Adenoma hipofisario ectópico del seno esfenoidal persistente tras cirugía manejado con tratamiento conservador / Ectopic pituitary adenoma in the sphenoid sinus persistent after surgery managed with conservative treatment

Los adenomas hipofisarios ectópicos (EPA) constituyen un reto diagnóstico, dada su escasa prevalencia y variada presentación en la que puede incluirse un síndrome de hipersecreción de hormonas hipofisarias. La clínica suele ser larvada e inespecífica, no presentan ninguna característica radiológica diferencial y el diagnóstico habitualmente es anatomopatológico. Sin embargo, a pesar de ser tumores benignos, pueden presentar un comportamiento agresivo, con invasión ósea y difícil resección completa, por lo que un diagnóstico de sospecha precoz podría resultar en un tratamiento más eficaz y con un menor número de complicaciones. Presentamos el caso de una paciente con un adenoma hipofisario ectópico silente en el seno esfenoidal con inmunohistoquímica positiva para Hormona de crecimiento (GH) y prolactina que presentaba restos tumorales tras la intervención quirúrgica y ha sido manejada con tratamiento médico conservado, con buenos resultados.

Ectopic pituitary adenomas constitute a diagnostic challenge, given their low prevalence and varied presentation in which a pituitary hormone hypersecretion syndrome may be included. Clinical symptoms are usually latent and nonspecific, they have no differential radiological characteristics and the diagnosis is usually anatomopathological. However, despite being benign tumors, they can exhibit aggressive behavior, with bone invasion and difficult complete resection, so a diagnosis of early suspicion could result in more effective treatment and fewer complications. We present the case of a patient with a silent ectopic pituitary adenoma in the sphenoid sinus with positive immunohistochemistry for Growth Hormone (GH) and prolactin who had tumor remnants after surgery and was managed with conservative medical treatment, with good results.

Macroprolactinoma clival ectópico: una forma rara de presentación de adenoma hipofisario / Ectopic clival macroprolactinoma: a rare presentation of pituitary adenoma

Los adenomas pituitarios son los tumores hipofisarios más frecuentes siendo una entidad rara cuando se trata de adenomas ectópicos, es decir, sin conexión con la glándula pituitaria. Se cree que derivan de células residuales del tracto de migración embriológico desde la bolsa de Rathke. Su presentación clínica es muy variable porque depende de la producción hormonal y del efecto masa en estructuras adyacentes. Generalmente suponen un reto diagnóstico debido a su baja frecuencia, la clínica variable de presentación y que no presentan características específicas en las pruebas de imagen. Generalmente el diagnóstico se realiza de manera retrospectiva tras la resección quirúrgica. Presentamos el caso de un varón de 56 años que se presentó con unos valores de prolactina de 6647.5 ng/ml (2.2-17.7) con clínica de hipogonadismo aislada que se resolvió con tratamiento médico sin precisar resección quirúrgica, con una disminución de la densidad radiológica y estabilización del tamaño y sin clínica compresiva ni alteración visual.

Pituitary adenomas are the most common hypophyseal tumors being a rare entity when they are ectopic, without connection to the pituitary gland. They are thought to arise from residual cells in the migration tract from Rathke´s pouch. Its clinical presentation is variable depending on the hormonal production and the pressure effect on adjacent structures. They usually are a diagnostic challenge due to their low frequency, wide range of clinical presentation and not showing specific features on imaging techniques. The diagnosis is made usually retrospectively after surgical resection. We report the case of a 56 years old male that presented with a prolactine value of 6647.5 ng/ml (2.2-17.7) and isolated hypogonadism symptoms that resolved with medical treatment without surgery, diminishing the radiological density and stabilizing the size without having compresive symptoms nor visual disturbances.

Mean platelet volume in patients with prolactinoma

ABSTRACT Objective Prolactin is a multifunctional pituitary hormone. The effect of prolactin on platelet activation is not well understood. Prolactinomas are the most common type of pituitary adenomas, and they are medically responsive to dopamine agonists. Mean platelet volume (MPV) is a marker of platelet function and activation. The aim of this study was to evaluate MPV values before and 6 months of cabergoline treatment when normoprolactinemia was achieved. Subjects and methods A total of 101 newly diagnosed prolactinoma patients and 102 healthy control subjects were included in the study. Patients with hematological disorders that affect MPV and those on medications were excluded. Prolactin, platelet count and MPV levels were recorded before and 6 months after the initiation of cabergoline treatment (0.5 to 1 mg, two times a week). Results There was no significant difference in platelet count and MPV before and after 6 months of treatment with cabergoline in patients with prolactinoma compared with the control group (p > 0.05). Conclusion Our results showed that MPV, a marker of platelet function, was unchanged in patients with prolactinoma.

Prolactinomas: evolution after menopause

ABSTRACT Objetive The aim was to assess the evolution of tumor size and prolactin (PRL) levels in patients with micro and macroprolactinomas diagnosed and treated with dopamine agonists during fertile age, and the effects of suspension of drugs after menopause. Retrospective study, 29 patients with prolactinomas, 22 microadenomas and 7 macroadenomas, diagnosed during their fertile age were studied in their menopause; treatment was stopped in this period. Age at menopause was 49 ± 3.6 years. The average time of treatment was 135 ± 79 months. The time of follow-up after treatment suspension was 4 to 192 months. Results Pre-treatment PRL levels in micro and macroadenomas were 119 ± 57 ng/mL and 258 ± 225 ng/mL, respectively. During menopause after treatment suspension, and at the latest follow-up: in microadenomas PRL levels were 23 ± 13 ng/mL and 16 ± 5.7 ng/mL, respectively; in macroadenomas, PRL levels were 20 ± 6.6 ng/mL 5t5and 25 ± 18 ng/mL, respectively. In menopause after treatment suspension, the microadenomas had disappeared in 9/22 and had decreased in 13/22. In the group of patients whose tumor had decreased, in the latest follow-up, tumors disappeared in 7/13 and remained unchanged in 6/13. In macroadenomas, after treatment suspension 3/7 had disappeared, 3/7 decreased and 1/7 remained unchanged. In the latest control in the 3 patients whose tumor decreased, disappeared in 1/3, decreased in 1/3 and there was no change in the remaining. Conclusions Normal PRL levels and sustained reduction or disappearance of adenomas were achieved in most of patients, probably due to the decrease of estrogen levels. Dopamine agonists might be stopped after menopause in patients with prolactinomas.

Change in Somatostatinergic Tone of Acromegalic Patients according to the Size of Growth Hormone-Producing Pituitary Tumors

The aim of this study was to investigate the relationship between somatostatinergic tone (SST) and the size of growth hormone (GH)-producing pituitary tumors. GH levels of 29 patients with newly diagnosed acromegaly were measured using a 75-gram oral glucose tolerance test (OGTT), an insulin tolerance test (ITT), and an octreotide suppression test (OST). Differences between GH levels during the ITT and the OGTT (DeltaGH(IO)), and between the OGTT and the OST at the same time point (DeltaGH(OS)) were compared according to the size of the tumor and the response pattern to the OST. DeltaGH(IO) of macroadenomas (n=22) was non-significantly higher than those of microadenomas while DeltaGH(OS) of macroadenomas were significantly higher than those of microadenomas. According to further analyses of macroadenomas based on the response pattern to the OST, GH levels during the ITT were significantly higher in non-responders. DeltaGH(OS) showed near-significant differences between responders and non-responders. In conclusion, as the size of the pituitary tumor increases, the effect of glucose on SST appears to be attenuated. Macroadenomas that are non-responders to the OST possess a portion of GH secretion exceeding the range of regulation by SST.

Resistance to octreotide LAR in acromegalic patients with high SSTR2 expression: analysis of AIP expression / Resistência ao octreotide LAR em pacientes acromegálicos com alta expressão do SSTR2: avaliação da expressão do AIP

We present here the clinical and molecular data of two patients with acromegaly treated with octreotide LAR after non-curative surgery, and who presented different responses to therapy. Somatostatin receptor type 2 and 5 (SSTR2 and SSTR5), and aryl hydrocarbon receptor-interacting protein (AIP) expression levels were analyzed by qPCR. In both cases, high SSTR2 and low SSTR5 expression levels were detected; however, only one of the patients achieved disease control after octreotide LAR therapy. When we analyzed AIP expression levels of both cases, the patient whose disease was controlled after therapy exhibited AIP expression levels that were two times higher than the patient whose disease was still active. These two cases illustrate that, although the currently available somatostatin analogs bind preferentially to SSTR2, some patients are not responsive to therapy despite high expression of this receptor. This difference could be explained by differences in post-receptor signaling pathways, including the recently described involvement of AIP. Arq Bras Endocrinol Metab. 2012;56(8):501-6.

Apresentamos os dados clínicos e moleculares de dois pacientes com acromegalia tratados com octreotide LAR após cirurgia não curativa, com diferentes respostas a essa terapia medicamentosa. As expressões do receptor de somatostatina tipo 2 e 5 (SSTR2 e SSTR5) e da proteína de interação com o receptor aril hidrocarbono (AIP) foram analisadas por qPCR. Em ambos os casos, foi encontrada uma expressão elevada de SSTR2 e baixa do SSTR5. No entanto, o controle da doença foi obtido após tratamento com octreotide LAR em apenas um dos pacientes. Quando analisamos a expressão do AIP em ambos os casos, o paciente cuja doença foi controlada após a terapia medicamentosa apresentou uma expressão duas vezes maior do que a do paciente não controlado com o tratamento. Conclui-se que esses dois casos ilustram que, embora os análogos de somatostatina atualmente disponíveis se liguem preferencialmente ao SSTR2, alguns pacientes não respondem ao tratamento, apesar de uma elevada expressão desse receptor. Isso poderia ser explicado por alterações nas vias de sinalização pós-receptor, incluindo o envolvimento recentemente descrito da AIP. Arq Bras Endocrinol Metab. 2012;56(8):501-6.

Temozolomide in aggressive pituitary adenomas and carcinomas

Temozolomide is an alkylating agent used in the treatment of gliomas and, more recently, aggressive pituitary adenomas and carcinomas. Temozolomide methylates DNA and, thereby, has antitumor effects. O6-methylguanine-DNA methyltransferase, a DNA repair enzyme, removes the alkylating adducts that are induced by temozolomide, thereby counteracting its effects. A Medline search for all of the available publications regarding the use of temozolomide for the treatment of pituitary tumors was performed. To date, 46 cases of adenohypophysial tumors that were treated with temozolomide, including 30 adenomas and 16 carcinomas, have been reported. Eighteen of the 30 (60%) adenomas and 11 of the 16 (69%) carcinomas responded favorably to treatment. One patient with multiple endocrine neoplasia type 1 and an aggressive prolactin-producing adenoma was also treated and demonstrated a good response. No significant complications have been attributed to temozolomide therapy. Thus, temozolomide is an effective treatment for the majority of aggressive adenomas and carcinomas. Evidence indicates that there is an inverse correlation between levels of O6-methylguanine-DNA methyltransferase immunoexpression and therapeutic response. Alternatively, high-level O6-methylguanine-DNA methyltransferase immunoexpression correlates with an unfavorable response. Here, we review the use of temozolomide for treating pituitary neoplasms.

Recovery pattern of hypothalamo-pituitary-testicular axis in patients with macroprolactinomas after treatment with cabergoline.

Background & objectives: Hyperprolactinaemia affects testicular functions by influencing hypothalamo-pituitary-testicular (HPT) axis at various levels. Available literature on the level of defect, time course of improvement of gonadal functions and its relation with decline in prolactin levels is scanty. We carried out this study to evaluate the HPT axis in patients with macroprolactinomas, before and six months after cabergoline therapy. Methods: Fifteen men with macroprolactinomas underwent gonadotropin and testosterone response to their respective stimuli before and after six months of cabergoline therapy. Results: Serum prolactin levels decreased after six months of therapy. Pretreatment, mean lutenizing and follicle stimulating hormones (LH and FSH) levels were 2.0 ± 0.4 and 1.4 ± 0.2 IU/l, respectively. However, LH and FSH responses to GnRH were preserved in majority of the patients and LH peaked to 12.1 ± 2.3 IU/l (P<0.01), while FSH to 2.9 ± 0.4 IU/l suggesting the influence of hyperprolactinaemia at the level of hypothalamus with preserved gonadotrope reserve. After cabergoline therapy, there was an increase in basal as well as stimulated LH and FSH levels, though these were not statistically significant when compared to respective pretherapy levels. Basal testosterone (T) levels significantly improved after therapy, but peak T response to hCG was similar at both pre- and post treatment. A significant correlation was observed between peak LH and peak T at baseline (r=0.53, P<0.01) and it further strengthened after therapy (r=0.70, P<0.01). After cabergoline therapy, there was significant improvement in seminal volume, sperm count and motility and sperm count correlated with peak FSH response (r=0.53, P<0.05). Interpretation & conclusions: Hyperprolactinaemia affects testicular functions probably by influencing at the level of hypothalamus resulting in subnormal basal secretion of gonadotropins required for optimal testicular functions.

Clomiphene fails to revert hypogonadism in most male patients with conventionally treated nonfunctioning pituitary adenomas / Clomifeno não reverte o hipogonadismo na maioria dos homens com adenomas pituitários não funcionais tratados de forma convencional

OBJETIVE: To evaluate the effect of clomiphene in men with hypogonadism and conventionally treated nonfunctioning pituitary adenomas (NFPA). PATIENTS AND METHODS: Open label, single-arm, prospective trial. Nine hypogonadal men (testosterone < 300 ng/dL and low/normal LH) with previously treated NFPA. Clomiphene (50 mg/day orally) for 12 weeks. Testosterone, estradiol, LH, FSH, prolactin and erectile function were evaluated before and after 10 days, 4, 8 and 12 weeks of clomiphene treatment. RESULTS: After clomiphene treatment, testosterone and erectile function improved in only one patient. In the remaining eight patients, testosterone levels decreased whereas LH, FSH, and estradiol remained unchanged. Insulin sensitivity increased in unresponsive patients. CONCLUSIONS: Compared with hypogonadal men with prolactinomas under dopaminergic therapy, clomiphene treatment failed to restore normal testosterone levels in most patients with conventionally treated NFPA.

OBJETIVO: Avaliar o efeito do clomifeno em homens com hipogonadismo e adenoma hipofisário não funcionante (NFPA) previamente tratados. PACIENTES E MÉTODOS: Aberto, braço único, prospectivo. Nove homens hipogonádicos (testosterona < 300 ng/dL e LH normal/baixo) com NFPA previamente tratados. Clomifeno (50 mg/dia oral) por 12 semanas. Testosterona, estradiol, LH, FSH, prolactina e função erétil foram avaliados antes e após 10 dias, 4, 8 e 12 semanas de clomifeno. RESULTADOS: Após clomifeno, a testosterona e a função erétil melhoraram em um paciente. Em outros oito pacientes, os níveis de testosterona reduziram enquanto os níveis de LH, FSH, e estradiol permaneceram inalterados. A sensibilidade à insulina aumentou nos não respondedores. CONCLUSÕES: Em contraste com homens hipogonádicos com prolactinomas tratados com agonistas dopaminérgicos, a maioria dos hipogonádicos com NFPA falha em restaurar os níveis de testosterona durante o uso de clomifeno.

Cystic craniopharyngioma: intratumoral chemotherapy with alpha interferon / Craniofaringioma cístico: quimioterapia intratumoral com interferon alfa

OBJECTIVE: To assess whether the cystic craniopharyngiomas can be controlled with the use of intratumoral applications of interferon alpha. METHOD: Nineteen patients with the diagnosis of cystic craniopharyngioma were treated with intratumoral chemotherapy with interferon alpha from January 2002 to April 2006. All patients underwent placement of an intracystic catheter connected to an Ommaya reservoir. Through this reservoir were made applications during chemotherapy cycles. Each cycle corresponded to application of 3,000,000 units of interferon alpha three times per week on alternate days totalizing 36,000,000 units. Response to treatment was evaluated by calculating the tumor volume on MRI control after one, three and six months after the end of each cycle. Patients who developed worsening of symptoms or who had insignificant reduction in tumor volume during follow-up underwent repeat cycle chemotherapy. RESULTS: Four patients received four cycles of chemotherapy, three patients received three cycles, six patients received two cycles and six patients received one. The lower percentage of reduction in tumor volume was 60 percent and the bigger reduction was 98.37 percent. Eleven patients had a reduction greater than 90 percent. Five patients had a tumor reduction between 75 and 90 percent and in three patients the tumors were reduced by less than 75 percent. No deaths occurred during treatment and side effects of interferon alpha were well tolerated. No treatment was discontinued. Follow-up after the last application ranged from one year and five months to three years and nine months. CONCLUSION: The intratumoral chemotherapy with interferon alpha decreases the volume of cystic craniopharyngiomas and so far can be considered a new therapeutic alternative.

OBJETIVO: Avaliar se os craniofaringiomas císticos podem ser controlados com aplicações intratumorais de interferon alfa. MÉTODO: De janeiro de 2002 a abril de 2006, 19 pacientes foram submetidos à colocação de um cateter intracístico conectado a reservatório de Ommaya para aplicações intratumorais de ciclos de 36.000.000 de unidades de interferon alfa. A resposta ao tratamento foi avaliada pelo cálculo do volume tumoral na ressonância magnética de controle ao término de cada ciclo. RESULTADOS: Os pacientes receberam de um a quatro ciclos de quimioterapia. Onze pacientes apresentaram uma redução do volume tumoral maior que 90 por cento; cinco pacientes apresentaram uma redução entre 75 por cento e 90 por cento e três pacientes uma redução menor de 75 por cento. Não houve óbitos durante o tratamento e os efeitos colaterais do inferferon alfa foram bem tolerados. Nenhum tratamento foi interrompido. CONCLUSÃO: A quimioterapia intratumoral com interferon alfa diminui o volume dos craniofaringeomas císticos e pode ser considerada uma nova alternativa terapêutica.

Biochemical acromegaly in patients with prolactinoma during treatment with dopaminergic agonists / Acromegalia bioquímica em pacientes com prolactinoma em tratamento com agonistas dopaminérgicos

OBJECTIVE: To evaluate the frequency of subclinical acromegaly (in the absence of clinical phenotype but biochemically uncontrolled) in patients with prolactinoma during treatment with dopaminergic agonists. SUBJECTS AND METHODS: One hundred twenty one patients without a phenotype suggestive of acromegaly were studied. RESULTS: Initially, the laboratory diagnosis of acromegaly was unequivocal (elevated IGF-1 for gender and age with nadir GH > 1 μg/L) in two patients, and likely (elevated IGF-1 with nadir GH > cut-off but < 1 μg/L) in another patient. In two other patients, this diagnosis was possible (normal IGF-1 with nadir GH > 1 μg/L). Repetition of the tests 6 months after withdrawal of the dopaminergic agonist confirmed the diagnosis of subclinical acromegaly (elevated IGF-1 for gender and age with nadir GH > 1 μg/L) in these 5 patients. False-positive results were excluded in all cases. CONCLUSION: In patients with prolactinomas, acromegaly should be investigated not only in cases with a clinical phenotype.

OBJETIVO: Avaliar a frequência de acromegalia subclínica (na ausência de fenótipo clínico, mas bioquimicamente não controlada) em pacientes com prolactinoma em tratamento com agonistas dopaminérgicos. SUJEITOS E MÉTODOS: Cento e vinte e um pacientes sem fenótipo de acromegalia foram estudados. RESULTADOS: Inicialmente, o diagnóstico laboratorial de acromegalia foi inequívoco (IGF-1 elevado para sexo e idade com nadir do GH > 1 μg/L) em dois pacientes, e provável (IGF-1 elevado com nadir do GH > valor de corte ensaio-específico mas < 1 μg/L) em outro paciente. Em outros dois, esse diagnóstico foi possível (IGF-1 normal com nadir do GH > 1 μg/L). A repetição dos testes seis meses após a suspensão dos agonistas dopaminérgicos confirmou o diagnóstico de acromegalia subclínica (IGF-1 elevado para sexo e idade com nadir do GH > 1 μg/L) em cinco desses pacientes. Os resultados falso-positivos foram excluídos em todos os casos. CONCLUSÃO: Em pacientes com prolactinomas, a acromegalia deveria ser investigada não apenas nos casos com fenótipo clínico.

Long term treatment of a thyrotropin-secreting microadenoma with somatostatin analogues / Tratamento de longa duração com análogos da somatostatina de um microadenoma tirotrofinoma

Thyrotropin (TSH) secreting pituitary adenomas (TSH-omas) account for < 1 percent of all pituitary adenomas and are a rare cause of hyperthyroidism. The diagnosis is often made at the stage of macroadenoma because of the aggressive nature of the tumor and due to the fact that patients are mistakenly treated for more common primary hyperthyroidism for a long time. First line therapy is transsphenoidal resection of the tumor, which can cure one-third of the patients completely. However, if surgery is not possible or curative, pituitary radiotherapy and/or somatostatin analogs (SSA) can be useful. We report the case of a 54-year-old woman treated 20 years earlier for a mistakenly suspected primary hyperthyroidism. Given the persistence of symptoms she was studied further and was diagnosed with a thyrotropinoma. Despite the delay in diagnosis and prior thyroid ablation, a microadenoma was found. As transsphenoidal surgery was not considered effective, medical therapy with a somatostatin analogue was initiated. Currently, at four years of follow-up, the patient continues on this treatment and remains euthyroid and asymptomatic. We report a case of successful long-term treatment with SSA, after unsuccessful surgery.

Tirotrofinomas (TSH-omas) representam < 1 por cento dos adenomas hipofisários. Eles são uma causa muito rara de hipertireoidismo. O diagnóstico é frequentemente feito na fase de macroadenoma em consequência da natureza agressiva do tumor e do feito de que os doentes são tratados inicialmente por engano e por um longo tempo para hipertireoidismo primário. A terapêutica de primeira linha é a ressecção transesfenoidal do tumor, que cura um terço dos pacientes completamente. Contudo, se a cirurgia não for possível ou curativa, a radioterapia da pituitária e/ou o tratamento com análogos da somatostatina (SSA) podem ser úteis. Relatou-se o caso de uma mulher de 54 anos, tratada há 20 anos por uma suspeita equivocada de hipertireoidismo primário. Dada a persistência dos sintomas, foram realizados mais exames e a paciente foi diagnosticada com TSH-oma. Apesar do diagnóstico tardio e da ablação prévia com iodo radioativo, encontrou-se um microadenoma. Como a cirurgia transesfenoidal não foi considerada eficaz, iniciou-se o tratamento da paciente com SSA. Atualmente, após quatro anos de acompanhamento, a paciente continua com o tratamento e permanece eutireoidea e assintomática. Neste artigo, relatou-se a eficácia da terapia medicamentosa com SSA em longo prazo, após cirurgia não eficaz.

Utilidad de la cabergolina en pacientes portadores de prolactinoma resistentes o intolerantes a bromocriptina / Usefulness of cabergoline in patients with prolactinemia and resistant or intolerant to bromocriptine

Introducción: La terapia de elección de los prolactinomas son los agonistas dopaminérgicos, cuyo principal exponente es la bromocriptina, sin embargo, hay pacientes que no responden o presentan severos efectos secundarios (resistentes o intolerantes a bromocriptina, respectivamente). El objetivo en este estudio fue valorar la respuesta al uso de cabergolina en pacientes con prolactinomas, intolerantes o resistentes a bromocriptina Material y métodos: Se estudiaron 27 pacientes (25 mujeres y dos varones) en quienes se realizó determinación basal de prolactina y cada mes hasta completar tres meses, registrando los datos asociados a hiperprolactinemia y los efectos secundarios. La dosis inicial fue de 0.25 mg los lunes y jueves durante la primera semana, y 0.5 mg a partir de la segunda. El análisis estadístico incluyó la prueba de Shapiro-Wilk, Kruskal-Wallis y Anova. Resultados: 22 pacientes presentaron microadenomas y cinco macroadenomas. En los intolerantes (n = 11) el valor inicial de prolactina de 61.45 ± 19.82 disminuyó al tercer mes a 4.94 ± 1.79 (p < 0.024). En los resistentes (n = 16), el valor basal fue 119.53 ± 11.52; 15 pacientes redujeron significativamente a 12.95 ± 3.66 (p < 0.005) al tercer mes de tratamiento. En ambos, los signos atribuibles a la hiperprolactinemia mejoraron significativamente, con poca incidencia de efectos secundarios. Conclusiones: La cabergolina es útil en la mayoría de los pacientes considerados intolerantes o resistentes a la bromocriptina.

BACKGROUND: Dopaminergic agonists are the treatment of choice for prolactinomas with bromocriptine (BCE) being the primary agent used. There is a group of patients who are not responders to such therapy or have severe side effects (resistant or intolerant to BCE, respectively). We undertook this study to evaluate the response to the administration of cabergoline (CBG) in patients intolerant or resistant to BCE. METHODS: Twenty seven patients (25 females and 2 males) were recruited with prolactin-pituitary tumors, obtaining basal serum prolactin (PRL) samples and again each month up to 3 months. We recorded signs associated with hyperprolactinemia and secondary effects of CBG. The initial dose was 0.25 mg twice weekly during the first week, with an increase to 0.5 mg twice weekly from the second week until the conclusion of the study. Statistical analysis included Shapiro-Wilk, Kruskal-Wallis and ANOVA tests. RESULTS: Twenty two patients had microadenomas and five had macroadenomas. In the intolerant group (n= 11), the initial PRL value (61.45 +/- 19.82) decreased by the third month to 4.94 +/- 1.79 (p<0.024). In the resistant group (n= 16), basal PRL values were 119.53 +/- 11.52. In 15 of these patients, the PRL value significantly decreased to 12.95 +/- 3.66 ng/ml (p<0.005) by the third month of treatment. In both groups the signs related to hyperprolactinemia significantly improved, with a low incidence of secondary effects due to CBG. CONCLUSIONS: CBG is useful in most patients considered as intolerant or resistant to BCE.

Efficacy and Safety of Cabergoline as First Line Treatment for Invasive Giant Prolactinoma

Although cabergoline is effective in the treatment of micro- and macro-prolactinoma, little is known about its efficacy in the treatment of invasive giant prolactinoma. We investigated the efficacy and safety of cabergoline in 10 male patients with invasive giant prolactinoma. Before treatment, mean serum prolactin level was 11,426 ng/mL (range, 1,450-33,200 ng/mL) and mean maximum tumor diameter was 51 mm (range, 40-77 mm). Three months after initiation of cabergoline treatment, serum prolactin concentrations decreased more than 97% in 9 patients; at last follow-up (mean treatment duration, 19 months), the mean decrease in serum prolactin concentrations was 98%, with 5 patients having normal serum prolactin levels. At first MRI follow-up (3-12 months after initiation of cabergoline), the mean reduction in tumor size was 85+/-4% (range, 57-98%). Cabergoline treatment for more than 12 months caused a greater reduction in tumor size compared to the treatment for less than 12 months (97+/-1% vs. 78+/-7%, P<0.05). These findings indicate that cabergoline treatment led to a significant and rapid reduction in serum prolactin concentrations and tumor size in patients with giant prolactinoma. Therefore, cabergoline represents an effective and well-tolerated treatment for invasive giant prolactinoma.

Somatostatin receptors subtypes 2 and 5, dopamine receptor type 2 expression and gsp status as predictors of octreotide LAR® responsiveness in acromegaly / Expressão dos receptores da somatostatina subtipos 2 e 5 e do receptor da dopamina tipo 2 e gsp status como preditores de resposta ao octreotide LAR® na acromegalia

We present two acromegalic patients in which clinical and molecular data are discussed in regard to their ability to predict long term octreotide LAR® therapy response. Case reports: Patient 1: female, 36 years old at diagnosis. Basal GH and IGF-I at diagnosis were 133 ng/mL and 181 percent above the upper limit of reference values (ULRV), respectively. Growth hormone during acute test with subcutaneous octreotide decreased from 133 to 13 ng/mL. Patient started on primary octreotide LAR® therapy (20mg q28 days) and achieved biochemical parameters of disease control after 6 months. Molecular analysis of tumor fragments: gsp +; quantitative analysis of SSTR (somatostatin receptor) and DR (dopamine receptor) mRNA - SSTR2 23954; SSTR5 2407; DR2 total 17016 copies. Patient 2: male, 38 years old at diagnosis. Basal GH and IGF-I at diagnosis were 120 ng/mL and 114 percent ULRV, respectively. Patient underwent non-curative trans-sphenoidal surgery. Post-operative GH and IGF-I were 112 ng/mL and 137 percent ULRV, respectively. Growth hormone during acute test with subcutaneous octreotide decreased from 112 to 7 ng/mL. Octreotide LAR® therapy (20 mg q28 days) was then initiated. After 6 months of treatment, patient did not attain biochemical control of disease and displayed increased tumor volume. Molecular analysis of tumor fragments: gsp not done; quantitative analysis of SSTR and DR mRNA - SSTR2 416; SSTR5 3767; DR2 total 3439 copies. In conclusion, these two cases illustrate how laboratory data can be conflicting as predictors of octreotide LAR® responsiveness and how molecular analysis of tumor fragments can help explain different behaviors in clinically similar patients.

Apresentamos dois pacientes acromegálicos nos quais dados clínicos e moleculares são discutidos quanto à sua capacidade de predizer a resposta a longo prazo ao tratamento com octreotide LAR®. Relato dos casos: Paciente 1: Feminina, 36 anos de idade ao diagnóstico. GH e IGF-I ao diagnóstico 133 ng/mL e 181 por cento acima do limite superior do valor de referência (LSVR), respectivamente. GH durante o teste agudo com octreotide subcutâneo diminuiu de 133 para 13 ng/mL. Foi iniciado tratamento primário com octreotide LAR® (20 mg q28 dias) e a paciente alcançou os parâmetros bioquímicos de controle de doença depois de seis meses. Análise molecular do tumor: gsp +; análise quantitativa do mRNA de SSTR (receptores de somatostatina) e DR (receptor de dopamina) - SSTR2 23.954; SSTR5 2.407; DR2 total 17.016 cópias. Paciente 2: Masculino, 38 anos de idade ao diagnóstico. GH e IGF-I ao diagnóstico 120 ng/mL e 114 por cento LSVR, respectivamente. Paciente foi submetido à cirurgia trans-esfenoidal não-curativa. GH e IGF-I pós-operatórios 112 ng/mL e 137 por cento LSVR, respectivamente. GH durante o teste agudo diminuiu de 112 para 7 ng/mL. Foi iniciado tratamento com octreotide LAR® (20 mg q28 dias). Após seis meses o paciente não alcançou controle bioquímico e apresentou aumento do volume tumoral. Análise molecular do tumor: gsp não estudado; análise quantitativa do mRNA de SSTR e DR - SSTR2 416; SSTR5 3.767; DR2 total 3.439 cópias. Em conclusão, estes dois casos ilustram como dados laboratoriais podem ser conflitantes enquanto preditores de resposta ao tratamento com octreotide LAR® e como a análise molecular de fragmentos do tumor pode ajudar a explicar comportamentos diferentes em pacientes clinicamente semelhantes.

Rational use of glucocorticoid during pituitary surgery--a pilot study.

BACKGROUND & OBJECTIVE: The conventionally used perioperative glucocorticoid replacement protocol in patients with pituitary tumours is far from optimal. In this study we evaluated the validity of a modified protocol for perioperative glucocorticoid replacement in non-functioning pituitary macroadenomas. METHODS: A total of 24 consecutive patients with non functioning pituitary macroadenomas were included in this interventional study. Patients with a pre-operative 0800 h cortisol of > or = 350 nmol/l (> or = 12.6 microg/dl) did not receive glucocorticoid replacement during perioperative (d(0)-d-(2)) period, while those with < or = 100 nmol/l (< or = 3.6 microg/dl) received glucocorticoid replacement. Those patients with 0800 h cortisol value between > 100-349 nmol/l (> 3.6-12.6 microg/dl) required them to undergo an insulin induced hypoglycaemia (IIH). In response to IIH, patients with a peak cortisol of < 550 nmol/l (< 19.8 microg/dl) received glucocorticoid replacement. Post-operatively, patients on day 3 with 0800 h cortisol of < or = 100 nmol/l (< or = 3.6 microg/dl) received hydrocortisone 10 mg/m(2) per day; those between > 100-449 nmol/l (> 3.6-16 microg/dl) received hydrocortisone replacement only if they had symptoms of adrenal insufficiency (AI) or during stress; while patients with > or = 450 nmol/l (> or = 16.0 microg/dl) did not receive any glucocorticoid replacement. Retesting was done at 12 wk in 23 subjects based on the algorithm. RESULTS: Pre-operatively, 8 (35%) patients were hypocortisolic and received glucocorticoid supplementation, thereby sparing 15 (65%) subjects from glucocorticoid replacement. On d(3) of surgery, 13 (57%) patients were hypocortisolic, but only 6 with serum cortisol of < or = 100 nmol/l (< or = 3.6 microg/dl), had symptoms and were substituted with glucocorticoid. Remaining seven patients, with serum cortisol between >100-349 nmol/l (> 3.6-12.6 microg/dl), were asymptomatic and advised glucocorticoid support only during stress but none required. Overall, 17 (74%) patients were spared from unnecessary glucocorticoid support. At 12 wk, 13 (57%) patients were hypocortisolic and only 6 either with serum cortisol level of < or = 100 nmol/l (< or = 3.6 microg/dl) or symptomatic for AI received glucocorticoids. Post-operative complications including diabetes insipidus and CSF leak remarkably decreased. INTERPRETATION & CONCLUSION: The protocol used was safe and spared unnecessary use of glucocorticoids peri- and post-operatively. However, more number of patients are to be studied to substantiate the validity of this protocol.

Aspectos clínicos y moleculares de los tumores hipofisarios / The clinical and molecular aspects of our experience with pituitary tumours

Presentamos la experiencia que hemos tenido a lo largo de los años sobre el tratamiento de los tumores hipofisarios. Describimos de qué modo, por los cambios constantes en los estándares farmacoterapéuticos, evaluamos la eficacia y la tolerabilidad de diferentes fórmulas (bromocriptina, quinagolida y carbegolina) en prolactinomas y en pacientes con acromegalia (análogos de la somatostatina: octreotida LAR y lanreotida). También se documentó la aparición de apoptosis en somatotropinomas pretratados con lanreotida o con octreotida LAR en los tejidos de tumores hipofisarios. Observamos que las concentraciones de grelina eran inferiores en los pacientes que no recibieron este tratamiento. También examinamos la expresión de grelina en los somatotropinomas hipofisarios. Asimismo, investigamos la expresión de survivina -péptido que participa en la inhibición de la apoptosis- en diferentes tipos de adenomas hipofisarios (somatotrofos, no funcionantes y prolactinomas). Observamos que el ARNm de la survivina estaba presente en los tumores hipofisarios, pero no hubo ninguna diferencia en la expresión de survivina entre los grupos de tumores. Actualmente estamos planeando otros estudios con nuevos análogos de la somatostatina (SOM 230)y pegvisomant en casos de pacientes acromegálicos. También nos concentramos en la creación de nuevos métodos isotópicos de diagnóstico y en el tratamiento de los pacientes con tumores hipofisarios (centellograma hipofisario con análogos de la somatostatina marcados con tecnecio 99 y terapia con uso de isótopos que emiten radiación beta [itrio 90] y alfa).

Discordância entre IGF-1 e GH pós-sobrecarga de glicose no rastreamento de acromegalia em paciente com macroprolactinoma: relato de caso e revisão sobre o tema / Discrepancy between IGF-1 and GH during 75 g oral glucose tolerance test measures to acromegaly screening in a patient with macroprolactinoma: case report and literature review

Neste artigo, descrevemos o caso de um paciente com diagnóstico de macroprolactinoma, que apresentava valores discordantes entre IGF-1 (elevado) e GH (hormônio de crescimento) pós-teste de tolerância oral à glicose (normal) realizados para pesquisa de co-secreção de GH pelo tumor. Houve normalização dos níveis de prolactina após uso de bromocriptina, porém, durante o acompanhamento, o paciente persistiu com níveis elevados de IGF-1 sem clínica aparente, sugerindo tratar-se de possível forma subclínica de acromegalia. Após o desenvolvimento de novos métodos laboratoriais, mais sensíveis, para a dosagem de GH, casos de discordância entre esses testes vêm sendo observados, levando alguns autores a sugerir que o nadir de GH pós-teste de tolerância à glicose oral (TTGO) para diagnóstico e tratamento da acromegalia pode ser bem menor do que o limite considerado atualmente (1,2). Assim, se isto for confirmado, casos subclínicos ou oligossintomáticos de acromegalia serão diagnosticados mais precocemente.

We describe a patient with macroprolactinoma and discrepant insulin-like growth factor (IGF-1) concentration (elevated) and growth hormone (GH) values during a 75 g oral glucose tolerance test (normal), that were measured to evaluate the co-secretion of GH by tumor. With the bromocriptin use, the patient achieved normalization of prolactin, but persisted with high levels of IGF1, suggesting to be subclinical acromegaly. After the development of new more sensitive GH assays, cases of discrepant GH and IGF-1 results have been observed and taken to some authors to suggest that GH nadir concentration during 75 g OGTT used to acromegaly diagnosis and treatment could be lower than values considered currently normal. Thus, if this is confirmed, subclinical and oligosymptomatic acromegaly cases could have earlier diagnoses.