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Open access

Huda M Elsharkasi, Suet C Chen, Lewis Steell, Shuko Joseph,  Naiemh Abdalrahaman, Christie Mccomb, Blair Johnston, John Foster, Sze Choong Wong, and S. Faisal Ahmed

Objective: To investigate the role of 3T-MRI in assessing musculoskeletal health in children and young people.

Design: Bone, muscle and bone marrow imaging was performed in 161 healthy participants with a median age of 15.0 yrs (range, 8.0, 30.0).

Methods: Detailed assessment of bone microarchitecture (CISS sequence, voxel size 0.2x0.2x0.4mm3), bone geometry (TSE sequence, voxel size 0.4x0.4x2mm3) and bone marrow (1H-MRS, PRESS sequence, single voxel size 20x20x20mm3), size and muscle adiposity (Dixon, voxel size 1.1x1.1x2mm3).

Results: There was an inverse association of apparent bone volume/total volume (appBV/TV) with age (r, -0.5, p<0.0005). Cortical area, endosteal and periosteal circumferences and muscle cross-sectional area showed a positive association to age (r >0.49, p<0.0001). In those over 17 yrs of age, these parameters were also higher in males than females (p<0.05). This sex difference was also evident for appBV/TV and bone marrow adiposity (BMA) in the older participants (p<0.05). AppBV/TV showed a negative correlation with BMA (r, -0.22, p=0.01) which also showed an association with muscle adiposity (r, 0.24, p=0.04). Cortical geometric parameters were highly correlated with muscle area (r >0.57, p<0.01).

Conclusions: In addition to providing deep insight into the normal relationships between bone, fat and muscle in young people, these novel data emphasize the role of MRI as a non-invasive method for performing a comprehensive and integrated assessment of musculoskeletal health in the growing skeleton.

Open access

Muriel Houang, Thao Nguyen-Khoa, Thibaut Eguether, Bettina Ribault, Séverine Brabant, Michel Polak, Irène Netchine, and Antonin Lamazière

Neonatal screening for congenital adrenal hyperplasia (CAH) faces many specific challenges. It must be done using a performant analytical approach that combines sensitivity and specificity to capture the potential causes of mortality during the first week of life, such as salt wasting and glucocorticoid deficiency. Here, we confirm that maternal inhaled corticosteroid intake during pregnancy is a possible cause of missed CAH diagnosis. Thanks to liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) analysis, we were able to quantify endogenous steroid metabolites and also detect the presence of exogenous steroids in the dried blood spot of a newborn. Adding LC-MS/MS analysis as second-tier test, especially one that includes both 17-hydroxyprogesterone and 21-deoxycortisol measurements, would probably improve CAH diagnosis. In familial neonatal screening one could also look for maternal corticosteroid therapies that are hidden to prevent false-negative tests.

Open access

Fidéline Bonnet-Serrano, Maxime Barat, Anna Vaczlavik, Anne Jouinot, Lucas Bouys, Christelle Laguillier-Morizot, Corinne Zientek, Catherine Simonneau, Etienne Larger, Laurence Guignat, Lionel Groussin, Guillaume Assie, Jean Guibourdenche, Ioannis Nicolis, Marie-Claude Menet, and Jerome Bertherat

Objective: Large response of steroids precursors, including 17-hydroxyprogesterone, to ACTH has been described in adrenocortical tumors, suggesting the existence of intra-tumoral enzymatic deficiencies. This study aimed to compare steroidogenesis enzymes activity in unilateral and bilateral benign tumors using serum steroid profiling in LC-MS/MS in basal state and after ACTH 1-24 stimulation.

Design and Methods: A serum profile of seven consecutive adrenal steroids was determined in LC-MS/MS in basal state (T0) and after ACTH 1-24 stimulation (T60) in 35 patients with bilateral adrenocortical tumors (BL), 38 patients with unilateral tumors (UL) and 37 control subjects (CT). Response amplitude of each individual steroid was evaluated by T60/T0 ratio whereas enzymatic activity was assessed by downstream/upstream steroid ratio. Adrenal volume was quantified by a semi-automatic segmentation method.

Results: For the seven steroids assayed, the amplitude of response to ACTH was higher in BL than in UL and in CT. The difference between BL and UL persisted even after matching patients on adrenal volume. On glucocorticoids pathway, enzymatic activity of CYP11B1 was significantly decreased in BL (78.3 [43.1-199.4]) in comparison to both UL (122.7 [13.8-228.4], p = 0.0002) and CT (186.8 [42.1-1236.3], p<0.0001). On mineralocorticoids and androgens pathways, enzymatic activity of CYP11B2 and CYP17A1-17,20 lyase was also lower in BL than UL and CT.

Conclusions: Decreased activity of distal steroidogenesis enzymes CYP11B1, CYP11B2 and CYP17A1-17,20 lyase, responsible for an explosive response to ACTH of upstream precursors in bilateral tumors, limits the synthesis of bioactive steroids, in particular cortisol, despite the increase in adrenal mass.

Open access

Paola Parra Ramírez, Patricia Martín Rojas-Marcos, Miguel Paja Fano, Marga González Boillos, Eider Pascual-Corrales, Ana García-Cano, Jorge Gabriel Ruiz-Sanchez, Almudena Vicente, Emilia Gómez-Hoyos, Rui Ferreira, Iñigo García Sanz, Mònica Recasens, Begoña Pla Peris, Rebeca Barahona San Millan, María José Picón César, Patricia Díaz Guardiola, Juan Jesús García González, Carolina Perdomo, Laura Manjón, Rogelio García-Centeno, Juan Carlos Percovich, Ángel Rebollo Román, Paola Gracia Gimeno, Cristina Robles Lázaro, Manuel Morales, Felicia Hanzu, and Marta Araujo-Castro

Objective

To compare the presentation and evolution of primary aldosteronism (PA) in the elderly (≥65 years) and young patients (<65 years).

Methods

A retrospective multicenter study was performed in 20 Spanish hospitals of PA patients in follow-up between 2018 and 2021.

Results

Three hundred fifty-two patients with PA <65 years and 88 patients ≥65 years were included. Older PA patients had a two-fold higher prevalence of type 2 diabetes, dyslipidemia, and cerebrovascular disease, but these differences disappeared after adjusting for hypertension duration. At diagnosis, diastolic blood pressure was lower than in young patients (83.3 ± 11.54 vs 91.6 ± 14.46 mmHg, P < 0.0001). No differences in the rate of overall correct cannulation (56.5% vs 42.3%, P = 0.206) or the diagnosis of unilaterality (76.9% vs 62.5%, P = 0.325) in the adrenal venous sampling (AVS) was observed between the elderly and young groups. However, there was a lower proportion of PA patients who underwent adrenalectomy in the elderly group than in the younger group (22.7% (n  = 20) vs 37.5% (n  = 132), P = 0.009). Nevertheless, no differences in the rate of postsurgical biochemical (100% (n  = 14) vs 92.8% (n  = 90), P = 0.299) and hypertension cure (38.6% (n  = 51) vs 25.0% (n  = 5), P = 0.239) were observed between both groups.

Conclusion

Older patients with PA have a worse cardiometabolic profile than young patients with PA that it is related to a longer duration of hypertension. However, the results of the AVS, and adrenalectomy are similar in both groups. Therefore, the management of elderly patients with PA should be based not only on age, but rather on the overall medical, physical, social, and mental characteristics of the patients.

Open access

Huifei Sophia Zheng, Jeffrey G. Daniel, Julia M. Salamat, Laci Mackay, Chad D. Foradori, Robert J. Kemppainen, Satyanarayana R. Pondugula, Ya-Xiong Tao, and Chen-Che Jeff Huang

Glucocorticoids have short- and long-term effects on adrenal gland function and development. RNA sequencing (RNA-seq) was performed to identify early transcriptomic responses to the synthetic glucocorticoid, dexamethasone (Dex), in vitro and in vivo. In total, 1,711 genes were differentially expressed in the adrenal glands of the 1-h Dex-treated mice. Among them, only 113 were also considered differentially expressed genes (DEGs) in murine adrenocortical Y-1 cells treated with Dex for 1 h. Gene ontology analysis showed that the upregulated DEGs in the adrenal gland of the 1-h Dex-treated mice were highly associated with the development of neuronal cells, suggesting the adrenal medulla had a rapid response to Dex. Interestingly, only 4.3% of Dex-responsive genes in the Y-1 cell line under Dex treatment for 1 h were also differentially expressed under Dex treatment for 24 h. The heatmaps revealed that most early-responsive DEGs in Y-1 cells during 1 h of treatment exhibited a transient response. The expression of these genes under treatment for 24 h returned to basal levels similar to that during control treatment. In summary, this research compared the rapid transcriptomic effects of Dex stimulation in vivo and in vitro. Notably, adrenocortical Y-1 cells had a transient early response to Dex treatment. Furthermore, the DEGs had a minimal overlap in the 1-h Dex-treated group in vivo and in vitro.

Open access

Melody Lok-Yi Chan, Sammy Wing-Ming Shiu, Ching-Lung Cheung, Anskar Yu-Hung Leung, and Kathryn Choon-Beng Tan

The inducible degrader of low-density lipoprotein receptor (IDOL) is an E3 ubiquitin ligase involved in the post-transcriptional regulation of LDL receptor (LDLR). Statins lower plasma LDL by activating transcription of hepatic LDLR expression, and we have determined whether statins modulate IDOL expression and influence LDLR protein abundance. IDOL expression in monocytes and serum IDOL level was determined in statin-treated familial hypercholesterolemia (FH) patients and compared with control subjects. Serum IDOL level was also evaluated in a group of untreated FH patients before and after the initiation of statin. The mechanism underlying the inhibitory effect of statin on IDOL expression was investigated in vitro. In statin-treated FH patients, serum IDOL level and its expression in monocytes was reduced compared with control (P < 0.05). In contrast, untreated FH patients had higher serum levels of IDOL and proprotein convertase subtilisin/kexintype 9 (PCSK9) than control (P < 0.05), and serum IDOL level decreased after statin therapy (P < 0.05) whereas an increase was observed in PCSK9 level (P < 0.01). In vitro, atorvastatin significantly decreased IDOL abundance in a dose-dependent manner in cultured macrophages and hepatocytes with a concomitant increase in LDLR expression. The transcription of IDOL was restored by adding either an LXR agonist T0901317 or oxysterol 22(R)-hydroxycholesterol, indicating that statin inhibited IDOL expression by reducing LXR activation. The LXR-IDOL-LDLR axis can be modulated by statins in vitro and in vivo. Statins inhibit IDOL expression by reducing LXR activation and upregulate LDLR, and statins exert the opposite effect on IDOL and PCSK9.

Open access

Carmen Sydlik, Ilja Dubinski, Susanne Bechtold, and Heinrich Schmidt

Thyroid stimulating hormone is generally regarded as a standard parameter for evaluation of thyroid function. However, relying on this hormone alone can be misleading. Therefore, thyroxine/free-thyroxine levels are used in patients with levothyroxine substitution for adjustment of therapy. Even with normal values for free-thyroxine, decreased values for the free- triiodothyronine/ free-thyroxine ratio have already been described in adults. In this study, the free-triiodothyronine/ free-thyroxine ratio of 25 children with congenital hypothyroidism was compared with 470 healthy children seen for other reasons then thyroid dysfunction. Mean free thyroxine in congenital hypothyroidism was just below the upper limit of normal and significantly higher than in control group. Mean values for free triiodothyronine showed no significant difference between the two groups. The mean value for free triiodothyronine/ free thyroxine ratio in control group was 3.23. Significantly lower ratios were found in the congenital hypothyroidism group with a mean value of 2.5, due to higher values for free thyroxine compared to free triiodothyronine. Furthermore, an increased free triiodothyronine/ free thyroxine ratio was found at higher thyroid stimulating hormone values due to lower values for free thyroxine. In this study, we demonstrate that the free triiodothyronine/ free thyroxine ratio was significantly lower in children with congenital hypothyroidism compared to the control group. This is most likely due to the higher values for free thyroxine in this group compared to similar values for free triiodothyronine in both groups. Further studies with differentiated thyroid hormone therapy are needed in order to understand the role of peripheral euthyroidism.

Open access

Elizabeth J. de Koster, Olga Husson, Eveline W.c.m. van Dam, G. Sophie Mijnhout, Romana T Netea-Maier, Wim J.g. Oyen, Marieke Snel, Lioe-Fee De Geus-Oei, and Dennis Vriens

Objective: This study assessed the health-related quality of life (HRQoL) in patients undergoing FDG-PET/CT for an indeterminate (Bethesda III/IV) thyroid nodule. FDG-PET/CT accurately rules out malignancy and prevents 40% of futile diagnostic surgeries in these nodules.

Design: Secondary analyses of HRQoL data from a randomised controlled multicentre trial (NCT02208544) in 126 patients from 15 hospitals in the Netherlands.

Methods: Longitudinal HRQoL assessment was performed using the EuroQol 5-dimension 5-level (EQ-5D-5L), the RAND 36-item Health Survey v2.0 (RAND-36), and the Thyroid Patient-Reported Outcome (ThyPRO) questionnaire on baseline, 3, 6, and 12 months, relative to the date of the FDG-PET/CT scan.

Results: Patients who were randomised to active surveillance following an FDG-negative nodule instead of diagnostic surgery, reported stable HRQoL scores throughout the year. Univariate analysis indicated better HRQoL for patients undergoing surveillance than surgical patients with benign histopathology on multiple physical and psychosocial domains. Univariate within-group analysis suggested both temporary and continued HRQoL deteriorations in patients with benign histopathology over time. Multivariate within-group analysis demonstrated no significant longitudinal HRQoL changes in patients undergoing active surveillance. In contrast, in patients with benign histopathology, worse HRQoL was observed with regard to ThyPRO cognitive impairment (p=0.01) and cosmetic complaints (p=0.02), whereas goitre symptoms (p<0.001) and anxiety (p=0.04) improved over time. In patients with malignant histopathology, anxiety also decreased (p=0.05).

Conclusions: The reassurance of a negative FDG-PET/CT resulted in sustained HRQoL throughout the first year of active surveillance. Diagnostic surgery for a nodule with benign histopathology resulted in more cognitive impairment and physical problems including cosmetic complaints, but improved goitre symptoms and anxiety. Anxiety also reduced in patients with malignant histopathology.

Open access

Eleftherios E Deiktakis, Eleftheria Ieronymaki, Peter Zarén, Agnes Hagsund, Elin Wirestrand, Johan Malm, Christos Tsatsanis, Ilpo T Huhtaniemi, Aleksander Giwercman, and Yvonne Lundberg Giwercman

Objective

During androgen ablation in prostate cancer by the standard gonadotropin-releasing hormone (GnRH) agonist treatment, only luteinizing hormone (LH) is permanently suppressed while circulating follicle-stimulating hormone (FSH) rebounds. We explored direct prostatic effects of add-back FSH, after androgen ablation with GnRH antagonist, permanently suppressing both gonadotropins.

Methods

The effects of recombinant human (rFSH) were examined in mice treated with vehicle (controls), GnRH antagonist degarelix (dgx), dgx + rFSH, dgx + flutamide, or dgx + rFSH + flutamide for 4 weeks. Prostates and testes size and expression of prostate-specific and/or androgen-responsive genes were measured. Additionally, 33 young men underwent dgx-treatment. Seventeen were supplemented with rFSH (weeks 1–5), and all with testosterone (weeks 4–5). Testosterone, gondotropins, prostate-specific antigen (PSA), and inhibin B were measured.

Results

In dgx and dgx + flutamide treated mice, prostate weight/body weight was 91% lower than in controls, but 41 and 11%, respectively, was regained by rFSH treatment (P = 0.02). The levels of seminal vesicle secretion 6, Pbsn, Nkx3.1, beta-microseminoprotein, and inhibin b were elevated in dgx + rFSH-treated animals compared with only dgx treated (all P < 0.05). In men, serum inhibin B rose after dgx treatment but was subsequently suppressed by testosterone. rFSH add-back had no effect on PSA levels.

Conclusions

These data provide novel evidence for the direct effects of FSH on prostate size and gene expression in chemically castrated mice. However, in chemically castrated men, FSH had no effect on PSA production. Whether FSH effects on the prostate in humans also require suppression of the residual adrenal-derived androgens and/or a longer period of rFSH stimulation, remains to be explored.