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Division of Endocrinology, Ospedale Niguarda (R.C., R.A., M.B., D.D.), I-20162 Milan, Italy; Endocrine Unit, Ospedali Riuniti (M.M., G.P., M.A., A.M.P.), Bergamo I-24100, Italy; and Department of Neurosurgery, Carlo Besta Institute (G.L., S.L.), Besta I-20133, Milan, Italy
Address all correspondence and requests for reprints to: Dr. R. Cozzi, Viale Ezio 5, I-20149 Milan, Italy. E-mail: renatocozzi{at}tiscali.it.
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Abstract |
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 Top Abstract IntroductionPatients and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Neurosurgery (NS) is usually considered the first choice treatment (4). Pharmacotherapy has been used to reduce GH/IGF-I hypersecretion in patients unsuitable or unwilling to undergo NS or after its failure, or in selected cases as primary treatment (PT) (5). Depot somatostatin analogs (SA), such as lanreotide-SR (LAN) (6) and octreotide (OC)-long-acting repeatable (LAR) (7), administered at 14- to 28-d intervals, are able to reduce hormonal hypersecretion in most patients and normalize IGF-I levels in many of them. Recently, Freda (8), summarizing the literature data, showed achievement of safe GH levels in 56% of patients treated with OC-LAR and in 49% of those treated with LAN. The figures for IGF-I normalization were 66% and 48%, respectively. Moreover, SA have been demonstrated to induce tumor shrinkage (up to 50% of basal volume) in 30% of the patients.
OC-LAR is a long-acting release form of the SA OC that was developed to maintain a prolonged (28-d) suppression of GH/IGF-I hypersecretion and avoid its drawbacks, such as multiple daily injections or the use of portable pumps. It consists of OC acetate incorporated in biodegradable capsules containing the (poly-DL-lactide-coglycolide)-glucose-initiated polymer (9).
The aim of this study was to retrospectively evaluate the effects of a very prolonged treatment with OC-LAR on GH/IGF-I levels and on tumor size in a large series of acromegalic patients. The durability of GH/IGF-I normalization, the different responses to the drug in subgroups of patients, and the predictivity of short-term results on the final outcome were also evaluated.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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One hundred ten patients with acromegaly (48 males and 62 females; age, 21–85 yr; median, 55 yr) attending 2 centers were retrospectively evaluated after a minimum follow-up of 18 months on OC-LAR. All of them had active disease according to the clinical picture, GH levels not suppressible to less than 1 µg/liter by oral glucose load, and elevated age-matched IGF-I levels. Chronic treatment had been carried out in the patients who showed a GH and/or IGF-I decrease of at least 20%, compared with the baseline, after a 6-month trial with OC-LAR.
OC-LAR had been administered as adjuvant treatment (AT) in 59 patients; 29 had been previously treated by NS, 7 by radiotherapy (RT), and 23 by both. NS had been performed at least 6 months before the start of OC-LAR treatment, and RT at least 6 yr before. In 51 patients SA had been the PT; 12 patients were de novo, and 39 had been previously treated by sc OC only. Pituitary magnetic resonance imaging (MRI) showed macroadenoma in 61 patients, microadenoma in 15 (invading the cavernous sinus in 8), residual pituitary adenoma after NS in 19, empty sella in 10, and normal pituitary gland in 5. Hyperprolactinemic patients requiring dopamine agonist treatment had been previously excluded from the study.
Any drug treatment aimed at decreasing GH hypersecretion had been withdrawn at least 3 months before the start of the study, whereas replacement treatments with L-T4, cortisone acetate, testosterone, ethinyl estradiol, and progesterone had been regularly carried out as needed.
Procedures
Treatment with OC-LAR had been started at the dose of 20 mg, administered im every 28 d for three injections. Thereafter, the OC-LAR schedule had been individually tailored with the aim to achieve normal age-adjusted IGF-I levels and a mean GH less than 2.5 µg/liter. The dose had been up-titrated to 30 mg when IGF-I remained above the age-matched normal range or decreased to 10 mg when IGF-I decreased below 50% (arbitrarily chosen as cut-off) of the upper limit of normal range (%ULNR).
Control evaluations had been performed at 3-month intervals on an out-patient basis, on the same day of the administration of the drug, before the injection was given, with a careful clinical evaluation (detailing frequency and intensity of headache, paresthesias, perspiration, swelling, fatigue, arthralgia, and snoring, and recording adverse events) and blood analysis. Blood samples had been collected in the morning hourly for at least 3 h after an overnight fast and rest while the patients were supine and awake, with an indwelling needle inserted in an antecubital vein and kept patent by slow infusion of saline. GH concentrations had been assayed in each sample (in Results the reported value is the mean of all the samples); IGF-I had been assayed in the first sample.
Neuroradiological control, to evaluate tumor size changes, had been performed in the PT group in patients with macroadenoma or microadenoma and in the AT group in patients with large remnant (>15 mm) before the start of treatment, at 6-month intervals during the first year, and yearly thereafter. Liver ultrasound examination had been performed before the start of treatment and yearly thereafter.
Methods
GH (Diagnostic Products, Los Angeles, CA) and IGF-I (Nichols Institute Diagnostics, San Juan de Capistrano, CA) were assayed in duplicate by immunometry and RIA after acid-ethanol extraction, respectively. The GH detection limit was 0.01 µg/liter. Standards were calibrated against First International Reference Preparation 80/505 (1 ng = 2.6 µIU) for GH and against WHO 87/518 for IGF-I. Intra- and interassay coefficients of variation were 2.9–4.6% and 4.2–6.6% for GH, and 3.7 and 7.2% for IGF-I. Age-related reference ranges (mean ± 2 SD) for IGF-I are 114–492 µg/liter in patients 25–39 yr old, 90–360 µg/liter in patients 40–54 yr old, and 71–290 µg/liter in patients older than 55 yr.
MRI was performed with a Gyroscan (ACS-NT, Philips Electronic Instruments, Mahway, NJ; 1.5 Tesla), using T1-weighted thin sections (3 mm thick, with 0.1 factor distance interleaved), obtaining sagittal and coronal images of the pituitary before and after iv gadolinium administration. The patients were placed in the same position on each imaging occasion to obtain slices as comparable as possible. All parameters were kept constant for each imaging session. The neuroradiologist evaluating the scans was blind to the clinical and endocrine data. On each scan the largest diameter of the tumor was measured on coronal (vertical diameter) and axial sections (anteroposterior and transverse), calculating the approximate volume of the adenoma, after correction for magnification factor, as the volume of a rotating ellipsoid with the formula (10): volume = 
(ventral x anteroposterior x transverse)/6. The shrinkage of the tumor was arbitrarily considered significant when its volume was reduced at least 25% compared with pretreatment values.
Statistical analysis
Values are expressed as the mean ± SE unless otherwise stated. IGF-I values are expressed both as absolute values and as %ULNR. Analyses were performed by GB-Stat (Silver Spring, MD) 6.5.4 PPC on raw data or after transformation of hormonal data as a percentage of the baseline. Data were analyzed by parametric tests, because they passed preliminary Kolgomorov-Smirnov tests for normality. Continuous data were analyzed by completely randomized ANOVA, followed by Newman-Keuls test, ANOVA for repeated measures, followed by Dunnett’s test, t test for paired or unpaired data, and Pearson correlation test, as appropriate. Multiple regression analysis and logistic regression analysis were performed only on data that were significantly correlated in pairwise comparisons. Categorical data were analyzed by 
2 test, with Fisher’s correction as appropriate. Survival analysis was performed using the Kaplan-Meier method, and differences between subgroups were evaluated by log-rank test. The predictive value of hormonal results obtained at 3 and 6 months on final outcome was formally evaluated by constructing receiver-operating characteristic (ROC) curves, plotting sensitivity and specificity. All statistical tests were two-tailed, and P < 0.05 was considered significant.
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Results |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Hormonal levels
Figure 1
shows that OC-LAR had significantly suppressed GH and IGF-I levels by the first evaluation. Mean GH decreased from 20.7 ± 2.4 µg/liter at baseline to 3.6 ± 0.5 µg/liter at 3 months and remained suppressed until the end of the follow-up (final value, 2.2 ± 0.2 µg/liter; P < 0.0001). IGF-I fell from 770 ± 26 to 379 ± 19 µg/liter at 3 months and to 276 ± 15 µg/liter at the end of the observation period (P < 0.0001). Even though after 6-month treatment the drug dose was not significantly increased in the whole group, IGF-I levels were progressively further suppressed after the first 3–6 months of treatment, whereas GH levels remained constant. No tachyphylaxis was observed throughout the study period. There was a direct correlation (r = 0.2; P = 0.03427) between the length of follow-up and the decline in IGF-I, i.e. the longer the former, the greater the latter.
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shows that OC-LAR treatment decreased GH to below 2.5 µg/liter in 79 patients (72%) and to less than 1 µg/liter in 30 of them (27% of the entire series). Normal age-matched IGF-I levels were reached in 83 patients (75%). In the remaining patients the mean IGF-I decline was 36% (range, 6–73%). Figure 2 shows a progressive increase in the rate of IGF-I normalization (61% at 12 months, 68% at 24 months, and 79% at 36 months) and of GH levels below 2.5 µg/liter (54%, 62%, and 73%, respectively) during the study. By Kaplan-Meier analysis the rate of both safe GH (<2.5 µg/liter) and IGF-I normalization was 68% at 36 months. Neither basal hormonal levels nor length of follow-up were different between patients who achieved hormonal normalization and those who did not.
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shows individual basal and final GH and IGF-I values. Mean basal GH/IGF-I levels were higher in PT patients than in AT patients [27.7 ± 4 vs. 14.7 ± 2.7 µg/liter (P = 0.009) and 833 ± 41 vs. 716 ± 33 µg/liter (P = 0.02), respectively]. OC-LAR treatment achieved similar suppression in the two groups, taking into account both absolute values [GH, 2.3 ± 0.2 vs. 2.1 ± 0.3 µg/liter (P = 0.7126); IGF-I, 291 ± 21 vs. 263 ± 21 µg/liter (P = 0.3313)] and percent decrease [GH, -83 ± 3% vs. -77 ± 3% (P = 0.1494); IGF-I, -62 ± 3% vs. -62 ± 3% (P = 0.9718)] as well as similar rates of normal GH and IGF-I [GH <2.5 µg/liter, 37 of 51 (73%) vs. 42 of 59 (71%; P = 0.6424); normal IGF-I, 34 of 51 (67%) vs. 46 of 59 (78%; P = 0.2419)].
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Discordant results were observed in 25 patients; in 14 of them GH levels remained above 2.5 µg/liter despite IGF-I normalization, whereas in 11 patients IGF-I values were still above the age-matched normal range despite safe GH levels.
Figure 4a shows that patients starting with higher GH levels (fourth quartile) achieved a greater percent hormonal suppression, i.e. basal GH levels were directly correlated with the percent suppression during treatment (r = 0.398; P < 0.0001). However final GH levels were different according to basal quartiles (1.4 ± 0.2, 2.3 ± 0.3, 2.2 ± 0.2, and 2.9 ± 0.5 µg/liter, respectively, in the four subgroups; P = 0.02). Figure 4b shows that the rate of normal GH/IGF-I was similar among the four subgroups [89%, 55%, 65%, and 64% for GH (P = 0.0659) and 86%, 70%, 85%, and 61% for IGF-I (P = 0.0839)]. Also, final IGF-I values, expressed as %ULNR, were similar (70 ± 6%, 83 ± 11%, 73 ± 9%, and 99 ± 9%, respectively; P = 0.089).
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The final OC-LAR dosage was 10 mg in 28 patients (25.4%), 20 mg in 36 patients (32.7%), 30 mg in 42 patients (38.2%), and 40 mg in 4 patients (3.6%). At the retrospective evaluation, the drug dose was significantly correlated with both basal levels (for GH: r = 0.39; P < 0.0001; for IGF-I: r = 0.21; P = 0.0295) and final results (for GH: r = 0.52; P < 0.0001; for IGF-I: r = 0.64; P = 0.0295). Patients treated with the lower OC-LAR dose had lower basal GH levels and achieved greater GH/IGF-I percent decrease, obtaining a significantly higher rate of safe GH and normal IGF-I values. In contrast, patients treated with higher doses had higher basal GH levels at the start of treatment and obtained lower hormonal suppression (Table 1).
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In patients attaining IGF-I levels less than 50%ULNR on treatment, the interval between each subsequent injection was prolonged. The same suppression of GH/IGF-I hypersecretion was maintained in 18 patients (16.4%) after interval elongation up to 63 d (i.e. 35 d, 3 patients; 42 d, 8 patients; 49 d, 4 patients; 56 d, 2 patients; 63 d, 1 patient; data not shown).
In 67 patients who maintained a fixed schedule of OC-LAR (i.e. no change in dosage or time interval between injections), a progressive suppression of IGF-I levels (P < 0.01 from the third month), but not of GH, was observed, even in the subgroup of 54 patients not previously treated with RT (data not shown).
With regard to age, Fig. 5 shows that basal GH and IGF-I levels were similar in younger and older patients [arbitrarily defined with respect to the median age in this series, i.e. below and above 55 yr, respectively; 21.9 ± 3.4 vs. 19.6 ± 3.5 µg/liter (P = 0.6261) and 758 ± 32 vs. 782 ± 41 µg/liter (P = 0.6409), respectively]. OC-LAR treatment produced similar GH suppression, but a greater IGF-I decline was observed in older patients (-57 ± 3% vs. -67 ± 3%; P = 0.0142). Final IGF-I levels were lower in elderly patients (312 ± 22 vs. 240 ± 19 µg/liter; P = 0.0161). IGF-I values expressed as %ULNR were significantly higher at study entry in older patients than in younger ones (197 ± 9% vs. 270 ± 14%; P < 0.0001). Superimposable values were obtained at the end of follow-up (81 ± 6% vs. 83 ± 7%; P = 0.4596). The drug dose was 23 ± 1 mg every 28 d in younger patients and 19.6 ± 1.3 mg every 28 d in older ones (P = 0.0294).
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At the retrospective evaluation, all patients who ultimately achieved both safe GH and normal age-matched IGF-I had GH below 5 µg/liter at 3 months and IGF-I below 550 µg/liter at 6 months. By multiple regression analysis, the final GH was best correlated with the GH level at 3 months (multiple r = 0.8654; P < 0.0001); the contribution of basal hormonal levels was minor (P = 0.021 for GH; P = 0.0249 for IGF-I). The final IGF-I was best correlated with the IGF-I value at 6 months (multiple r = 0.8387; P < 0.0001); the contributions of GH at 3 months and of drug dose were minor (P = 0.0065 and P = 0.0372, respectively). By logistic regression analysis (2 = 50.5787; P < 0.0001), the achievement of both safe GH and normal IGF-I was best correlated to the GH levels obtained at 3 months (P = 0.012) and the IGF-I levels obtained at 6 months (P = 0.0246).
Figure 6 shows ROC curves obtained by plotting GH levels after 3 months of OC-LAR treatment against the final achievement of safe GH, and IGF-I values after 6 months against normal final IGF-I. The GH level of 4 µg/liter at 3 months has a 68% sensitivity and a 94% specificity in predicting the final GH below 2.5 µg/liter. Likewise, the IGF-I level of 400 µg/liter at 6 months has a 76% sensitivity and a 82% specificity in predicting the final normalization of IGF-I levels.
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No increase in tumor size was observed in any patient. Tumor size reduction (ranging from 25–70% of basal volume) was observed at MRI control in 38 of 83 assessed patients (45.8%). The effect of treatment on tumor size was significantly correlated to the size of the adenoma; patients with macroadenoma obtained a higher rate of shrinkage than patients with microadenoma or remnant tumor (76%, 64%, and 11%, respectively; P < 0.0001). In contrast, basal hormonal levels, GH/IGF-I percent suppression, or drug dose did not influence the outcome of treatment in this respect. Tumor size reduction was only correlated to PT status (P = 0.0184) by logistic regression analysis (2 = 51.3381; P < 0.0001). Tumor shrinkage was observed in 33 of 43 patients in the PT group (76.7%). Among them, tumor shrank in 23 of 32 patients previously treated with OC (71.8%) and in 10 of 11 naive patients (90.9%).
Side effects
No patient was withdrawn from the study because of adverse effects of OC-LAR. There were no significant changes in routine biochemistry and hematology. No clinically meaningful increase in fasting glucose levels was observed (data not shown). Among the 23 diabetic patients, hyperglycemia reverted in 2, improved in 2, and worsened in 1. An increase in hemoglobin A1C above the upper limit of normal occurred in 20 nondiabetic patients (18%); it ranged between 6–6.5% in 16 patients (14.5%) and above 6.5% in 1 patient.
Liver ultrasound examination detected gallstones before OC-LAR treatment in 16 patients. Twenty patients (18%) showed new biliary abnormalities (sludge or stones) on OC-LAR, 9 of whom required symptomatic treatment with biliary salts.
Nine patients (8%) complained of transient gastrointestinal side effects (nausea, abdominal floating) that did not require withdrawal from treatment.
Local pain at the injection site was reported by 15 patients; it decreased at the following injections in most of them.
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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The introduction of OC (11, 12, 13, 14, 15), the first SA overcoming the very short half-life of natural somatostatin, represented a real revolution in the treatment of acromegaly. Recently, two SA analogs with more prolonged duration of action (up to 14–28 d) have been developed: LAN (6) and OC-LAR (7). OC-LAR (7, 16, 17) is able to reduce hormonal hypersecretion with monthly injections, achieving safe GH levels in 56% of patients and IGF-I normalization in 66%, according to the review by Freda (8).
Our data confirm the effectiveness of OC-LAR in controlling hormonal hypersecretion in acromegaly. According to updated criteria of cure for acromegaly (18), safe GH levels were achieved in 72% of patients, and IGF-I normalization was achieved in 75% at the final evaluation. A continuous decline in IGF-I values was obtained even in patients treated with a fixed drug dose. This result was not dependent on previous RT, because it was observed even when the patients previously irradiated were excluded from analysis. In addition, chronic treatment produced a progressive increase in the rate of patients attaining normal IGF-I, as shown by Kaplan-Meier analysis. Otherwise, the treatment produced a progressive increase in the rate of patients with safe GH levels, but no further suppression of its levels. This discrepancy allows us to hypothesize a possible treatment-induced change in the biological activity of the GH molecule.
The sustained suppression of GH/IGF-I hypersecretion throughout the study, without tachyphylaxis in any patient even after many years, confirms previously reported data (12). Our rates of GH/IGF-I normalization rank better than those previously reported and summarized by Freda (8). Patients in our series were both sensitive and only partially responsive to SA, showing a decrease in GH levels of at least 20% compared with basal values. However, due to the retrospective nature of this study, performed on patients followed-up for at least 18 months, a selection bias cannot be ruled out. It is conceivable that patients unresponsive to OC-LAR were switched to alternative treatment options, if available, and did not reach the 18-month follow-up period required for admission in the study. However, no patient was lost to follow-up, and all are still receiving treatment with the drug. In our opinion the very long-lasting duration of treatment in this study might account for the difference from other reported results. Indeed, the increasing IGF-I normalization rate with ongoing time (60% of patients after 12 months and 79% after 36 months, by survival analysis) suggests that the prolongation for many years of OC-LAR treatment in acromegaly might achieve an even higher rate of IGF-I normalization.
Discordant results in the achievement of safe GH and normal IGF-I levels were observed in 23% of patients in this series. This finding was reported in a similar proportion of patients by Wass (19), who observed normal GH values with elevated IGF-I levels in 8% and normal IGF-I values with still high GH levels in 19% of cases. The former type of discordance might be explained by the persistence of a lower, but continuously released, tonic GH secretion capable of inducing an exaggerated stimulation of IGF-I synthesis (20). It must be remembered that the cut-off of 2.5 µg/liter was chosen on an epidemiological basis (2, 3), without a substantial physiopathological background. The concomitant finding of normal IGF-I and pathological GH could be explained by a putative treatment-induced loss of biological activity of the GH molecule, as previously suggested by us (see above).
A continuous spectrum of responsiveness to treatment was observed in our series. Moreover, a consistent minority of patients (namely 16%) maintained GH/IGF-I suppression even when injected at more prolonged intervals (up to 9 wk). An accurate titration of treatment in both dosage and timing is therefore mandatory to optimize results and is cost saving, as previously reported (21).
The final outcome of treatment on GH/IGF-I levels was not correlated with the basal levels; the percentage of GH/IGF-I normalization was not different, in fact, among patients with different basal GH quartiles. This finding, although surprising, is unquestionable. On the one hand, the range of basal GH levels in this series is large enough to be representative of the general population affected by acromegaly; on the other hand, it stems from a large variety of concordant statistical tests. Moreover, we observed that patients starting from higher basal GH levels obtained greater suppression with treatment.
In our series the results obtained in the PT patients were quite similar to those obtained in the AT group in both suppression and rate of normalized GH/IGF-I levels. Newman et al. (22), in a large multicentric retrospective unrandomized study, first reported that medical treatment of acromegaly was equally effective as PT and AT. Even though a prospective randomized trial comparing PT and AT has not yet been performed, the choice of PT in acromegaly is strongly supported by many considerations. First, neurosurgical results are strictly operator-dependent (23, 24, 25). Second, the results of RT have been largely debated in recent years, with widely contrasting results (26, 27, 28). Even radiosurgical techniques such as gamma knife, which are still under investigation, do not seem to fulfill early promises (29). By contrast, promising results have been recently reported for primary medical treatment of acromegaly (30, 31, 32).
Our results confirm previously reported data showing a greater sensitivity to SA of older patients (33). Moreover, we show that these subjects were more severely affected by the disease, as demonstrated by the significantly higher levels of IGF-I, expressed as %ULNR, at the treatment start than in the younger patients. Despite the greater severity of the disease, OC-LAR-induced hormonal suppression was greater in older patients, restoring the physiologically age-related lower IGF-I levels and thus achieving a superimposable %ULNR with the younger group at the final evaluation.
The most exciting finding of this work is the demonstration that the short-term results are predictive of the final outcome. This was reported previously (34), but lacked the formal evaluation allowed by ROC analysis. We did show that the GH values obtained after 3 months of OC-LAR treatment as well as the IGF-I levels obtained after 6 months of treatment can confidently predict the achievement of safe GH levels and normal IGF-I values, respectively. Multivariate analysis showed that GH/IGF-I levels at 3–6 months were indeed the best predictors of the final results, far better than basal GH/IGF-I levels before the start of treatment, the length of follow-up, or the drug dose.
Significant tumor size shrinkage was observed in 46% of patients in the entire series. In patients with a large remnant after previous neurosurgical treatment, shrinkage was observed in only 11%. In contrast, OC-LAR shrank the tumor in 77% of patients of the PT group, and in this subgroup tumor shrinkage was observed in 91% of naive patients. Different rates of shrinkage during chronic SA treatment were reported, ranging from 17% in patients treated with LAN to 43% in patients treated with OC-LAR (8). The results obtained in our series stress that the comparison of results obtained by medical treatment in different series is always difficult due to the different proportions of patients previously subjected to different treatment modalities. When considering only PT patients treated with depot SA, however, the rate of shrinkage is much higher [80–88% in the series treated with OC-LAR (16, 30, 35) and 78% in those treated with 60 mg LAN (36)]. These striking data were recently confirmed also in prospective studies. In the United Kingdom Primary Octreotide Study (32), the tumor shrank in all 27 patients, and the Italian Multicentre Study on OC-LAR as First Line Therapy (37) showed a 33 ± 70% tumor volume reduction in 33 naive patients.
In conclusion, in our series of patients (sensitive or partial responder to OC-LAR), treatment achieved safe GH in 72% of PT and in 71% of AT patients and normal IGF-I in 67% and 78%, respectively. Tumor size reduction was obtained in 76% of macroadenomas and 64% of microadenomas, up to 91% in naive patients. Tachyphylaxis was never observed. The predictive value of short-term results at 3–6 months on the long-term effectiveness of the treatment is a useful tool to detect patients who will probably experience long-term normalization of GH/IGF-I levels. Even though the problem of life-long cost of medical treatment must be taken into account, these data support the use of PT with OC-LAR in acromegaly, at least in some groups of patients with poor surgical prognosis (i.e. the elderly and those with large and/or invasive tumors).
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Footnotes |
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Received January 22, 2003.
Accepted April 1, 2003.
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N. R. Biermasz, A. M. Pereira, J. W. A. Smit, J. A. Romijn, and F. Roelfsema Morbidity after Long-Term Remission for Acromegaly: Persisting Joint-Related Complaints Cause Reduced Quality of Life J. Clin. Endocrinol. Metab., May 1, 2005; 90(5): 2731 - 2739. [Abstract] [Full Text] [PDF]
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D. Selvarajah, J. Webster, R. Ross, and J. Newell-Price Effectiveness of adding dopamine agonist therapy to long-acting somatostatin analogues in the management of acromegaly Eur. J. Endocrinol., April 1, 2005; 152(4): 569 - 574. [Abstract] [Full Text] [PDF]
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J. S. Bevan The Antitumoral Effects of Somatostatin Analog Therapy in Acromegaly J. Clin. Endocrinol. Metab., March 1, 2005; 90(3): 1856 - 1863. [Abstract] [Full Text] [PDF]
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I. E Bonapart, R. van Domburg, S. M T H ten Have, W. W de Herder, R. A M Erdman, J. A M J L Janssen, and A. J. van der Lely The 'bio-assay' quality of life might be a better marker of disease activity in acromegalic patients than serum total IGF-I concentrations Eur. J. Endocrinol., February 1, 2005; 152(2): 217 - 224. [Abstract] [Full Text] [PDF]
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J. Ayuk, M. C. Sheppard, R. N. Clayton, A. S. Bates, and P. M. Stewart Evidence for the Use of IGF-I as a Predictor of Mortality in Acromegaly Is Lacking J. Clin. Endocrinol. Metab., November 1, 2004; 89(11): 5867 - 5868. [Full Text] [PDF]
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R. Attanasio, R. Baldelli, R. Pivonello, S. Grottoli, L. Bocca, V. Gasco, M. Giusti, G. Tamburrano, A. Colao, and R. Cozzi Lanreotide 60 mg, a New Long-Acting Formulation: Effectiveness in the Chronic Treatment of Acromegaly J. Clin. Endocrinol. Metab., November 1, 2003; 88(11): 5258 - 5265. [Abstract] [Full Text] [PDF]
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, first; 
, second; 
, for the third; 
, fourth). B, Percentage of patients achieving safe GH and normal age-matched IGF-I according to basal GH quartiles. *, P < 0.05 vs. lower quartiles.
