Marcos Manavela

Cabergoline monotherapy in the long-term treatment of Cushing's disease

BACKGROUND Cabergoline is a long-acting dopamine receptor agonist used to treat prolactinomas. Identification of D(2) receptors in corticotroph tumors led to clinical trials of cabergoline therapy in limited cases of Nelsons syndrome, ectopic ACTH-secreting tumors, and recently Cushings disease (CD). OBJECTIVE To evaluate the long-term efficacy of cabergoline monotherapy in patients with CD. METHODS Retrospective analysis of non-randomized clinical therapy with cabergoline in 30 patients with CD treated in academic centers of Buenos Aires and Montreal. Cabergoline was initiated at 0.5-1.0 mg/week and adjusted up to a maximal dose of 6 mg/week based on urinary free cortisol (UFC) levels. Complete response to cabergoline was defined as a sustained normalization of UFC with at least two normal values measured at 1-3 months interval; partial response was defined as a decrease of UFC to <125% of the upper limit of normal, and treatment failure as UFC ≥ 125% of it. RESULTS Within 3-6 months, complete response was achieved in 11 patients (36.6%) and partial response in 4 patients (13.3%). After long-term therapy, nine patients (30%) remain with a complete response after a mean of 37 months (range from 12 to 60 months) with a mean dose of 2.1 mg/week of cabergoline. Two patients escaped after 2 and 5 years of complete response, but one patient transiently renormalized UFC after an increase in cabergoline dosage. No long-term response was maintained in four initial partial responders. CONCLUSIONS Cabergoline monotherapy can provide an effective long-term medical therapy for selected patients with CD, but requires close follow-up for dose adjustments.

Alterations in biomarkers of cardiovascular disease (CVD) in active acromegaly

Objectives  In acromegalic patients, cardiovascular and metabolic comorbidities contribute to enhance mortality. Available data on the lipoprotein profile of these patients are controversial. Our aim was to characterize the lipoprotein profile and emergent biomarkers of cardiovascular disease in active acromegalic patients in comparison with sex‐ and age‐matched healthy controls.

Temozolomide Therapy for Aggressive Pituitary Tumors: Results in a Small Series of Patients from Argentina

We evaluated results of temozolomide (TMZ) therapy in six patients, aged 34–78 years, presenting aggressive pituitary tumors. In all the patients tested O6-methylguanine-DNA methyltransferase (MGMT) immunoexpression in surgical specimens was absent. Patients received temozolomide 140–320 mg/day for 5 days monthly for at least 3 months. In two patients minimum time for evaluation could not be reached because of death in a 76-year-old man with a malignant prolactinoma and of severe neutro-thrombopenia in a 47-year-old woman with nonfunctioning pituitary adenoma. In two patients (a 34-year-old acromegalic woman and a 39-year-old woman with Nelsons syndrome) no response was observed after 4 and 6 months, respectively, and the treatment was stopped. Conversely, two 52- and 42-year-old women with Cushings disease had long-term total clinical and radiological remissions which persisted after stopping temozolomide. We conclude that TMZ therapy may be of variable efficacy depending on—until now—incompletely understood factors. Cooperative work on a greater number of cases of aggressive pituitary tumors should be crucial to establish the indications, doses, and duration of temozolomide administration.

The Association of Cushing's Disease and Primary Empty Sella Turcica

The empty sella turcica is defined as the extension of the subarachnoid space toward the intrasellar region with displacement of the pituitary towards the posteroinferior wall. By autopsy studies, the incidence in the general population is around 20%. The association of Cushings disease (CD) and empty sella has been infrequently reported. In our group, from a total of 68 patients with CD studied by magnetic resonance imaging (MRI), we found the presence of a primary empty sella syndrome (ESS) in 11 (16%). Of these, 9 had partial and 2 total ESS, and in four of them a microadenoma could be identified. Remission, ascertained by subnormal postoperative cortisol levels in blood and/or urine was obtained in 5 of 6 patients operated on by the transphenoidal route. Following surgery, 2 patients presented cerebrospinal fluid (CSF) leakage, 2 diabetes insipidus, and 2 some form of hypopituitarism, figures apparently higher than in non-ESS patients with CD. Ketoconazole was indicated as second line treatment in 2 patients and as primary therapy in 4, resulting in normal urinary free cortisol (UFC) values, with no complications. The relationship of ESS and CD is probably fortuitous given that the frequency of ESS in the general population is similar. Although in empty sella both surgery and radiotherapy seem to have greater risk of complications, surgery remains the first line treatment. Nevertheless, chronic treatment with ketoconazole could be a useful first choice, particularly when no adenoma is seen, or in those who have contraindications for surgery.

GH levels and insulin sensitivity are differently associated with biomarkers of cardiovascular disease in active acromegaly

Acromegaly is characterized by GH excess and insulin resistance. It is not known which of these disorders is responsible for the increased atherogenic risk in these patients.

Increased oxidized low density lipoprotein associated with high ceruloplasmin activity in patients with active acromegaly

Objective  Active acromegaly is associated with increased mortality from cardiovascular causes. Several studies have shown increased atherogenic risk factors and biomarkers of inflammation and atherosclerosis in association with growth hormone excess. The aim of this study was to evaluate oxidized low density lipoprotein (oxLDL) levels and some modulators of LDL oxidative modification in patients with acromegaly.

LONG-TERM MANAGEMENT WITH OCTREOTIDE OR CABERGOLINE IN ECTOPIC CORTICOTROPIN HYPERSECRETION: CASE REPORT AND LITERATURE REVIEW

OBJECTIVE To describe the corticotropin response to long-term octreotide or cabergoline administration in a patient with ectopic corticotropin secretion who underwent adrenalectomy. METHODS We describe the clinical, radiologic, and biochemical findings of the study patient over the course of 18 years. RESULTS A 40-year-old woman was evaluated for Cushing syndrome. On the basis of biochemical indices, Cushing disease was diagnosed and pituitary exploration was performed. No cure was achieved. Computed tomography of the chest revealed a right lung nodule due to a lung carcinoid tumor that was then surgically excised. Because of persistent hypercortisolism, total adrenalectomy was performed. Subsequently, corticotropin levels rose dramatically and hyperpigmentation developed while serum cortisol was in the reference range. The patient was treated with octreotide for 3 years and then with cabergoline for 8 years. While taking octreotide, corticotropin values decreased, accompanied by depigmentation and development of signs of adrenal insufficiency, which led to the reinstitution of supplemental hydrocortisone. Cabergoline induced a similar long-lasting effect on the clinical and biochemical parameters observed. Eight years later, she is still treated with cabergoline, and no lung tumor has been detected. CONCLUSIONS In this patient with ectopic Cushing syndrome, treatment with either octreotide or cabergoline markedly reduced corticotropin levels and hyperpigmentation.

Experience from the Argentine Pegvisomant Observational Study: Preliminary Data

The GH receptor antagonist pegvisomant is an efficient agent to achieve biochemical control of acromegaly in those cases refractory to surgery and medical therapy with somatostatin analogs. We conducted an observational multicenter study consisting of data collection in accordance with the standard management of patients with acromegaly in everyday practice. We reviewed the medical records of 28 patients, 23 females, who were treated with pegvisomant due to the lack of biochemical response or intolerance to the somatostatin analogs. The objective was to monitor long-term safety and efficacy of the antagonist. 82% of the patients had previous pituitary surgery, 53.6% radiotherapy and 96.4% received medical therapy for acromegaly. Only 19.2% of the patients had pituitary residual tumor size larger than 1 cm, the remainder harbored a microadenoma or no visible tumor in the pituitary images. In terms of biochemical efficacy, IGF-I levels decreased to normal ranges in 45% and 58.8% of patients after 3 and 6 months of treatment, respectively, the daily mean dose of pegvisomant being 9.6+/-1.1 mg. Adverse events, potentially related to pegvisomant were reported in 6 patients (21.4%), local injection site reaction and elevated liver enzymes being the most frequent. Tumor size did not show enlargement in the evaluated population (15 patients) during the period of the study. This paper presents preliminary data from a small observational study in Argentina which represents the first database in our country.

Aggressive tumors and difficult choices in acromegaly.

PurposeThe current article looks at some of the factors associated with pituitary adenomas displaying unusually aggressive biological and clinical behaviour in patients with acromegaly.MethodsThis was a retrospective, narrative review of previously published evidence chosen at the authors’ discretion and presented from the perspective of a Latin American case study.Findings and ConclusionsAlthough most pituitary tumors in acromegalic patients are benign and non-aggressive many can behave more aggressively, compromising local surrounding structures. These lesions tend to respond poorly to somatostatin analogs, have a higher risk of recurrence after surgery and, thus, a worse prognosis. Patients with more aggressive tumors constitute a particular challenge, as they often require several therapeutic approaches and may be difficult to manage, especially when options are restricted due to limited resources.

Skin reaction and fever after treatment with pegvisomant in a patient with acromegaly

BACKGROUND Pegvisomant is a growth hormone receptor antagonist approved for the treatment of acromegaly. Documented adverse effects include headache, injection-site reactions, flulike syndrome, and reversible elevation of hepatic enzymes. Skin manifestations at the injection site are reported in approximately 11% of patients and are characterized as erythematous, self-limited reactions that neither require treatment nor lead to drug discontinuation. OBJECTIVE This report describes a skin reaction and fever occurring after treatment with pegvisomant in a patient with acromegaly. CASE SUMMARY The patient was a 54-year-old white woman with acromegaly (weight, 85 kg; height, 170 cm). At the time of consultation, her medication regimen was levothyroxine 150 microg/d for hypothyroidism and amlodipine 5 mg/d for hypertension. She started treatment with the somatostatin analogue octreotide acetate 20 mg every 4 weeks, which was then adjusted to 30 mg. Treatment was associated with only partial suppression of insulinlike growth factor-1 concentrations (from 980 ng/mL to 352, 632, and 480 ng/mL at 3, 6, and 9 months, respectively). At this point, octreotide was discontinued and treatment was initiated with pegvisomant 10 mg/d SC. This treatment was initially well tolerated, but after 11 days, she developed an intense erythematous pruriginous reaction at the injection site accompanied by fever (39 degrees C) for 48 hours and, simultaneously, similar lesions at each site of the previous injections. Pegvisomant was discontinued and methylprednisolone 40 mg/d was started, followed by complete disappearance of the lesions in 5 days. Based on the Naranjo algorithm, the adverse reaction observed was probably related to pegvisomant treatment (score = 6). CONCLUSIONS We report a patient with acromegaly who developed a skin reaction and fever probably associated with pegvisomant administration. The reaction subsided 5 days after the drug was discontinued and methylprednisolone treatment was given.