Efficacy of radiotherapy in normalizing serum IGF-I, acid-labile subunit (ALS) and IGFBP-3 levels in acromegaly

OBJECTIVE: Radiotherapy (RT) has been used for many years in order to complete the cure of unsuccessfully operated acromegalic patients. Several studies have shown its efficacy in normalizing GH levels, while reports about IGF-I normalization are conflicting. Moreover, data regarding other markers of disease activity, such as IGFBP-3 and acid-labile subunit (ALS), i.e. the other two components of the circulating 150 kDa complex, are lacking. DESIGN: Retrospective study. PATIENTS AND MEASUREMENTS: Sixty-seven acromegalic patients (20 males and 47 females, aged 40 \ub1 6 years) who underwent postoperative RT (in fractionated doses for a total of 40-75 Gy) were followed-up for 11 \ub1 6 years (range: 1-26 years, median: 10 years). Serum GH and IGF-I levels off medical therapy were measured in all patients; ALS and IGFBP-3 were measured in 11 patients with normalization of IGF-I concentrations. Computed tomography or nuclear magnetic resonance imaging periodically assessed possible development of pituitary deficiency along with imaging of the hypothalamic-pituitary region. RESULTS: Forty-one out of 67 patients (58%) achieved GH levels < 2.5 \u3bcg/l by 1-15 years after RT (mean 8 \ub1 6) and 37/67 patients (55%) had normal or low IGF-I levels 1-26 years after RT (mean: 12 \ub1 6), a normalization of both parameters being seen in 37 patients. GH < 2.5 \u3bcg/l and normal IGF-I levels were achieved in 17/26 (65%) patients followed-up for at least 15 years. ALS and IGFBP-3 concentrations paralleled IGF-I levels in all patients studied. With respect to secondary pituitary insufficiency, acquired ACTH deficiency was found in 25 patients, TSH deficiency in 20, gonadotropin deficiency in 23 and GH deficiency in seven. In total, two cases of meningioma and one pineal tumour, possibly related to RT, were seen 9-22 years after RT. CONCLUSIONS: RT is an effective, although slow-acting, therapeutic tool for acromegaly, with 'safe' GH levels and normal IGF-I concentrations being achieved in 65% of patients after 15 years. IGF-I levels normalize more slowly than GH levels. Radiotherapy is able to normalize the concentration of all three components of the circulating 150 kDa complex. Checks for loss of pituitary function and appearance of second brain tumours must be carried out life-long

Gamma-Knife Radiosurgery in Acromegaly: A 4-Year Follow-Up Study

Stereotactic radiosurgery by gamma-knife (GK) is an attractive therapeutic option after failure of microsurgical removal in patients with pituitary adenoma. In these tumors or remnants of them, it aims to obtain the arrest of cell proliferation and hormone hypersecretion using a single precise high dose of ionizing radiation, sparing surrounding structures. The long-term efficacy and toxicity of GK in acromegaly are only partially known. Thirty acromegalic patients (14 women and 16 men) entered a prospective study of GK treatment. Most were surgical failures, whereas in 3 GK was the primary treatment. Imaging of the adenoma and target coordinates identification were obtained by high resolution magnetic resonance imaging. All patients were treated with multiple isocenters (mean, 8; range, 3\u201311). The 50% isodose was used in 27 patients (90%). The mean margin dose was 20 Gy (range, 15\u201335), and the dose to the visual pathways was always less than 8 Gy. After a median follow-up of 46 months (range, 9\u201396), IGF-I fell from 805 \u3bcg/liter (median; interquartile range, 640\u2013994) to 460 \u3bcg/liter (interquartile range, 217\u2013654; P = 0.0002), and normal age-matched IGF-I levels were reached in 7 patients (23%). Mean GH levels decreased from 10 \u3bcg/liter (interquartile range, 6.4\u201315) to 2.9 \u3bcg/liter (interquartile range, 2\u20135.3; P < 0.0001), reaching levels below 2.5 \u3bcg/liter in 11 (37%). The rate of persistently pathological hormonal levels was still 70% at 5 yr by Kaplan-Meier analysis. The median volume was 1.43 ml (range, 0.20\u20133.7). Tumor shrinkage (at least 25% of basal volume) occurred after 24 months (range, 12\u201336) in 11 of 19 patients (58% of assessable patients). The rate of shrinkage was 79% at 4 yr. In no case was further growth observed. Only 1 patient complained of side-effects (severe headache and nausea immediately after the procedure, with full recovery in a few days with steroid therapy). Anterior pituitary failures were observed in 2 patients, who already had partial hypopituitarism, after 2 and 6 yr, respectively. No patient developed visual deficits. GK is a valid adjunctive tool in the management of acromegaly that controls GH/IGF-I hypersecretion and tumor growth, with shrinkage of adenoma and no recurrence of the disease in the considered observation period and with low acute and chronic toxicit

Radiation techniques for acromegaly

Radiotherapy (RT) remains an effective treatment in patients with acromegaly refractory to medical and/or surgical interventions, with durable tumor control and biochemical remission; however, there are still concerns about delayed biochemical effect and potential late toxicity of radiation treatment, especially high rates of hypopituitarism. Stereotactic radiotherapy has been developed as a more accurate technique of irradiation with more precise tumour localization and consequently a reduction in the volume of normal tissue, particularly the brain, irradiated to high radiation doses. Radiation can be delivered in a single fraction by stereotactic radiosurgery (SRS) or as fractionated stereotactic radiotherapy (FSRT) in which smaller doses are delivered over 5-6 weeks in 25-30 treatments. A review of the recent literature suggests that pituitary irradiation is an effective treatment for acromegaly. Stereotactic techniques for GH-secreting pituitary tumors are discussed with the aim to define the efficacy and potential adverse effects of each of these techniques

Effects of two different somatostatin analogs on glucose tolerance in acromegaly

Impaired glucose tolerance is present in many acromegalic patients and treatment with somatostatin analogs has variable effects on glycemic control. The aim of this study was to compare the effects of 2 somatostatin analogs on glucose metabolism, lanreotide slow release (L-SR) and octreotide long acting release (O-LAR), in 10 patients with acromegaly (2 of whom with overt Type 2 diabetes mellitus). Glucose and insulin levels in fasting conditions and in response to OGTT, evaluated as AUC, insulin resistance (IR) evaluated by homeostatic model assessment (HOMA-IR), glycosylated hemoglobin (HbA1c), GH, IGF-I, were assessed during L-SR and O-LAR treatment. Mean fasting glucose, glucose response to OGTT and HbA1c levels in 8 non-diabetic patients did not significantly change after L-SR therapy while they all increased after O-LAR treatment (p<0.05 vs baseline and L-SR). Mean HOMA-IR values calculated in acromegalic patients before medical therapy were higher than in normal subjects (p<0.005) and showed a significant decrease during both treatments (p<0.05). In the 2 diabetic acromegalic patients a worsening in glucose metabolism was observed during O-LAR treatment but not during L-SR. GH and IGF-I levels significantly decreased with both drugs and normalized respectively in 38% and 12% with L-SR, 50% and 25% with O-LAR. In conclusion, both drugs decreased IR in acromegalic patients; O-LAR seems to be more detrimental to glucose metabolism than L-SR, despite being more effective in reducing GH and IGF-I levels

New therapeutic options for acromegaly

Acromegaly is a slowly developing disfiguring disease characterized by chronic growth hormone (GH) and insulin-like growth factor-I (IGF-I) excess and caused by a pituitary somatotroph adenoma. It is associated to 2- to 3 fold increased mortality, compared to normal population, mostly due to cardiovascular and cerebro-vascular diseases, and to several co-morbid systemic illnesses, such as diabetes mellitus, hypertension, severe arthropathies, a specific cardio-myopathy, goitre, sleep-apnoea, intractable headache. The morbidity and excess mortality of acromegaly are usually the consequence of the metabolic actions of excess GH and IGF-I secretion, while only in rare patients mortality is due to the mass effects of the pituitary tumour. Since, serum IGF-I concentrations within age-adjusted normal range, and a tight GH control have to be achieved to normalize life-expectancy in these patients, an aggressive, and often multi-modality treatment is required for acromegaly. In recent years, new drugs, and new formulations of old drugs, have been developed that are able to effectively inhibit GH secretion or GH action, and may represent important adjuncts or even alternatives to the traditional approaches of surgery and radiotherapy. This review briefly summarizes the therapeutic options nowadays available for acromegaly. A brief note about innovative drugs under study, is also given

Long-term evaluation of postoperative acromegalic patients in remission with previous and newly proposed criteria

Criteria to define remission of acromegaly have changed over years. Since 2000, criteria for cure are normal IGF-I levels and a nadir GH after oral glucose tolerance test (OGTT) of less than 1 \u3bcg/liter, although recent studies have suggested to lower this cutoff value. This study reevaluated long-term disease activity of acromegalic patients, who were previously considered in remission, using these criteria. The study included 70 of 146 patients operated on between 1984 and 1996 who were considered cured based on normal IGF-I levels, GH values less than 2.5 \u3bcg/liter, and/or disappearance of abnormal GH response to TRH/GnRH. Among these 70 patients, 16 were lost to follow-up, three died, and 11 (one of whom had disease recurrence) only gave a phone interview. Forty patients participated in the study and were reevaluated for IGF-I levels and post-OGTT GH nadir after 14.3 \ub1 4.2 (mean \ub1 SD) yr from surgery. In all patients, normal IGF-I levels and a post-OGTT GH nadir of less than 1 \u3bcg/liter were found. In particular, 19 patients had a GH nadir of less than 0.19 \u3bcg/liter, i.e. the upper limit (mean + 2 SD) found in 30 controls, whereas 21 patients had a nadir between 0.19 and 0.77 \u3bcg/liter. No significant differences in hormonal parameters and comorbidities between the two subgroups were observed. These data showed that lowering the post-OGTT GH cutoff value within the normal range does not seem to better discriminate patients with different disease activity or long-term recurrence risk. Copyrigh

Evaluation of insulin resistance in acromegalic patients before and after treatment with somatostatin analogues

Many studies have recently shown that simple computer-solved indices, based on fasting glucose and insulin levels, closely mirror the euglycemic clamp technique in studying insulin resistance or pancreatic insulin secretion. Few data are at present available on the evaluation of these novel indices in acromegalic patients, known to be GH-dependent insulin-resistant subjects, in particular during medical treatment with somatostatin analogues. Indeed, these drugs are able to inhibit not only GH and IGF-I levels, but also insulin and glucagon pancreatic secretion, with contrasting effects on glucose metabolism. In this study, insulin resistance was evaluated by the homeostasis model assessment (HOMA-IR) and insulin sensitivity by quantitative insulin check index (QUICKI) in 27 normoglycemic acromegalic patients, before and after 6-month therapy with somatostatin analogues (lanreotide-SR 30-60 mg every 7-28 days in 15 and octreotide-LAR 20-30 mg every 28 days in 12). Thirty-five age- and sex-matched healthy subjects and 17 surgically treated acromegalic patients (5 cured and 12 not cured) were studied as control groups. Before medical treatment, HOMA-IR was higher in acromegalic patients than in healthy controls (4\ub13 vs 1.7\ub10.7, p<0.05), while QUICKI was lower (0.33\ub10.04 vs 0.36\ub10.03, p<0.05). During medical therapy, HOMA-IR decreased to 2.4\ub11.6 (p<0.05) and became similar to that recorded in both healthy subjects and surgically treated patients. However, fasting glucose was increased and fasting insulin was decreased. QUICKI did not significantly change from basal values. No differences were observed between patients who normalized or not hormonal levels. The effects of the 2 drugs, though higher glucose levels were seen in patients treated with octreotide-LAR. In conclusion, this study demonstrates that medical treatment is able to improve insulin resistance, even if only successful surgery is able to completely normalize both HOMA-IR and QUICKI

Increased glucose-dependent insulinotropic polypeptide (GIP) secretion in acromegaly

Objective: Acromegaly is often associated with fasting and postprandial hyperinsulinemia, and the mechanisms involved are only partly understood. Hypersecretion of incretins such as glucose-dependent insulinotropic polypeptide (GIP) could play a role in determining hyperinsulinemia in acromegaly, but the available data are inconsistent. The aim of this study was to characterize the fasting and postprandial pattern of plasma GIP and insulin in a group of acromegalic patients. Design and Methods: Eleven non-diabetic patients with newly diagnosed acromegaly and 11 sex- and age-matched healthy subjects were studied. Blood samples were taken at regular intervals in fasting conditions and for 3 h after a standard solid-liquid meal for growth hormone (GH), GIP and insulin measurements. Results: Not only insulin, but also fasting and postprandial GIP levels were significantly higher in the patients with acromegaly than the healthy subjects (P < 0.01). In the former group fasting GIP levels and the integrated GIP response to the meal correlated significantly with GH basal levels (r = 0.83, P < 0.01 and r = 0.65, P < 0.05, respectively). Moreover, multivariate linear regression analysis showed that the presence of acromegalic status was associated with higher fasting and postprandial GIP levels independently of sex, age, fasting and postprandial plasma glucose and insulin levels, and the occurrence of normal or impaired glucose tolerance. Conclusion: This study provides evidence that in patients with acromegaly fasting and postprandial GIP levels are abnormally high. GIP hypersecretion in turn might play a role in the pathogenesis of hyperinsulinemia that characterizes acromegaly