1. Surgery is the primary treatment for acromegaly but cure rates depend on tumor size, with microadenomas having higher cure rates than macroadenomas. Drug therapy and radiation are also options. 2. Treatment aims to control GH and IGF-I levels to reduce complications like heart disease, arthritis, and sleep apnea. Biochemical remission is defined as GH < 1 ug/L and age-normalized IGF-I levels. 3. While surgery and drug therapy can provide remission, optimal management also requires monitoring and treating comorbidities to improve quality of life long-term.

1. Surgery of Acromegaly
Dr. Ari Sami Hussain Nadhim
MBCHB,FICMS(Neurosurg.),FRCS,FACS,FAANS
Assist.Prof. Of Neurosurgery
Consultant Neurosurgeon
University of Sulaimani
School Of Medicine
May 2016

2. Acromegaly
Marie's disease

3. a chronic disease characterized by enlargement of the bones of the
head, the soft parts of the feet and hands, and sometimes other
structures, due to excessive secretion of growth hormone by the
pituitary gland.
Said in contemporary literature to have been coined 1885 by
French physician
Dr. Pierre Marie.

5. Incidence
• 2.8-6 cases per million per year

6. • Acromegaly is a rare hormonal disorder
• Prevalence: ~60 cases/million population1
• Incidence: 3.3 new cases/million/year1
• Mortality rate 2 to 4 times that of general
population2
1 NIDDK. Acromegaly. [www.niddk.nih.gov/health/endo/pubs/acro/acro.htm]
2. Wass J (ed). Handbook of Acromegaly. UK: BioScientifica Ltd, P. 19, 2001.

7. Complications
• High blood pressure (hypertension)
• Cardiovascular disease, particularly enlargement of the heart
(cardiomyopathy)
• Osteoarthritis
• Diabetes mellitus
• Goiter
• Precancerous growths (polyps) on the lining of your colon
• Sleep apnea, a condition in which breathing repeatedly stops and starts
during sleep
• Carpal tunnel syndrome
• Reduced secretion of other pituitary hormones (hypopituitarism)
• Uterine fibroids, benign tumors in the uterus
• Spinal cord compression
• Vision loss

8. • Early treatment of acromegaly can prevent
these complications from developing or
becoming worse.
• If untreated, acromegaly and its complications
can lead to premature death.

9. Most patients with acromegaly are diagnosed
with a macroadenoma
• Pituitary macroadenoma
– Large tumour
– Diagnosed in 75% of
patients
– Usually not cured by surgery
• Pituitary microadenoma
– Small tumour
– Diagnosed in 25% of
patients
– Likely to be cured by surgery
Image courtesy of A. Klibanski, MD.

11. • The diagnostic process took 2.9 (SD 4.53) years, during
which 3.4 (SD 2.99) physicians were consulted.
• Women waited longer [4.1 (SD 5.53) years] than men
[1.6 (SD 2.69) years; p = 0.001] for the correct
diagnosis, and consulted more doctors in the process
[4.0 (SD 2.99) vs. 2.7 (SD 2.84) doctors, p < 0.001,
respectively].
• In 48.5 % of patients, acromegaly was diagnosed by an
endocrinologist (men: 45.1 %; women: 52.4 %). Overall
disease duration from symptom onset until last surgery
was 5.5 (SD 6.85) years, with no sex differences.

12. Acromegaly – treatment options
• Surgical removal of
the tumour
• Drug therapy
• Radiation therapy
of the pituitary
Melmed S, Casanueva FF, Cavagnini P, et al. J Clin Endocrinol Metab. 2002 Sep;87(9):4054–8.

13. Treatment options – surgery
• Prompt relief of pressure and
lowering of GH levels
• Facial appearance and soft tissue
swelling may improve within days
• Cure rate dependent on tumour
size
• Depends on skill of surgeon
• Complications of surgery
• Patient monitored for years post-
surgery
• Hormone levels may not return
completely to normal
• Additional drug treatment may be
required
• Surgery contraindicated in
presence of co-morbidity
Melmed S, Casanueva FF, Cavagnini P, et al. J Clin Endocrinol Metab. 2002 Sep;87(9):4054–8.
NIDDK. Acromegaly. www.niddk.nih.gov/health/endo/pubs/acro/acro.htm.

14. Significant residual tumour
often remains after surgery
Image courtesy of A. Klibanski, MD.

15. Author No Criteria for remission Patients achieving
criteria for remission (%)
Abosch (1998) 254 GH <5µg/l 76
Swearingen (1998) 162 GH <2.5µg/l
OGTT <2µg/l
N IGF-I 57
Ahmed (1999) 139 GH <5mU/l 67
Gittoes (1999) 66 GH <5mU/l
OGTT <2mU/l 64
Biermasz (2000) 59 GH <5µg/l
N IGF-I 44–46
Kreutzer (2001) 57 GH <2.5µg/l
OGTT <1µg/l
N IGF-I 61–70
Surgical outcome analysis

16. • In most surgically treated acromegalic
patients, including all those in whom
biochemical remission has been achieved and
those in whom GH levels have been
significantly reduced but not normalized,
prompt regression of several symptoms can be
expected postoperatively.

17. • Currently, the reported success of
– intrasellar surgery varies between 75 and 95% for
intrasellar microadenomas, and
– between 45 and 68% for noninvasive
macroadenomas, if undertaken by experienced
surgeons who perform at least 50 case surgeries per
year
• Although the first approach in treatment is trans-
sphenoidal surgery, a trans-cranial approach is
required in some situations such as suprasellar
tumor expansion.
Clinical experiences and success rates of acromegaly treatment: the single center results of
62 patients. BMC Endocr Disord. 2014 Dec 16;14:97.Evran M1, Sert M, Tetiker T.

18. • Somatostatin analogues are the medical
treatment of choice in acromegaly, as first-line
or post-surgical therapy, and have proven
efficacy in pituitary tumor volume reduction
(TVR).
The effects of somatostatin analogue therapy on pituitary tumor volume in patients
with acromegaly. Pituitary. 2015 Aug 20. Colao A1, Auriemma RS, Pivonello R.

19. Pre-operative
treatment
Primary medical
treatment
• Before surgery
• Treatment for 3–6 months
• Mainly for macroadenomas
• Improves outcome of operation
• Instead of surgery
• Treatment for years
• Mainly for macroadenomas
• Treatment goals:
• Normalised GH/IGF-I
• Tumour control/
shrinkage
Primary medical therapy: two different
indications

20. • Some studies have shown that with use of
somatostatin analogs, biochemical remission is
attained, and tumors become smaller in size .
• Several long-term retrospective studies have
reviewed the effects of SA given postoperatively
and/or primarily, and have reported a wide
variation of biochemical remission rates of
between 34 and 95%
Clinical experiences and success rates of acromegaly treatment: the single center results
of 62 patients. BMC Endocr Disord. 2014 Dec 16;14:97. Evran M1, Sert M, Tetiker T.

21. • Long-term treatment (i.e. 10-15 years) with
SRA, improves the biochemical response rate
up to 80% of the patients
• Clinically significant tumor shrinkage (>20%) is
obtained in 75% of the patients
Current therapies and mortality in acromegaly.J Med Life. 2015 Oct-Dec; 8(4):
411–415. S Găloiu and C Poiană

22. Defining control in acromegaly (2010)
Outcome Criteria* Management
Active
disease
Random GH >1 µg/L and
nadir after OGTT ≥0.4 µg/L
Periodic MRI
Elevated IGF-1 Monitor and actively treat comorbidities
Clinically active Actively treat or change treatment
Controlled
disease
Random GH <1 µg/L and
nadir after OGTT <0.4 µg/L
Periodic, but less frequent MRI
(eg, every 2–3 years)
Age-sex normalized IGF-1 No change to current treatment;
consider reducing SRL dose
*Strong recommendations: assessment of GH during an OGTT and total IGF-1 after surgery; random GH for patients
on SRLs; if discrepancy in biochemical results, GH sampling 3–5 times over 2 hours; always use reliable standardized
assays and ultrasensitive assay for IGF-1 and GH measurement
Giustina A et al. J Clin Endocrinol Metab 2010;95:3141–8

23. • Optimal management of acromegaly is based on
three pillars:
– control of GH and IGF-I hypersecretion,
– tumour size control and
– optimisation of QoL by comprehensive management
of the comorbidities commonly associated with
acromegaly, such as
– diabetes mellitus,
– hypertension,
– obstructive sleep apnea and
– dyslipidaemia.

24. Surgery
• Trans-sphenoidal surgery is the primary
treatment for patients with small and, therefore,
curable tumors or for large adenomas causing
impingement of the optic chiasm.
• Surgical results depend on
– preoperative GH and IGF-I levels,
– tumor invasiveness and
– surgical skills

25. • In these cases experienced surgeons can achieve
remission rates of about 80%, defined as postoperative
normalization of IGF-I levels and suppression of GH
levels to < 1 mg/l after an oral glucose load.
• These rates drop to 20-30% for macroadenomas
(diameter ≥ 1 cm).
• For macroadenomas that are not entirely surgically
resectable (e.g., those with cavernous sinus extension)
surgery may be considered with the goal of debulking
the tumor mass.

26. Treatment options – radiotherapy
• Can be used with or
following other therapies
• Tumour regrowth is rare
• Relatively few adverse
events apart from
hypopituitarism
• Viewed as adjunctive therapy
• Slow onset of efficacy often
necessitates initial addition of
drug therapy
• Hypopituitarism develops in
>60% patients
• Potential for optic nerve
damage
• Risk of secondary malignancy
NIDDK. Acromegaly. www.niddk.nih.gov/health/endo/pubs/acro/acro.htm.
Melmed S, Casanueva FF, Cavagnini P, et al. J Clin Endocrinol Metab. 2002 Sep;87(9):4054–8.

27. Conventional radiation therapy:
delayed effects
Eastman RC, et al. Endocrinol Metab Clin North Am. 1992;21:693-712.
100
90
80
70
60
50
40
30
20
10
0
0 5 10 15 20 25 30
Years of Follow-Up
Patients(%)
GH <5 ng/mL
GH <10 ng/mL

28. RADIOTHERAPY VERSUS RADIOSURGERY IN
TREATING PATIENTS WITH ACROMEGALY: A
SYSTEMATIC REVIEW AND META-ANALYSIS.
Abu Dabrh AM, Asi N, Farah WH, et.al. Endocr Pract.2015 Aug;21(8):943-56.

29. • Outcomes evaluated were:
– serum insulin-like growth factor-I (IGF-I) and
– growth hormone (GH) levels,
– biochemical remission,
– all-cause mortality,
– hypopituitarism,
– headaches, and
– secondary malignancies
• The final search yielded 30 eligible studies
assessing 2,464 patients.

30. • Compared to RT, SRS was associated with
– a nonsignificant increase in remission rate at the
latest follow-up period (52% vs. 36%; P = .14) and
– a significantly lower follow-up IGF-I level (-409.72
μg/L vs. -102 μg/L, P = .002).
• SRS had a lower incidence of hypopituitarism
than RT; however, the difference was not
statistically significant (32% vs. 51%,
respectively; P = .05).

31. • The 5-year remission rates following Gamma
Knife is between 29 and 60%.
Clinical experiences and success rates of acromegaly treatment: the single center results of
62 patients. BMC Endocr Disord. 2014 Dec 16;14:97.Evran M1, Sert M, Tetiker T.

32. Acromegaly – mortality
• Increased mortality rate (2- to 4-fold)1
• Main determinant: most recent serum GH
concentration2
• Elevated IFG-I also associated with increased
mortality2
• Post-treatment GH levels < 2.5 ng/ml are
associated with reduced mortality3
1. Wass J (ed). Handbook of Acromegaly. UK: BioScientifica Ltd, P. 19, 2001
2. Stewart PM. Trends Endocrinol Metab. 2000; 11(4): 128–32.
3. Giustina A. J Clin Endocrinol Metab. 2000; 85: 526–529.

33. • In a meta-analysis,
– Dekkers reported an overall standard mortality
ratio (SMR) of
• 1.72 in all studied patients (n=16 studies),
• 1.32 in operated patients by transsphenoidal approach
and
• 1.09 in patients with GH<1 μg/ L, similar with the
reference population.
Current therapies and mortality in acromegaly. J Med Life. 2015 Oct-Dec; 8(4):
411–415. S Găloiu and C Poiană.

34. • The best predictor markers of mortality in
operated patients were:
– GH at last follow up,
– GH three years postoperatively and
– IGF1 levels at last follow up.
• Behind these data, there are studies reporting
better surgery results in patients with acromegaly
pre-treated with somatostatin receptor
analogues (SRA)

35. • The use of an endoscopic endonasal approach
with 3D technology provides several
advantages:
– length of stay,
– rate of complications,
– post-operative recovery and
– novice surgeons' training.

36. • Forty-one patients after TSS for somatotroph
pituitary adenoma and 23 patients with naive
acromegaly serving as positive controls were
enrolled in the study.
• even apparent normalization of GH and IGF-I
levels after successful adenomectomy does
not ensure a permanent cure.
Svetozar S. Damjanovic, Aleksandar N. Neskovic, Milan S. Petakov, .et.al, Clinical Indicators of
Biochemical Remission in Acromegaly: Does Incomplete Disease Control Always Mean Therapeutic
Failure? Clin Endocrinol. 2005;62(4):410-417.

37. Conclusion
• that more than two-thirds of patients who
underwent a surgical procedure achieved
normal IGF-I and mGH values, with the higher
success rate among those with a pituitary
microadenoma.

38. • This study shows that cardiac indices, insulin
resistance and body composition were not
different between patients with complete
biochemical remission and those with
discordant GH and IGF-I levels.
• It appears that even incomplete disease
control after TSS can result in improvement of
these clinical markers

39. • What is Active Acromegaly and Which
Parameters do we Have?
S. J. C. M. M. Neggers, N. R. Biermasz, A. J. van der Lely, What is Active Acromegaly
and Which Parameters do we Have?Clin Endocrinol. 2012;76(5):609-614.

40. • Growth hormone (GH) and insulin-like growth
factor 1 (IGF1) concentrations are the main
biochemical markers used to measure the
response to treatment.
• Both GH and IGF1 have been associated with
prognosis, in particular mortality.

41. • Acromegaly is a condition that reduces life
expectancy, a fact validated by three detailed
epidemiologic studies.
• Over the period of one study, Wright and
associates observed that the death rate
among acromegalic patients was more than
twice that of a control population.
• Cardiovascular disease, cerebrovascular
disease, malignant tumors, and respiratory
disease accounted for 24%, 15%, 15.5%, and
15.5% of deaths, respectively.

42. • Diabetes also responds to surgery in a
predictably favorable fashion; for patients in
whom GH levels are normalized, resolution of
diabetes and glucose intolerance has been
reported in up to 80% to 100% of cases

43. DEFINING ENDOCRINOLOGIC
REMISSION
• The criteria employed to define remission in
earlier series, such as reduction of basal GH
levels to less than 10 ng/mL, may have been
too liberal; patients thought to have been
cured on this basis continued to have active
acromegaly

44. • It is preferable to speak in terms of remission
rather than cure, because the long-term
outcome of surgically treated somatotroph
adenomas is not definitively known, and no
endocrinologic criteria, however stringent, can
guarantee that the patient will remain
permanently free of disease.

45. • If remission is to be based on any critical GH
level, the only prognostically justifiable
criterion is a mean GH level of less than 2.5
ng/mL.
• Reductions below this threshold have been
identified as the most important factor
associated with reducing mortality in
acromegaly.

46. • Using a postoperative GH level of less than 5 ng/mL as
the remission criterion, Ross and Wilson analyzed the
results of 30 published surgical series and identified an
overall endocrine remission rate of 60% in 771
patients.
• Similar results were reported by Zervas in a multicenter
survey of 1256 acromegalic patients.
• When the remission criteria included a basal GH level
• of less than 5 ng/mL, the overall rate of endocrine
remission was 66%.
• When surgery is used as the sole primary therapy, and
in the absence of any prior therapy, endocrine
remission can be expected in 42% to 84% of patients

47. • This is illustrated in the 222-patient series of
Fahlbusch and coworkers.
• A 71% remission rate was observed when a GH
level of less than 5 ng/Ml was used, but the rate
dropped to 57% when remission was defined on
the basis of suppressibility of GH to less than 2
ng/ mL on OGTT.
• Similarly, Losa and coworkers reported a
remission rate of 55% when a GH concentration
of less than 1 ng/mL and normal IGF-1 levels
were used to define remission.

48. Tumor Recurrence
• When strict criteria are used, such as
suppression of GH levels to less than 1 ng/mL
on OGTT and normalization of IGF-1 levels, a
durable remission is usually achieved, and
recurrence tends to be uncommon.
• The rate of recurrence in several large series
has ranged from 0% to 18% during mean
follow-up periods of 2.9 to 8.9 years,
• the rate of recurrence is approximately 6%.

49. Postoperative Monitoring and
Management
• After surgery, GH and IGF-1 levels should be
assessed, and if they are normal, the patient can
be followed up annually or as required.
• Patients with persistent disease should be treated
with Sandostatin-LAR with monitoring of GH and
IGF-1 levels until the dose is optimized.
• They can then be followed up every 6 months.
• If GH levels remain increased despite a maximum
dose of octreotide, then combined medical
therapy with octreotide and dopamine agonists,
preferably cabergoline, should be tried.

50. • Radiotherapy should be considered when
medical therapy with octreotide and
dopamine agonists fails to achieve a
biochemical remission.
• A colonoscopy is recommended for all
patients at diagnosis, and every 3 to 5 years
thereafter, if polyps are found.