 108
Colao—JCEM 1997 22 37
Kristof—Acta Neurochir 1999 11 13
Biermasz—JCEM 1999 19 19
Abe—Eur J Endocrinol 2001 90 57
French Acromegaly Registry—
OCT/LAN 86 105
ENEA 2004
TOTAL: Pre-operative SRIF 292
Untreated 339

20. French Acromegaly Registry–
ENEA 2004, Sorrento;
OCT/LAN (86), Untreated (105)
Surgical Remission Rate
Pre-treated Untreated
No. % No. %
All 86 55 105 51
Noninvasive 40 67 54 65
Remission rate improved in patients
pre-treated for 4-6 months

21. Pre-surgical Treatment (292)
Untreated (339)
Summary of 6 Publications
Surgical Remission Rate
Pre-treated Untreated
No. % No. %
All 292 63.4 339 54.5
Noninvasive 166 83.7 169 74

22. Odds Ratio Plot
(Fixed Effects)
Mantel-Haenszel chi-square = 0.7341; P = 0.3916
Odds ratio meta-analysis plot [fixed effects]
stratum 1 French Registry 1.14 (0.62, 2.10)
stratum 2 Abe & Ludecke 0.65 (0.28, 1.48)
stratum 3 Biermasz NR 0.61 (0.12, 2.98)
stratum 4 Kristof RA 0.53 (0.07, 3.79)
stratum 5 Colao A 2.84 (0.83, 9.77)
stratum 6 5.74 (1.42, 32.93)
Stevenaert & Beckers
stratum 7 0.98 (0.29, 3.10)
combined [fixed] 1.18 (0.84, 1.66)
0.01 0.1 0.2 0.5 1 2 5 10 100
odds ratio (95% confidence interval)

23. UK Primary
Octreotide Study:
Individual Growth
Hormone
Response
(sc Oct, Oct-LAR)
Bevan JS et al. J Clin Endocrinol
Metab. 2002;87:4554-4563.

24. Tumor Changes After Primary OCT Therapy
Expressed as a Percentage of the Pre-treatment
Volume in 20 Macroadenomas
120%
Percentage of Original Size
100%
80%
60%
40%
20%
0%
Baseline 12 Weeks 24 Weeks 48 Weeks
Bevan J. et al., J Clin Endocrinol Metab. 2002; 87:4554-4563.

25. Tumor Shrinkage in Patients With
Previously Untreated Acromegaly
(a) (b)
0 Microadenomas 0
-10 -10
Shrinkage (%)
Shrinkage (%)
-20 -20 Lanreotide SR
-30 -30
Macroadenomas
-40 -40 Octreotide LAR
-50 -50
-60 -60
-70 -70
T0 T12 T24 T0 T12 T24
Months of Therapy Months of Therapy
Amato G. Clin Endocrinol. 2002;56:65

26. Effect of Octreotide on GH Levels
in Acromegaly
400
300
Growth Hormone (µg/L)
200
100
70 Pre-treatment
60 During Treatment
50
40
30
25
20
15
10
5
2.5
% Normal % Normal % Normal % Normal % Normal % Normal
IGF-1: 30% IGF-1: 53% IGF-1: 63% IGF-1: 75% IGF-1: 86% IGF-1: 83%
Newman et al. J Clin Endocrinol Metab. 1998;83:3034-3040.

27. Surgical Debulking Improves Hormonal Control
of Acromegaly by SST analogs (OCT, LAN)
(retrospective; 1-33 months, 300-1500 µg/day)
Baseline Preoperative Postoperative SST Baseline Postoperative SST
washout Preoperative washout
sst sst
Petrossians P, JCEM, 2005; 152:61

29. SSTR2 and SSTR5 expression in GH-secreting adenomas
(according to in vivo GH suppression by Octreotide)
Saveanu A, JCEM 2001; 86:140

30. BIM-23244, a bispecific (SSRR2 + SSTR5) analog
Saveanu A, JCEM 2001; 86:140

31. SST2 and D2DR expression in 11 GH-secreting tumors
Saveanu A, JCEM 2002; 87:5545

32. A Chimeric Somatostatin-Dopamine Molecule, BIM-23A387
OCT-responsive OCT-partially responsive
Saveanu A, JCEM 2002; 87:5545

33. SOM-230, a somatostatin analog with
broad spectrum binding affinity
(Receptor subtype affinity (IC50, nM
Compound SSTR1 SSTR2 SSTR3 SSTR4 SSTR5
SRIF-14 2.26 0.23 1.43 1.77
Octreotide 1140 0.56 34 7030 7
Lanreotide 2330 0.75 107 2100 5.2
SOM-230 9.3 1 1.5 >100 0.16

34. Effect of Infused OCT and SOM230
on IGF-1 Plasma Levels in Rats
Weckbecker G, Endocrinology, 2002; 143:4123

35. GH release in cultured GH-secreting adenomas
Incubated with SOM-230
Hofland LJ, JCEM 2004; 89:1577

36. PRL release in cultured mixed PRL/GH-secreting
Adenomas incubated with SOM-230
Hofland LJ, JCEM 2004; 89:1577

37. In vivo GH suppression 2-8 h
after SOM-230 injection
N=8
N=3
Van der Hoek J, JCEM 2004; 89:638

38. GHR Antagonist Action
Pituitary
Tumor
• Blocks GH effect
GH B2036-PEG
• Normalizes IGF-I in 92% of X
patients
Liver
X
IGF-I

39. IGF-I in 112 Patients with Acromegaly
Treated with Pegvisomant or Placebo
800
placebo
Serum IGF-I (ng/ml)
600
10 mg
400
15 mg
20 mg
200
0 2 4 8 12
Time (weeks)
Trainer et al N Eng J Med. 2000:342;1171-1177

40. Change in Serum GH in Patients
With Acromegaly Treated With Daily
Pegvisomant or Placebo
25
20 mg *
15 mg *
20
Serum * P <0.001
15 vs. placebo
GH
(ng/ml)
10 10 mg
placebo
5
0 2 4 8 12
Time (weeks) Trainer et al. NEJM. 2000:342;1171-1177

41. Pegvisomant Impact on GH
and IGF-I Levels
Dose mg
200
GH 20
150
15
100
Delta (%)
50
0 0
–25
15
–50
IGF-I
20
–75 2 4 8 12
Weeks
Trainer, PJ et al. N. Engl. J. Med. Apr 2000;342:1171-7.

42. IGF-1 at Baseline and After
12 Months of Pegvisomant
2500
2000
Serum IGF-1 97% normalization of IGF-1 (n=90)
(ng/mL) 1500
1000
500
16-24 25-39 40-54 55+
Age (years)
van der Lely et al. Lancet. 2001;358:1754

43. Tumor Volume Changes in
92 Patients Receiving Daily Pegvisomant
for >6 Months
4
No Radiation
3 Radiation
Change 2
in
1
Volume
(cm3) 0
-1
-2
-3
0 6 12 18 24 30 36
Time (months)
van der Lely et al. Lancet. 2001;358:1754

44. Acromegaly Cotreated
with GHR Antagonist
and Octreotide
van der Lely, JCEM; 2001, 86:478

45. Cotreatment with Sandostatin-LAR
and daily Pegvisomant (10/15 mg)
Jorgensen JO, JCEM, 2005; 90:5627

46. IGF-1 before and after 6 weeks of combined treatment
SSTR (LAR/Autogel) analog monthly + Pegvisomant
(up to 80 mg) weekly
Feenstra J et al, Lancet 2005, 365:1644