Endocrine Connections最新文献

Objective: Androgen insensitivity syndrome (AIS) due to androgen receptor (AR) mutations create 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 little understood and underdiagnosed.

Design: in silico modelling and in vitro androgen bioassay of the mutated AR to identify its structural and physiological mechanism. Describing clinical features and responses to high dose testosterone treatment of three cases of MAIS cases across a six-generation family pedigree.

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

Results: The missense AR exon 8 mutation (nucleotide aga > gga, p.R872G arginine to glycine), known to cause increases ligand dissociation rate from mutant AR in binding assays, modelling shows the mutation weakens the closure energy of the "lid" of the ligand binding pocket allowing for easier ligand dissociation from binding site but with unimpaired in vitro androgen bioactivity. High dose testosterone treatment for 3 years in one young man caused increased virilisation and height growth but was ineffective for micropenis. Genetic counselling allowed effective prediction of MAIS risks in progeny for a carrier and non-carrier 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 case of MAIS.

Human chorionic gonadotropin (hCG) has structural similarities with 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 (GCT) 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 as non-seminomatous GCTs (NSGCT). 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 an NSCGT (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%) components of a choriocarcinoma (ChC). TSH was suppressed with high free thyroxine levels in two cases with NSCGT 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 hyperthyroxinemia. In conclusion, paraneoplastic β-hCG production, occurring in NSGCT 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.

Objective: To test whether postprandial hypoglycaemia is an extreme and repeatable phenotype of glucose metabolism. Secondly, we explored the genetic determinants of this phenotype.

Design and methods: We conducted this study using data from Pinggu Metabolic Disease Study database (n = 3,345). We selected subjects after an oral glucose tolerance test (OGTT) (2 h, glucose <3 mmol/L_ and compared clinical features with those of normal glucose tolerance (NGT). We additionally selected 75 subjects as super-healthy control group. Whole-exome sequencing (WES) was performed on postprandial hypoglycaemic and super-healthy controls. We also evaluated several candidate genes believed to be important in pancreatic hypoglycaemia.

Results: We found 13 participants (0.39%) had an OGTT 2 h glucose <3 mmol/L. Ten patients were men (76.9%). All 13 participants had insulin > 3 uU/mL when postprandial blood glucose levels were <3 mmol/L. WES analysis identified one gene, paternally expressed 3 (PEG3), which had three rare mutations in four patients (30.8%). Minor allele frequencies (MAF) of rare PEG3 mutations were significantly higher in subjects with postprandial hypoglycaemia than in super-healthy controls. Among all four subjects with PEG3 gene mutations, 71.4% were men, and their body mass index (BMI) was significantly lower than that of the NGT.

Conclusions: Postprandial hypoglycaemia is an extreme and reproducible phenotype in the general population. PEG3 mutations may represent a potential genetic aetiology for postprandial hypoglycaemia. Further research with larger and more diverse populations and a broader genetic focus is needed to understand the genetic basis of postprandial hypoglycaemia.

Purpose: Patients with adult growth hormone deficiency (AGHD) are at 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 due to 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 due to 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 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 lowering level in alkyl PE (PE-O) and alkyl PC (PC-O). AGHD individuals with non-alcoholic 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 due to iGCT. These findings can potentially guide future research and the development of monitoring and intervention strategies.

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: To evaluate the correlation between the serum prolactin (PRL) level and carotid intimate-media thickness (CIMT) in patients with type 2 diabetes mellitus (T2DM).

Methods: In this study, 1500 participants were divided into three groups based on the serum PRL levels: hypoprolactinemia group (PRL ≤ 7 μg/L); normal PRL level group (7 μg/L < PRL ≤ 25 μg/L); and homeostatic functionally increased transient PRL group (25 μg/L < PRL ≤ 100 μg/L). The independent-sample Kruskal-Wallis test was used to compare the CIMT among the three groups. The Spearman correlation test was used to examine the relationship between the CIMT, serum PRL level, and clinical data. Multivariate linear regression analysis was used to determine the independent factors that influence the CIMT.

Result: Individuals in the homeostatic functionally increased transient PRL group had a significantly lower CIMT compared to the hypoprolactinemia and normal PRL level groups (P < 0.001). The CIMT was positively correlated with age, systolic blood pressure, body mass index, duration of T2DM, luteinizing hormone and follicle-stimulating hormone levels, and negatively correlated with alanine transaminase and aspartate transaminase activities, the estimated glomerular filtration rate, and PRL. Multivariate linear regression analysis revealed that only PRL was negatively associated with the CIMT, while age and the systolic blood pressure were positively associated with the CIMT.

Conclusion: In patients with T2DM, a PRL level within the mildly elevated range is negatively correlated with the CIMT. A mildly elevated serum PRL level may be a protective factor for preventing thickening of the CIMT.

Amino-terminal propeptide of type 1 procollagen (P1NP) and carboxy-terminal crosslinked telopeptide of type 1 collagen (CTX-I) are markers of bone metabolism. We examined the effect of vitamin D3 supplementation on these markers and their relationship with growth and bone parameters in 12-month-old infants. In a randomized, double-blinded, Vitamin D intervention in infants (VIDI) study, 987 infants received daily vitamin D3 supplementation of 10 μg (Group-10) or 30 μg (Group-30) from age 2 weeks to 24 months. We conducted a secondary analysis of the original VIDI trial. At 12 months of age, P1NP (n=812) and CTX-I (n=786) concentrations were analyzed, and anthropometrics and total bone mineral content, volumetric bone mineral density, cross-sectional area and polar moment of inertia of tibia were measured by peripheral quantitative computed tomography. Growth rate in weight and length was calculated from birth to 12 months. Vitamin D dose did not influence mean (SD) levels of CTX-I (group-10: 0.90 (0.31); group-30: 0.89 (0.31) (p<0.53). Mean difference of P1NP (CI 95%) comparing group-10 with group-30 was 35 (-103, 33) ng/ml (p=0.31) in boys and -63 (-4, 130) ng/ml (p=0.064) in girls, respectively. In group-10 girls had higher mean (SD) value of P1NP (1509 (362) ng/mL) than boys (1407 (297) ng/mL) (p=0.003); no sex differences were observed in group-30 (girls: 1446 (359); boys: 1442 (359), p=0.91) or CTX-I. P1NP associated positively with growth rate in length (B (CI 95%] 0.0003 (0.0001, 0.001), p=0.022) in the whole cohort, but not in subgroups divided by intervention group nor sex, adjusted for birth size and parental heights and corrected for multiple testing. P1NP associated positively with growth rate in weight (0.01 (0.0003, 0.01), p<0.001). An inverse association was observed between CTX-I and length (cm) in the whole cohort (-0.90 (-1.40, -0.40), p=0.005) and in group-30 (-1.05 (-1.72, -0.39), p=0.011). Further, CTX-I associated negatively with weight (SDS) in the whole cohort (-0.33 (-0.55, -0.12), p=0.015) and growth rate in weight (-0.43 (-0.66, -0.20), p=0.005), persisting in group-30 and in boys, but not in group-10 or in girls. Neither marker was associated with bone parameters.The observed sex difference in P1NP might suggest that higher vitamin D dose resulted in a small decrease in bone collagen matrix formation in girls but not in boys. P1NP and CTX-I associate with growth and body size, but not with bone mineralization in infancy.

Background: Somatic GNAS mutations are acknowledged as a significant etiological factor for acromegaly. However, the relationship between GNAS mutation status, clinical characteristics and gender has not been adequately investigated. This study aims to address these gaps by examining GNAS mutations and delineating the detailed clinical profile of affected patients within a Chinese acromegaly cohort.

Methods: Our study encompassed 97 individuals newly diagnosed with acromegaly, who underwent surgical treatment between May 2015 and January 2022. We obtained DNA from frozen pituitary adenomas to screen for GNAS hotspot mutations and assessed the associated clinical characteristics.

Results: In our cohort, 44.3% (43/97) of patients exhibited somatic GNAS mutations. Patients with mutations were predominantly male (58.1% vs. 33.3%, p=0.015), experienced longer diagnosis delays [72.0 (48.0, 120.0) vs 36.0 (21.0, 75.0) months, p=0.002], had smaller maximum tumor diameters (1.75±0.83 vs. 2.23±0.89 cm, p=0.008), and demonstrated higher rates of GH secretion per unit tumor volume [18.93 (9.67, 30.12) vs 10.91 (2.80, 20.40) ng/mL/cm3, p=0.005]. Regarding gender-specific differences, GNAS mutations in male patients were linked to significantly higher baseline GH levels [24.40 (14.40, 36.30) vs. 10.55 (5.25, 16.95) ng/mL, p=0.002], while female patients with mutations had notably smaller tumor sizes (1.55±0.55 cm vs. 2.32±0.85 cm, p<0.001).

Conclusion: GNAS mutations are prevalent among Chinese acromegaly patients, correlating with reduced pituitary tumor sizes and enhanced GH secretion functions. Our findings underscore the influence of gender on the clinical manifestations of GNAS mutations. Accordingly, we recommend that future clinical and foundational researches on acromegaly give heightened consideration to gender-specific differences.

Aims and background: Curcumin's function in affecting cancer metabolic reprogramming remains poorly understood. Herein, we aimed to elucidate a novel link between Curcumin and the glucose uptake metabolism and glucose transporters (GLUTs) status in SW1736 cell line derived from anaplastic thyroid cancer.

Materials and methods: TheMTT test and flow cytometry was employed to test cell viability and cell death. For glucose uptake detection, ''GOD-PAP'' enzymatic colorimetric assay was applied to measure the direct glucose levels inside of the cells. Determination of GLUT1 and GLUT3 mRNA and protein expression in SW1736 cells was performed by qRT-PCR and western blotting. Also, the scratch wound healing assay was conducted for cell migration.

Results: The data indicated that Curcumin-induced cell death is independent of apoptosis in this type of thyroid cancer cell line. Furthermore, significantly reduced GLUT1 and GLUT3 expression was observed after treatment with Curcumin, resulting in the inhibition of glucose uptake (p < 0.05). Scratch assay indicated the inhibition of cell migration in SW1736 cells treated by Curcumin (p < 0.05).

Conclusion: It can be concluded that GLUTs as metabolic targets can be blocked specifically by Curcumin for thyroid cancer prevention. Curcumin, as a promising anti-cancer agent, inhibits the growth of SW1736 anaplastic thyroid cancer cell line by regulating glucose uptake pathway and cell death. Altogether, these results suggest that the glucose pathway may be an important target for therapeutic intervention to sensitize tumor cells to cell death process by inhibition of glucose transporters.

Introduction: The aim of this study was to define functional and anatomical pituitary disease at the time of presentation following immune checkpoint inhibitor (ICI) therapy and to describe any changes in pituitary function over time.

Methods: We conducted a retrospective observational audit of patients on ICI therapy at our centre between January 2013 and September 2023. We reviewed all patients on ICI therapy under the care of the oncology department at University Hospital Plymouth, a 1000-bedded hospital serving a population of 500,000 people. From this group, we identified all individuals referred to the endocrinology department with a suspected diagnosis of adrenal insufficiency. Patients were established on adrenal steroid replacement and subsequently underwent formal pituitary testing. People were included if they had pituitary disease, as evidenced by low ACTH, other pituitary dysfunction and/or abnormalities on pituitary imaging.

Results: Nine hundred and fifty-four patients received ICI therapy during the study period, and 37 (a prevalence of 3.9%) developed hypothalamic-pituitary-adrenal axis dysfunction. Their mean age was 65 years, and 70% were male. About 86.5% of the total patients affected were treated for metastatic malignancies. Ten of the 37 patients died during follow-up as a direct consequence or complication of their primary cancer diagnosis. The median interval for the onset of symptoms was 4 months. Following repeated testing, there was no recovery in cortisol or ACTH levels for any individual. Other permanent anterior pituitary hormone defects were unusual. Hypophysitis associated with immunotherapy appears to specifically target the corticotrophs, with no evidence of recovery over time. There was a specific abnormality seen in MRI scans of 7 of 27 patients who had scans, which appeared to be a particular feature of immune-mediated hypophysitis. These were confined to the anterior aspect of the pituitary gland, appearing as striations, and were not visible on any of the scans performed more than 3 months after the likely onset of the disease.

Conclusion: These data show that immune-related hypophysitis is a common complication of immune checkpoint inhibitor therapy. This may result in an imaging abnormality within the areas of the pituitary that are richest in corticotrophs. The endocrine consequence of this is a permanent defect in ACTH and, therefore, cortisol production.