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Department of Molecular and Clinical Endocrinology and Oncology (A.C., R.P., R.S.A., M.Galdi., G.L.), Section of Endocrinology, Department of Clinical and Experimental Medicine (M.Galde.), Section of Cardioangiology, and Department of Neurological Sciences (P.C., L.M.C., F.E.), Section of Neurosurgery, Federico II University of Naples, 80131 Naples, Italy
Address all correspondence and requests for reprints to: Annamaria Colao, M.D., Ph.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.
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Abstract |
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Design: This was a retrospective, comparative, nonrandomized study.
Patients: Fifty-six patients treated with SSA and 33 operated on by transsphenoidal approach participated in the study. For the purposes of this study, only controlled patients were included.
Measurements: Primary outcome measures were changes in left ventricular mass index, diastolic (early to atrial mitral flow velocity), and systolic performance (left ventricular ejection fraction). Secondary outcome measures were reduction of total to high-density lipoprotein-cholesterol ratio as a cardiovascular risk parameter, and improvement of glucose profile and pituitary function as indirect causes of cardiovascular improvement.
Results: SSA and surgery groups were similar for gender, age, estimated disease duration, GH and IGF-I levels, and severity of cardiomyopathy lipid and glucose profile. Twelve months after treatment in both groups, left ventricular mass index, early to atrial mitral flow velocity, diastolic blood pressure, and heart rate decreased significantly, whereas only in SSA-treated patients, left ventricular ejection fraction increased significantly. The total to high-density lipoprotein-cholesterol ratio significantly reduced only in SSA-treated patients, whereas fasting glucose levels significantly decreased only in surgery-treated patients. A normal pituitary function was found in 46.4% of SSA- and 36.4% of surgery-treated patients, with results unchanged in the former and slightly reduced in the latter.
Conclusions: Twelve months after first-line treatment with SSA or surgery, we found a similar improvement in left ventricular hypertrophy and diastolic filling. In contrast, systolic function improved more evidently in SSA-treated patients. Both a direct effect of SSA and a more preserved pituitary function might explain these results.
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Introduction |
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A direct comparison between the results of surgery or SSAs as first-line treatment on cardiovascular complication in acromegaly has never been performed. SSAs could have potential direct beneficial effects on the cardiovascular system as clearly demonstrated on the conduction system in which SSAs cause bradycardia and so directly improve arrhythmias (21). More recently SSAs have also been suggested to play direct effect also on cardiac performance. Smith et al. (22) have shown that somatostatin receptors (sst)-1, sst-2, sst-4, and sst-5 are coexpressed in both atrial and ventricular tissue: human cardiac myocytes expressed mRNA for only sst-1 and sst-2, whereas human cardiac fibroblasts expressed all four subtypes.
To investigate whether first-line surgery or SSAs have a different outcome on cardiomyopathy, we designed this retrospective study. Primary outcome measures were changes in left ventricular mass (LVM) and diastolic and systolic performance. Secondary outcome measures were reduction of total to high-density lipoprotein (HDL)-cholesterol ratio as a cardiovascular risk parameter and improvement of glucose profile and pituitary function as indirect causes of cardiovascular improvement.
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Subjects and Methods |
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Inclusion criteria
Patients treated with first-line surgery via transsphenoidal route by microscopic and/or endoscopic approach or with first-line depot SSA treatment, achieving control of the disease, and with available follow-up after 12 months of treatment.
Exclusion criteria
Patients receiving second surgery within 3 months from first surgery, requiring combined dopamine agonists and SSAs because of a mixed GH/prolactin-secreting tumor, receiving the sc octreotide for longer than 15 d or requiring surgery or SSAs as second-line treatment before the completion of the 12 months or with a follow-up shorter than 6 months after surgery or pharmacotherapy.
Cure criteria
According to Giustina et al. (23), acromegaly was considered to be controlled if mean fasting GH levels were 2.5 µg/liter or less in presence of normal IGF-I levels for sex and age. Nadir GH after an oral glucose tolerance test (oGTT) of 1 µg/liter or less is also an option to evaluate disease control according with the 2000 Consensus Statement (23). However, oGTT is generally not routinely performed in patients receiving SSAs because GH-induced glucose suppression is likely to be mediated by the endogenous somatostatin tone (24). To avoid ascertainment bias, disease control after surgery and SSAs was based only on fasting GH and IGF-I levels. The diagnosis of acromegaly was defined as previously reported (1) by high serum GH levels during a 6-h time course, not suppressible less than 1 µg/l after oGTT and high plasma IGF-I levels for age [expressed as value upper limit of normal (ULN) range].
For the purpose of this study, only the patients with controlled acromegaly were included to provide a period of follow-up long enough to investigate changes in cardiomyopathy parameters.
Patients
Of 215 patients treated, 145 received first-line SSAs and 70 received surgery. Of the 145 SSA-treated patients, 32 patients were excluded because of treatment shorter than 12 months, 14 because of long-term use of sc octreotide, two were lost at follow-up, and 41 were considered noncontrolled after 6–12 months of treatment and subsequently underwent a second-line surgery. Of the 70 operated patients, 37 were excluded as not controlled and underwent a second-line SSA treatment. Therefore, in this study were included files of 89 patients (Fig. 1
), 56 treated with SSA and 33 treated with surgery (Table 1). The prevalence of microadenomas and intrasellar macroadenomas (35 vs. 27, respectively) and that of extrasellar and/or invasive macroadenomas (21 vs. six, P = 0.094) was similar between the two groups.
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As for our routine procedure, at diagnosis all the patients undergo a complete metabolic and endocrine screening. After an overnight fasting, serum IGF-I levels were assayed twice in a single sample at the time 0 of the GH profile; GH levels were calculated as the mean value of at least five (up to eight) samples drawn every 30 min over a period of 3–6 h, and the average value was considered for the statistical analysis; fasting total cholesterol, HDL cholesterol, glucose, and insulin levels were also measured. The total to HDL-cholesterol ratio, index of cardiovascular risk, was calculated (25). At diagnosis and 12 months after surgery or SSA (in a subset of patients as reported in Table 2), the oGTT was performed by measuring GH, glucose, and insulin levels every 30 min for 2 h after the oral administration of 75 g of glucose diluted in 250 ml of saline solution. Diabetes mellitus was diagnosed when fasting glucose was above 7 mmol/liter (126 mg/dl) at two consecutive measurements or when 2 h after the oGTT, glucose was 11.1 mmol/liter or greater (200 mg/dl). Impaired glucose tolerance was diagnosed when fasting glucose was less than 7 at baseline and was between 7.7 mmol/liter or greater and less than 11.1 mg/dl 2 h after the oGTT (26). Insulin resistance was estimated by the homeostasis model assessment (HOMA) score using the formula by Matthews et al. (27) [fasting serum insulin (microunits per milliliter) x fasting plasma glucose (millimoles per liter)/22.5]. The conversion factors (milligrams per deciliter to millimoles per liter) for cholesterol was 0.02586 and glucose was 0.05551. Magnetic resonance imaging of the sellar region was performed in all patients at diagnosis and 3 and 12 months after surgery or SSA.
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This is a retrospective, nonrandomized study to compare the outcome of first-line surgery or SSAs on acromegalic cardiomyopathy. Primary outcome measures were changes of LVM index (LVMi) as measure of left ventricular (LV) hypertrophy, early to atrial mitral flow velocity (E/A) as measure of diastolic function, and LV ejection fraction (LVEF) as measure of systolic function. Secondary outcome measures were changes in the total to HDL cholesterol ratio; glucose tolerance, measured as fasting glucose levels and HOMA reduction; and improvement of pituitary function.
In this study we included the results recorded at diagnosis and 12 months after either surgery of SSA treatment. In the SSA-treated patients, GH and IGF-I levels and lipid and glucose profile were collected the day before the next drug injection.
Diagnosis of hypopituitarism (28)
Gonadotropin deficiency was established on the basis of low testosterone levels (<3 µg/liter) in men or low 17 β-estradiol levels (<50 ng/liter) in premenopausal women and on low FSH and LH levels (<2 UI/liter) in postmenopausal women; TSH deficiency was established on the basis of low TSH levels (<0.5 mIU/liter) in presence of free T3 and free T4 levels below or in the lower part of the normal range; ACTH deficiency was established on the basis of low morning cortisol levels (<50 µg/liter) or less than 200 µg/liter after administration of 250 µg im synacthen. None of our patients had diabetes insipidus.
Treatment protocol
To investigate individual patient’s tolerability, before starting SSA, all patients received an acute test with octreotide at a dose of 0.1 mg in the morning after an overnight fast and at least 2 h of bed rest (29). Of the 56 patients, 42 were treated with octreotide-LAR (10–40 mg every 28 d) and 14 with LAN (30–120 mg every 28 d). The dosages were up-titrated to control GH and IGF-I levels, which was obtained in all patients.
Echocardiography
Echocardiography by M-mode, two-dimensional, and pulsed Doppler-derived mitral inflow during three to five consecutive cardiac cycles, according to the recommendations of the American Society of Echocardiography (30). The following measurements were determined on M-mode tracing: interventricular septum thickness, LV internal end-diastolic diameter (LVID) and posterior wall thickness, LVM calculation by the Devereux’s formula (31): LVM = 1.04 [(interventricular septum thickness +LVID+ posterior wall thickness)3 – (LVID)3] – 14 g. An LVMi of 135 g/m2 or greater in men and 110 g/m2 or greater in women was considered as cutoff points for left ventricular hypertrophy. Diastolic function was evaluated by pulsed Doppler mitral inflow as E/A ratio, indicating the normal pattern of ventricular diastolic filling at 1 or greater. Left ventricular systolic function was evaluated by ejection fraction (LVEF) normal when greater than 50%. Structural alterations in the cusps and annuluses of the heart valves were diagnosed by thickened and bright echoes on both M-mode and cross-sectional echocardiogram, using established diagnostic criteria (32). The diagnosis of valve stenosis or valve prolapse was made on the basis of morphologic assessment and Doppler echocardiography. Significant regurgitation was defined as a regurgitant jet on the color and pulsed Doppler echocardiogram extending more than 2 cm behind the plane of the aortic or mitral valve and pandiastolic (aortic regurgitation) or pansystolic (mitral regurgitation) regurgitant flow of more than 2 m/sec on continuous-wave Doppler. Regurgitation was classified as mild, moderate, or severe on the basis of the extent to which retrograde flow filled the atrium or the ventricle (less than one third, to two thirds, or more than two thirds).
Assays
GH levels were assayed by immunoradiometric assays. The sensitivity of the assay was 0.2 µg/liter until 2002 or 0.05 µg/liter thereafter. The intra- and interassay coefficients of variation (CVs) were, respectively, 4.5 and 7.9%. Serum IGF-I was measured by immunoradiometric assay after ethanol extraction (Diagnostic System Laboratories Inc., Webster, TX). The normal ranges in 20 or less, 21–30, 31–40, 41–50, 51–60, 61–70, and older than 70-yr-old men were 180–625, 118–475, 102–400, 100–306, 95–270, 88–250, and 78–200 µg/liter, respectively, whereas in women they were 151–530, 118–450, 100–390, 96–288, 90–250, 82–200, and 68–188 µg/liter, respectively. The sensitivity of the assay was 0.8 µg/liter. The intraassay CVs were 3.4, 3.0, and 1.5% for low, medium, and high points of the standard curve, respectively. The interassay CVs were 8.2, 1.5, and 3.7% for low, medium, and high points of the standard curve. Data are shown as ULN (normal = 
1).
Statistical analysis
Results were expressed as mean ± SD unless otherwise specified. The statistical analysis was performed by MedCalc Software for Windows (MedCalc, Mariakerke, Belgium) package using nonparametric tests. The comparison between surgery- and SSA-treated patients (at study entry and end) was performed by the Mann-Whitney U test. The comparison between baseline and 12 months after treatment results in the surgery- and SSA-treated patients was performed by the Wilcoxon signed rank test. The significance was set at 5% and is reported as two-sided P values. For categorical variables, differences were analyzed by the 
2 test and Fisher’s exact test. Correlation test was used to evaluate whether percent GH and IGF-I suppression after surgery or SSAs were correlated with percent changes of LVMi, E/A, or LVEF: for this purpose the Spearman’s rho with the 95% confidence interval was calculated.
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Results |
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)
First-line treatment with SSAs or surgery groups were similar for gender, age, estimated disease duration, GH, and IGF-I levels. Only the tumor volume was significantly smaller in surgically treated than in SSA-treated patients. The severity of cardiomyopathy was also similar as well as impairment of lipid and glucose profile and insulin resistance index (Table 2). Structural alterations of the mitral and aortic valves (fibrosis, fibrosclerosis, or thickening of the annulus or leaflets) were found in 38 and 42 of SSA-treated patients and 22 (P = 0.91) and 19 (P = 0.14) patients treated with surgery, respectively. None of the patients had mitral prolapse; eight of SSA patients and none of surgery patients had aortic ectasia (P = 0.058).
According with inclusion criteria, all patients normalized GH and IGF-I levels. As expected the posttreatment tumor volume was significantly greater in SSA-treated than surgery-treated patients (Table 2). Percent tumor shrinkage in this series was by 56.9 ± 23.3% after SSA and 99.9 ± 0.2% after surgery (P < 0.0001).
Primary end point: SSA therapy vs. surgery on cardiomyopathy (Table 2)
In both groups, LVMi, E/A, diastolic blood pressure, and heart rate decreased significantly, whereas only in SSA-treated patients, LVEF increased significantly. After 12 months of treatment, E/A was significantly higher and heart rate was significantly lower in the SSA-treated than the surgery-treated patients. Percent changes in LVMi, E/A, and LVEF were significantly lower and higher, respectively, in SSA-treated than the surgery-treated patients (Fig. 2). Decrease of diastolic blood pressure but not of systolic blood pressure was observed in both groups; heart rate was significantly lower after 12 months in SSA-treated than surgery-treated patients (Table 2). The prevalence of LV hypertrophy and diastolic and systolic dysfunction was significantly reduced only in the SSA-treated cohort (Table 3). In contrast, the prevalence of arrhythmias and hypertension did not significantly change in both cohorts (Table 3). Only a minority of patients had mitral or aortic regurgitation (mild in all cases): no change was observed after either SSA or surgery (Table 3). Treatment with angiotensin-convertase inhibitors was performed in 11 SSA-treated patients (19.6%) and seven of those surgery treated (12.5%, P = 0.96) and β-blockers in one patient in both groups.
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Secondary end point: SSA therapy vs. surgery on lipid and glucose profile and residual pituitary function
The total to HDL-cholesterol ratio significantly decreased only in SSA-treated patients, whereas fasting glucose levels significantly decreased only in surgery-treated patients (Table 2). However, because of a significant reduction of insulin levels, the HOMA index significantly decreased in both groups. Glucose abnormalities, however, did not significantly change in both groups (Table 3).
At diagnosis a normal pituitary function was found in 20 of 56 SSA-treated patients (35.7%) and 21 of 33 surgery-treated patients (63.6%; P = 0.020), deficit in one axis in 26.8 and 18.2% patients (P = 0.51) and two axes or more in 37.5 and 18.2% patients (P = 0.094) (Table 4). After treatment, a normal pituitary function was found in 46.4 and in 36.4%, in SSA- and surgery-treated patients, resulting in no change in the former and slightly reduced in the latter (Table 4). In SSA-treated patients, the prevalence of two deficits reduced significantly after 12 months, whereas no difference was noted in the surgery group (Table 4). In SSA-treated patients, improvement was observed in FSH and LH axes; reduced TSH levels in the absence of changes in thyroid hormone levels was also noted. In the surgery group, four patients improved their pituitary function (12.1%), 15 remained stable (45.5%), whereas 14 (42.4%) acquired one (eight of 14), two (five of 14), or three deficits (one of 14 patients). Replacement therapy was, however, started in only five men requiring testosterone and another three women requiring T4 (eight of 14; 57.1%); gonadotropins deficiency was not replaced in five postmenopausal women and another two men aged above 70 yr because testosterone levels were in the lower normal range (2.9–3.2 µg/liter).
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Discussion |
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In recent years, the issue of first-line therapy of acromegaly has been highly debated based on the following concepts: 1) surgery is successful in microadenomas and enclosed macroadenomas of limited efficacy in large adenomas, which represent the majority of GH-secreting pituitary tumors (8, 17, 33), and it is rather safe but not devoid of potential complications (34, 35) and should be performed only in experienced centers having one neurosurgeon specialized in the treatment of pituitary tumors (11, 12) to ensure an optimal outcome and safety; and 2) depot somatostatin analogs are effective in controlling acromegaly in about 50% of patients in different series, and results are less dependent on tumor size (8, 13, 14, 17, 33, 36), improve clinical signs and symptoms, even when IGF-I levels are not normalized (13), and reduce cardiovascular morbidity and sleep apnea (15) so reducing the anesthetic risk (37), and inducing tumor shrinkage (14, 16). First-line SSA therapy is, however, still suggested only in selected patients with high perioperative morbidity or in those who refuse surgery (8). Therefore, SSA therapy is generally used as adjuvant treatment after unsuccessful surgery. Major drawbacks of lifelong primary treatment with SSA are the high costs of the drugs, the requirement of lifelong treatment that limits compliance, and the prevalence of side effects. In general, side effects do not limit therapy, but a number of studies reported 3–5% dropout rates, in one study up to 25% (13).
Of the still unknown information related to the efficacy of treatment of acromegaly is the effect on cardiovascular morbidity. It is well known that longstanding GH and IGF-I excess in acromegaly causes a specific cardiomyopathy that characteristically has biventricular hypertrophy, reduced diastolic filling, and, more rarely, reduced systolic performance (15). Suppression of GH and IGF-I has been widely reported to improve the acromegalic cardiomyopathy (15). However, the vast majority of data concern treatment with SSA, and only a few are related to postsurgery cardiovascular morbidity (15). Very recently De Marinis et al. (20) reported a similar efficacy of surgery and SSA in a small series of patients followed for 12 months after successful treatment of acromegaly. They confirmed that a reduction in the LV hypertrophy with an improvement in diastolic function in both patients with controlled disease and those with poorly controlled disease undergoing SSA treatment (20). Apparently they did not find any difference in echocardiographic parameters between SSA and surgery (20). The series of patients was, however, small, and the patients treated with SSA received previous unsuccessful surgery so that the analysis of SSA treatment was biased, and no information was available for cardiovascular risk parameters, glucose profile, and pituitary deficiencies.
In 1990 we begun a systematic evaluation of cardiac morphology and function by echocardiography and common cardiovascular risk factors (lipid profile, fibrinogen levels, and insulin resistance) to investigate the effect of different therapies on the acromegalic cardiomyopathy. This database has subsequently been approved by our institutional Ethical Committee in 1997.
The results of this study, even with the limitation of being retrospective and nonrandomized, demonstrate that successful treatment with acromegaly is followed by a significant improvement of several aspects of cardiovascular morbidity, mainly left ventricular hypertrophy and, likely consequently, diastolic filling. However, disease control achieved with surgery or SSA is also followed by some different cardiovascular results. We have already reported that SSAs have a remarkable effect on heart rate and arrhythmias (38): even if the difference was not statistically significant, none of the six patients with arrhythmias before starting SSA required a specific treatment, compared with the only patient cured by surgery. More importantly, systolic function improved significantly only in SSA-treated patients. We previously reported that insufficiency systolic function at rest, as measured by echocardiography, is not frequent in acromegaly, whereas its response on effort is impaired in most patients, even in the young (15). Indeed, in this cohort, a value of ejection fraction, the parameter we used as a surrogate of systolic function, resulted to be lower than 50% (the normal threshold value) in 25% of the SSA cohort and 21.2% of the surgery cohort, even if in the former, the residual pituitary function was more frequently impaired. We observed an increase in the mean ejection fraction values 12 months after SSA, whereas they remained stable in the surgery group: consequently systolic function normalized more frequently in the SSA- than the surgery-treated patients. Whether this result is obtained because of direct effects of SSA on cardiomyocytes as recently suggested (22) or is indirectly caused by subtle changes in the remaining pituitary function cannot be ruled out from these data. As for cardiac valve disease, we previously demonstrated that apparently no difference in the prevalence of cardiac valve disease after treatment of acromegaly (39) as also confirmed by van der Klaauw et al. (40). In this study, we also confirm that no significant change occurs in cardiac valve disease after 12 months of SSA or surgery.
It is, however, of interest that the two different approaches have differential effects on lipids and glucose profile that indirectly relate with cardiovascular risk. It is known that glucose tolerance is better after surgery than after SSA (41), even if we did not find any significant dose-dependent detrimental effects of octreotide-LAR on glucose tolerance, even at high doses (42). It is well accepted, anyway, that suppression of insulin levels might impair glucose tolerance in individual patients, but generally this phenomenon is short lasting and is overcome by the beneficial effect on glucose tolerance of suppressed GH levels.
Data comparing lipid profile after SSA or surgery are lacking, and overall data on lipid profile are rather conflicting (15). Whether the differential effect we found in reducing the total to HDL cholesterol ratio depends also on different pituitary function posttreatment remains to be determined.
The issue of the preservation of pituitary function after SSA and surgery has been very scantly reported. In general surgery is considered safe and beneficial for pituitary function. In fact, we did not find any difference in the prevalence of one, two, or three pituitary deficits in SSA- or surgery-treated patients. The prevalence of intact pituitary function decreased significantly after surgery, even if the effect was minor and mainly played on gonadotropins levels, but this patient cohort started with a more frequent normal pituitary function before treatment.
Conclusion
In this retrospective study, 12 months after first-line treatment with SSA or surgery, we found a significant improvement in left ventricular hypertrophy and diastolic filling. In contrast, systolic function improved more evidently in SSA-treated patients. Whether this is a direct effect of SSAs or is mediated by a more preserved pituitary function cannot be ruled out from the current study. Importantly, arrhythmias disappeared in all SSA-treated patients. Because our results derive from a nonrandomized study, they suggest that cardiovascular morbidity after first-line treatment of acromegaly should be investigated in detail to more carefully investigate the consequences that SSAs or surgery has on the cardiovascular system, the most important cause of death in this disease (2, 3, 4, 5, 6, 7).
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Footnotes |
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Disclosure Statement: None of the authors have conflict of interest to disclose.
First Published Online April 29, 2008
Abbreviations: CV, Coefficient of variation; E/A, early to atrial mitral flow velocity; HDL, high-density lipoprotein; HOMA, homeostasis model assessment; LAN, lanreotide; LAR, long-acting release; LV, left ventricular; LVEF, LV ejection fraction; LVID, LV internal end-diastolic diameter; LVM, LV mass; LVMi, LVM index; oGTT, oral glucose tolerance test; SSA, somatostatin analog; sst, somatostatin receptor; ULN, upper limit of normal.
Received February 8, 2008.
Accepted April 17, 2008.
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