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Open access

Muriel Houang, Thao Nguyen Khoa, Thibaut Eguether, Bettina Ribaut, Séverine Brabant, Michel Polak, Irène Netchine, and Antonin Lamaziere

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

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.

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 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.

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 up-regulate LDLR, and statins exert opposite effect on IDOL and PCSK9.

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 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.

Open access

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.

Open access

Laurent Maïmoun, Denis Mariano-Goulart, Helena Huguet, Eric Renard, Patrick Lefebvre, Marie-Christine Picot, Anne-Marie Dupuy, Jean-Paul Cristol, Philippe Courtet, Vincent Boudousq, Antoine Avignon, Sébastien Guillaume, and Ariane Sultan

Objectives

The two-fold aim of this study was: (i) to determine the effects of undernutrition on the myokines in patients with restrictive anorexia nervosa (AN) and (ii) to examine the potential link between myokines and bone parameters.

Methods

In this study, 42 young women with restrictive AN and 42 age-matched controls (CON) (mean age, 18.5 ± 4.2 years and 18.6 ± 4.2 years, respectively) were enrolled. aBMD and body composition were determined with DXA. Resting energy expenditure (REEm), a marker of energy status, was indirectly assessed by calorimetry. Bone turnover markers and myokines (follistatin, myostatin and irisin) were concomitantly evaluated.

Results

AN patients presented low aBMD at all bone sites. REEm, bone formation markers, myostatin and IGF-1 were significantly lower, whereas the bone resorption marker and follistatin were higher in AN compared with controls. No difference was observed between groups for irisin levels. When the whole population was studied, among myokines, only myostatin was positively correlated with aBMD at all bone sites. However, multiple regression analyses showed that in the AN group, the independent variables for aBMD were principally amenorrhoea duration, lean tissue mass (LTM) and procollagen type I N-terminal propeptide (PINP). For CON, the independent variables for aBMD were principally LTM, age and PINP. Whatever the group analysed, none of the myokines appeared as explicative independent variables of aBMD.

Conclusion

This study demonstrated that despite the altered myokine levels in patients with AN, their direct effect on aBMD loss and bone turnover alteration seems limited in comparison with other well-known disease-related factors such as oestrogen deprivation.

Open access

Vânia Benido Silva, Liliana Fonseca, Maria Teresa Pereira, Joana Vilaverde, Clara Pinto, Fernando Pichel, Maria do Céu Almeida, and Jorge Dores

Objective

Metformin has emerged as a safe and effective pharmacological alternative to insulin in gestational diabetes mellitus (GDM), being associated with lower maternal weight gain and hypoglycemia risk. Nevertheless, glycemic control is unaccomplished in a considerable proportion of women only treated with metformin. We aim to determine the metformin monotherapy failure rate in GDM and to identify predictors of its occurrence.

Design and methods

This was a retrospective multicenter study including pregnant women with GDM patients who started metformin as a first-line pharmacological treatment (n  = 2891). A comparative analysis of clinical and analytical data between the group of women treated with metformin monotherapy and those needing combined therapy with insulin was performed.

Results

In 685 (23.7%) women with GDM, combined therapy to achieve adequate glycemic control was required. Higher pregestational BMI (OR 1.039; CI 95% 1.008–1.071; P-value = 0.013), higher fasting plasma glucose (PG) levels in oral glucose tolerance test (OGTT) (OR 1.047; CI 95% 1.028–1.066; P-value <0.001) and an earlier gestational age (GA) at metformin introduction (0.839; CI 95% 0.796–0.885, P-value < 0.001) were independent predictive factors for metformin monotherapy failure. The best predictive cutoff values were a fasting PG in OGTT ≥87 mg/dL and GA at metformin introduction ≤29 weeks.

Conclusions

In 685 (23.7%) women, combined therapy with insulin to reach glycemic control was required. Higher pre-gestational BMI, fasting PG levels in OGTT ≥87 mg/dL and introduction of metformin ≤29 weeks of GA were independent predictive factors for metformin monotherapy failure. The early recognition of these characteristics can contribute to the establishment of individualized therapeutic strategies and attain better metabolic control during pregnancy.

Open access

Randi Ugleholdt, Åse Krogh Rasmussen, Pernille A H Haderslev, Bjarne Kromann-Andersen, and Claus Larsen Feltoft

Patients with pheochromocytoma and paraganglioma (PPGL) are treated with α-adrenoceptor antagonists to improve peroperative hemodynamics. However, preoperative blood pressure targets differ between institutions. We retrospectively compared per- and postoperative hemodynamics in 30 patients with PPGL that were pretreated with phenoxybenzamine aiming at different blood pressure targets at two separate endocrine departments. All patients were subsequently undergoing laparoscopic surgery at Department of Urology, Herlev University hospital. Fourteen patients were treated targeting to symptomatic and significant orthostatic hypotension and 16 patients to a seated blood pressure below 130/80 mmHg. As a control group, we included 34 patients undergoing laparoscopic adrenalectomy for other reasons. The group titrated to orthostatic hypotension required a higher dose of phenoxybenzamine to achieve the blood pressure target. This group had less intraoperative systolic and diastolic blood pressure fluctuation (Mann–Whitney U test; P  < 0.05) and less periods with heart rate above 100 b.p.m. (Mann–Whitney U test; P = 0.04) as compared to the group with a preoperative blood pressure target below 130/80 mmHg. Peroperative use of intravenous fluids were similar between the two groups, but postoperatively more intravenous fluids were administered in the group with a target of ortostatism. Overall, the control group was more hemodynamic stable as compared to either group treated for PPGL. We conclude that phenoxybenzamine pretreatment targeting ortostatic hypotension may improve peroperative hemodynamic stability but causes a higher postoperative requirement for intravenous fluids. Overall, PPGL surgery is related to greater hemodynamic instability compared to adrenalectomy for other reasons.

Open access

Alberto Battezzati, Andrea Foppiani, Gianfranco Alicandro, Arianna Bisogno, Arianna Biffi, Giorgio Bedogni, Simona Bertoli, Giulia De Carlo, Erica Nazzari, and Carla Colombo

Objective

Diabetes is a frequent comorbidity in cystic fibrosis (CF), related to multiple unfavorable outcomes. During the progression of β-cell dysfunction to diabetes, insulin deficiency could possibly reduce the anabolic support to grow even in the absence of significant glycemic derangements. To test this hypothesis, we evaluated whether prepuberal insulin secretory indices are independent predictors of adult height.

Design

Observational cohort study.

Research design and methods

A longitudinal analysis of 66 CF patients (33 females) from an ongoing cohort received at prepuberal age (median age of 12 years) modified 3-h oral glucose tolerance tests with 30-min insulin and C-peptide sampling, modeling of insulin secretory and sensitivity parameters, anthropometric evaluation. The latter was repeated when adults after a median follow-up of 9 years.

Results

In alternative models, we found a positive association with either basal insulin secretion (mean 0.22, 95% CI 0.01, 0.44 z-scores) or prepuberal β-cell glucose sensitivity (mean 0.23, 95% CI 0.00, 0.46 z-scores) and adult height, while total insulin secretion was negatively related to adult height (mean −0.36, 95% CI −0.57, −0.15 z-scores or mean −0.42, 95% CI −0.69, −0.16 z-scores, respectively). The high total insulin secretion of low adult height patients was mainly due to late (>60 min) secretion and was associated with a worse glucose response during OGTT.

Conclusions

Abnormal insulin secretion associated with high glucose response during OGTT predicts a decrease in adult height z-score. Our results suggest that insulin secretory defects in CF affect growth prior to the development of fasting hyperglycemia.