Correlation analysis between short-term insulin-like growth factor-I and glucose intolerance status after transsphenoidal adenomectomy in acromegalic patients: a large retrospective study from a single center in China

ABSTRACT Objectives: Our study aimed to investigate the associations of glucose tolerance status with insulin-like growth factor-I (IGF-I) and other clinical laboratory parameters of acromegalic patients before and after the patients underwent transsphenoidal adenomectomy (TSA) by conducting a single-center, retrospective study. Subjects and methods: A total of 218 patients with acromegaly who had undergone TSA as the first treatment were retrospectively analyzed. Serum IGF-I, growth hormone (GH) and glucose levels were measured before and after surgery. Results: The follow-up levels for random GH, GH nadir, and the percentage of the upper limit of normal IGF-I (%ULN IGF-I) were decreased significantly. The percentages of normal (39.0%), early carbohydrate metabolism disorders (33.0%) and diabetes mellitus (28.0%) changed to 70.2%, 16.5% and 13.3%, respectively, after TSA. %ULN IGF-I at baseline was higher in the diabetes mellitus (DM) group than in the normal glucose tolerance group and impaired glucose tolerance (IGT) /impaired fasting glucose (IFG) groups before TSA, and the DM group exhibited a greater reduction in %ULN IGF-I value after surgery. The follow-up %ULN IGF-I value after surgery was significantly lower in the improved group, and Pearson's correlation analysis revealed that the reductions in %ULN IGF-I corresponded with the reductions in glucose level. Conclusion: This study examined the largest reported sample with complete preoperative and follow-up data. The results suggest that the age- and sex-adjusted IGF-I level, which reflects altered glucose metabolism, and the change of it are associated with improved glucose tolerance in acromegalic patients both before and after TSA.

Long term follow-up of growth hormone-secreting pituitary adenomas submitted to endoscopic endonasal surgery / Seguimento de longo prazo de adenomas hipofisários secretores do hormônio do crescimento submetidos à cirurgia endoscópica endonasal

ABSTRACT Objective The aim of this study was to evaluate the results of the endoscopic transsphenoidal technique for growth hormone (GH)-secreting adenomas. Methods A retrospective analysis based on medical records of 23 acromegalic patients submitted to endoscopic transsphenoidal surgery. Biochemical control was defined as basal GH < 1ng/ml, nadir GH < 0.4ng/ml after glucose load and age-adjusted IGF-1 normal at the last follow-up. Results The overall endocrinological remission rate was 39.1%. While all microademonas achieved a cure, just one third of macroadenomas went into remission. Suprasellar extension, cavernous sinus invasion and high GH levels were associated with lower rates of disease control. The most common complication was diabetes insipidus and the most severe was an ischemic stroke. Conclusion The endoscopic transsphenoidal approach is a safe and effective technique to control GH-secreting adenomas. The transcavernous approach may increase the risk of complications. Suprasellar and cavernous sinus extensions may preclude gross total resection of these tumors.

RESUMO Objetivo O objetivo do estudo é analisar os resultados da cirurgia de ressecção endoscópica transesfenoidal para adenomas secretores do hormônio do crescimento (GH). Métodos Revisão retrospectiva baseada em análise de prontuários de 23 pacientes acromegálicos submetidos à cirurgia endoscópica. Remissão foi definida por GH < 1ng/ml, nadir de GH ≤ 0,4ng/ml no teste oral de tolerância a glicose e IGF-1 normal para idade. Resultados A taxa de remissão endocrinológica foi 39,1%. Enquanto todos microadenomas alcançaram controle hormonal, apenas um terço dos macroadenomas obtiveram remissão. Extensão suprasselar, invasão do seio cavernoso e altos níveis de GH foram associados a menores taxas de controle da doença. A complicação mais comum foi diabetes insipidus e a mais grave foi acidente vascular encefálico isquêmico. Conclusão A abordagem endoscópica transesfenoidal é segura e efetiva para controle de adenomas hipofisários secretores de GH. A abordagem ao seio cavernoso pode aumentar a morbidade da cirurgia. Extensões suprasselares e no seio cavernoso podem dificultar a ressecção completa e o controle da doença.

Treatment of acromegaly patients at the Federal University of Triângulo Mineiro (UFTM): Experience Report

OBJECTIVE: To evaluate the effectiveness of the treatment of acromegaly patients at the Federal University of Triangulo Mineiro. METHODS: Cross-sectional and retrospective study of thirty cases treated over a period of two decades. RESULTS: 17 men (56.7%) aged 14-67 years and 13 women aged 14-86 years were analyzed. Twenty-one patients underwent transphenoidal surgery, whichwas associated with somatostatin receptor ligands in 11 patients (39.3%), somatostatin receptor ligands + radiotherapyin 5 patients (17.8%), radiotherapy in 3 patients (10.7%), and radiotherapy + somatostatin receptorligands + cabergoline in 1 patient (3.6%). Additionally, 2 patients underwent radiotherapy and surgeryalone. Six patients received somatostatin receptor ligands before surgery, and 2 were not treated due to refusal and death. Nine patients have died, and 20 are being followed; 13 (65%) have growth hormonelevels o1 ng/mL, and 11 have normal insulin-like growth factor 1 levels. CONCLUSION: The current treatment options enable patients seen in regional reference centers to achieve strict control parameters, which allows them to be treated close to their homes.

Resultados de la cirugía de los somatotropinomas por acceso transnasal endoscópico usando la técnica de neuronavegación / Results of somatotropinoma surgery through endoscopic transnasal approach using the neuronavigation technique

Introducción: El tratamiento de elección para los tumores hipofisarios productores de hormona de crecimiento es la cirugía. El por ciento de recurrencia es elevado, pero, en gran medida, está en relación con la experiencia de los cirujanos, la técnica empleada y el trabajo multidisciplinario. Desde el año 2011 se constituyó un equipo multidisciplinario para guiar la conducta y el seguimiento de estos pacientes, que serían intervenidos empleando la técnica endoscópica con neuronavegación. Objetivo: describir los resultados de la cirugía de los adenomas hipofisarios productores de hormona de crecimiento con la técnica de neuronavegación. Métodos: estudio descriptivo que incluyó la revisión de las historias clínicas de 18 pacientes con tumores hipofisarios productores de la hormona de crecimiento, evaluados y remitidos para tratamiento quirúrgico endoscópico con neuronavegación. Las variables analizadas fueron: la edad, el sexo, la prueba de tolerancia a la glucosa para medir hormona de crecimiento antes y 7 días después de la cirugía, las características del tumor, las complicaciones posquirúrgicas y la evolución. Resultados: de los 18 casos, 66,6 por ciento eran del sexo masculino. El 33,4 por ciento tenía un tumor con crecimiento hacia el suelo de la silla turca, y las complicaciones posquirúrgicas fueron mínimas: el 16,7 por ciento presentó una diabetes insípida transitoria, e igual porcentaje una fístula de líquido cefalorraquídeo. En el 55 por ciento se identificó la remisión bioquímica a la semana de la intervención. Conclusiones: la cirugía de tumores hipofisarios productores de hormona de crecimiento empleando la técnica endoscópica con neuronavegador ofrece ventajas para los pacientes, con una evolución satisfactoria desde el punto de vista clínico y bioquímico, así como una baja frecuencia de complicaciones(AU)

Introduction: Treatment of choice for growth hormone-producing hypophysial tumors is surgery. The recurrence percentage is high but, to a great extent, is related to the surgeon´s experience, the surgical technique and the multidisciplinary work. Since 2011, a multidisciplinary team was created to guide the behavior and the follow-up of these patients who would be operated on by using the endoscopic technique based on the neuronavigation. Objective: to describe the results of the growth hormone-producing hypophysial adenomas surgery by using the neuronavigation technique. Methods: a descriptive study that included checking of the medical records of 18 patients diagnosed with growth hormone-producing hypophysial tumors and referred for endoscopic surgical treatment through neuronavigation. The analyzed variables were age, sex, tolerance test for glucose to measure growth hormone before and 7 days after surgery, the characteristics of the tumor, the postsurgical complications and the progress. Results: of this group of 18 patients, 66.6 percent were males 33.4 percent had tumors growing into the floor of the Turkish saddle and the postsurgical complications were minimal: 16.7 percent presented with transient diabetes insipidus and the same percentage had a cerebrospinal fluid fistula. Biochemical remission was detected in 55 percent of patients one week after the surgery. Conclusions: growth hormone-producing hypophysial tumors surgery using the endoscopic technique with neuronavigator provides advantages for patients, with satisfactory recovery from the clinical and biochemical viewpoint as well as low frequency of complications(AU)

Postoperative structural complications after microscopic transsphenoidal surgery of GH secreting pituitary adenomas / Complicações estruturais pós-operatórias após microcirurgia transesfenoidal de adenomas pituitários produtores de GH

Objective: Analyzing the rate of structural complications after transsphenoidal surgery for removal of growth hormone (GH) secreting pituitary adenomas. Methods: Retrospective study of 58 patients who underwent microscopic transsphenoidal neurosurgery for GH secreting pituitary adenomas exeresis in Curitiba, Parana state, Brazil, between 1998 and 2011 by the same neurosurgeon. The Criteria for diagnosis of complications were clinical. Results: Five (8,6%) of the 58 patients who underwent transsphenoidal surgery developed postoperative anatomical complications, which was due to sixth cranial nerve palsy (3,4%), surgical wound infection (1,7%) and CSF fistula (3,4%). Conclusion: The rate of postoperative complications observed in the present study is likely the literature review. There is a drop in the rate of complications with increasing experience of the neurosurgeon.

Objetivo: Analisar a taxa de complicações anatômicas após cirurgia transesfenoidal para remoção de adenoma hipofisário produtor de hormônio do crescimento (GH). Métodos: Estudo retrospectivo de 58 pacientes operados por microcirurgia transesfenoidal para exérese de adenomas pituitários produtores de GH em Curitiba, Paraná, Brasil, entre 1998 e 2011, realizados pelo mesmo neurocirurgião. Diagnóstico das complicações foi clínico. Resultados: Dos 58 pacientes submetidos à cirurgia transesfenoidal, 5 (8,6%) desenvolveram complicações anatômicas, 3,4% foram em decorrência de paresia temporária do sexto nervo craniano, 1,7%, de infecção da ferida operatória, e 3,4%, de fístula liquórica. Conclusão: A taxa de complicações pós-operatórias observada no presente estudo está semelhante à da revisão literária. Há uma queda no índice de complicações conforme aumenta a experiência do neurocirurgião.

Manejo multidisciplinario de la acromegalia / Multidisciplinary management of acromegaly

Acromegaly is a chronic disease caused in most cases by hypophysiary adenoma. It is of complex management due to the high variability of the causing lesion and its clinical repercussion. Surgical outcomes are poor with remission rates of 80 percent for microadenomas and 50 percent for macroadenomas. The author's experience in treating 38 patients with this pathology as well as the remission results of the illness and the complications are presented herein. Handling alternatives and associated complications are discussed and a clinical case is presented to show the therapeutical options in more complex cases.

La acromegalia es una enfermedad crónica causada en la mayoría de los casos por un adenoma hipofisario. Su manejo es complejo por la gran variabilidad de la lesión causante y su repercusión clínica. Los resultados quirúrgicos son pobres, con tasas de remisión de la enfermedad en promedio de un 80 por ciento en microadenomas y 50 por ciento en macroadenomas. Se presenta la experiencia del autor en el manejo de esta patología en 38 pacientes, los resultados de remisión de la enfermedad. Se discute las alternativas de manejo, complicaciones asociadas y se ilustra con un caso clínico para demostrar las opciones terapéuticas en los casos más complejos.

Adenomas hipofisarios en la infancia / Pituitary adenomas in childhood

Los adenomas hipofisarios son raros en la población pediátrica, constituyen menos del 3 por ciento de los tumores supratentoriales en el niño, con una incidencia anual de 0,1 por millón de niños. El objetivo de nuestro trabajo fue caracterizar el comportamiento de esta entidad, así como los resultados del tratamiento quirúrgico. Realizamos un estudio descriptivo retrospectivo en pacientes menores de 16 años, diagnosticados y tratados en nuestro centro, en el período comprendido entre Enero de 1991 y junio del 2010. Nuestra muestra quedó conformada por 6 pacientes, la edad promedio fue de 11 años, predominó el sexo femenino y la raza no tuvo predilección. Las alteraciones endocrinas fueron las formas más frecuentes de presentación. El diagnóstico imagenológico se realizó con la Tomografía Computarizada y la Resonancia Magnética Nuclear, en la valoración oftalmológica, la campimetría alcanzó una alta sensibilidad y desde el punto de vista hormonal, la prolactina y la GH fueron las comprometidas. Predominaron los macroadenomas y las lesiones funcionantes. Estas lesiones en su mayoría fueron intervenidas a través de abordajes frontopterional y transesfenoidales, nuestro grupo presentó dos complicaciones, una fístula de líquido cefalorraquídeo y un aracnoidocele. Predominaron los buenos resultados. No tuvimos fallecidos en relación con la cirugía.

Cura bioquímica en pacientes con adenomas de la hipófisis productores de hormona de crecimiento con tratamiento quirúrgico y radioterapéutico: experiencia de 7 años / Biochemical cure in patients with growth hormone-secreting pituitary adenoma treated with surgery and radiotherapy: 7 years experience

Introducción: Los adenomas de la hipófisis representan el 10 al 25 por ciento de las neoplasias intracraneales. La acromegalia es definida como el crecimiento anormal y exagerado de las extremidades, producido por la sobresecreción de hormona de crecimiento. Es una enfermedad rara con una prevalencia de 60 por millón y una incidencia de 3-4 nuevos casos por millón por año. Métodos: Se incluyeron 59 pacientes con diagnóstico de acromegalia, en el periodo de 2000-2007. Evaluamos la respuesta endocrinológica al tratamiento, basado en el análisis clínico, de imagen y bioquímica de GH e IGF-1. Resultados: Los resultados revelaron reducción de GH y de IGF-1, 67 por ciento con niveles por debajo de 2.5ng/ml de GH, 58 por ciento con niveles de IGF-1 por debajo de 250 ng/ml. 15 pacientes (25 por ciento) presentaron criterios clínicos y bioquímicos de cura, 7 (46 por ciento) posterior al procedimiento quirúrgico, 4 (27 por ciento) posterior a cirugía y radioterapia, 3 (20 por ciento) cirugía más radiocirugía, y un paciente (7 por ciento) requirió los tres procedimientos. 23 pacientes (39 por ciento), no presentaron niveles significativos de reducción y fueron considerados no curados. Conclusiones: Estos resultados sugieren que la acromegalia continua siendo una enfermedad que requiere un tratamiento multimodal, sospecha clínica y búsqueda acuciosa para un diagnóstico temprano, a fin de obtener mejores resultados en estos pacientes. La cirugía continúa siendo el tratamiento primario de la acromegalia secundaria a adenomas de la hipófisis productores de GH. En pacientes con lesiones extensas o invasión se cuenta con nuevas terapias como la radiocirugía y continúan desarrollándose tratamientos médicos con excelentes resultados adyuvantes en el tratamiento.

Introduction: Pituitary adenomas account for the 10-25 percent of intracranial tumors. Acromegaly is defined as abnormal and excessive growth of the extremities, caused by growth hormone oversecretion. It is a rare disease with a prevalence of 60 per million and an incidence of 3-4 new cases per million per year. Methods: We included 59 patients diagnosed with acromegaly, in the period 2000-2007. Endocrinology assess, response to treatment based on clinical analysis, imaging and biochemical GH and IGF-1. Results: The results showed reduction of GH and IGF-1, 67 percent with levels below 2.5ng/ml of GH, 58 percent with IGF-1 levels below 250 ng/ml. 15 patients (25 percent) had clinical and biochemical criteria for cure, 7 (46 percent) after the surgical procedure, 4 (27 percent) after surgery and radiotherapy, 3 (20 percent) surgery over radiosurgery, and one patient (7 percent) required three procedures. 23 patients (39 percent) showed no significant levels of reduction and were considered not cured. Conclusions: These results suggest that the acromegaly remains a disease that requires a multimodal treatment, clinical suspicion and thorough search for an early diagnosis in order to obtain better results in these patients. Surgery remains the primary treatment of acromegaly secondary to pituitary adenomas producing GH. In patients with extensive lesions or invasion we have new therapies such as radiosurgery and continue to develop medical treatments with excellent results in the adjuvant treatment.

[Trans-sphenoidal surgery in 95 acromegalic patients: clinical and radiological findings]

Acromegaly, a multisystem disease, produced by growth hormone [GH] secreting pituitary adenomas, has devastating effects shortening life expectancy; thus control of the disease is vital. Surgical removal of adenomas is the primary and standard treatment in these patients. In this study, results of trans-sphenoidal surgery in 95 patients admitted consecutively to the Shohada-e Tadjrish Hospital, over 9 years beginning 1996, were analyzed. Data were collected retrospectively from files of all patients admitted to our hospital, over 9 years, and operated using a trans-sphenoidal approach. Clinical and radiological evaluations were reviewed and intra-operative findings, postoperative complications, immediate hormonal assay results and long term follow ups were analyzed. Forty eight patients were female and 47 male [1/1 ratio] with mean age of 39.2 +/- 12 years. Acromegalic features were present in almost every patient with a mean duration of 46 +/- 43 months. Macroadenomas were discovered in 70 patients and microadenomas in the other 25; there was no mortality. Postoperative complications were as follows: Temporary Dl in 80, CSF rhinorrhea in 11 and meningitis in 4 [all were managed conservatively with only one case of permanent Dl]; 79 patients had follow up [mean 13 +/- 12 months]; 64% of patients [76% of microadenomas and 62% of macroadenomas] had remission [post-operative GH < 5 ng/mL], but with remission criteria of GH < 2.5 ng/mL there was 51% remission rate [65% of microadenomas and 44% of macroadenomas]. In five patients, following initial surgery, there was recurrence after 1 to 4 years, which was controlled in 4 of with a second trans-sphenoidal surgery, with the remaining one case being referred for radiotherapy

[Prognostic factors for surgical cure in acromegaly]

Surgery is the treatment of choice in acromegaly. To determine the prognostic factors for surgical cure in growth hormone secreting pituitary adenomas, we studied 35 patients who underwent surgery between 1986 and 2005. We compared the clinical, biological and tumoral characteristics of the cured group [n=19] and those of the non cured group [n=16]. A young age and in invasive adenoma were factors for a poor surgical prognosis. Other factors for bad surgical prognosis are reported in the literature such as a preoperative GH level higher than 50 ng/ml, a monohormonal finding at immunohistochemistry and no GH suppression after surgery

Resultados do tratamento cirúrgico na acromegalia com um único neurocirurgião e meta-análise cumulativa / Outcome of surgical treatment for acromegaly performed by a single neurosurgeon and cumulative meta-analysis / Outcome of surgical treatment for acromegaly performed by a single neurosurgeon and cumulative meta-analysis

Avaliamos retrospectivamente os resultados da cirurgia transesfenoidal num grupo de acromegálicos operados por um único neurocirurgião, comparando-os com uma meta-análise cumulativa de 10 séries (1.632 pacientes) publicadas entre 1992-2005. Estudamos 28 pacientes (17M/11F; 44,1 ± 12,7 anos; 27 com macroadenomas, sendo 86 por cento invasivos), acompanhados por 21,4 ± 17,6 meses após a cirurgia; eles foram classificados de acordo com a atividade da acromegalia em: 1) doença controlada (DC): GH basal ou médio < 2,5 ng/ml ou GH nadir no TTOG < 1ng/ml e IGF-1 normal; 2) não controlada (DNC): GH basal ou médio > 2,5 ng/ml ou nadir no TTOG > 1 ng/ml e IGF-1 elevado; 3) inadequadamente controlada (DIC): GH normal e IGF-1 elevado ou GH elevado e IGF-1 normal. Após a cirurgia, os níveis de GH reduziram de 61,7 ± 101,1 ng/ml para 7,2 ± 13,7 ng/ml (p< 0,001), e os de IGF-1 de 673,1 ± 257,7 ng/ml para 471,2 ± 285 ng/ml (p= 0,01). A taxa de remissão bioquímica foi de 57 por cento [10 pacientes (35,5 por cento) com DC e 6 (21,5 por cento) com DIC], similar àquela obtida na meta-análise de cirurgias de macroadenomas. Sete dos 28 pacientes foram submetidos à re-intervenção (4 operados em outro hospital e 3 pelo nosso neurocirurgião), sendo 5 (71,5 por cento) classificados como DC no pós-operatório. Invasão de seio cavernoso foi mais prevalente nos DNC e DIC, e desvio de haste hipofisária no grupo DNC. A taxa de remissão foi maior nas séries em que apenas um único cirurgião realizou os procedimentos (66 por cento vs. 49 por cento; p< 0,05). Em conclusão, esses dados comprovam que a experiência do neurocirurgião pode aumentar significativamente as taxas de remissão do tratamento cirúrgico da acromegalia, especialmente em tumores maiores e mais invasivos, e que a re-intervenção realizada por cirurgião experiente deve ser considerada nos algoritmos de abordagem terapêutica desta doença.

The aim of this retrospective study was to evaluate the results of transsphenoidal surgery in a group of patients with acromegaly who were operated by the same neurosurgeon. Our results were compared to those from a cumulative meta-analysis of 10 series (1,632 patients) published between 1992­2005. We followed 28 patients (17M/11F; 44.1 ± 12.7 yr; 27 with macroadenomas; 86 percent being invasive) during 21.4 ± 17.6 months after treatment. Patients were classified according to disease activity as follows: 1) controlled (CD): basal or mean GH < 2.5 ng/ml or nadir GH (OGTT) < 1 ng/ml and normal IGF-1; 2) uncontrolled (UCD): basal or mean GH > 2.5 ng/ml or nadir GH > 1 ng/ml and elevated IGF-1; 3) inadequately controlled (ICD): normal GH and elevated IGF-1 or elevated GH and normal IGF-1. After surgery, GH levels decreased from 61.7 ± 101.1 ng/ml to 7.2 ± 13.7 ng/ml (p< 0.001) and mean IGF-1 from 673.1 ± 257.7 ng/ml to 471.2 ± 285 ng/ml (p= 0.01). Biochemical remission rate was 57 percent [10 (35.5 percent) patients with CD and 6 (21.5 percent) with ICD], similar to the mean remission rate observed in the meta-analysis of surgical outcome of macroadenomas. Seven of 28 patients were submitted to surgical re-intervention (4 had been previously operated elsewhere and 3 by our neurosurgeon), with CD observed in 5 (71.5 percent) on follow-up. Cavernous sinuses invasion was more prevalent in UCD and ICD, whereas infundibular stalk deviation occurred only in patients with UCD. Remission rate was significantly higher in series where all surgical procedures were performed by the same surgeon (66 percent vs. 49 percent; p< 0.05). Thus, the surgeon's experience significantly improves the surgical outcome in acromegaly, especially in patients harboring large and invasive tumors, and re-intervention performed by an experienced surgeon should be considered in the algorithms for clinical management of this disease.