Since 1997 there is an online National Registry of acromegalic patients in Spain (REA). We aimed to study changes in acromegaly treatment and outcomes over the last four decades in Spain. In REA clinical and biochemical data are collected at diagnosis and updated every one to 2 years. We analyzed the first treatment received and the different treatments administered according to decade of diagnosis of acromegaly: prior to 1980, 1980-1989, 1990-1999 and 2000-2009. Surgical cure rates according to pretreatment with long-acting somatostatin receptor ligands (SRLs) were also analyzed. 1,658 patients were included of which 698 had accurate follow-up data. Treatment of acromegaly changed over time. Surgery was the main treatment option (83.8 %) and medical treatment was widely used (74.7 %) both maintained over decades, while radiation therapy declined (62.8, 61.6, 42.2 and 11.9 % over decades, p < 0.001). First treatment type also changed: surgery was the first line option up until the last decade in which medical treatment was preferred (p < 0.001). Radiotherapy was barely used as first treatment. Treatment combinations changed over time (p < 0.001). The most common treatment combination (surgery plus medical therapy), was received by 24.4, 16.4, 25.3 and 56.5 % of patients over decades. Medical treatment alone was performed in 7.3, 6, 7.2 and 14.7 % over decades. Type of medical treatment also changed, SRLs becoming the first medical treatment modality in the last decades, whereas dopamine agonist use declined (p < 0.001). Surgical cure rates improved over decades (21, 21, 36 and 38 %, p = 0.002) and were not influenced by SRL pre-surgical use. Acromegaly treatment has changed in Spain in the last four decades. Surgery has been the main treatment option for decades; however, medical therapy has replaced surgery as first line in the last decade and radiotherapy rates have clearly declined. SRLs are the most used medical treatment.

Leptin, the product of the ob gene, is a recently discovered hormone secreted by adipocytes. Cushing's syndrome is a disease state usually associated with weight gain due to the accumulation of adipose tissue. In order to study the effect of chronic glucocorticoid excess upon serum leptin levels; in the present work, four patients with recently diagnosed Cushing's syndrome and a group of control subjects matched for age, sex and body mass index (BMI) were studied. Serum leptin concentrations, measured by radioimmunoassay, were assessed in samples taken every 60 minutes over a 24 hour period. Assessment of leptin concentrations over 24 hours, by means of the area under curve showed a twofold increase in serum leptin levels in patients with Cushing's syndrome (mean+/-SEM 54.3+/-14) in comparison to control subjects (29.3+/-4.4; p<0.05). In conclusion, our data show that leptin levels are markedly increased in Cushing's syndrome patients. The relevance of this finding to the increased body fat present in patients with Cushing's syndrome merits further studies.

Acromegaly is caused by somatotroph cell adenomas (somatotropinomas [ACROs]), which secrete GH. Human and rodent somatotroph cells express the RET receptor. In rodents, when normal somatotrophs are deprived of the RET ligand, GDNF (Glial Cell Derived Neurotrophic Factor), RET is processed intracellularly to induce overexpression of Pit1 [Transcription factor (gene : POUF1) essential for transcription of Pituitary hormones GH, PRL and TSHb], which in turn leads to p19Arf/p53-dependent apoptosis. Our purpose was to ascertain whether human ACROs maintain the RET/Pit1/p14ARF/p53/apoptosis pathway, relative to nonfunctioning pituitary adenomas (NFPAs). Apoptosis in the absence and presence of GDNF was studied in primary cultures of 8 ACROs and 3 NFPAs. Parallel protein extracts were analyzed for expression of RET, Pit1, p19Arf, p53, and phospho-Akt. When GDNF deprived, ACRO cells, but not NFPAs, presented marked level of apoptosis that was prevented in the presence of GDNF. Apoptosis was accompanied by RET processing, Pit1 accumulation, and p14ARF and p53 induction. GDNF prevented all these effects via activation of phospho-AKT. Overexpression of human Pit1 (hPit1) directly induced p19Arf/p53 and apoptosis in a pituitary cell line. Using in silico studies, 2 CCAAT/enhancer binding protein alpha (cEBPα) consensus-binding sites were found to be 100% conserved in mouse, rat, and hPit1 promoters. Deletion of 1 cEBPα site prevented the RET-induced increase in hPit1 promoter expression. TaqMan qRT-PCR (real time RT-PCR) for RET, Pit1, Arf, TP53, GDNF, steroidogenic factor 1, and GH was performed in RNA from whole ACRO and NFPA tumors. ACRO but not NFPA adenomas express RET and Pit1. GDNF expression in the tumors was positively correlated with RET and negatively correlated with p53. In conclusion, ACROs maintain an active RET/Pit1/p14Arf/p53/apoptosis pathway that is inhibited by GDNF. Disruption of GDNF's survival function might constitute a new therapeutic route in acromegaly.

Our clinical profile of memory deficits related to CS relates chronic exposure to hypercortisolemia to impaired attentional-dependent working memory and delayed recall process, suggesting that cortisol levels play a critical role in the modulation of learning and memory. Possible damage to hippocampus and extrahippocampal areas is discussed.

ACROSTUDY carried out with the Spanish cohort confirmed that PEG has a favorable safety and efficacy profile. The percentage of patients considered under control was similar to data reported globally and in other local ACROSTUDY results.

Aim The ACROPRAXIS program aims to describe the management of acromegaly in Spain and provide guidance. Methods Ninety-three endocrinologists were organized into 13 panels to discuss the practical issues in managing acromegaly. Based on the key learnings, an online Delphi survey with 62 statements was performed, so those statements achieving consensus could be used as guidance. Statements were rated on a 9-point scale (9, full agreement; consensus > 66.6% of response in the same tertile). Results Ninety-two endocrinologists (98.8%) answered two rounds of the survey (mean age 47.6 years; 59.8% women; median 18.5 years of experience). Consensus was achieved for 49 (79%) statements. Diagnosis: The levels of insulin-like growth factor I (IGFI) is the preferred screening test. If IGFI levels 1–1.3 ULN, the test is repeated and growth hormone (GH) after oral glucose tolerance test (OGTT) is assessed. A pituitary magnetic resonance is performed after biochemical diagnosis. Treatment: Surgery is the first treatment choice for patients with microadenoma or macroadenoma with/without optical pathway compression. Pre-surgical somatostatin analogues (SSA) are indicated when surgery is delayed and/or to reduce anaesthesia-associated risks. After unsuccessful surgery, reintervention is performed if the residual tumor is resectable, while if non-resectable, SSA are administered. Follow-up First biochemical and clinical controls are performed 1–3 months after surgery. Disease remission is considered if random GH levels are < 1 µg/L or OGTT is < 1 or ≤ 0.4 µg/L, depending on the assay’s sensitivity. Conclusion Current clinical management for acromegaly is homogeneous across Spain and generally follows clinical guidelines.

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Purpose Recent data indicate that extended dosing intervals (EDIs) with lanreotide autogel 120 mg are effective and wellreceived among patients with acromegaly who have achieved biochemical control with monthly injections of long-acting somatostatin analogues (SSAs). We further evaluated the effectiveness of lanreotide autogel 120 mg delivered at EDIs (>4 weeks) in routine clinical practice. Methods Cross-sectional, multicentre, observational study conducted to determine the effectiveness-measured by control of serum insulin-like growth factor 1 (IGF-1)-of lanreotide autogel 120 mg at dosing intervals >4 weeks for ≥6 months in selected patients with acromegaly treated in routine clinical practice (NCT02807233). Secondary assessments included control of growth hormone (GH) levels, treatment adherence, patient satisfaction, and quality of life (QoL) using validated questionnaires (EQ-5D, AcroQoL, and TSQM-9). Patients who received radiotherapy within the last 6 months were excluded. Results Among 109 patients evaluated, mean (SD) age was 59.1 (13.2) years. IGF-1 values were normal (mean [SD]: 175.0 [74.5], 95% CI: 160.8-189.1) in 91.7% of cases and normal in 91.4% of patients without previous radiotherapy treatment (n = 81). GH levels were ≤2.5 and ≤1 ng/mL, respectively, in 80.6% and 58.3%. Most patients were treated either every 5-6 (57.8%) or 7-8 weeks (38.5%), with 2.8% treated greater than every 8 weeks. The mean AcroQoL score was 63.0 (20.1). The mean global treatment satisfaction score (TSQM-9) was 75.1 (16.6). Treatment adherence (defined as no missed injections) was 94.5%. Conclusion Lanreotide autogel 120 mg at intervals of >4 weeks provided IGF-1 control in more than 90% of patients with acromegaly. Treatment satisfaction and adherence were good. These findings support use of extended dosing intervals in patients who have achieved good biochemical control with long-acting SSAs.