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.
Muriel Houang, Thao Nguyen Khoa, Thibaut Eguether, Bettina Ribaut, Séverine Brabant, Michel Polak, Irène Netchine, and Antonin Lamaziere
Francesca Marini, Francesca Giusti, Teresa Iantomasi, Federica Cioppi, and Maria Luisa Brandi
Multiple endocrine neoplasia type 1 (MEN1) is a rare, inherited cancer syndrome characterized by the development of multiple endocrine and non-endocrine tumors. MEN1 patients show a reduction of bone mass and a higher prevalence of early onset osteoporosis, compared to healthy population of the same age, gender, and ethnicity. During the monitoring and follow-up of MEN1 patients, the attention of clinicians is primarily focused on the diagnosis and therapy of tumors, while the assessment of bone health and mineral metabolism is, in many cases, marginally considered. In this study, we retrospectively analyzed bone and mineral metabolism features in a series of MEN1 patients from the MEN1 Florentine database. Biochemical markers of bone and mineral metabolism and densitometric parameters of bone mass were retrieved from the database and were analyzed based on age ranges and genders of patients and presence/absence of the three main MEN1-related endocrine tumor types. Our evaluation confirmed that patients with a MEN1 diagnosis have a high prevalence of earlyonset osteopenia and osteoporosis, in association with levels of serum and urinary markers of bone turnover higher than the normal reference values, regardless of their different MEN1 tumors. Fifty percent of patients younger than 26 years manifested osteopenia and 8.3% had osteoporosis, in at least one of the measured bone sites. These data suggest the importance of including biochemical and instrumental monitoring of bone metabolism and bone mass in the routine medical evaluation and follow-up of MEN1 patients and MEN1 carriers as important clinical aspects in the management of the syndrome.
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 Gomez-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 Garcia-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 elderly (≥65 years) and young patients (<65 years).
Methods: A retrospective multicenter study performed in 20 Spanish hospitals of PA patients in follow-up between 2018-2021.
Results: 352 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 by 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 correctly 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 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 with a longer duration of the 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 characteristic of the patients.
Xiaoya Zheng, Heng Xiao, Jian Long, Qiang Wei, Liping Liu, Liping Zan, and Wei Ren
Programmed cell death protein-1 (PD-1) inhibitors are widely used for the treatment of hepatocellular carcinoma (HCC). Thyroid dysfunction is common in patients treated with this therapy, although the dynamic changes in thyroid function and sonographic features remain unclear.
We analyzed 38 patients with HCC who received anti-PD-1 therapy at our hospital. Demographic, clinical, laboratory, and ultrasound data were extracted from electronic medical records. The grading of thyroid nodules was based on the American College of Radiology Thyroid Imaging Reporting and Data System classification. Statistical analyses were performed using GraphPad Prism 5.0.
Fifteen patients (40%) had hypothyroidism, among which six had hypothyroidism at baseline, three had overt hypothyroidism, and six had subclinical hypothyroidism after anti-PD1 therapy. The proportion of patients with euthyroid function and thyroid antibody positivity was significantly lower than that of patients with thyroid dysfunction (10% vs 39%, P < 0.05). Nine patients (24%) had irregular echo patterns on sonographic imaging, six of whom had irregular echo patterns present during the treatment, but only one had them persist until the end of treatment. At baseline, the classification of most thyroid nodules was grade 3, with a significant increase in grade 4A and 4B classifications during treatment, though most nodules remained grade 3 at the end of treatment. There were no significant differences in survival rates between the euthyroid and thyroid dysfunction groups.
Anti-PD-1 therapy-induced thyroid dysfunction was accompanied by changes in thyroid function, antibodies, and ultrasonography. Therefore, in patients receiving anti-PD-1 therapy, close, dynamic monitoring of thyroid function, antibodies, and ultrasonographic characteristics is necessary.
Brendan J Nolan, Aviva S Frydman, Shalem Y Leemaqz, Meg Carroll, Mathis Grossmann, Jeffrey D Zajac, and Ada S Cheung
The role of micronised progesterone in hormone regimens for transgender individuals undergoing feminising hormone therapy remains uncertain. We aimed to determine the effect of oral micronised progesterone on sleep quality, psychological distress, and breast development in transgender individuals undergoing feminising hormone therapy.
Prospective case–control study. Twenty-three transgender individuals on stable oestradiol treatment newly commencing 100 mg oral progesterone (n = 23) and controls continuing standard care (n = 19) were assessed over 3 months.
Pittsburgh Sleep Quality Index (PSQI), Kessler psychological distress scale (K10), and Tanner stage to assess breast development were assessed at 0 and 3 months. Non-parametric analysis of covariance was used to compare differences between groups.
Compared with controls over 3 months, there was no difference in PSQI (P = 0.35), K10 (P = 0.64), or Tanner stage (P = 0.42). There was no significant difference in the proportion of individuals with clinically significant improvement in PSQI (25% vs 22%, P = 0.84). One individual had a significant deterioration in psychological distress that improved following the cessation of progesterone.
Low-dose progesterone was not associated with changes in sleep quality, psychological distress, or breast development over 3 months follow-up, though there was significant inter-individual variability. Larger, placebo-controlled trials are required to further evaluate different doses of progesterone in feminising hormone therapy regimens.
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 up-regulate LDLR, and statins exert opposite effect on IDOL and PCSK9.
Eng-Loon Tng, Yee Sian Tiong, Aye Thida Aung, Nicole Ya Yuan Chong, and Zhemin Wang
Evidence on the efficacy and safety of anticoagulation in preventing stroke and thromboembolic events in people with thyrotoxic atrial fibrillation is scarce.
We evaluated the efficacy and safety of anticoagulation in people with thyrotoxic atrial fibrillation.
Our study protocol was published in the International Prospective Register of Systematic Reviews (registration no. CRD42020222782). Four databases and two systematic review registers were searched through 25 November 2020 for interventional and observational studies comparing anticoagulation therapy with active comparators, placebo, or no treatment in people with thyrotoxic atrial fibrillation. Random-effects meta-analysis and sensitivity analysis were performed. Quality of evidence was described using the GRADE framework.
In the study, 23,145 records were retrieved. One randomized controlled trial and eight cohort studies were ultimately included. Effect estimates on the efficacy and safety of anticoagulation were extracted. Meta-analysis using the inverse variance and random-effects methods was conducted on four cohort studies with 3443 participants and 277 events. Anticoagulation in people with thyrotoxic atrial fibrillation reduced the risk of ischemic stroke and systemic thromboembolism by 3% (95% CI: 1–6%). Warfarin may prevent ischemic stroke in people with thyrotoxic atrial fibrillation if the CHA2DS2-VASc score exceeds 1 and when atrial fibrillation persists beyond 7 days. Direct oral anticoagulants may be associated with fewer bleeding events than warfarin.
Anticoagulation prevents ischemic stroke and systemic thromboembolism in people with thyrotoxic atrial fibrillation. Direct oral anticoagulants may be associated with fewer bleeding events.
Muhammad Fahad Arshad, Ahmed Iqbal, James Weeks, Ines Fonseca, Alia Munir, and William Bennet
To evaluate ‘real-world’ safety and efficacy of the European Society of Endocrinology guidelines for the treatment of severe symptomatic hyponatraemia using hypertonic saline (HTS).
Retrospective, observational, cohort study, examining the use of HTS for severe symptomatic hyponatraemia at Sheffield Teaching Hospitals between 2017 and 2020.
Patients were identified from pharmacy records and demographic, clinical, and treatment data extracted.
Out of 112 patients (females:males = 61:51), the mean age ± s.d. was 66.3± 16.0 years and mean pre-treatment serum sodium ± s.d. was 113.8 ± 6.4 mmol/L. Overall, overcorrection rates at 24 and 48 h (>10 and >18 mmol/L) were 44.9 and 19.6%, respectively, while 19.6% of patients were treated for overcorrection. Above-target rise in sodium (>5 mmol/L) after first and second boluses was noted in 22.6 and 34.6% of patients, respectively. In-hospital and 12-month mortality was 7.1 and 18.7%, respectively, with no cases of osmotic demyelination. The mean venous blood gas (VBG) sodium was 1.9 mmol/L lower than paired serum sodium (n = 36) (113.6 ± 6.6 vs 115.7 ± 7.8 mmol/L).
We report real-world data demonstrating that a significant number of patients overcorrected using current guidelines. Also, several patients had above-target rise in sodium after one bolus of HTS, and sodium measurement should be considered before the second bolus unless ongoing severe symptoms persist. A point of care VBG sodium concentration was useful for this purpose. In addition to careful monitoring, a cautious but anticipatory overcorrection prevention strategy should be considered in the first 24 h.
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 GnRH agonist treatment, only LH is permanently suppressed, while circulating 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 four weeks. Prostates and testes sizes 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, PSA, and inhibin B was 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 Svs6, Pbsn, Nkx3-1, Msmb 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 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 prostate in humans also requires suppression of the residual adrenal-derived androgens and/or a longer period of rFSH stimulation, remains to be explored.
Marília D'Elboux Guimarães Brescia, Karine Candido Rodrigues, André Fernandes d'Alessandro, Wellington Alves Filho, Willemijn Y. van der Plas, Schelto Kruijff, Sérgio Samir Arap, Sergio Pereira de Almeida Toledo, Fábio Luiz de Menezes Montenegro, and Delmar Muniz Lourenço Junior
Background: Potential influences of the parathyroidectomy (PTx) on quality of life (QoL) in multiple endocrine neoplasia type 1-related primary hyperparathyroidism (HPT/MEN1) are unknown.
Method: Short Form 36 Health Survey Questionnaire was prospectively applied in 30 HPT/MEN1 patients submitted to PTx (20, subtotal; 10, total with autograft), before, 6 and 12 months (mo.) after surgery. Parameters analyzed included QoL, age, HPT-related symptoms, general pain, comorbidities, biochemical/hormonal response, PTx type and parathyroid volume.
Results: Asymptomatic patients were younger (30 vs 38 years; p=0.04) and presented higher QoL scores (physical component score, PCS, 92.5 vs 61.2 p=0.0051; mental component score, MCS, 82.0 vs 56.0, p=0.04) than symptomatic ones. In both groups, QoL remained stable one year after PTx, independently of number of comorbidities. Preoperative general pain was negatively correlated with PCS (r =-0.60, p=0.0004) and MCS (r=-0.57, p=0.0009). Also, moderate/intense pain was progressively (6/12mo.) more frequent in cases developing hypoparathyroidism. The PTx type and hypoparathyroidism did not affect the QoL at 12mo. although remnant parathyroid tissue volume did have a positive correlation (p=0.0490; r=0.3625) to PCS 12mo. after surgery. Patients with 1-2 comorbidities had as pre-PTx PCS (p=0.0015) as 12mo. post-PTx PCS (p=0.0031) and MCS (p=0.0365) better than patients with 3-4 comorbidities.
Conclusion: A variable QoL profile was underscored in HPT/MEN1 reflecting multiple factors associated to this complex disorder as comorbidities, advanced age at PTx and presence of preoperative symptoms or of general pain perception. Our data encourage the early indication of PTx in HPT/MEN1 by providing known metabolic benefits to target-organs and avoiding potential negative impact on QoL.