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Department of Internal Medicine/Endocrine Section (A.G.), University of Brescia, Brescia, Italy; Veterans Affairs Medical Center (A.B.), Ann Arbor, Michigan; Endocrine Section, Department of Medicine, Santiago de Compostela University (F.F.C.), Spain; Division of Endocrinology and Metabolism, Ospedale San Luca, University of Milan (F.C.), Milan, Italy; Department of Medicine, University of Illinois at Chicago (L.F.), Chicago, Illinois; Department of Endocrinology, Garvan Institute of Medical Research, St. Vincents Hospital (K.H.), Sydney, Australia; Department of Medicine, Division of Endocrinology and Metabolism, University of Virginia School of Medicine (J.V.), Charlottesville, Virginia; Department of Endocrinology, Radcliffe Infirmary (J.W.), Oxford, United Kingdom; Department of Medicine, Schlosspark Klinik (K.v.W.), Berlin, Germany; and Cedars-Sinai Research Institute, University of CaliforniaLos Angeles School of Medicine (S.M.), Los Angeles, California 90048
Address correspondence and requests for reprints to: Shlomo Melmed, Cedars-Sinai Medical Center,8700 Beverly Boulevard, Room 2015, Los Angeles, California 90048. E-mail: melmed{at}csmc.edu
| Abstract |
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| Therapeutic Goals |
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| Baseline Biochemical Parameters |
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| Dynamic Testing |
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Failure of GH suppression after glucose loading in the appropriate clinical context suggests the diagnosis of acromegaly, but the results should always be considered in conjunction with an IGF-I measurement because other conditions can cause discordantly elevated GH levels. Using all current commercial assays, the cut-off GH value separating normal subjects from those with acromegaly is less than 1 µg/L. However, with the introduction of newer more sensitive assays it is anticipated that a lower cut-off value can be defined in the future (6).
A paradoxical rise in serum GH provides no additional value beyond that attained by failure to suppress GH. Care needs to be taken in interpretation of the test in the immediate postoperative period due to effects of concomitant glucocorticoid administration and other perioperative medications, including glucose, dopamine, opiates, and anesthetics. Although no data exist regarding the superiority of 75 or 100 g glucose, it is recommended that 75 g be used to achieve a level of standardization. The attained blood glucose levels are of importance with respect to the diagnosis of diabetes mellitus, but do not affect interpretation of the GH result. Although GH responses may differ between male and female subjects and show some influence of age, these factors are not considered important for diagnostic interpretation of the GH response to glucose.
False-positive responses (i.e. failure of normal suppression) may occur in patients with diabetes mellitus, liver disease, renal disease, adolescence, and anorexia nervosa. False negative responses (i.e. normal suppression) may be encountered in acromegaly itself. However, in both situations interpretation should be tempered by the simultaneous availability of IGF-I levels and consideration of the associated clinical findings.
Stimulatory tests
TRH and GnRH stimulation tests of GH secretion have been used as a second tier evaluation of abnormal GH dynamics in the diagnosis of acromegaly and in assessing responses to therapeutic intervention (7). These tests offer no advantage over the OGTT and, as serious side effects may occasionally occur in response to TRH, their use is not recommended for diagnosis. Nearly all patients with acromegaly respond to GH secretagogues, and all have paradoxical inhibitory responses to galanin. However, none of these agents is of proven value in the evaluation of patients with acromegaly at the present time.
Although nearly all patients respond to GHRH stimulation (8), this agent is not of value in the diagnosis of GH-secreting tumors nor in distinguishing them from those with ectopic GHRH secretion. In suspected cases of the rarely encountered latter condition, a serum GHRH level is the preferred test.
| Assays |
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| Using Cure Criteria for Evaluating Treatment |
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Control is achieved when all attributes of disordered GH secretion are restored to normal. Biochemically, this is evident when circulating IGF-I is reduced to an age-adjusted normal range and nadir GH after an oral glucose load is less than 1 µg/L.
Surgery
Ideally, the GH-secreting adenoma should be completely resected, with preservation or subsequent restoration of pituitary function (12). Surgical effectiveness varies greatly depending on expertise in pituitary surgery, both the size and extension of the anatomic mass, and the preoperative level of GH (13, 14, 15, 16). Tumor resection generally results in a rapid and substantial reduction of serum GH levels immediately postoperatively and corresponding lowering of IGF-I levels in the weeks following surgery.
Historically, patients have been classified as "cured" or "noncured." This concept was based on outcomes of surgical interventions with imprecise biochemical evaluation and is misleading for patients and clinicians. If rigorous criteria are used for the interpretation of surgical results (GH nadir after OGTT <1 µg/L), approximately 80% of patients with microadenomas and substantially less than 50% of patients with macroadenomas can be defined as controlled. Patients in whom disease has been controlled, as defined by older criteria, may, in fact, demonstrate increased GH secretion when retested 1 or more years after surgery (17).
Medical treatment
After long-term somatostatin receptor ligand administration, GH
levels are suppressed to less than 2.5 µg/L in 65% of patients and
IGF-I levels are normalized in
70% of patients (18, 19). New
slow-release formulations of long-acting somatostatin receptor ligands
result in persistent GH and IGF-I suppression after im depot injection
(20, 21). Drug levels peak at 28 days and are sustained for over 4
weeks. Persistently controlled mean GH levels (<2 µg/L) are achieved
in over 70% of octreotide-sensitive patients (20). Lanreotide injected
every 14 days provides similar GH and IGF-I control (21). High doses of
long-acting dopamine receptor agonists rarely normalize IGF-I levels
(22, 23), but data on long-term control of GH and IGF-I with these
agents is not yet available. Future treatment options may include
receptor-subtype selective somatostatin ligands and GH receptor
antagonists (24).
Radiotherapy
Beneficial effects of radiotherapy on GH levels are delayed, and about 90% of patients achieve random GH levels of less than 5 µg/L after 18 yr (25). Ineffectiveness of radiotherapy in lowering IGF-I despite attenuation of GH levels has been reported (26). However, shrinkage or at least prevention of continued pituitary tumor mass growth is usually achieved with radiotherapy. Stereotactic radiosurgery is currently under investigation, and early results show that after 1.4 yr, 8 of 16 patients achieve GH levels less than 5 µg/L (27).
| Interpretation of Treatment Outcomes |
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| Clinical outcomes |
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The association between acromegaly and malignant diseases is not resolved fully. There is increased general mucosal hypertrophy in active acromegaly, which is reflected in the appearance of colonic polyps in a high proportion of acromegalic patients, even at an unusually young age. Colonic polyps are often of a premalignant nature (31). Thus, even though conflicting data exist regarding incidence and mortality from colon cancer in acromegaly, aggressive diagnostic vigilance is justified. All patients should have pan-colonoscopy at diagnosis, and this procedure should be repeated periodically as determined by individual risk factors, including presence of polyps, family history, and presence of skin tags. Screening for breast and prostate cancer should be conducted according to standards used in the general population. Additional basic research assessing GH/IGF-I effects on neoplastic transformation and reevaluation of the clinical use of IGF-I as a marker of disease activity are needed.
The aim of treatment is to control the disease by suppressing GH
hyperactivity, reducing the size or impeding the growth of the
pituitary mass, and eliminating secondary comorbid complications. Such
control of acromegaly may be achieved through either single or combined
surgery, radiotherapy, and/or medical treatment. Patients can, thus, be
classified depending on the degree of disease control. Good control
implies that the patient does not exhibit GH hyperactivity, as measured
by available assays, and should enjoy a mortality risk similar to the
general population. Inadequate control implies the presence of GH
hypersecretion, but minimally enhanced morbidity. Nevertheless,
morbidity is inexorable in these patients and ultimately becomes
life-threatening. Poor control implies that parameters of GH
hyperactivity are present with a high risk of morbidity and mortality.
Thus, control of acromegaly depends on evolution of the disease and on
therapeutic outcomes (Table 2
).
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| Footnotes |
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1 Participants: M. Arosio, A. Barkan, A. Beckers, A.
Bollati, M. Boscaro, P. M. Bouloux, M. Bronstein, A. Burattin, P.
Caron, F. F. Casa-nueva, F. Cavagnini, P. Chanson, R. N.
Clayton, D. Cocchi, A. M. Colao, E. Degli Uberti, M. Doga, E.
Erfurth, S. Ezzat, L. Frohman, R. Gaillard, M. Gasperi, M. Giovanelli,
A. Giustina, G. Giustina, A. Grossman, R. Gunnarsson, K. Ho, I.
Jackson, P. Jaquet, J. Jorgensen, D. Kleinberg, E. Laws, G. Lombardi,
M. Losa, D. Ludecke, P. Maffei, G. Maira, J. Marek, G. Marini, E.
Martino, C. Mascadri, S. Melmed, F. Minuto, H. Orskov, A. Pedtroncelli,
A. Pinchera, H. Quabbe, M. Sheppard, N. Sicolo, G. Tamburrano, G.
Tolis, A. Van Der Lely, J. D. Veldhuis, K. Von Werder, J.
A. H. Wass, and S. Webb. ![]()
Supported by an unrestricted educational grant by Ipsen
Pharmaceuticals to the University of Brescia (Brescia, Italy).
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