Eva Fernandez-Rodriguez

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.

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.

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.

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.

Hypopituitarism After Traumatic Brain Injury

The prevalence of hypopituitarism after traumatic brain (TBI) injury is widely variable in the literature; a meta-analysis determined a pooled prevalence of anterior hypopituitarism of 27.5%. Growth hormone deficiency is the most prevalent hormone insufficiency after TBI; however, the prevalence of each type of pituitary deficiency is influenced by the assays used for diagnosis, severity of head trauma, and time of evaluation. Recent studies have demonstrated improvement in cognitive function and cognitive quality of life with substitution therapy in GH-deficient patients after TBI.

Update on prognostic factors in acromegaly: Is a risk score possible?

Certain clinical conditions and markers have recently been demonstrated to modify the natural history of acromegaly in affected patients. Thus, some clinical, histological, radiological and molecular factors are associated with more aggressive pituitary tumors that have higher biochemical activity, higher tumor volumes and decreased tumoral and biochemical responses to current therapies. However, these factors do not seem to have an equal influence on the prognosis of patients with acromegaly. We present a review of the factors that influence the clinical course of patients with acromegaly and propose a risk value for each factor that will allow prognostic scoring for affected patients by considering a combination of these factors.

Severe hypertension and hypokalemia as first clinical manifestations in ectopic Cushing's syndrome

Ectopic ACTH production occurs in about 10% of all cases of Cushings syndrome, and about 25% of cases of ACTH-dependent Cushings syndrome. Diverse tumor types are able to produce ACTH ectopically, including small cell lung carcinoma. Ectopic ACTH secretion by malignant neoplasm has been reported to have earlier and more aggressive metabolic effects. We report a 59-year-old male patient with severe hypertension, metabolic alkalosis and hypokalemia as the first clinical manifestations of an ACTH-secreting small cell lung carcinoma, although the typical phenotypic features of Cushings syndrome were not present. Ectopic Cushings syndrome should always be ruled out in patients with severe hypertension and hypokalemia.

Documento de consenso del área de conocimiento de Neuroendocrinología de la Sociedad Española de Endocrinología y Nutrición para el abordaje del hipopituitarismo durante la transición

The transition period from child to adult represents a crucial phase in the growth process where multiple physical and psychosocial changes occur. It has been arbitrarily defined as the period extending from late puberty to full adult maturity (i.e., from mid to late teenage years until 6-7 years after achievement of final height). The aim of this guideline is to emphasize the importance of adequate hormone replacement during this period and to review reassessment of pituitary function. In patients with GH deficiency diagnosed in childhood, an attempt is made to answer when to retest GH secretion, when to treat and how they should be monitored. Thyroxine, glucocorticoid, and sex steroid replacement are also reviewed.

Nell’acromegalia la delezione dell’esone 3 del recettore del GH si associa a una migliore risposta alla terapia con pegvisomant

RiassuntoNei pazienti acromegalici la delezione genomica dell’esone 3 a livello del recettore del GH (GHR) è stata associata a un differente quadro biochimico e a una differente risposta alla terapia. Lo scopo di questo studio è stato quello di valutare se i diversi genotipi del GHR influenzino l’efficacia della terapia con pegvisomant. Sono stati studiati 44 pazienti acromegalici con malattia attiva e resistenti alla terapia con analoghi della somatostatina.RisultatiLa prevalenza dei pazienti con mancata delezione dell’esone 3 del GHR (fl-GHR) e quelli con genotipo omozigote o eterozigote per tale delezione (d3-GHR) era rispettivamente del 41, 2 e 57%. Non sono state osservate differenze nei livelli di GH e IGF-1 prima della terapia con pegvisomant in relazione alle varianti polimorfiche del GHR. I pazienti con delezione dell’esone 3 richiedevano una dose di pegvisomant di circa il 20% più bassa e minor tempo per normalizzare i livelli di IGF-1. L’analisi di regressione lineare multipla ha individuato come unici predittori significativi della dose di pegvisomant il sesso maschile e la delezione dell’esone 3 del GHR e come unico predittore del tempo di normalizzazione dell’IGF-1 la dose di pegvisomant utilizzata.In conclusione, la delezione dell’esone 3 del recettore del GH sembra predire una migliore risposta alla terapia con pegvisomant nei pazienti acromegalici.