Relationship between growth hormone and Somatomedin-C levels in untreated acromegaly, after surgery and radiotherapy and during medical therapy with Sandostatin (SMS 201–995)

Abstract. Several conflicting reports have been published with regard to the relationships between circulating growth hormone (GH), Somatomedin-C (SM-C) levels and clinical activity during different stages of therapy of acromegaly. We did not find a significant correlation between (fasting, post-prandial and mean 24-h) plasma GH and SM-C concentrations in twenty-two untreated acromegalic patients. There was a statistical significant correlation, however, if only the GH levels below 100 μg l^-1 were considered (n=18 patients, P<0·01). The distribution of molecular forms of GH (‘little’, ‘big’ and ‘big-big’) did not differ between the four patients with GH levels above 100 μg l^-1 and in four patients with levels between 40 μg l^-1 and 80 μg l^-1. Therefore, it is suggested that GH levels of 80–100 μg l^-1 maximally activate Somatomedin-C production in man and that further increases in GH in general will not result in a further increase in SM-C generation. There was a significant correlation between GH and SM-C levels in forty-nine acromegalic patients after surgery and/or radiotherapy (P<0·001). In twenty-three of thirty-one patients with elevated SM-C levels the disease was subjectively still active, while this was the case in none of the patients with normal SM-C levels. In eight patients the disease was considered not to be clinically active any more, despite slightly increased SM-C levels. During long-term therapy of ten acromegalic patients for 16–108 weeks (mean 66±10) with 200–300 μg Sandostatin subcutaneously, clinical activity of the disease disappeared well before mean 24–h GH and SM-C levels reached the normal levels. There was a close correlation between mean 24-h GH and SM-C levels during Sandostatin therapy (P<0·001). ‘Clinical cure’ during this medical treatment was reached in five patients, as reflected by disappearance of subjective complaints, normalization of SM-C levels and 24-h mean GH levels of 2·8±0·2 μg l^-1. Conclusions: (i) in untreated acromegaly, circulating GH and SM-C levels correlate well up to GH concentrations of 100 μg l^-1. A further increase in GH does not result in a corresponding further increase in SM-C levels, suggesting a maximally activated production, without further GH-dependent capacity. (ii) Clinical ‘cure’ of acromegaly often occurs before normalization of the circulating SM-C levels. (iii) The measurement of plasma SM-C concentrations can be used well to adjust the dose and frequency of Sandostatin administration in acromegaly. This avoids the need of measuring extensive 24-h GH profiles.     

Dramatic improvement of severe dilated cardiomyopathy in an acromegalic patient after treatment with octreotide and trans-sphenoidal surgery

Severe congestive heart failure developed in an acromegalicpatient, and was successfully treated with octreotide followedby trans-sphenoidal surgery. Clinical, hormonal echocardiographicand haemodynamic findings as well as histological heart examinationbefore and after treatment revealed tliat over-production ofgrowth hormone may induce the myocardial cell degeneration responsiblefor mechanical heart dysfunction. In addition, this unique exampledemonstrates the reversibility of myocardial damage followingoctreotide and trans-sphenoidal surgery, leading to significantimprovement in cardiac function with minimal diastolic dysfunctionand moderate interstitial fibrosis.     

The place of medical treatment of acromegaly: current status and perspectives

Introduction: Acromegaly is characterized by elevated growth hormone (GH) and insulin-like growth factor-I (IGF-I) levels and by progressive somatic disfigurement and systemic manifestations, which lead to a mortality rate higher than the general population. Therefore, diagnosis and properly treatment should be performed as soon as possible.

Areas covered: This article focuses on the state of the art of acromegaly medical treatment. Somatostatin analogs, dopamine agonists and GH receptor antagonist were reviewed. Somatostatin analogs, the first-choice pharmacotherapy, can be used as primary or pre-operative treatment or as secondary therapy after failed surgery. Dopamine agonists have been used in patients with slightly elevated hormone levels and/or mixed GH/prolactin adenomas. Pegvisomant is indicated for resistant to somatostatin analogs/dopamine agonists. Combined treatment is also an option for resistant cases. Other non-conventional therapies and perspectives of treatment were also been discussed.

Expert opinion: The control of disease activity in acromegaly is of paramount importance. Medical treatment is an important option for cases in which surgery was unsuccessful or not indicated. Despite the achievements in medical treatment, somatotropic tumor aggressiveness and/or resistance to the drugs currently available remain a concern. Therefore, novel therapy targets based on molecular pathogenesis of GH-secreting tumors are currently in development, aiming at fulfilling this important gap.     

Cardiovascular Effects of a Single Slow Release Lanreotide Injection in Patients with Acromegaly and Left Ventricular Hypertrophy

In our study we assessed the effects of a single i.m. injection of slow-release Lanreotide (30 mg) (SR-L), a new long-acting somatostain analog, on circulating GH levels, baseline cardiac function (M-mode, 2D guided, doppler-echocardiographic study) and cardiopulmonary response to exercise (cycloergometric test, performed using a computer drived, electrically braked cycle ergometer), tested at baseline, after 7 and 14 days from the injection in 10 acromegalic patients (5 M, 5 F, mean age 57.7 ± 3.1 yrs, body mass index (BMI) 27 ± 0.8 kg/m², blood pressure 141 ± 6.5/82 ± 3 mmHg). SR-L administration decreased GH levels in acromegalic patients (mean±SEM) from 16.1 ± 6.9 to 10.8 ± 5.1 µg/L (p = 0.045) after 7 days and to 11.9 ± 5 µg/L (p = 0.078) after 14 days from the injection. Moreover, we observed a significant (p<0.05) decrease in systolic blood pressure and heart rate at the 7th (135 ± 6.1 vs 141 ± 6.5 mmHg, and 68 ± 2.1 vs 74 ± 2.1 bpm) and 14th (137 ± 6.2 vs 141 ± 6.5 mmHg, and 72 ± 2 vs 74 ± 2.1 bpm) day of the study with respect to the baseline values. After SR-L administration we also found an increase in ejection fraction (69 ± 2 vs 63 ± 2.3% at 7th day, p = 0.006; 65 ± 2.3 vs 63 ± 2.3% at the 14th day, p = 0.027) and shortening fraction (40.8 ± 1.8 vs 36.6 ± 1.9% at 7th day, p = 0.005; 38.7 ± 1.8 vs 36.6 ± 1.9% at the 14th day, p = 0.045). The positive acute cardiac response to SR-L injection was also demonstrated by the increase in A/E velocity ratios at 7th (1.14 ± 0.1 vs 0.98 ± 0.07, p = 0.016) and 14th (1.04 ± 0.08 vs 0.98 ± 0.07, p = 0.008) day of the study. After SR-L injection, exercise capacity and VO₂ at anaerobic thresold were also increased with respect to the baseline test: 61.1 ± 8.2 vs 38.9 ± 6.8 watts (p = 0.002) and 1012.4 ± 71.5 vs 915.3 ± 77.8 mL/min (p = 0.033) after 7 days, and 61.4 ± 7.2 vs 38.9 ± 6.8 watts (p = 0.002) and 1010.1 ± 62.5 vs 915.3 ± 77.8 mL/min (p = 0.010) after 14 days from the injection. In conclusion, these results suggest that in acromegalic patients: (1) SR-L causes a rapid improvement in baseline cardiac function and in cardiopulmonary performance during exercise in acromegaly; (2) the endocrine (decrease in GH levels) and echocardiographic responses to SR-L are maximal after 7 days from the injection, whereas the effect of SR-L on the exercise performance are longer lasting.     

Current status and future opportunities for controlling acromegaly

Growth-hormone (GH) secreting adenomas, including acromegaly, account for approximately one-sixth of all pituitary adenomas and are associated with mortality rates at least twice that of the general population. The ultimate goal of therapy for acromegaly is normalization of morbidity and mortality rates achieved through removal or reduction of the tumor mass and normalization of insulin-like growth factor I (IGF-I) levels. Previously published efficacy results of current treatment modalities (surgery, conventional radiation, and medical therapy with dopamine agonists and somatostatin analogs) are often difficult to compare because of the different criteria used to define cure (some of which are now considered inadequate). For each of these modalities, pooled data from a series of acromegaly studies were reviewed for rates of IGF-I normalization, a currently accepted definition of cure. The results showed overall cure rates of approximately 10% for bromocriptine, 34% for cabergoline, 36% for conventional radiation, 50–90% for surgery for microadenomas and less than 50% for macroadenomas, and 54–66% for octreotide. These cure rates based on IGF-I normalization are generally less than those reported for cure based solely on GH levels. Novel new therapies for acromegaly include the somatostatin analog, lanreotide, Gamma Knife radiosurgery, and pegvisomant, the first in its class of new GH receptor antagonists. Although it does not appear that Gamma Knife radiosurgery results in significantly higher cure rates or fewer complications, it does provide a notable improvement in delivery compared with conventional radiation. Early studies have reported IGF-I normalization in 48% of lanreotide-treated patients and up to 97% of pegvisomant-treated.     

Functional changes are associated with tracheal structural abnormalities in patients with acromegaly

Introduction

Although impaired pulmonary function and respiratory sleep disorders are described as responsible for increased mortality in acromegalic patients, little is known about the tracheal abnormalities in this group of patients. Thus, the objectives of this study were to describe the tracheal structural abnormalities and correlate these changes with the respiratory function and clinical data of acromegalic patients.

Material and methods

This is a cross-sectional study that was carried out at two university hospitals. Twenty acromegalic patients underwent spirometry, forced oscillation technique, and computed tomography (CT) assessments. Dyspnea and daytime sleepiness were assessed using the Modified Medical Research Council (MMRC) scale and the Epworth Sleepiness Scale (ESS), respectively. Forty matched subjects served as controls.

Results

The acromegalic patients exhibited larger median ratios between forced expiratory flow and forced inspiratory flow at 50% of the forced vital capacity (FEF_50%/FIF_50%) (2.05 vs. 1.06, p = 0.0001) compared with healthy volunteers. In the CT analysis, acromegalic patients exhibited larger median differences between their cervical and thoracic tracheal diameters (Δ tracheal diameters) (3 vs. 1 mm; p = 0.003). An association was found between FEF_50%/FIF_50% and the following variables: mean resistance (Rm), cervical tracheal diameter, and Δ tracheal diameters. Rm also exhibited a negative correlation with cervical tracheal diameter. Neither the MMRC scale nor the ESS exhibited any significant correlation with large airway obstruction (LAO) indices or with the measured tracheal diameters.

Conclusions

Acromegalic patients have tracheal structural abnormalities which are associated with functional indicators of LAO but not with clinical data.     

Efficacy of Combined Treatment with Lanreotide and Cabergoline in Selected Therapy-Resistant Acromegalic Patients

The aim of this study was to evaluate the efficacy of a 6-month treatment with lanreotide (LAN) (60–90 mg/month) alone and combined with cabergoline (CAB) (1.5-3 mg/week) in 10 acromegalic patients previously demonstrated to be poor responders to octreotide (OCT) (0.6 mg/day) alone and combined with quinagolide (CV) (0.6 mg/day).All patients had previously undergone unsuccessful surgery and none of them received radiotherapy. Immunohistochemistry showed intense positive GH staining in all adenomas, positive PRL staining in 5 adenomas and faint ACTH or FSH/LH positive staining in other 2 adenomas. Moderately elevated serum PRL levels (35 and 47 ng/ml) were recorded in two patients. Fasting plasma IGF-I and serum GH levels were assayed at baseline and 30, 60, 90 and 120 days after each treatment. Gallbladder ultrasonography and sellar MRI were performed before and after 6 months of OCT and LAN treatments.After OCT treatment circulating GH and IGF-I levels remained elevated in all patients, while after 3 months of combined OCT+CV treatment, serum GH levels were suppressed (below 2.5 ng/ml) in only 1 patient. Significant increase of the percent GH (83.9±4.3 vs. 70.3±5.6%, p<0.01) and IGF-I suppression (54±4.4 vs. 45.3±5.7, p<0.01) and decrease of the nadir of GH (8.5±1.2 vs. 14.6±1.9 ng/ml, p<0.01) and IGF-I (400.9±32.8 vs. 462.1±45.1 ng/ml) were obtained with the combined treatment when compared to OCT treatment alone. After a 15–30 days wash-out, circulating GH and IGF-I levels significantly increased up to pretreatment level in all patients. After 6 months of treatment with LAN, suppression of serum GH was achieved in 1 patient, but no difference in GH (66.3±6.3%) and IGF-I (43.9±4.6%) suppression was recorded in comparison to OCT treatment. After 3 months of treatment with LAN combined with CAB, suppression of serum GH and normalization of plasma IGF-I levels was achieved in 4 and 5 patients, respectively. Percent suppression of GH (88.1±2.1%) and IGF-I (57.5±2.8%) was significantly greater with the combined treatment than with LAN treatment alone. In the 7 patients with evident residual mass no change was documented by magnetic resonance imaging (MRI). None of the patients withdrew LAN+CAB treatment for poor tolerance, one patient had mild hypotension. Sludge was shown after 6 months of LAN treatment in one patient without notable change after 3 months of LAN+CAB treatment.In conclusion, the treatment with dopaminergic drugs such as CV and CAB, significantly increased the efficacy of somatostatin analogs, and can be used in combined therapy in poorly responsive patients.