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Original Studies |
Cedars-Sinai Research Institute, University of California School of Medicine (S.M.), Los Angeles, California 90048; Rhode Island Hospital/Brown University School of Medicine (I.J.), Providence, Rhode Island 02903; New York University Medical Center (D.K.), New York, New York 10016; and Neuroendocrine Clinical Center, Massachusetts General Hospital, Harvard Medical School (A.K.), Boston, Massachusetts 02114
Address all correspondence and requests for reprints to: Dr. Shlomo Melmed, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Room B-131, Los Angeles, California 90048-1865.
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Abstract |
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 Top Abstract IntroductionPathophysiology of AcromegalyDiagnosis of AcromegalyTreatment Goals for Acromegaly:...Nonsurgical Treatment Options...Treatment Algorithm for...ConclusionsReferences |
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Introduction |
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TopAbstractIntroductionPathophysiology of AcromegalyDiagnosis of AcromegalyTreatment Goals for Acromegaly:...Nonsurgical Treatment Options...Treatment Algorithm for...ConclusionsReferences |
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Due to its insidious nature, the diagnosis of acromegaly may be considerably delayed. In epidemiological studies of acromegalic patients, the diagnosis was preceded by approximately 4–10 yr or more of active disease (2, 3, 6). The mortality rate for acromegalics is 2–3 times that of the general population, but with effective treatment survival can be improved to that of the age-matched population (7).
Treatment protocols for the acromegalic patient have evolved over time, reflecting the availability of novel diagnostic and therapeutic regimens, new pharmacological agents, and a greater understanding of the disease process. Initial therapy is surgical in most cases, with follow-up treatment consisting of medical therapy and/or various forms of radiation. A wide range of treatment protocols exists as a result of institutional differences in treatment and a lack of experience in treating the small number of acromegalic patients, yet standardized protocols reflecting optimal current treatment are critical to ensure efficacious treatment of these patients. The treatment guidelines presented here were developed based on a thorough review of the literature and the extensive experience of the authors in treating patients with acromegaly.
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Pathophysiology of Acromegaly |
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TopAbstractIntroductionPathophysiology of AcromegalyDiagnosis of AcromegalyTreatment Goals for Acromegaly:...Nonsurgical Treatment Options...Treatment Algorithm for...ConclusionsReferences |
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Impact of pathophysiology: morbidity and mortality
As reported previously, the morbidity and mortality associated with acromegaly are considerable. However, it is important to note that no prospective long term studies addressing these issues have been conducted to date. The mortality rate associated with acromegaly is at least twice the expected value (6). A study by Wright et al. (6) demonstrated that mortality rates were significantly lower for acromegalic patients previously treated by irradiation than those for untreated patients (P < 0.001). Other epidemiological studies have confirmed the elevated mortality rate associated with acromegaly and the ability of effective GH-lowering treatment to improve the mortality rate (2, 3, 7, 14, 15, 16, 17). The most frequent causes of death are cardiovascular and respiratory complications (15). Cardiovascular disease and diabetes in particular were poor portents of survival, contributing significantly to mortality. Patients with acromegaly may also be at increased risk for cardiac hypertrophy, hypertension, arthritis, sleep apnea, and development of other neoplastic lesions, particularly in the colon. However, the long term impact of colonic lesions on morbidity and mortality has not been established. Sleep apnea is a significant cause of morbidity, and it may be both obstructive and central (18). A study by Rajasoorya et al. (15) demonstrated that the single most important determinant of long term survival was the magnitude of the last known GH level.
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Diagnosis of Acromegaly |
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TopAbstractIntroductionPathophysiology of AcromegalyDiagnosis of AcromegalyTreatment Goals for Acromegaly:...Nonsurgical Treatment Options...Treatment Algorithm for...ConclusionsReferences |
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Acromegaly is characterized by progressive cosmetic disfigurement and systemic organ manifestations, including arthropathy, neuropathy, and cardiomyopathy (5, 8, 14, 19). Patients may exhibit coarsened facial features, exaggerated growth of the hands and feet, and soft tissue hypertrophy. Other characteristics may include hyperhydrosis, goiter, osteoarthritis, carpal tunnel syndrome, fatigue, visual abnormalities, increased number of skin tags, colon polyps, sleep apnea and somnolence, reproductive disorders, and cardiovascular disease (i.e. congestive heart failure, arrhythmia, hypertension) (8). Few, if any, patients present with all signs and symptoms; the majority of patients manifest a combination of acral changes, arthralgia, increased sweating, and physical weakness.
Diagnostic tests
The diagnosis of acromegaly is based on clinical findings, elevated serum IGF-I levels, and the inability to suppress serum GH during an oral glucose tolerance test (OGTT) (8, 20). A single measurement of GH provides inadequate information regarding GH elevation, because GH is secreted in a pulsatile manner (5). Therefore, the use of a random GH measurement in the diagnosis of acromegaly can lead to both false positive and false negative results. During an OGTT in normal patients, serum GH should suppress under 1 ng/mL if the two-site immunoradiometric or chemiluminescent assay are used, or to less than 2 ng/mL if the regular GH RIA is used. For over 80% of acromegalics, GH levels will remain above 2 ng/mL. Improved assays with increased sensitivity have suggested that GH levels should normally be suppressed during OGTT to less than 0.057 ng/mL in men and less than 0.71 ng/mL in women (21). As these assays become more widely used, diagnostic criteria for acromegaly may be further refined. Although clinically impractical on a routine basis, frequent serial blood samples obtained over a 24-h period can be used to generate a more dynamic and complete GH profile for diagnostic testing (5, 19). In healthy individuals, normal GH levels should be less than 1 ng/mL for at least 50% of the values measured during the day (22).
In contrast to GH levels, plasma levels of IGF-I are more stable, and an elevated IGF-I level in a patient with appropriate clinical suspicion is almost always indicative of acromegaly (9, 23). For accurate control comparison, the IGF-I level must be age and gender matched. If GH and IGF-I levels suggest acromegaly, the presence of a pituitary adenoma should be confirmed using magnetic resonance imaging (MRI) (1). In rare cases, a pituitary mass may not be identified. Although this may be due to an occult pituitary microadenoma or a partially empty sella, an ectopic tumor secreting GH or GHRH may rarely be present. Circulating GHRH blood levels or chest and abdominal imaging confirm peripheral ectopic GHRH secretion (8). However, in the rare case of a hypothalamic GHRH-secreting tumor, circulating GHRH levels may be normal.
The measurement of IGF-binding protein-3 (IGFBP-3) levels may also be useful in the diagnosis of acromegaly. In the circulation, both IGF-I and IGF-II are bound to a heterodimeric, GH-dependent glycoprotein. In patients with confirmed somatotroph adenomas, increased IGFBP-3 levels have been reported to be a sensitive marker of GH elevation and may be elevated despite normal IGF-I levels (24). However, the diagnostic utility of IGFBP-3 requires validation in larger numbers of patients as suggested by the results of other studies (25).
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Treatment Goals for Acromegaly: Defining a Cure |
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TopAbstractIntroductionPathophysiology of AcromegalyDiagnosis of AcromegalyTreatment Goals for Acromegaly:...Nonsurgical Treatment Options...Treatment Algorithm for...ConclusionsReferences |
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Ideally, the GH-producing adenoma should be removed completely, with preservation or subsequent restoration of pituitary function. The likelihood of surgical cure will vary greatly depending on whether the patient is treated at a center with expertise in pituitary surgery and also on both the size and extension of the mass. Surgical tumor excision is indicated for most patients with small, well localized microadenomas (27, 28, 29) unless there is a contraindication to surgery. This procedure generally results in a rapid and substantial reduction of serum GH levels immediately postoperatively and normalization of IGF-I levels in the weeks following surgery, particularly when the patient is treated by an experienced pituitary surgeon. Nevertheless, only approximately 70–80% of patients with microadenomas and less than 50% of patients with macroadenomas achieve a circulating GH level less than 5 ng/mL after surgery (27, 28). Overall, in a review of 1360 patients from 30 surgical series, approximately 60% of patients had GH levels suppressed to less than 5 ng/mL (27, 30). Furthermore, of patients who are defined as cured, many will experience tumor growth and increased secretion of GH when retested 1 or more yr postsurgery. Accordingly, using these criteria many patients experience remission of their disease rather than a cure (5, 26, 28). It should be noted that reduction in tumor size by surgery is of major clinical importance only if compression of the optic pathways or other neuronal structures is relieved.
Occasionally, after surgery a patient may exhibit suppressed GH secretion without normalization of the IGF-I level. In these cases, if there is 1) clinical evidence of disease, 2) several measurements confirming that the IGF-I level is elevated, and 3) other ancillary evidence of hypersomatotropism, patients should receive a 6-month trial of medical treatment. For those patients, the benefits of medical treatment in terms of reduced mortality and morbidity must be weighed against the burden and risks of additional treatment.
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Nonsurgical Treatment Options for Acromegaly |
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TopAbstractIntroductionPathophysiology of AcromegalyDiagnosis of AcromegalyTreatment Goals for Acromegaly:...Nonsurgical Treatment Options...Treatment Algorithm for...ConclusionsReferences |
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, whereas the
advantages and disadvantages are listed in Table 2.
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Somatostatin is an endogenous molecule that exerts a variety of physiological effects, including inhibition of GH secretion. Due to the short half-life of native somatostatin, longer acting and selective somatostatin analogs (i.e. octreotide, lanreotide, vapreotide) have been used to treat acromegaly. Octreotide is at least 40 times more potent than somatostatin and has a serum half-life of approximately 2 h after sc injection (31, 32). Octreotide reduces GH hypersecretion in approximately 95% of acromegalic patients within 30–60 min of injection and ameliorates clinical and metabolic anomalies associated with the disease (18, 26, 33, 34, 35, 36, 37). In recent long term studies, GH levels were suppressed to less than 5 ng/mL in 65% of patients and to less than 2 ng/mL in 40% of patients. Importantly, octreotide was shown to normalize IGF-I levels in approximately 60% of patients (38, 39). For example, in a study by Newman et al. (39), 56 of 87 treated patients (64%) achieved normal IGF-I levels. Tumor shrinkage occurs with octreotide, but it is generally modest. Studies of patients for more than 14 yr have shown that the effects of octreotide are well sustained over time (17, 31, 38, 39, 40).
The primary side-effect associated with octreotide therapy is increased risk of asymptomatic cholesterol gallstone development, which occurs in up to 25% of patients. Short term side-effects that often resolve with continued treatment include abdominal pain, diarrhea, fat malabsorption, nausea, and flatulence (38, 39). Clinically insignificant bradycardia occurs in approximately 25% of patients.
Octreotide is generally administered in divided doses of 100–250 µg, three times daily, up to a maximum of 1500 µg over a 24-h period (32). Consistent GH suppression has also been obtained with a continuous sc pump infusion of octreotide (41, 42, 43); however, new formulations of long acting octreotide and lanreotide produce consistent GH and IGF-I suppression with a once monthly (30, 44, 45, 46, 47, 48, 49, 50) or biweekly (49, 50) im depot injection. Long acting formulations of somatostatin analogs are currently in the late phases of regulatory approval worldwide.
Dopamine agonists
Dopamine agonists (e.g. bromocriptine and pergolide)
bind to pituitary dopamine type 2 (D2) receptors and
suppress GH secretion in some patients with acromegaly, although the
precise mechanism of action remains unclear (51). Historically,
bromocriptine provided subjective symptom relief for patients before
the availability of other pharmacological treatments (5, 52, 53, 54). In a
minority of patients, bromocriptine reduced GH levels, but GH and IGF-I
levels are rarely normalized with this treatment modality (51, 55, 56).
In fact, less than 20% of patients achieve GH levels less than 5
ng/mL, and less than 10% of patients will achieve normalization of
IGF-I levels (Fig. 1) (8, 51). Subjective
clinical improvement unrelated to a reduction in GH levels is evident
in some patients (52, 57, 58), and tumor shrinkage occurs in a minority
of patients (59). Bromocriptine in doses up to 20 mg/day is given
orally (every 6 h) for optimum treatment efficacy (53). An
increase in the bromocriptine dose to more than 20 mg/day has not
conferred clinical advantage (57, 60, 61). Side-effects associated with
this treatment include nausea, vomiting, abdominal spasm, nasal
stuffiness, arrhythmia, effects on the central nervous system, sleep
disturbances, fatigue, transient postural hypotension, and cold-induced
peripheral vasospasm (ergotism) (51, 62). A long acting formulation of
bromocriptine has been studied, but a recent report indicated that it
did not normalize GH or IGF-I levels in acromegalic patients (56). This
study also reported that cabergoline, a new, long acting dopamine
agonist, also failed to normalize either GH or IGF-I levels.
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Both conventional and heavy particle (proton beam) irradiation
have been used to treat acromegaly. The beneficial effects of
radiotherapy on GH levels are dose dependent and delayed (63, 64, 65, 66, 67). It
is not until up to 20 yr after therapy that 90% of patients have GH
levels less than 5 ng/mL (Fig. 2).
Furthermore, results from a number of pivotal studies from major
radiotherapy treatment centers have shown that approximately 50% of
patients achieve adequate GH suppression within 10 yr after radiation
(8, 65, 68, 69, 70). During the interim between treatment and optimal GH
reduction, patients may require adjunctive medical therapy. Several
factors may render radiotherapy ineffective in treating acromegaly
(25). Recently, Barkan et al. (71) reported the
ineffectiveness of radiotherapy in lowering IGF-I levels despite the
attenuation of GH levels. Cranial radiotherapy frequently results in
abnormal hypothalamic-pituitary function, including hypothyroidism and
gonadal dysfunction (65, 67, 72, 73), which require target hormone
replacement. Rarely, other adverse effects, such as visual disturbances
(including blindness), the development of a secondary brain malignancy,
brain necrosis, and brain damage, have been reported (74, 75). More
focused irradiation of the adenoma, such as that achieved with
stereotactic radiosurgery, may reduce the occurrence of these
side-effects. Although stereotactic radiosurgery (e.g.
-knife) is currently under investigation, studies reported to date
have not definitively shown an advantage over conventional fractionated
external beam radiotherapy with regard to the clinical outcome of the
acromegaly (68, 76).
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Treatment Algorithm for Acromegaly |
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TopAbstractIntroductionPathophysiology of AcromegalyDiagnosis of AcromegalyTreatment Goals for Acromegaly:...Nonsurgical Treatment Options...Treatment Algorithm for...ConclusionsReferences |
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).
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). An immediate cure after surgery
should result in GH levels less than 2 ng/mL (OGTT) and a normalized
IGF-I level. These patients should be evaluated 6 weeks postsurgery
with measurement of GH and IGF-I levels. MRI may be performed at 3
months if the values have not normalized. If GH levels during OGTT are
greater than 2 ng/mL, the IGF-I level is elevated, or there is tumor
persistence after surgery, medical therapy should be initiated.
Although radiation therapy may also be considered by some, because of
the disadvantages outlined above, the authors recommend it only if
medical treatment fails. Sometimes, IGF-I levels remain elevated
postsurgery despite normalization of GH. The decision to treat or
monitor these patients is based on clinical criteria of disease
activity. For patients with minimally elevated GH levels postsurgery,
octreotide or dopamine agonist therapy may be appropriate, and the
selection should be made based on expected efficacy and factors such as
cost, patient quality of life, and compliance. For patients with
significantly elevated GH levels postsurgery, octreotide is the therapy
of choice based on its superior ability to reduce GH and IGF-I levels
compared with dopamine agonists (54, 55, 77, 78, 79). Two hours after an
initial octreotide injection, measurements of GH and IGF-I levels
should be determined to confirm therapeutic efficacy. If this
measurement reveals that GH and/or IGF-I levels are elevated, it may be
necessary to increase either the dose or the frequency of injection or
to consider administration by pump infusion. If these steps are
unsuccessful, dopamine agonists may be tried in conjunction with
octreotide, or additional surgery may be required.
For patients in whom the likelihood of a surgical cure is not good
(e.g. 40% chance of a persistent biochemical cure),
octreotide therapy should be considered as the first line treatment
(Fig. 3). Alternately, surgery should be performed with the clear aim
of debulking tumor mass without necessarily achieving a biochemical
cure. The cost-effectiveness of this approach, however, is not yet
proven. If octreotide therapy fails to reduce GH levels to less than 2
ng/mL or if IGF-I levels remain elevated, the dose and/or frequency of
administration should be increased. If these steps are unsuccessful, a
dopamine agonist should be added to the octreotide therapy (55, 77, 78, 79). This recommendation is based on published data from small
numbers of patients suggesting that the combination of these agents may
result in additive or synergistic activity. However, the use of this
combination may be limited due to adverse events (especially from very
high doses of dopamine agonist), cost, and patient compliance. If this
two-drug therapy also fails, radiotherapy, surgery, investigational
treatments, or a combination of these should be considered.
For the patient who is unwilling to accept the implications of the
surgical procedure or for whom surgery is contraindicated for other
reasons, first line octreotide therapy may be appropriate (Fig. 1);
however, there have been no double blind, randomized prospective
studies comparing surgery with primary medical therapy. Nevertheless,
the future availability of long acting somatostatin analogs may result
in the use of medical therapy for first time treatment of acromegaly,
particularly for patients with large lesions and a relatively small
likelihood of surgical cure.
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Conclusions |
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TopAbstractIntroductionPathophysiology of AcromegalyDiagnosis of AcromegalyTreatment Goals for Acromegaly:...Nonsurgical Treatment Options...Treatment Algorithm for...ConclusionsReferences |
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, the advent of long acting
formulations of octreotide may lessen the role of surgery in the near
future (80). Other future treatment options may include GH antagonists
(81) and somatostatin analogs that are receptor subtype selective (82).
The appropriate use of treatment options currently available coupled
with the advent of novel treatment approaches will ensure the optimal
care of acromegalic patients and lead to a reduction in the substantial
morbidity and mortality associated with this disorder.
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Footnotes |
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Received December 31, 1997.
Revised April 20, 1998.
Accepted April 28, 1998.
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References |
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TopAbstractIntroductionPathophysiology of AcromegalyDiagnosis of AcromegalyTreatment Goals for Acromegaly:...Nonsurgical Treatment Options...Treatment Algorithm for...ConclusionsReferences |
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D. C. Danila, J. N. S. Haidar, X. Zhang, L. Katznelson, M. D. Culler, and A. Klibanski Somatostatin Receptor-Specific Analogs: Effects on Cell Proliferation and Growth Hormone Secretion in Human Somatotroph Tumors J. Clin. Endocrinol. Metab., July 1, 2001; 86(7): 2976 - 2981. [Abstract] [Full Text] [PDF]
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G. A. Kaltsas, A. M. Isidori, D. Florakis, P. J. Trainer, C. Camacho-Hubner, F. Afshar, I. Sabin, J. P. Jenkins, S. L. Chew, J. P. Monson, et al. Predictors of the Outcome of Surgical Treatment in Acromegaly and the Value of the Mean Growth Hormone Day Curve in Assessing Postoperative Disease Activity J. Clin. Endocrinol. Metab., April 1, 2001; 86(4): 1645 - 1652. [Abstract] [Full Text]
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R. Baldelli, A. Colao, P. Razzore, M.-L. Jaffrain-Rea, P. Marzullo, E. Ciccarelli, E. Ferretti, D. Ferone, D. Gaia, F. Camanni, et al. Two-Year Follow-Up of Acromegalic Patients Treated with Slow Release Lanreotide (30 mg) J. Clin. Endocrinol. Metab., November 1, 2000; 85(11): 4099 - 4103. [Abstract] [Full Text]
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G. Barrande, M. Pittino-Lungo, J. Coste, D. Ponvert, X. Bertagna, J. P. Luton, and J. Bertherat Hormonal and Metabolic Effects of Radiotherapy in Acromegaly: Long-Term Results in 128 Patients Followed in a Single Center J. Clin. Endocrinol. Metab., October 1, 2000; 85(10): 3779 - 3785. [Abstract] [Full Text]
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S. D. Pack, L. S. Kirschner, E. Pak, Z. Zhuang, J. A. Carney, and C. A. Stratakis Genetic and Histologic Studies of Somatomammotropic Pituitary Tumors in Patients with the "Complex of Spotty Skin Pigmentation, Myxomas, Endocrine Overactivity and Schwannomas" (Carney Complex) J. Clin. Endocrinol. Metab., October 1, 2000; 85(10): 3860 - 3865. [Abstract] [Full Text]
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J. S. Powell, S. L. Wardlaw, K. D. Post, and P. U. Freda Outcome of Radiotherapy for Acromegaly Using Normalization of Insulin-Like Growth Factor I to Define Cure J. Clin. Endocrinol. Metab., May 1, 2000; 85(5): 2068 - 2071. [Abstract] [Full Text]
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A. Giustina, A. Barkan, F. F. Casanueva, F. Cavagnini, L. Frohman, K. Ho, J. Veldhuis, J. Wass, K. von Werder, and S. Melmed Criteria for Cure of Acromegaly: A Consensus Statement{dagger} J. Clin. Endocrinol. Metab., February 1, 2000; 85(2): 526 - 529. [Abstract] [Full Text]
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P. U. Freda and S. L. Wardlaw Diagnosis and Treatment of Pituitary Tumors J. Clin. Endocrinol. Metab., November 1, 1999; 84(11): 3859 - 3866. [Full Text]
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S. Melmed Tight Control of Growth Hormone: An Attainable Outcome for Acromegaly Treatment J. Clin. Endocrinol. Metab., October 1, 1998; 83(10): 3409 - 3410. [Full Text]
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, Represents anticipated change
to the algorithm given the future availability of long acting
somatostatin analog formulations. 
, Follow-up should include MRI 1
yr after surgery and serial GH and IGF-I levels. ß, GH, and
IGF-I level tests should be conducted using an OGTT and 2-h
postoctreotide injection.