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Background and Objective: Currently, the management for pituitary apoplexy (PA) has been promoted toward a more conservative approach, particularly for patients with low-grade PA scores. Our aim was to investigate trends in PA management and compare clinical presentation, therapeutic approaches, and outcomes before and after 2017, additionally to evaluate long-term outcomes in conservatively treated patients., Methods: Spanish multicenter, retrospective study. Statistical analyses compared clinical presentation and outcomes between periods, adjusting for confounders., Results: A total of 215 patients with PA and nonfunctioning pituitary adenoma were included, with the median age of 62.2 years and 68.4% were male patients. Of which 94 (43.7%) were diagnosed before 2017 and 121 (56.3%) in 2017 or later. Conservative treatment increased from 17% before to 30.6% in the recent period (odd ratio 0.47, 95% CI 0.24-0.90, P 0.02) This trend remained significant after adjusting for hospital, age, and Knosp grade (odd ratio 0.46, 95% CI 0.22-0.89, P = .03). However, surgery remained the most frequently used therapeutic option in both periods. There were no statistically significant differences in outcomes at 3 months between periods. Surgery compared with conservative management was associated with higher permanent arginine vasopressin deficiency in both periods (0 vs 17.9%, P = .07 before 2017; 0 vs 16.7%, P = .01 after). Up to 89.7% of patients treated conservatively, presented more than 25% spontaneous tumor shrinkage, and 74.4% had more than 50% tumor reduction., Conclusion: Although conservative management increased in the last years, surgery remains the predominant option. Patients managed conservatively experience a lower risk of permanent arginine vasopressin deficiency, and a high proportion exhibit clinically significant tumor shrinkage over time., (Copyright © Congress of Neurological Surgeons 2024. All rights reserved.)

Context: Few data exist about the clinical course of acromegaly, surgical and medical outcomes in patients with GH- and prolactin cosecreting pituitary adenomas (GH&PRL-PAs). Nevertheless, some series described a more aggressive clinic-radiological behavior than in growth hormone-secreting pituitary adenomas (GH-PAs)., Objective: This work aims to evaluate differences in clinical presentation and in surgical outcomes between GH-PAs and GH&PRL-PAs., Methods: A multicenter retrospective study was conducted of 604 patients with acromegaly who underwent pituitary surgery. Patients were classified into 2 groups according to serum PRL levels at diagnosis and immunohistochemistry (IHC) for PRL: a) GH&PRL-PAs when PRL levels were above the upper limit of normal (ULN) and IHC for GH and PRL was positive or PRL levels were greater than 100 ng/dL and PRL IHC was not available (n = 130) and b) GH-PA patients who did not meet the previously mentioned criteria (n = 474)., Results: GH&PRL-PAs represented 21.5% (n = 130) of patients with acromegaly. The mean age at diagnosis was lower in GH&PRL-PAs than in GH-PAs (P < .001). GH&PRL-PAs were more frequently macroadenomas (90.6% vs 77.4%; P = .001) and tended to be more invasive (33.6% vs 24.7%; P = .057) than GH-PAs. Furthermore, they had presurgical hypopituitarism more frequently (odds ratio 2.8; 95% CI, 1.83-4.38). Insulin-like growth factor ULN levels at diagnosis were lower in patients with GH&PRL-PAs (median 2.4 [interquartile range (IQR) 1.73-3.29] vs 2.7 [IQR 1.91-3.67]; P = .023). There were no differences in the immediate (41.1% vs 43.3%; P = .659) or long-term postsurgical acromegaly biochemical cure rate (53.5% vs 53.1%; P = .936) between groups. However, there was a higher incidence of permanent arginine-vasopressin deficiency (AVP-D) (7.3% vs 2.4%; P = .011) in GH&PRL-PA patients., Conclusion: GH&PRL-PAs are responsible for 20% of acromegaly cases. These tumors are more invasive, larger, and cause hypopituitarism more frequently than GH-PAs and are diagnosed at an earlier age. The biochemical cure rate is similar between both groups, but patients with GH&PRL-PAs tend to develop permanent postsurgical AVP-D more frequently., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Pasireotide long-acting release (PAS-LAR) is a second-generation somatostatin receptor ligand (SRL) approved for acromegaly treatment. This meta-analysis aimed to evaluate the real-world effectiveness and safety of PAS-LAR in patients with acromegaly resistant to first-generation somatostatin receptor ligands (fgSRL). A systematic literature search was conducted in PubMed and Web of Science for real-world studies on PAS-LAR in acromegaly published between 2014 and 2023. Random-effects meta-analyses were performed on biochemical control rates, tumor shrinkage, and metabolic parameters. Twelve studies comprising 409 patients were included. The pooled rate of insulin-like growth factor 1 (IGF-1) control was 57.9% [95% CI: 48.4-66.8] and the percentage of patients with tumor shrinkage was 33.3% [95%CI: 19.7-50.4]. Significant reductions were observed in growth hormone standardized mean difference (SMD) 0.6 ng/mL [95% CI: 0.3 to 1.0] and IGF-1 levels SMD 0.9 ULN [95% CI: 0.4 to 1.4]. However, as expected, a worsening in glucose metabolism was noted as an increase in fasting glucose SMD - 0.8 mg/dL [95% CI: -1.0 to -0.5, p < 0.01], glycated hemoglobin SMD - 0.5% [95% CI: -0.7 to -0.2]. and type 2 diabetes mellitus prevalence SMD - 11.5% (95% CI: -17.5 to -5.5). PAS-LAR demonstrated higher effectiveness in real-world settings, with over 60% of patients achieving IGF-1 control compared to the around 30% efficacy observed in clinical trials. These findings suggest that PAS-LAR is an effective option for acromegaly patients resistant to fgSRL, but careful monitoring of glucose levels is essential. The high heterogeneity observed across studies emphasizes the need for identifying PAS-LAR response biomarkers to set-up individualized treatment approaches for optimizing patient outcomes., Competing Interests: Declarations. Institutional review board statement: Not applicable. Informed consent: Not applicable. Conflict of interest: B.B., MA, MM and M.P.D. have received consulting fees, research support, or participated in clinical trials supported by Pfizer, Ipsen, and/or Recordati. C.T. has received fees for speaker lectures from Gedeon Richte., (© 2024. The Author(s).)

Aim: To investigate the impact of pituitary surgery on glucose metabolism and to identify predictors of remission of diabetes after pituitary surgery in patients with acromegaly., Methods: A national multicenter retrospective study of patients with acromegaly undergoing transsphenoidal surgery for the first time at 33 tertiary Spanish hospitals (ACRO-SPAIN study) was performed. Surgical remission of acromegaly was evaluated according to the 2000 and 2010 criteria., Results: A total of 604 acromegaly patients were included in the study with a total median follow up of 91 months (interquartile range [IQR] 45-163). At the acromegaly diagnosis, 23.8% of the patients had diabetes mellitus (DM) with a median glycated hemoglobin (HbA1c) of 6.9% (IQR 6.4-7.9) [51.9 mmol/mol (IQR 46.4-62.8)]. In the multivariate analysis, older age (odds ratio [OR] 1.02, 95% CI 1.00-1.05), dyslipidemia (OR 5.25, 95% CI 2.81 to 9.79), arthropathy (OR 1.39, 95% CI 2.82 to 9.79), and higher IGF-I levels (OR 1.30, 95% CI 1.05 to 1.60) were associated with a greater prevalence of DM. At the last follow-up visit after surgery, 21.1% of the DM patients (56.7% of them with surgical remission of acromegaly) experienced diabetes remission. The cure rate of DM was more common in older patients (hazard ratio [HR] 1.77, 95% CI 1.31 to 2.43), when surgical cure was achieved (HR 2.10, 95% CI 1.01 to 4.37) and when anterior pituitary function was not affected after surgery (HR 3.38, 95% CI 1.17 to 9.75)., Conclusion: Glucose metabolism improved in patients with acromegaly after surgery and 21% of the diabetic patients experienced diabetes remission; being more frequent in patients of older age, and those who experienced surgical cure and those with preserved anterior pituitary function after surgery., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Pituitary apoplexy (PA) is the paradigm of endocrine and neurosurgical emergency., Objective: To evaluate the comorbidities, risk factors, clinical presentation, pituitary apoplexy score (PAS) and the outcomes of surgical vs. conservative management of PA in Spain., Methods: Spanish multicenter, observational study of 301 patients with acute PA. Statistical analyses compared risk factors, clinical presentation and outcomes between the surgical and conservative treatment groups, adjusting for potential confounders. The prevalence of cardiovascular risk factors in patients with pituitary apoplexy was compared with the Spanish population and with patients with non-functioning pituitary adenomas., Results: Median age was 59.3 years, 201 (66.8%) were men and non-functioning adenomas (77.9%) were the most common tumor type. The prevalence of diabetes (20.3% vs 13.9%, p<0.01), hypertension (48.8% vs 33.4%, p<0.01) and dyslipidemia (44.2% vs 23.3%, p<0.01), exceeded the Spanish age-adjusted population prevalence. Overall, 209 (69.4%) underwent surgery and 92 (30.6%) received conservative treatment. Surgical patients had larger tumors (26.2 vs 21.0 mm, p<0.01), chiasmal compression more frequently (77.2% vs 53.4%, p<0.01) and higher values of PAS. In the follow-up, while there were no statistically significant differences in anterior pituitary hormonal deficits between treatments, permanent vasopressin deficiency was more frequent after surgery (14.8% vs 3.3%, p<0.01)., Conclusion: There is a high burden of cardiovascular risk factors among patients with PA suggesting that metabolic factors may play a potential role in the development of PA. This underscores the need for comprehensive management of these conditions in addition to treating the apoplexy itself in this population. Surgical management has a relevant place in PA approach mainly in patients with higher PAS. However, it leads permanent vasopressin deficit more frequently than conservative approach., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

Precision, personalized, or individualized medicine in pituitary neuroendocrine tumors (PitNETs) has become a major topic in the last few years. It is based on the use of biomarkers that predictively segregate patients and give answers to clinically relevant questions that help us in the individualization of their management. It allows us to make early diagnosis, predict response to medical treatments, predict surgical outcomes and investigate new targets for therapeutic molecules. So far, substantial progress has been made in this field, although there are still not enough precise tools that can be implemented in clinical practice. One of the main reasons is the excess overlap among clustered patients, with an error probability that is not currently acceptable for clinical practice. This overlap is due to the high heterogeneity of PitNETs, which is too complex to be overcome by the classical biomarker investigation approach. A systems biology approach based on artificial intelligence techniques seems to be able to give answers to each patient individually by building mathematical models through the interaction of multiple factors, including those of omics sciences. Integrated studies of different molecular omics techniques, as well as radiomics and clinical data are necessary to understand the whole system and to finally achieve the key to obtain precise biomarkers and implement personalized medicine. In this review we have focused on describing the current advances in the area of PitNETs based on the omics sciences, that are clearly going to be the new tool for precision medicine.

Competing Interests: Conflict of interest: None declared.

Although predictors of response to first-generation somatostatin receptor ligands (fg-SRLs), and to a lesser extent to pasireotide, have been studied in acromegaly for many years, their use is still not recommended in clinical guidelines. Is there insufficient evidence to use them? Numerous biomarkers including various clinical, functional, radiological and molecular markers have been identified. The first ones are applicable pre-surgery, while the molecular predictors are utilized for patients not cured after surgery. In this regard, factors predicting a good response to fg-SRLs are specifically: low basal GH, a low GH nadir in the acute octreotide test, T2 MRI hypointensity, a densely granulated pattern, high immunohistochemistry staining for somatostatin receptor 2 (SSTR2), and E-cadherin. However, there is still a lack of consensus regarding which of these biomarkers is more useful or how to integrate them into clinical practice. With classical statistical methods, it is complex to define reliable and generalizable cut-off values for a single biomarker. The potential solution to the limitations of traditional methods involves combining systems biology with artificial intelligence, which is currently providing answers to such long-standing questions that may eventually be finally included into the clinical guidelines and make personalized medicine a reality. The aim of this review is to describe the current knowledge of the main fg-SRLs and pasireotide response predictors, discuss their current usefulness, and point to future directions in the research of this field., Competing Interests: Declaration of Competing Interest MM and MPD have received funding for advisory boards or for being a speaker from Pfizer, Novartis, Ipsen and Recordati. MAC has received funding for being a speaker from Recordati. The REMAH (Registro Español Molecular de Adenomas Hipofisarios) initiative was supported by Novartis. All authors declare that they have received financial support for attending educational programs not directly related to this manuscript., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Medical treatment of acromegaly is currently performed through a trial-error approach using first generation somatostatin receptor ligands (fgSRLs) as first-line drugs, with an effectiveness of about 50%, and subsequent drugs are indicated through clinical judgment. Some biomarkers can predict fgSRLs response. Here we report the results of the ACROFAST study, a clinical trial in which a protocol based on predictive biomarkers of fgSRLs was evaluated., Methods and Subjects: prospective trial (21 university hospitals) comparing the effectiveness and time-to control of two treatment protocols during 12 months: A) A personalized protocol in which first option were fgSRLs as monotherapy or in combination with pegvisomant or, pegvisomant as monotherapy depending on the short Acute Octreotide Test (sAOT) results, tumor T2 Magnetic Resonance (MRI) signal or immunostaining for E-cadherin and, B) A control group with treatment always started by fgSRLs and the other drugs included after demonstrating inadequate control., Results: Eighty-five patients participated; 45 in the personalized and 40 in the control group. More patients in the personalized protocol achieved hormonal control compared to those in the control group (78% vs 53%, p < 0.05). Survival analysis revealed a hazard ratio for achieving hormonal control adjusted by age and sex of 2.53 (CI 1.30-4.80). Patients from personalized arm were controlled in a shorter period of time (p = 0.01)., Conclusion: Personalized medicine is feasible using a relatively simple protocol and allows a higher number of patients achieving control in a shorter period of time., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Objective: The aim of this study is to compare the response to first-line medical treatment in treatment-naive acromegaly patients with pure growth hormone (GH)-secreting pituitary adenoma (GH-PA) and those with GH and prolactin cosecreting PA (GH&PRL-PA)., Design: This is a retrospective multicentric study of acromegaly patients followed from 2003 to 2023 in 33 tertiary Spanish hospitals with at least 6 months of first-line medical treatment., Methods: Baseline characteristics, first-line medical treatment strategies, and outcomes were analyzed. We employed a multiple logistic regression full model to estimate the impact of some baseline characteristics on disease control after each treatment modality., Results: Of the 144 patients included, 72.9% had a GH-PA, and 27.1% had a GH&PRL-PA. Patients with GH&PRL-PA were younger (43.9 ± 15.0 vs 51.9 ± 12.7 years, P < .01) and harboring more frequently macroadenomas (89.7% vs 72.1%, P = .03). First-generation somatostatin receptor ligand (fgSRL) as monotherapy was given to 106 (73.6%) and a combination treatment with fgSRL and cabergoline in the remaining 38 (26.4%). Patients with GH&PRL-PA received more frequently a combination therapy (56.4% vs 15.2%, P < .01). After 6 months of treatment, in the group of patients under fgSRL as monotherapy, those patients with GH&PRL-PA had worse control compared to GH-PAs (29.4% vs 55.1%, P = .04). However, these differences in the rate of disease control between both groups disappeared when both received combination treatment with fgSRL and cabergoline., Conclusion: In GH&PRL-PA, the biochemical control achieved with fgSRL as monotherapy is substantially worse than in patients harboring GH-PA, supporting the inclusion of cabergoline as first-line medical treatment in combination with fgSRLs in these subgroups of patients., Competing Interests: Conflict of interest: The authors declare no conflict of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Endocrinology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Introduction: Growth hormone (GH)-secreting pituitary tumors (GHomas) are the most common acromegaly cause. At diagnosis, most of them are macroadenomas, and up to 56% display cavernous sinus invasion. Biomarker assessment associated with tumor growth and invasion is important to optimize their management., Objectives: The study aims to identify clinical/hormonal/molecular biomarkers associated with tumor size and invasiveness in GHomas and to analyze the influence of pre-treatment with somatostatin analogs (SSAs) or dopamine agonists (DAs) in key molecular biomarker expression., Methods: Clinical/analytical/radiological variables were evaluated in 192 patients from the REMAH study (ambispective multicenter post-surgery study of the Spanish Society of Endocrinology and Nutrition). The expression of somatostatin/ghrelin/dopamine system components and key pituitary/proliferation markers was evaluated in GHomas after the first surgery. Univariate/multivariate regression studies were performed to identify association between variables., Results: Eighty percent of patients harbor macroadenomas (63.8% with extrasellar growth). Associations between larger and more invasive GHomas with younger age, visual abnormalities, higher IGF1 levels, extrasellar/suprasellar growth, and/or cavernous sinus invasion were found. Higher GH1 and lower PRL/POMC/CGA/AVPR1B/DRD2T/DRD2L expression levels (P < .05) were associated with tumor invasiveness. Least Absolute Shrinkage and Selection Operator's penalized regression identified combinations of clinical and molecular features with areas under the curve between 0.67 and 0.82. Pre-operative therapy with DA or SSAs did not alter the expression of any of the markers analyzed except for DRD1/AVPR1B (up-regulated with DA) and FSHB/CRHR1 (down-regulated with SSAs)., Conclusions: A specific combination of clinical/analytical/molecular variables was found to be associated with tumor invasiveness and growth capacity in GHomas. Pre-treatment with first-line drugs for acromegaly did not significantly modify the expression of the most relevant biomarkers in our association model. These findings provide valuable insights for risk stratification and personalized management of GHomas., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Endocrinology.)

The objective of the study was to evaluate the efficacy of second-line therapies in patients with acromegaly caused by a growth hormone (GH) and prolactin (PRL) co-secreting pituitary neuroendocrine tumor (GH&PRL-Pit-NET) compared to their efficacy in patients with acromegaly caused by a GH-secreting pituitary neuroendocrine tumor (GH-Pit-NET). This is a multicenter retrospective study of patients with acromegaly on treatment with pasireotide and/or pegvisomant. Patients were classified in two groups: GH&PRL-Pit-NETs when evidence of hyperprolactinemia and immunohistochemistry (IHC) for GH and PRL was positive or if PRL were >200 ng/dL regardless of the PRL-IHC and GH-Pit-NETs when the previously mentioned criteria were not met. A total of 28 cases with GH&PRL-Pit-NETs and 122 with GH-Pit-NETs met the inclusion criteria. GH&PRL-Pit-NETs presented at a younger age, caused hypopituitarism, and were invasive more frequently than GH-Pit-NETs. There were 124 patients treated with pegvisomant and 49 with pasireotide at any time. The efficacy of pegvisomant for IGF-1 normalization was of 81.5% and of pasireotide of 71.4%. No differences in IGF-1 control with pasireotide and with pegvisomant were observed between GH&PRL-Pit-NETs and GH-Pit-NETs. All GH&PRL-Pit-NET cases treated with pasireotide (n = 6) and 82.6% (n = 19/23) of the cases treated with pegvisomant normalized PRL levels. No differences in the rate of IGF-1 control between pegvisomant and pasireotide were detected in patients with GH&PRL-Pit-NETs (84.9% vs 66.7%, P = 0.178). We conclude that despite the more aggressive behavior of GH&PRL-Pit-NETs than GH-Pit-NETs, no differences in the rate of IGF-1 control with pegvisomant and pasireotide were observed between both groups, and both drugs have shown to be effective treatments to control IGF-1 and PRL hypersecretion in these tumors.

Pituitary neuroendocrine tumors (PitNETs) account for approximately 15% of all intracranial neoplasms. Although they usually appear to be benign, some tumors display worse behavior, displaying rapid growth, invasion, refractoriness to treatment, and recurrence. Increasing evidence supports the role of primary cilia (PC) in regulating cancer development. Here, we showed that PC are significantly increased in PitNETs and are associated with increased tumor invasion and recurrence. Serial electron micrographs of PITNETs demonstrated different ciliation phenotypes (dot-like versus normal-like cilia) that represented PC at different stages of ciliogenesis. Molecular findings demonstrated that 123 ciliary-associated genes (eg, doublecortin domain containing protein 2, Sintaxin-3, and centriolar coiled-coil protein 110) were dysregulated in PitNETs, representing the upregulation of markers at different stages of intracellular ciliogenesis. Our results demonstrate, for the first time, that ciliogenesis is increased in PitNETs, suggesting that this process might be used as a potential target for therapy in the future., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Hospitalized COVID-19 patients may present acute malnutrition which could influence morbidity and mortality. In the first wave of the pandemic severe weight loss was observed in many hospitalized patients. This pilot study evaluates the usefulness of an electronic automatized alarm for the early quantification of a low food intake as a predictor of the risk of malnutrition using COVID-19 disease as a model of severe illness., Methods: Observational prospective nutritional screening with a daily automatized warning message to the Endocrinology and Nutrition Service provided by the Information Systems. All adult patients admitted for COVID-19 from November 2020 to February 2021 were included. When diet intake was <50% during consecutive 48h, an automated message was generated identifying the patient as "at nutritional risk (NR)" and additional specialist nutritional evaluation and therapy was performed within the next 24h., Results: 205 patients out of 1176 (17.4%) were detected by automatized alarm and were considered as presenting high NR; 100% were concordant by the validated nutritional screening SNAQ. Nutritional support after detection was: 77.6% dietary adaptation+oral supplements; 9.3% enteral nutrition (EN); 1.5% parenteral nutrition (PN); 1% EN+PN and 10.7% no intervention is performed due to an end-of-life situation. Median weight loss during admission was 2.5kg (p25 0.25-p75: 6kg). Global mortality was 6.7% while in those detected by automatized alarm was 31.5%., Conclusions: The implementation of an electronic NR screening tool was feasible and allowed the early nutritional assessment and intervention in COVID-19 hospitalized patients and can be useful in patients hospitalized for other pathologies., (Copyright © 2024 SEEN and SED. Published by Elsevier España, S.L.U. All rights reserved.)

Introduction: People with the human immunodeficiency virus (PWH) who were diagnosed long ago are more prone to age-related conditions and comorbidities than the general population. We hypothesized that older PWH have endocrine abnormalities that may influence the patient's health status., Methods: Mean hormonal values across the thyrotropic, somatotropic, corticotropic, and gonadal axis, and percentage of subjects with abnormal values, were compared between PWH aged ≥50 years (n=30) and people without HIV (n=30) (Over50 cohort). Clinical factors were also analyzed as independent variables., Results: PWH had a higher prevalence of comorbidities (36.67% PWH and 20.69% controls had ≥3 comorbidities). Male PWH exhibited lower estradiol levels than male controls (29.75±7.68 pg/mL vs. 35.45 ± 10.04 pg/mL; p = 0.0041). Abnormal concentrations of testosterone were found in 35% of male PWH compared to 55% of male controls (mostly above reference values). Cortisol levels were significantly lower among PWH (9.97 ± 4.33 μg/dL vs. 13.56 ± 3.39 μg/dL; p = 0.002); 16.6% of PWH exhibited abnormally low levels (<5 μg/dL), compared to 0% of controls, and 3 PWH met criteria for a definitive diagnosis of adrenal insufficiency (<3.6 μg/dL). For the somatotropic axis, growth hormone (GH) levels were significantly lower in male PWH than in controls (p = 0.0394). No significant differences were found in relation to the thyroid axis., Conclusion: Hormones are generally similar between the chronic PWH who are receiving ART treatment and the general control population, except for cortisol in both sexes and testosterone and estradiol in men. Some special attention should be given to cortisol in PWH due to a presumably higher risk of adrenal complications., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background and Aims: Predictors of first-generation somatostatin receptor ligands (fgSRLs) response in acromegaly have been studied for over 30 years, but they are still not recommended in clinical guidelines. Is there not enough evidence to support their use? This systematic review aims to describe the current knowledge of the main predictors of fgSRLs response and discuss their current usefulness, as well as future research directions., Methods: A systematic search was performed in the Scopus and PubMed databases for functional, imaging, and molecular predictive factors., Results: A total of 282 articles were detected, of which 64 were included. Most of them are retrospective studies performed between 1990 and 2023 focused on the predictive response to fgSRLs in acromegaly. The usefulness of the predictive factors is confirmed, with good response identified by the most replicated factors, specifically low GH nadir in the acute octreotide test, T2 MRI hypointensity, high Somatostatin receptor 2 (SSTR2) and E-cadherin expression, and a densely granulated pattern. Even if these biomarkers are interrelated, the association is quite heterogeneous. With classical statistical methods, it is complex to define reliable and generalizable cut-off values worth recommending in clinical guidelines. Machine-learning models involving omics are a promising approach to achieve the highest accuracy values to date., Conclusions: This survey confirms a sufficiently robust level of evidence to apply knowledge of predictive factors for greater efficiency in the treatment decision process. The irruption of artificial intelligence in this field is providing definitive answers to such long-standing questions that may change clinical guidelines and make personalized medicine a reality., (Copyright © 2023. Published by Elsevier Inc.)

Introduction: We previously described that a short version of the acute octreotide test (sAOT) can predict the response to first-generation somatostatin receptor ligands (SRLs) in patients with acromegaly. We have prospectively reassessed the sAOT in patients from the ACROFAST study using current ultra-sensitive GH assays. We also studied the correlation of sAOT with tumor expression of E-cadherin and somatostatin receptor 2 (SSTR2) ., Methods: A total of 47 patients treated with SRLs for 6 months were evaluated with the sAOT at diagnosis and correlated with SRLs' response. Those patients whose IGF1 decreased to <3SDS from normal value were considered responders and those whose IGF1 was ≥3SDS, were considered non-responders . The 2 hours GH value (GH 2h ) after s.c. administration of 100 mcg of octreotide was used to define predictive cutoffs. E-cadherin and SSTR2 immunostaining in somatotropinoma tissue were investigated in 24/47 and 18/47 patients, respectively., Results: In all, 30 patients were responders and 17 were non-responders. GH 2h was 0.68 (0.25-1.98) ng/mL in responders vs 2.35 (1.59-9.37) ng/mL in non-responders (p<0.001). GH 2h = 1.4ng/mL showed the highest ability to identify responders (accuracy of 81%, sensitivity of 73.3%, and specificity of 94.1%). GH 2h = 4.3ng/mL was the best cutoff for non-response prediction (accuracy of 74%, sensitivity of 35.3%, and specificity of 96.7%). Patients with E-cadherin-positive tumors showed a lower GH 2h than those with E-cadherin-negative tumors [0.9 (0.3-2.1) vs 3.3 (1.5-12.1) ng/mL; p<0.01], and patients with positive E-cadherin presented a higher score of SSTR2 (7.5 ± 4.2 vs 3.3 ± 2.1; p=0.01)., Conclusion: The sAOT is a good predictor tool for assessing response to SRLs and correlates with tumor E-cadherin and SSTR2 expression. Thus, it can be useful in clinical practice for therapeutic decision-making in patients with acromegaly., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Marques-Pamies, Gil, Valassi, Hernández, Biagetti, Giménez-Palop, Martínez, Carrato, Pons, Villar-Taibo, Araujo-Castro, Blanco, Simón, Simó-Servat, Xifra, Vázquez, Pavón, García-Centeno, Zavala, Hanzu, Mora, Aulinas, Vilarrasa, Librizzi, Calatayud, de Miguel, Alvarez-Escola, Picó, Sampedro, Salinas, Fajardo-Montañana, Cámara, Bernabéu, Jordà, Webb, Marazuela and Puig-Domingo.)

Objective: Hyperintensity signal in T2-weighted magnetic resonance imaging (MRI) has been related to better therapeutic response during pasireotide treatment in acromegaly. The aim of the study was to evaluate T2 MRI signal intensity and its relation with pasireotide therapeutic effectiveness in real-life clinical practice., Design, Patients and Measurements: Retrospective multicentre study including acromegaly patients treated with pasireotide. Adenoma T2-weighted MRI signal at diagnosis was qualitatively classified as iso-hyperintense or hypointense. Insulin-like growth factor (IGF-I), growth hormone (GH) and tumour volume reduction were assessed after 6 and 12 months of treatment and its effectiveness evaluated according to baseline MRI signal. Hormonal response was considered 'complete' when normalization of IGF-I levels was achieved. Significant tumour shrinkage was defined as a volume reduction of ≥25% from baseline., Results: Eighty-one patients were included (48% women, 50 ± 1.5 years); 93% had previously received somatostatin receptor ligands (SRLs) treatment. MRI signal was hypointense in 25 (31%) and hyperintense in 56 (69%) cases. At 12 months of follow-up, 42/73 cases (58%) showed normalization of IGF-I and 37% both GH and IGF-I. MRI signal intensity was not associated with hormonal control. 19/51 cases (37%) presented a significant tumour volume shrinkage, 16 (41%) from the hyperintense group and 3 (25%) from the hypointense., Conclusions: T2-signal hyperintensity was more frequently observed in pasireotide treated patients. Almost 60% of SRLs resistant patients showed a complete normalization of IGF-I after 1 year of pasireotide treatment, regardless of the MRI signal. There was also no difference in the percentage tumour shrinkage over basal residual volume between the two groups., (© 2023 The Authors. Clinical Endocrinology published by John Wiley & Sons Ltd.)

Prolactin (PRL) and growth hormone (GH) are peptide hormones that bind to the class 1 cytokine receptor superfamily, a highly conserved cell surface class of receptors. Both hormones control their own secretion via a negative autocrine loop in their own mammosomatotroph, lactotroph or somatotroph. In this regard, GH and PRL are regulated by similar signaling pathways involving cell growth and hormone secretion. Thus, GH and PRL dysregulation and pituitary neuroendocrine tumor (PitNET) development may have common pathogenic pathways. Based on cell linage, lactotroph and somatotroph PitNETs come from pituitary-specific POU-class homeodomain transcription factor (Pit-1). Mammosomatotroph and plurihormonal PitNETs are a unique subtype of PitNETs that arise from a single-cell population of Pit-1 lineage. In contrast, mixed somatotroph-lactotroph PitNETs are composed of two distinct cell populations: somatotrophs and lactotrophs. Morphologic features that distinguish indolent PitNETs from locally aggressive ones are still unidentified, and no single prognostic parameter can predict tumor aggressiveness or treatment response. In this review, we aim to explore the latest research on lactotroph and somatotroph PitNETs, the molecular mechanisms involved in PRL and GH axis regulation and the signaling pathways involved in their aggressiveness, particularly focused on mammosomatotroph and mixed subtypes. Finally, we summarize epidemiological, clinical, and radiological features of these exceptional tumors. We aim to shed light, from basic to clinical settings, on new perspectives and scientific gaps in this field.

Context: There are no data on mortality of acromegaly diagnosed in older individuals., Objective: This work aimed to compare clinical characteristics, growth hormone-related comorbidities, therapeutic approaches, and mortality rate of patients diagnosed before or after 2010 and to assess overall mortality rate compared with the general Spanish population., Methods: A retrospective evaluation was conducted among Spanish tertiary care centers of 118 patients diagnosed with acromegaly at age 65 or older. Kaplan-Meier curves were constructed to trace survival, and Cox proportional hazard models were used to assess the risk factors associated with mortality. We also compared mortality with that of the Spanish population by using age- and sex-adjusted standardized mortality ratios (SMRs)., Results: No differences were found in first-line treatment or biochemical control, between both periods except for faster biochemical control after 2010. Twenty-nine (24.6%) patients died, without differences between groups, and had a median of follow-up 8.6 years (103, [72.3] months). Overall SMR was 1.02 (95% CI, 0.57-1.54), (0.60; 95% CI, 0.35-1.06) for men and (1.80; 95% CI, 1.07-2.94) for women. The most common cause of death was cardiovascular disease (CVD)., Conclusion: The mortality in patients with acromegaly diagnosed in older individuals was no different between both periods, and there was no overall SMR difference compared with the general Spanish population. However, the SMR was higher in women. As CVD is the leading cause of mortality, it seems advisable to initiate an intense CVD protective treatment as soon as acromegaly is diagnosed, particularly in women, in addition to tight acromegaly control to prevent excess mortality., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Longitudinal evaluation of thyroid function throughout pregnancy in the same subject could offer precise information about its dynamics as a physiological mechanism of adaption to the requirements. In this study, we evaluated longitudinal trajectories of maternal thyroid function during pregnancy by a latent class growth analysis and explored their association with maternal-fetal outcomes., Methods: A prospective observational study was carried out, including 414 healthy pregnant women, from the first trimester to delivery. Thyroid function and autoimmunity were measured in the three trimesters. Clinical data during pregnancy were obtained. Longitudinal mixed model techniques were performed to explore trajectories of gestational thyroid function., Results: Three different longitudinal trajectories were obtained from maternal thyrotropin (TSH) levels: low-increasing TSH (class 1) in 86% of cases, high-increasing TSH (class 2) in 9.7%, and decreasing TSH (class 3) in 4.3%. No statistical differences in free thyroxine levels were found among the three classes. Differences in maternal age (P = 0.027) and initial maternal weight (P = 0.043) were observed among the groups. In logistic regression analysis, maternal age correlated with longitudinal trajectories. The three longitudinal classes remain when women with thyroid autoimmunity (TAI) are excluded. Multinomial logistic regression showed maternal age correlated with longitudinal trajectories independently of TAI status., Conclusions: Three differentiated TSH trajectories were found in healthy pregnant women living in Catalonia, as previously described. No association with obstetric outcomes was observed in these different chronological thyroid pathways, but maternal age might condition the longitudinal mechanism of thyroid function regulation throughout pregnancy.

Background: Patients with Cushing's disease (CD) in remission maintain an increased cardiovascular risk. Impaired characteristics of gut microbiome (dysbiosis) have been associated with several cardiometabolic risk factors., Methods: Twenty-eight female non-diabetic patients with CD in remission with a mean ± SD) age of 51 ± 9 years, mean ( ± SD) BMI, 26 ± 4, median (IQR) duration of remission, 11(4) years and 24 gender-, age, BMI-matched controls were included. The V4 region of the bacterial 16S rDNA was PCR amplified and sequenced to analyse microbial alpha diversity (Chao 1 index, observed number of species, Shannon index) and beta diversity analysis through the Principal Coordinates Analysis (PCoA) of weighted and unweighted UniFrac distances. Inter-group difference in microbiome composition was analysed using MaAsLin2., Results: The Chao 1 index was lower in CD as compared with controls (Kruskal-Wallis test, q = 0.002), indicating lower microbial richness in the former. Beta diversity analysis showed that faecal samples from CS patients clustered together and separated from the controls (Adonis test, p<0.05). Collinsella , a genus form of the Actinobacteria phylum was present in CD patients only, whereas Sutterella , a genus from Proteobacteria phylum , was scarcely detectable/undetectable in CD patients as well as Lachnospira , a genus of the Lachnospiraceae family of the Firmicutes phylum. In CS, the Chao 1 index was associated with fibrinogen levels and inversely correlated with both triglyceride concentrations and the HOMA-IR index (p<0.05)., Conclusions: Patients with CS in remission have gut microbial dysbiosis which may be one of the mechanisms whereby cardiometabolic dysfunctions persist after "cure"., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Valassi, Manichanh, Amodru, Fernández, Gaztambide, Yañez, Martel-Duguech, Puig-Domingo and Webb.)

The increase in life expectancy is accompanied with an increased consultation of age-related pathologies including endocrine disorders. Two main areas are focusing the attention of medical and social research in older population: the diagnosis and care of this heterogeneous population, and the interventional measures potentially useful to mitigate age-related functional declines and to increase health and quality of lifespan. Thus, better understanding the physiopathology of aging and establishing accurate diagnostic and personalized approaches are a priority and currently an unmet need of the medical community. The endocrine system plays a major role in survival and lifespan through regulating vital processes such as energy consumption and optimizing the stress response among others. The aim of this paper is to review the physiological evolution of the main hormonal functions in aging and its clinical translation to improve our approach to the aging patient.

Introduction: Different medical therapies have been developed for pituitary adenomas. However, Non-Functioning Pituitary Neuroendocrine Tumors (NF-PitNET) have shown little response to them. Furthermore, epithelial-mesenchymal transition (EMT) has been linked to resistance to medical treatment in a significant number of tumors, including pituitary adenomas., Methods: We aimed to evaluate the expression of EMT-related markers in 72 NF-PitNET and 16 non-tumoral pituitaries. To further explore the potential usefulness of medical treatment for NF-PitNET we assessed the expression of somatostatin receptors and dopamine-associated genes., Results: We found that SNAI1, SNAI2 , Vimentin, KLK10, PEBP1 , Ki-67 and SSTR2 were associated with invasive NF-PitNET. Furthermore, we found that the EMT phenomenon was more common in NF-PitNET than in GH-secreting pituitary tumors. Interestingly, PEBP1 was overexpressed in recurrent NF-PitNET, and could predict growth recurrence with 100% sensitivity but only 43% specificity. In parallel with previously reported studies, SSTR3 is highly expressed in our NF-PitNET cohort. However, SSTR3 expression is highly heterogeneous among the different histological variants of NF-PitNET with very low levels in silent corticotroph adenomas., Conclusion: NF-PitNET showed an enhanced EMT phenomenon. SSTR3 targeting could be a good therapeutic candidate in NF-PitNET except for silent corticotroph adenomas, which express very low levels of this receptor. In addition, PEBP1 could be an informative biomarker of tumor regrowth, useful for predictive medicine in NF-PitNET., Competing Interests: MP-D, EV, GuS, IS, GX, PC-S, BB, GeS, SW declare to have received funds from Novartis, Ipsen, and Pfizer as lecturers. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest., (Copyright © 2023 Gil, Marques-Pamies, Valassi, Serra, Salinas, Xifra, Casano-Sancho, Carrato, Biagetti, Sesmilo, Marcos-Ruiz, Rodriguez-Lloveras, Rueda-Pujol, Aulinas, Blanco, Hostalot, Simó-Servat, Muñoz, Rico, Ibáñez-Domínguez, Cordero, Webb, Jordà and Puig-Domingo.)

Objective: To investigate longitudinal changes in the liver stiffness measurement (LSM) in the general adult population without known liver disease and to describe its association with metabolic risk factors, with a special focus on subjects with non-alcoholic fatty liver disease (NAFLD) and dysglycemia., Material and Methods: A longitudinal adult population-based cohort study was conducted in Catalonia. LSM was measured by transient elastography (TE) at baseline and follow-up (median: 4.2 years). Subgroup with NAFLD and dysglycemia were analyzed. Moderate-to-advanced liver fibrosis was defined as LSM ≥8.0 kPa and LSM ≥9.2 kPa respectively., Results: Among 1.478 subjects evaluated, the cumulative incidence of LSM ≥8.0 kPa and ≥9.2 kPa at follow-up was 2.8% and 1.9%, respectively. This incidence was higher in NAFLD (7.1% for LSM ≥8.0 kPa and 5% for LSM ≥9.2 kPa) and dysglycemia (6.2% for LSM ≥8.0 kPa and 4.7% for LSM ≥9.2 kPa) subgroups. In the global cohort, the multivariate analyses showed that dysglycemia, abdominal obesity and atherogenic dyslipidemia were significantly associated with progression to moderate-to-advanced liver fibrosis. Female sex was negatively associated. In subjects with NAFLD, abdominal obesity and dysglycemia were associated with changes in LSM to ≥8.0 kPa and ≥9.2 kPa at follow-up. A decline in LSM value to <8 kPa was observed in 64% of those subjects with a baseline LSM ≥8.0 kPa., Conclusions: In this population study, the presence of abdominal obesity and dysglycemia were the main risk metabolic factors associated with moderate-to-advanced liver fibrosis development over time in general populations as well as in subjects with NAFLD., Competing Interests: Author JF-N has received advisory and or speaking fees from Astra-Zeneca, Ascensia, Boehringer Ingelheim, GSK, Lilly, MSD, Novartis, NovoNordisk and Sanofi; he has received research grants to the institution from Astra-Zeneca, GSK, Lilly, MSD, Novartis, NovoNordisk, Sanofi and Boehringer. Author KC has received research support as principal investigator from National Institutes of Health NIH, Cirius, Inventiva, Janssen, Novartis, Novo Nordisk, and Zydus. He is consultant for Allergan, AstraZeneca, BMN, Cirius, Coherus, Deuterex, Janssen, Genentech, Gilead, Merck, Novo Nordisk, Pzifer, Poxel. Author DM has received advisory and/or speaking fees from Almirall, AstraZeneca, Boehringer Ingelheim, Lilly, MSD, Novartis, Novo Nordisk and Sanofi. He has received research grants to the institution from AstraZeneca, GSK, Lilly, MSD, Novartis, NovoNordisk, Sanofi and Boehringer Ingelheim. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Julián, Ballesta, Pera, Pérez-Montes de Oca, Soldevila, Caballería, Morillas, Expósito, Martínez–Escudé, Puig-Domingo, Franch-Nadal, Torán, Cusi, Julve, Mauricio and Alonso.)

Introduction: Diabetes mellitus (DM) and hyperglycemia are important risk factors for poor outcomes in hospitalized patients with coronavirus disease 2019 (COVID-19). The aim of the present study was to analyze the factors associated with the composite outcome of the necessity of invasive mechanical ventilation (IMV) or admission to the intensive care unit (ICU) in subjects with severe COVID-19 infection treated with dexamethasone comparing patients with DM vs. patients without DM., Research Design and Methods: An observational retrospective cohort study was performed, including hospitalized subjects with a diagnosis of SARS-CoV-2 pneumonia. Inclusion criteria were: age ≥18 years old with severe COVID-19 disease requiring daily intravenous 6 mg dexamethasone treatment for 10 days. Exclusion criteria were: <18 years old, non-severe illness and/or patients in charge of ICU. Variables related to clinical and analytical parameters, glycemic control, acquired-hospital superinfections, mortality, IMV requirement, ICU admission and length of stay were included., Results: Two hundred and nine individuals with COVID-19 disease treated with dexamethasone were included. One hundred twenty-five out of these subjects (59.8%) were patients with DM. Overall, from the 209 subjects, 66 (31.6%) required IMV or were admitted to the ICU, with significant differences between patients with DM (n=50) vs. patients without DM (n=16) (76% vs. 24%, p=0.002). Among the group of subjects with DM (n=125), those who required IMV or were admitted to the ICU showed higher serum concentrations of C-reactive protein, interleukin-6, D-dimer, ferritin and pro-calcitonin and significantly lower serum concentrations of albumin compared to those who did not require IMV or were not admitted to the ICU. Besides, between these two groups of patients with DM, we observed no differences in glycemic parameters, including median capillary blood glucose values, glycosylated hemoglobin, coefficient of variability and hypoglycemic episodes. In the multinomial analysis, factors independently associated with the composite outcome of IMV or admission to the ICU in the insulin-treated group were the National Early Warning Score (NEWS) 2 score (OR 1.55 [1.17-2.17], p=0.005) and the presence of hospital-acquired superinfections (OR 35.21 [5.11-386.99], p=0.001)., Conclusions: In our study, parameters related to glycemic control were not associated with IMV requirement nor admission to the ICU in patients with DM and severe COVID-19 disease receiving daily 6 mg of dexamethasone for 10 days. However, hospital-acquired superinfections and disease severity at admission were independent factors associated with this composite outcome., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Batule, Soldevila, Figueredo, Julián, Egea-Cortés, Reyes-Ureña, Casabona, Mateu, Paredes, Clotet, López, Puig-Domingo and Alonso.)

Background & Aims: Patients affected by COVID-19 may develop disease related malnutrition (DRM) due to the catabolic situation, symptoms that interfere with intake and prolonged hospital stay. This study aims to know the percentage of patients admitted for COVID-19 who required artificial nutrition (AN), their clinical characteristics, as well as the prevalence of DRM and the risk of sarcopenia at hospital discharge and after 6 months., Material and Methods: Observational, prospective study, with successive inclusion of adult patients admitted for COVID-19 in whom institutional nutritional support (NS) care protocol was applied. Those who received AN underwent a nutritional screening by Short Nutritional Assessment Questionnaire (SNAQ) and an assessment by Subjective Global Assessment (SGA) at hospital discharge, as well as a screening for sarcopenia (SARC-F test) and SNAQ re-test 15 days and 6 months after by a phone call. Symptoms related to food intake, anthropometric and analytical data were also collected., Results: We evaluated 936 patients with a mean age of 63.7 ± 15.3 years; predominantly male (59.7%), overweight 41%, obesity 40.4%; hypertension 52.9%; diabetes mellitus 26.6% and cancer 10.4%. The stay hospital length was 17.3 ± 13.8 days and 13.6% patients died during hospitalization. The modality of nutritional support was: 86.1% dietary adaptation + oral nutritional supplements (ONS); 12.4% enteral nutrition (EN) by nasogastric (NG) tube; 0.9% parenteral nutrition (PN) and 0.6% EN plus PN. Focusing on patients who received AN, follow-up post discharge was possible in 62 out of 87 who survived. Of these, at the time of hospital discharge, 96.7% presented nutritional risk by SNAQ and 100% malnutrition by SGA (20% B; 80% C). During admission, 82.3% presented intense anorexia and the mean weight loss was 10.9 ± 6 Kg (p < 0.001). Fifteen days after being discharged, 12.9% still had anorexia, while hyperphagia appeared in 85.5% of the patients and risk of sarcopenia by SARC-F was present in 87.1% of them. Six months after discharge, 6.8% still had anorexia and 3.4% hyperphagia, with a global weight gain of 4.03 ± 6.2 Kg (p=<0.0001). Risk of malnutrition was present in only 1.7% of the patients, although risk of sarcopenia persisted in 49.2%., Conclusion: All patients admitted by COVID-19 for whom EN or PN were indicated following an institutional protocol still presented malnutrition at hospital discharge, and almost all showed risk of sarcopenia, that persisted in almost half of them at 6 months. These findings suggest that nutritional and functional problems persist in these patients after discharge, indicating that they require prolonged nutritional support and monitoring., Competing Interests: Conflict of interest The authors declare that there are no conflicts of interest., (Copyright © 2021 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Context: Some reports suggest that acromegaly in elderly patients has a more benign clinical behavior and could have a better response to first-generation long-acting somatostatin receptor ligands (SRL). However, there is no specific therapeutic protocol for this special subgroup of patients., Objective: This study aimed at identifying predictors of response to SRL in elderly patients., Design: Multicentric retrospective nationwide study of patients diagnosed with acromegaly at or over the age of 65 years., Results: One-hundred and eighteen patients (34 men, 84 women, mean age at diagnosis 71.7 ± 5.4 years old) were included. Basal insulin-like growth factor type 1 (IGF-1) above the upper limit of normal (ULN) and growth hormone (GH) levels (mean ± SD) were 2.7 ± 1.4 and 11.0 ± 11.9 ng/ml, respectively. The mean maximal tumor diameter was 12.3 ± 6.4 mm, and up to 68.6% were macroadenoma. Seventy-two out of 118 patients (61.0%) underwent surgery as primary treatment. One-third of patients required first-line medical treatment due to a rejection of surgical treatment or non-suitability because of high surgical risk. After first-line surgery, 45/72 (63.9%) were in disease remission, and 16/34 (46.7%) of those treated with SRL had controlled disease. Patients with basal GH at diagnosis ≤6 ng/ml had lower IGF-1 levels and had smaller tumors, and more patients in this group reached control with SRL (72.7% vs. 33.3%; p < 0.04) [OR: 21.3, IC: 95% (2.4-91.1)], while male patients had a worse response [OR: 0.09, IC 95% (0.01-0.75)]. The predictive model curve obtained for SRL response showed an AUC of 0.82 CI (0.71-0.94)., Conclusions: The most frequent phenotype in newly diagnosed acromegaly in the elderly includes small adenomas and moderately high IGF-1 levels. GH at diagnosis ≤6 ng/ml and female gender, but not age per se , were associated with a greater chance of response to SRL., Competing Interests: BB, MP, AV, CA-E, AV, RC, IB, SG, FC, SW, and MP-D have received consulting fees or research support or participated in clinical trials supported by from Pfizer, Ipsen, Quiasma, and/or Recordati. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Biagetti, Iglesias, Villar-Taibo, Moure, Paja, Araujo-Castro, Ares, Álvarez-Escola, Vicente, Álvarez Guivernau, Novoa-Testa, Guerrero Perez, Cámara, Lecumberri, García Gómez, Bernabéu, Manjón, Gaztambide, Cordido, Webb, Menéndez-Torre, Díez, Simó and Puig-Domingo.)

Background: Up to 30% of differentiated thyroid cancer (DTC) will develop advanced-stage disease (aDTC) with reduced overall survival (OS)., Objective: The aim of this study is to characterize initial diagnosis of aDTC, its therapeutic management, and prognosis in Spain and Portugal., Methods: A multicentre, longitudinal, retrospective study of adult patients diagnosed with aDTC in the Iberian Peninsula was conducted between January 2007 and December 2012. Analyses of baseline characteristics and results of initial treatments, relapse- or progression-free survival ((RP)FS) from first DTC diagnosis, OS, and prognostic factors impacting the evolution of advanced disease were evaluated., Results: Two hundred and thirteen patients (median age: 63 years; 57% female) were eligible from 23 hospitals. Advanced disease presented at first diagnosis (de novo aDTC) included 54% of patients, while 46% had relapsed from early disease (recurrent/progressive eDTC). At initial stage, most patients received surgery (98%) and/or radioiodine (RAI) (89%), with no differences seen between median OS (95% CI) (10.4 (7.3-15.3) years) and median disease-specific-survival (95% CI) (11.1 (8.7-16.2) years; log-rank test P = 0.4737). Age at diagnosis being <55 years was associated with a lower risk of death (Wald chi-square (Wc-s) P < 0.0001), while a poor response to RAI to a higher risk of death ((Wc-s) P < 0.05). In the eDTC cohort, median (RP)FS (95% CI) was of 1.7 (1.0-2.0) years after RAI, with R0/R1 surgeries being the only common significant favourable factor for longer (RP)FS and time to aDTC ((Wc-s) P < 0.05)., Conclusion: Identification of early treatment-dependent prognostic factors for an unfavourable course of advanced disease is possible. An intensified therapeutic attitude may reverse this trend and should be considered in poor-performing patients. Prospective studies are required to confirm these findings.

Predicting which acromegaly patients could benefit from somatostatin receptor ligands (SRL) is a must for personalized medicine. Although many biomarkers linked to SRL response have been identified, there is no consensus criterion on how to assign this pharmacologic treatment according to biomarker levels. Our aim is to provide better predictive tools for an accurate acromegaly patient stratification regarding the ability to respond to SRL. We took advantage of a multicenter study of 71 acromegaly patients and we used advanced mathematical modelling to predict SRL response combining molecular and clinical information. Different models of patient stratification were obtained, with a much higher accuracy when the studied cohort is fragmented according to relevant clinical characteristics. Considering all the models, a patient stratification based on the extrasellar growth of the tumor, sex, age and the expression of E-cadherin, GHRL, IN1-GHRL, DRD2, SSTR5 and PEBP1 is proposed, with accuracies that stand between 71 to 95%. In conclusion, the use of data mining could be very useful for implementation of personalized medicine in acromegaly through an interdisciplinary work between computer science, mathematics, biology and medicine. This new methodology opens a door to more precise and personalized medicine for acromegaly patients., (© 2022. The Author(s).)

Background: The Global Leadership Initiative on Malnutrition (GLIM) criteria were recently proposed to build a global consensus on the diagnostic criteria for malnutrition. This study aimed to evaluate the GLIM criteria for its prognostic significance in outpatients with heart failure (HF), and to compare them to a previous validated method, such as the Mini Nutritional Assessment (MNA)., Methods: This was a post hoc observational analysis of a prospectively recruited cohort, which included 151 subjects that attended an outpatient HF clinic. At baseline, all patients completed the nutritional screening MNA short form and the nutritional assessment MNA. In a post hoc analysis, we evaluated the GLIM criteria at baseline. The outcomes were based on data from a five-year follow-up. The primary endpoint was all-cause mortality. Secondary endpoints were cardiovascular (CV) mortality and recurrent HF-related hospitalizations. We also investigated whether the GLIM criteria had better prognostic power than the MNA., Results: Abnormal nutritional status was identified in 19.8% of the patients with the GLIM criteria and in 25.1% with the MNA. In the multivariate analyses (age, sex, NYHA functional class, diabetes, and Barthel index), nutritional status assessed by the MNA, but not by the GLIM criteria, was an independent predictor of all-cause mortality, CV mortality, and recurrent HF-related hospitalizations during the five-year follow-up., Conclusions: Malnutrition assessed by MNA, but not by the GLIM criteria, was an independent predictor of all-cause mortality, CV mortality, and recurrent HF-related hospitalization in our cohort of outpatients with HF.

Background: The basal−bolus insulin regimen is recommended in hospitalized patients with diabetes mellitus (DM), but has an increased risk of hypoglycemia. We aimed to compare dipeptidyl peptidase 4 inhibitors (DPP4-i) and basal−bolus insulin glycemic outcomes in hospitalized type 2 DM patients. Methods and patients: Our prospective randomized study included 102 elderly T2DM patients (82 ± 9 years, HbA1c 6.6% ± 1.9). Glycemic control: A variability coefficient assessed by continuous glucose monitoring (Free Style® sensor), mean insulin dose and hypoglycemia rates obtained with the two treatments were analyzed. Results: No differences were found between groups in glycemic control (mean daily glycemia during the first 10 days: 152.6 ± 38.5 vs. 154.2 ± 26.3 mg/dL; p = 0.8). The total doses Kg/day were 0.40 vs. 0.20, respectively (p < 0.001). A lower number of hypoglycemic events (9% vs. 15%; p < 0.04) and lower glycemic coefficient of variation (22% vs. 28%; p < 0.0002) were observed in the basal−DPP4-i compared to the basal−bolus regimen group. Conclusions: Treatment of inpatient hyperglycemia with basal insulin plus DPP4-i is an effective and safe regimen in old subjects with T2DM, with a similar mean daily glucose concentration, but lower glycemic variability and fewer hypoglycemic episodes compared to the basal bolus insulin regimen.

Obesity, the growing pandemic of the 21st century, is associated with multiple organ dysfunction, either by a direct increase in fatty organ content or by indirect modifications related to general metabolic changes driven by a specific increase in biologic products. The pituitary gland is not protected against such a situation. Different hypothalamic-pituitary axes experience functional modifications initially oriented to an adaptive situation that, with years of obesity, turn to maladaptive dynamics that contribute to perpetuating obesity and specific symptoms of their hormonal nature. This paper reviews the recent knowledge on obesity-related pituitary dysfunction and its pathogenic mechanisms and discusses potential therapeutic actions aimed at contributing to ameliorating the complex treatment of severe cases of obesity.

Although SARS-CoV-2 viral attacks starts by the interaction of spike protein (S Protein) to ACE2 receptor located at the cell surface of respiratory tract and digestive system cells, different endocrine targets, endocrine organs and metabolic conditions are of fundamental relevance for understanding disease progression and special outcomes, in particular those of fatal consequences for the patient. During pandemic, moreover, a specific phenotype of COVID-19 metabolic patient has been described, characterized by being at particular risk of worse outcomes. In the present paper we describe the mechanism of viral interaction with endocrine organs, emphasizing the specific endocrine molecules of particular relevance explaining COVID-19 disease evolution and outcomes., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Betamethasone, a glucocorticoid used to induce lung maturation when there is a risk of preterm delivery, can affect the immune system maturation and type 1 diabetes (T1D) incidence in the progeny. It has been described that prenatal betamethasone protects offspring from experimental T1D development. The main aim of this study was to evaluate the possible association between betamethasone prenatal exposure and T1D in humans. Research Design and Methods . A retrospective case-control study with a total of 945 children, including 471 patients with T1D and 474 healthy siblings, was performed. Participants were volunteers from the Germans Trias i Pujol Hospital and DiabetesCero Foundation. Parents of children enrolled in the study completed a questionnaire that included questions about weeks of gestation, preterm delivery risk, weight at birth, and prenatal betamethasone exposure of their children. Multiple logistic regression was used to detect the association between betamethasone exposure and T1D., Results: We compared T1D prevalence between subjects prenatally exposed or unexposed to betamethasone. The percent of children with T1D in the exposed group was 37.5% (21 of 56), and in the unexposed group was 49.52% (410 of 828) ( p = 0.139). The percentage of betamethasone-treated subjects with T1D in the preterm group (18.05%, 13 of 72) was significantly higher than that found in the control group (12.5%, 9 of 72) ( p = 0.003). The odds ratio for T1D associated with betamethasone in the univariate logistic regression was 0.59 (95% confidence interval, 0.33; 1.03 [ p = 0.062]) and in the multivariate logistic regression was 0.83 (95% confidence interval, 0.45; 1.52 [ p = 0.389])., Conclusions: The results demonstrate that the prenatal exposure to betamethasone does not increase T1D susceptibility, and may even be associated with a trend towards decreased risk of developing the disease. These preliminary findings require further prospective studies with clinical data to confirm betamethasone exposure effect on T1D risk., Competing Interests: The other authors report no conflicts of interest in this work., (Copyright © 2022 David Perna-Barrull et al.)

Objective: Registers of diagnoses and treatments exist in different forms in the European countries and are potential sources to answer important research questions. Prevalence and incidence of thyroid diseases are highly dependent on iodine intake and, thus, iodine deficiency disease prevention programs. We aimed to collect European register data on thyroid outcomes to compare the rates between countries/regions with different iodine status and prevention programs., Design: Register-based cross-sectional study., Methods: National register data on thyroid diagnoses and treatments were requested from 23 European countries/regions. The provided data were critically assessed for suitability for comparison between countries/regions. Sex- and age-standardized rates were calculated., Results: Register data on ≥1 thyroid diagnoses or treatments were available from 22 countries/regions. After critical assessment, data on medication, surgery, and cancer were found suitable for comparison between 9, 10, and 13 countries/regions, respectively. Higher rates of antithyroid medication and thyroid surgery for benign disease and lower rates of thyroid hormone therapy were found for countries with iodine insufficiency before approx. 2001, and no relationship was observed with recent iodine intake or prevention programs., Conclusions: The collation of register data on thyroid outcomes from European countries is impeded by a high degree of heterogeneity in the availability and quality of data between countries. Nevertheless, a relationship between historic iodine intake and rates of treatments for hyper- and hypothyroid disorders is indicated. This study illustrates both the challenges and the potential for the application of register data of thyroid outcomes across Europe.

Prostate cancer (PCa) is the most commonly diagnosed malignant neoplasm in men in the Western world. Localized low-risk PCa has an excellent prognosis thanks to effective local treatments; however, despite the incorporation of new therapeutic strategies, metastatic PCa remains incurable mainly due to disease heterogeneity and the development of resistance to therapy. The mechanisms underlying PCa progression and therapy resistance are multiple and include metabolic reprogramming, especially in relation to lipid metabolism, as well as epigenetic remodelling, both of which enable cancer cells to adapt to dynamic changes in the tumour. Interestingly, metabolism and epigenetics are interconnected. Metabolism can regulate epigenetics through the direct influence of metabolites on epigenetic processes, while epigenetics can control metabolism by directly or indirectly regulating the expression of metabolic genes. Moreover, epidemiological studies suggest an association between a high-fat diet, which can alter the availability of metabolites, and PCa progression. Here, we review the alterations of lipid metabolism and epigenetics in PCa, before focusing on the mechanisms that connect them. We also discuss the influence of diet in this scenario. This information may help to identify prognostic and predictive biomarkers as well as targetable vulnerabilities.

Acromegaly is caused by excess growth hormone (GH) produced by a pituitary tumor. First-generation somatostatin receptor ligands (SRLs) are the first-line treatment. Several studies have linked E-cadherin loss and epithelial-mesenchymal transition (EMT) with resistance to SRLs. Our aim was to study EMT and its relationship with SRLs resistance in GH-producing tumors. We analyzed the expression of EMT-related genes by RT-qPCR in 57 tumors. The postsurgical response to SRLs was categorized as complete response, partial response, or nonresponse if IGF-1 was normal, had decreased more than 30% without normalization, or neither of those, respectively. Most tumors showed a hybrid and variable EMT expression profile not specifically associated with SRL response instead of a defined epithelial or mesenchymal phenotype. However, high SNAI1 expression was related to invasive and SRL-nonresponsive tumors. RORC was overexpressed in tumors treated with SRLs before surgery, and this increased expression was more prominent in those cases that normalized postsurgical IGF-1 levels under SRL treatment. In conclusion, GH-producing tumors showed a heterogeneous expression pattern of EMT-related genes that would partly explain the heterogeneous response to SRLs. SNAI1 and RORC may be useful to predict response to SRLs and help medical treatment decision making.

Introduction and Objectives: Several types of lipoproteins beyond low-density lipoproteins (LDL) are causally related to cardiovascular disease. We aimed to analyze an advanced lipoprotein profile in individuals with normal and impaired glucose metabolism from different cohorts of a Mediterranean region., Methods: Cross-sectional study in 929 participants (463 normoglycemia, 250 prediabetes, and 216 type 2 diabetes mellitus) with normal renal function, free from cardiovascular disease, and without lipid-lowering treatment. Conventional and advanced (nuclear magnetic resonance [NMR] spectroscopy) lipoprotein profiles were analyzed., Results: Compared with men, normoglycemic women showed lower serum triglyceride and LDL cholesterol concentrations, lower total LDL particles (P) as well as their subclasses and their cholesterol and triglyceride content, higher high-density lipoproteins (HDL)-P and all HDL-related variables (P≤ .05 for all comparisons). Compared with normoglycemic participants, diabetic participants showed higher large and small very LDL-P concentrations (P <.05) and lower total HDL-P and medium HDL-P concentrations (P <.05). Waist circumference and Fatty Liver Index were positively associated with a proatherogenic profile., Conclusions: Women had a better advanced lipoprotein profile than did men. Adiposity indexes related to insulin-resistance were positively associated with a proatherogenic lipid profile. NMR revealed altered lipoprotein particles other than LDL in participants with diabetes, frequently associated with an increased cardiovascular risk. Our findings support the usefulness of extended lipoprotein analysis by NMR spectroscopy to uncover new therapeutic targets to prevent cardiovascular events in at-risk participants., (Copyright © 2021 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.)

Introduction: Computer-aided diagnostic (CAD) programs for malignancy risk stratification from ultrasound (US) imaging of thyroid nodules are being validated both experimentally and in real-world practice. However, they have not been tested for reliability in analyzing difficult or unclear images., Methods: US images with indeterminate characteristics were evaluated by five observers with different experience in US examination and by a commercial CAD program. The nodules, on which the observers widely agreed, were considered concordant and, if there was little agreement, not concordant or difficult to assess. The diagnostic performance of the readers and the CAD program was calculated and compared in both groups of nodule images., Results: In the group of concordant thyroid nodules (n = 37), the clinicians and the CAD system obtained similar levels of accuracy (77.0% vs 74.2%, respectively; P = 0.7) and no differences were found in sensitivity (SEN) (95.0% vs 87.5%, P = 0.2), specificity (SPE) (45.5 vs 49.4, respectively; P = 0.7), positive predictive value (PPV) (75.2% vs 77.7%, respectively; P = 0.8), nor negative predictive value (NPV) (85.6 vs 77.7, respectively; P = 0.3). When analyzing the non-concordant nodules (n = 43), the CAD system presented a decrease in accuracy of 4.2%, which was significantly lower than that observed by the experts (19.9%, P = 0.02)., Conclusions: Clinical observers are similar to the CAD system in the US assessment of the risk of thyroid nodules. However, the AI system for thyroid nodules AmCAD-UT® showed more reliability in the analysis of unclear or misleading images.

Pituitary neuroendocrine tumors (PitNETs) constitute, together with other tumors of the sellar region, 15-25% of intracranial neoplasms. In 2017, the World Health Organization proposed a new classification of PitNETs. The main innovation with respect to the 2004 classification was the recommendation to include in the immunohistochemical evaluation of PitNETs the determination of the transcription factors of the 3 pituitary cell lineages: Pit-1, Tpit and SF-1. Additionally, other clinicopathological classifications with a predictive capacity of tumor behavior during follow-up were proposed. Given these changes, it is appropriate to adapt the knowledge generated during the last 15 years to the daily practice of the treatment and monitoring of PitNETs at the Centers of Excellence in Pituitary Pathology. This document includes the positioning of the Spanish Society of Endocrinology and Nutrition (SEEN) and the Spanish Society of Pathology (SEAP) on the classification and denomination of the PitNETs and the information that the pathologist should provide to the clinician to facilitate the treatment and monitoring of these tumors., (Copyright © 2021 Sociedad Española de Anatomía Patológica. Publicado por Elsevier España, S.L.U. All rights reserved.)

People with diabetes are at greater risk for negative outcomes from COVID-19. Though this risk is multifactorial, poor glycaemic control before and during admission to hospital for COVID-19 is likely to contribute to the increased risk. The COVID-19 pandemic and restrictions on mobility and interaction can also be expected to impact on daily glucose management of people with diabetes. Telemonitoring of glucose metrics has been widely used during the pandemic in people with diabetes, including adults and children with T1D, allowing an exploration of the impact of COVID-19 inside and outside the hospital setting on glycaemic control. To date, 27 studies including 69,294 individuals with T1D have reported the effect of glycaemic control during the COVID-19 pandemic. Despite restricted access to diabetes clinics, glycaemic control has not deteriorated for 25/27 cohorts and improved in 23/27 study groups. Significantly, time in range (TIR) 70-180 mg/dL (3.9-10 mmol/L) increased across 19/27 cohorts with a median 3.3% (- 6.0% to 11.2%) change. Thirty per cent of the cohorts with TIR data reported an average clinically significant TIR improvement of 5% or more, possibly as a consequence of more accurate glucose monitoring and improved connectivity through telemedicine. Periodic consultations using telemedicine enables care of people with diabetes while limiting the need for in-person attendance at diabetes clinics. Reports that sustained hyperglycaemia and early-stage diabetic ketoacidosis may go untreated because of the lockdown and concerns about potential exposure to the risk of infection argue for wider access to glucose telemonitoring. Therefore, in this paper we have critically reviewed reports concerning use of telemonitoring in the acute hospitalized setting as well as during daily diabetes management. Furthermore, we discuss the indications and implications of adopting telemonitoring and telemedicine in the present challenging time, as well as their potential for the future., (© 2021. The Author(s).)

Background: Total 25-OH-vitamin D (25(OH)D) levels are decreased in patients with obesity, but few data exist regarding free-vitamin D3 (f25(OH)D3) concentrations. We aimed to evaluate the effect of bariatric surgery on 25(OH)D and f25(OH)D3 in a cohort of patients with morbid obesity., Methods: Twenty-four patients submitted to sleeve gastrectomy (SG) (mean age 48 years, body mass index (BMI) 48.16±10.73k/m 2 ) were evaluated before and 1 year after surgery. Anthropometric data, parathormone (PTH), calcium, alkaline phosphatase, 25(OH)D, and f25(OH)D3 were recorded., Results: 25(OH)D and f25(OH)D3 correlated well before and after SG. Baseline determinations did not correlate with BMI, but they inversely correlated with BMI 1 year after surgery (r s =-0.46, p=0.02 and r s =-0.60, p=0.002, respectively). Post-surgery % total body weight loss (%TBWL) was 27.4±13.8 %; f25(OH)D3 concentrations increased significantly (5.28±2.29 pg/mL vs 6.64±2.25 pg/mL; p=0.03), whereas 25(OH)D did not change. Patients who achieved a BMI <35 kg/m 2 1 year after surgery had significantly higher concentrations of f25(OH)D3 (7.9±1 pg/mL vs 4.8±1.1, p<0.001) and 25(OH)D (30.9±9.4 ng/mL vs 22.3±13.4; p=0.03) compared to those who remained with BMI >35 kg/m 2 ., Conclusion: There is a significant inverse relationship between BMI and both f25(OH)D3 and 25(OH)D 1 year after surgery. Only f25(OH)D3 concentrations increased 1 year after surgery, which could be explained by a greater f25(OH)D3 sequestration before SG in the adipose tissue, potentially due to the more liposoluble nature of f25(OH)D3 than the protein-bound form 25(OH)D., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Changes that COVID-19 induced in endocrine daily practice as well as the role of endocrine and metabolic comorbidities in COVID-19 outcomes were among the striking features of this last year. The aim of this statement is to illustrate the major characteristics of the response of European endocrinologists to the pandemic including the disclosure of the endocrine phenotype of COVID-19 with diabetes, obesity and hypovitaminosis D playing a key role in this clinical setting with its huge implication for the prevention and management of the disease. The role of the European Society of Endocrinology (ESE) as a reference point of the endocrine community during the pandemic will also be highlighted, including the refocusing of its educational and advocacy activities.

Obesity is an important public health issue that has been on the rise over the last decades. It calls for effective prevention and treatment. Bariatric surgery is the most effective medical therapy for weight loss in morbid obesity, but we are in need for less aggressive treatments. Glucagon-like-peptide-1 receptor agonists are a group of incretin-based drugs that have proven to be productive for obesity treatment. Through activation of the GLP-1 receptor they not only have an important role stimulating insulin secretion after meals, but with their extrapancreatic actions, both peripheral and central, they also help reduce body weight by promoting satiety and delaying gastric emptying. Liraglutide in a dose of 3 mg is currently the only drug of this group that is approved by the FDA to treat obesity, with weight losses up to 8.5 kg in relatively short periods of time. Here we review the data so far collected of GLP-1 use for obesity with and without diabetes, including the recent data of oral semaglutide.

Background: Recent guidelines recommend establishing a local reference interval (RI) for thyroid function. We aimed to establish trimester-specific RIs for thyrotropin (TSH) and free thyroxine (FT4) in a cohort of healthy pregnant women in Catalonia (Spain)., Methods: A prospective observational study was conducted with 332 healthy pregnant women, from the first trimester (1T) to delivery. TSH was measured using an Architect ® immunoassay (Abbott) and FT4 by two immunoassays, Architect ® (Abbott) and Cobas ® (Roche), in the three trimesters. FT4 was also measured by liquid chromatography mass spectrometry (LC/MS/MS) in the 1T., Results: TSH (µUI/mL) increased throughout pregnancy (1T: 0.03-3.78; 2T: 0.51-3.53; 3T: 0.50-4.32; p < 0.0001) and FT4 (pmol/L) progressively decreased (Architect ® 1T: 10.42-15.96; 2T: 8.37-12.74; 3T: 8.24-12.49; p < 0.0001; and Cobas ® : 1T: 11.46-19.05; 2T: 9.65-14.67; 3T: 8.88-14.54; p < 0.0067). The FT4 RI during 1T determined LC/MS/MS was 8.75-18.27. Despite the 1T FT4 results measured by LC/MS/MS and with the two immunoassays being significantly correlated, the results obtained by the three methods were found to be non-interchangeable., Conclusions: We established trimester-specific RIs for TSH and for FT4 with immunoassays in our population. We also validated the 1T FT4 using LC/MS/MS to confirm the results of FT4 lower than the 2.5th percentile or higher than the 97.5th percentile.