European Journal of Endocrinology最新文献

Objective: Data on pituitary neuroendocrine tumors (PitNETs) surgically treated during pregnancy is limited, and no studies have compared these cases to those treated in non-pregnant women. This study aimed to describe the clinical, radiological, and histological profiles of patients treated surgically for PitNETs during pregnancy and evaluate long-term prognosis.

Design: This study was multicentric, observational and retrospective.

Methods: We included 10 patients from 5 university hospitals who underwent surgical treatment for PitNETs during pregnancy or within 12 months postpartum, along with 30 matched non-pregnant controls treated surgically for PitNETs. Clinical and histological data, as well as progression-free survival without additional treatment, were compared between pregnant and non-pregnant patients.

Results and conclusions: Among the 10 PitNETs, 4 were corticotropic, 2 gonadotropic, 2 lactotropic, and 2 somatotropic. The primary surgical indication (tumour syndrome with or without failure of medical treatment) was similar between the two groups: 7/10 vs 19/30 (p = 1.00). There was no statistically significant difference in volume (p = 0.072) or radiological invasion markers (optic chiasm compression, p = 0.059, and cavernous sinus invasion, p = 0.274). However, PitNETs in pregnant women showed higher mitotic activity (p = 0.038) and were more frequently classified as grade 2b (Trouillas clinicopathological classification; p=0.049). The need for second-line treatment was also more frequent (p = 0.005). PitNETs requiring surgical treatment during pregnancy are characterized by increased proliferative activity and progression after surgery. Despite this, the long-term prognosis remains favorable. These results need confirmation in a larger study.

Introduction: ARMC5 is the most prevalent gene predisposing to Primary Bilateral Macronodular Adrenal Hyperplasia (PBMAH), but germline KDM1A variants have been identified in the rare PBMAH associated with food-dependent Cushing's syndrome (FDCS). The purpose of this work was to assess the frequency of KDM1A variants in a large series of PBMAH patients.

Methods: 301 consecutive PBMAH index cases from 8 international Endocrinology departments were included. Clinical, biological and imaging data were collected retrospectively.

Results: 10 (3.3%) patients carried a germline KDM1A pathogenic or likely pathogenic variant, 60 (19.9%) carried a germline ARMC5 alteration, 231 (76.8%) had no identified genetic predisposition. FDCS was present in all patients with KDM1A variants and absent in the 2 other groups. KDM1A patients had a higher 24h urinary free cortisol (3.0-fold ULN vs 1.36 for ARMC5 patients and 0.66 for wild-type patients, respectively, p=0.0001). In accordance with FDCS pathophysiology, patients with KDM1A variants had a lower morning fasting plasma cortisol (192 nmol/L vs 407 and 428, respectively, p=0.0003) and a higher midnight plasma cortisol (487 nmol/L vs 297 and 171.96, respectively, p=0.0004). Morning/midnight plasma cortisol ratio below 0.65 holds 100% sensitivity and specificity for the detection of FDCS. All patients with KDM1A variants were women, vs 65% of ARMC5 patients and 67% of wild-type patients (p=0.0337).

Conclusion: KDM1A germline pathogenic variants are rare in PBMAH and account for less than 5% of index cases. KDM1A seems constantly associated with FDCS, which can be evoked in front of a morning/midnight plasma cortisol ratio below 0.65.

Background: Mild autonomous cortisol secretion (MACS) is common in adrenal adenomas, including patients with primary aldosteronism (PA) with aldosterone-producing adenomas (APA). This study investigated the impact of MACS on cardiac remodeling and diastolic dysfunction in patients with APA.

Methods: We prospectively enrolled 483 patients with APA. MACS was defined as a cortisol level >1.8 μg/dL after an overnight dexamethasone-suppression test (DST). Clinical, biochemical, and echocardiographic data were collected at baseline and one-year following targeted treatments.

Results: In this prospective cohort, 21% of patients with APA had concurrent MACS. Patients with MACS were older, had a higher prevalence of diabetes, larger adrenal tumor size, higher left ventricular mass index (LVMI), and worse diastolic function (E/e'). Multivariable linear regression analysis showed that concurrent MACS with APA was an independent risk factor for higher LVMI and worse E/e'. Among patients who underwent adrenalectomy, both those with and without MACS showed significant improvements in LVMI and E/e'. In contrast, among patients who received mineralocorticoid receptor antagonist (MRA) treatment, significant LVMI improvement was only observed in patients without MACS. MRA therapy did not improve E/e' regardless of the presence or absence of MACS.

Conclusions: The presence of MACS in patients with PA was associated with worse cardiac hypertrophy and diastolic dysfunction. Surgical adrenalectomy was able to effectively reverse cardiac remodeling in patients with PA and concurrent MACS; however, MRA therapy was not associated with significant improvements in cardiac function. These findings highlight the independent deleterious effects of cortisol on cardiovascular disease in PA.

Objective: Given the promising effects of GLP-1/GIP/glucagon receptor triagonists on weight loss in animals and humans, improved understanding of underlying mechanism is required. We investigated a direct lipolytic effect of a specific GLP-1/GIP/glucagon receptor triagonist on human adipose tissue to disentangle central and peripheral effects as potential drivers of weight loss.

Design and methods: Isolated primary adipocytes from subcutaneous adipose tissue biopsies of 22 non-diabetic subjects [63.0 (57.0-69.5) years] were incubated with increasing concentrations of isoprenaline, GLP-1, GIP, glucagon, or a GLP-1/GIP/glucagon receptor triagonist. Glycerol concentration was measured following stimulation to assess lipolysis. mRNA expression of adipose tissue receptors was analyzed in parallel.

Results: Glycerol concentration only increased by isoprenaline, GIP (+13%), and GLP-1/GIP/glucagon receptor triagonist (+28%) but not by GLP-1 or glucagon. This effect was not related to age or body mass index (BMI). Higher adipose tissue GIP receptor mRNA expression was related to elevated glycerol release after GIP and GLP-1/GIP/glucagon receptor triagonist stimulation.

Conclusions: Direct lipolytic effects of GIP seem to exist in human subcutaneous adipose tissue. This might be targetable by multiple receptor agonists, especially with a high GIP receptor affinity. Such a mechanism can potentiate the beneficial effect on weight loss and will therefore represent a promising target of future research.

Clinical trial registration number: The trial was registered at German Clinical Trials Register (drks.de) as DRKS00010049.

Selection in clinical research does not necessarily result in selection bias. To understand when selection leads to bias, we discuss collider-conditioning bias, which is a common and often self-inflicted type of selection bias. Collider-conditioning bias may be difficult to recognize and paying more attention to the bias could therefore increase the quality of research. In this paper, we aim to increase awareness and understanding of the topic.

Monogenic obesity, characterized by severe, early-onset obesity due to single-gene defects, often resists traditional weight management strategies. This report presents real-life experiences on the efficacy and safety of setmelanotide, an MC4R agonist, in 4 prepubertal children (ages 3-9) with LEPR and POMC deficiencies. Findings indicate that setmelanotide is effective at lower doses in our patients with POMC deficiency (0.3-0.5 mg/day) than the patients with LEPR deficiency (2.5 mg/day). Treatment was generally well-tolerated, with injection site reactions and hyperpigmentation as common side effects. As novel findings, gonadotropin-related effects such as hypothalamo-pituitary-gonadal axis activation and testicular descent were observed in 2 patients. Growth deceleration was noted in 2 children, and recovery from central hypothyroidism in 1 patient with POMC deficiency. Overall, setmelanotide appears to be effective and well-tolerated in young children with monogenic obesity. However, further studies are necessary to evaluate the long-term effects of early intervention on growth and pubertal development.

Objective: Cardiovascular disease in acromegaly patients remains a major cause of morbidity and all-cause mortality. This systematic review investigates the effect of the first growth hormone-lowering intervention on cardiac parameters.

Design: Systematic review.

Methods: Studies evaluating cardiac parameters following the first intervention in acromegaly published up to February, 25, 2022 were included in this systematic review. Risk of bias was assessed using a modified Newcastle-Ottawa Scale and Joanna Briggs Institute Critical Appraisal Checklist. Primary treatment modalities included (transsphenoidal) surgery and medical treatment with first-generation somatostatin receptor ligands. Cardiac outcome measures were divided into cardiac structure (left ventricular hypertrophy [LVH], [indexed] left ventricular mass [LVM/LVMi]) and cardiac function (left ventricular ejection fraction [LVEF] and E/A ratio).

Results: Twenty-six studies (17 cohort studies and 9 case reports) were included out of 2541 potential studies. The risk of bias analysis categorized, 24 studies as low risk and 2 studies as intermediate risk. Disease-associated changes in cardiac structure and function generally improved in most studies following primary treatment. Left ventricular mass/left ventricular mass index significantly decreased in 9/15 studies and the prevalence of LVH in 3/13 studies. Left ventricular ejection fraction significantly increased in 9/14 studies and the E/A ratio in 6/7 studies. Despite the limited number of studies, cardiac structure improved more in patients achieving biochemical remission than in those failing to achieve biochemical remission.

Conclusions: Acromegaly associated structural and functional myocardial changes improve with both medical and surgical treatment. Normalizing or even reducing growth hormone/insulin-like growth factor 1 levels may be key in the prevention of further progression of cardiac involvement in acromegaly and adverse cardiac outcomes.

Objective: To evaluate the association between various regimens and combinations of menopausal hormone therapy (MHT) and the risk of cardiovascular disease (CVD) in clinical practice.

Design: This was a population-based cohort study.

Methods: This population-based cohort study used data from the Health Insurance Review and Assessment Service. The data of women who reported entering menopause at ≥40 years of age with no history of CVD in the national health examination between 2011 and 2014 were extracted. A total of 134 298 pairs were included in the MHT and non-MHT groups after 1:1 propensity score matching. The participants were followed until December, 31, 2020.

Results: During a median follow-up of 7.9 (IQR 6.9-8.9) years, the incidences of CVD were 146 per 100 000 person/year and 179 per 100 000 person/year for the non-MHT and MHT groups, respectively. After adjusting for covariates, MHT use was associated with an increased CVD risk (hazard ratio [HR], 1.22 [1.14-1.31]) compared with the non-MHT group; the risk was based on an increased risk of stroke and coronary artery revascularization. Tibolone (HR, 1.38, [1.27-1.50]) was associated with increased CVD, but estrogen alone or combined estrogen/progestogen was not. There was no difference in CVD risk, regardless of the type of estrogen agent used. For combined estrogen/progestogen therapy, dydrogesterone was associated with reduced CVD risk.

Conclusions: There was an increased risk of CVD in MHT users. By regimen, tibolone use was associated with increased risk of CVD, whereas estrogen either alone or in combination with progestogen was not. There was no difference according to the type of estrogen. The type of progestogen seems to modify the results, since dydrogesterone was associated with reduced CVD risk.

Adrenal incidentalomas (AI) are increasingly detected during imaging performed for conditions unrelated to adrenal pathology. Numerous studies have shown that the presence of AI is associated with a higher frequency of hypertension, type 2 diabetes, dyslipidemia, obesity, and osteoporosis. This increased morbidity is mostly related to mild autonomous cortisol secretion, which is the most common hormonal abnormality in these patients. It is well known that glucocorticoid excess affects the hippocampus and prefrontal cortex, brain structures involved in mood regulation and cognitive processes, leading to a wide range of psychiatric symptoms, including depression. While these effects are well-documented in patients with Cushing's syndrome, data on mental health changes in patients with AIs remain scarce. Additionally, the few existing studies have several limitations, leaving important clinical questions unanswered. Consequently, the extent to which AIs are associated with impaired mental health and whether patients would benefit from surgical treatment remains unclear. Addressing these challenges is crucial for developing adequate management strategies. This review explores potential psychological and psychiatric implications of AIs. By synthesizing existing literature, we aim to explain the relationship between AIs and mental health disorders, providing a background for future research and clinical practice guidelines.

Objective: Rebound vertebral fractures (VFs) after Denosumab (Dmab) withdrawal have been documented, highlighting the need for further research into this phenomenon and the importance of a well-planned strategy for discontinuing Dmab.

Methods: From the TriNetX US network, we enrolled osteoporosis patients aged 50 years or older who had withdrawn from at least two doses of Dmab and compared them with a matched cohort who had received at least one dose of zoledronate (ZOL) before discontinuation. We analyzed hazard ratios (HR) with 95% confidence intervals (CI) and conducted Kaplan-Meier analyses, along with subgroup analyses, drug discontinuation modification, and sensitivity analyses.

Results: After matching propensity scores (n = 10,422) between the two cohorts (Dmab: 11,104 and ZOL: 15,976), we found that the risks of VFs (HR = 1.479, 95% CI = 1.222-1.789) and its subcategories-thoracic (1.309, 1.023-1.674), lumbar (1.865, 1.425-2.440), and collapsed fractures (1.928, 1.462-2.542)-as well as all-cause mortality (1.588, 1.475-1.710), were significantly higher in the Dmab group compared with the ZOL group. Stratified analyses showed increased VF risks in Dmab patients who were female, aged 50-64, 65 years or older, and white, regardless of fracture history compared with those using ZOL.

Conclusion: After adjusting for drug discontinuation, Dmab showed an increased risk of VFs within the first two years, contributing to an elevated overall mortality risk. Sensitivity analyses revealed consistent results across different regions.