[Outcome of somatostatin analogue treatment in acromegaly]. / A szomatosztatinanalóg kezelés eredményei acromegaliában.

UNLABELLED: During the past decade the importance of medical therapy, especially treatment with somatostatin analogues has increased significantly in patients with active acromegaly. AIMS: Authors analyzed the outcome of somatostatin analogue treatment in acromegalic patients evaluated and followed up at the 2nd Department of Medicine, Faculty of Medicine, Semmelweis University, during the past 10 years. PATIENTS AND METHODS: Changes in serum growth hormone (GH) and insulin-like growth factor-1 (IGF-1) concentration, as well as morphologic changes of pituitary adenomas followed by MRI scans were evaluated and compared in 32 acromegalic patients (26 women, 6 men) during long-term somatostatin analogue treatment (mean+/-SE, 3.1+/-0.3 years, range, 1-7 years). Primary somatostatin analogue treatment was applied in 10 patients (7 women and 3 men), whereas 15 patients (14 women and 1 man) had pituitary surgery and 7 patients (5 women and 2 men) underwent both pituitary surgery and irradiation therapy prior to somatostatin analogue treatment. RESULTS: After a 3-month treatment with somatostatin analogues, both serum GH and IGF-1 levels decreased significantly and they remained around the same decreased levels throughout the treatment period. Serum GH decreased from 15.7+/-4.9 to 5.5+/-1.4 ng/ml, and serum IGF-1, expressed as a percentage of the upper limit of age- and sex-adjusted reference value, decreased from 204+/-14% to 135+/-12% at the end of treatment. The efficacy of somatostatin analogue treatment was not influenced by surgical or surgical and irradiation therapies which were applied prior to medical treatment. At the end of treatment 36.7% of patients had safe serum GH (<2.5 ng/ml), while serum IGF-1 returned below the upper limit of age- and sex-adjusted reference range in 41.4% of patients. Pituitary MRI showed regression of the adenoma in 46% of patients, and none of the patients had progression of the pituitary adenoma. CONCLUSIONS: Somatostatin analogues are effective therapeutic options for acromegalic patients when primary surgical treatment cannot be performed due to complications and associated disorders, or in patients whose acromegaly remains active after pituitary surgery or after pituitary surgery and irradiation.

Overrepresentation of the N363S variant of the glucocorticoid receptor gene in patients with bilateral adrenal incidentalomas.

CONTEXT: Some variants of the glucocorticoid receptor (GR) gene have been found to alter glucocorticoid sensitivity and have been associated with altered metabolic profiles. OBJECTIVE: The objective of the study was to examine whether N363S and ER22/23K variants of the GR gene may be associated with the development of adrenal incidentalomas and whether these variants may contribute to metabolic abnormalities frequently present in these patients. DESIGN, SETTING, AND PATIENTS: The study included 99 patients with unilateral and 44 patients with bilateral adrenal incidentalomas, 102 population-matched control subjects, and 100 patients with type 2 diabetes mellitus. MAIN OUTCOME MEASURES: Metabolic and hormonal parameters and GR gene variants were determined. RESULTS: When compared with control subjects, the carrier frequency for the N363S variant was markedly and significantly higher in patients with bilateral (7.8 vs. 20.5%, P < 0.05) but not in those with unilateral incidentalomas (7.1%) or in patients with type 2 diabetes (13.0%). Type 2 diabetes occurred more frequently in patients with bilateral, compared with those with unilateral incidentalomas (40.9 vs. 22.2%, P < 0.05). In patients with bilateral incidentalomas, a significant association of the N363S variant with impaired glucose homeostasis but not with body mass index, hypertension, hyperlipidemia, or history of coronary artery disease was found. The carrier frequency of the ER22/23EK variant was similar in all groups, and this variant failed to show any association with metabolic abnormalities. CONCLUSION: These results suggest that the N363S variant of the GR gene may play a role in the pathogenesis of bilateral adrenal incidentalomas, although the mechanism still remains to be investigated.

[Radiotherapy of pituitary tumours]. / A hypophysisdaganatok radioteráipiáija.

In this article, the role of conventional radiotherapy and radiosurgery in the management of pituitary tumors is discussed. After a brief review about the mechanism of action and different techniques of irradiation therapy, the therapeutic effectiveness and side effects are analysed in the various types of pituitary tumors. Conventional fractionated radiotherapy has long been used to control growth and/or hormonal secretion of residual or recurrent pituitary tumors. Nevertheless, there is still a controversy concerning patient selection for radiotherapy, because several potentially significant side effects including hypopituitarism may develop. Stereotactic radiosurgical methods may have several advantages over conventional radiotherapy; they can be applied, for example, in patients with residual or recurrent pituitary tumors who had previously received conventional radiotherapy. However, long-term follow-up data with these relatively new techniques are still limited.

Fasting intact proinsulin is a highly specific predictor of insulin resistance in type 2 diabetes.

OBJECTIVE: In later stages of type 2 diabetes, proinsulin and proinsulin-like molecules are secreted in increasing amounts with insulin. A recently introduced chemiluminescence assay is able to detect the uncleaved "intact" proinsulin and differentiate it from proinsulin-like molecules. This investigation explored the predictive value of intact proinsulin as an insulin resistance marker. RESEARCH DESIGN AND METHODS: In total, 48 patients with type 2 diabetes (20 women and 28 men, aged 60 +/- 9 years [means +/- SD], diabetes duration 5.1 +/- 3.8 years, BMI 31.2 +/- 4.8 kg/m2, and HbA1c 6.9 +/- 1.2%) were studied by means of an intravenous glucose tolerance test and determination of fasting values of intact proinsulin, insulin, resistin, adiponectin, and glucose. Insulin resistance was determined by means of minimal model analysis (MMA) (as the gold standard) and homeostatis model assessment (HOMA). RESULTS: There was a significant correlation between intact proinsulin values and insulin resistance (MMA P<0.05 and HOMA P<0.01). Elevation of intact proinsulin values above the reference range (>10 pmol/l) showed a very high specificity (MMA 100% and HOMA 92.9%) and a moderate sensitivity (MMA 48.6% and HOMA 47.1%) as marker for insulin resistance. Adiponectin values were slightly lower in the insulin resistant group, but no correlation to insulin resistance could be detected for resistin in the cross-sectional design. CONCLUSIONS: Elevated intact proinsulin seems to indicate an advanced stage of beta-cell exhaustion and is a highly specific marker for insulin resistance. It might be used as arbitrary marker for the therapeutic decision between secretagogue, sensitizer, or insulin therapy in type 2 diabetes.

Cross-sectional investigation on the accuracy of alternate site glucose testing using the Soft-Sense glucose meter.

QUESTIONS UNDER STUDY: The aim of this study was to evaluate possible differences in the results of blood glucose testing with the Soft-Sense blood glucose monitoring system (Abbott MediSense, Wiesbaden, Germany; not yet available in Switzerland) using different sites for drawing whole blood samples. METHODS: In total, 66 patients participated in the study. Blood glucose measurements were performed with the Soft-Sense device taking capillary blood from the forearm and the fingertip. The results were compared with blood glucose measurements by means of a laboratory reference method using blood from the fingertips. RESULTS: 276 blood glucose data sets could be obtained and were used for the examination of the accuracy of blood glucose measurements at both different sites. Blood glucose results obtained from the arm with Soft-Sense correlated well and were nearly parallel with the results achieved from the fingertip with a laboratory reference method (regression analysis: slope = 0.981; intercept = 0.045 mmol/l (0.819 mg/dl); correlation coefficient r = 0.943). Error grid analysis showed 99.2% of the measurements within clinically acceptable zones A and B. In addition, finger stick measurements done with the Soft-Sense device and the reference method revealed a strong correlation (regression analysis: slope = 0.959; intercept = -0.042 mmol/l (0.748 mg/dl); correlation coefficient r = 0.972). Error grid analysis showed 98.9% of all blood glucose readings within clinically acceptable zones A and B. Mean absolute percent deviations were 9.3+/- 8.1% for the finger tests and 11.2+/- 8.7% for the arm tests. If blood glucose values exceeded 11.1 mmol/l (200 mg/dl), measurements revealed from the forearm were slightly lower than the measurements obtained from the fingertips. CONCLUSIONS: The results indicate that the automated blood glucose monitoring device Soft-Sense provides accurate results independent of the measuring site. As with other alternate site testing devices, nearly painless blood collection at the forearm might help to increase patients readiness to perform more frequent measurements by self blood glucose monitoring, which is a known prerequisite of improved blood glucose control.

[Experience in treating acromegalic patients with long-acting octreotide]. / Acromegaliás betegek tartós hatású octreotid kezelésével szerzett tapasztalatok.

The authors report clinical observations in 12 acromegalic patients treated with long-acting octreotide (Sandostatin LAR, Novartis, 20 mg intramuscular injection per 28 days administered for 6-36 months). Clinically and hormonally active acromegaly was evidenced in all patients by the presence of typical clinical symptoms, increased serum growth hormone and insulin-like growth factor I concentrations, and by non-suppressible serum growth hormone levels after oral glucose administration. In all patients previous treatments (transsphenoidal surgery, pituitary irradiation and bromocriptine therapy) were uneffective or contraindicated, or they were refused by the patients. Octreotide test (Sandostatin, Novartis, 100 g subcutaneously) performed in all patients before treatment precisely predicted the hormonal effectiveness of long-acting octreotide treatment. Three-six months after therapy serum growth hormone levels decreased from 13.6 +/- 3.9 ng/ml (mean +/- SD) to 3.4 +/- 1.7 ng/ml, while insulin-like growth factor I concentrations decreased from 483 +/- 127 ng/ml to 248 +/- ng/ml. Of the 12 patients 7 (58%) had serum growth hormone levels considered as safe values (< 2.5 ng/ml), whereas in 9 patients (75%) serum insulin-like growth factor I concentrations returned to age- and sex-matched normals. Repeat pituitary magnetic resonance imaging performed in 8 patients treated longer than 1 year revealed a decrease of tumor size in 3 patients (37%). There was a considerable clinical improvement during treatment: severe headache, which was present in most patients, as well as perspiration, joint pain, swelling of extremities, and weakness markedly decreased or disappeared. These results indicate that long-acting octreotide offers a very effective treatment of choice in acromegalic patients in whom other previous therapies were ineffective, contraindicated, or refused.

Rapid progression of amyotrophic lateral sclerosis in an acromegalic patient after surgical resection of a growth hormone-producing pituitary adenoma.

INTRODUCTION: Insulin-like growth factor-1 (IGF-1) promotes the survival of neurons, mediates neuritic growth, and in 1 clinical trial human recombinant IGF-1 delayed the progression of functional impairment and decline of health-related quality of life in patients with amyotrophic lateral sclerosis (ALS). CASE REPORT: We describe a case of a 65-year-old woman with a 2-year history of symptoms and signs of acromegaly because of a pituitary microadenoma. The patient posed a challenging diagnostic dilemma because of the presence of dysarthria, which was initially considered as the consequence of acromegaly. After octreotide long-acting release (LAR) treatment, the patient underwent uneventful pituitary surgery. Although postoperative evaluation indicated a cure of acromegaly, progressive bulbar symptoms developed, which were followed by upper limb weakness and muscle atrophy. Neurologic investigations confirmed the diagnosis of ALS and riluzole therapy was given. One year after surgery growth-hormone deficiency was diagnosed, but a trial with human recombinant growth hormone failed to produce any significant improvement. Two years after surgery the patient died of a sudden respiratory arrest. Histopathologic examination of the brain and spinal cord confirmed the diagnosis of ALS. CONCLUSIONS: This is the first report showing a rapid progression of ALS after a surgical cure of coexisting acromegaly presumably because of cessation of high endogenous IGF-I levels.

11beta-hydroxysteroid dehydrogenase activity in acromegalic patients with normal or impaired carbohydrate metabolism.

The 11beta-hydroxysteroid dehydrogenase isoenzymes (11beta-HSD) catalyse the interconversion of cortisol (F) and cortisone (E). Earlier studies demonstrated that growth hormone (GH) and insulin resistance may exert opposite effects on the conversion of E to F by 11beta-HSD type 1. Therefore, in the present study we determined F and E concentrations in 562 plasma samples obtained from acromegalic patients during an active phase (76 patients) and after cure of the disease (68 patients). In addition, we examined whether type 2 diabetes mellitus or impaired glucose tolerance, which are frequently associated with active acromegaly could influence plasma F and E levels in these patients. We found that plasma F concentrations were similar in patients with active acromegaly and in those who were cured with pituitary surgery, irradiation and/or medical therapy (mean+/-S.E., 12.4+/-0.3 and 12.7+/-0.4 microg/dl, respectively). However, plasma E levels were significantly higher in patients with active compared to those with cured acromegaly (2.8+/-0.1 and 2.2+/-0.1 microg/dl, respectively; p<0.001), resulting in a lower F/E ratio in patients with active disease (4.6+/-0.1 vs. 5.9+/-0.2 in the cured group of patients; p<0.001). When the effect of altered carbohydrate homeostasis on plasma F and E was analysed, the results indicated significantly lower plasma E levels and higher F/E ratios in active acromegalic patients with type 2 diabetes mellitus or impaired glucose tolerance compared to those with normal carbohydrate metabolism (E, 2.5+/-0.1 and 3.0+/-0.1 microg/dl, respectively; F/E, 5.1+/-0.2 and 4.4+/-0.1; p<0.001), whereas plasma F concentrations were similar in these two groups (12.1+/-0.4 and 12.6+/-0.3 microg/dl, respectively). These findings indicate that disease activity exerts a significant impact on 11beta-HSD in acromegalic patients, which is further modified with altered carbohydrate homeostasis, frequently present in patients with active disease.

Treatment of pituitary tumors: radiation.

In this paper, the role of conventional radiotherapy and radiosurgery in the management of pituitary tumors is reviewed. After a short summary of the mechanism of action of irradiation therapy and the types of different irradiation techniques, the therapeutic effects and side effects are analyzed in patients with different types of pituitary tumors, including our own experience with conventional radiotherapy and radiosurgery in patients with acromegaly. Conventional fractionated radiotherapy has long been used to control growth and/or hormonal secretion of residual or recurrent pituitary tumors. However, patient selection for conventional radiotherapy still remains a controversial issue, because a number of potentially significant side effects, including hypopituitarism and other complications, have been described. Stereotactic radiotherapy/radiosurgery methods have several potential advantages over conventional radiotherapy, including their use in patients with residual or recurrent pituitary tumors who had previously been treated by conventional radiotherapy, but long-term follow-up data with these relatively new techniques are still limited.