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Departments of Molecular and Clinical Endocrinology and Oncology (A.C., D.F., P.M., G.L.), Neurosurgery (P.C.), and Neuroradiology (S.C.), "Federico II" University of Naples, 80131 Naples, Italy; and Novartis Pharmaceutics (V.B., I.L.), 4002 Basel, Switzerland
Address correspondence and requests for reprints to: Annamaria Colao, M.D., Department of Molecular and Clinical Endocrinology and Oncology, "Federico II" University of Naples, via S. Pansini 5, 80131 Naples, Italy. E-mail: colao{at}unina.it
Abstract
The effects of a 12- to 24-month treatment with depot long-acting octreotide (OCT-LAR) on hormone profile, tumor mass, and clinical symptoms were reported in 36 patients with active acromegaly [GH, 34.2 ± 5.6 µg/L; insulin-like growth factor I (IGF-I), 784.5 ± 40.4 µg/L]. Fifteen patients were de novo whereas 21 had previously undergone unsuccessful surgery.
Serum GH (P < 0.0001) and IGF-I levels
(P < 0.0001) significantly decreased as early as
after the first injection of OCT-LAR and progressively declined during
the 12–24 months of treatment both in de novo and in
operated patients. At the last follow-up, GH hypersecretion was
controlled (
2.5 µg/L) in 69.4% whereas normal IGF-I levels were
achieved in 61.1% of patients. GH and IGF-I suppression during OCT-LAR
treatment was similar in de novo and operated patients
as shown by nadir GH (2.3 ± 0.6 vs. 2.2 ±
0.6 µg/L) and IGF-I (323.1 ± 34.9 vs. 275.5
± 33.0 µg/L), percent suppression of GH (92.7 ± 2.0
vs. 85.9 ± 3.3%) and IGF-I (57.4 ± 4.9
vs. 61.5 ± 4.6%), and prevalence of GH (73.3
vs. 76.2%) and IGF-I (53.3 vs. 71.4%)
control. A decrease in tumor volume was observed in 12 of 15 de
novo patients, whereas no shrinkage was detected in 4 of 9
operated patients. No patient had tumor reexpansion during OCT-LAR
treatment. Significant clinical improvement was obtained in all
patients; heart rate, systolic blood pressure, and diastolic blood
pressure significantly decreased in the entire population. A mild but
significant increase of blood glucose levels, followed by a decrease of
serum insulin levels, was observed after 3 months of treatment: this
effect subsided with treatment continuation. OCT-LAR treatment was well
tolerated by most patients.
In conclusion, long-term treatment with OCT-LAR was effective in controlling GH and IGF-I hypersecretion in most patients with acromegaly, when applied either as primary therapy or as adjunctive therapy after surgery. Tumor shrinkage was observed in de novo patients during OCT-LAR treatment, suggesting that it can be successfully applied as primary therapy in patients bearing invasive tumors, who are less likely to be cured after surgery.
PHARMACOTHERAPY WITH SOMATOSTATIN analogs
is currently regarded as a potential option for the primary therapy of
acromegaly. In fact, sc octreotide (OCT) administration in de
novo acromegalic patients induced suppression of GH and
insulin-like growth factor I (IGF-I) levels that was similar to that
observed in patients who received OCT treatment after surgery
(1). This finding has opened the question of the best
treatment strategy in acromegaly. The availability of the slow-release
formulation of OCT (OCT-LAR) has further improved the medical approach
to this systemic disease. OCT-LAR was developed to enable once-monthly
administration, producing stable blood concentrations of the drug,
resulting in sustained GH and IGF-I suppression (2). In a
dose-ranging study, OCT-LAR was shown to suppress GH and IGF-I levels
to a similar extent as the sc formulation in 21 acromegalic patients
(3). In a multicenter study, OCT-LAR administered im at
4-week intervals to 151 patients responsive to sc OCT, induced control
of GH (2.5 µg/L) and IGF-I secretion in 69.8% and 65.8%
vs. 65.8% and 63.1% during prior treatment with sc OCT,
respectively (4). Similar data have been reported in small
series of patients treated for 12–36 months (5, 6, 7, 8).
Systemic and local tolerability as well as patients’ compliance were
reported to be very good (4, 5, 6, 7, 8).
Because data concerning the long-term efficacy of this drug, mostly on tumor mass, are still scant, we investigated the effects of a 12- to 24-month OCT-LAR treatment on hormone profile, tumor mass, and clinical symptoms in 36 acromegalic patients. The potential difference in applying OCT-LAR treatment as primary therapy or after surgery was also investigated.
Patients and Methods
Patients
Thirty-six patients with active acromegaly (21 women and 15 men;
age range, 24–77 yr; median, 56 yr) and never treated before with
somatostatin analogs, except for a short (3 months) treatment before
surgery, were enrolled into the study after their informed consent had
been obtained. Twenty-one patients had previously undergone
unsuccessful surgery. The laboratory diagnosis of acromegaly was
defined by high serum GH levels (34.2 ± 5.6 µg/L; mean ±
SEM) during a 6-h time course, not suppressible below 2
µg/L after a 75-g oral glucose tolerance test (oGTT) and high plasma
IGF-I levels for age (784.5 ± 40.4 µg/L) (9). Two
patients suffered from overt diabetes mellitus and did not receive
oGTT. The presumed duration of acromegaly was assessed by comparison of
patients’ photographs taken during a one- to three-decade span and by
interviews to estimate the date the onset of acral enlargement. In this
series, disease duration ranged between 5 and 35 yr (16.9 ± 1.4
yr). The patients’ profile at study entry is shown in Table 1
. To improve the clinical conditions
(10), 16 of the 21 patients operated on had received
somatostatin analog treatment with sc OCT at a dose of 0.1 mg three
times a day (5 patients), lanreotide at a dose of 30 mg every 14 days
(8 patients), and OCT-LAR at a dose of 20 mg every 28 days (3
patients): in these patients the assessment of disease activity was
performed at least 3 months after surgery. The only exclusion criteria
for de novo patients was the presence of visual field
defects or other neurological symptoms due to tumor mass.
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At study entry plasma IGF-I levels were assayed twice in a single sample, whereas the value of serum GH was calculated as the mean of a 6-h blood sampling (0800–1400 h with 30-min sampling). During treatment, the final GH level was calculated as the average value from at least three blood samples collected, at 15-min intervals, the morning before the next injection of OCT-LAR. At this time point, plasma IGF-I concentrations were assayed as single sampling. Hormonal and clinical evaluations were carried out before, monthly for the first 3 months, and quarterly during the treatment. Hormone normalization after OCT-LAR treatment was considered when basal GH values were 2.5 µg/L or lower as fasting sample or 1 µg/L or lower after glucose load, together with IGF-I values within the normal range for age (11, 12). Blood pressure was measured at study entry and quarterly during OCT-LAR treatment in the right arm, with the subjects in a relaxed sitting position. Before and after 12 and 24 months of treatment, the average of six measurements (three taken by each of two examiners) with a mercury sphygmomanometer was taken. Hypertension was diagnosed when diastolic blood pressure (DBP) values were more than 90 mm Hg and was graded as mild when between 91 and 104 mm Hg, moderate when 105–114 mm Hg, and severe when more than 115 mm Hg, in line with WHO criteria (13). Among the 36 patients, 13 (36.1%) had mild hypertension. Fasting glucose, triglycerides, and total cholesterol levels were measured by standard procedures. At study entry impaired glucose tolerance was diagnosed after oGTT (75 g glucose diluted in 250 mL saline solution, measuring blood glucose every 30 min for 2 h). Diabetes mellitus was diagnosed when fasting glucose was above 7 mmol/L at two consecutive measurements or when 2 h after the oGTT, glucose was 11.1 mmol/L or higher (14). Impaired glucose tolerance was diagnosed when glucose was between 7 and 11.1 mmol/L 2 h after the oGTT with an additional value 11.1 mmol/L or lower between 0 and 2 h after the oGTT (14). Among the 36 patients, 2 (5.5%) had diabetes mellitus and 6 (16.7%) had glucose intolerance. Fasting insulin levels were also measured in all patients. In all patients gallbladder and biliary system ultrasonography was performed before and every 6 months during OCT-LAR treatment.
Treatment protocol
All patients, but the 16 who were treated with somatostatin
analogs before surgery, received an acute test with sc OCT at a dose of
0.1 mg to investigate individual patient tolerability to somatostatin
analogs (15). In all patients OCT-LAR was initially
administered im at a dose of 20 mg every 28 days for 3 months. Then,
the dose of OCT-LAR was increased to 30 mg every 28 days on the basis
of GH levels above 5 µg/L in 15 patients (16). After 12
months of treatment the dose of OCT-LAR was further increased to 40 mg
every 28 days in seven patients (1, 2, 18, 20, 21, 27, and 29; Table 1
)
and was decreased to 10 mg every 28 days in two elderly patients (14
and 15; Table 1) who achieved fasting GH levels below 1 µg/L. At the
end of the study, the dose of OCT-LAR was 10 mg in 2 patients (5%), 20
mg in 14 patients (38.9%), 30 mg in 11 patients (30.5%), and 40 mg in
8 patients (22.2%) (Table 1). One man died of a heart attack 2 months
after beginning therapy, and two women died during the follow-up: the
former after 48 months of treatment for uterus carcinoma at the age of
58 yr, and the latter after 30 months of treatment for cachexia due to
the nutritional problems caused by hesofageal acalasia at the age of 81
yr. Thirty-five patients completed the 12-month follow-up, 32 patients
completed the 18-month follow-up, and 28 patients completed the
24-month follow-up (Table 1).
Assays
Serum GH levels were measured by immunoradiometric assay (IRMA) (HGH-CTK-IRMA; Sorin, Saluggia, Italy). The sensitivity of the assay was 0.2 µg/L; 1 µg/L corresponds to 2.5 mU/L. The intra- and interassay coefficients of variation (CV) were 4.5% and 7.9%, respectively. Plasma IGF-I was measured by IRMA after ethanol extraction using DSL kits (Diagnostic Systems Laboratories, Inc., Webster, TX). The sensitivity of the assay was 0.8 µg/L. The intra-assay CV were 3.4%, 3.0%, and 1.5% for the low, medium, and high points on the standard curve, respectively. The interassay CV were 8.2%, 1.5%, and 3.7% for the low, medium, and high points on the standard curve. Fasting GH levels were considered above the normal range when higher than 2.5 µg/L. In our laboratories the normal IGF-I range in 20–30, 31–40, 41–50, and over 50-yr-old subjects was 110–502, 100–494, 100–303, and 78–258 µg/L, respectively.
Magnetic resonance imaging (MRI) studies
MRI studies were performed on clinical 0.5T and 1T scanners,
using T1-weighted gradient recalled-echo (repetition time, 200–300
milliseconds; echo time, 10–12 milliseconds; flip angle, 90 degree,
four signal averages) in the sagittal and coronal planes. In each
measurement 7–11 slices were obtained, with a slice thickness of 2–3
mm and an in-plane spatial resolution of 0.7–0.97 mm (the matrix was
192–256 x 256 on a field of view of 24–25 cm on the sagittal
plane and 160–256 x 256 on a field of view of 18–20 cm in the
coronal plane). The acquisitions were repeated before and after the
administration of 0.1 mmol gadolinium chelate (diethylene-triamine
pentacetate). MRI was performed before and after 3, 6, 12, and 24
months of OCT-LAR treatment in de novo patients and before
and after 12 and 24 months in operated patients. In de novo
patients shrinkage was established on tumor volume calculated by the Di
Chiro and Nelson formula: volume = height x length x
width x 
/6 (17) and on the maximal tumor
diameter, whereas in patients previously operated on shrinkage was
established only on the maximal tumor diameter. Tumor shrinkage was
evaluated as a reduction of the pretreatment tumor volume or maximal
tumor diameter, respectively, in a semiquantitative way as: less than
25% or less than 10%, no shrinkage; 26–50% or 11–20%, mild
shrinkage; 51–75% or 21–30%, moderate shrinkage; more than 75% or
more than 30%, notable shrinkage. The radiologist (S.C.) was blind in
respect to the status of the patient.
Visual perimetry
In all patients the assessment of visual field defects, by Goldmann-Friedmann perimetry, and visual acuity was performed at baseline. The ophthalmologic examination was repeated every 6 months during the follow-up in the patients with visual disturbances.
Statistical analysis
The statistical analysis was performed by means of an
SPSS, Inc. (Cary, NC) package. The effect of OCT-LAR was
analyzed by the paired Student’s t test, ANOVA,
2 test, and linear regression analysis,
where appropriate. Data are reported as mean ±
SEM.
Results
Effect of long-term OCT-LAR treatment on GH and IGF-I levels
A significant decrease of circulating GH (from 34.2 ± 5.6 to
12.5 ± 2.5 µg/L, P < 0.0001) and IGF-I levels
(from 784.5 ± 40.4 to 582.2 ± 42.1 µg/L,
P < 0.0001) was observed early after the first
injection of OCT-LAR. At this time point, GH and IGF-I decrease was
similar in the 16 patients who received the short presurgical treatment
with somatostatin analogs and the remaining patients (data not shown).
Serum GH (3.5 ± 0.7 µg/L, P < 0.0001) and
IGF-I levels (335 ± 26.2 µg/L, P < 0.0001)
progressively declined during the first 12 months of treatment both in
de novo (Fig. 1) and in
operated patients (Fig. 2). After 12
months of treatment with OCT-LAR, the percent GH and IGF-I suppression
was 83.8 ± 3.2% and 55.2 ± 3.3%, respectively. In the 28
patients treated for 24 months serum GH (from 3.5 ± 0.8 to
2.4 ± 0.5 µg/L, P = 0.04) and IGF-I levels
(from 333.2 ± 31.2 to 290.1 ± 30.0 µg/L,
P = 0.001) were further decreased compared with the
12-month follow-up. After 1, 3, 6, 12, 18, and 24 months of OCT-LAR
treatment, in the whole population GH hypersecretion was controlled
(2.5 µg/L) in 16.7%, 34.3%, 60%, 68.6%, 71.8%, and 71.4%,
whereas normal IGF-I levels were achieved in 20%, 20%, 42.8%,
48.6%, 56.3%, and 67.8%, respectively. At the last follow-up GH
levels were 1 µg/L or lower in 15 patients (41.7%), 1.1–2.5 µg/L
in 11 patients (30.6%), 2.6–5 µg/L in 5 patients (14.3%), and
higher than 5 µg/L in 5 patients.
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Effect of 12–24 months of OCT-LAR treatment on tumor shrinkage
A remarkable decrease in tumor volume was observed in de
novo patients during OCT-LAR treatment (Fig. 3). After 3 months only five patients had
a mild-to-moderate shrinkage. In contrast, at the last follow-up
shrinkage was absent in three patients (20%), mild in three (20%),
moderate in six (40%), and notable in three patients. Two patients
with microadenoma had disappearance of their tumors after 6–12 months
of treatment. In one patient with microadenoma a remarkable tumor
decrease was observed after 3 months of OCT-LAR treatment at a dose of
20 mg every 28 days (Fig. 4). Tumor
shrinkage was evaluated in only 9 of the 21 operated patients (Table 1): shrinkage was absent in 4, mild in 1, moderate in 3, and notable in
1 patient. After 12 and 24 months of treatment, no difference was found
in the maximal tumor diameter both in the eight de novo
(11.1 ± 2.7 vs. 10.3 ± 2.5 mm) and in the nine
operated patients (10.7 ± 2.2 vs. 10.2 ± 2.2
mm). At the last follow-up, the decrease in the maximal tumor diameter
was slightly but not significantly higher in de novo
(31.1 ± 7.6%) than in operated patients (14.8 ± 4.4%). In
de novo patients, no correlation was found between tumor
volume and age, disease duration and baseline GH and IGF-I levels, or
between the percent tumor reduction and percent GH/IGF-I suppression or
the dose of OCT-LAR. No patient had tumor reexpansion during OCT-LAR
treatment. No de novo patient had visual field defects at
study entry whereas 4 of the 21 operated patients had temporal
quadrantopsia that did not significantly improve during OCT-LAR
treatment.
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All patients obtained significant clinical improvement during OCT-LAR treatment: specifically, patients reported improvement of headache (n = 10), hyperhidrosis (n = 15), asthenia (n = 5), and osteo-articular pain and mobility (n = 22). Reduction of soft tissue swelling was noted by all patients. In addition, during treatment, heart rate [from 92.1 ± 1.6 to 86.0 ± 1.2 beats per minute (bpm) after 12 months and 83.9 ± 1.6 bpm after 24 months, P < 0.01], systolic blood pressure (from 138.6 ± 1.5 to 134.4 ± 1.2 mm Hg after 12 months and 132.4 ± 1.5 mm Hg after 24 months, P < 0.01), and DBP (from 88.9 ± 1.1 to 86.3 ± 0.9 bpm after 12 months and 84.9 ± 1.0 bpm after 24 months, P < 0.05) significantly decreased in the population as a whole. Among the 13 patients with mild hypertension, only 3 still had DBP above 90 mm Hg and remained under specific antihypertensive treatment. The patient who died of a heart attack had mild hypertension and was specifically treated at study entry. No difference was observed in the clinical improvement between de novo and operated patients. Similarly, with the exclusion of the two diabetic patients, no difference was found in blood glucose, triglycerides, and total cholesterol levels before and after 12–24 months of treatment, although a mild but significant increase of blood glucose levels (5.3 ± 0.3 vs. 5.9 ± 0.2 mmol, P < 0.05) followed by a decrease of serum insulin levels (17.7 ± 3.4 vs. 10.5 ± 3.1 mU/L, P < 0.05) was observed after 3 months of treatment. However, at the end of OCT-LAR treatment blood glucose (5.5 ± 0.3 mmol/L) and insulin (15.0 ± 3.2 mU/L) were similar to pretreatment values. Both diabetic patients reduced insulin requirements during OCT-LAR treatment, and one of the six patients with impaired glucose tolerance required additional treatment with glucose-lowering drugs.
Tolerability
OCT-LAR treatment was well tolerated by most patients: abdominal discomfort was reported by 10 (27.8%), steatorrhea by 4 (11.1%), flatulence by 10, and hair loss by 4 patients. These side effects spontaneously disappeared in seven cases and after treatment with pancreatic enzymes in the others. Hair loss stopped after 3–6 months. Asymptomatic gallstones were detected in two patients whereas in another patient colecystectomy for acute colecystitis was performed after 12 months of treatment. This latter patient was withdrawn from OCT-LAR treatment.
Discussion
Acromegaly is a chronic and slowly developing disease that causes progressive disability and shortens life (18, 19). Its optimal treatment is the selective removal of the GH-secreting pituitary adenoma, which should, consequently, result in the normalization of GH and IGF-I secretion, without causing secondary hypopituitarism and with minimal side effects and morbidity. Trans-sphenoidal surgery seems to be the most appropriate therapeutic measure and is associated with very low morbidity and a low recurrence rate (20, 21, 22). However, the results of surgery reported from many centers over the last 20 yr are difficult to compare with our practice because the criteria used to define the control of acromegaly have changed (12) and the success of surgery has improved with the increasing experience of pituitary surgeons and the improvement in surgical technique (23). However, in one recent series of 115 patients undergoing trans-sphenoidal surgery (20), remission after surgery alone was achieved in 61%, but in only 53% of patients with macroadenoma. A similar result was reported by Swearingen et al. (21). Therefore, it is presently accepted that disease control after surgery alone can be achieved in a high proportion of cases with relatively small enclosed adenomas (11, 24, 25). In patients with invasive adenomas it is, therefore, necessary to use pharmacotherapy to achieve disease control (11, 24, 25). The treatment with somatostatin analogs, particularly OCT (26), has been widely shown to rapidly and effectively reduce GH hypersecretion and to decrease IGF-I concentrations. On the other hand, a recent multicenter study has demonstrated that no difference existed in the GH and IGF-I suppression after sc OCT treatment between patients treated with this drug primarily and those treated after unsuccessful surgery (1). This relevant result has opened the question as to whether surgery should still be considered as primary therapy of all patients with acromegaly. The recent availability of somatostatin analogs provided in slow-release formulations such as lanreotide (27, 28, 29, 30), and OCT-LAR (4, 5, 6, 7, 8) has further improved patients’ compliance to long-term treatment.
In accord with previous studies (4, 5, 6, 7), the results of the present study show that treatment with OCT-LAR is highly effective in controlling GH and IGF-I hypersecretion in the majority of acromegalic patients (71.4% and 67.8%, respectively). In particular, a significant decrease of GH and IGF-I levels was noted after the first injection of 20 mg OCT-LAR. Interestingly, although de novo patients presented with higher GH levels at study entry than operated patients, the final therapeutic effect of OCT-LAR was identical in these two subgroups of acromegalics. These results confirmed those reported by Newman et al. (1) in a multicenter trial involving a large cohort of patients treated with sc OCT.
Following the decrease of GH and IGF-I levels, significant improvement of clinical symptoms was experienced by the majority of our patients: in particular, they reported improvement in the articular mobility at the hands and knees, and 10 of 11 patients had dramatic improvement of headache. Besides these effects, we observed an early impairment of glucose tolerance that was, however, short-lasting and an overall improvement of blood pressure during OCT-LAR treatment. A clinically insignificant reduction of heart rate was also noted, confirming previous results obtained with sc OCT (31).
One of the most relevant results of this study is that 53.3% of patients treated with OCT-LAR as primary therapy had a moderate-to-notable decrease of tumor volume with an average value of 53.1 ± 6.7% tumor reduction after 12 months of treatment, leading to tumor disappearance in two patients bearing microadenoma at study entry. In de novo patients, the shrinking effect of OCT-LAR was progressive during long-term treatment although the most dramatic tumor reduction was observed at the 3-month follow-up (29.8 ± 5.1 after 3 months vs. 7.9 ± 3%, 18.8 ± 4.2% and 5.4 ± 3.1% after 6, 12, and 24 months, respectively). The effect on tumor size of OCT-LAR has already been reported to occur in 29–72% of patients (8): however, the majority of these patients had already been treated by surgery and/or radiotherapy. The degree of tumor reduction varied from 20% (3, 32) to 100% (5) and was reported both in micro- and in macroadenomas (8). These results are in line with those observed in our patients. However, in the present study the reduction in the maximal tumor diameter was slightly lower in operated than in de novo patients (14.8 ± 4.4 vs. 31.1 ± 7.6%). Whether surgical manipulation of the tumor, causing fibrosis and histological changes in tumor tissue, can be considered responsible for the scant shrinking effect of OCT-LAR therapy in remnant tumors or whether the irregularity of the morphology of remnant tumors does not allow a precise estimation by MRI of remnant size cannot be ruled out. A similar result was, however, recorded in another large series of patients treated with lanreotide, another slow-release formulation (33).
The incidence of side effects was scant, and patients’ compliance to the long-term treatment was excellent. These results are in agreement with previous studies of shorter duration (4, 5, 6, 7). However, one patient was withdrawn from OCT-LAR because of acute colecystitis treated by colecystectomy.
In conclusion, long-term treatment with OCT-LAR was effective in normalizing GH and IGF-I levels in as many as 69.2% and 73.7% of patients with acromegaly, respectively, without any difference when applied as either primary therapy or as adjunctive therapy after surgery. The incidence of side effects during treatment was scant, even in patients treated with 40 mg every 28 days. Interestingly, notable tumor shrinkage was observed in de novo patients during OCT-LAR treatment, most evident as early as after 3 months. On this basis, OCT-LAR can be considered as a very effective and well tolerated treatment for acromegaly and can be successfully applied as primary therapy in patients bearing invasive tumors, who are less likely to be cured after surgery. In fact, even considering that the cost of the medical treatment is currently rather elevated, in these patients the global cost of the treatment includes that of the unsuccessful surgery and of the medication.
Acknowledgments
We are indebted to Prof. E. R. Laws Jr. (Department of Neurosurgery, University of Virginia, Charlottesville, VA) for kindly revising the manuscript.
Footnotes
1 Partially supported by Grant 9906153187 from MURST Rome and by a
Grant 8680/98 from Regione Campania Ricerca Finalizzata DGR. 
Received August 17, 2000.
Revised December 18, 2000.
Revised February 22, 2001.
Accepted March 16, 2001.
References
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
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|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
S. L. Fougner, J. Bollerslev, F. Latif, J. K. Hald, T. Lund, J. Ramm-Pettersen, and J. P. Berg Low Levels of Raf Kinase Inhibitory Protein in Growth Hormone-Secreting Pituitary Adenomas Correlate with Poor Response to Octreotide Treatment J. Clin. Endocrinol. Metab., April 1, 2008; 93(4): 1211 - 1216. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
 C Susini and L Buscail Rationale for the use of somatostatin analogs as antitumor agents Ann. Onc., December 1, 2006; 17(12): 1733 - 1742. [Abstract] [Full Text] [PDF]
|
|
|
|
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 Developed in Collaboration With the European Heart, D. P. Zipes, A. J. Camm, M. Borggrefe, A. E. Buxton, B. Chaitman, M. Fromer, G. Gregoratos, G. Klein, A. J. Moss, et al. ACC/AHA/ESC 2006 Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death) J. Am. Coll. Cardiol., September 5, 2006; 48(5): e247 - e346. [Full Text] [PDF]
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 Writing Committee Members, D. P. Zipes, A. J. Camm, M. Borggrefe, A. E. Buxton, B. Chaitman, M. Fromer, G. Gregoratos, G. Klein, A. J. Moss, et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: A report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death) Developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society Europace, September 1, 2006; 8(9): 746 - 837. [Full Text] [PDF]
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A. Colao, R. Pivonello, R. S. Auriemma, F. Briganti, M. Galdiero, F. Tortora, F. Caranci, S. Cirillo, and G. Lombardi Predictors of Tumor Shrinkage after Primary Therapy with Somatostatin Analogs in Acromegaly: A Prospective Study in 99 Patients J. Clin. Endocrinol. Metab., June 1, 2006; 91(6): 2112 - 2118. [Abstract] [Full Text] [PDF]
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R. Cozzi, M. Montini, R. Attanasio, M. Albizzi, G. Lasio, S. Lodrini, P. Doneda, L. Cortesi, and G. Pagani Primary Treatment of Acromegaly with Octreotide LAR: A Long-Term (Up to Nine Years) Prospective Study of Its Efficacy in the Control of Disease Activity and Tumor Shrinkage J. Clin. Endocrinol. Metab., April 1, 2006; 91(4): 1397 - 1403. [Abstract] [Full Text] [PDF]
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A. Colao, R. Pivonello, R. S Auriemma, M. C. De Martino, M. Bidlingmaier, F. Briganti, F. Tortora, P. Burman, I. A Kourides, C. J Strasburger, et al. Efficacy of 12-month treatment with the GH receptor antagonist pegvisomant in patients with acromegaly resistant to long-term, high-dose somatostatin analog treatment: effect on IGF-I levels, tumor mass, hypertension and glucose tolerance. Eur. J. Endocrinol., March 1, 2006; 154(3): 467 - 477. [Abstract] [Full Text] [PDF]
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A. Colao, R. Attanasio, R. Pivonello, P. Cappabianca, L. M. Cavallo, G. Lasio, A. Lodrini, G. Lombardi, and R. Cozzi Partial Surgical Removal of Growth Hormone-Secreting Pituitary Tumors Enhances the Response to Somatostatin Analogs in Acromegaly J. Clin. Endocrinol. Metab., January 1, 2006; 91(1): 85 - 92. [Abstract] [Full Text] [PDF]
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 J Ayuk and M C Sheppard Growth hormone and its disorders Postgrad. Med. J., January 1, 2006; 82(963): 24 - 30. [Abstract] [Full Text] [PDF]
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P. U. Freda, L. Katznelson, A. J. van der Lely, C. M. Reyes, S. Zhao, and D. Rabinowitz Long-Acting Somatostatin Analog Therapy of Acromegaly: A Meta-Analysis J. Clin. Endocrinol. Metab., August 1, 2005; 90(8): 4465 - 4473. [Abstract] [Full Text] [PDF]
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S. Melmed, R. Sternberg, D. Cook, A. Klibanski, P. Chanson, V. Bonert, M. L. Vance, D. Rhew, D. Kleinberg, and A. Barkan A Critical Analysis of Pituitary Tumor Shrinkage during Primary Medical Therapy in Acromegaly J. Clin. Endocrinol. Metab., July 1, 2005; 90(7): 4405 - 4410. [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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P. Petrossians, L. Borges-Martins, C. Espinoza, A. Daly, D. Betea, H. Valdes-Socin, A. Stevenaert, P. Chanson, and A. Beckers Gross total resection or debulking of pituitary adenomas improves hormonal control of acromegaly by somatostatin analogs Eur. J. Endocrinol., January 1, 2005; 152(1): 61 - 66. [Abstract] [Full Text] [PDF]
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J. Ayuk, R. N. Clayton, G. Holder, M. C. Sheppard, P. M. Stewart, and A. S. Bates Growth Hormone and Pituitary Radiotherapy, But Not Serum Insulin-Like Growth Factor-I Concentrations, Predict Excess Mortality in Patients with Acromegaly J. Clin. Endocrinol. Metab., April 1, 2004; 89(4): 1613 - 1617. [Abstract] [Full Text] [PDF]
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 A. Colao, D. Ferone, P. Marzullo, and G. Lombardi Systemic Complications of Acromegaly: Epidemiology, Pathogenesis, and Management Endocr. Rev., February 1, 2004; 25(1): 102 - 152. [Abstract] [Full Text] [PDF]
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J. van der Hoek, W. W. de Herder, R. A. Feelders, A.-J. van der Lely, P. Uitterlinden, V. Boerlin, C. Bruns, K. W. Poon, I. Lewis, G. Weckbecker, et al. A Single-Dose Comparison of the Acute Effects between the New Somatostatin Analog SOM230 and Octreotide in Acromegalic Patients J. Clin. Endocrinol. Metab., February 1, 2004; 89(2): 638 - 645. [Abstract] [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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D. R. Clemmons, K. Chihara, P. U. Freda, K. K. Y. Ho, A. Klibanski, S. Melmed, S. M. Shalet, C. J. Strasburger, P. J. Trainer, and M. O. Thorner Optimizing Control of Acromegaly: Integrating a Growth Hormone Receptor Antagonist into the Treatment Algorithm J. Clin. Endocrinol. Metab., October 1, 2003; 88(10): 4759 - 4767. [Abstract] [Full Text] [PDF]
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R. Cozzi, R. Attanasio, M. Montini, G. Pagani, G. Lasio, S. Lodrini, M. Barausse, M. Albizzi, D. Dallabonzana, and A. M. Pedroncelli Four-Year Treatment with Octreotide-Long-Acting Repeatable in 110 Acromegalic Patients: Predictive Value of Short-Term Results? J. Clin. Endocrinol. Metab., July 1, 2003; 88(7): 3090 - 3098. [Abstract] [Full Text] [PDF]
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A. Ben-Shlomo and S. Melmed The Role of Pharmacotherapy in Perioperative Management of Patients with Acromegaly J. Clin. Endocrinol. Metab., March 1, 2003; 88(3): 963 - 968. [Full Text] [PDF]
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J. S. Bevan, S. L. Atkin, A. B. Atkinson, P.-M. Bouloux, F. Hanna, P. E. Harris, R. A. James, M. McConnell, G. A. Roberts, M. F. Scanlon, et al. Primary Medical Therapy for Acromegaly: An Open, Prospective, Multicenter Study of the Effects of Subcutaneous and Intramuscular Slow-Release Octreotide on Growth Hormone, Insulin-Like Growth Factor-I, and Tumor Size J. Clin. Endocrinol. Metab., October 1, 2002; 87(10): 4554 - 4563. [Abstract] [Full Text] [PDF]
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J. Ayuk, S. E. Stewart, P. M. Stewart, and M. C. Sheppard Long-Term Safety and Efficacy of Depot Long-Acting Somatostatin Analogs for the Treatment of Acromegaly J. Clin. Endocrinol. Metab., September 1, 2002; 87(9): 4142 - 4146. [Abstract] [Full Text] [PDF]
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P. U. Freda Somatostatin Analogs in Acromegaly J. Clin. Endocrinol. Metab., July 1, 2002; 87(7): 3013 - 3018. [Full Text] [PDF]
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A. Colao, L. Spinelli, A. Cuocolo, S. Spiezia, R. Pivonello, C. di Somma, D. Bonaduce, M. Salvatore, and G. Lombardi Cardiovascular Consequences of Early-Onset Growth Hormone Excess J. Clin. Endocrinol. Metab., July 1, 2002; 87(7): 3097 - 3104. [Abstract] [Full Text] [PDF]
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 F. Frick, M. Bohlooly-Y, D. Linden, B. Olsson, J. Tornell, S. Eden, and J. Oscarsson Long-term growth hormone excess induces marked alterations in lipoprotein metabolism in mice Am J Physiol Endocrinol Metab, December 1, 2001; 281(6): E1230 - E1239. [Abstract] [Full Text] [PDF]
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