Introduction
Diagnosis
Goals of Therapy
Pharmacologic Therapy
Conclusion

Goals of Therapy

The goals of therapy for patients with acromegaly include reduction of biochemical disease markers (both GH and IGF-1 levels), removal or control of tumor mass, relief of signs and symptoms of disease, and reduced mortality rates to those seen in the general population. Control of GH and IGF-1 levels is critical as both an indicator of treatment success after initial therapy and as a monitor of disease status during follow-up. Suppression of GH levels to < 1 mcg/L after OGTT is the target when using the older GH assays,[16,17] whereas GH </= 0.4 mcg/L after OGTT is the target when using newer, more sensitive GH assays.[16, 18-20] Control of IGF-1 levels should also be achieved on the basis of age- and sex-based control values. Tight biochemical control substantially improves the signs and symptoms (morbidities) of acromegaly, such as cardiac dysfunction, diabetes, obstructive sleep apnea, and hyperhidrosis,[21] as well as decreasing mortality rates.[3,22,23]

Among the treatment approaches available to achieve these goals, transsphenoidal adenoma resection is currently the first line of treatment for most patients with small, well-circumscribed lesions. Patients who present with tumors causing visual field defects are candidates for urgent surgical treatment.[1] Surgery immediately lowers GH and IGF-1 levels and removes the tumor mass,[1,16] with a low relapse rate achieved in patients who maintain normalized GH and IGF-1 levels during follow-up.[3,16,24] Patients who achieve optimal surgical remission are those with noninvasive, well-encapsulated, smaller tumors. Physician experience is also critical, with optimal outcomes linked to the surgeon's experience and skill.[25] Surgery alone, however, is not sufficient to successfully treat patients with invasive or larger tumors. For these patients, surgery may decrease the tumor burden, but it must be followed by adjuvant pharmacologic therapy and/or radiation therapy to achieve optimal GH and IGF-1 control.[1,16]

Currently, pharmacologic therapy with somatostatin analogs is the most effective adjuvant therapy, with studies showing that about 75% of patients achieve control of excess GH and IGF-1 that remained uncontrolled by surgery.[8,16,26,27] For patients who fail somatostatin adjuvant treatment, other pharmacologic agents, such as a dopamine agonist or a GH receptor agonist, alone or, rarely, in conjunction with radiation therapy to the pituitary are indicated.[16] If adjuvant radiation therapy is used, it is usually combined with an adjuvant pharmacologic agent because of the delayed effects of radiation therapy.[1]

A role for pharmacologic agents as primary treatment of acromegaly is suggested by several studies that show comparable rates of GH and IGF-1 control in patients treated with surgery and those treated with somatostatin analogs.[8,16,26-30] Primary pharmacologic treatment may be indicated for patients with prognostic factors indicative of surgical failure, such as large and invasive tumors, and for patients for whom surgery is contraindicated.[1] Indications for primary pharmacologic therapy include tumors with a poor likelihood of cure (large and/or invasive tumors), tumors with no compressive sellar features, and patients in whom surgery is either not desired or is contraindicated (eg, frail patients or those at unacceptable high anesthetic or surgical risk).[16]
 

References

AACE Guidelines. American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the Diagnosis and Treatment of Acromegaly. Endocr Pract. 2004;10:214-225.
Freda PU. Acromegaly: diagnostic pitfalls. Endocrinologist. 2004;14:277-287.
Swearingen B, Barker FG II, Katznelson L, et al. Long-term mortality after transsphenoidal surgery and adjunctive therapy for acromegaly. J Clin Endocrinol Metab. 1998;83:3419-3426. Abstract
Holdaway IM, Rajasoorya RC, Gamble GD. Factors influencing mortality in acromegaly. J Clin Endocrinol Metab. 2004;89:667-674. Abstract
Freda PU. Advances in the diagnosis of acromegaly. Endocrinologist. 2000;10:237-244.
Molitch ME. Clinical manifestations of acromegaly. Endocrinol Metab Clin North Am. 1992;21:597-614. Abstract
Wright AD, Hill DM, Lowy C, Fraser TR. Mortality in acromegaly. Q J Med. 1970;39:1-16. Abstract
Cozzi R, Attanasio R, Montini M, et al. Four-year treatment with octreotide-long-acting repeatable in 110 acromegalic patients: predictive value of short-term results? J Clin Endocrinol Metab. 2003;88:3090-3098.
Lamberts SW, Uitterlinden P, Schuijff PC, et al. Therapy of acromegaly with Sandostatin: the predictive value of an acute test, the value of serum somatomedin-C measurements in dose adjustment and the definition of a biochemical "cure." Clin Endocrinol (Oxf). 1988;29:411-420. Abstract
Trainer PJ, Drake WM, Katznelson L, et al. Treatment of acromegaly with the growth hormone-receptor antagonist pegvisomant. N Engl J Med. 2000;342:1171-1177. Abstract
van der Lely AJ, Hutson RK, Trainer PJ, et al. Long-term treatment of acromegaly with pegvisomant, a growth hormone receptor antagonist. Lancet. 2001;358:1754-1759. Abstract
Ho KY, Weissberger AJ. Characteristics of 24-hour growth hormone secretion in acromegaly: implications for diagnosis and therapy. Clin Endocrinol (Oxf). 1994;41:75-83. Abstract
Hartman ML, Veldhuis JD, Vance ML, et al. Somatotropin pulse frequency and basal concentrations are increased in acromegaly and are reduced by successful therapy. J Clin Endocrinol Metab. 1990;70:1375-1384. Abstract
Barkan AL, Beitins IZ, Kelch RP. Plasma insulin-like growth factor-I/somatomedin-C in acromegaly: correlation with the degree of growth hormone hypersecretion. J Clin Endocrinol Metab. 1988;67:69-73. Abstract
Jaquet P, Guibout M, Jaquet C, et al. Circadian regulation of growth hormone secretion after treatment in acromegaly. J Clin Endocrinol Metab. 1980;50:322-328. Abstract
Donangelo I, Melmed S. Primary medical therapy of GH-secreting adenomas. In: Lanzino G, Laws E, eds. Transsphenoideal Surgery. New York: Elsevier. In press.
Melmed S, Casanueva FF, Cavagnini F, et al. Guidelines for acromegaly management. J Clin Endocrinol Metab. 2002;87:4054.
Costa ACF, Rossi A, Martinelli CE, et al. Assessment of disease activity in treated acromegalic patients using a sensitive GH assay: should we achieve strict normal GH levels for a biochemical cure? J Clin Endocrinol Metab. 2002;87:3142.
Freda PU, Reyes CM, Nuruzzaman AT, et al. Basal and glucose-suppressed GH levels less than 1 mcg/L in newly diagnosed acromegaly. Pituitary. 2003;6:175.
Gullu S, Keles H, Delibasi T, et al. Remission criteria for the follow-up of patients with acromegaly. Eur J Endocrinol. 2004;150:465.
Clemmons DR, Van Wyk JJ, Ridgway EC, et al. Evaluation of acromagaly by radioimmunoassay of somatomedin-C. N Engl J Med. 1979;301:1138-1142. Abstract
Bates AS, Evans AJ, Jones P, Clayton RN. Assessment of GH status in acromegaly using serum growth hormone, serum insulin-like growth factor-1 and urinary growth hormone excretion. Clin Endocrinol (Oxf). 1995;42:417-423. Abstract
Bates AS, Van't Hoff W, Jones JM, Clayton RN. An audit of outcome of treatment in acromegaly. Q J Med. 1993;86:293-299. Abstract
Kreutzer J, Vance ML, Lopes MBS, et al. Surgical management of GH-secreting pituitary adenomas: an outcome study using modern remission criteria. J Clin Endocrinol Metab. 2001;86:4072.
Clayton RN. How many surgeons to operate on acromegalic patients? Clin Endocrinol. 1999;50:557.
Attanasio R, Baldelli R, Pivonello R, et al. Lanreotide 60 mg, a new long-acting formulation: effectiveness in the chronic treatment of acromegaly. J Clin Endocrinol Metab. 2003;88:5258.
Ayuk J, Stewart SE, Stewart PM, et al. Efficacy of Sandostatin LAR (long-acting somatostatin analogue) is similar in patients with untreated acromegaly and in those previously treated with surgery and/or radiotherapy. Clin Endocrinol. 2004;60:375-381.
Newman CB, Melmed S, George A, et al. Octreotide as primary therapy for acromegaly. J Clin Endocrinol Metab. 1998;83:3034.
Ayuk J, Stewart SE, Stewart PM, et al. Long-term safety and efficacy of depot long-acting somatostain analogs for the treatment of acromegaly. J Clin Endocrinol Metab. 2002;87:4142.
Baldelli R, Colao A, Razzore P, et al. Two-year follow-up of acromegalic patients treated with slow release lanreotide (30 mg). J Clin Endocrinol Metab. 2000;85:4099.
Murray RD, Kim K, Ren SG, Chelly M, Umehara Y, Melmed S. Central and peripheral actions of somatostatin on the growth hormone-IGF-I axis. J Clin Invest. 2004;114:349-356. Abstract
Muller AF, van der Lely AJ. Pharmacological therapy for acromegaly. A critical review. Drugs. 2004;16:1817-1838.
Hofland LJ, Lamberts SW. The pathophysiological consequences of somatostatin receptor internalization and resistance. Endocr Rev. 2003;24:28-47. Abstract
Freda PU. Somatostatin analogs in acromegaly. J Clin Endocrinol Metab. 2002;87:3013-3018. Abstract
Lancranjan I, Bruns C, Grass P, et al. Sandostatin LAR: a promising therapeutic tool in the management of acromegalic patients. Metabolism. 1996;45:67-71. Abstract
Stewart PM, Kane KF, Stewart SE, Lancranjan I, Sheppard MC. Depot long-acting somatostatin analog (Sandostatin-LAR) is an effective treatment for acromegaly. J Clin Endocrinol Metab. 1995;80:3267-3272. Abstract
Breier BH, Gallaher BW, Gluckman PD. Radioimmunoassay for insulin-like growth factor-I: solutions to some potential problems and pitfalls. J Endocrinol. 1991;128:347-357. Abstract
Colao A, Ferone D, Marzullo P, et al. Long-term effects of depot long-acting somatostatin analog octreotide on hormone levels and tumor mass in acromegaly. J Clin Endocrinol Metab. 2001;86:2779.
Davies PH, Stewart SE, Lancranjan L, et al. Long-term therapy with long-acting octreotide (Sandostatin-LAR) for the management of acromegaly. Clin Endocrinol (Oxf). 1998;48:311-316. Abstract
Lancranjan I, Atkinson AB. Results of a European multicenter study with Sandostatin LAR in acromegalic patients. Sandostatin LAR Group. Pituitary. 1999;1:105-114. Abstract
al-Maskari M, Gebbie J, Kendall-Taylor P. The effect of a new slow-release, long-acting somatostatin analogue, lanreotide, in acromegaly. Clin Endocrinol (Oxf). 1996;45:415-421. Abstract
Heron I, Thomas F, Dero M, et al. Pharmacokinetics and efficacy of a long-acting formulation of the new somatostatin analog BIM 23014 in patients with acromegaly. J Clin Endocrinol Metab. 1993;76:721-727. Abstract
Caron P, Morange-Ramos I, Cogne M, Jaquet P. Three year follow-up of acromegalic patients treated with intramuscular slow-release lanreotide. J Clin Endocrinol Metab. 1997;82:18-22. Abstract
Cannavo S, Squadrito S, Curto L, et al. Results of a two-year treatment with slow release lanreotide in acromegaly. Horm Metab Res. 2000;32:224-229. Abstract
Chanson P, Leselbaum A, Blumberg J, Schaison G. A 12-month multicenter study of 58 acromegalic patients. French Multicenter Study Group on Lanreotide in acromegaly. Pituitary. 2000;2:269-276. Abstract
Colao A, Marzullo P, Ferone D, et al. Effectiveness and tolerability of slow release lanreotide treatment in active acromegaly. J Endocrinol Invest. 1999;22:40-47.
Giusti M, Ciccarelli E, Dallabonzana D, et al. Clinical results of long-term slow-release lanreotide treatment of acromegaly. Eur J Clin Invest. 1997;27:277-284. Abstract
Marek J, Hana V, Krsek M, et al. Long-term treatment of acromegaly with the slow-release somatostatin analogue lanreotide. Eur J Endocrinol. 1994;131:20-26. Abstract
Suliman M, Jenkins R, Ross R, et al. Long-term treatment of acromegaly with the somatostatin analogue SR-lanreotide. J Endocrinol Invest. 1999;22:409-418. Abstract
Verhelst JA, Pedroncelli AM, Abs R, et al. Slow-release lanreotide in the treatment of acromegaly: a study in 66 patients. Eur J Endocrinol. 2000;143;577-584. Abstract
Morange I, De Boisvilliers F, Chanson P, et al. Slow release lanreotide treatment in acromegalic patients previously normalized by octreotide. J Clin Endocrinol Metab. 1994;79:145-151. Abstract
Giusti M, Gussoni G, Cuttica CM, Giordano G. Effectiveness and tolerability of slow release lanreotide treatment in active acromegaly: six-month report on an Italian multicenter study. Italian Multicenter Slow Release Lanreotide Study Group. J Clin Endocrinol Metab. 1996;81:2089-2097. Abstract
Amato G, Mazziotti G, Rotondi M, et al. Long-term effects of lanreotide SR and octreotide LAR on tumor shrinkage and GH hypersecretion in patients with previously untreated acromegaly. Clin Endocrinol. 2002;56:65.
Bevan JS. The antitumoral effects of somatostatin analog therapy in acromegaly. J Clin Endocrinol Metab. 2005;90:1856-1863. Abstract
Melmed S, Sternberg R, Cook D, et al. A critical analysis of pituitary tumor shrinkage during primary medical therapy in acromegaly. J Clin Endocrinol Metab. 2005 Apr 12;[Epub ahead of print].
Ezzat S, Snyder PJ, Young WF, et al. Octreotide treatment of acromegaly. A randomized, multicenter study. Ann Intern Med. 1992;117:711-718. Abstract
Lamberts SW, van der Lely AJ, de Herder WW, et al. Octreotide. N Engl J Med. 1996;334:246-254. Abstract
Giustina A, Veldhuis JD. Pathophysiology of the neuroregulation of growth hormone secretion in experimental animals and human. Endocr Rev. 1998;19:717-797. Abstract
Jaffe CA, Barkan AL. Treatment of acromegaly with dopamine agonists. Endocrinol Metab Clin North Am. 1992;21:713-735. Abstract
Abs R, Verhelst J, Maiter D, et al. Cabergoline in the treatment of acromegaly: a study of 64 patients. J Clin Endocrinol Metab. 1998;83:374-378. Abstract
Webster J, Piscitelli G, Polli A, et al. A comparison of cabergoline and bromocriptine in the treatment of hyperprolactinemic amenorrhea. N Engl J Med. 1994;331:904-909. Abstract
Biller BMK, Molitch ME, Vance ML, et al. Treatment of prolactin-secreting macroadenoma with the once-weekly dopamine agonist cabergoline. J Clin Endocrinol Metab. 1996;81:2338-2343. Abstract
Ferrari CI, Abs R, Bevan JS, et al. Treatment of macroprolactinoma with cabergoline: a study of 85 patients. Clin Endocrinol (Oxf). 1997;46:409-413. Abstract
Delgrange E, Donckier J. Prolactinomas apparently resistant to quinagolide respond to cabergoline therapy. J Clin Endocrinol Metab. 1997;82:2755-2756.
Cozzi R, Attanasio R, Lodrini S, et al. Cabergoline addition to depot somatostatin analogues in resistant acromegalic patients: efficacy and lack of predictive value of prolactin status. Clin Endocrinol. 2004;61:209.
Clemmons DR, Chihara K, Freda PU, et al. Optimizing control of acromegaly: integrating a growth hormone receptor antagonist into the treatment algorithm. J Clin Endocrinol Metab. 2003;88:4759-4767. Abstract
Trainer PJ, Drake WM, Perry LA, et al. Modulation of cortisol metabolism by the growth hormone receptor antagonist pegvisomant in patients with acromegaly. J Clin Endocrinol Metab. 2001;86:2989-2992. Abstract
Parkinson C, Drake WM, Wieringa G, et al. Serum lipoprotein changes following IGF-I normalization using a growth hormone receptor antagonist in acromegaly. Clin Endocrinol (Oxf). 2002;56:303-311. Abstract
Sesmilo G, Fairfield WP, Katznelson L, et al. Cardiovascular risk factors in acromegaly before and after normalization of serum IGF-I levels with the GH antagonist pegvisomant. J Clin Endocrinol Metab. 2002;87:1692-1699. Abstract
van der Lely AJ, Muller A, Janssen JA, et al. Control of tumor size and disease activity during cotreatment with octreotide and the growth hormone receptor antagonist pegvisomant in an acromegalic patient. J Clin Endocrinol Metab. 2001;86:478-481. Abstract
Karavitaki N, Wass JAH. Pegvisomant: a new treatment modality for acromegaly. Hormones. 2004;3:27-36.
Herman-Bonert VS, Zib K, Scarlett JA, Melmed S. Growth hormone receptor antagonist therapy in acromegalic patients resistant to somatostatin analogs. J Clin Endocrinol Metab. 2000;85:2958-2961.