The association between treatment and systemic inflammation in acromegaly.

OBJECTIVE: Acromegaly is characterized by an excess of growth hormone (GH) and insulin like growth-factor 1 (IGF1), and it is strongly associated with cardiovascular diseases (CVD). Both acute and long-lasting pro-inflammatory effects have been attributed to IGF1. Previous results suggest the presence of systemic inflammation in treated patients. Here we assessed the association between treatment of acromegaly, systemic inflammation and vascular function. DESIGN: Ex vivo cytokine production and circulating inflammatory markers were assessed in peripheral blood from treated and untreated acromegaly patients (N = 120), and compared them with healthy controls. A more comprehensive prospective inflammatory and vascular assessment was conducted in a subgroup of six treatment-naive patients with follow-up during treatment. RESULTS: Circulating concentrations of VCAM1, E-selectin and MMP2 were higher in patients with uncontrolled disease, whereas the concentrations of IL18 were lower. In stimulated whole blood, cytokine production was skewed towards a more pro-inflammatory profile in patients, especially those with untreated disease. Prospective vascular measurements in untreated patients showed improvement of endothelial function during treatment. CONCLUSIONS: Acromegaly patients are characterized by a pro-inflammatory phenotype, most pronounced in those with uncontrolled disease. Treatment only partially reverses this pro-inflammatory bias. These findings suggest that systemic inflammation could contribute to the increased risk of CVD in acromegaly patients.

Endoscopic Endonasal Approach to Giant Pituitary Adenomas: Surgical Outcomes and Review of the Literature.

OBJECTIVE: To present the outcomes of endoscopic endonasal surgery for giant pituitary adenomas and discuss the extent of resection to minimize morbidity and mortality. METHODS: We retrospectively reviewed medical records of 44 patients with giant pituitary adenomas who underwent endoscopic endonasal surgery. Clinical presentation, laboratory results, imaging studies, clinical outcomes, extent of resection, and complications were collected and analyzed. Factors affecting long-term outcome according to surgical technique were identified and analyzed. RESULTS: Radical resection (RR) was defined as either gross total resection or near-total resection (90%-100% of the tumor). There were 28 patients (63.6%) who underwent RR, 10 patients (22.7%) who underwent subtotal resection, and 6 patients (13.6%) who underwent partial resection. Visual improvement was achieved in 27 patients (81.8%). Thirteen patients (72.2%) with pituitary dysfunction had improvement in at least 1 preoperative endocrinological dysfunction. RR rates for dumbbell and multilobular tumors were 44.4% and 28.6%, respectively. Surgical complications were observed in 14 (31.8%) patients. Major vascular injury occurred in 3 patients (6.8%). Mean follow-up period was 38.5 months (range, 1-70 months). No patients with RR had recurrence or residual tumor progression. Ten patients (22.7%) received adjuvant radiation therapy after resection. Two patients were reoperated on for tumor regrowth, and 3 patients (including the 2 patients with tumor regrowth) were lost to follow-up. CONCLUSIONS: Long-term follow-up results and low recurrence rate of tumors indicate that RR is effective to decrease morbidity and mortality.

Prevalence and characteristics of sellar masses in the city of Al Ain, United Arab Emirates: 2010 to 2016.

BACKGROUND: The prevalence of sellar masses (SMs) is reported in Europe and North America but only limited data are available from the Middle East and North Africa (MENA) region. OBJECTIVES: Assess the prevalence and characteristics of SMs in Al Ain city, United Arab Emirates. DESIGN: Retrospective, descriptive multicenter study. SETTING: Three endocrine centers in Al Ain. PATIENTS AND METHODS: All patients diagnosed with SMs in the city of Al Ain, Emirate of Abu Dhabi, between 2011 and 2016 were evaluated. Cases were identified using ICD 9 and 10 codes and demographic and clinical data were collected. The prevalence rate was calculated for patients alive and residing in Al Ain city until 31 December 2016. MAIN OUTCOME MEASURES: Clinical presentations and prevalence rate. SAMPLE SIZE: 272. RESULTS: The mean (SD) age on presentation was 40.8 (14.3) years (range: 6-114 years, median: 40.0). The 170 (61.8%) females and 128 (46.5%) were native citizens of the United Arab Emirates. Two hundred and forty five (90%) patients had pituitary adenomas (PAs) while 27 (10%) had non-pituitary sellar lesions. The four most common SMs were prolactinoma (n=139, 51.1%), nonfunctioning adenoma (NFA) (n= 69, 25.4%), somatotroph adenoma (n=32, 11.8%) and craniopharyngioma (n=15, 5.5%). Patients with prolactinoma, corticotroph adenoma, and Rathke's cleft cyst had small sellar masses (<1 centimeter) while the majority of patients with other SMs had macroadenomas. Hypogonadism and growth hormone deficiency was present in 41.8% and 20.5% of the patients, respectively. Of 268 patients with available data, 82 patients underwent surgery while 25 patients received radiotherapy. At the end of 2016, 197 patients were residing in Al Ain city. The overall prevalence of SMs was 25.7/100 000 with PAs constituting most of these masses (n=177) for a prevalence of 23.1/100 000. CONCLUSIONS: This is the first study of SMs in the United Arab Emirates and the MENA region. Prolactinoma and NFA were the two most common SMs. Further studies are needed to explore the reasons for the lower prevalence of SMs in our region compared with other countries. LIMITATIONS: Retrospective design, relatively small sample size. CONFLICT OF INTEREST: None.

Evaluation of the thyroid characteristics of patients with growth hormone-secreting adenomas.

BACKGROUND: Acromegaly is highly associated with thyroid disorders. However, the clinical characteristics of thyroid nodules in individuals with acromegaly who present with thyroid diseases have not been completely elucidated. METHODS: Overall, 134 consecutive participants with growth hormone (GH)-secreting adenoma (n = 67) and non-functioning (NF) pituitary adenoma (n = 67) were recruited from the outpatient and inpatient patient department of The First Affiliated Hospital, Jinan University from August 2015 to August 2017. Thyroid ultrasonography was performed using an ultrasound system. The cytopathological results of fine-needle aspiration biopsy were analyzed by a pathologist according to the Bethesda system. Twenty-one patients with GH-secreting adenoma and thyroid disease underwent transsphenoidal pituitary adenoma resection and were followed up for 1 year. RESULTS: The prevalence of thyroid disease increased in the GH-secreting adenoma group compared with that in the NF pituitary adenoma group. The number of hypoechoic, isoechogenic, heterogeneous, and vascular thyroid nodules increased in patients with GH-secreting adenoma plus thyroid disease compared with that in patients with NF pituitary adenoma plus thyroid disease. Finally, we found significant decreases in the morphology of solid nodules and significant increases in the morphology of cystic nodules after surgery compared with those before surgery in the cured group. Moreover, the numbers of heterogeneous and vascular thyroid nodules decreased significantly after surgery compared with those before surgery in the cured group. However, the characteristics of the thyroid nodules did not change after surgery compared with those before surgery in the non-cured group. CONCLUSIONS: The numbers of hypoechoic, isoechoic, heterogeneous, and vascular thyroid nodules increased in patients with GH-secreting adenomas. In these patients, surgery resulted in significant changes from solid to cystic nodules and also reduced the numbers of heterogeneous and vascular thyroid nodules.

Pediatric pituitary adenomas.

BACKGROUND: Pediatric pituitary adenomas are a rare medical entity that makes up a small portion of intracranial tumors in children and adolescents. Although benign, the majority of these lesions are secreting functional tumors with the potential for physiological sequela that can profoundly affect a child's development. FOCUS OF REVIEW: In this review, we discuss the medical and surgical management of these tumors with a focus on clinical presentation, diagnostic identification, surgical approach, and associated adjuvant therapies. We will also discuss our current treatment paradigm using endoscopic, open, and combined approaches to treat these tumors. The management of pituitary tumors requires a multidisciplinary team of surgeons, endocrinologists, and neuroanesthesiologists as well as neurocritical care specialists to deliver comprehensive care.

A Novel Mutation of Aryl Hydrocarbon Receptor Interacting Protein Gene Associated with Familial Isolated Pituitary Adenoma Mediates Tumor Invasion and Growth Hormone Hypersecretion.

BACKGROUND: Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene were identified in nearly 20% of families with familial isolated pituitary adenoma. Some variants of AIP have been confirmed to induce tumor cell proliferation and invasiveness; however, the mechanism is still unclear. METHODS: A novel missense mutation (c.512C>T, p.T171I) was discovered in 3 patients from a Chinese family with familial isolated pituitary adenoma. In silico and multiplex ligation-dependent probe amplification analysis predicted the mutation to be pathogenic. GH3 and 293FT cell lines were used to verify the variant's effect on cell proliferation (Cell Counting Kit-8), invasiveness (Transwell) and growth hormone (GH) secretion (enzyme-linked immunosorbent assay) by transfection with different vectors: control, blank vector, wild-type AIP, p.T171I variant (experimental group), p.Q315* variant, and AIP small interfering RNA. Furthermore, Zac1, Sstr2, interleukin (IL)-6, and Stat3/phosphorylation-Stat3 expression (reverse transcription polymerase chain reaction, Western blot) in each group was also evaluated. RESULTS: The experimental group, p.Q315* variant group, and AIP small interfering RNA-overexpressing group promoted cell proliferation at 24 and 48 hours, respectively (compared with the control group; P < 0.01 for both). Similarly, the cells in the experimental group manifested more invasion and GH secretion compared with the control group (P < 0.01 and P < 0.05, respectively). Furthermore, the experimental group cells expressed less Sstr2 (a prerequisite for the responsiveness to somatostatin analogues) and Zac1 (tumor suppressor gene), but more IL-6 and phosphorylated-Stat3 (GH-secretion related). CONCLUSIONS: The novel AIP mutation c.512C>T (p.T171I) is a pathogenic variant that promoted cell proliferation, invasiveness, and GH secretion through regulation of Sstr2, Zac1, and IL-6/phosphorylated-Stat3 expression.

Quantification of specific growth patterns and frequency of the empty sella phenomenon in growth hormone-secreting pituitary adenomas.

PURPOSE: To assess and quantify the prevalence and co-occurence of a sellar floor lowering and empty sella phenomenon in patients with GH (growth hormone)-secreting pituitary adenoma. METHODS: A total number of 159 acromegalic patients were included in this study, as well as two control groups (150 patients with non-GH-secreting adenomas and 50 patients without pituitary adenomas). Magnetic resonance images of all patients were evaluated for presence of an empty sella, downward and lateral tumor extension, and maximum superoinferior diameter of the mass. Additionally, these values were correlated with growth hormone and IGF-1 levels. RESULTS: The empty sella phenomenon was detected significantly more often in patients with a GH-secreting adenoma with a prevalence of 22% vs. 5.3% in non-GH-secreting adenomas (p < 0.001) or 8% in the healthy control group (p = .036). Moreover, GH-secreting adenomas presented with a significant rate of downward tumor extension (74.8% vs. 35.5%; p < 0.001), whose extent correlated inversely but weakly with the GH hormone level (r = - 0.17; p = .036). It was also found that a decreased superoinferior diameter and higher ratio of intrasellar to suprasellar extension are predictive quantitative values for the presence of a GH-secreting adenoma (area under curve, 0.712). CONCLUSIONS: GH-secreting pituitary adenomas are frequently associated with an empty sella phenomenon. Moreover, GH-secreting adenomas are frequently accompanied by an enhanced, quantitatively measurable impression of the sellar floor. Hypothetically, this is caused by tumor-induced local bone remodeling processes.

Decreasing mortality and changes in treatment patterns in patients with acromegaly from a nationwide study.

CONTEXT: New therapeutic strategies have developed for the management of acromegaly over recent decades. Whether this has improved mortality has not been fully elucidated. OBJECTIVE: The primary aim was to investigate mortality in a nationwide unselected cohort of patients with acromegaly. Secondary analyses included time trends in mortality and treatment patterns. DESIGN: A total of 1089 patients with acromegaly were identified in Swedish National Health Registries between 1987 and 2013. To analyse time trends, the cohort was divided into three periods (1987-1995, 1996-2004 and 2005-2013) based on the year of diagnosis. MAIN OUTCOME MEASURES: Using the Swedish population as reference, standardized mortality ratios (SMRs) were calculated with 95% confidence intervals (CIs). RESULTS: Overall SMR was 2.79 (95% CI: 2.43-3.15) with 232 observed and 83 expected deaths. Mortality was mainly related to circulatory diseases (SMR: 2.95, 95% CI: 2.35-3.55), including ischemic heart disease (2.00, 1.35-2.66) and cerebrovascular disease (3.99, 2.42-5.55) and malignancy (1.76, 1.27-2.26). Mortality decreased over time, with an SMR of 3.45 (2.87-4.02) and 1.86 (1.04-2.67) during the first and last time period, respectively (P = .015). During the same time periods, the frequency of pituitary surgery increased from 58% to 72% (P < 0.001) and the prevalence of hypopituitarism decreased from 41% to 23% (P < 0.001). CONCLUSIONS: Excess mortality was found in this nationwide cohort of patients with acromegaly, mainly related to circulatory and malignant diseases. Although still high, mortality significantly declined over time. This could be explained by the more frequent use of pituitary surgery, decreased prevalence of hypopituitarism and the availability of new medical treatment options.

Aggressive somatotrophinomas lacking clinical symptoms: neurosurgical management.

We report our experience about somatotrophinomas without clinical manifestation of acromegaly having radiological- and surgical-verified invasion of the cavernous sinus. We present the clinical, radiological and hormonal status of three patients affected by invasive GH-secreting pituitary adenomas without clinical signs and symptoms of acromegaly with elevation of serum IGF-1 from a series of 142 pituitary adenomas operated in our institute with the aid of intraoperative magnetic resonance imaging (MRI). Total tumor removal was possible in two of the three cases; the patients show normal hormonal status and no recurrence at long-term follow-up. In the third case, due to the different features of the tumor, complete resection was not possible and a multimodal treatment was performed that allowed regularization of the hormonal status and control of the residual tumor. GH-secreting adenomas without clinical manifestation of acromegaly are uncommon lesions. Total microsurgical excision can be curative. However, in case of partial removal, a tailored adjuvant treatment should be considered to preserve the quality of life of the patient and avoid regrowth of the lesion. In not resectable tumors, preoperative medical treatment with somatostatin analogues is always an option.

Markers of proliferation and invasiveness in somatotropinomas.

Introduction In the search for markers of invasiveness of pituitary adenomas, we studied the expression of Ki-67 antigen, TOPO 2A (topoisomerase 2 alpha), AIP (Aryl Hydrocarbon Receptor-Interacting Protein) and VEGF (Vascular Endothelial Growth Factor) in somatotropinomas. Material and Methods We retrospectively studied a group of 31 patients who underwent pituitary tumour surgery. Expression of Ki-67, TOPO 2A, AIP and VEGF in surgical specimens was determined by immunohistochemistry. Relations between quantitatively determined markers and clinical symptoms, tumour features, and MR imaging, were analysed. Acromegaly was confirmed by hormonal tests in all patients studied. Local invasiveness (cavernous sinus penetration, optic chiasm compression or suprasellar extension) was observed in 18/31 patients (58,1%). Results Ki-67 was expressed in 77.4%, TOPO 2A in 87.1%, AIP in 83.8%, and VEGF in 87.1% of 31 cases of somatropinoma. Median values of Ki-67, TOPO 2A, AIP and cytoplasmic VEGF indices were 1.2% [IQR=2.2], 1.5% [IQR=1.6], 21.26% [IQR=20.1] and 20.4% [IQR=15.4], respectively. Ki-67, TOPO 2A, AIP and VEGF expression was not correlated with age nor with patient gender (p > 0.05). Only Ki-67 and TOPO 2A correlated with tumour size (for Ki-67: r=0.42, p=0.025; for TOPO 2A: r=0.53, p=0.003). Ki-67 and TOPO 2A levels were significantly higher in invasive compared to noninvasive somatropinomas (Ki67 mean values: 1.85±1.33% vs. 0.95±1.07%, p=0.024; TOPO 2A mean values: 2.19±1.63% vs. 1.45±1.23%, , p=0.011). Conclusions Ki-67, TOPO 2A, AIP and VEGF were expressed in over 70% of all somatotropinomas. Only Ki-67 and TOPO 2A expression correlated with tumour size and tumour invasiveness.

The assessment of total antioxidant capacity and superoxide dismutase levels, and the possible role of manganese superoxide dismutase polymorphism in acromegaly.

Oxidative status is attributed to endothelial dysfunction and might be one of the key mechanisms of endothelial dysfunction in acromegaly. In this study, we aimed to investigate the effect of acromegaly on superoxide dismutase (SOD) and total antioxidant capacity (TAC) levels, and the possible influence of human manganese superoxide dismutase (MnSOD) polymorphism on these levels. 51 acromegaly patients and 57 age and sex matched healthy subjects were recruited to the study in Bezmialem Vakif University Hospital between 2011 and 2014. The median SOD and TAC levels were 42.7 (33-60) pg/mL and 1,313.7 (155-1,902) µM in acromegaly; and 46.3 (38-95) pg/mL and 1,607.3 (195-1,981) µM in healthy subjects (p < 0.001, p < 0.001). SOD levels were decreased in controlled and uncontrolled patients compared to healthy subjects (p = 0.05 and p = 0.002, respectively). Controlled and uncontrolled acromegaly displayed significantly decreased levels of TAC compared to healthy subjects (p < 0.05 and p < 0.001, respectively). SOD levels were not associated with MnSOD polymorphisms in acromegaly. In conclusion, this study showed that acromegaly was associated with decreased levels of SOD and TAC, and controlling the disease activity could not adequately improve these levels.

The efficacy of medical treatment in patients with acromegaly in clinical practice.

Although somatostatin analogues (SSAs) are recommended as the first-line medical therapy for acromegaly, dopamine agonists (DAs) are also a therapeutic option for treatment. We aimed to assess and compare the efficacies of DAs and SSAs in treating acromegaly in clinical practice. We included 89 patients with acromegaly who took DAs (bromocriptine [BCT], n = 63; cabergoline [CAB], n = 11) or SSAs (n = 15) as a primary medical therapy for more than 3 months in the Seoul National University Hospital. The CAB (45.5%) and SSA (33.3%) groups achieved random GH levels of <2.5 ng/mL and the normal IGF-1 levels were significantly higher than in the BCT group (11.1%) (p = 0.009). We further included all the patients with acromegaly (n = 132) who had taken CAB, BCT, and SSAs as first- or second-line medical therapy. The CAB group showed similar efficacy as the SSA group in terms of the GH and insulin-like growth factor-1 (IGF-1) levels (57.6% for random GH level <2.5 ng/mL, 42.4% for normal IGF-1 levels, 36.4% for both). Logistic regression analysis revealed that medications, age, GH level, or IGF-1 level before medication, hyperprolactinemia, and prior gamma-knife surgery or radiation therapy, did not affect the therapeutic response. High pretreatment GH levels predicted poor treatment outcomes (odds ratio [95% confidence interval] = 0.95 [0.90-0.99]). CAB was effective in treating acromegaly at a relatively lower cost in patients with low pretreatment GH levels.

Familial isolated pituitary adenomas (FIPA). Case report of four families and review of literature.

Background The majority of pituitary adenomas are sporadic, but about 5% of them occur in a familial setting, predominantly in multiple endocrine neoplasia type 1 and Carney complex. Familial isolated pituitary adenomas (FIPA), unrelated to the syndromes mentioned above, were also described. The clinical course of FIPA differs significantly from sporadic cases, and is characterized by a larger tumor size, more aggressive course and younger patients' age at the moment of recognition. Objectives The aim of this retrospective study is to present 4 families in which two closely related people were diagnosed with pituitary adenomas. Probably these cases are clinical manifestations of FIPA. Material and methods Eight patients within four families, presenting with anterior pituitary tumors were described. The authors analyzed medical and family histories of the patients, their imaging pictures (pituitary MRI/CT) and hormonal tests. Results Family 1.: two sisters with acromegaly in the course of macroadenoma. Family 2.: two brothers with clinically nonsecreting macroadenomas. Family 3.: father and daughter with clinically nonsecreting macroadenomas. Family 4.: young man with acromegaly caused by macroadenoma and a daughter of his mother`s sister with microprolactinoma. CONCLUSIONS: Familial isolated pituitary adenomas are more common than it was previously thought, therefore, specific questioning regarding family history should be a part of the workup of all patients with pituitary adenomas. Genetically induced pituitary tumors often have aggressive behavior in terms of tumor expansion and resistance to different treatment options and often involve a multidisciplinary approach that combines endocrine, neurosurgical, and radiological specialists.

3D Volumetric Measurements of GH Secreting Adenomas Correlate with Baseline Pituitary Function, Initial Surgery Success Rate, and Disease Control.

There is scarce data on the clinical utility of volume measurement for growth hormone (GH)-secreting pituitary adenomas. The current study objective was to assess the association between pituitary adenoma volumes and baseline endocrine evaluation, initial surgical success rate, and disease control among patients with acromegaly. A retrospective cohort study was conducted at a clinical research center including patients with acromegaly due to GH-secreting pituitary adenomas. Baseline hormonal evaluation and adenoma characteristics according to MRI were collected. Volumetric measurements of pituitary adenomas were performed using a semi-automated lesion segmentation and tumor-volume assessment tools. Rates of post-operative medical treatment, radiation therapy, and re-operation were gathered from the patients' medical records. Twenty seven patients (11 females) were included, median age 21.0 years (interquartile range 29 years, range 3-61 years). Patients harboring adenomas with a volume <2 000 mm3 had higher chance to achieve disease remission [94.1% (n=16) vs. 50.0% (n=4), p<0.05]. Adenoma volumes positively correlated with baseline plasma GH levels before and after oral glucose administration, and with plasma IGF-I and PRL levels. Adenoma volume had negative correlation with morning plasma cortisol levels. Finally, patients harboring larger adenomas required 2nd surgery and/or medical treatment more often compared with subjects with smaller adenomas. Accurate 3D volume measurement of GH-secreting pituitary adenomas may be used for the prediction of initial surgery success and for disease control rates among patients with a GH-secreting pituitary adenomas and performs better than standard size assessments.

PREDICTORS OF QUALITY OF LIFE IN 165 PATIENTS WITH ACROMEGALY: RESULTS FROM A SINGLE-CENTER STUDY.

OBJECTIVE: Even if treated, acromegaly has a considerable impact on patient quality of life (QoL); despite this, the exact clinical determinants of QoL in acromegaly are unknown. This study retrospectively examines a cohort of treated patients with acromegaly, with the aim of identifying these determinants. METHODS: Retrospective survey analysis, with 165 patients included in the study. All patients completed a survey, which included demographic data and the clinical details of their disease, the Short Form-36 Health Survey (SF-36), the revised Beck Depression Inventory (BDI-II), and the Bern Embitterment Inventory (BEI). Stepwise regression was used to identify predictors of QoL. RESULTS: The strongest predictors of the physical component score of the SF-36 were (in order of declining strength of association): Delay between first presentation of the disease and diagnosis, body mass index (BMI), number of doctors visited before the diagnosis of acromegaly, and age at diagnosis. For the mental component score, the strongest predictors were: number of doctors visited, previous radiotherapy, and age at study entry; and, for the BDI-II score: number of doctors visited, previous radiotherapy, age at study entry, and employment status at the time of diagnosis. The following were predictors of the BEI score: number of doctors visited, and age at study entry. CONCLUSION: Diagnostic delay and lack of diagnostic acumen in medical care provision are strong predictors of poor QoL in patients with acromegaly. Other identified parameters are radiotherapy, age, BMI, and employment status. An efficient acromegaly service should address these aspects when devising disease management plans. ABBREVIATIONS: BDI-II = Beck Depression Inventory II BEI = Bern Embitterment Inventory BMI = body mass index IGF-1 = insulin-like growth factor 1 MCS = mental component summary (score) PCS = physical component summary (score) QoL = quality of life SDS = standard deviation score SF-36 = Short Form-36 Health Survey.

Impact of AIP and inhibitory G protein alpha 2 proteins on clinical features of sporadic GH-secreting pituitary adenomas.

INTRODUCTION: In sporadic acromegaly, downregulation of AIP protein of the adenomas associates with invasive tumor features and reduced responsiveness to somatostatin analogues. AIP is a regulator of Gai signaling, but it is not known how the biological function of the Gai pathway is controlled. AIM: To study GNAS and AIP mutation status, AIP and Gai-2 protein expressions, Ki-67 proliferation indices and clinical parameters in patients having primary surgery because of acromegaly at a single center between years 2000 and 2010. RESULTS: Sixty patients (F/M, 31/29), mean age 49 (median 50), mean follow-up 7.7 years (range 0.6-14.0) underwent primary surgery. Four adenoma specimens (6.8%) harbored an AIP and 21 (35.6%) an activating GNAS (Gsp+) mutation. Altogether 13/56 (23%) adenomas had low AIP protein levels, and 14/56 (25%) low Gai-2 staining. In regression modeling, AIP expression associated with Gai-2 (P = 2.33 × 10-9) and lower Ki-67 (P = 0.04). In pairwise comparison, low AIP protein predicted high GH at last follow-up (mean 7.7 years after surgery, q = 0.045). Extent of treatments given for acromegaly associated with higher preoperative GH (P = 7.94 × 10-4), KNOSP (P = 0.003) and preoperative hypopituitarism (P = 0.03) and remission at last follow-up with change in 3-month postoperative IGF1 (P = 2.07 × 10-7). CONCLUSIONS: We demonstrate, for the first time, that AIP protein expression associates with Gai-2 protein intensities in sporadic somatotropinomas, suggesting a joint regulation on somatostatin signaling. Low AIP level associates with higher proliferative activity and predicts high GH concentrations after long-term follow-up. The AIP mutation rate of 6.8% is fairly high, reflecting the genetic composition of the Finnish population.

CLINICAL OUTCOMES AND SELF-REPORTED SYMPTOMS IN PATIENTS WITH ACROMEGALY: AN 8-YEAR FOLLOW-UP OF A LANREOTIDE STUDY.

OBJECTIVE: The aim of this study was to evaluate the proportion of patients with acromegaly who remained on long-term lanreotide depot after completion of an open-label multicenter phase III clinical trial (SALSA: A Multi Center Open Label Study to Assess the Ability of Subjects With Acromegaly or Their Partners to Administer Somatuline Autogel), compare baseline and long-term follow-up symptoms scores, and correlate scores with individual longitudinal clinical outcomes. METHODS: Records of all subjects previously enrolled at the Massachusetts General Hospital site of SALSA were reviewed. Those who remained on lanreotide were interviewed and asked to complete a questionnaire that they had filled out in SALSA in 2007 regarding their current symptomatology and injection side effects, as well as to complete the Acromegaly Quality of Life Questionnaire. Furthermore, clinical, biochemical, and radiographic data related to acromegaly and its comorbidities were tracked throughout follow-up. RESULTS: Six out of 7 patients chose to remain on lanreotide, and 5 of them continued lanreotide depot through last follow-up, for up to 8 years or in 1 case until death. In all cases, lanreotide remained well tolerated, and insulin-like growth factor-1 levels and pituitary imaging remained well controlled on stable doses. While comorbidities persisted or developed, the self-reported symptom score after up to 8 years of therapy showed a significant decrease in frequency or resolution in symptoms that were reported at baseline. CONCLUSION: This study shows a significant decrease in frequency or resolution in self-reported symptoms in well-controlled patients receiving long-term lanreotide therapy. ABBREVIATIONS: AcroQoL = Acromegaly Quality of Life Questionnaire GH = growth hormone GI = gastrointestinal IGF-1 = insulin-like growth factor-1 SALSA = A Multi Center Open Label Study to Assess the Ability of Subjects With Acromegaly or Their Partners to Administer Somatuline Autogel.

The Mexican Acromegaly Registry: Clinical and Biochemical Characteristics at Diagnosis and Therapeutic Outcomes.

CONTEXT: Acromegaly is a systemic disorder caused by a GH-secreting pituitary adenoma. As with other rare diseases, acromegaly registries developed in various European countries have provided us with important information. OBJECTIVE: The objective of the study was to analyze the epidemiological, clinical, biochemical, and therapeutic data from the Mexican Acromegaly Registry (MAR). SETTING: The setting of the study was a nationwide patient registry. DESIGN AND METHODOLOGY: The MAR was created in 2009. It gathers data from 24 participating centers belonging to three different institutions using a specifically designed on-line platform. Only patients diagnosed after 1990 were included in the program. RESULTS: A total of 2057 patients (51% female, mean age at diagnosis 41.1 ± 24.5 y) have been registered for an estimated prevalence of 18 cases per 1 million inhabitants. Hypertension, glucose intolerance, diabetes, and dyslipidemia were present in 27%, 18.4%, 30%, and 24% of the patients, respectively. The IGF-1 level at diagnosis and the concomitant presence of hypertension were significantly associated with the development of diabetes. Transsphenoidal surgery was the primary treatment in 72% of the patients. Pharmacological treatment, mostly with somatostatin analogs, was administered primarily and adjunctively in 26% and 54% of the patients, respectively. Treatment choice varied among the three participating institutions, with the predominance of pharmacological therapy in two of them and of radiation therapy in the third. Therapeutic outcomes were similar to those reported in the European registries. CONCLUSIONS: The MAR is the largest and first non-European registry of the disease. Our findings highlight important within-country differences in treatment choice due to variations in the availability of resources.

Coexisting diseases modifying each other's presentation - lack of growth failure in Turner syndrome due to the associated pituitary gigantism.

Introduction: Turner syndrome presents with one of the most frequent chromosomal aberrations in female, typically presented with growth retardation, ovarian insufficiency, facial dysmorphism, and numerous other somatic stigmata. Gigantism is an extremely rare condition resulting from an excessive growth hormone (GH) secretion that occurs during childhood before the fusion of epiphyseal growth plates. The major clinical feature of gigantism is growth acceleration, although these patients also suffer from hypogonadism and soft tissue hypertrophy. Case report: We presented a girl with mosaic Turner syndrome, delayed puberty and normal linear growth for the sex and age, due to the simultaneous GH hypersecretion by pituitary tumor. In the presented case all the typical phenotypic stigmata related to Turner syndrome were missing. Due to excessive pituitary GH secretion during the period while the epiphyseal growth plates of the long bones are still open, characteristic stagnation in longitudinal growth has not been demonstrated. The patient presented with delayed puberty and primary amenorrhea along with a sudden appearance of clinical signs of hypersomatotropinism, which were the reasons for seeking medical help at the age of 16. Conclusion: Physical examination of children presenting with delayed puberty but without growth arrest must include an overall hormonal and genetic testing even in the cases when typical clinical presentations of genetic disorder are absent. To the best of our knowledge, this is the first reported case of simultaneous presence of Turner syndrome and gigantism in the literature.

Early lung function abnormalities in acromegaly.

BACKGROUND: Acromegaly is an insidious disorder caused by a pituitary growth hormone (GH)-secreting adenoma resulting in high circulating levels of GH and insulin-like growth factor I (IGF-I). Respiratory disorders are common complications in acromegaly, and can severely impact on quality of life, eventually affecting mortality. OBJECTIVES: The present study aimed to explore structural and functional lung alterations of acromegalic subjects. METHODS: We enrolled 10 consecutive patients (M/F: 5/5) affected by acromegaly. In all patients, magnetic resonance imaging (MRI) revealed the presence of pituitary tumor. All patients underwent clinical, lung functional, biological, and radiological assessments. Ten healthy age-matched subjects also served as controls. RESULTS: No statistically significant differences in lung function were detected between acromegalic and healthy subjects (p ≥ 0.05 for all analyses). However, the diffusing capacity for CO (TLCO) was significantly lower in the acromegalic group than in healthy subjects (TLCO% predicted: 78.1 ± 16 vs. 90 ± 6 %, respectively, p = 0.04; KCO% predicted: 77 ± 16 vs. 93 ± 5 %, p = 0.02, respectively). None of the lung function parameters correlated with duration of the disease, or with inflammatory marker of the airways. In acromegalics, biological (exhaled NO concentrations) and imaging (total lung volume, TLV, and mean lung density, MLD) evaluations were within normal values. The TLV measured by HRCT was 3540 ± 1555 ml in acromegalics, and the MLD was -711 ± 73 HU. None of the lung functional, radiological, and biological findings correlated with GH or IGF-I levels, and no correlation was found with duration of disease. CONCLUSIONS: In the current study, lung function evaluation allowed to detect early involvement of lung parenchyma, as assessed by TLCO and KCO, even in the absence of parenchymal density alterations of the lung by HRCT. These findings suggest to routinely include the carbon monoxide diffusing capacity in the lung function assessment for an early intervention in acromegaly.