Approach Considerations
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. [7] Radiation treatment usually is reserved for recalcitrant cases. The cost of providing care for acromegaly may need to be considered. [29] Surgery may lower it by avoiding lifelong pharmacological therapy.
Radiotherapy and medical treatment are important because in long-term studies, surgery has been found to cure only approximately 60% of patients with acromegaly. [30] 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 Endocrine Society (ENDO) in 2014 address important clinical issues regarding the evaluation and management of acromegaly. [31, 32] Recommendations include the following:
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For most patients with acromegaly, surgical removal of the pituitary gland tumor should be considered the primary treatment
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An imaging study should be performed at least 12 weeks postsurgery to determine whether any residual tumor tissue is present
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Patients should be evaluated for any damage caused by the pituitary tumor and for the development of hypopituitarism
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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.
Pharmacologic Therapy
The goals of medical therapy for GH excess are as follows:
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Remove or shrink the pituitary mass
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Restore GH secretory patterns to normal
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Restore serum total IGF-I and IGF binding protein 3 (IGFBP-3) levels to normal
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Retain normal pituitary secretion of other hormones
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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.
Somatostatin analogues
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. [33]
Primary treatment with depot octreotide and lanreotide has been found to induce tumor shrinkage in newly diagnosed acromegaly. [9]
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 two 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. [34]
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. [34]
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. [34]
Pasireotide’s approval was based on two 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). [35, 36]
The risk for hyperglycemia needs to be considered with use of pasireotide. In one open-label, multicenter safety study, hyperglycemia-related adverse events were reported in 45.5% of patients but were typically manageable. [37, 38]
Dopamine-receptor agonists
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
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
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. [39] In those cases in which a somatostatin analogue has failed to control acromegaly, cabergoline adjunction normalized IGF-I levels in about 50% of cases.
GH-receptor antagonists
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. However, pegvisomant does not have direct antiproliferative effects on the underlying pituitary adenoma. [40]
Normalization of IGF-I levels occurs in as many as 90% of patients treated daily with this drug for 3 months. Patients receiving pegvisomant monotherapy require regular pituitary imaging in order to monitor for possible increase in tumor size. Adverse events in patients on pegvisomant therapy include skin rashes, lipohypertrophy at injection sites, and idiosyncratic liver toxicity (generally asymptomatic transaminitis that is reversible upon drug discontinuation), thus necessitating regular patient monitoring. [41]
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. [42]
Combination therapy with pegvisomant and cabergoline or somatostatin analogues is also being investigated for efficacy. [43, 44]
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. [45]
Radiation Therapy
In general, radiation therapy is recommended if GH hypersecretion is not normalized with surgery. Radiation prevents further growth of the tumor in more than 97% of patients after surgical resection. [46] However, radiation treatment takes years to reduce/normalize GH/IGF-I levels. [47] 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. [46] 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. [48]
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. [49] Results are influenced by many factors, including adenoma histology, adenoma volume, and radiation dose.
Transsphenoidal Surgery
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:
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The likelihood of a surgical cure greatly depends on the surgeons' expertise and on the size and extension of the mass
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Intraoperative GH measurements can improve the results of tumor resection
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Transsphenoidal surgery to resect tumors is as safe in children as it is in adults
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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. [50]
If surgery does not normalize GH secretion, options include pituitary radiation and medical therapy.
Long-Term Monitoring
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. [39]
In a majority of cases of acromegaly, multimodal treatment with surgery, medical therapy, and radiotherapy provides biochemical control as defined by Endocrine Society (ENDO) guidelines as a reduction of GH levels to < 1.0 ng/ml and normalization of IGF1 levels. [31] Biochemical control is associated with reduced mortality, and patients require long-term monitoring of GH and IGF1 levels for early identification and treatment of recurrent disease. [51]
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). [52]
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. [53] Echocardiography may document a cardiomyopathy with left ventricular hypertrophy, diastolic and systolic dysfunction, aortic and mitral regurgitation, and increased aortic root diameters. [54] Other cardiovascular complications include concentric biventricular hypertrophy and cardiomyopathy, hypertension, arrhythmias, atherosclerosis, coronary artery disease, and cardiac dysfunction. [55] Sleep apnea is also common in patients with acromegaly and may exacerbate cardiovascular dysfunction. [56] Because cardiorespiratory complications are not reversed with biochemical control, patients should be screened periodically for the common cardiovascular and respiratory manifestations of acromegaly. [55, 56]
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Gigantism and Acromegaly. Image shows a coauthor of this article with a statue of Robert Wadlow, who was called the Alton giant. The tallest person on record, he was 8 feet 11 inches tall at the time of his death.
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Gigantism and Acromegaly. A 12-year-old boy with McCune-Albright syndrome. His growth-hormone excess manifested as tall stature, coarse facial features, and macrocephaly.
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Gigantism and Acromegaly. Robert Wadlow, 19 years of age, with his father (postcard photo prior to 1937). Courtesy of Wikimedia Commons (https://commons.wikimedia.org/wiki/File:Robert_Wadlow_postcard.jpg).
