Endocrine Connections最新文献

Objective: Hypercalcaemia is often considered as an emergency because of a potential risk of life-threatening arrhythmias or coma. However, there is little evidence, apart from case studies, that hypercalcaemia can be immediately life-threatening. The aim of our study was to prospectively assess whether hypercalcaemia (Ca ≥ 3 mmol/L) was associated with immediately life-threatening complications.

Design and methods: We conducted a prospective observational study aiming to include the first one hundred patients aged ≥18 who had a calcium concentration ≥3 mmol/L, admitted to the emergency department (ED). The primary outcome was the number of life-threatening cardiac arrhythmias (ventricular tachycardia, ventricular fibrillation, sinus arrest and second- or third-degree atrioventricular blocks) or neurological complications defined by a Glasgow Coma Scale score <9 during the stay in the ED. The secondary outcomes were correlation between calcium concentrations and ECG (electrocardiogram) QTc intervals, Glasgow Coma Scale scores and mortality during the following 12-month follow-up period.

Results: The median calcium concentration was 3.3 mmol/L (3.1-3.7). Cancer was the first cause of hypercalcaemia. No patient presented a life-threatening cardiac arrhythmia during their stay in the ED. Three patients presented a life-threatening neurological complication. There was no correlation between calcaemia and QTc intervals or Glasgow Coma Scale score. Prognosis was poor, and 43 patients died during the 12 months.

Conclusions: We found no cases of immediately life-threatening cardiac arrhythmias. Three patients had indeed a life-threatening neurological complication but always had at least one other major factor that could severely alter mental status, such as profound metabolic acidosis.

Significance statement: This paper aims to revisit what most physicians, whether specialists or not, consider to be scientifically proven facts concerning the immediate threat caused by hypercalcaemia. Its novelty is threefold: first, this is the only prospective study that exists to date studying the life-threatening consequences of hypercalcaemia; second, having included one hundred patients, we found no life-threatening cardiac arrhythmias, which is not what would be expected if one reads guidelines concerning hypercalcaemia; and third, life-threatening neurological complications were very rare and only occurred in patients with at least one other major cause of altered neurological status, such as severe metabolic acidosis or hypernatraemia.

Background: Prostate cancer therapy with surgical or chemical castration with gonadotropin-releasing hormone (GnRH) agonists has been linked to elevated follicle-stimulating hormone (FSH) levels, which may contribute to secondary health disorders, including atherosclerosis and diabetes. Although recent findings suggest a role for FSH beyond the reproductive system, its metabolic impact remains unclear and difficult to disentangle from that of androgens. In this study, we examined the metabolic changes induced by FSH and distinguished them from those caused by testosterone.

Methods: Plasma samples from temporarily medically castrated young men (n = 33) treated with FSH and/or testosterone were characterized by proteomics and metabolomics approaches. All subjects received GnRH antagonists. Sixteen men were randomized to recombinant FSH (300 IU 3 times/week) for 5 weeks, while seventeen men served as controls. After 3 weeks, all men received 1000 mg intramuscular testosterone undecanoate. Blood samples were collected at the start, after 3 weeks and after 5 weeks. The proteome and metabolome signatures were characterized in all samples.

Results: FSH significantly upregulates key proteins involved in the modulation of inflammatory response and innate immune system (P ≤ 0.03) and dysregulates lipid metabolism, evidenced by downregulation of multiple apolipoproteins (P ≤ 0.04) and increased levels of cholesterol and glycerophospholipids (P ≤ 0.03). In addition, low FSH levels were correlated with a reduction in the active form of vitamin D (P < 0.02). These results highlight the short-term metabolic impacts of FSH in males.

Conclusions and clinical implications: Our findings underlined the FSH effect on extragonadal systems and its connection to metabolic disorders often seen as secondary effects of prostate cancer treatment.

Introduction: Cardiovascular disease is the most common cause of death in Turner syndrome (TS) for which arterial hypertension has a direct influence and is a key modifiable risk factor.

Objective: To investigate the prevalence and patterns of hypertension diagnosis and management in adult patients with TS who are registered in a large international multicentre database (TS-HTN study).

Methods: Retrospective multicentre observational study of patients aged ≥18 years included in the I-TS (International-TS) registry (2020-2022), using registry and participating centre-collected data.

Results: Twelve international centres participated, including 182 patients with a median age of 28 years (IQR 23-37.2). Arterial hypertension was recorded in 13.2% (n = 24). The median age at hypertension diagnosis was 27 years (range 10-56), with 92% aged less than 50 years at diagnosis. The majority (75%) were classified as primary hypertension (n = 18). In binomial regression analysis, higher body mass index was the only parameter significantly associated with the occurrence of hypertension (B = 1.487, P = 0.004). Among patients with aortic disease (n = 9), 50% had systolic BP ≥ 130 mmHg and 66.6% had diastolic BP ≥ 80 mmHg during the last clinic review. Angiotensin-converting enzyme inhibitors were the most common (n = 16) medication prescribed, followed by angiotensin receptor blockers (n = 6), beta-blockers (n = 6) and calcium channel blockers (n = 6).

Conclusions: Arterial hypertension is common in TS and occurs at a young age. Overweight/obesity was a notable risk factor for hypertension. The frequency of suboptimal BP control among high-risk patients highlights the importance of increased awareness and TS-specific consensus guidance on management.

Introduction and objectives: Isolated hypogonadotropic hypogonadism (IHH) may be associated with pituitary gland and olfactory system disorders. We aimed to correlate findings of magnetic resonance imaging (MRI) of the pituitary gland and olfactory system in IHH patients with the patients' olfactory phenotype.

Patients and methods: The present research was a single-center retrospective case-control study. MRI patterns of the pituitary gland and olfactory system were studied in 46 patients, of whom 29 (63%) were classified on the basis of olfactometry as having Kallmann syndrome (KS) (16 patients with anosmia and 13 patients with hyposmia) and 17 (37%) as having normosmic IHH (nIHH). Results were compared with age- and sex-matched healthy controls. Genetic diagnosis was conducted in all IHH patients based on next-generation sequencing.

Results: Almost 70% prevalence of pituitary hypoplasia was observed in IHH subjects. Olfactory bulb (OB) abnormalities were identified in 80.4% of all patients, both the KS (82.8%) and the nIHH (76.5%) subjects. Incidence of unilaterally abnormal, hypoplastic olfactory sulcus (OS) was equally frequent in nIHH and KS. Statistically, piriform cortical thickness was significantly lower in all patient groups than in controls.

Conclusions: MRI cannot exclusively differentiate between KS and nIHH, as both conditions may present with OB and OS abnormalities. A surprisingly high frequency of olfactory system abnormalities was observed in nIHH patients, while anterior pituitary hypoplasia was prevalent across all IHH patients. Notably, OB abnormalities were more predominant in KS patients than in those with nIHH.

Metabolic syndrome (MetS) is associated with osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs) and accumulation of arterial calcifications (ACs). Metformin (MET) inhibits this transdifferentiation in vitro. Here, we evaluate the in vivo efficacy of oral MET to reduce AC in a model of MetS. Twenty young male Wistar rats were divided into two groups: one received water and the other received water plus 20% fructose to induce MetS. After 14 days, and for another 4 weeks, MET (100 mg/kg per day) was added to half of each group's drinking source, thus C (water), F (fructose), M (MET) and FM (fructose + MET). Serum and adipose tissue were collected. Aortas were dissected for histomorphometric and immunohistochemical analysis, ex vivo calcification studies and isolation of VSMCs to measure their alkaline phosphatase activity (ALP), collagen production, extracellular mineralization, gene expression of RUNX2 and receptor for advanced glycation end-products (AGEs) (RAGE), and elastic fiber production. F group showed parameters compatible with MetS. Aortic tunica media from F showed decreased elastic-to-muscular layer ratio, increased collagen content and increased levels of the AGEs structure carboxymethyl-lysine. Aortic arches from F presented a tendency for higher ex vivo calcification. VSMCs from F showed increased ALP, collagen secretion, mineralization and expression of RUNX2 and RAGE, and decreased elastic fiber production. All these effects were reverted by MET cotreatment (FM group). In vitro, AGEs-modified bovine serum albumin upregulated RAGE expression of control VSMCs, and this was prevented by MET in an AMP kinase-dependent manner. Thus, experimental MetS induces RAGE upregulation and osteogenic transdifferentiation of aortic VSMCs curbed by oral treatment with MET.

Objectives: Inflammasomes are associated with various autoimmune diseases. Herein, we aimed to study the occurrence of inflammasomes in peripheral blood mononuclear cells (PBMCs) from patients with autoimmune thyroiditis (AIT), and the relationship between their abundance and the inflammatory response index of AIT. Furthermore, we examined the effect of iodine on inflammasomes containing NLR family pyrin domain-containing 3 (NLRP3) and inflammasome activation of helper T (Th) cell differentiation regulation in cultured PBMCs.

Methods: We collected PBMCs and serum samples from 50 patients with AIT with normal thyroid function and 50 controls matched for age and sex. In PBMCs, the mRNA and protein expressions of certain inflammasome constituents (e.g., NLRP1, NLRP3, absent in melanoma 2 (AIM2) and caspase-1), interleukin (IL)-1β and IL-18 were assessed using qRT-PCR and western blotting. Enzyme-linked immunosorbent assays (ELISAs) assessed the serum levels of IL-1β and IL-18. Flow cytometry was employed to examine NLRP3 expression on CD14+ monocytes and Th1 and Th17 cell percentages in the groups. AIT- or healthy control-derived PBMCs were stimulated using sodium iodide, with or without lipopolysaccharide (LPS) for 72 h.

Results: PBMCs from patients with AIT had significantly higher levels of pro-IL-18, pro-IL-1β and NLRP3 than did the PBMCs from the healthy controls (P < 0.05). Compared with those from the controls, AIT-derived PBMCs had enhanced levels of active IL-18 and active caspase-1 p20 (P < 0.05), whereas their abundance of active IL-1β was similar (P > 0.05). In serum, the AIT group had enhanced levels of IL-18 compared with the healthy controls (P < 0.05) but had similar levels of IL-1β (P > 0.05). NLRP3 expression on CD14+ monocytes from AIT patients was significantly augmented compared with the healthy controls (P< 0.01). Significantly increased percentages of Th1 and Th17 cells were detected in AIT patients compared with those in the healthy participants (P < 0.001). Sodium iodide treatment upregulated NLRP3 expression in PBMCs during 72 h of culture (P < 0.001). The percentage of Th1 and Th17 cells in AIT patients increased in an iodine-dependent manner (P < 0.01). Iodine had no significant effect on the number of these cells in the healthy control group (P > 0.05).

Conclusion: AIT-derived PBMC NLRP3 activity and expression increased. Iodine might regulate the immune and inflammatory response of patients with AIT by activating NLRP3 and promoting Th1 and Th17 cell differentiation.

It is estimated that by the year 2050, 16% of the world's population will be 65 years old and above. As the global aging population continues to grow, there is an increasing focus on thyroid disorders among older individuals. Thyrotropin is widely used in diagnosing subclinical thyroid diseases due to its high sensitivity as an indicator of changes in thyroid function. However, thyrotropin levels change with age, and different reference intervals have been proposed in various studies. The variation in thyrotropin ranges among older adults is probably caused by the heterogeneity of the studied population. This review aims to provide an overview of the existing literature on thyrotropin reference intervals in older adults and their distinction as adaptive or pathologic. Recent research indicates that older individuals may have slightly elevated levels of thyrotropin and higher upper limits of reference intervals. Therefore, a higher thyrotropin threshold for diagnosing and treating subclinical hypothyroidism in the elderly seems reasonable.

Objective: Androgen insensitivity syndrome (AIS) due to androgen receptor (AR) mutations creates a spectrum of clinical presentations based on residual AR function with the mildest impairment creating mild AIS (MAIS) whose undefined molecular mechanism and subtle clinical features leave it less understood and underdiagnosed.

Design: In silico modeling and in vitro androgen bioassay of the mutated AR are used to identify its structural and physiological mechanism. Clinical features and responses to high-dose testosterone treatment of three cases of MAIS across a six-generation family pedigree are described.

Methods: Structural and dynamic in silico molecular modeling and in vitro yeast-based androgen bioassays of the mutant AR are employed. Three cases of MAIS with consistent (gynecomastia and micropenis) and variable (infertility) clinical features across generations are reported, and the effects of high-dose testosterone treatment are studied.

Results: The missense AR exon 8 mutation (nucleotide aga → gga, p.R872G arginine to glycine), known to cause an increased ligand dissociation rate in mutant AR in binding assays, was analyzed. Modeling shows that the mutation weakens the closure energy of the 'lid' of the ligand-binding pocket, allowing easier ligand dissociation from the binding site but with unimpaired in vitro androgen bioactivity. High-dose testosterone treatment for 3 years in one young man caused increased virilization and height growth but was ineffective for treating micropenis. Genetic counseling allowed effective prediction of MAIS risks in progeny for carrier and noncarrier sisters.

Conclusions: The differential diagnosis and clinical management of MAIS is reviewed. The novel molecular mechanism of an AR ligand-binding domain mutation in MAIS may be present in other cases of MAIS.

Human chorionic gonadotropin (hCG) has structural similarities with thyroid-stimulating hormone (TSH) and may stimulate TSH receptors at higher concentrations. During pregnancy, placental hCG causes TSH suppression, contributing to hyperemesis. However, in males, clinical manifestations caused by excess hCG are rare. Herein, we describe complications of life-threatening thyroid storm caused by paraneoplastic hCG secretion from testicular germ cell tumours (GCTs) and aim to identify high-risk groups through retrospective analysis in n = 20 males (aged 17-55 years) with testicular hCG-positive GCTs. Seven hCG-positive testicular GCTs were classified as seminoma, and 13 were classified as non-seminomatous GCTs (NSGCTs). In 3/7 males with seminomas (43%), serum β-hCG concentrations were mildly elevated (median: 0.3 U/L; range: 0.3-82.1 U/L). In contrast, β-hCG was increased in 12/13 (92%) males with a NSGCT (median: 71.1 U/L; range: 0.3-1,600,000 U/L). In 10/13 males with NSGCT (77%), we detected components of embryonal cell carcinoma (EC), and in 7/13 (54%), we detected components of a choriocarcinoma (ChC). TSH was suppressed with high free thyroxine levels in two cases with NSGCT and excessively elevated β-hCG concentrations, but there was no TSH suppression in a further case with high β-hCG. One patient with NSGCT and high β-hCG levels presented with thyroid storm and imminent decompensation refractory to anti-thyroid treatment, requiring a total thyroidectomy. In the second patient, anti-thyroid treatment was initiated shortly after the diagnosis, successfully normalizing hyperthyroxinaemia. In conclusion, paraneoplastic β-hCG production, occurring in NSGCTs with components of ECs or ChCs, is a rare cause of thyrotoxicosis. Early recognition and treatment are critical to prevent a life-threatening thyroid storm.

Purpose: Patients with adult growth hormone deficiency (AGHD) are at an increased risk of metabolic syndrome. Despite extensive research efforts in recent decades, the lipid metabolism pattern of AGHD has yet to be thoroughly characterized.

Methods: In this study, we used lipidomics analysis of fasting serum samples from 30 AGHD patients with intracranial germ cell tumors (iGCTs) and 30 age-, gender- and body mass index (BMI)-matched healthy controls to investigate the serum lipidomic pattern of AGHD patients with iGCTs. We meticulously quantified 534 serum lipids from 29 classes using high-coverage targeted lipidomics technology in conjunction with a robust bioinformatics pipeline.

Results: Our results revealed an AGHD-specific dynamic change in the serum lipidomic profile, manifested by higher overall levels of many lipid subclasses, including triacylglycerols (TAGs), diacylglycerols (DAGs), phosphatidylglycerols, phosphatidylethanolamines (PE), phosphatidylcholines (PC), phosphatidylinositols, ceramides and bis(monoacylglycerol)phosphates, than in healthy controls and a distinct lower level for alkyl PE (PE-O) and alkyl PC (PC-O). AGHD individuals with nonalcoholic fatty liver disease showed specific changes in higher TAG and DAG subclass levels. Alterations in lipid profiles may contribute to metabolic dysregulation in AGHD patients. TAGs, PCs and PE fatty acids positively correlated with BMI, fasting insulin, insulin resistance index and adverse lipid parameters. In contrast, ether-linked PE-O, PC-O and LysoPE-O showed a negative correlation.

Conclusions: This study has significantly expanded the current understanding of lipid dysregulation in AGHD patients with iGCT. These findings can potentially guide future research and development of monitoring and intervention strategies.