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Original Studies |
Departments of Molecular and Clinical Endocrinology and Oncology (A.Co., P.M., D.F., G.L.), Internal Medicine I (L.S., D.B.), Biomorphological and Functional Sciences, National Council for Research, Nuclear Medicine (A.Cu., M.S.), "Federico II" University of Naples, 80131 Naples, Italy; Scientific Institute for Research and Care Neuromed (A.Cu.), Pozzilli, Italy; and Novartis Pharma A.G. (V.B., I.L.), 4002 Basel, Switzerland
Address correspondence and requests for reprints to: Annamaria Colao, 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
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Abstract |
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The aim of the present study was to investigate the early effect of OCT-LAR treatment on the left ventricular (LV) structure and performance in 15 somatostatin analog-naive patients with acromegaly (GH, 94.8 ± 24.9 mU/L; IGF-I, 757.9 ± 66.6 µg/L), focusing on the early effect of GH and IGF-I suppression on the heart. Cardiac structure was investigated by echocardiography, whereas LV performance was investigated by gated-blood-pool scintigraphy, before and after 3 and 6 months of treatment with OCT-LAR.
OCT-LAR was initially administered im, at a dose of 20 mg every 28 days, for 3 months. In six patients, the dose was then increased to 30 mg every 28 days to achieve disease control, which was considered when fasting and/or glucose-suppressed GH values were below 7.5 and 3.0 mU/L, respectively, together with IGF-I values within the normal range for age.
The treatment with OCT-LAR for 6 months induced a significant decrease of GH (to 12.9 ± 3.0 mU/L) and IGF-I levels (to 340.3 ± 40.2 µg/L) in all 15 patients. After 6 months of treatment, the percent IGF-I suppression was 52.8 ± 4.4%, and serum GH/IGF-I levels were normalized in 9 patients. A significant decrease of LV mass index (LVMi), interventricular septum thickness, and LV posterior wall thickness was observed in all 15 patients after 3 and 6 months of OCT-LAR treatment: LVMi was decreased by 19.1 ± 2.0% without any difference in patients with (19.9 ± 2.7%) or without disease control (17.8 ± 3.3%). Among the 11 patients with LV hypertrophy, 6 normalized their LVMi after treatment.
At study entry, an inadequate LV ejection fraction (LVEF) at rest (<50%) was found in 5 patients (33.3%), whereas an impaired response of LVEF at peak exercise (<5% increase of basal value) was found in 9 patients (60%). A significant increase in LVEF, both at rest (from 51.6 ± 2.6 to 58.1 ± 1.7%, P < 0.01) and at peak exercise (from 51.6 ± 2.3 to 60.2 ± 2.4%, P < 0.001) was found in patients with (as compared with those without) disease control (from 55.2 ± 3.8 to 58.0 ± 4% and from 61.8 ± 4.6 to 61.8 ± 3.4%, respectively). Among the 5 patients with inadequate LVEF at rest, all but 1 regained a normal LVEF after 6 months of treatment; whereas, among the 9 patients with an impaired response of the LVEF at peak exercise, 3 patients normalized, 4 improved, and 2 impaired their responses after treatment. The percent of IGF-I suppression was significantly correlated with the percent increase of resting LVEF (r = 0.644, P < 0.01). Exercise duration (from 6.0 ± 0.7 to 7.3 ± 0.7 min) and capacity (from 69.0 ± 8.2 to 80 ± 7.8 watts) were increased in the 15 patients considered as a whole, but the improvement in the exercise response was significant only in patients with disease control (P < 0.01 and P < 0.05, respectively) who also had an increase in the peak ejection rate (P = 0.03). No change in hemodynamic parameters, either at rest or at peak exercise, was found after treatment with OCT-LAR in the 15 patients.
In conclusion, the results of the present study demonstrate that OCT-LAR im injections every 28 days induces a sustained suppression of GH levels and IGF-I levels in all acromegalic patients, allowing achievement of disease control in 60% of patients after 6 months of treatment. The sustained suppression of IGF-I levels was followed by a significant reduction of LVMi in all patients already after 3 months of treatment, with recovery of LV hypertrophy in 6 of 11 patients. In contrast, LV performance was significantly improved only in patients achieving normalization of their hormone levels. These data suggest that the treatment with OCT-LAR, by inducing a rapid suppression of circulating GH and IGF-I levels, could produce an early improvement of the cardiac abnormalities of acromegaly, thus contributing to reversal of the poor prognosis for cardiovascular diseases of these patients.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Recently, the slow-release form of OCT (Sandostatin LAR, OCT-LAR) has become available for clinical use in acromegaly and neuroendocrine tumors. In this formulation, OCT is incorporated in microspheres of a biodegradable polymer, poly(DL-lactide-co-glycolide glucose) (27), thus allowing the im injection every 28 days. OCT-LAR induced suppression of GH levels below 6.0 or 7.5 mU/L in 39–75% of patients, and it normalized IGF-I levels for age in 64–88% of patients (28). Together with its efficacy in inhibiting GH and IGF-I secretion, OCT-LAR was characterized by an excellent patients’ compliance (27, 28, 29, 30).
The aim of the present study was to investigate the effect of a short-term treatment with OCT-LAR on LV structure and performance in a cohort of somatostatin analog-naive patients with acromegaly, focusing on the early effect of GH and IGF-I suppression on the heart. Cardiac structure was investigated by echocardiography, whereas LV performance was investigated by gated-blood-pool scintigraphy before and after 3 and 6 months of treatment with OCT-LAR.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Fifteen patients with active acromegaly (10 women, 5 men; age
range, 24–77 yr) were enrolled in the study after their informed
consent had been obtained. Eleven out of 15 patients had previously
undergone unsuccessful surgery, 3 of them were operated on twice, and 1
of them had also been irradiated 15 yr before entering the study. None
of the 15 patients had ever received treatment with somatostatin
analogs, except for an acute test with OCT (100 µg sc). The diagnosis
of acromegaly was established by high-mean serum GH levels (94.8
± 24.9 mU/L; mean ± SEM) during an 8-h time course,
not suppressible below 6.0 mU/L after 75 g oral glucose tolerance
test, and by high plasma IGF-I levels for age (757.9 ± 66.6
µg/L) (25). Four out of 15 patients (nos. 5, 9, 12, and 14; Table 1
) suffered from hypertension [diastolic
blood pressure (DBP) 
90 mm Hg], which was untreated in all but
1 (no. 5), who was treated with angiotensin convertase
enzyme-inhibitors. None of the 15 patients suffered from overt
diabetes mellitus. The presumed duration of acromegaly was estimated by
comparison of patients’ photographs taken during a 1- to 3-decade span
and by interviews to date the onset of acral enlargement. In this
series, disease duration ranged between 5–25 yr (12.3 ± 1.3 yr;
median, 10 yr). Patients’ profile at study entry is shown in Table 1.
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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). Then all
patients received an acute test with sc OCT, at the dose of 100 µg,
to investigate individual patients’ tolerance to the drug (31).
OCT-LAR was initially administered im, at a dose of 20 mg every 28
days, for 3 months. During treatment, the final GH level was calculated
as the average value from at least 3 blood samples collected, at 15-min
intervals, the day before the injection, and is reported as nadir GH in
Table 1
. At this time-point, plasma IGF-I concentrations were assayed
as single sampling. After 3 months of treatment, the dose of OCT-LAR
was increased to 30 mg every 28 days, in patients still having GH
levels above 15 mU/L, to achieve GH/IGF-I normalization. Dose increment
was performed in seven patients (nos.1, 3, 5, 8, 10, 12, and 13;
Table 1). Hormonal and clinical evaluations were carried out before
treatment, monthly for the first 3 months, and then after 6 months of
treatment. Disease control after OCT-LAR treatment was considered when
fasting and/or glucose- suppressed GH values were below 7.5 and 3.0
mU/L, respectively, together with IGF-I values within the normal range
for age (25).
Echocardiographic study
M-mode, 2-dimensional, and pulsed Doppler echocardiographic
studies were performed with commercially available ultrasound systems
(Sonos 2500, Hewlett-Packard Co., Andover, MA), using a
2.5-mHz transducer, during 3–5 consecutive cardiac cycles. The records
were made by one investigator (L. Spinelli), blind in respect to
patients’ response to treatment. All patients were studied when
leaving, in the left lateral recumbent position, after a 10-min resting
period, according to the recommendations of the American Society of
Echocardiography (32). The following measurements were recorded on
M-mode tracing: interventricular septum thickness (IVST) and posterior
wall thickness (LVPWT); calculation of the LVM was made using the
Devereux’s formula, according to the Penn convention, with the
following regression-corrected cube formula: LVM =
1.04[(IVST+LVID+PWT)3 -
(LVID)3] - 14 g. LV hypertrophy was
considered when LVM values, corrected for body surface area [LVM index
(LVMi)], were 135 g/m2 in males and 110
g/m2 in females. In the present series, 11 out of
15 patients had a clear-cut LV hypertrophy (nos.1, 2, 5–9, 11, and
13–15; Table 1). The echocardiogram was performed before and after 3
and 6 months of treatment with OCT-LAR.
Gated-blood-pool cardiac scintigraphy
In vivo labeling of red blood cells was performed with 555 MBq (15 mCi) of 99mTc. Radionuclide angiography was performed at rest and during dynamic physical exercise, as previously described (12, 26). A small-field-of-view gamma camera (Starcam 300 A/M, General Electric, Milwaukee, WI), equipped with a low-energy all-purpose collimator, was used. Exercise studies were performed, using a bicycle ergometer with a restraining harness, to minimize patient motion under the camera. Exercise loads were increased by 25 watts, every 2 min, until angina (limiting dyspnea or fatigue developed). Heart rate and systolic blood pressure (SBP) and DBP were monitored by cuff sphygmomanometer, during exercise, at each stage. No patient developed high-grade ventricular arrhythmias necessitating termination of exercise. Radionuclide angiography studies were performed using a standard commercial software system (General Electric). Indexes of LV function were derived by computer analysis of the background-corrected time-activity curve, as previously reported (12, 26). The peak ejection rate (PER) was computed in LV counts/sec, normalized for the number of counts at end-diastole, and expressed as end-diastolic volume (EDV)/sec. The blood pool angiography was performed before, and 3 and 6 months after treatment with OCT-LAR.
Assays serum
GH levels were measured by immunoradiometric assay (IRMA) using commercially available kits (HGH-CTK-IRMA Sorin, Saluggia, Italy). The sensitivity of the assay was 0.6 mU/L (1 µg/L corresponds to 3 mU/L). The intra- and interassay coefficients of variation (CVs) were 4.5 and 7.9%, respectively. Plasma IGF-I was measured by IRMA after ethanol extraction, using DSL kits (Webster, TX). The sensitivity of the assay was 0.8 µg/L. The normal IGF-I range in our laboratory was 100–502, 100–303, and 78–258 µg/L for patients 20–40, 41–60, and over 60 yr old, respectively. The intraassay CV values were 3.4, 3.0, and 1.5% for low, medium, and high point on the standard curve, respectively. The interassay CV values were 8.2, 1.5, and 3.7% for low, medium, and high point on the standard curve.
Statistical analysis
The statistical analysis was performed by means of a SPSS, Inc. (Cary, NC) package. The effect of OCT-LAR treatment was analyzed with the Student’s t test for paired data and with two-tailed and repeated- measures ANOVAs, where appropriate. Linear regression was performed to evaluate the existence of correlation between patients’ age, disease duration, GH and IGF-I levels, and suppression on structural (IVST, LVPWT, and LVMi) and functional systolic parameters (PER and LVEF). Data are reported as mean ± SEM.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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, Table 2). The percent GH and IGF-I suppression
after 6 months of treatment were 79.0 ± 5.7% and 52.8 ±
4.4%, ranging from 32.0–98.2% and from 30.3–89.1%, respectively.
After 3 months of treatment, at the dose of 20 mg injected every 28
days, disease control was obtained in 3 patients (nos. 2, 4, and 15);
but in 6 others (nos. 6, 7, 9, 11, 12, and 14), GH levels decreased
below 15 mU/L. Therefore, these 9 patients continued the treatment with
OCT-LAR at the dose of 20 mg every 28 days; while in the remaining 6
(nos. 1, 3, 5, 8, 10, and 13), the dose was increased to 30 mg im every
28 days. After 6 months of treatment, disease control was achieved in 9
patients (60%, nos. 2, 4, 6, 7, 9, 11, 12, 14, and 15). In the
remaining 6 patients, both GH and IGF-I levels were significantly
decreased after treatment, as compared with basal values (from
126.3 ± 48.9 to 24.0 ± 4.2 mU/L and from 830.8 ± 91.0
to 476.5 ± 59.5 µg/L, respectively; Fig. 2; Table 3). In these 6 patients, serum GH and
IGF-I levels were decreased by 70.9 ± 9.7% and 42.5 ±
3.7% of basal values, respectively.
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, Table 2). The
average percent decrease in LVMi was 19.1 ± 2%, ranging from
5.2–37%. Among the 11 patients with LV hypertrophy, 6 normalized
their LVMi after treatment (nos. 2, 5, 7, 8, 13, and15): 3 of them were
among the 9 normalizing hormone levels, whereas the remaining 3 were
among those presenting still-elevated hormone levels. When the results
of treatment were analyzed separately, in line with the response to the
treatment, LVMi was similarly decreased after 6 months in both groups
(Fig. 2, Table 3). In fact, LVMi was decreased by 19.9 ± 2.7% in
patients with disease control and by 17.8 ± 3.3% in those
without disease control (P = 0.6). No correlation was
found between the percent GH and IGF-I suppression and the percent LVMi
reduction in these patients. Similarly, no difference was found in the
percent LVMi reduction after OCT-LAR treatment in patients with
(19.7 ± 2.6%) and without hypertension (18.8 ± 2.7%,
P = 0.8).
The effect of a 6-month treatment with OCT-LAR on heart rate and blood
pressure at rest and at peak exercise are shown in Table 2. No
difference was found in hemodynamic parameters, either at rest or at
peak exercise, after treatment. Among the four patients with DBP
90 mm Hg at study entry, blood pressure remained unchanged during
treatment (data not shown). Also, no change in SBP and DBP was found
after treatment when patients were analyzed separately in line with
hormone levels normalization (Table 3). A trend toward a decrease in
heart rate was found in patients with GH and IGF-I normalization during
OCT-LAR treatment, either at rest and at peak exercise (Table 3).
At study entry, an inadequate LVEF at rest (<50%) was found in 5 out
of 15 patients (33.3%; nos. 4, 6, 11, 13, and 14; Table 1) whereas an
impaired response of LVEF at peak exercise (<5% increase of basal
value) was found in 9 patients (60%; nos. 2, 3, 5, 7–9, 11, 12, and
15). Only 2 out of 15 patients (nos. 1 and 10, Table 1) had a normal
LVEF at rest and at peak exercise that remained normal throughout the
study. As shown in Table 2, no significant change was observed in the
average values of LVEF at rest and at peak exercise in the 15 patients.
However, when the results were analyzed, in line with the response to
the treatment, a significant increase in LVEF, both at rest and at peak
exercise, was found in patients who achieved disease control, as
compared with those who did not (Table 3). The results of LVEF at rest
and at peak exercise, before and after 6 months of treatment with
OCT-LAR in individual patients, is shown in Fig. 3. The exercise-induced change in LVEF
(
LVEF) at the 3-month follow-up was increased in patients achieving
disease control (from 0.9 ± 5.1 to 7.5 ± 7.1%) and
decreased in the remaining patients (from 12.6 ± 6.3 to
-0.5 ± 4.3%, Fig. 4). However,
after 6 months of OCT-LAR treatment, the LVEF was 3.9 ± 4.8%
and 6.7 ± 2.7% (P = 0.5) in patients with or
without disease control, respectively. Among the 5 patients with
inadequate LVEF at rest, all but one (no.13) regained a normal LVEF
after 6 months of treatment, whereas none of the remaining 10 patients
impaired their resting LVEF after treatment. Patient no. 13, who had an
impaired LVEF at rest before treatment (41%), had a partial
improvement of her LVEF, both at rest (46%) and at peak exercise (from
46 to 55%) after treatment; however, her response at peak exercise was
normal, both before and after OCT-LAR treatment (from 12.1 to 16.4%).
Among the 9 patients with an impaired response of the LVEF at peak
exercise, 3 normalized, all achieving disease control (nos. 2, 7, and
12), 4 improved (nos. 3, 5, 8, and 9), and 2 impaired their responses
after treatment (nos. 11 and 15). No change in PER was found after
treatment in the 15 patients considered as a whole (Table 2).
However, patients achieving disease control had a significant increase
of PER (P = 0.03) after 6 months of treatment with
OCT-LAR (Table 3).
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A significant inverse correlation was found between patients’ age and
the response of heart rate (r = -0.661, P =
0.007) and LVEF at peak exercise (r = -0.614, P
< 0.01), as well as exercise capacity (r = -0.784,
P < 0.001). At baseline, but not after OCT-LAR
treatment, GH levels were significantly correlated with the LVEF
(r = 0.68, P = 0.005), exercise capacity (r =
0.605, P = 0.02), and disease duration (r = -0.5,
P < 0.001). Serum IGF-I levels were correlated with
SBP levels at rest (r = -0.578, P = 0.02), and
the percent suppression of IGF-I levels was significantly correlated to
the percent increase of resting LVEF (r = 0.64, P
< 0.01). Neither age nor disease duration was correlated with the
percent suppression of IGF-I, the percent decrease in LVMi, or the
percent increase in the LVEF at rest.
OCT-LAR was well tolerated by all patients. Gastrointestinal discomfort and pain at the injection site was reported by 5 and 3 patients, respectively. In none of the 15 patients was withdrawal from treatment necessary. In 2 patients, treatment with pancreatic enzymes was added during the first days after injection, to reduce the intestinal symptoms.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Abnormalities of both cardiac structure and function are considered the most important determinants of morbidity and reduction in life expectancy in acromegaly (1, 2, 3, 4, 5). Hypertrophy, diastolic and systolic abnormalities of the LV, were demonstrated to affect the majority of patients with acromegaly at their diagnosis (6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16). Cardiac impairment was demonstrated even in patients with young age and short disease duration, indicating that the heart is one of the target organs of the action of GH and IGF-I (12, 13, 14). In further support of the literature data, 73.3% of the patients enrolled in the present study presented LV hypertrophy; and 33.3% and 60%, inadequacy of the LVEF at rest and at peak exercise, respectively. Whether cardiac performance can be improved by suppressing GH and IGF-I levels in acromegaly is still unknown. Most studies reported a significant decrease of LVM, IVST, and free right ventricular wall after treatment with sc OCT and lanreotide (17, 18, 19, 20, 21, 22), indicating that, after lowering GH and IGF-I levels, the cardiac size was reduced, in 2 studies as early as 1–2 weeks after beginning treatment (21, 33). However, systolic function, when evaluated by echocardiography, was apparently unaffected by the treatment with somatostatin analogs, except in patients with overt heart failure (23). This negative effect could be attributable both to the evidence that the majority of acromegalic patients have a normal LVEF at rest (12) and to the difficulty in measuring the LVEF using echocardiography (34). However, even using the radionuclide angiography, which allows a more precise estimation of LVEF (35, 36), we could not observe any increase in the LVEF, either at rest or at peak exercise, in a small group of patients treated with sc OCT for 12–24 months (24). On the other hand, the level of GH and IGF-I suppression during treatment could play a crucial role in interpreting the changes in cardiac performance; in fact, 2 recent preliminary retrospective studies reported that the lower the serum GH level after treatment, the lower the mortality (4, 37). In a previous study, we demonstrated that the LV performance was significantly improved in patients achieving disease control after 1 yr of treatment with sc OCT but not in those with persistence of elevated hormone levels, who had, conversely, a significant impairment of LVEF at peak exercise (26). However, only 3 out of 13 patients successfully treated with sc OCT for 1 yr normalized their LVEF response at peak exercise (26). This finding suggested that a longer period of treatment or a more sustained IGF-I suppression could be necessary to completely recover the impaired cardiac performance in acromegalic patients.
Very recently, the slow-release long-acting formulation of OCT has become available for treating acromegaly. OCT-LAR, at the dose of 20 mg given in im injections every 28 days, allows suppression of GH levels below 15 mU/L in 86–100%, below 6–7.5 mU/L in 39–75%, and below 3.0 mU/L in 24–40% of patients (28). Serum IGF-I levels were reported to be normalized in 64–88% of patients (28). To investigate whether the more sustained suppression of GH and IGF-I levels by OCT-LAR could recover cardiac performance earlier than the sc formulation, we designed this study, which included only naive patients. Even if the cohort of patients is rather small, it is constituted by acromegalic patients with active disease who were never treated with any somatostatin analog before entering this study. Thus, the results observed in this study could reflect the early effects of the suppression/normalization of GH and IGF-I hypersecretion on the heart.
OCT-LAR, administered at doses of 20–30 mg im every 28 days, induced a notable reduction in GH and IGF-I levels in all patients. Normalization of GH and IGF-I levels, as recommended by currently accepted criteria (25, 38), was achieved after 6 months in 9 out of 15 patients, but a significant inhibition of IGF-I values, up to 42.5 ± 3.7% (as compared with baseline) was observed in the remaining 6 patients. The suppression of GH and IGF-I levels was notable already after 3 months, even if the prevalence of IGF-I normalization was rather low (3 out of 15 patients): at this follow-up a significant decrease in LVMi, IVST, and LVPWT was observed. An average percent decrease in LVMi of 19.1 ± 2% (range, 5.2–37%) was observed in our series. An early effect on the LVMi was already reported by Lim et al. (33) in 10 patients after sc OCT and by Baldelli et al. (21) in 13 patients after lanreotide treatment. The recovery from LV hypertrophy in our patients was observed in 54.5% of patients, similar to that (60%) reported by Baldelli et al. (21). Interestingly, in contrast with the changes in functional parameters that occurred only in patients achieving GH and IGF-I normalization, the reduction in LVMi was observed in all patients, independent from the normalization of hormone levels. It should be also considered that a decrease in LVM, after treatment with sc OCT, was reported in patients affected with primary hypertrophic cardiomyopathy (39, 40), suggesting that the decrease of the LVM can be attributable not only to an endocrine mechanism, by decreasing circulating GH and IGF-I, but probably also to a direct autocrine and/or paracrine effect of OCT on the intracardiac GH/IGF-I axis.
LVEF at rest, which was impaired in 5 patients at study entry, recovered in all but 1 after 6 months of treatment, whereas none of the remaining 10 patients impaired their resting LVEF after treatment. The remaining patient (no.13) did not normalize GH and IGF-I and had a subnormal LVEF at rest although maintaining an adequate response on effort. In addition, among the 9 patients with an impaired response of the LVEF at peak exercise, 3 controlled patients recovered and 4 (1 with and 3 without disease control) improved their responses after treatment. Two elderly women impaired their responses after treatment, although achieving disease control; both patients had a rather long estimated disease duration (15 and 20 yr), and both increased significantly the LVEF at rest. These findings suggest that in elderly patients with a long disease duration, a prolonged period of treatment is necessary before cardiac function can be completely recovered. In fact, we have previously reported that in elderly patients, functional abnormalities of diastolic and systolic function are more severe than in younger patients (12), likely depending on the period of heart exposition to GH and IGF-I excess. Therefore, it could be assumed that the longer the disease duration and the higher the patient’s age, the longer the duration of treatment before recovery of systolic abnormalities can be documented. The possibility that in some patients cardiac abnormalities can never be recovered can not be ruled out.
The improvement of systolic function could also be attributable to hemodynamic changes, peculiarly of heart rate and vascular resistance, both highly sensitive to circulating and locally produced IGF-I concentrations. The treatment with OCT was reported to modify heart rate (26, 41, 42), likely affecting the conduction system (43), but it was not able to significantly modify blood pressure. In the present study, neither SBP nor DBP were affected by OCT-LAR treatment, whereas a trend toward a decrease in heart rate (both at rest and at peak exercise) was observed in patients who normalized hormone levels. On the other hand, no difference in the decrease of LVMi after OCT-LAR treatment was observed in patients with or without hypertension.
In accordance with an improved physical performance, both exercise duration and exercise workload were significantly increased in the patients as a whole, but peculiarly in those achieving disease control after treatment. Similar data were reported in different cohorts of patients who had undergone radionuclide angiography (26) and in another smaller group of patients subjected to treadmill exercise, both groups having been treated with OCT for 1 yr (41). At partial contrast with a previous study (26), we did not find any impairment in cardiac performance after 6 months in the patients not achieving hormone normalization. It should be pointed out that our previous observation considered a longer period of treatment, whereas 6 months can be a rather short period of time, as compared with the natural history of acromegaly.
In conclusion, the results of the present study demonstrate that OCT-LAR im injections every 28 days induce a sustained suppression of GH levels and IGF-I levels in all acromegalic patients, allowing achievement of disease control in 60% of patients after 6 months of treatment. The sustained suppression of IGF-I levels was followed by a significant reduction of LVMi in all patients already after 3 months of treatment, with recovery of LV hypertrophy in 6 of 11 patients. In the patients who achieved disease control, normalization of the LVEF at rest (in all) and at peak exercise (in 3) and improvement of exercise duration and capacity were observed. These data suggest that the treatment with OCT-LAR, by inducing an early and prolonged suppression of circulating GH and IGF-I levels, could improve the cardiac abnormalities of acromegaly earlier than with the sc formulation, thus contributing to reversing the poor prognosis for cardiovascular diseases of these patients. The early effect of OCT-LAR can be also considered helpful before surgery, to reduce the risk of cardiological complication during anesthesia (44, 45).
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Acknowledgments |
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Footnotes |
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Received December 6, 1999.
Revised March 28, 2000.
Accepted May 16, 2000.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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ko R, Ruchala M, Sawicka J, Kotwocka M, Liebert
W, Sowiñski J. 2000 Short-term pre-surgical treatment with
somatostatin analogues, octreotide and lanreotide, in acromegaly. J
Endocrinol Invest. 23:12–18.[Medline]
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S. Bhayana, G. L. Booth, S. L. Asa, K. Kovacs, and S. Ezzat The Implication of Somatotroph Adenoma Phenotype to Somatostatin Analog Responsiveness in Acromegaly J. Clin. Endocrinol. Metab., November 1, 2005; 90(11): 6290 - 6295. [Abstract] [Full Text] [PDF]
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H. Bihan, C. Espinosa, H. Valdes-Socin, S. Salenave, J. Young, S. Levasseur, P. Assayag, A. Beckers, and P. Chanson Long-Term Outcome of Patients with Acromegaly and Congestive Heart Failure J. Clin. Endocrinol. Metab., November 1, 2004; 89(11): 5308 - 5313. [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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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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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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A. Colao, D. Ferone, P. Marzullo, P. Cappabianca, S. Cirillo, V. Boerlin, I. Lancranjan, and G. Lombardi Long-Term Effects of Depot Long-Acting Somatostatin Analog Octreotide on Hormone Levels and Tumor Mass in Acromegaly J. Clin. Endocrinol. Metab., June 1, 2001; 86(6): 2779 - 2786. [Abstract] [Full Text] [PDF]
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