Growth Hormone Excess: Implications and Management.

Acromegaly is described as the oversecretion of growth hormone (GH) and, subsequently, insulin-like growth factor 1 (IGF-1), ascribed in most cases to a pituitary adenoma. This disease presents a progressive disfigurement, along with other systemic manifestations, which altogether diminishes the quality of life in the patients. Prolonged exposure to abnormally high levels of GH and IGF-1 levels results in cardiovascular, cerebrovascular, and pulmonary dysfunction which overall produces a fall in life expectancy. Timely diagnosis and further treatment decreased the mortality rate of the patients and showed an improvement in the quality of life. Surgical procedures, advanced radiation therapy tools, and the availability of pharmacological compounds that act on pituitary growth hormone-producing cells have enabled an improved approach to treating the disease. Pharmacological treatment is currently an important management option, and it may also be the first-line treatment in patients with acromegaly who do not benefit from or are ineligible for first-line surgical procedures. From its inception until 2021, we used a comprehensive search strategy on Medline/PubMed, Scopus, Embase, Web of Science, and the Cochrane Library electronic databases. All human research articles and review articles published in English were considered for the review. In this review, we describe the clinical implications and management of patients with acromegaly, consisting of scientific improvements underlying the developing understanding of pathogenesis and diagnosis, associated comorbidities and mortality rate with the disease, and major improvements in the treatment of the disease, along with novel strategies including quality of life and patient-reported outcomes.

Lack of delayed neurocognitive side effects of Gamma Knife radiosurgery in acromegaly: the Later-Ac study.

INTRODUCTION: Persistent growth hormone hypersecretion can be observed in roughly 50% of patients operated for somatotroph adenomas, requiring additional treatments. Despite its proven antisecretory efficacy, the use of Gamma Knife radiosurgery (GK) is limited probably due to the lack of data on long-term side effects, including potential cognitive consequences. METHODS: The LATe Effects of Radiosurgery in Acromegaly study was a cross-sectional exposed/unexposed non-randomized study. The primary objective was to determine the long-term neurocognitive effects of GK focusing on memory, executive functions, and calculation ability. Exposed patients had been treated by GK for acromegaly at least 5 years before inclusion. Unexposed patients (paired for age) had to be cured or controlled at last follow-up without any radiation technique. Patients of both groups were cured or controlled at the last follow-up. RESULTS: Sixty-four patients were evaluated (27 exposed and 37 unexposed). Mean follow-up after GK was 13 ± 6 years (including 24 patients followed for at least 10 years). While up to 23.8% of the patients of the whole cohort presented at least one abnormal cognitive test, we did not observe any significant difference in neurocognitive function between both groups. During the follow-up, 11 patients presented at least one new pituitary deficiency (P = 0.009 for thyroid-stimulating hormone deficiency with a higher rate in exposed patients), two presented a stroke (1 in each group), and one presented a meningioma (12 years after GK). CONCLUSIONS: While GK exposes patients to a well-known risk of pituitary deficiency, it does not seem to induce long-term cognitive consequences in patients treated for acromegaly.

More than a decade of real-world experience of pegvisomant for acromegaly: ACROSTUDY.

OBJECTIVE: To report the final long-term safety and efficacy analyses of patients with acromegaly treated with pegvisomant from the ACROSTUDY. DESIGN: Global (15 countries), multicentre, non-interventional study (2004-2017). METHODS: The complete ACROSTUDY cohort comprised patients with acromegaly, who were being treated with pegvisomant (PEGV) prior to the study or at enrolment. The main endpoints were long-term safety (comorbidities, adverse events (AEs), pituitary tumour volumes, liver tests) and efficacy (IGF1 changes). RESULTS: Patients (n = 2221) were treated with PEGV for a median of 9.3 years (range, 0-20.8 years) and followed up for a median of 7.4 years (range, 0-13.9 years). Before PEGV, 96.3% had received other acromegaly treatments (surgery/radiotherapy/medications). Before PEGV treatment, 87.2% of patients reported comorbidities. During ACROSTUDY, 5567 AEs were reported in 56.5% of patients and of these 613 were considered treatment-related (in 16.5% of patients) and led to drug withdrawal in 1.3%. Pituitary imaging showed a tumour size increase in 7.1% of patients; the majority (71.1%) reported no changes. Abnormal AST or ALT liver tests occurred in 3.2% of patients. IGF1 normalization rate improved over time, increasing from 11.4% at PEGV start to 53.7% at year 1, and reaching 75.4% at year 10 with the use of ≥30 mg PEGV/day in an increasing proportion of patients. CONCLUSION: This comprehensive review of the complete cohort in ACROSTUDY confirmed the overall favourable benefit-to-risk profile and high efficacy of PEGV as mono- and combination therapy in patients with an aggressive course/uncontrolled/active acromegaly requiring long-term medical therapy for control.

Predictors for Remission after Transsphenoidal Surgery in Acromegaly: A Dutch Multicenter Study.

CONTEXT: Transsphenoidal surgery (TSS) is the primary treatment of choice in acromegaly. It is important to identify patients in whom surgical cure is not attainable at an early stage, both to inform patients on expected treatment outcome and to select those who are more likely to need additional therapy. OBJECTIVE: To identify predictors for remission after TSS in acromegaly. METHODS: Large multicenter study with retrospective data collection from 3 tertiary neurosurgical referral centers in The Netherlands. We analyzed clinical data since 2000 from 3 cohorts (Groningen, Nijmegen, and Rotterdam, total n = 282). Multivariate regression models were used to identify predictors of early biochemical remission (12 weeks to 1 year postoperatively) according to the 2010 consensus criteria, long-term remission (age- and sex-normalized insulin-like growth factor 1 [IGF-1] and the absence of postoperative treatment until last follow-up), and relative IGF-1 and growth hormone [GH] reduction. RESULTS: A larger maximum tumor diameter (odds ratio [OR] 0.91, 95% CI 0.87-0.96, P ≤ .0001) was associated with a lower chance of early biochemical remission. A larger maximum tumor diameter (OR 0.93, 95% CI 0.89-0.97, P = .0022) and a higher random GH concentration at diagnosis (OR 0.98, 95% CI 0.96-0.99, P = .0053) were associated with a lower chance of long-term remission. CONCLUSION: Maximum tumor diameter and random GH concentration at diagnosis are the best predictors for remission after TSS in acromegaly.

AIP variant causing familial prolactinoma.

Pathogenic variants in the aryl hydrocarbon receptor-interacting protein (AIP) gene are increasingly recognised as a cause of familial isolated pituitary adenoma. AIP-associated tumours are most commonly growth hormone (GH) producing. In our cohort of 175 AIP mutation positive patients representing 93 kindreds, 139 (79%) have GH excess, 19 have prolactinoma (17 familial and 2 sporadic cases) and out of the 17 clinically non-functioning tumours 4 were subsequently operated and found to be GH or GH & prolactin immunopositive adenoma. Here we report a family with an AIP variant, in which multiple family members are affected by prolactinoma, but none with GH excess. To our knowledge this is the first reported family with an AIP pathogenic variant to be affected solely by prolactinoma. These data suggest that prolactinoma families represent a small subset of AIP mutation positive kindreds, and similar to young-onset sporadic prolactinomas, AIP screening would be indicated.

Surgical and Pharmacological Outcomes in Acromegaly: Real-Life Data From the Mexican Acromegaly Registry.

CONTEXT: Acromegaly registries constitute a valuable source of therapeutic outcome information in real-life. OBJECTIVE: The objective of this work is to analyze surgical and pharmacological outcomes in the Mexican Acromegaly Registry (MAR). DESIGN AND METHODS: Data were extracted from the MAR informatic platform. Surgical remission was defined by a postoperative postglucose (GH) of less than 1 ng/mL and an insulin-like growth factor 1 (IGF-1) of less than 1.2 × upper limit of normal (ULN). Pharmacological remission was defined by a basal GH of less than 1 ng/mL and an IGF-1 of less than 1.2 × ULN. RESULTS: A total of 650 surgical outcomes were analyzed (94.6% transsphenoidal). Surgical remission was achieved in 40.15%, whereas 44.15% remained biochemically active. Persistently active disease after surgery was significantly associated with harboring an invasive macroadenoma, a basal GH of greater than 10 ng/mL, and/or an IGF-1 of greater than 2 × ULN at diagnosis on bivariate and multivariate analysis. The outcome of monotherapy with first-generation somatostatin analogs (SSAs) was evaluated in 267 patients (adjunctive in 65%), of whom 28.4% achieved remission. Persistently active disease was significantly associated with harboring an invasive macroadenoma as well as with pretreatment basal GH and IGF-1 levels of greater than 10 ng/mL and greater than 2 × ULN, respectively, on bivariate and multivariate analysis. Combined therapy with SSA and cabergoline was analyzed in 100 patients, of whom 19% achieved remission and 44% remained active; in this subset of patients, only a pretreatment IGF-1 of greater than 2 × ULN was significantly associated with persistent disease activity. CONCLUSION: Surgical and pharmacological outcomes in acromegaly are highly dependent on tumor size/invasiveness as well as on the degree of hypersomatotropinemia.

Acromegaly: Update on Management and Long-Term Morbidities.

Acromegaly is a systemic disease associated with great morbidity and increased mortality if not adequately treated. In the past decades much improvement has been achieved in its treatment and in the knowledge of its comorbidities. We provide an update of acromegaly management with current recommendations. We also address long-term comorbidities emphasizing the changing face of the disease in more recent series, with a decrease of cardiovascular disease severity and an increased awareness of comorbidities like bone disease, manifested mainly as vertebral fractures and the change in the main cause of death (from cardiovascular disease to cancer in more recent series).

Differentiated thyroid carcinoma in sporadic and familial presentations of acromegaly: A case series.

BACKGROUND: In acromegaly, chronic growth hormone (GH) and insulin-like growth factor-1 (IGF-1) exacerbate comorbidities in multiple organs. Differentiated thyroid carcinoma (DTC) has been reported as being a comorbid condition in acromegaly. Acromegaly is usuallysporadic, but 5% of cases may be genetic. The most frequent inheritable form of acromegaly is related to germline mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene. Epidemiological data on the relationship between active acromegaly, its familial forms and DTC are sparse. We present the investigation of a FIPA family (familial isolated pituitary adenoma) with homogeneous acromegaly and 6 sporadic acromegaly patients with DTC. PATIENTS AND METHODS: A study of 59 acromegaly patients assessed thyroid nodules on ultrasound and fine-needle aspiration biopsy following the ATA 2015 criteria. We diagnosed 7 differentiated thyroid carcinomas. Resected thyroid carcinoma tissues were stained using an anti-AIP antibody. Analysis of germline and tumor-derived DNA for variants in the AIP and MEN1 genes were performed in the FIPA kindred. RESULTS: We describe one FIPA patient and 6 sporadic acromegaly cases with DTC. The FIPA family (AIP mutation negative) consisted of two sisters, one of whom had a DTC with intermediate risk and incomplete structural response to therapy. In our study, DTC in sporadic acromegaly had a low recurrence rate (6/6), and excellent response to therapy (6/6). Immunohistochemistry for AIP showed similar or increased staining intensity in DTC versus normal thyroid tissue. CONCLUSION: In our cohort of sporadic and familial forms of acromegaly with DTC, AIP did not appear to influence thyroid cancer progression.

Thyroid and colorectal cancer screening in acromegaly patients: should it be different from that in the general population?

The literature on an association between acromegaly and cancer is particularly abundant on either colorectal cancer or thyroid cancer, and an endless debate is ongoing whether patients with acromegaly should be submitted to specific oncology screening and surveillance protocols. The aim of the present work is to review the most recent data on the risk of either colorectal cancer or thyroid cancer in acromegaly and discuss the opportunity for specific screening in relation to the accepted procedures in the general population.

Progression of vertebral fractures in long-term controlled acromegaly: a 9-year follow-up study.

OBJECTIVE: Growth hormone (GH) and insulin-like growth factor 1 (IGF-1) excess results in both reversible and irreversible musculoskeletal damage, including increased vertebral fracture (VF) risk. The prevalence of VFs is approximately 60% in controlled acromegaly patients, and these VFs can progress in time. We aimed to identify the course of VFs in a cohort of acromegaly patients in long-term remission and their associated risk factors during prolonged follow-up. METHODS: Thirty-one patients with acromegaly (49% female, median age 60 years (IQR 53-66)), who were in remission for ≥2 years, were included in this longitudinal, prospective, follow-up study. Spine radiographs of vertebrae Th4 to L4 were assessed for VFs using the Genant score, at baseline, after 2.6 years and 9.1 years. Progression was defined as either a new fracture or a ≥1-point increase in Genant score. RESULTS: The prevalence of VF at baseline was 87% (27/31 patients). Progression of VFs was observed in eleven patients (35.5%) during the 9.1-year follow-up period, with a total incidence rate of 65.5 per 1000 person years (males 59.8 per 1000 person years vs females 71.6 per 1000 person years). Patients treated with surgery or radiotherapy had a higher risk of VF progression in this cohort (P = 0.030). CONCLUSIONS: In this cohort of long-term, well-controlled acromegalic patients, the prevalence and progression of VFs was high, showing that the deleterious effects of GH and IGF-1 excess on bone persist despite achievement of longstanding remission.

Prevalence, incidence, comorbidities, and treatment patterns among Japanese patients with acromegaly: a descriptive study using a nationwide claims database.

Epidemiological data of rare diseases are important for understanding disease burden, improving treatment, and planning healthcare systems. However, those of acromegaly in Japan are not well known. Our study aimed to describe the prevalence, incidence, prediagnostic comorbidities, and treatment patterns of patients with acromegaly in Japan. Using the National Database of Health Insurance Claims and Specific Health Checkups of Japan, we retrospectively identified 12,713 patients with acromegaly aged ≥20 years between January 2014 and December 2017 (the prevalence cohort), 2,552 newly diagnosed patients between January 2013 and December 2017 (the incidence and comorbidity cohort), and 2,125 patients enrolled in the database at least 365 days after the diagnosis (the treatment-pattern cohort). The average annual prevalence in 2015-2017 was 9.2 cases per 100,000 in the prevalence cohort, and the average annual incidence in 2013-2017 was 0.49 cases per 100,000 in the incidence and comorbidity cohort. The most common prediagnostic comorbidities included hypertension (43%), diabetes (37%), and hyperlipidemia (27%). In the treatment-pattern cohort, 54% and 45% of patients received surgery and medical treatment as the primary treatment, respectively. Between the first surgery and 365 days after diagnosis, 15% of the patients in this cohort received medical treatment as the secondary treatment, mostly with somatostatin analogs (83%). Of the 1,569 patients who underwent surgery, 29% received medical treatment before surgery. The prevalence and incidence of acromegaly in Japan were similar to those in other countries. This epidemiological study provides the basis for better management of acromegaly nationwide.

Acromegaly and joint pain: is there something more? A cross-sectional study to evaluate rheumatic disorders in growth hormone secreting tumor patients.

PURPOSE: The aim of the present study was to evaluate the rheumatic profile in acromegalic patients to better characterize joint pain. METHODS: The immunological pattern (rheumatoid factor; antinuclear antibodies-ANA, extractable nuclear antigens-ENA-Ab; anti-citrullinated protein antibodies; erythrocyte sedimentation rate) was evaluated in 20 acromegaly subjects (AS) and 20 control subjects (CS). Bilateral joint ultrasound of hands/wrists and nail capillaroscopy were also performed. RESULTS: Articular pain was more frequent in AS than in CS (p = 0.027). No difference was detected in immunological parameters. ANA and ENA-Ab were positive in only 10% of AS and in 5% of CS, while no difference was found in anti-citrullinated protein antibodies. No difference was detected between rheumatoid factor positivity, but threefold higher IgG were detected in AS compared to CS. The erythrocyte sedimentation rate was significantly higher in AS than CS (p = 0.040), while in AS, there was a trend in increased Power Doppler (PWD) articular uptake. The capillaroscopic evaluation showed a significant difference in almost each parameter (presence and number of tortuous capillaries, capillary enlargements, and hemorrhages), showing a moderate-to-severe microangiopathy in AS. CONCLUSION: The results of our study suggest that joint damage in acromegaly has not an autoimmune etiology. Increased erythrocyte sedimentation rate levels and PWD alteration in acromegalic population reflect a possible inflammatory nature, while the capillaroscopic findings suggest a moderate-to-severe microangiopathy that could help to identify patients with a greater macroangiopathic risk.

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.

The Course of Obstructive Sleep Apnea Syndrome in Patients With Acromegaly During Treatment.

BACKGROUND: Obstructive sleep apnea syndrome (OSAS) is common in active acromegaly and negatively influences quality of life, morbidity, and mortality. This prospective study with 3 predetermined timepoints and a standardized treatment protocol investigates changes in sleep parameters during the first 2.5 years of acromegaly treatment. METHODS: Before initiation of acromegaly treatment (medical pretreatment followed by surgery), polysomnography (PSG) was performed in 27 consecutive patients with treatment-naive acromegaly. PSG was repeated after 1 year (N = 24) and 2.5 years (N = 23), and anthropometric and biochemical parameters were obtained. RESULTS: At baseline, 74.1% of the patients was diagnosed with OSAS. The respiratory disturbance index (RDI; P = 0.001), oxygen desaturation index (ODI; P = 0.001), lowest oxygen saturation (LSaO2; P = 0.007) and the Epworth Sleepiness Scale (ESS; P < 0.001) improved significantly during treatment, with the greatest improvement in the first year. After 2.5 years of treatment, all patients had controlled acromegaly. Of the 16 patients with repeated PSG and OSAS at baseline, 11 (68.8%) were cured of OSAS. Changes in RDI, ODI, LSaO2, and ESS correlated with insulin-like growth factor 1 levels. CONCLUSION: OSAS has a high prevalence in active acromegaly. There is a substantial decrease in prevalence and severity of OSAS following acromegaly treatment, with the largest improvement during the first year. Most patients recover from OSAS following surgical or biochemical control of the acromegaly. Therefore, a PSG is advised after diagnosis of acromegaly. When OSAS is present, it should be treated and PSG should be repeated during acromegaly treatment.

Acromégalie : améliorer la prise en charge: Acromegaly: improving care.

Acromegaly is characterized by increased release of growth hormone (GH) and, consequently, Insulin-Like Growth Factor I (IGF-I), most often by a pituitary adenoma. Prolonged exposure to excess hormone leads to progressive somatic disfigurement and a wide range of systemic manifestations that are associated with increased mortality. Transsphenoidal adenomectomy is the treatment of choice of GH-secreting pituitary tumors but surgical cure is not achieved in around 50% of patients, then adjuvant treatment is necessary. Mortality in acromegaly is normalized with biochemical control and has decreased in the last decade with the increased use of adjuvant therapy. Both GH and IGF-I are currently biomarkers for assessing disease activity in patients with acromegaly. However, discordance between GH and IGF-I results is encountered in a quarter of treated patients. The impacts of such a discrepancy over mortality and morbidity and the risk of biochemical and/or clinical recurrence are unclear. Moreover, despite a good biochemical control, some symptoms persist, leading to a decreased quality of life. Back pain due to vertebral fractures seem to be frequent in these patients and underdiagnosed. In patients with acromegaly, bone mineral density is not a reliable predictor of fracture risk. A more accurate evaluation of bone microstructural alterations associated with GH hypersecretion and vertebral fractures may be provided by new radiological devices analyzing alteration of trabecular microarchitecture, leading to a better prevention. © 2019 Published by Elsevier Masson SAS. All rights reserved. Cet article fait partie du numéro supplément Les Must de l'Endocrinologie 2019 réalisé avec le soutien institutionnel de Ipsen-Pharma.

Central Hypothyroidism Related to Pituitary Adenomas: Low Incidence of Central Hypothyroidism in Patients With Acromegaly.

CONTEXT: The most frequent cause of central hypothyroidism (CeH) is pituitary adenomas, but the mechanisms remain unclear. OBJECTIVE: We investigated serum thyroid levels and GH/IGF-1 in central hypothyroidism in untreated patients with pituitary nonfunctioning and GH-secreting adenomas. DESIGN: This was a retrospective cross-sectional study of cases collected from Gunma University and Toranomon Hospitals between 2007 and 2016. PATIENTS: One-hundred thirty-nine cases of nonfunctioning pituitary adenoma (NFPA) and 150 cases of GH-secreting pituitary adenoma (GHPA) were analyzed. MAIN OUTCOME MEASURES: The correlations between thyroid levels, several clinicopathological parameters, and GH/IGF-1 were examined. RESULTS: Twenty-four percent of NFPA patients had CeH. The severity did not correlate with tumor size, age, or sex, and all cases had normal TSH levels. In contrast, only 8.7% of GHPA patients had CeH; approximately half had normal TSH levels and approximately half had low TSH levels. Serum TSH levels in GHPA patients were significantly lower and free T4 (FT4) and free T3 levels were higher than those in patients with NFPA. Furthermore, approximately one-fourth of GHPA patients had normal FT4 and low TSH levels. In addition, serum FT4 levels and serum TSH levels were positively and negatively correlated, respectively, with serum IGF-1 levels. Furthermore, IGF-1 levels in patients with GHPA decreased with age. CONCLUSIONS: (i) NFPA patients with CeH had TSH levels within a normal range. (ii) GHPA patients had a low incidence of CeH, which may be a result of stimulated thyroid function by GH/IGF-1. (iii) We found an age-dependent decrease in serum IGF-1 levels in patients with GHPA.

Association between KISS1 rs5780218 promoter polymorphism and onset of growth hormone secreting pituitary adenoma.

OBJECTIVES: This study analyzed the KISS1 c.-145delA (rs5780218) promoter polymorphism in a cohort of patients with growth hormone secreting pituitary adenoma (somatotropinoma) and controls, to investigate its role in the incidence of acromegaly and to assess patient/tumor characteristics. Material and methods rs5780218 allelic and genotypic distributions were compared between 49 somatotropinoma patients and 167 healthy controls. rs5780218 was also assessed in relation to patient characteristics and tumor aggressiveness, as characterized by tumor invasion and resistance to conventional therapy. The relationship between KISS1 mRNA expression and the rs5780218 genotype was also assessed in available pituitary tumor samples. RESULTS: The homozygous -/- variant genotype was associated with high rates of somatotropinoma (P<0.01), but not with tumor invasiveness, patient characteristics or hormonal remission. KISS1 mRNA expression was much lower in somatotropinomas carrying the deleted allele than in homozygous wild type AA. CONCLUSIONS: In this pilot study, the rs5780218 promoter polymorphism was evaluated in pituitary adenoma, and showed a possible association with the incidence of somatotropinoma but not with tumor progression.

Changes in metabolic parameters and cardiovascular risk factors after therapeutic control of acromegaly vary with the treatment modality. Data from the Bicêtre cohort, and review of the literature.

CONTEXT: Untreated acromegaly is associated with increased morbidity and mortality due to malignant, cardiovascular, and cerebrovascular disorders. Effective treatment of acromegaly reduces excess mortality, but its impact on cardiovascular risk factors and metabolic parameters are poorly documented. AIM: We analyzed changes in cardiovascular risk factors and metabolic parameters in patients receiving various treatment modalities. PATIENTS AND METHODS: We retrospectively studied 96 patients with acromegaly, both at diagnosis and after IGF-I normalization following surgery alone (n = 51) or medical therapy with first generation somatostatin analogues (SSA, n = 23), or pegvisomant (n = 22). Duration of follow-up was 77 (42-161) months, 75 (42-112) months, and 62 (31-93) months, in patients treated with surgery alone, SSA, and pegvisomant, respectively. In all the cases except four, patients treated medically had underwent previous unsuccessful surgery. RESULTS: IGF-I normalization was associated with increased body weight, decreased systolic blood pressure (SBP) in hypertensive patients, decreased fasting plasma glucose (FPG) and HOMA-IR and HOMA-B levels, increased HDL cholesterol (HDLc); whereas, LDL cholesterol (LDLc) was not significantly different. Plasma PCSK9 levels were unchanged in patients with available values. Cardiovascular and metabolic changes varied with the treatment modality: surgery, but not pegvisomant, had a beneficial effect on SBP; FPG decreased after surgery but increased after SSA; the decline in HOMA-IR was only significant after surgery; pegvisomant significantly increased LDLc and total cholesterol; whereas SA increased HDLc and had no effect on LDLc levels. CONCLUSION: Treatments used to normalize IGF-I levels in patients with acromegaly could have differential effects on cardiovascular risk factors and metabolic parameters.

Silent somatotropinomas.

Silent somatotroph pituitary neuroendocrine tumors (or silent growth hormone pituitary neuroendocrine tumors, SGH-PitNET) are neoplasias with positive immunostaining for growth hormone (GH), in patients with no signs and symptoms of acromegaly nor biochemical evidence of GH hypersecretion. From a clinical stand-point they are considered and managed as non-functioning pituitary tumors, since they usually come to evidence due to mass-effects (headache, visual impairment, hypopituitarism) or as asymptomatic pituitary incidentalomas. SGH-PitNET have deserved little attention in the medical literature, and no specific guidelines exist regarding their management. However, identification of a particular tumor lineage through immunostaining patterns of non-functioning pituitary tumors may determine postoperative medical therapy in the near future. This review updates the current knowledge about the epidemiologic, clinical, pathological and molecular characteristics of this particular type of pituitary tumors.

Screening of AIP Gene Variations in a Cohort of Turkish Patients with Young-Onset Sporadic Hormone-Secreting Pituitary Adenomas.

Aims: Aryl hydrocarbon receptor-interacting protein (AIP) gene mutations have long been associated with apparently sporadic pituitary adenomas (PAs) with a prevalence range of 0-12%. The aim of this study was to evaluate the frequency of germline AIP variations in a large cohort of apparently sporadic PAs diagnosed before the age of 40 years, who did not exhibit hypercalcemia and/or MEN1 syndrome components during long-term follow-up. Materials and Methods: A total of 97 patients, diagnosed with functional PAs ≤40 years old, composed of somatotropinoma (n = 55), prolactinoma (n = 25), and corticotrophinoma (n = 17), were recruited for this study. Fifty-one of these patients [somatotropinoma (n = 30), prolactinoma (n = 15), and corticotrophinoma (n = 11)] were previously reported as AIP mutation-negative by Sanger sequencing. The entire coding sequence of the AIP gene, along with exon/intron boundaries and the untranslated regions of 41 newly recruited patients, were sequenced for germline variations. In addition, all patients were subjected to multiplex ligation-dependent probe amplification to detect copy number variations in the AIP gene. Results: The AIP c.911G>A: p.Arg304Gln (rs104894190) variant was detected in only two patients with functional PA: one with somatotropinoma [in 1/55 (1.8%)] and one with prolactinoma [in 1/25 (4%)]. None of the corticotrophinomas revealed AIP gene alterations. Thus, the overall prevalence of AIP variation was 2.1% in our cohort. Conclusions: Germline AIP gene variations among Turkish patients with apparently sporadic PAs are relatively rare among patients ≤40 years old. None of the patients in our cohort revealed any obviously pathogenic AIP variants.