Prevalence, Clinical and Biochemical Spectrum, and Treatment Outcome of Acromegaly With Normal Basal GH at Diagnosis.

Context: The term micromegaly has been used to describe a subset of patients who have elevated IGF-1 levels but apparently normal basal GH (bGH) concentrations and often a glucose-suppressed GH of <1 ng/mL. Objective: To evaluate the prevalence, clinical spectrum, and therapeutic outcome of acromegaly with normal bGH at diagnosis. Design and Methods: Retrospective analysis of a cohort of patients with acromegaly diagnosed and treated at a tertiary care center. Results: A cohort of 528 patients with acromegaly was stratified according to bGH at diagnosis: group 1, <2 ng/mL, n = 16; group 2, 2 to 9.9 ng/mL, n = 202; group 3, 10 to 99 ng/mL, n = 294; and group 4, ≥100 ng/mL, n = 16. Patients in group 1 (normal bGH) constituted 3% of the total cohort and were significantly older and more likely to be male than patients in the other groups. The frequency of acromegalic symptoms, signs, and comorbidities was similar between the four patient groups. Patients in group 1 more often harbored microadenomas (75%) and had significantly lower median IGF-1 and postglucose GH levels. Surgical success rates were similar between patients from groups 1 (53.8%), 2 (54.1%), and 3 (36.9%), whereas only 13.3% of patients in group 4 achieved remission. Conclusion: Normal bGH acromegaly is uncommon in real life. These patients have some distinctive features that argue against this being simply acromegaly in its early stages.

Persistence of Diabetes and Hypertension After Multimodal Treatment of Acromegaly.

Context: Diabetes and hypertension are frequent comorbidities of acromegaly. Objective: To analyze the course of diabetes and hypertension at diagnosis and after multimodal therapy in a large cohort of patients with acromegaly. Design and Setting: Retrospective study at a tertiary care center. Patients and Methods: A total of 522 patients with acromegaly treated according to a preestablished protocol. Main Outcome Measures: Prevalence of diabetes and hypertension and its relationship with biochemical indices of acromegalic control. Results: The cohort was stratified according to disease activity upon last visit to clinic: (1) surgical remission (n = 122), (2) pharmacologically controlled (n = 92), (3) active disease (n = 148), (4) insulinlike growth factor (IGF)-1 discordance (n = 64), and (5) growth hormone (GH) discordance (n = 96). The prevalence of diabetes and hypertension at diagnosis was 30% and 37%, respectively, and did not change upon the last visit (30.6% and 38%). Both comorbidities were more prevalent at diagnosis and on the last visit than in the general population. Diabetes was less prevalent on the last visit in patients who achieved surgical remission than in those who persisted with active disease (25% vs 40%, P = 0.01). Upon multivariate analysis, diabetes was associated with an IGF-1 at diagnosis >2× upper limit of normal, with the persistence of active acromegaly, the presence of hypertension upon the last visit, with the presence of a macroadenoma, and with female sex. Conclusion: Our findings underscore the importance of an integral approach when managing these patients, focusing not only on the control of GH and IGF-1 levels but also on the timely diagnosis and the specific treatment of each comorbidity.

An FSH and TSH pituitary adenoma, presenting with precocious puberty and central hyperthyroidism.

A 19-year-old woman with a history of isosexual precocious puberty and bilateral oophorectomy at age 10 years because of giant ovarian cysts, presents with headaches and mild symptoms and signs of hyperthyroidism. Hormonal evaluation revealed elevated FSH and LH levels in the postmenopausal range and free hyperthyroxinemia with an inappropriately normal TSH. Pituitary MRI showed a 2-cm macroadenoma with suprasellar extension. She underwent successful surgical resection of the pituitary tumor, which proved to be composed of two distinct populations of cells, each of them strongly immunoreactive for FSH and TSH, respectively. This mixed adenoma resulted in two different hormonal hypersecretion syndromes: the first one during childhood and consisting of central precocious puberty and ovarian hyperstimulation due to the excessive secretion of biologically active FSH and which was not investigated in detail and 10 years later, central hyperthyroidism due to inappropriate secretion of biologically active TSH. Although infrequent, two cases of isosexual central precocious puberty in girls due to biologically active FSH secreted by a pituitary adenoma have been previously reported in the literature. However, this is the first reported case of a mixed adenoma capable of secreting both, biologically active FSH and TSH. LEARNING POINTS: Although functioning gonadotrophinomas are infrequent, they should be included in the differential diagnosis of isosexual central precocious puberty.Some functioning gonadotrophinomas are mixed adenomas, secreting other biologically active hormones besides FSH, such as TSH.Early recognition and appropriate treatment of these tumors by transsphenoidal surgery is crucial in order to avoid unnecessary therapeutic interventions that may irreversibly compromise gonadal function.

THE PREVALENCE OF COLONIC POLYPS IN PATIENTS WITH ACROMEGALY: A CASE-CONTROL, NESTED IN A COHORT COLONOSCOPIC STUDY.

OBJECTIVE: Acromegaly is associated with an increased risk of colonic polyps. The magnitude of such risk is controversial, and the characteristics that distinguish patients who develop polyps from those who do not are not well established. This study was performed to determine the prevalence of colonic polyps upon the diagnosis of acromegaly and to compare the clinical and biochemical features of patients with and without polyps. METHODS: Out of 165 patients who underwent a full colonoscopy upon diagnosis of acromegaly, 53 were found to harbor colonic lesions (cases), whereas the remaining 112 were used as controls. Demographic, clinical, and biochemical characteristics were compared between the 2 groups. RESULTS: The prevalence of colonic polyps was 32%, with an estimated relative risk of 6.21 (95% confidence interval [CI] 4.08-9.48). Adenomatous and nonadenomatous polyps were found in 22 and 31 patients, respectively. The most common location was the descending colon. Compared to patients without polyps, subjects with polyps were somewhat older and had significantly higher insulin-like growth factor-1 (IGF-1) levels and a higher prevalence of diabetes. Upon multivariate analysis, only IGF-1 level at diagnosis remained significantly associated with colonic polyps in general and with hyperplastic polyps in particular. CONCLUSION: Acromegaly is associated with an elevated risk of developing colonic polyps, particularly, distally located hyperplastic lesions. Except for a higher IGF-1 level at diagnosis, no distinctive clinical or biochemical features can be found among those who develop polyps compared to those who do not. ABBREVIATIONS: CI = confidence interval GH = growth hormone IGF-1 = insulin-like growth factor 1 IQR = inter-quartile range RR = relative risk ULN = upper limit of normal.

AIP mutations in young patients with acromegaly and the Tampico Giant: the Mexican experience.

Although aryl hydrocarbon receptor-interacting protein (AIP) mutations are rare in sporadic acromegaly, their prevalence among young patients is nonnegligible. The objectives of this study were to evaluate the frequency of AIP mutations in a cohort of Mexican patients with acromegaly with disease onset before the age of 30 and to search for molecular abnormalities in the AIP gene in teeth obtained from the "Tampico Giant". Peripheral blood DNA from 71 patients with acromegaly (51 females) with disease onset <30 years was analysed (median age of disease onset of 23 years) and correlated with clinical, biochemical and imaging characteristics. Sequencing was also carried out in DNA extracted from teeth of the Tampico Giant. Five patients (7 %) harboured heterozygous, germline mutations of the AIP gene. In two of them (a 9-year-old girl with gigantism and a young man with symptoms of GH excess since age 14) the c.910C>T (p.Arg304Ter), well-known truncating mutation was identified; in one of these two cases and her identical twin sister, the mutation proved to be a de novo event, since neither of their parents were found to be carriers. In the remaining three patients, new mutations were identified: a frameshift mutation (c.976_977insC, p.Gly326AfsTer), an in-frame deletion (c.872_877del, p.Val291_Leu292del) and a nonsense mutation (c.868A > T, p.Lys290Ter), which are predicted to be pathogenic based on in silico analysis. Patients with AIP mutations tended to have an earlier onset of acromegaly and harboured larger and more invasive tumours. A previously described genetic variant of unknown significance (c.869C > T, p.Ala299Val) was identified in DNA from the Tampico Giant. The prevalence of AIP mutations in young Mexican patients with acromegaly is similar to that of European cohorts. Our results support the need for genetic evaluation of patients with early onset acromegaly.

HEALTH-RELATED QUALITY OF LIFE IN PATIENTS WITH NONFUNCTIONING PITUITARY ADENOMAS UNDERGOING POSTOPERATIVE RADIATION THERAPY: A CASE-CONTROL STUDY.

OBJECTIVE: Nonfunctioning pituitary adenomas (NFPAs) can be associated with significant morbidity including a compromised quality of life (QoL). Radiotherapy (RT) is listed as one of the contributing factors to QoL impairment in these patients, however the evidence supporting this association is scarce and conflicting. Here we evaluate health-related QoL (HRQoL) impairment in patients with NFPA and to what extent this is due to RT. METHODS: HRQoL was evaluated with the short form-36 questionnaire (SF-36), which explores 8 domains pertaining physical, emotional, and mental well being. We assessed 50 patients with NFPA subjected to RT after pituitary surgery, and their results were compared to those from 127 subjects who had undergone surgery but not RT. Both groups were matched for age, sex, and metabolic and cardiovascular comorbidities. The SF-36 was applied a median of 72 months after RT in the group of cases and 78 months after the last surgical procedure in the control group. RESULTS: Both groups scored equally low in the 8 areas explored by the survey. In a multiple linear regression model, age was significantly associated with worse physical health scores, whereas female sex was associated with worse general health perception and lower emotional role and physical role scores. The presence of a visual field defect was significantly associated with a worse social role functioning score. CONCLUSION: QoL in patients with NFPAs is significantly compromised in most scales evaluated by the SF-36 survey. However, RT itself does not affect QoL.

Inflammatory Cytokine Profile Associated with Metabolic Syndrome in Adult Patients with Type 1 Diabetes.

OBJECTIVE: To compare the serum concentration of IL-6, IL-10, TNF, IL-8, resistin, and adiponectin in type 1 diabetic patients with and without metabolic syndrome and to determine the cut-off point of the estimated glucose disposal rate that accurately differentiated these groups. DESIGN: We conducted a cross-sectional evaluation of all patients in our type 1 diabetes clinic from January 2012 to January 2013. Patients were considered to have metabolic syndrome when they fulfilled the joint statement criteria and were evaluated for clinical, biochemical, and immunological features. METHODS: We determined serum IL-6, IL-8, IL-10, and TNF with flow cytometry and adiponectin and resistin concentrations with enzyme linked immunosorbent assay in patients with and without metabolic syndrome. We also compared estimated glucose disposal rate between groups. RESULTS: We tested 140 patients. Forty-four percent fulfilled the metabolic syndrome criteria (n = 61), 54% had central obesity, 30% had hypertriglyceridemia, 29% had hypoalphalipoproteinemia, and 19% had hypertension. We observed that resistin concentrations were higher in patients with MS. CONCLUSION: . We found a high prevalence of MS in Mexican patients with T1D. The increased level of resistin may be related to the increased fat mass and could be involved in the development of insulin resistance.

High prevalence of metabolic syndrome in a mestizo group of adult patients with primary hyperparathyroidism (PHPT).

BACKGROUND: Primary hyperparathyroidism (PHPT) and metabolic syndrome (MS) have been independently related to cardiovascular morbidities, however this association is still controversial. Mexican population has a high prevalence of metabolic syndrome, however its frequency seems to be even higher than expected in patients with PHPT. METHODS: We retrospectively reviewed the charts of patients that underwent parathyroidectomy for PHPT in a referral center and used the criteria from the National Cholesterol Educational Program (NCEP)/Adult Treatment Panel III (ATP III) to define MS before surgery. We compared the characteristics between the patients with and without MS. RESULTS: 60 patients were analyzed, 77% were female and 72% had a single parathyroid adenoma. MS was present in 59% of the patients, this group was significantly older (57 vs. 48 years, p = 0.01) and they had lower iPTH (115 vs. 161 ng/ml, p = 0.017). Other parameters did not show differences. CONCLUSIONS: MS is frequent in our population diagnosed with primary hyperparathyroidism, adverse cardiovascular parameters are common and significant differences in calcium metabolism compared to the non-MS group are present.

Clinical characteristics and treatment outcome of 485 patients with nonfunctioning pituitary macroadenomas.

Background. Nonfunctioning pituitary adenomas (NFPAs) are the most common benign lesions of the pituitary gland. Objective. To describe our experience with the management of NFPA. Study Design and Methods. Retrospective evaluation of NFPA patients managed between 2008 and 2013. We analyzed data regarding clinical presentation, imaging diagnosis, hormonal status, surgical, radiotherapeutic, and pharmacological treatment, and outcome. Results. 485 patients (54% men, mean age 53 ± 14 years) were followed for a median of 6.5 years. Visual field abnormalities and headaches were the presenting complaints in 87% and 66%, respectively. The diagnosis of NFPA was made incidentally in 6.2%, and 8% presented with clinical evidence of apoplexy. All patients harbored macroadenomas, with a median volume of 10306 mm(3); 57.9% had supra- or parasellar invasion and 19.6% had tumors larger than 4 cm. Central hypothyroidism, hypogonadism, and hypocortisolism were present in 47.2%, 35.9%, and 27.4%, respectively. Surgical resection was performed at least once in 85.7%. Tumor persistence was documented in 27% and was related to the size and invasiveness of the lesion. In selected cases, radiotherapy proved to be effective in controlling or preventing tumor growth. Conclusions. The diagnosis and treatment of NFPA are complex and require a multidisciplinary approach.

Octreotide LAR treatment of acromegaly in "real life": long-term outcome at a tertiary care center.

OBJECTIVE: To report our day-to day experience with the long-term use of octreotide LAR in the treatment of acromegaly. PATIENTS AND METHODS: Patients with acromegaly managed between 2003 and 2012 with octreotide LAR for a median of 27 months (interquartile ranges 12-60) and who had not received radiation therapy or concomitant treatment with cabergoline were retrospectively evaluated. Both primarily treated patients (n = 33) and patients who received octreotide after failed pituitary surgery (adjunctive treatment, n = 124) were included. Full biochemical response was defined as the achievement of a GH <2.5 ng/mL and an IGF-1 <1.2 times the upper limit of normal (× ULN); we also evaluated efficacy using a GH cut off of <1 ng/mL. RESULTS: Over 60% of the patients achieved a GH of <2.5 ng/mL. The combined GH (<2.5 ng/mL) and IGF-1 (<1.2 × ULN) target was achieved by 35.5 and 33.6% of the patients treated primarily and adjunctively, respectively; these figures dropped to 22.6 and 23% when using a GH target of <1 ng/mL. All patients reported a significant improvement in acromegalic symptoms. Lower pretreatment GH and IGF-1 levels were both associated with a higher probability of achieving the composite biochemical target. CONCLUSION: Currently recommended GH and IGF-1 targets are reached by <36% of patients treated with octreotide LAR in a day-to day practice context. Nevertheless, in most instances a clinical benefit and an improvement in biochemical markers can be clearly documented.

Cytoplasmic expression of SSTR2 and 5 by immunohistochemistry and by RT/PCR is not associated with the pharmacological response to octreotide / La expresión citoplásmica de SSTR2 y 5 por inmunohistiquímica y por RT/PCR no se correlaciona con la respuesta farmacológica a octreótido

OBJECTIVE: To evaluate expression of somatostatin receptor subtypes 2 and 5 (SSTR 2 and 5) by RT/PCR and immunohistochemistry (IHC) in GH-secreting adenomas, seeking correlations with response to octreotide. METHODS: SSTR2 and 5 expression was tested by IHC (n = 37), RT/PCR (n = 36) or both (n = 13) in GH-secreting adenomas from 60 patients with acromegaly who had undergone pituitary surgery; 36 had been treated preoperatively with octreotide LAR for 3-6 months, and were categorized as responders (achievement of GH < 2.5 ng/mL and a normal age-adjusted IGF-1), partial responders (GH and IGF-1 reduction > 50% and > 30%, respectively) or non-responders. IHC was performed on a tissue microarray using specific antibodies directed to the carboxyl terminus of SSTR2 and 5. RESULTS: SSTR5 was the predominantly expressed receptor subtype by both IHC and RT/PCR in all tumors tested, regardless of whether they came from octreotide-naïve, octreotide-responsive, or octreotide-resistant patients. Immunostaining was concentrated in the cytoplasm. Neither SSTR2 nor SSTR5 expression correlated with baseline or post-octreotide GH or IGF-1 levels or tumor volume by either method. The agreement rate between RT/PCR and IHC was 77% in all 13 adenomas in which both methods were used. CONCLUSIÓN: Expression of these receptors does not guarantee an adequate response to somatostatin analogs; other functional aspects of this interaction, such as receptor homo- and heterodimerization, and the resulting signaling cascade, probably play a role in determining whether a patient will respond or not to these agents

OBJETIVOS: Evaluar la expresión de los receptores somatostatinérgicos 2 y 5 (SSTR 2 y 5) por RT/PCR e inmunohistoquímica (IHQ) en adenomas productores de GH, buscando correlaciones con la respuesta a octreótido. MÉTODOS: Se analizó la expresión de SSTR2 y SSTR5 mediante IHQ (n = 37), RT/PCR (n = 36) o ambas (n = 13) en adenomas productores de GH de 60 pacientes con acromegalia sometidos a cirugía; 36 habían recibido tratamiento preoperatorio con octreótido LAR durante 3-6 meses y fueron categorizados como respondedores (GH < 2.5 ng/mL e IGF-1 normal para edad), respondedores parciales (reducción de GH e IGF-1 a > 50% y > 30%, respectivamente) y no respondedores. La IHQ se realizó en una micromatriz de tejido, usando anticuerpos dirigidos contra el extremo carboxilo de SSTR 2 y 5. RESULTADOS: SSTR5 fue el receptor predominante en todos los tumores, tanto por IHQ como por RT/PCR, independientemente de si provenían de pacientes tratados (sensibles o resistentes) o no tratados con octreótido. La inmunotinción se localizó fundamentalmente en el citoplasma. No encontramos correlaciones entre la expresión de estos receptores por ninguno de los dos métodos con los niveles basales y post-octreótido de GH e IGF-1 ni con el volumen tumoral. La concordancia entre RT/PCR e IHQ fue del 77% en los 13 adenomas en los que ambos métodos fueron utilizados. CONCLUSIONES: La expresión de estos receptores no garantiza la respuesta farmacológica a análogos de la somatostatina; otros aspectos funcionales como la homo y heterodimerización, y la cascada de señalización producida, probablemente están involucrados en la determinación de la respuesta de cada paciente a estos agentes

Successful mortality reduction and control of comorbidities in patients with acromegaly followed at a highly specialized multidisciplinary clinic.

CONTEXT: Acromegaly is usually due to the excessive secretion of GH by a pituitary adenoma. It is frequently accompanied by comorbidities that compromise quality of life and results in elevated mortality rates. OBJECTIVE: To evaluate mortality and morbidity in patients with acromegaly receiving multimodal care. SETTING: Tertiary care center. DESIGN, PATIENTS, AND METHODS: Retrospective evaluation of 442 patients (65.4% women; mean age, 43.5 ± 13.1 y) followed for a median of 6 years (interquartile range [IQR], 3-10). RESULTS: Twenty-two patients died during the study period (4.9%), representing a total standardized mortality ratio (SMR) of 0.72 (95% confidence interval [CI], 0.41-1.03). Standardized mortality ratios were 1.5 and 0.44 for patients whose last GH was above and below 2.5 ng/mL, respectively; 1.17 and 0.16 for those whose last GH was above and below 1 ng/mL, respectively; and 0.94 and 0.46 for those whose last IGF-1 was above and below 1.2 times the upper limit of normal (ULN), respectively. The prevalence of diabetes mellitus, hypertension, heart disease, and cancer was 30%, 35%, 8%, and 4.7%, respectively. The most common cause of death was cancer. On multivariate analysis, diabetes, heart disease, and cancer were related to a baseline GH > 10 ng/mL; the presence of cancer and the last IGF-1 were significant predictors of mortality. Survival decreased as the latest GH levels increased from < 1 ng/mL to > 5 ng/mL and as IGF-1 increased from < 1.2 to > 2 times the ULN. CONCLUSIONS: Mortality in acromegaly can be successfully reduced, provided patients are treated using a multimodal approach with careful management of comorbidities.

Pituitary apoplexy in nonfunctioning pituitary macroadenomas: a case-control study.

OBJECTIVE: Pituitary apoplexy (PA) is an endocrinologic emergency characterized by headache, visual abnormalities, and hemodynamic instability in the context of hemorragic infarction of a pituitary adenoma. Our goal was to estimate the incidence, precipitating factors, clinical characteristics, and outcome of PA in a cohort of patients with nonfunctioning pituitary macroadenomas (NFPMAs). METHODS: A retrospective, case-control study of 46 patients with PA and 47 controls matched for age, gender, and tumor invasiveness. Clinical, hormonal, and tumoral charactersitics, as well as the presence of potential precipitating factors and long-term outcome were evaluated using both bivariate and multivariate analysis. RESULTS: The prevalence of PA was 8%. Cases and controls were similar in regards to the prevalence of diabetes, hypertension, use of antiplatelet agents, and the presence of headaches and visual field defects. Oculomotor paralysis was present in 18% of cases and in none of the controls (P = .001). Prior use of dopamine agonists was significantly more frequent among cases than in controls on both bivariate and multivariate analysis. Pituitary hormone deficiencies were more common among cases than in controls on bivariate but not on multivariate analysis. Early and late surgical treatment was carried out in 11 and 25 patients, respectively; 11 patients were managed conservatively. Visual and endocrine outcomes were similar among the 3 groups. CONCLUSION: PA represents a life-threatening medical emergency. Prior use of dopamine agonists and the presence of oculomotor abnormalities clearly distinguished patients with NFPMA who developed PA from those who did not.

Cytoplasmic expression of SSTR2 and 5 by immunohistochemistry and by RT/PCR is not associated with the pharmacological response to octreotide.

OBJECTIVE: To evaluate expression of somatostatin receptor subtypes 2 and 5 (SSTR 2 and 5) by RT/PCR and immunohistochemistry (IHC) in GH-secreting adenomas, seeking correlations with response to octreotide. METHODS: SSTR2 and 5 expression was tested by IHC (n=37), RT/PCR (n=36) or both (n=13) in GH-secreting adenomas from 60 patients with acromegaly who had undergone pituitary surgery; 36 had been treated preoperatively with octreotide LAR for 3-6 months, and were categorized as responders (achievement of GH <2.5ng/mL and a normal age-adjusted IGF-1), partial responders (GH and IGF-1 reduction >50% and >30%, respectively) or non-responders. IHC was performed on a tissue microarray using specific antibodies directed to the carboxyl terminus of SSTR2 and 5. RESULTS: SSTR5 was the predominantly expressed receptor subtype by both IHC and RT/PCR in all tumors tested, regardless of whether they came from octreotide-naïve, octreotide-responsive, or octreotide-resistant patients. Immunostaining was concentrated in the cytoplasm. Neither SSTR2 nor SSTR5 expression correlated with baseline or post-octreotide GH or IGF-1 levels or tumor volume by either method. The agreement rate between RT/PCR and IHC was 77% in all 13 adenomas in which both methods were used. CONCLUSION: Expression of these receptors does not guarantee an adequate response to somatostatin analogs; other functional aspects of this interaction, such as receptor homo- and heterodimerization, and the resulting signaling cascade, probably play a role in determining whether a patient will respond or not to these agents.

Vitamin D deficiency among medical residents and its relationship with metabolic indices.

OBJECTIVE: To evaluate different elements of the calciotropic system in a group of house staff physicians, comparing them with age, gender, and body mass index (BMI) matched controls. METHODS: We measured vitamin D, calcium, phosphorus, parathyroid hormone (PTH), glucose, insulin (estimating the insulin resistance index by the homeostatic model [HOMA]), and lipid levels in 20 medical residents and 20 age-, gender-, and BMI-matched controls. We looked for correlations between elements of the calciotropic system and metabolic indices. RESULTS: Medical residents and controls were similar in regard to gender distribution, weight, height, BMI, abdominal circumference, as well as systolic and diastolic blood pressure. No differences were found between the two groups in regard to low-density lipoprotein (LDL)-cholesterol, high-density lipoprotein (HDL)-cholesterol, plasma insulin levels, and HOMA-IR. Vitamin D and calcium levels were significantly lower among the medical residents (P = .001 and P = .003, respectively), whereas PTH concentrations tended to be higher. We found an inverse correlation between triglyceride concentrations and vitamin D (r = -0.31, P = .04). CONCLUSION: Vitamin D deficiency among resident physicians is frequent and could have metabolic effects. Our findings highlight the consequences of the lack of sun exposure due to occupational reasons. We recommend a higher intake of vitamin D during this period.

Expression of Ki-67, PTTG1, FGFR4, and SSTR 2, 3, and 5 in nonfunctioning pituitary adenomas: a high throughput TMA, immunohistochemical study.

CONTEXT: Nonfunctioning pituitary adenomas (NFPA) are the most common pituitary neoplasms. There is no clinical, biochemical, or histopathological marker that would accurately predict recurrence of NFPA. OBJECTIVE: The aim of this study was to evaluate a large group of NFPA for the presence of potential markers of biological behavior. DESIGN AND SETTING: A cross-sectional study using a high throughput tissue microarray technology was conducted at tertiary care centers. MATERIALS AND METHODS: Seventy-four gonadotroph and null cell adenomas were included in the tissue microarray. Using highly specific antibodies and appropriate controls, we determined the expression of Ki-67, pituitary tumor transforming gene 1, the N-terminally truncated pituitary tumor-derived fibroblast growth factor receptor-4 (FGFR4), as well as somatostatin receptor subtypes 2, 3, and 5 (SSTR2, -3, and -5), in an attempt to establish correlations and/or associations with clinical characteristics of the patients. RESULTS: Median Ki-67 index was 1.49 (interquartile range, 0.62-2.49). Pituitary tumor transforming gene 1 nuclear immunoreactivity was found in all but one tumor (median percentage of positive nuclei, 11.44); immunopositivity for FGFR4 was found in the majority of the tumors, with variable levels of expression. The immunostaining score for SSTR2 was significantly higher than that for SSTR3 or SSTR5. FGFR4 expression correlated positively with SSTR2 and SSTR5 immunostaining scores (r = 0.59; P < 0.001; and r = 0.46; P < 0.001, respectively). Multivariate analysis revealed that the Ki-67 index was significantly associated with a tumor size greater than 3 cm (odds ratio, 2.32; 95% confidence interval, 1.17-4.58) as well as with tumor recurrence (odds ratio, 1.4; 95% confidence interval, 1.03-1.89). CONCLUSIONS: Ki-67 is the most consistent marker of biological behavior in NFPA. The finding of significant amounts of SSTR2 and SSTR5 may have therapeutic implications regarding the use of somatostatin analogs in preventing tumor recurrence.

Discontinuation of octreotide LAR after long term, successful treatment of patients with acromegaly: is it worth trying?

BACKGROUND: Somatostatin analogs (SA) have been used for over 25 years in the treatment of acromegaly. A major disadvantage is the need to continue therapy indefinitely. OBJECTIVE: To evaluate the feasibility of discontinuing therapy in well-controlled patients with acromegaly treated chronically with SA. DESIGN AND METHODS: Of the 205 subjects on octreotide LAR, we selected those who met the following criteria: two or more years of treatment, a stable dose and injection interval of 20  mg every 8 weeks or longer for the previous year, no history of radiation, no cabergoline for the previous 6 months, a GH <1.5  ng/ml, and an IGF1 <1.2×upper limit of normal (ULN). Octreotide LAR was stopped and both GH and IGF1 were measured monthly for 4 months; a glucose-suppressed GH value and magnetic resonance imaging were obtained at the 4th month, thereafter, basal GH and IGF1 were measured q. 3 months, for 12-18 months. Patients were removed from the study if GH or IGF1 rose to 1.5  ng/ml or 1.2×ULN respectively. RESULTS: Twelve patients (ten women, mean age 48±13 years) were studied. Seven patients (58.3%) relapsed biochemically within 1 year of having stopped the SA; two patients relapsed by GH and IGF1 criteria, the remaining five patients kept GH levels within target. Five patients (41.7%) remain in remission after 12 months of follow-up. Non-recurring patients were on longer injection intervals but no other characteristic was associated with a successful withdrawal. CONCLUSION: Withdrawal of SA is possible in a small but distinct subset of patients, particularly in those who are very well controlled on relatively low doses administered at long intervals.

Efficacy and safety of radiotherapy in acromegaly.

BACKGROUND AND AIMS: Transsphenoidal surgery remains the treatment of choice in acromegaly, yet 40-50% of patients require secondary forms of therapy such as radiation therapy (RT) and somatostatin analogues (SA). We undertook this study to evaluate the efficacy and safety of RT in acromegaly. METHODS: Forty patients with acromegaly treated with RT (mean dose, 52 Gy) after failed pituitary surgery between 1993 and 2007 were analyzed; all were clinically and biochemically active. Patients were evaluated with yearly hormonal measurements [basal and glucose-suppressed growth hormone (GH), IGF-1, thyroid-stimulating hormone (TSH), free T4, cortisol, luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone or estradiol and prolactin (PRL)] and with magnetic resonance imaging every 2 years. RESULTS: Mean age of patients was 52.9 ± 12.1 years and 85% were female. All subjects had been followed for 1 year, 75% for 3 years, 70% for 5 years and 35% for 10 years. The median basal GH level fell from a baseline of 8.8 ng/mL to 2.27 ng/mL at 5 years (p = 0.001) and to 1.88 ng/mL at 10 years (p = 0.001). A GH <1 ng/mL was achieved by 46% and 57% of the patients at 5 and 10 years of follow-up, respectively. The proportion of patients achieving a normal IGF-1 was 36% at 5 years and 43% at 10 years. Before RT, hypothyroidism, hypocortisolism and hypogonadism were present in 44%, 26% and 74% of patients, respectively. After 5 years of follow-up (n = 28), these figures increased to 51%, 41% and 79% and over a third of the group had panhypopituitarism. One patient developed optic neuritis and another patient was diagnosed with a meningioma 10 years after RT. No cerebrovascular events or deaths occurred. CONCLUSIONS: RT is an effective, low-cost and reasonably safe means of controlling acromegalic activity, particularly useful in parts of the world where SA are not readily available.

[Elevated stimulated thyroglobulin levels in the identification of persistent papillary thyroid carcinoma]. / Importancia de las elevaciones moderadas en la tiroglobulina estimulada en la identificación de persistencia de carcinoma papilar de tiroides.

BACKGROUND: Persistence of papillary thyroid carcinoma is usually associated with elevated stimulated thyroglobulin levels. AIM OF THE STUDY: To evaluate the association between moderately elevated stimulated thyroglobulin levels and the persistence of papillary thyroid carcinoma one year after thyroidectomy and radioiodine ablation. METHODS: Out of a cohort of 97 patients with papillary thyroid carcinoma, we selected those with available stimulated thyroglobulin level measurements (in the absence of thyroglobulin antibodies) after one year of initial treatment with surgery and radioiodine. The subjects were stratified according to whether the stimulated thyroglobulin level was between 1-10 ng/ml or above 10 ng/ml. RESULTS: Twenty-seven patients were included in the study, 11 with a stimulated thyroglobulin level between 1-10 ng/ml, and 16 with values greater than 10 ng/ml. Median age and gender proportion was similar between both groups. As expected, median stimulated thyroglobulin levels were significantly greater in the second group (5.1 vs. 42 ng/ml; p < 0.001). A stratified analysis aiming at associating stimulated thyroglobulin levels with disease persistence yielded an overall risk of 0.58 (95% CI: 0.1-3.09; p = 0.52) for those subjects with levels between 1-10 ng/ml, while for those with levels > 10 ng/ml the overall risk was 1.71 (95% CI: 0.32-9.1; p = 0.52). The positive predictive value for a stimulated thyroglobulin level between 1-10 ng/ml was 64%. CONCLUSION: A moderately elevated stimulated thyroglobulin level is an uncertain predictor of papillary thyroid carcinoma persistence.

Clinical and biochemical characteristics of acromegalic patients with different abnormalities in glucose metabolism.

To determine the prevalence of diabetes, glucose intolerance and impaired fasting glucose in Mexican patients with acromegaly and establish associations with clinical, anthropometric and biochemical variables. 257 patients with acromegaly were evaluated by a 75 g-oral glucose tolerance test with measurements of both GH and glucose (0, 30, 60, 90 120 min) as well as baseline IGF-1. Normal glucose tolerance (NGT), impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and diabetes (DM) were defined based on the 2003 ADA criteria. NGT, IFG, IGT and DM were found in 27.6, 8.9, 31.6 and 31.9% of the subjects, respectively; 42 of the DM patients were unaware of the diagnosis. Patients with diabetes were older than subjects in the other 3 categories (P = 0.001), and the proportion of women was significantly higher in the DM (74%) and IGT (68%) groups than in the NGT group (52%) (P = 0.004). Odds ratio for the development of DM was 3.29 (95% CI 3.28-3.3). GH and IGF-1 levels were comparable among the different groups. In a multivariable analysis DM was significantly associated with age, presence of a macroadenoma, disease duration and a basal GH > 30 µg/dl. DM and probably IGT are more prevalent in acromegaly than in the general Mexican population. DM was more frequent in females of all ages, in subjects with severely elevated GH concentrations, in patients with macroadenomas, and long-standing disease duration. The odds ratio for DM in our subjects with acromegaly is more than 3 times higher than in the general population.