Ignacio Bernabeu

High prevalence of AIP gene mutations following focused screening in young patients with sporadic pituitary macroadenomas

BACKGROUND Aryl hydrocarbon receptor interacting protein (AIP) mutations (AIPmut) cause aggressive pituitary adenomas in young patients, usually in the setting of familial isolated pituitary adenomas. The prevalence of AIPmut among sporadic pituitary adenoma patients appears to be low; studies have not addressed prevalence in the most clinically relevant population. Hence, we undertook an international, multicenter, prospective genetic, and clinical analysis at 21 tertiary referral endocrine departments. METHODS We included 163 sporadic pituitary macroadenoma patients irrespective of clinical phenotype diagnosed at <30 years of age. RESULTS Overall, 19/163 (11.7%) patients had germline AIPmut; a further nine patients had sequence changes of uncertain significance or polymorphisms. AIPmut were identified in 8/39 (20.5%) pediatric patients. Ten AIPmut were identified in 11/83 (13.3%) sporadic somatotropinoma patients, in 7/61 (11.5%) prolactinoma patients, and in 1/16 non-functioning pituitary adenoma patients. Large genetic deletions were not seen using multiplex ligation-dependent probe amplification. Familial screening was possible in the relatives of seven patients with AIPmut and carriers were found in six of the seven families. In total, pituitary adenomas were diagnosed in 2/21 AIPmut-screened carriers; both had asymptomatic microadenomas. CONCLUSION Germline AIPmut occur in 11.7% of patients <30 years with sporadic pituitary macroadenomas and in 20.5% of pediatric patients. AIPmut mutation testing in this population should be considered in order to optimize clinical genetic investigation and management.

The Exon 3-Deleted Growth Hormone Receptor Is Associated with Better Response to Pegvisomant Therapy in Acromegaly

CONTEXT The deletion of exon 3 in the GH receptor (GHR) has been associated with a different biochemical picture and response to therapy in acromegaly. OBJECTIVE The aim of the study was to determine whether or not the GHR genotype influences the efficacy of pegvisomant treatment. DESIGN AND SETTING A cross-sectional study was conducted in six Spanish university hospitals. PATIENTS Forty-four acromegalic patients with active disease and resistance to somatostatin analogs participated in the study. RESULTS The prevalence of the full-length GHR and the exon 3-deleted GHR homozygous and heterozygous genotypes was 41, 2, and 57%, respectively. There were no differences in IGF-I or GH pre-pegvisomant levels related to GHR genotype. The exon 3-deleted patients required approximately 20% lower doses of pegvisomant per kilogram of weight (28 +/- 11 compared to 22 +/- 7 mg per kg of weight; P = 0.033) to normalize IGF-I. A stepwise multivariate linear regression analysis (R(2) = 0.27; P = 0.003) identified male gender (beta = -0.79; P = 0.03) and d3-GHR genotype (beta = -0.64; P = 0.007) as the only significant predictors of the dose of pegvisomant per kilogram of weight. In addition, d3-GHR carriers required fewer months for IGF-I normalization (P < 0.01). A stepwise multivariate linear regression analysis (R(2) = 0.40; P = 0.001) revealed that the only significant predictor of the time to IGF-I normalization was the dose of pegvisomant per kilogram of weight (beta = 0.451; P = 0.001). CONCLUSIONS The exon 3 deletion in the GHR predicts an improved response to pegvisomant therapy in acromegaly.

Long-term treatment of acromegalic patients resistant to somatostatin analogues with the GH receptor antagonist pegvisomant: its efficacy in relation to gender and previous radiotherapy

CONTEXT Pegvisomant is an effective treatment for somatostatin analogue-resistant acromegaly, but the determinants defining the response to this treatment are largely unknown. OBJECTIVE To investigate the efficacy of pegvisomant treatment in resistant acromegalic patients (e.g. serum IGF1 at least 1.25 x upper normal limit) in a clinical setting and the factors conditioning this response. DESIGN AND SETTING A retrospective cross-sectional study performed in six Spanish University hospitals from 2004 to 2007. Patients Forty-four acromegalic patients (61.4% female, mean age: 49+/-14), 95% of whom had undergone pituitary surgery and 61% having received pituitary radiotherapy. The mean follow-up was 22.7+/-11.2 months. Main outcome measures IGF1 levels reflected treatment efficacy, and the influence of gender, age, weight, previous radiotherapy and duration of treatment was assessed. RESULTS IGF1 normalisation was achieved in 84% of the patients. Male gender (P<0.05), previous irradiation (P<0.05) and the treatment duration (r=0.364, P<0.02) were associated with a better response to pegvisomant therapy. There was a significant decrease in HbA1c (P<0.001) and in the mean insulin dose (P<0.01) in acromegalic diabetic patients. Although 25% of patients experienced mild adverse events, pegvisomant was only withdrawn in four patients due to side effects (two cases of tumour growth, one liver dysfunction and one headache). CONCLUSIONS Long-term pegvisomant is a very effective therapy in resistant acromegaly. Male gender and prior radiotherapy influence the therapeutic response rate.

Coadministration of lanreotide Autogel and pegvisomant normalizes IGF1 levels and is well tolerated in patients with acromegaly partially controlled by somatostatin analogs alone

OBJECTIVE To evaluate the efficacy and safety of coadministered lanreotide Autogel (LA; 120  mg/month) and pegvisomant (40-120  mg/week) in acromegaly. DESIGN This is a 28-week, multicenter, open-label, single-arm sequential study. METHODS Patients (n=92) biochemically uncontrolled, on somatostatin analogs (SSAs) or using pegvisomant monotherapy entered a 4-month run-in taking LA (120  mg/month). Patients uncontrolled after the run-in period (n=57) entered a 28-week coadministration period, receiving LA 120  mg/month plus pegvisomant (60  mg once weekly, adapted every 8 weeks based on IGF1 levels to 40-80  mg once weekly or 40 or 60  mg twice weekly). RESULTS In total, 33 (57.9%) patients had normalized IGF1 following coadministration (P<0.0001 versus 30% minimum clinically relevant); median pegvisomant dose in normalized patients was 60  mg/week. IGF1 normalized at any time during coadministration in 45 (78.9%) patients (P<0.0001) with median pegvisomant dose at 60  mg/week. Being nondiabetic (odds ratio (OR): 4.65) and older (OR, upper versus lower quartile: 3.40) showed increased likelihood of normalization. Symptom reduction was greatest for arthralgia (-0.6 ± 1.6) and soft tissue swelling (-0.6 ± 1.8). Five patients reported treatment-emergent adverse events causing treatment withdrawal: three serious (treatment related - thrombocytopenia, urticaria; not treatment related - abdominal pain/vomiting) and two nonserious (hepatotoxicity and cytolytic hepatitis, both elevating alanine aminotransferase to >5 × upper limit of normal with normalization after withdrawal). CONCLUSIONS In patients partially controlled by SSAs, LA (120  mg/month) plus pegvisomant normalized IGF1 in 57.9% of patients after 7 months, at a median effective pegvisomant dose of 60  mg/week, and 78.9% at any time. In these patients, results suggest a pegvisomant-sparing effect versus daily pegvisomant monotherapy.

Somatotroph Tumor Progression during Pegvisomant Therapy: A Clinical and Molecular Study

CONTEXT There is concern that pegvisomant could be associated with a higher risk of tumor growth. The rate and possible determinants of this tumor growth are unknown. OBJECTIVE The objective of the study was to investigate the clinical, immunohistological, and molecular factors conditioning tumor growth in patients taking pegvisomant. DESIGN AND SETTING This was a cross-sectional study performed from 2004 to 2010 in four university hospitals in Spain. PATIENTS Seventy-five acromegalic patients with active disease resistant to somatostatin analogs treated with pegvisomant were followed up for a mean of 29 ± 20 months. MAIN OUTCOME MEASURES Magnetic resonance images before initiation of pegvisomant, at 6 months, and then yearly were examined in all patients. Immunohistological and molecular studies were performed in tumors that grew. RESULTS A significant increase in tumor size was observed in five patients (6.7%). Absence of previous irradiation (P = 0.014) and shorter duration of prepegvisomant somatostatin analog therapy (P < 0.001) were associated with an increased risk of tumor growth. A stepwise multivariate linear regression analysis (R(2) = 0.334, P < 0.001) identified the duration of somatostatin analog therapy prior to pegvisomant (beta = -4.509, P = 0.014) as the only significant predictor of tumor growth. In those tumors that grew, GH expression and insulin receptor expression were higher (P = 0.033 in both cases) than in the control group. CONCLUSIONS No previous radiotherapy, shorter duration of prepegvisomant somatostatin analog therapy, and higher tumor expression of GH and insulin receptor could be risk factors for tumor growth during pegvisomant therapy.

Cabergoline treatment in acromegaly: pros

Many options are available for the treatment of acromegaly, including surgery, radiotherapy, and medical treatment. Cabergoline (CAB), a dopamine agonist with high affinity for dopamine receptor type 2, has been used both in monotherapy and in conjunction with somatostatin analogs (SSAs). Although it is administered orally and has a relatively lower-cost in comparison with SSAs, few studies have demonstrated its usefulness, there is a lack of randomized-controlled trials and other drugs (SSAs and pegvisomant) with more data in the literature are available; these issues are the main drawbacks of adopting CAB for the treatment of acromegaly.

Pituitary Stalk Dysgenesis-Induced Hypopituitarism in Adult Patients: Prevalence, Evolution of Hormone Dysfunction and Genetic Analysis

Objectives: To investigate the prevalence of pituitary stalk dysgenesis (PSD) in adult hypopituitary patients by describing the chronology of hormone deficiencies and their potential correlation with traumatic delivery, mutations in genes required for pituitary development and function and pituitary stalk visibility on MRI. Design: Retrospective and prospective study involving 231 hypopituitary patients, including 26 diagnosed with PSD. Clinical, biochemical and radiological studies were reviewed. Molecular analyses of HESX1, LHX4,PROP1 and POU1F1 genes were performed prospectively. Results: PSD was present in 11.2% of hypopituitary patients. PSD was diagnosed before 14 years of age in 46.2% of cases, between 14 and 18 years of age in 23%, and in adulthood in 30.8%. Perinatal complications or gene mutations were present in 26.9 and 4.3% of patients, respectively. At first assessment, 92.3% of patients had growth hormone (GH) deficiency. 26.9% presented as combined pituitary deficiencies and 7.6% as panhypopituitarism. Hormone deficiencies were progressive during follow-up in 84.6%. 96% progressed to multiple deficiencies and 46% to panhypopituitarism. No significant association was found between hormonal dysfunction and previous perinatal damage or breech delivery (p = 0.17), PROP1 mutations (p = 0.26) or pituitary stalk visibility on MRI (p = 0.52). No mutations in POU1F1, HESX1 and LHX-4 genes were detected. Conclusion: In this study, PSD prevalence in adult hypopituitary patients was 11.2%. Typical clinical presentation includes isolated or combined pituitary hormone deficiencies during the pediatric age, which usually progress to combined or complete hypopituitarism in adulthood. Phenotype is highly variable depending on hormone profile and age at onset.

Epidemiology, mortality rate and survival in a homogeneous population of hypopituitary patients

Hypopituitarism is associated with higher prevalence of cardiovascular risk factors and premature death. Furthermore, some clinical and therapeutic features of hypopituitarism have been associated with a worse prognosis.

Hypopituitarism following traumatic brain injury: determining factors for diagnosis.

Neuroendocrine dysfunction, long recognized as a consequence of traumatic brain injury (TBI), is a major cause of disability that includes physical and psychological involvement with long-term cognitive, behavioral, and social changes. There is no standard procedure regarding at what time after trauma the diagnosis should be made. Also there is uncertainty on defining the best methods for diagnosis and testing and what types of patients should be selected for screening. Common criteria for evaluating these patients are required on account of the high prevalence of TBI worldwide and the potential new cases of hypopituitarism. The aim of this review is to clarify, based on the evidence, when endocrine assessment should be performed after TBI and which patients should be evaluated. Additional studies are still needed to know the impact of post-traumatic hypopituitarism and to assess the impact of hormone replacement in the prognosis.

Pegvisomant-induced cholestatic hepatitis with jaundice in a patient with Gilbert's syndrome

We report on a patient with active acromegaly and Gilberts syndrome who developed severe hepatic dysfunction during pegvisomant (PEGv) monotherapy. She was partially resistant to all previous therapies, including long-acting somatostatin analogs and cabergoline. Five months after starting PEGv therapy, with an already normalized IGF1, she developed cholestatic liver dysfunction with jaundice. Liver or biliary diseases including biliary sludge, cholelithiasis or liver steatosis were excluded. A liver biopsy was in keeping with drug-induced liver injury. The discontinuation of PEGv was followed by full clinical and biochemical recovery in 6 weeks. PEGv therapy was not resumed. Apart from a minimal increase of bilirubin levels, no liver function test abnormalities were found during the 4-year follow-up period after the PEGv was discontinued. Drug-induced liver injury is the most serious systemic adverse event resulting from PEGv therapy. Since patients with mild and asymptomatic liver disease could be at a higher risk of PEGv-induced hepatotoxicity, frequent monitoring of hepatic enzymes should be required in these cases.