European Journal of Endocrinology最新文献

Pituitary apoplexy (PA) is a rare but potentially life-threatening endocrine emergency caused by sudden hemorrhage or infarction usually within a pituitary tumor. Clinical presentation is highly variable, ranging from isolated headache to severe visual loss or altered consciousness. Prompt recognition, multidisciplinary evaluation, and timely management are essential to improve outcomes. Recent prospective and real-world studies have challenged the traditional view that urgent surgery is always required. Conservative management has been proposed to be a safe and effective option, although comparisons with the outcomes after surgical intervention are limited by differences in the severity of the clinical picture at presentation of the PA. Clinical decisions remain complex and must consider tumor size, symptom progression, radiological features, and individual comorbidities. The Pituitary Apoplexy Score (PAS) helps guide management but has limitations, as it does not capture key variables such as persistent headache or evolving visual symptoms. Immediate management focuses on hemodynamic stabilization, stress-dose glucocorticoid administration, and neuro-ophthalmological monitoring. Surgical decompression should be considered in patients with progressive visual deterioration or altered consciousness. Follow-up must include hormonal reassessment, ophthalmological evaluation, and imaging surveillance. Although rare, recurrence of PA and tumor regrowth may occur, requiring long-term monitoring. This review provides an updated and pragmatic approach for the diagnosis, acute care, and long-term follow-up of PA, summarizing current evidence and highlighting ongoing controversies, including surgical timing and predictors of conservative treatment failure.

Objective: Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment but are associated with immune-related adverse events (irAEs), including pituitary dysfunction. Combination immunotherapy with PD-1 and CTLA-4 inhibitors increases the risk of pituitary irAEs compared to PD-1 monotherapy; however, their detailed characteristics remain unclear. We aimed to clarify the clinical features of pituitary irAEs induced by combination immunotherapy.

Design: In this retrospective cohort study, we compared patients treated with combination therapy of nivolumab and ipilimumab (Nivo/Ipi) to those receiving nivolumab monotherapy (Nivo). We analyzed clinical data including presenting symptoms, laboratory findings, pituitary MRI results, and coexisting irAEs.

Results: Pituitary irAEs were more frequent in the Nivo/Ipi group (17.4%) than in the Nivo group (2.7%) and developed earlier (median onset: 63 vs. 153 days, respectively). All 15 patients in the Nivo group presented with isolated ACTH deficiency (IAD), whereas the Nivo/Ipi group included 8 cases of IAD and 8 cases of combined pituitary hormone deficiency (CPHD). In the Nivo/Ipi group, CPHD occurred significantly earlier than IAD (median onset: 40 vs. 84 days) and was associated with a higher incidence of headache and pituitary swelling on MRI. Furthermore, 75% of patients with CPHD also experienced non-endocrine irAEs. Two CPHD patients experienced worsening of symptoms and pituitary dysfunction following re-administration of Nivo/Ipi.

Conclusion: Pituitary irAEs are more frequent and develop earlier in patients receiving Nivo/Ipi. CPHD and IAD, induced by this combination immunotherapy, exhibit distinct clinical courses. Recognizing these differences is crucial for the optimal management of pituitary irAEs during combination immunotherapy.

Non-functioning pituitary neuroendocrine tumors (NF-PitNETs) represent one of the most common and heterogenous sellar pathology, and are nowadays still orphan of an effective pharmacological therapy that could substitute surgery or support in case of persistency/recurrence. In fact, despite NF-PitNETs are generally benign tumors, they can be characterized by supra- or extra-sellar growth with invasion of the cavernous sinus and/or involvement of the optical chiasm. For these reasons, lots of studies tried to unveil the molecular mechanisms underlying resistance and tumoral cells growth, so as to identify new possible therapeutic targets and novel drugs that could improve NF-PitNETs treatment. This review aims to summarize the new biological targets and therapeutic strategies that have been proposed so far, trying to give rise to novel approaches and paving the way for personalized strategies for patients harboring NF-PitNETs. In addition, further studies related to the complex mechanisms involved in NF-PitNETs resistance to the available therapies could provide the basis for the development of both prognostic biomarkers useful for patients' management and novel targets for the pharmacological treatment of these tumors.

Objective: To examine body image (BI) concerns in women with polycystic ovary syndrome (PCOS) by comparing perceptions with normative data, assessing links with psychological distress, clinical features, disordered eating, and quality of life (QoL), and identifying body image cut-offs that predict psychological risk.

Design: Mixed-methods observational study conducted in the United Kingdom (June 2023-October 2024).

Methods: Women with PCOS (n=171) completed validated questionnaires assessing BI (Multidimensional Body-Self Relations Questionnaire - Appearance Scale), depression, anxiety, disordered eating, and QoL; 41 also participated in semi-structured interviews. Moderation by ethnicity and socioeconomic status (SES) was examined.

Results: Women with PCOS reported greater BI-distress than normative data, driven by elevated body mass index (BMI) and hirsutism. Poorer BI was linked to higher depression, anxiety, disordered eating, and reduced QoL. ROC-analyses identified self-classified weight scores (SW)≥4.25 as the cut-off for depression and overweight preoccupation (OP)≥2.88 for anxiety. In adjusted models, higher SW scores predicted nearly fivefold greater depression risk, while elevated OP scores conferred a fourfold higher anxiety risk and doubled disordered eating risk. Together with BMI, OP and SW predicted most PCOS-QoL domains, with the strongest effects in weight-related QoL. Socioeconomic deprivation amplified OP effects on disordered eating, while ethnicity showed minimal influence. Qualitative findings echoed these results, with weight gain, hirsutism, negative diagnostic experiences, and social withdrawal emerging as key distress drivers.

Conclusion: BI concerns are central to psychological morbidity and reduced QoL in PCOS. Establishing OP and SW cut-offs enables early risk stratification, while acknowledging SES influences may support equitable, patient-centred care.

Background: The Itabaianinha cohort in Brazil carries a homozygous growth hormone-releasing hormone (GHRH) receptor (GHRH-R) gene mutation, causing congenital isolated GH deficiency (GHD). Affected individuals present with severe short stature, central obesity, hypercholesterolemia, and marked reductions in serum GH, IGF-I, and IGFBP 3 concentrations yet show no premature atherosclerosis and maintain a normal lifespan. IGF-I mostly circulates bound to IGFBPs and requires proteolytic cleavage for IGF-I receptor activation. Pregnancy-associated plasma protein A (PAPP-A) is an important IGF-dependent cleavage enzyme, binding to IGFBP 4 and releasing IGF-I. PAPP-A activity is inhibited by stanniocalcin-2 (STC2). The IGFBP 4-STC2-PAPP-A axis (ISPa) has emerged as a key regulator of IGF-I bioactivity.

Methods: We evaluated the ISPa in: (1) GHD subjects with homozygous GHRH-R c.57 + 1G→A mutation, (2) heterozygotes (HTZ), and (3) homozygous wild-type controls (HMZ). Parameters from the ISPa were measured at LMU Klinikum, Munich. Additional biochemical parameters were analyzed at the Federal University of Sergipe, Brazil.

Results: As expected, GHD subjects had markedly low GH, IGF-I, IGF-II, free IGF-I, and IGFBP 3 (P < .001), while HTZ resembled HMZ subjects. STC2, PAPP-A, and PAPP-A-STC2 complex concentrations did not differ between groups. However, PAPP-A2 and intact IGFBP 4 were higher in the GHD subjects (P < .05 and P < .01). Notably, IGF-I and IGFBP 3 positively correlated with IGF-II, whereas intact IGFBP 4 and PAPP-A2 showed inverse correlations with IGF-I and IGF-II.

Conclusion: Our findings suggest altered IGF-I bioavailability regulation via the ISPa in congenital lifetime GHD, leading to increased PAPP-A2 proteolytic activity, reduced PAPP-A enzymatic activity, and reduced sequestration of PAPP-A2 by STC2.

Objective: Glucagon-like peptide-1 (GLP-1) plays an important modulatory role in sodium and water homeostasis. Recent studies demonstrated that long-term treatment with GLP-1 receptor agonists (RAs) reduces fluid intake and urine output. To the best of our knowledge, no direct effect of GLP-1 on vasopressin has been observed. This secondary analysis aimed to investigate changes in copeptin levels in euvolemic participants treated with the GLP-1 RA dulaglutide versus placebo.

Design: Secondary analysis of two randomized, double-blind, placebo-controlled, cross-over trials in 34 patients with primary polydipsia and 20 healthy participants.

Methods: Participants received a 3-week intervention with dulaglutide (Trulicity) 1.5 mg or placebo (.9% sodium chloride) subcutaneously once weekly. Blood for copeptin analysis was collected at 08:00 after each treatment phase. To estimate the treatment effect of dulaglutide, we derived the absolute within-subject differences of copeptin between dulaglutide and placebo and used the Wilcoxon rank test for statistical analysis.

Results: All 54 participants of the two cross-over trials were included. Median age was 27 years [interquartile range (IQR), 24-37.5 years], and 63% were female. Median body mass index (BMI) was 23 kg/m2 (IQR, 20.8-24.8). After 3-week treatment, dulaglutide was associated with a significant suppression of copeptin with a median within-subject difference of -.7 pmol/L (p = .047), corresponding to a 12% reduction compared to placebo. Treatment-induced changes in copeptin were not significantly correlated with GLP-1-mediated reductions in blood pressure, BMI, or incidence of nausea.

Conclusions: Our analysis provides evidence that the GLP-1-RA dulaglutide inhibits the vasopressin system and proposes physiological mechanisms that may explain the role of GLP-1 in sodium and water balance.

Introduction: Brown adipose tissue (BAT) thermogenesis is mediated by sympathetic nervous system activation and enhanced by thyroid hormones via upregulation of uncoupling protein 1. Studying thyroid hormone response to cooling in populations with habitual cold exposure may give new insights to the role of thyroid hormones in non-shivering thermogenesis.

Methods: Twenty-one participants (11 Greenlanders, 10 Danes) underwent a cross-over protocol with experimental sessions of cooling and thermal comfort, followed by [18F]FDG positron emission tomography/computed tomography scans. Serial blood samples were collected to assess thyrotropin (TSH), total triiodothyronine (TT3), total thyroxine (TT4), and thyroglobulin (Tg) before, during, and after cooling.

Results: Cooling induced an increase in TSH (Danes: 0.24 mIU/L, P < .001; Greenlanders: 0.15 mIU/L, P = .009). TT3 also increased in response to cooling (Danes: 0.15 nmol/L, Greenlanders: 0.09 nmol/L, Pboth < .001). Greenlanders had lower TSH and higher TT3 levels compared to Danes (baseline 0.27 nmol/L, P = .009) with an attenuated TT3 response to cooling (-0.07 nmol/L, P  =  .009). The T3/T4 ratio was elevated during cold exposure compared to thermoneutral conditions in both Danes (P < .001) and Greenlanders (P = .022), and Greenlanders had consistently higher T3/T4 ratios compared to Danes (baseline, P = .001; after cooling, P = .023). Finally, Tg levels were higher in participants with low- compared to high-BAT volume (7.27 µg/L, P = .008).

Conclusion: Serial measurements of thyroid hormones and thyroglobulin with gold-standard detection of BAT activity documented distinct thyroid responses to cooling. The findings suggested a physiological preparedness to acute cold exposure in individuals with cold adaptation, irrespective of origin.

Context: No effective therapies are available for patients with advanced adrenocortical carcinoma (ACC) progressing after standard therapy: EDP (etoposide, adriamycin, and cisplatin) and mitotane (EDP-M regimen). These patients have poor prognosis with a median life expectancy of 6-7 months. Immunotherapy in this setting is promising. Concomitant chemotherapy administration can enhance the efficacy of immunotherapy, as demonstrated in other malignancies.

Objective: This retrospective study aims to explore the activity of a combination of cisplatin and nivolumab administered to patients with ACC who have previously undergone chemotherapy and mitotane treatment.

Patients and methods: Cisplatin, 25 mg/m2 on day 1, and nivolumab, 240 mg on day 2, every 2 weeks, were administered to advanced/metastatic ACC with disease progression to EDP-M regimen plus/minus other chemotherapeutic regimens. The primary endpoint was the disease response according to RECIST. Secondary endpoints were clinical benefit, disease control rate (DCR), overall survival (OS), progression-free survival (PFS), and safety.

Results: Twenty-three patients were enrolled between January 2023 and March 2025. The median follow-up was 15.1 months. Eight patients [34.8% (95% CI, 15.3%-54.2%)] obtained a partial response and 4 patients (17.3%) a stable disease; therefore, 12 patients (52.2%) obtained a clinical benefit. The DCR after 6 months was obtained in 39.1% [95% CI, 19.7%-61.5%] of patients. The median PFS was 4.3 months [95% CI, 3.9-13.0], and the median OS was 18.9 months [95% CI, 15.8-not reached]. Chemo-immunotherapy combination was well tolerated, and most toxicities were limited to grade G1-2 according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) criteria. One patient discontinued treatment after 1 cycle, due to grade 3 immune-related hepatitis.

Conclusion: The combination of cisplatin and nivolumab is an active regimen in advanced, previously treated, ACC patients. The long survival achieved in this patient population with a poor prognosis is promising.

Objective: Androgen abuse for performance- and image-enhancement is increasing despite preventive efforts, yet no controlled trials have evaluated harm reduction strategies. This trial assessed whether a harm reduction intervention could reduce androgen abuse in males.

Design: Historically controlled trial.

Methods: This 1-year prospective intervention study included 99 male amateur athletes planning to start an androgen cycle. Outcomes were compared to a historical cohort study (n = 100) from our research group receiving no intervention. The intervention comprised individualized counseling and medical assessments. Primary outcomes included cumulative androgen dose, cycle duration, and weekly dosage. Secondary outcomes included within-participant deviation from planned abuse.

Results: Baseline characteristics were largely comparable, although intervention participants reported slightly more weekly training time and lower intended cumulative cycle dose. Twelve percent refrained from initiating a cycle due to the intervention. The mean cumulative androgen dose was 13 087 (95% CI -16 564 to -9609) mg lower in the intervention group (6323 ± 5229 mg) compared to controls (19 410 ± 16 497 mg). Within-person differences showed an average reduction of 8729 (95% CI -11 297 to -6287) mg in the intervention group compared to controls. Multivariable regression confirmed that the interventions' effect was independent of baseline differences. No significant enabling effect was observed.

Conclusion: This is the first controlled study to demonstrate that a harm reduction intervention can reduce androgen exposure among men planning to abuse androgens. These findings support harm reduction as a promising strategy to mitigate health risks associated with androgen abuse. Future studies should confirm generalizability and monitor for potential enabling effects.

Clinical trial registration number: Registration number P2117, study number NL77191.028.21.