Thyroid autoimmune disorders in patients with acromegaly.

PURPOSE: Disorders of the hypothalamic-pituitary-thyroid axis are common in patients with acromegaly and thyroid enlargement is present in the majority of them. The exact prevalence of goiter in patients with acromegaly remains uncertain and the presence of thyroid autoimmunity has not been extensively evaluated so far. METHODS: We retrospectively evaluated thyroid biochemical and morphological findings in 116 acromegalic patients who attended our hospital. Serum TSH, total thyroxine levels and anti-thyroid peroxidase (ATPO) antibodies were measured by standard ultrasensitive techniques in all the patients. Thyroid ultrasound was performed in 75 out of them. The antibody control group was composed by healthy Argentinean individuals who attended the blood bank of our hospital in whom ATPO antibodies were measured. RESULTS: Twenty-nine out of the 116 acromegalic patients (25 %) showed elevated titers of thyroid antibodies (79 % were women and 21 % men). The control group had a 10 % prevalence of thyroid autoimmunity. The prevalence of goiter by ultrasound was 36 %, being more common in females (41 %) than in males (28 %). Thirty-five percent of patients who presented thyroid nodules and 44 % of patients with ultrasound diagnosed goiters had positive thyroid autoimmunity. There was no significant correlation between the presence of nodules and IGF-1 levels, duration of disease or age. CONCLUSION: We found a high prevalence of thyroid autoimmunity in our patients with acromegaly as compared to the normal population. Thyroid autoimmunity seems to be an additional mechanism for the development of thyroid disorders in acromegaly.

Macrocorticotropinoma shrinkage and control of hypercortisolism under long-term cabergoline therapy: case report.

Cushing's disease is the result of chronic overproduction of ACTH by a pituitary tumor. Although the optimal treatment is surgical removal of the adenoma, medical treatment might be an option in selected cases. A 40-year old woman with Cushing's disease was treated with cabergoline, a neuromodulatory drug, for a corticotrophic macroadenoma. Treatment was initiated at a weekly dose of 0.5 mg and then, on the basis of the evolution of UFC values, adjusted until it reached 6 mg/week. With cabergoline treatment the patient was asymptomatic, the pituitary adenoma showed a significant shrinkage on MRI and urinary cortisol excretion remained within the normal range during 7 years. We show the effectiveness of cabergoline in maintaining long-term biochemical control of hypercortisolism with significant reduction and stabilization of macroadenoma volume in a patient with Cushing's disease.

Perspectivas de la terapia genica en tumores tiroideos / Scope of gene Therapy in thyroid cancer

La terapia genica puede ser definida como la modalidad terapeutica en la cual se introduce material genetico dentro de una celula para modificar su funcion . Las enfermedades que resultan de la herencia de un unico gen mutado son las que presentan mayores posibilidades de ser tratadas con terapia genica. Sin embargo, el cancer parece ser originado por una acumulacion de varias alteraciones geneticas, por lo que el reemplazo de todos los genes alterados parece ser una tarea desalentadora. Se han explorado hasta el momento varias alternativas de terapia genica en el cancer tiroideo. La mayoria de estas estrategias estan dirigidas a la introduccion de genes para incrementar las terapias ya existentes. En este articulo, revisamos los diferentes vectores usados para el trnsporte de genes y las estrategias investigadas hasta el momento, in vitro e in vivo, para el tratamiento de los tumores tiroideos malignos. Aunque la terapia genica se encuentra todavia en etapa experimental, durante los ultimos años se ha observado un avance significativo que demuestra un beneficio de esta terapia aplicada a una variedad de neoplasias, que podria incluir a los carcinomas tiroideos.

Androgen-secreting adrenal adenomas.

BACKGROUND: The androgen source in women with hirsutism and signs of virilism may be the ovary or adrenal gland. CASES: Three patients with androgen excess are reported. Two had hyperandrogenemia and Cushing syndrome with an adrenal mass greater than 5.5 cm; the third had a small adrenal adenoma secreting only testosterone and responsive to human chorionic gonadotropin. In all cases, the pathologic report from surgery and the long-term resolution of symptoms confirmed the benign nature of the tumors. CONCLUSION: Basal and dynamic hormonal tests cannot precisely differentiate ovarian from adrenal tumors. Adrenal adenomas must be considered as a cause of hyperandrogenic syndrome.

The association of Cushing's disease and primary empty sella turcica.

The empty sella turcica is defined as the extension of the subarachnoid space toward the intrasellar region with displacement of the pituitary towards the posteroinferior wall. By autopsy studies, the incidence in the general population is around 20%. The association of Cushing's disease (CD) and empty sella has been infrequently reported. In our group, from a total of 68 patients with CD studied by magnetic resonance imaging (MRI), we found the presence of a primary empty sella syndrome (ESS) in 11 (16%). Of these, 9 had partial and 2 total ESS, and in four of them a microadenoma could be identified. Remission, ascertained by subnormal postoperative cortisol levels in blood and/or urine was obtained in 5 of 6 patients operated on by the transphenoidal route. Following surgery, 2 patients presented cerebrospinal fluid (CSF) leakage, 2 diabetes insipidus, and 2 some form of hypopituitarism, figures apparently higher than in non-ESS patients with CD. Ketoconazole was indicated as second line treatment in 2 patients and as primary therapy in 4, resulting in normal urinary free cortisol (UFC) values, with no complications. The relationship of ESS and CD is probably fortuitous given that the frequency of ESS in the general population is similar. Although in empty sella both surgery and radiotherapy seem to have greater risk of complications, surgery remains the first line treatment. Nevertheless, chronic treatment with ketoconazole could be a useful first choice, particularly when no adenoma is seen, or in those who have contraindications for surgery.

Alterations in the retinoblastoma pathway of cell cycle control in parathyroid tumors.

Mutations in proto-oncogenes and tumor suppressor genes have been associated with tumor development and/or progression in many neoplasms. It has been reported that parathyroid tumors have deletions affecting the retinoblastoma gene (RB), and overexpression of cyclin D1 (Cyc D1). The aim of the present study was to evaluate the alterations in the components of the pRB pathway in parathyroid adenomas and parathyroid aggressive tumors, including patterns of expression of pRB, Cyc D1, and p16/INK4A. Paired normal and tumor DNA from 6 parathyroid adenomas and 5 aggressive tumors were analyzed for loss of heterozygosity (LOH) at the RB locus. The expression of pRB, Cyc D1 and p16 was studied in 4 adenomas and 5 aggressive tumors. RB LOH was found in 1 of 6 adenomas, and in 1 of 2 informative aggressive tumors. Immunohistochemical analysis revealed undetectable pRB in 4 of 5 aggressive tumors and presence of pRB in all adenomas. Conversely, Cyc D1 expression was found in 3 of 4 aggressive tumors, but was undetectable in the adenomas. Expression of p16 was identified only in one aggressive tumor. Thus, alterations in the pRB pathway seem to prevail in the aggressive form of parathyroid neoplasms. Our results warrant further investigation of these cell cycle regulators in order to determine their potential role as tumor markers in parathyroid tumors.

Absence of mutations in the p53 tumor suppressor gene in non-invasive Cushing adenomas.

A lot of evidence supports the existence of a monoclonal origin for pituitary tumors, and several genetic alterations have already been confirmed as necessary or sufficient for unrestrained cellular growth and pituitary function. The p53 gene, a known tumor-suppressor gene (TSG), encodes a protein that exerts antiproliferative effects such as cell-growth arrest and apoptosis in response to several types of stimuli. In fact, several human cancers are believed to be caused by p53 mutations. In the case of pituitary tumors, p53 protein accumulation has been described in ACTH-secreting pituitary adenomas. Since increased amounts of the p53 protein are often related to mutations of its gene, we decided to explore the existence of p53 mutations in the tumor tissues of 9 patients bearing non-invasive corticotropinomas, excised by the transphenoidal route. We screened mutations in exons 5 to 8 of the p53 gene by the PCR-SSCP analysis. We were not able to find any mutation in the exons investigated. Our results are in close accordance with those obtained previously for other types of pituitary tumors.

[Diagnostic imaging in Cushing's disease and its correlation with postsurgical clinical course]. / Diagnóstico por imágenes en la enfermedad de Cushing y su correlación con la evolución postquirúrgica.

UNLABELLED: The purpose of this paper was to assess the accuracy of computed tomography (CT) and magnetic resonance (MR) in the preoperative identification of corticotropin-secreting pituitary adenomas and to evaluate the concordance with the postoperative outcome. A total of 44 images of patients with Cushing's disease were retrospectively taken into consideration; 23 CT and 29 MR were evaluated. Patients were subdivided into remission or persistence, following the postoperative outcome and biochemical tests. In 13 out of 23 CT performed, an adenoma was found, the remaining 10 being negative. TC sensitivity was 56.5%. Twenty five MR were positive and 4 were negative. The overall sensitivity of MR in detecting ACTH-secreting adenoma was greater (86.0%, P: 0.0373, after Yates correction). After operation, 31 patients (70.5%, Cl 0.70 +/- 0.13) were considered to be in remission (27 total remission and 4 partial remission); 23 had had preoperative visualization of the pituitary tumor and 8 negative neuroradiological evaluation. Thirteen patients had persistence of disease as shown by sustained hypercotisolism in biochemical tests. In 11 of these patients, an adenoma had been preoperatively identified whereas in the remaining 2 no evidence of tumor lesion had been detected. An histologically proven tumor was found in 33 patients but findings were negative in the remaining 11 cases. Lack of histological evidence of an ACTH-secreting adenoma was more frequent in patients with persistent hypercortisolism (P < 0.0078). IN CONCLUSION: 1) MR seems to be more sensitive than CT for detecting ACTH-secreting adenomas (P: 0.037, after Yates correction); 2) no relationship was disclosed between the absence of imaging signs of adenoma and the postsurgical outcome; 3) the remission rate was significantly higher in patients with positive than in those with negative histological findings.

Glucocorticoids: their role on gonadal function and LH secretion.

The aim of the study was to investigate gonadal function and LH reserve in patients on chronic therapy with supraphysiological doses of GC. We clinically evaluated 17 male subjects (aged 23-56 years-old) on chronic GC therapy. In four subjects (aged 23-39 years-old) randomly selected, three basal blood samples were drawn and pooled for measurement of SHBG, total, free and bioavailable testosterone. Following baseline samples, a GnRH stimulation test was performed. Starting with a priming of 5 micrograms, a bolus of 50 micrograms of GnRH was injected intravenously and samples obtained every 30 minutes for assessment of LH. Four healthy men (aged 24-28 years-old) were used as controls. Patients on steroids referred decreased libido (58%) and impotence (52%) and lower back pain (41%). Total, free and bioavailable serum testosterone were significantly lower than controls (p < 0.01, p < 0.05 and p < 0.05, respectively) while SHBG levels persisted unchanged. Baseline LH and its rise after GnRH was normal. This study shows that chronic GC administration involves gonadal function reducing sexual steroids without changes in baseline and stimulated LH secretion. In addition, the priming with physiological doses of GnRH optimizes the pituitary response to higher GnRH doses.

[Tc-99-sestamibi scan in the preoperative localization of abnormal hyperfunctioning parathyroid glands]. / Uso del Tc-99m-sestamibi en la localización preoperatoria de paratiroides anormales hiperfuncionantes.

Hyperparathyroidism is a relatively frequent condition mostly due to a solitary parathyroid adenoma. Although it has been claimed that surgical exploration is the best way to visualize the abnormal parathyroid gland, several imaging techniques have been proposed to localize it in order to simplify and shorten the surgical procedure. Echography, thalium-technetium scintigraphy, computerized tomography and nuclear magnetic resonance have shown a mean sensitivity of 75% which can be increased to about 90% by combining 2 or more of these procedures. In this study, we evaluated the utility of Tc-99m-sestamibi scintigraphy in 13 patients with hyperparathyroidism (11 primary, 2 secondary). High resolution neck echography was carried out in all of the cases. Cervical scans were obtained 10-15 min and 3 hours after giving an i.v. injection of 25 mCi Tc-99m-sestamibi in all the patients; suppression studies with combined 131-I were also done. Positive scans were obtained in 11 out of the 13 patients. Abnormal parathyroid glands were found and surgically excised in all the cases (10 adenomas, 1 carcinoma, 2 hyperplasias). Echographic localization had a sensitivity of only 33.3%. On the contrary, Tc-99m-sestamibi showed a sensitivity of 56% for the whole group, increasing to 82% in the 11 patients with primary hyperparathyroidism whereas the positive predictive value was of 91% and 90%, respectively. We conclude that Tc-99m-sestamibi is a very useful tool in localizing abnormal parathyroid glands and should be the first choice before reoperation after surgical failure or before the first parathyroid surgery whenever it is desired to shorten the surgical and anesthetic duration.

[Night suppression with high doses of dexamethasone and metyrapone tests for the etiological diagnosis of Cushing syndrome]. / Supresión nocturna con alta dosis de dexametasona y test de metopirona en el diagnóstico etiológico del Síndrome de Cushing.

Different approaches are used to determine the cause of Cushing's syndrome (CS). In this study we evaluated the validity of nocturnal high dose dexamethasone and metyrapone tests in patients with CS of different etiology. A total of 61 patients (51 women, 10 men), aged 13-61, were studied. Definitive etiological diagnosis was established on imaging, surgical and pathological findings, and/ or the clinical evolution after treatment. On that basis, the patients were classified as follows: 41 with Cushing's disease, 16 with adrenal tumors (11 adenomas and 5 carcinomas) and 4 with ectopic CS. Nocturnal dexamethasone (8 mg) test was carried out in all the patients; in 43 out of the 61 patients, 11-deoxicortisol responses to metyrapone were also determined. The sensitivity, specificity, accuracy and positive predictive power for the diagnosis of pituitary CS were calculated for both tests. For the nocturnal dexamethasone test, values were 85, 100, 90 and 100%, respectively (n = 61); the sensitivity and specificity increased to 95 and 97% by repeating the test in six false negative patients. Results for the metyrapone test were 90, 85, 88 and 93%, respectively (n = 43). When both tests were considered together, the values were 97, 100, 98 and 100% higher, although not significantly, than those for each separate test (n = 43). In conclusion, we believe that the combination of metyrapone and nocturnal high dose dexamethasone tests carried out on an outpatient basis has enough sensitivity, specificity, diagnostic accuracy and positive predictive value to be employed as an easy and low cost strategy in the etiological diagnosis of CS.

Long-term low-dose glucocorticoid therapy in hyperandrogenized women: utility and effects on bone mineral content and hypothalamic-pituitary-adrenocortical function.

The effect of chronic low-dose glucocorticoid administration on bone mineral content and corticotrope reserve was investigated in 12 hyperandrogenized women treated with 1-6 mg oral evening doses of 16 beta-methylprednisone for 12-58 months. The hypothalamic-pituitary-adrenal axis was evaluated in 9 patients by a standard metyrapone test after 45-75 days off steroid therapy. All the patients had a normal rise in serum 11-deoxycortisol after metyrapone. Bone densitometry was assessed at the end of therapy using dual photon absorptiometry. No significant differences between patients and age-matched hyperandrogenic controls were found either in spine (1.048 +/- 0.096 vs. 1.023 +/- 0.175 g/cm2) or femoral neck (0.863 +/- 0.115 vs. 0.899 +/- 0.216 g/cm2), respectively. In conclusion, absence of quantitative bone mass reduction and normal corticotrope reserve were observed even after 58 months of daily steroid administration.

[Infrequent clinical manifestations in a patient with eosinophilic granuloma]. / Manifestaciones clínicas infrecuentes en un paciente con granuloma eosinófilo.

We report the case of a 54 year old male with diabetes insipidus and diabetes mellitus who developed, twenty years later, signs of hypogonadotropic hypogonadism, secondary adrenal insufficiency and primary hypothyroidism with positive serum antithyroglobulin antibodies. At that time, an osteolytic lesion on the left temporal bone was localized by radiologic studies. A bone biopsy confirmed the diagnosis of eosinophilic granuloma. Laboratory tests also showed anemia, hypergammaglobulinemia and accelerated eritrosedimentation rate which constitute atypical manifestations of this rare disease in adults. The probable etiopathogenic mechanisms are discussed: while some authors have described an autoimmune primary defect, others have suggested a primary viral infection as the cause of Hand-Schuller-Christian disease. The association of direct and indirect evidence of immunologic alterations in our patient is suggestive of an autoimmune origin.

Manifestaciones clinicas infrecuentes en un paciente con granuloma eosinofilo / Unfrequent clinical manifestations in a patient with an eosinophilic granuloma

Se presenta el caso de un paciente de 54 años de edad, con antecedentes de diabetes insípida y diabetes mellitus de 20 años de evolución, en quien se diagnosticó un granuloma eosinófilo por medio de la biopsia de una lesión osteolítica en el hueso temporal izquierdo. Simultáneamente, se detectó la existencia de hipogonadismo hipogonadotropo, insuficiencia corticotropa e hipotiroidismo primario con anticuerpos antitiroglobulina positivos. El estudio del paciente evidenció además anemia, hipergammaglobulinemia y eritrosedimentación acelerada, manifestaciones humorales infrecuentes en el granuloma eosinófilo, enfermedad por cierto rara en el adulto. Se analizan las características clínicas, endocrinas y radiológicas que presenta este caso y los probables mecanismos patogénicos que podrían estar involucrados. La posibilidad de una alteración del sistema inmune como base de los trastornos observados es sugerida por múltiples evidencias directas e intdirectas

Nocturnal high-dose dexamethasone suppression test in the aetiological diagnosis of Cushing's syndrome.

Seventeen patients with well-proven Cushing's syndrome (13 with Cushing's disease, 3 with adrenal tumour and 1 presenting ectopic ACTH syndrome caused by bronchial carcinoid) were investigated by using a single-dose 8 mg dexamethasone nocturnal test. The results obtained were compared with those of the classical 8 mg Liddle's test, metyrapone stimulation, plasma ACTH concentration and with the final diagnosis reached through surgery, pathologic anatomy, and/or clinical and biochemical follow-up of the patients after treatment. The diagnostic efficacy or the predictive power of the test (defined as the ratio between the number of cases in which the diagnosis was correctly predicted and the total number of cases), was at least 82.4% vs 84.6% for the classical 8 mg Liddle's test. This percentage increased to 94.1% when the results of repeated tests on three patients with conflicting data were included. It is concluded that the nocturnal high-dose dexamethasone suppression test is a valuable tool in the aetiological diagnosis of Cushing's syndrome.