Combined treatment with octreotide LAR and pegvisomant in patients with pituitary gigantism: clinical evaluation and genetic screening.

INTRODUCTION: Pituitary gigantism is a rare condition caused by growth hormone secreting hypersecretion, usually by a pituitary tumor. Acromegaly and gigantism cases that have a genetic cause are challenging to treat, due to large tumor size and poor responses to some medical therapies (e.g. AIP mutation affected cases and those with X-linked acrogigantism syndrome). MATERIALS AND METHODS: We performed a retrospective study to identify gigantism cases among 160 somatotropinoma patients treated between 1985 and 2015 at the University Hospital of Caracas, Venezuela. We studied clinical details at diagnosis, hormonal responses to therapy and undertook targeted genetic testing. Among the 160 cases, eight patients (six males; 75 %) were diagnosed with pituitary gigantism and underwent genetic analysis that included array comparative genome hybridization for Xq26.3 duplications. RESULTS: All patients had GH secreting pituitary macroadenomas that were difficult to control with conventional treatment options, such as surgery or primary somatostatin receptor ligand (SRL) therapy. Combined therapy (long-acting SRL and pegvisomant) as primary treatment or after pituitary surgery and radiotherapy permitted the normalization of IGF-1 levels and clinical improvement. Novel AIP mutations were the found in three patients. None of the patients had Xq26.3 microduplications. CONCLUSIONS: Treatment of pituitary gigantism is frequently challenging; delayed control increases the harmful effects of GH excess, such as, excessive stature and symptom burden, so early diagnosis and effective treatment are particularly important in these cases.

Biochemical and quality of life responses to octreotide-LAR in acromegaly.

OBJECTIVES: AcroQoL is a questionnaire developed to assess quality of life in patients with acromegaly, covering physical and psychological dimensions. This study was designed to determine AcroQoL score changes and concentrations of growth hormone (GH) and insulin-like growth factor 1 (IGF-1), before and after treatment with octreotide-LAR (oct-LAR) in acromegaly. METHODS: Retrospective observational study of 28 acromegalic patients with a mean age of 45 years (range 28-64), evaluated over a 4-year period, before and during treatment with oct-LAR in clinical practice conditions. RESULTS: Baseline AcroQoL score (53 ± 15) improved after oct-LAR treatment (70 ± 15) globally for the 28 patients (p < 0.001). Three patients in whom AcroQoL score did not improve over time had severe headaches, which did not disappear. In patients who normalized, both GH (<2.5 µg/L) and IGF-1, AcroQoL score increased on average by 22 points (p = 0.003); when GH and IGF-1 improved, but did not normalize, AcroQol score increased on average by 16 points (p = 0.008). In 6 patients with discordant results, AcroQol score tended to improve if IGF-1 normalized (n = 4, p = 0.066), but not if IGF-1 remained high. CONCLUSION: Oct-LAR therapy in acromegaly improved quality of life scores in parallel to biochemical markers, except in patients with severe headaches. The AcroQoL questionnaire is an additional tool to establish therapeutic effectivity.

A practical approach to acromegaly management in Latin America.

INTRODUCTION: Evidence-based treatment guidelines have undoubtedly advanced medical practice and supported optimal management of acromegaly, but their application may be hampered by limited access to the latest treatment options. METHODS: In this retrospective, narrative review, the authors revisited existing treatment guidelines for acromegaly in Latin America. These were considered in conjunction with published evidence chosen at the authors' discretion. FINDINGS: In a socially and economically diverse region, such as Latin America, any regional practice guidelines need to appreciate that recommended treatment options, such as surgery by expert pituitary surgical teams and drug therapies, especially somatostatin analogs, are often not available due to limited resources. In these instances, physicians may be obliged to apply less effective therapeutic options. CONCLUSIONS: The current article looks at the practical aspects of acromegaly management in Latin America and discusses this in the context of existing guidelines. Furthermore, we consider potential strategies to make better use of resources through combination and multimodal approaches to treatment.

Management of acromegaly in Latin America: expert panel recommendations.

Although there are international guidelines orienting physicians on how to manage patients with acromegaly, such guidelines should be adapted for use in distinct regions of the world. A panel of neuroendocrinologists convened in Mexico City in August of 2007 to discuss specific considerations in Latin America. Of major discussion was the laboratory evaluation of acromegaly, which requires the use of appropriate tests and the adoption of local institutional standards. As a general rule to ensure diagnosis, the patient's GH level during an oral glucose tolerance test and IGF-1 level should be evaluated. Furthermore, to guide treatment decisions, both GH and IGF-1 assessments are required. The treatment of patients with acromegaly in Latin America is influenced by local issues of cost, availability and expertise of pituitary neurosurgeons, which should dictate therapeutic choices. Such treatment has undergone profound changes because of the introduction of effective medical interventions that may be used after surgical debulking or as first-line medical therapy in selected cases. Surgical resection remains the mainstay of therapy for small pituitary adenomas (microadenomas), potentially resectable macroadenomas and invasive adenomas causing visual defects. Radiotherapy may be indicated in selected cases when no disease control is achieved despite optimal surgical debulking and medical therapy, when there is no access to somatostatin analogues, or when local issues of cost preclude other therapies. Since not all the diagnostic tools and treatment options are available in all Latin American countries, physicians need to adapt their clinical management decisions to the available local resources and therapeutic options.

Primary hypertrophic osteoarthropathy due to a novel SLCO2A1 mutation masquerading as acromegaly.

SUMMARY: A 20-year-old man with an 8-year history of progressive enlargement of his hands and feet, coarsening facial features, painful joints and thickened, oily skin was referred for investigation of acromegaly. On examination, the subject was of normal height and weight. He had markedly increased skin thickness around the forehead, eyelids and scalp with redundant skin folds. Bilateral painful knee swelling was accompanied by enlargement of the extremities, and his fingers were markedly clubbed. Routine hematological, biochemical and hormonal blood tests, including GH and IGF-1 were normal. The clinical picture suggested primary hypertrophic osteoarthropathy (PHOA) rather than acromegaly and radiological studies were supportive of this, demonstrating increased subperiosteal bone formation and increased bone density and cortical thickening. There was widespread joint disease, with narrowing of joint spaces, whereas the knees demonstrated effusions and calcification. A skull X-ray revealed calvarial hyperostosis and a normal sellar outline. Family history was negative. Genetic studies were performed on peripheral blood leukocyte DNA for mutations in the two genes associated with PHOA, 15-hydroxyprostaglandin dehydrogenase (HPGD; OMIM: 601688) and solute carrier organic anion transporter family member 2A1 (SLCO2A1; OMIM: 601460). The sequence of HPGD was normal, whereas the subject was homozygous for a novel pathological variant in SLCO2A1, c.830delT, that predicted a frameshift and early protein truncation (p.Phe277Serfs*8). PHOA, also known as pachydermoperiostosis, is a rare entity caused by abnormal prostaglandin E2 metabolism, and both HPGD and SLCO2A1 are necessary for normal prostaglandin E2 handling. High prostaglandin levels lead to bone formation and resorption and connective tissue inflammation causing arthropathy, in addition to soft tissue swelling. LEARNING POINTS: The differential diagnosis of enlarged extremities, coarsened facial features, skin changes and increased sweating in suspected acromegaly is quite limited and primary hypertrophic osteoarthropathy (PHOA) is one of the few conditions that can mimic acromegaly at presentation.PHOA is not associated with abnormalities in GH and IGF-1 secretion and can be readily differentiated from acromegaly by hormonal testing.Clubbing in the setting of diffuse enlargement of joints and extremities in addition to skin changes should alert the physician to the possibility of PHOA, as clubbing is not a usual feature of acromegaly. Underlying causes of secondary hypertrophic osteoarthroapthy (e.g. bronchial neoplasia) should be considered.PHOA is a very rare condition caused by abnormalities in prostaglandin metabolism and has two known genetic causes (HPGD and SLCO2A1 mutations). SLCO2A1 gene mutations lead usually to autosomal recessive PHOA; fewer than 50 SLCO2A1 mutations have been described to date and the current case is only the second in a Hispanic patient.Treatment of primary hypertrophic osteoarthropathy is focused on the management of joint pain usually in the form of non-steroidal anti-inflammatory drug therapy.

Improvement of acromegaly after octreotide LAR treatment.

Octreotide is a somatostatin analog that inhibits growth hormone release showing higher potency than natural somatostatin so it has proved to be effective in acromegaly treatment. The objective of present study was to establish the effects of octreotide LAR (long acting release) preparation in patients with active acromegaly. The following parameters were assessed: clinical response, safety of medication, GH and IGF-1 serum concentrations and pituitary tumor size. Eleven patients (6 men and 5 women) range 41.4 years old with diagnosis of active acromegaly were included. Octreotide was administered at 0.1 mg subcutaneusly dose three times daily for four weeks to test the drug tolerability. Afterwards patients received octreotide LAR 20 mg intramuscularly separated by 28 days periods with an option to continue for 8 months. Basal average GH serum concentrations was 27.6 ng/mL. After 6 months treatment reduction to 5.03 +/- 5.38 ng/mL in 9 patients (p < 0.001) was observed. Basal IGF-1 average serum concentration was 889.55 +/- 167.29 ng/mL with a reduction value to 483.00 +/- 239.71 ng/mL in 9 of 11 patients after 6 months treatment (p < 0.005). The drug was well tolerated with few adverse effects Diarrhea, flatulence and steatorrhea were observed during the administration of subcutaneous octreotide in 18.2% of patients. Two patients had symptomatic biliary lithiasis that was successfully removed by surgery. Clinical symptoms improved and some of them dissapeared such as headaches and sweatings. Tumor shrinkage was observed in 66.7% of cases. Monthly injections of 20 mg of octreotide LAR were effective to reduce GH and IGF-1 levels in patients with active acromegaly accompanied by improvement of clinical symptoms and significant tumor size reduction.

Tratamiento de los prolactinomas y tumores secretores de hormona de crecimiento

Los adenomas hipofisarios representan el 10% de todos los tumores intracraneales diagnosticados y 25% de los tumores cerebrales que son intervenidos quirúrgicamente. Los objetivos del tratamiento de un paciente con un adenoma de la pituitaria son: eliminar el efecto de la masa tumoral (compresión sobre estructuras vecinas) disminuir la producción excesiva de hormonas, restaurar la función normal de la pituitaria y evitar la recurrencia. El tratamiento de elección para todos los prolactinomas es con un agonista de la dopamina. La bromocriptina y la cabergolina son efectivas para reducir el tamaño del tumor y para restaurar la función gonadal. El tratamiento quirúrgico debe recomendarse sólo cuando falla el tratamiento médico. Los tumores de la pituitaria productores de hormona de crecimiento son tratados preferentemente mediante adenomectomía transesfenoidal, pero la normalización de los niveles de HC y de IGF-1 ocurre en menos de la mitad de los pacientes con macroadenomas; por lo tanto, un importante número de pacientes acromegálicos requiere un tratamiento adicional. Los análogos de la somatostatina son en la actualidad los medicamentos que más usados para el control de la acromegalia. En grupos especiales de pacientes, el tratamiento con agonistas de la dopamina y somatostatina parece que suprimen mejor los niveles de HC que cuando se administran esos fármacos en forma separada. El Pegvisomant, un antagonista del receptor de la HC promete lograr un alto porcentaje de normalización de la IGF-1 en pacientes con acromegalia.

Pituitary adenomas represent 10% of all the diagnosed intracraneal tumors, and 25% of the surgically treated brain tumors. The goals of treatment in a patient with a pituitary adenoma include elimination of the mass effect, lowering excessive hormone production, restoration of normal pituitary function, and prevention of recurrence. The primary therapy for all prolactinomas is a dopamine agonist. Bromocriptine and cabergoline are both effective in reducing the size of the tumor and restoring gonadal funtion. Surgery should be recommended only when medical therapy have failed. Growth hormone secreting pituitary tumors are usually treated first with surgical resection by a transphenoidal adenomectomy, but strict normalization of HC and IGF-1 values occur in less than half of patients with a macroadenoma, therefore a substantial number of acromegalic patients require aditional therapy. Somatostatin analogs are at present the most widely used drugs for control of acromegaly with excellent results. In selected patients combined treatment with dopamine agonist and somatostatin seems to suppress HC levels better than either drug given separately. Pegvisomant is a HC receptor antagonist that promises a very high HC rate of normalization of IGF-1 in patients with acromegaly.

Tumores de hipófisis / Hypophyseal tumours

Los recientes avances en biología molecular, radioinmunoánalisis, neuroradiología y microcirugía transesfenoidal, han incrementado en forma importante nuestros conocimientos a cerca de la fisiopatología de los tumores hipofisarios, permitiéndonos hacer un diagnóstico más preciso y tratamiento acertado de esta entidad. A veces defectos en la regulación hipotalámica contribuyen a la tumorogénesis y resultan en recurrencia o persistencia del tumor a pesar de haberse practicado cirugía con resección total de adenoma. En este trabajo se analizarán en varios capítulos los aspectos clínicos, diagnóstico y terapéutica de los tumores hipofísarios más frecuentes.

Tumores de hipófisis / Tumors of the pituitary gland

La acromegalia es una patología producida por hipersecreción de hormona de crecimiento, generalmente debida a un adenoma hipofisario, y muy raras veces resultante de la secreción ectópica de GRH o GH. Las manifestaciones clínicas se traducen en agrandamiento acral, intolerancia a la glucosa, hipertensión, artropatía y enfermedad cardiovascular como las más importates. El compromiso visual e hipopituitarismo se relacionan con el efecto de masa producido por el tumor. La morbilidad y mortalidad asociadas a esta enfermedad son importantes, por lo cual se debe tratar de realizar diagnóstico y terapéutica precoces. La cirugía transesfenoidal y las nuevas drogas, son nuestras principales armas en el tratamiento de la acromegalia. La radioterapia puede utilizarse como adyuvante, pero sabiendo que su efecto debemos esperarlo a largo plazo

El prolactinoma en pacientes masculinos: estudio de seis (6) casos / Prolactinomas in male patients: study of 6 cases

Se presentan 6 casos de adenomas hipofisarios secretores de Prolactina (Prl) en hombres con disfuncion sexual, disminucion de agudeza visual, y niveles de (Prl) mayores de 160 ng-dl con niveles bajos de Testosterona. Estos fueron comprobados por Tomografia Axial Computada y por cirugia transesfenoidal o transfrontal y posteriormente por histologia e inmuno-histoquimica. La recuperación posterior fue pobre, pero los sintomas oculares regresaron casi totalmente. En conclusion, el diagnóstico precoz del sindrome hiperprolactinemico en hombres, caracterizado por disminución de la libido e impotencia, puede conducir a curación si no se les deja llegar a desarrollar grandes tumores que compriman las estructuras vecinas

Tumores de hipófisis: enfoque clínico y terapéutico / Pituitary gland tumores: clinic and therapeutic focusing

El diagnóstico y clasificación de los adenomas hipofisarios constituye un trabajo de equipo, en el cual participan todos los especialistas comprometidos en el estudio y tratamiento de dichos tumores. Las muestras de tejido de los adenomas hipofisarios deben ser distribuidos equitativamente y fijadas en solución adecuadas, de modo que se puedan realizar los estudio histológicos, histoquimico y ultraestructural. La clasificación tradicional de los adenomas hipofisarios, basados en las propiedades tutoriales de sus células ha sido substituida por esquemas basadas en criterios funcionales, que permiten establecer correlaciones anatomo-clínicas y consideraciones terapéuticas y pronósticos. El diagnóstico de carcinoma hipofisario se debe reservar para aquellos tumores derivados de células de la adenohipófisis capaces de dar metástasis a distancia. La incorporación de novedosas técnicas de biología molecular, como la hibridizaciónin situ, al estudio de los adenomas hipofisarios, está ayudando a esclarecer aspectos oscuros, como es el "enigma" relativo a la naturaleza de los adenomas de células nulas