Pasireotide can induce sustained decreases in urinary cortisol and provide clinical benefit in patients with Cushing's disease: results from an open-ended, open-label extension trial.

PURPOSE: Report the efficacy and safety of pasireotide sc in patients with Cushing's disease during an open-ended, open-label extension to a randomized, double-blind, 12-month, Phase III study. METHODS: 162 patients entered the core study. 58 patients who had mean UFC ≤ ULN at month 12 or were benefiting clinically from pasireotide entered the extension. Patients received the same dose of pasireotide as at the end of the core study (300-1,200 µg bid). Dose titration was permitted according to efficacy or drug-related adverse events. RESULTS: 40 patients completed 24 months' treatment. Of the patients who entered the extension, 50.0% (29/58) and 34.5% (20/58) had controlled UFC (UFC ≤ ULN) at months 12 and 24, respectively. The mean percentage decrease in UFC was 57.3% (95% CI 40.7-73.9; n = 52) and 62.1% (50.8-73.5; n = 33) after 12 and 24 months' treatment, respectively. Improvements in clinical signs of Cushing's disease were sustained up to month 24. The most frequent drug-related adverse events in patients who received ≥1 dose of pasireotide (n = 162) from core baseline until the 24-month cut-off were diarrhea (55.6%), nausea (48.1%), hyperglycemia (38.9%), and cholelithiasis (31.5%). No new safety issues were identified during the extension. CONCLUSIONS: Reductions in mean UFC and improvements in clinical signs of Cushing's disease were maintained over 24 months of pasireotide treatment. The safety profile of pasireotide is typical for a somatostatin analogue, except for the frequency and degree of hyperglycemia; patients should be monitored for changes in glucose homeostasis. Pasireotide represents the first approved pituitary-targeted treatment for patients with Cushing's disease.

Pasireotide treatment significantly improves clinical signs and symptoms in patients with Cushing's disease: results from a Phase III study.

OBJECTIVE: Signs and symptoms of Cushing's disease are associated with high burden of illness. In this analysis, we evaluated the effect of pasireotide treatment on signs and symptoms in patients with Cushing's disease. DESIGN: Phase III study with double-blind randomization of two pasireotide doses. METHODS: Patients (n = 162) with persistent/recurrent or de novo Cushing's disease and urinary free cortisol (UFC) levels ≥1·5× upper limit of normal (ULN) were randomized to receive subcutaneous pasireotide (600/900 µg bid). At month 3, patients with UFC ≤2 × ULN and not exceeding the baseline value continued their randomized dose; all others received 300 µg bid uptitration. At month 6, patients could enter an open-label phase until month 12 with a maximal dose of 1200 µg bid. Changes in signs and symptoms of hypercortisolism over 12 months' treatment in patients still enroled in the study and with evaluable measurements were assessed in relation to degree of UFC control. RESULTS: Reductions in blood pressure were observed even without full UFC control and were greatest in patients who did not receive antihypertensive medications during the study. Significant reductions in total cholesterol and low-density lipoprotein (LDL)-cholesterol were observed in patients who achieved UFC control. Reductions in BMI, weight and waist circumference occurred during the study even without full UFC control. Adverse effects were typical of somatostatin analogues except for hyperglycaemia-related events, which were experienced by 72·8% of patients. CONCLUSIONS: In the largest Phase III study of medical therapy in Cushing's disease, significant improvements in signs and symptoms were seen during 12 months of pasireotide treatment, as UFC levels decreased.

Treatment of acromegaly: is there still a place for radiotherapy?

OBJECTIVE: To evaluate efficacy and safety of radiotherapy on acromegaly treatment. DESIGN AND PATIENTS: We followed retrospectively 99 acromegalic patients for at least one year after radiotherapy (RT). RT had been performed after unsuccessful surgery in 91 patients and as primary treatment in eight. Time elapsed between surgery and RT was 1.4 +/- 2.4 years. Mean follow-up after RT was 5.9 +/- 4.7 years (1-16 years). All patients were treated with linear accelerator, 89 by conventional (3240-6000 cGY) and ten by stereotactic RT. MEASUREMENTS: Biochemical remission was defined as GH < 2.5 ng/ml and IGF-I normalization. RESULTS: At latest follow-up, 54% of patients had serum GH level <2.5 ng/ml; 42% had normal IGF-I and 38% of patients achieved normalization of both. Controlled patients had lower baseline GH and IGF-I levels compared to uncontrolled ones. They achieved remission after 3.8 +/- 2.4 years, a significantly lower time length compared to maximum follow-up of uncontrolled (6.0 +/- 4.9 year). Results regarding GH and IGF-I levels were similar in patients treated either primarily or after surgery. No patient showed tumor growth. Visual field defects were observed in four, seizures in one, and mental disorders in two patients, although cognitive function were not properly assessed. At the last follow-up, 47% of patients had acquired at least one hormonal deficiency. CONCLUSIONS: There is still a place for RT in acromegaly treatment, mainly for: after non-curative surgery and poor response or inaccessibility to medical treatment; growth restraining of aggressive macroadenomas; co-morbidities that contraindicate surgery and surgery refusal. However, side effects and latency period to achieve disease control should be kept in mind.

Treatment of acromegaly with octreotide-LAR: extensive experience in a Brazilian institution.

OBJECTIVE: Somatostatin analogues have become the mainstay of the medical treatment of acromegaly. The aim of our study was to evaluate the efficacy and tolerability of octreotide-LAR (OCT-LAR) treatment in acromegalic patients. DESIGN: Prospective open trial. PATIENTS AND METHODS: Eighty acromegalic patients (46 women; 18-80 years) were treated with OCT-LAR. Mean +/- SD duration of follow-up was 16.6 +/- 6.6 months (6-24 months). Twenty-eight patients received OCT-LAR as primary treatment. The target was to achieve normal IGF-I levels. Clinical activity was evaluated by symptom score and fasting samples for GH and IGF-I serum concentrations, obtained under basal conditions as well as during treatment. Pituitary tumour volume was assessed by magnetic resonance imaging of the sella. A tumour volume reduction of at least 25% was considered significant. RESULTS: Clinical improvement was attained in most patients. Fifty-nine (74%) of them attained mean GH < 2.5 ng/ml and 33 (41%) achieved normal IGF-I by the 24th month of treatment. GH and IGF-I control increased throughout treatment. Regarding the 46 patients treated for at least 12 months there was a significant decrease of GH and IGF-I levels by the third month compared to basal levels, persisting with no subsequently variation. In the patient group that achieved normal serum IGF-1 during treatment (controlled group: n = 43) 20 patients maintained normal levels up to the latest follow-up, whereas 23 of them once again showed altered serum IGF-1-values of some measurements during follow-up, despite dose maintenance or elevation. Baseline percentage of the upper limit of IGF-I normal range, GH levels by the third month and length of treatment were predictive factors of IGF-I normalization. Tumour shrinkage occurred in 76% of primary patients. Among 21 diabetic patients, four worsened and five improved glycaemic control, based on glycated haemoglobin. One previously intolerant patient progressed to overt diabetes. Nine patients developed gall bladder sludge, other nine patients acquired microlithiasis and one patient developed gallstone pancreatitis. CONCLUSION: OCT-LAR is an effective agent in alleviating symptoms, suppressing GH, normalizing IGF-I and inducing tumour shrinkage in many acromegalic patients. Overall, OCT-LAR is well tolerated and should be recommended for nonsurgically cured acromegalics, and also be considered as primary therapy for selected cases, mainly for those with a low probability of surgical cure.

Treatment of acromegaly improves myocardial abnormalities.

BACKGROUND: Treatment for acromegaly decreases left ventricular (LV) mass, but it is not clear whether diastolic dysfunction is also reversible. With Doppler echocardiography, before and after effective therapy, we assessed the LV morphology and function of patients with acromegaly who were free of complications. METHODS: In 15 patients with active acromegaly (age range, 33.4 +/- 9.3 years), we compared LV Doppler echocardiographic indices, before and after transsphenoidal surgery or radiotherapy or before and after both procedures, noting a significant drop in plasma levels of growth hormone (<2.0 ng/mL after oral glucose tolerance testing). Patients did not have arterial hypertension, diabetes mellitus, thyroid dysfunction, or coronary artery disease. Occasionally, in this series, patients had no symptoms of heart failure, and patients who underwent treatment with somatostatin analog drugs were not included because they did not have a significant hormonal drop. The follow-up period after hormonal control was 2.7 +/- 1.7 years. We also studied 15 healthy control subjects matched for age, sex, and body surface area. RESULTS: Patients with acromegaly compared with healthy control subjects had increased LV mass index, relative wall thickness, and deteriorated diastolic function. After therapy, most of the abnormalities improved: LV mass index (104 +/- 21 g/m(2) x 87 +/- 21 g/m(2); P <.01), LV relative wall thickness (0.40 +/- 0.06 x 0.35 +/- 0.04; P <.01), proto/telediastolic transmitral peak flow velocity ratio (1.17 +/- 0.33 x 1.49 +/- 0.34; P <.001), and isovolumetric relaxation period (126 +/- 18 ms x 113 +/- 13 ms; P <.05). CONCLUSION: Treatment of acromegaly in patients without clinical heart failure improves both LV morphology and diastolic function. Avoidance of progression to more advanced forms of acromegalic cardiomyopathy should be possible.

Reavaliaçäo da secreçäo do hormônio do crescimento (GH) em pacientes com diagnóstico prévio de deficiência clássica de GH / Reavaluation of the growth hormone secretion in patients with diagnosis of classic GH deficiency

Reavaliamos a secreçäo de GH durante o teste da hipoglicemia induzida por insulina (ITT) em 32 pacientes (25 masculinos; IC de 4 a 20,6 anos) com diagnóstico de deficiência de GH "clássica"(DGH) baseado em dados auxológicos e laboratoriais. Todos eram pré-púberes e apresentaram pico de GH menor que 7,0 ng/ml em pelo menos dois testes de estímulo por ocasiäo do diagnóstico. A terapêutica com GH recombinante foi interrompida pelo menos 15 dias antes da reavaliaçäo. Pacientes com Tanner I de puberdade foram re-testados após a administraçäo de etinilestradiol (EE), 40mg/m2/dia por 2 dias. Pacientes com Tanner II e III foram reavaliados antes e após a administraçäo de EE. Pacientes com Tanner IV e V foram re-testados sem administraçao prévia de EE. Treze dos 32 pacientes (40,6 por cento) apresentaram normalizaçäo da resposta de GH na reavaliaçäo (pico de GH: 22,9+4,2 ng/ml; X+EP; variando de 7 a 52), sendo considerados como portadores de DGHt (DGH transitória). Os 19 pacientes restantes apresentaram diminuiçäo da secreçäo de GH na reavaliaçao (pico de GH: 1,3+0,2 ng/ml) em relaçao à época do diagnóstico (5,3 anos antes) e foram considerados como portadores de DGH permanente. Atrasos de idade óssea e velocidade de crescimento pré-tratamento näo foram diferentes entre ambos os grupos. Entretanto, o pico de GH durante o ITT realizado por ocasiäo do diagnóstico foi estatisticamente maior nos pacientes com DGHt comparado com aqueles com DGH permanente (3,8+0,4 ng/ml vs. 2,1+0,2 ng/ml, respectivamente). A ressonância magnéstica (RM) estava alterada em 14 de 15 pacientes com DGH permanente (13 com secçäo de haste hipofisária e um com ausência de sépto pelúcido), enquanto era normal em todos os sete com DGHt que realizaram este exame. Concluímos que a DGHt é freqüente em pacientes cujo diagnóstico de DGH "clássica"é feito durante o período pré-pubertário. Normalizaçäo da secreçäo de GH pode ocorrer durante a puberdade ou após a administraçäo de EE. Lesöes estruturais da regiäo hipotálamo-pituitária säo freqüentemente associadas com a DGH permanente.

Failure of Partial Hypophysectomy as Definitive Treatment in Cushing's Disease Owing to Nodular Corticotrope Hyperplasia: Report of Four Cases.

Nodular corticotrope hyperplasia is a rare pathology causing Cushing's syndrome owing to a primary pituitary disease or ectopic CRH production. In this study, we evaluated the laboratory and pathological findings and results of transsphenoidal pituitary surgery in four patients with Cushing's disease. Dynamic tests of pituitary-adrenal function (dexamethasone suppression, metyrapone, CRH, and DDAVP tests) were done before and after transsphenoidal pituitary surgery. Plasma and total urinary cortisol, serum 11-deoxycortisol, and plasma ACTH were determined by RIA. Hormonal dynamic tests and radiologic studies were compatible with a pituitary ACTH source. The transsphenoidal surgery revealed the presence of corticotrope hyperplasia confirmed by immunoperoxidase stain and a preserved reticulum framework in the removed pituitary tissue of these four patients. The pituitary surgery led to a short period of improvement in two of the patients (1 and 4), a 3-yr remission in one patient (patient 2), and no improvement in one (patient 3). We conclude that although our patients appear to have inadequate suppression with high-dose dexamethasone, there is no way to diagnose this pathology presurgically, and that total hypophysectomy, bilateral adrenalectomy, and irradiation are the only alternatives for definitive treatment. A CRH-secreting ectopic tumor could not be found in our patients either before or after surgery in the follow-up period.

Carcinoma de córtex adrenal produtor de esteróides: diagnóstico e terapêutica / Adrenal cortex carcinoma producer of steroids: diagnostic and therapeutic

Os autores estudaram 24 casos de carcinoma funcionante do cørtex adrenal com o objetivo de revisar o tratamento cir£rgico e quimioter pico. Procurou-se fazer correlaüoes com o tipo de cirurgia e a efi cia da quimioterapia com a sobrevida. Observou-se que tanto a adrenalectomia como a nefroadrenalectomia ofereceram resultados semelhantes em termos de sobrevida e significativamente a sobrevida. (Arq Bras Endocrinol Metab 1994; 38/1:16-22).