Gigantism and Acromegaly Treatment & Management
- Author: Alicia Diaz-Thomas, MD, MPH; Chief Editor: Stephen Kemp, MD, PhD more...
Most experts define cure, or adequate control, of growth hormone (GH) excess as a glucose-suppressed GH concentration of less than 2 ng/mL, as determined by radioimmunoassay (1 mcg/L by IRMA), and normalization of the serum insulinlike growth factor I (IGF-I) concentration.
However, no single treatment modality consistently achieves control of GH excess. For pituitary adenomas, transsphenoidal surgery is usually considered the first line of treatment, followed by medical therapy for residual disease. Radiation treatment usually is reserved for recalcitrant cases.
Radiotherapy and medical treatment are important because in long-term studies, surgery has been found to cure only approximately 60% of patients with acromegaly. Slow-release formulations of somatostatin are now widely used (including as a primary treatment) and appear to be safe and effective in 50-60% of the patients. A GH-receptor blocking agent, pegvisomant, appears to normalize IGF-I levels in almost all patients.
Guidelines released by the US Endocrine Society in 2014 address important clinical issues regarding the evaluation and management of acromegaly.[25, 26] Recommendations include the following:
For most patients with acromegaly, surgical removal of the pituitary gland tumor should be considered the primary treatment
An imaging study should be performed at least 12 weeks postsurgery to determine whether any residual tumor tissue is present
Patients should be evaluated for any damage caused by the pituitary tumor and for the development of hypopituitarism
Medical therapy should be administered only to patients with persistent postoperative disease
The guidelines also address the management of women with acromegaly who are pregnant or trying to conceive.
The goals of medical therapy for GH excess are as follows:
Remove or shrink the pituitary mass
Restore GH secretory patterns to normal
Restore serum total IGF-I and IGF binding protein 3 (IGFBP-3) levels to normal
Retain normal pituitary secretion of other hormones
Prevent recurrence of disease
Somatostatin and dopamine analogues and GH receptor antagonists are the mainstays of medical treatment for GH excess and are generally used when primary surgery fails to induce complete remission.
The most extensively studied and used somatostatin analogue, octreotide, binds to the somatostatin receptor subtypes II and V, inhibiting GH secretion. Octreotide suppresses the serum GH level to less than 2.5 mcg/L in 65% of patients with acromegaly and normalizes circulating IGF-I levels in 70% of patients. Tumor shrinkage, although generally modest, is seen in 20-50% of patients. Consistent GH suppression was achieved with a continuous subcutaneous pump infusion of octreotide in a pubertal boy with pituitary gigantism.
Studies of patients with GH excess for longer than 14 years have demonstrated that the effects of octreotide are well sustained over time. An anaphylactic reaction to octreotide has been described.
Primary treatment with depot octreotide and lanreotide has been found to induce tumor shrinkage in newly diagnosed acromegaly.
Long-acting formulations, including long-acting octreotide, lanreotide, and pasireotide, have been demonstrated to produce consistent GH and IGF-I suppression in patients with acromegaly with once-monthly or biweekly intramuscular depot injections. (Sustained-released preparations have not been formally tested in children with gigantism.)
In 2 Japanese studies, by Shimatsu et al, the sustained-release lanreotide Somatuline Depot (or lanreotide Autogel) was found to control elevated GH and IGF-I levels within the first weeks of treatment, as well as over a long-term period of administration. In an open-label, parallel-group, dose-response study, which included 29 patients with acromegaly and 3 with pituitary gigantism, 5 injections of lanreotide Autogel were administered over a 24-week period, in dosages of 60, 90, or 120 mg.
At week 4, serum GH levels of below 2.5 ng/mL and normalized IGF-I levels were found in 41% and 31% of patients, respectively. At week 24, the investigators found that serum GH levels of below 2.5 ng/mL and normalized IGF-I levels had been attained in 53% and 44% of patients, respectively.
In the second investigation, an open-label, long-term study of 30 patients with acromegaly and 2 with pituitary gigantism, lanreotide Autogel injections were administered every 4 weeks for a period of 52 weeks (13 injections). Patients initially received a 90-mg dose, which was subsequently adjusted based on clinical response. At week 52, serum GH levels of below 2.5 ng/mL and normalized IGF-I levels had been achieved in 47% and 53% of patients, respectively.
Pasireotide’s approval was based on 2 multicenter, phase 3 studies. One in medically naive patients with acromegaly who had prior surgery or in whom surgery was not an option, and the other in patients inadequately controlled on first-generation somatostatin analogs (ie, octreotide, lanreotide). The risk for hyperglycemia needs to be considered with use of pasireotide.[29, 30]
Dopamine-receptor agonists (eg, bromocriptine, cabergoline) bind to pituitary dopamine type 2 (D2) receptors and suppress GH secretion, although their precise mechanism of action remains unclear.
Prolactin levels are often adequately suppressed with these agents. However, circulating GH and IGF-I levels rarely normalize with this therapy. Less than 20% of patients achieve GH levels of less than 5 ng/mL, and less than 10% achieve normal IGF-I levels. Tumor shrinkage occurs in a few patients.
Dopamine-receptor agonists are generally used as adjuvant medical treatments for GH excess, and their effectiveness may be added to that of octreotide.
Although long-acting formulations are available, no data about the long-term control of GH and IGF-I with these agents are available.
Bromocriptine has an adjunctive role in the treatment of patients with GH excess who fail to achieve a cure by surgical treatment or who are to be treated with radiation. It has limited effectiveness, however, reducing the circulating GH level to less than 5 ng/mL in only 20% of patients with acromegaly and normalizing IGF-I concentration in only 10% of these patients. Shrinkage in tumor size also occurs, albeit in fewer than 20% of patients. Patients in whom prolactin is elevated are more likely to have a favorable response to bromocriptine.
Cabergoline, another dopamine-receptor agonist, is somewhat more effective than bromocriptine in reducing GH levels, with response rates of 46%. A meta-analysis found that cabergoline used as single-agent therapy in patients with acromegaly normalized IGF-I levels in one third of patients. In those cases in which a somatostatin analogue has failed to control acromegaly, cabergoline adjunction normalized IGF-I levels in about 50% of gases.
Tests of pegvisomant (Somavert), a novel hepatic GH-receptor antagonist, demonstrated effective suppression of GH and IGF-I levels in patients with acromegaly due to pituitary tumors or ectopic GHRH hypersecretion.
Normalization of IGF-I levels occurs in as many as 90% of patients treated daily with this drug for 3 months.
In the interim analysis of ACROSTUDY, a global noninterventional surveillance study of 1288 patients with acromegaly treated with pegvisomant for a mean period of 3.7 years (2.1-y mean follow-up), 63.2% of subjects had normal IGF-1 levels at a mean dose of 18 mg/day. The reported incidence of transaminitis, lipodystrophy, and increase in pituitary tumor size was low.
Combination therapy with pegvisomant and cabergoline or somatostatin analogues is also being investigated for efficacy.
Pegvisomant has not been formally tested in children; however, a case study described normalization of IGF-1 in a 12-year-old girl with pituitary gigantism treated with pegvisomant 20 mg/day.
In general, radiation therapy is recommended if GH hypersecretion is not normalized with surgery. Radiation prevents further growth of the tumor in more than 99% of patients after surgical resection.
However, radiation treatment takes to years reduce/normalize GH/IGF-I levels. About 60% of patients have a GH concentration of less than 5 ng/mL 10 years after radiotherapy.
Hypopituitarism is a predictable outcome of radiation treatment, occurring in 40-50% of patients within 10 years after irradiation. Some studies suggest that radiation is associated with the development of secondary tumors.
Newer modalities (eg, stereotactic fractionated radiotherapy, proton beam therapy) may have the advantage of a better target dose-conformation, but long-term outcome data are lacking at this time.
Stereotactic gamma-knife radiosurgery for recurrent or residual pituitary adenomas, when combined with microsurgery, is often effective in controlling pituitary adenoma growth and hormone hypersecretion. Results are influenced by many factors, including adenoma histology, adenoma volume, and radiation dose.
The primary goal of surgery is to normalize GH levels. For well-circumscribed pituitary adenomas, transsphenoidal surgery to completely remove the tumor is the treatment of choice, and it may be curative. The procedure can also rapidly improve symptoms caused by mass effect of the pituitary tumor. The following should be kept in mind concerning surgical treatment:
The likelihood of a surgical cure greatly depends on the surgeons' expertise and on the size and extension of the mass
Intraoperative GH measurements can improve the results of tumor resection
Transsphenoidal surgery to resect tumors is as safe in children as it is in adults
A transcranial approach is sometimes necessary
As determined by using the GH assays available to date, GH levels should be normalized (< 1 ng/mL for ≥50% of the points measured during the day) in all patients. Because this change is impractical to test, however, GH levels (< 1 ng/mL within 2 h after a glucose load) and serum IGF-I levels (within 2 standard deviations of the reference range adjusted for age, sex, and Tanner stage) are the best measures of a biochemical cure.
A remission rate of 80-85% can be expected for microadenomas and 50-65% for macroadenomas.
The postoperative GH concentration may predict remission rates. According to the results of one study, a postoperative GH concentration of less than 3 ng/dL was associated with a 90% remission rate, which declined to 5% in patients with a postoperative GH concentration of greater than 5 ng/dL.
A significant proportion of acromegalic patients who have undergone surgery have been found to have a change in biochemical status upon long-term follow-up. Most of these changes have occurred within the first postoperative year and were more likely to occur if the initial GH postglucose and IGF-I levels were discordant.
If surgery does not normalize GH secretion, options include pituitary radiation and medical therapy.
All patients with a history of GH excess require periodic, lifelong evaluation. In one series, the long-term recurrence rate for GH-secreting adenomas in children was 13.3% after surgery.
IGF-I levels appear to correlate better with clinical activity than do GH levels and should therefore be monitored.
Patients should also be evaluated for severe GH deficiency, which may occur in more than half of all patients treated for acromegaly (even those who have been cured by surgery alone).
Because an association exists between acromegaly and regurgitant valvular heart disease, patients with acromegaly require adequate cardiac evaluation and follow-up to establish whether valvular disease is present and, if so, to determine the extent and progression of valvular involvement.
Berg C, Petersenn S, Lahner H, Herrmann BL, Buchfelder M, Droste M, et al. Cardiovascular risk factors in patients with uncontrolled and long-term acromegaly: comparison with matched data from the general population and the effect of disease control. J Clin Endocrinol Metab. 2010 Aug. 95(8):3648-56. [Medline].
Nainggolan L. Gene Discovery in Giants Could Shed Light on Human Growth. Medscape Medical News. Available at http://www.medscape.com/viewarticle/836216.. Accessed: December 12, 2014.
Trivellin G, Daly AF, Faucz FR, Yuan B, Rostomyan L, Larco DO, et al. Gigantism and acromegaly due to Xq26 microduplications and GPR101 mutation. N Engl J Med. 2014 Dec 18. 371(25):2363-74. [Medline].
Al-Bedaia M, Al-Khenaizan AS. Acromegaly presenting as cutis verticis gyrata. Int J Dermatol. 2008 Feb. 47(2):164. [Medline].
Bush ZM, Vance ML. Management of acromegaly: is there a role for primary medical therapy?. Rev Endocr Metab Disord. 2008 Mar. 9(1):83-94. [Medline].
Colao A, Pivonello R, Auriemma RS, Briganti F, Galdiero M, Tortora F, et al. Predictors of tumor shrinkage after primary therapy with somatostatin analogs in acromegaly: a prospective study in 99 patients. J Clin Endocrinol Metab. 2006 Jun. 91(6):2112-8. [Medline].
Giustina A, Chanson P, Bronstein MD, Klibanski A, Lamberts S, Casanueva FF, et al. A consensus on criteria for cure of acromegaly. J Clin Endocrinol Metab. 2010 Jul. 95(7):3141-8. [Medline].
Colak Ozbey N, Kapran Y, Bozbora A, Erbil Y, Tascioglu C, Asa SL. Ectopic growth hormone-releasing hormone secretion by a neuroendocrine tumor causing acromegaly: long-term follow-up results. Endocr Pathol. 2009 Summer. 20(2):127-32. [Medline].
Uchoa HB, Lima GA, Corrêa LL, Vidal AP, Cavallieri SA, Vaisman M, et al. Prevalence of thyroid diseases in patients with acromegaly: experience of a Brazilian center. Arq Bras Endocrinol Metabol. 2013 Dec. 57(9):685-90. [Medline].
Soares BS, Eguchi K, Frohman LA. Tumor deletion mapping on chromosome 11q13 in eight families with isolated familial somatotropinoma and in 15 sporadic somatotropinomas. J Clin Endocrinol Metab. 2005 Dec. 90(12):6580-7. [Medline].
Melmed S, Casanueva FF, Klibanski A, Bronstein MD, Chanson P, Lamberts SW, et al. A consensus on the diagnosis and treatment of acromegaly complications. Pituitary. 2013 Sep. 16(3):294-302. [Medline]. [Full Text].
Oshino S, Nishino A, Suzuki T, et al. Prevalence of cerebral aneurysm in patients with acromegaly. Pituitary. 2013 Jun. 16(2):195-201. [Medline].
Stelmachowska-Banas M, Zdunowski P, Zgliczynski W. Abnormalities in glucose homeostasis in acromegaly. Does the prevalence of glucose intolerance depend on the level of activity of the disease and the duration of the symptoms?. Endokrynol Pol. 2009 Jan-Feb. 60(1):20-4. [Medline].
Dworakowska D, Gueorguiev M, Kelly P, Monson JP, Besser GM, Chew SL, et al. Repeated colonoscopic screening of patients with acromegaly: 15-year experience identifies those at risk of new colonic neoplasia and allows for effective screening guidelines. Eur J Endocrinol. 2010 Jul. 163(1):21-8. [Medline].
Loeper S, Ezzat S. Acromegaly: re-thinking the cancer risk. Rev Endocr Metab Disord. 2008 Mar. 9(1):41-58. [Medline].
Kurimoto M, Fukuda I, Hizuka N, Takano K. The prevalence of benign and malignant tumors in patients with acromegaly at a single institute. Endocr J. 2008 Mar. 55(1):67-71. [Medline].
Izzard AS, Emerson M, Prehar S, Neyses L, Trainer P, List EO, et al. The cardiovascular phenotype of a mouse model of acromegaly. Growth Horm IGF Res. 2009 Oct. 19(5):413-9. [Medline].
[Guideline] Katznelson L, Atkinson JL, Cook DM, Ezzat SZ, Hamrahian AH, Miller KK. American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the Diagnosis and Treatment of Acromegaly--2011 update: executive summary. Endocr Pract. 2011 Jul-Aug. 17(4):636-46. [Medline].
Wang M, Mou C, Jiang M, Han L, Fan S, Huan C, et al. The characteristics of acromegalic patients with hyperprolactinemia and the differences in patients with merely GH-secreting adenomas: clinical analysis of 279 cases. Eur J Endocrinol. 2012 May. 166(5):797-802. [Medline].
Almalki MH, Chesover AD, Johnson MD, Wilkins GE, Maguire JA, Ur E. Characterization of management and outcomes of patients with acromegaly in Vancouver over 30 years. Clin Invest Med. 2012 Feb 1. 35(1):E27-33. [Medline].
Sata A, Ho KK. Growth hormone measurements in the diagnosis and monitoring of acromegaly. Pituitary. 2007. 10(2):165-72. [Medline].
Daroszewski J, Bolanowski M, Kaluzny M, Siewinski M. The imbalance of cathepsin B-like activity in acromegalic patients--preliminary report. Neuro Endocrinol Lett. 2010. 31(2):256-60. [Medline].
Roelfsema F, Biermasz NR, Romijn JA, Pereira AM. Treatment strategies for acromegaly. Expert Opin Emerg Drugs. 2005 Nov. 10(4):875-90. [Medline].
[Guideline] Katznelson L, Laws ER Jr, Melmed S, et al. Acromegaly: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2014 Nov. 99(11):3933-51. [Medline].
[Guideline] Nainggolan L. New Guidelines for Acromegaly Include Advice on Pregnancy. Medscape Medical News. Nov 10 2014. [Full Text].
Azkur D, Yoldas T, Toyran M, Kocabas CN. A pediatric case of anaphylaxis due to octreotide. Asian Pac J Allergy Immunol. 2011 Dec. 29(4):361-3. [Medline].
Shimatsu A, Teramoto A, Hizuka N, Kitai K, Ramis J, Chihara K. Efficacy, safety, and pharmacokinetics of sustained-release lanreotide (lanreotide Autogel) in Japanese patients with acromegaly or pituitary gigantism. Endocr J. 2013. 60(5):651-63. [Medline].
Sheppard M, Bronstein MD, Freda P, Serri O, De Marinis L, Naves L, et al. Pasireotide LAR maintains inhibition of GH and IGF-1 in patients with acromegaly for up to 25 months: results from the blinded extension phase of a randomized, double-blind, multicenter, Phase III study. Pituitary. 2014 Aug 8. [Medline].
Gadelha MR, Bronstein MD, Brue T, Coculescu M, Fleseriu M, Guitelman M, et al. Pasireotide versus continued treatment with octreotide or lanreotide in patients with inadequately controlled acromegaly (PAOLA): a randomised, phase 3 trial. Lancet Diabetes Endocrinol. 2014 Nov. 2(11):875-84. [Medline].
Sandret L, Maison P, Chanson P. Place of cabergoline in acromegaly: a meta-analysis. J Clin Endocrinol Metab. 2011 May. 96(5):1327-35. [Medline].
van der Lely AJ, Biller BM, Brue T, Buchfelder M, Ghigo E, Gomez R, et al. Long-term safety of pegvisomant in patients with acromegaly: comprehensive review of 1288 subjects in ACROSTUDY. J Clin Endocrinol Metab. 2012 May. 97(5):1589-97. [Medline].
Higham CE, Atkinson AB, Aylwin S, Bidlingmaier M, Drake WM, Lewis A, et al. Effective combination treatment with cabergoline and low-dose pegvisomant in active acromegaly: a prospective clinical trial. J Clin Endocrinol Metab. 2012 Apr. 97(4):1187-93. [Medline].
Rix M, Laurberg P, Hoejberg AS, Brock-Jacobsen B. Pegvisomant therapy in pituitary gigantism: successful treatment in a 12-year-old girl. Eur J Endocrinol. 2005 Aug. 153(2):195-201. [Medline].
Castinetti F, Morange I, Dufour H, Regis J, Brue T. Radiotherapy and radiosurgery in acromegaly. Pituitary. 2009. 12(1):3-10. [Medline].
Weber DC, Momjian S, Pralong FP, Meyer P, Villemure JG, Pica A. Adjuvant or radical fractionated stereotactic radiotherapy for patients with pituitary functional and nonfunctional macroadenoma. Radiat Oncol. 2011 Dec 8. 6:169. [Medline]. [Full Text].
Jagannathan J, Yen CP, Pouratian N, Laws ER, Sheehan JP. Stereotactic radiosurgery for pituitary adenomas: a comprehensive review of indications, techniques and long-term results using the Gamma Knife. J Neurooncol. 2009 May. 92(3):345-56. [Medline].
Espinosa-de-Los-Monteros AL, Sosa E, Cheng S, Ochoa R, Sandoval C, Guinto G, et al. Biochemical evaluation of disease activity after pituitary surgery in acromegaly: a critical analysis of patients who spontaneously change disease status. Clin Endocrinol (Oxf). 2006 Mar. 64(3):245-9. [Medline].
Abe T, Tara LA, Lüdecke DK. Growth hormone-secreting pituitary adenomas in childhood and adolescence: features and results of transnasal surgery. Neurosurgery. 1999 Jul. 45(1):1-10. [Medline].
Ronchi CL, Giavoli C, Ferrante E, Verrua E, Bergamaschi S, Ferrari DI, et al. Prevalence of GH deficiency in cured acromegalic patients: impact of different previous treatments. Eur J Endocrinol. 2009 Jul. 161(1):37-42. [Medline].
van der Klaauw AA, Bax JJ, Roelfsema F, Bleeker GB, Holman ER, Corssmit EP, et al. Uncontrolled acromegaly is associated with progressive mitral valvular regurgitation. Growth Horm IGF Res. 2006 Apr. 16(2):101-7. [Medline].
Chahal HS, Stals K, Unterländer M, Balding DJ, Thomas MG, Kumar AV, et al. AIP mutation in pituitary adenomas in the 18th century and today. N Engl J Med. 2011 Jan 6. 364(1):43-50. [Medline].
Kannan S, Kennedy L. Diagnosis of acromegaly: state of the art. Expert Opin Med Diagn. 2013 Sep. 7(5):443-53. [Medline].