Yuzhu Teng, Jixing Zhou, Manyu Zhang, Penggui Wu, Lu Chen, Wenjin Cai, Juan Tong, Yan Han, Shuangqin Yan, Fangbiao Tao, Kun Huang
Objective: To explore the association between maternal thyroid peroxidase antibody (TPOAb) exposure and 5- to 6-year-old children's cardiometabolic risk (CMR).
Methods: A total of 2129 mother-child pairs were recruited from the Ma'anshan Birth Cohort (MABC) study. Serum TPOAb was retrospectively measured in pregnant women using an electrochemiluminescence immunoassay. CMR score was evaluated by the serum glycolipids, blood pressure, and waist circumference for children aged 5-6 years. Growth mixture modelling was used to fit trajectories of TPOAb levels throughout pregnancy. Multiple linear regression models and logistic regression models were used for statistical analyses.
Results: Two thousand one hundred twenty-nine mother-child pairs (mean [SD] age, 26.6 [3.6] years) were enrolled for the final study. Maternal TPOAb exposure in the first trimester increased children's overall CMR, glucose level, HOMA-IR, triglyceride level, boys' overall CMR, boys' glucose level, and girls' glucose level. TPOAb exposure in the first trimester was also associated with lower boys' high-density lipoprotein cholesterol (HDL-C) level. In the second trimester, maternal TPOAb exposure was positively associated with children's triglyceride level. Compared with low TPOAb trajectory, children with high maternal TPOAb trajectory had an increased risk of developing high CMR (OR = 3.40; 95% CI, 1.30-8.90), hyperglycemia (OR = 5.20; 95% CI, 2.20-12.28), insulin-resistance (adjusted OR = 2.12; 95% CI, 1.10-4.07), and hypertriglyceridemia (OR = 2.55; 95% CI, 1.06-6.14).
Conclusions: The first trimester of pregnancy is a critical period for maternal TPOAb exposure to affect CMR in children, with some sex specificity, mainly to the detriment of boys.
{"title":"Sex-specific effect of maternal thyroid peroxidase antibody exposure during pregnancy on 5- to 6-year-old children's cardiometabolic risk score: the Ma'anshan birth cohort study.","authors":"Yuzhu Teng, Jixing Zhou, Manyu Zhang, Penggui Wu, Lu Chen, Wenjin Cai, Juan Tong, Yan Han, Shuangqin Yan, Fangbiao Tao, Kun Huang","doi":"10.1093/ejendo/lvae105","DOIUrl":"10.1093/ejendo/lvae105","url":null,"abstract":"<p><strong>Objective: </strong>To explore the association between maternal thyroid peroxidase antibody (TPOAb) exposure and 5- to 6-year-old children's cardiometabolic risk (CMR).</p><p><strong>Methods: </strong>A total of 2129 mother-child pairs were recruited from the Ma'anshan Birth Cohort (MABC) study. Serum TPOAb was retrospectively measured in pregnant women using an electrochemiluminescence immunoassay. CMR score was evaluated by the serum glycolipids, blood pressure, and waist circumference for children aged 5-6 years. Growth mixture modelling was used to fit trajectories of TPOAb levels throughout pregnancy. Multiple linear regression models and logistic regression models were used for statistical analyses.</p><p><strong>Results: </strong>Two thousand one hundred twenty-nine mother-child pairs (mean [SD] age, 26.6 [3.6] years) were enrolled for the final study. Maternal TPOAb exposure in the first trimester increased children's overall CMR, glucose level, HOMA-IR, triglyceride level, boys' overall CMR, boys' glucose level, and girls' glucose level. TPOAb exposure in the first trimester was also associated with lower boys' high-density lipoprotein cholesterol (HDL-C) level. In the second trimester, maternal TPOAb exposure was positively associated with children's triglyceride level. Compared with low TPOAb trajectory, children with high maternal TPOAb trajectory had an increased risk of developing high CMR (OR = 3.40; 95% CI, 1.30-8.90), hyperglycemia (OR = 5.20; 95% CI, 2.20-12.28), insulin-resistance (adjusted OR = 2.12; 95% CI, 1.10-4.07), and hypertriglyceridemia (OR = 2.55; 95% CI, 1.06-6.14).</p><p><strong>Conclusions: </strong>The first trimester of pregnancy is a critical period for maternal TPOAb exposure to affect CMR in children, with some sex specificity, mainly to the detriment of boys.</p>","PeriodicalId":11884,"journal":{"name":"European Journal of Endocrinology","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016705","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yasir S Elhassan, Silke Appenzeller, Laura-Sophie Landwehr, Juliane Lippert, Dillon Popat, Lorna C Gilligan, Lida Abdi, Edwina Goh, Salvador Diaz-Cano, Stefan Kircher, Susanne Gramlich, Robert P Sutcliffe, Shakila Thangaratinam, Li F Chan, Martin Fassnacht, Wiebke Arlt, Cristina L Ronchi
Background: Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a rare cause of Cushing's syndrome. Individuals with PBMAH and glucose-dependent insulinotropic polypeptide (GIP)-dependent Cushing's syndrome due to ectopic expression of the GIP receptor (GIPR) typically harbor inactivating KDM1A sequence variants. Primary unilateral macronodular adrenal hyperplasia (PUMAH) with concomitant glucocorticoid and androgen excess has never been encountered or studied.
Methods: We investigated a woman with a large, heterogeneous adrenal mass and severe adrenocorticotropic hormone-independent glucocorticoid and androgen excess, a biochemical presentation typically suggestive of adrenocortical carcinoma. The patient presented during pregnancy (22nd week of gestation) and reported an 18-month history of oligomenorrhea, hirsutism, and weight gain. We undertook an exploratory study with detailed histopathological and genetic analysis of the resected adrenal mass and leukocyte DNA collected from the patient and her parents.
Results: Histopathology revealed benign macronodular adrenal hyperplasia. Imaging showed a persistently normal contralateral adrenal gland. Whole-exome sequencing of 4 representative nodules detected KDM1A germline variants, benign NM_001009999.3:c.136G > A:p.G46S, and likely pathogenic NM_001009999.3:exon6:c.865_866del:p.R289Dfs*7. Copy number variation analysis demonstrated an additional somatic loss of the KDM1A wild-type allele on chromosome 1p36.12 in all nodules. RNA sequencing of a representative nodule showed low/absent KDM1A expression and increased GIPR expression compared with 52 unilateral sporadic adenomas and 4 normal adrenal glands. Luteinizing hormone/chorionic gonadotropin receptor expression was normal. Sanger sequencing confirmed heterozygous KDM1A variants in both parents (father: p.R289Dfs*7 and mother: p.G46S) who showed no clinical features suggestive of glucocorticoid or androgen excess.
Conclusions: We investigated the first PUMAH associated with severe Cushing's syndrome and concomitant androgen excess, suggesting pathogenic mechanisms involving KDM1A.
{"title":"Primary unilateral macronodular adrenal hyperplasia with concomitant glucocorticoid and androgen excess and KDM1A inactivation.","authors":"Yasir S Elhassan, Silke Appenzeller, Laura-Sophie Landwehr, Juliane Lippert, Dillon Popat, Lorna C Gilligan, Lida Abdi, Edwina Goh, Salvador Diaz-Cano, Stefan Kircher, Susanne Gramlich, Robert P Sutcliffe, Shakila Thangaratinam, Li F Chan, Martin Fassnacht, Wiebke Arlt, Cristina L Ronchi","doi":"10.1093/ejendo/lvae106","DOIUrl":"10.1093/ejendo/lvae106","url":null,"abstract":"<p><strong>Background: </strong>Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a rare cause of Cushing's syndrome. Individuals with PBMAH and glucose-dependent insulinotropic polypeptide (GIP)-dependent Cushing's syndrome due to ectopic expression of the GIP receptor (GIPR) typically harbor inactivating KDM1A sequence variants. Primary unilateral macronodular adrenal hyperplasia (PUMAH) with concomitant glucocorticoid and androgen excess has never been encountered or studied.</p><p><strong>Methods: </strong>We investigated a woman with a large, heterogeneous adrenal mass and severe adrenocorticotropic hormone-independent glucocorticoid and androgen excess, a biochemical presentation typically suggestive of adrenocortical carcinoma. The patient presented during pregnancy (22nd week of gestation) and reported an 18-month history of oligomenorrhea, hirsutism, and weight gain. We undertook an exploratory study with detailed histopathological and genetic analysis of the resected adrenal mass and leukocyte DNA collected from the patient and her parents.</p><p><strong>Results: </strong>Histopathology revealed benign macronodular adrenal hyperplasia. Imaging showed a persistently normal contralateral adrenal gland. Whole-exome sequencing of 4 representative nodules detected KDM1A germline variants, benign NM_001009999.3:c.136G > A:p.G46S, and likely pathogenic NM_001009999.3:exon6:c.865_866del:p.R289Dfs*7. Copy number variation analysis demonstrated an additional somatic loss of the KDM1A wild-type allele on chromosome 1p36.12 in all nodules. RNA sequencing of a representative nodule showed low/absent KDM1A expression and increased GIPR expression compared with 52 unilateral sporadic adenomas and 4 normal adrenal glands. Luteinizing hormone/chorionic gonadotropin receptor expression was normal. Sanger sequencing confirmed heterozygous KDM1A variants in both parents (father: p.R289Dfs*7 and mother: p.G46S) who showed no clinical features suggestive of glucocorticoid or androgen excess.</p><p><strong>Conclusions: </strong>We investigated the first PUMAH associated with severe Cushing's syndrome and concomitant androgen excess, suggesting pathogenic mechanisms involving KDM1A.</p>","PeriodicalId":11884,"journal":{"name":"European Journal of Endocrinology","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11378072/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016704","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Noor C Gieles, Maurice A G M Kroon, Stephanie Both, Annemieke C Heijboer, Baudewijntje P C Kreukels, Martin den Heijer
Objective: Transgender women who underwent gonadectomy have lower serum testosterone concentrations than cisgender women. There is uncertainty regarding the dosing and side effects of supplementation of testosterone in transgender women. This study aimed to assess the feasibility of dosing testosterone to the cisgender female physiological range in transgender women. In addition, we explored changes in cardiovascular parameters, virilizing side effects, and clinical symptoms.
Design: This is an open-label, single-arm feasibility study. Participants initially went through a dose-titration phase with 2-week intervals of 0.07-0.09-0.13 mL (277-318-403 μg bioavailable testosterone) testosterone 2% gel to establish a dose leading to serum testosterone concentrations between 1.5 and 2.5 nmol/L. This dose was then continued for 8 weeks.
Methods: Participants applied daily transdermal testosterone 2% gel (Tostran®) at the prescribed dosage. Testosterone was measured every 2-4 weeks. Laboratory analyses, side effects, and clinical symptoms were evaluated.
Results: In total, 12 participants were included. Most participants required a dose of 0.07 mL (277 μg bioavailable testosterone) or 0.09 mL (318 μg bioavailable testosterone) to reach serum testosterone concentrations of 1.5-2.5 nmol/L. Continuing this dose, testosterone concentrations remained stable throughout the study. Changes in clinical outcomes were in the desired direction, and side effects were mild.
Conclusions: The use of testosterone supplementation in transgender women seems feasible and safe in the short term. Although dosing requires personalized titration, stable testosterone levels can be established. A blinded, placebo-controlled, randomized clinical trial is needed to study the clinical benefit.
{"title":"Addition of testosterone to endocrine care for transgender women: a dose-finding and feasibility trial.","authors":"Noor C Gieles, Maurice A G M Kroon, Stephanie Both, Annemieke C Heijboer, Baudewijntje P C Kreukels, Martin den Heijer","doi":"10.1093/ejendo/lvae103","DOIUrl":"10.1093/ejendo/lvae103","url":null,"abstract":"<p><strong>Objective: </strong>Transgender women who underwent gonadectomy have lower serum testosterone concentrations than cisgender women. There is uncertainty regarding the dosing and side effects of supplementation of testosterone in transgender women. This study aimed to assess the feasibility of dosing testosterone to the cisgender female physiological range in transgender women. In addition, we explored changes in cardiovascular parameters, virilizing side effects, and clinical symptoms.</p><p><strong>Design: </strong>This is an open-label, single-arm feasibility study. Participants initially went through a dose-titration phase with 2-week intervals of 0.07-0.09-0.13 mL (277-318-403 μg bioavailable testosterone) testosterone 2% gel to establish a dose leading to serum testosterone concentrations between 1.5 and 2.5 nmol/L. This dose was then continued for 8 weeks.</p><p><strong>Methods: </strong>Participants applied daily transdermal testosterone 2% gel (Tostran®) at the prescribed dosage. Testosterone was measured every 2-4 weeks. Laboratory analyses, side effects, and clinical symptoms were evaluated.</p><p><strong>Results: </strong>In total, 12 participants were included. Most participants required a dose of 0.07 mL (277 μg bioavailable testosterone) or 0.09 mL (318 μg bioavailable testosterone) to reach serum testosterone concentrations of 1.5-2.5 nmol/L. Continuing this dose, testosterone concentrations remained stable throughout the study. Changes in clinical outcomes were in the desired direction, and side effects were mild.</p><p><strong>Conclusions: </strong>The use of testosterone supplementation in transgender women seems feasible and safe in the short term. Although dosing requires personalized titration, stable testosterone levels can be established. A blinded, placebo-controlled, randomized clinical trial is needed to study the clinical benefit.</p>","PeriodicalId":11884,"journal":{"name":"European Journal of Endocrinology","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142008483","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Objective: Primary hypophysitis might be challenging to diagnose, and there is a lack of evidence regarding optimal treatment strategies due to rarity of the disease. We aim to investigate the clinical features and compare the outcomes of different management strategies of primary hypophysitis in a large group of patients recruited on a nationwide basis.
Design: A retrospective observational study.
Methods: The demographic, clinical, and radiologic features and follow-up data were collected in study protocol templates and analyzed.
Results: One hundred and thirteen patients (78.8% female, median age: 36 years) were included. Lymphocytic (46.7%) and granulomatous hypophysitis (35.6%) were the prevailing subtypes out of 45 patients diagnosed after pathologic investigations. Headache (75.8%) was the most common symptom, and central hypogonadism (49.5%) was the most common hormone insufficiency. Of the patients, 52.2% were clinically observed without interventions, 18.6% were started on glucocorticoid therapy, and 29.2% underwent surgery at presentation. Headache, suprasellar extension, and chiasmal compression were more common among glucocorticoid-treated patients than who were observed. Cox regression analysis revealed higher hormonal and radiologic improvement rates in the glucocorticoid-treated group than observation group (hazard ratio, 4.60; 95% CI, 1.62-12.84 and HR, 3.1; 95% CI, 1.40-6.68, respectively). The main indication for surgery was the inability to exclude a pituitary adenoma in the presence of compression symptoms, with a recurrence rate of 9%.
Conclusion: The rate of spontaneous improvement might justify observation in mild cases. Glucocorticoids proved superior to observation in terms of hormonal and radiologic improvements. Surgery may not be curative and might be considered in indeterminate, treatment-resistant, or severe cases.
{"title":"Evaluation and follow-up of patients diagnosed with hypophysitis: a cohort study.","authors":"Aysa Hacioglu, Zuleyha Karaca, Serhat Uysal, Hande Mefkure Ozkaya, Pınar Kadioglu, Ozlem Soyluk Selcukbiricik, Nurdan Gul, Sema Yarman, Damla Koksalan, Alev Selek, Zeynep Canturk, Berrin Cetinarslan, Demet Corapcioglu, Mustafa Sahin, Fatma Tugce Sah Unal, Afruz Babayeva, Mujde Akturk, Sema Ciftci, Hamide Piskinpasa, Hatice Sebile Dokmetas, Meric Dokmetas, Onur Sahin, Ayten Eraydın, Semin Fenkci, Sadettin Ozturk, Ersin Akarsu, Tulay Omma, Buruc Erkan, Sebnem Burhan, Esma Pehlivan Koroglu, Fusun Saygili, Elif Kilic Kan, Aysegul Atmaca, Gulsah Elbuken, Ziynet Alphan Uc, Suheyla Gorar, Zeliha Hekimsoy, Zafer Pekkolay, Hayri Bostan, Fahri Bayram, Goknur Yorulmaz, Selcuk Yusuf Sener, Kubra Turan, Ozlem Celik, Hakan Dogruel, Eda Ertorer, Ozlem Turhan Iyidir, Omercan Topaloglu, Guven Baris Cansu, Kursad Unluhizarci, Fahrettin Kelestimur","doi":"10.1093/ejendo/lvae101","DOIUrl":"10.1093/ejendo/lvae101","url":null,"abstract":"<p><strong>Objective: </strong>Primary hypophysitis might be challenging to diagnose, and there is a lack of evidence regarding optimal treatment strategies due to rarity of the disease. We aim to investigate the clinical features and compare the outcomes of different management strategies of primary hypophysitis in a large group of patients recruited on a nationwide basis.</p><p><strong>Design: </strong>A retrospective observational study.</p><p><strong>Methods: </strong>The demographic, clinical, and radiologic features and follow-up data were collected in study protocol templates and analyzed.</p><p><strong>Results: </strong>One hundred and thirteen patients (78.8% female, median age: 36 years) were included. Lymphocytic (46.7%) and granulomatous hypophysitis (35.6%) were the prevailing subtypes out of 45 patients diagnosed after pathologic investigations. Headache (75.8%) was the most common symptom, and central hypogonadism (49.5%) was the most common hormone insufficiency. Of the patients, 52.2% were clinically observed without interventions, 18.6% were started on glucocorticoid therapy, and 29.2% underwent surgery at presentation. Headache, suprasellar extension, and chiasmal compression were more common among glucocorticoid-treated patients than who were observed. Cox regression analysis revealed higher hormonal and radiologic improvement rates in the glucocorticoid-treated group than observation group (hazard ratio, 4.60; 95% CI, 1.62-12.84 and HR, 3.1; 95% CI, 1.40-6.68, respectively). The main indication for surgery was the inability to exclude a pituitary adenoma in the presence of compression symptoms, with a recurrence rate of 9%.</p><p><strong>Conclusion: </strong>The rate of spontaneous improvement might justify observation in mild cases. Glucocorticoids proved superior to observation in terms of hormonal and radiologic improvements. Surgery may not be curative and might be considered in indeterminate, treatment-resistant, or severe cases.</p>","PeriodicalId":11884,"journal":{"name":"European Journal of Endocrinology","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142072368","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Marianne C Astor, Kristian Løvås, Paal Methlie, Katerina Simunkova, Jörg Assmus, Eystein S Husebye
Objective: Previous studies indicate a possible bidirectional stimulatory relationship between parathyroid hormone (PTH) and adrenocortical hormones, but the pattern of adrenocortical secretion in hypoparathyroidism is unknown. We aimed to characterize the adrenocortical secretion in patients with postsurgical hypoparathyroidism, and whether continuous subcutaneous PTH (1-34) infusion alters secretion patterns.
Design: Crossover interventional study.
Methods: We recruited 10 patients with postsurgical hypoparathyroidism with very low PTH levels on stable treatment with active vitamin D and calcium. Cortisol, cortisone, and aldosterone levels were measured in microdialysate from subcutaneous tissue over 24 h, before and during continuous subcutaneous PTH (1-34) infusion. Cortisol was also assayed in serum, saliva, and urine, and aldosterone and ACTH in serum and plasma, respectively. Ten patients with primary hyperparathyroidism and 10 healthy volunteers matched for sex and age served as controls.
Results: Hypoparathyroid patients displayed both ultradian and circadian rhythmicity for tissue cortisol, cortisone, and aldosterone. Tissue aldosterone and cortisone levels were significantly lower in hypoparathyroid patients than in healthy controls, with no difference in tissue cortisol, but a higher cortisol to cortisone ratio. Treatment with PTH (1-34) increased tissue levels of aldosterone, cortisol, and cortisone and reduced the ratio of cortisol to cortisone.
Conclusion: Adrenocortical hormone levels are reduced in postsurgical hypoparathyroidism, and partly restored by short-term continuous subcutaneous PTH (1-34) therapy.
{"title":"Corticosteroid rhythms in hypoparathyroid patients.","authors":"Marianne C Astor, Kristian Løvås, Paal Methlie, Katerina Simunkova, Jörg Assmus, Eystein S Husebye","doi":"10.1093/ejendo/lvae102","DOIUrl":"10.1093/ejendo/lvae102","url":null,"abstract":"<p><strong>Objective: </strong>Previous studies indicate a possible bidirectional stimulatory relationship between parathyroid hormone (PTH) and adrenocortical hormones, but the pattern of adrenocortical secretion in hypoparathyroidism is unknown. We aimed to characterize the adrenocortical secretion in patients with postsurgical hypoparathyroidism, and whether continuous subcutaneous PTH (1-34) infusion alters secretion patterns.</p><p><strong>Design: </strong>Crossover interventional study.</p><p><strong>Methods: </strong>We recruited 10 patients with postsurgical hypoparathyroidism with very low PTH levels on stable treatment with active vitamin D and calcium. Cortisol, cortisone, and aldosterone levels were measured in microdialysate from subcutaneous tissue over 24 h, before and during continuous subcutaneous PTH (1-34) infusion. Cortisol was also assayed in serum, saliva, and urine, and aldosterone and ACTH in serum and plasma, respectively. Ten patients with primary hyperparathyroidism and 10 healthy volunteers matched for sex and age served as controls.</p><p><strong>Results: </strong>Hypoparathyroid patients displayed both ultradian and circadian rhythmicity for tissue cortisol, cortisone, and aldosterone. Tissue aldosterone and cortisone levels were significantly lower in hypoparathyroid patients than in healthy controls, with no difference in tissue cortisol, but a higher cortisol to cortisone ratio. Treatment with PTH (1-34) increased tissue levels of aldosterone, cortisol, and cortisone and reduced the ratio of cortisol to cortisone.</p><p><strong>Conclusion: </strong>Adrenocortical hormone levels are reduced in postsurgical hypoparathyroidism, and partly restored by short-term continuous subcutaneous PTH (1-34) therapy.</p><p><strong>Clinical trial registration number: </strong>NCT02986607.</p>","PeriodicalId":11884,"journal":{"name":"European Journal of Endocrinology","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016802","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Anne-Lise Lecoq, Katharina Schilbach, Laurence Rocher, Séverine Trabado, Karine Briot, Julia Herrou, Aurélie Forbes, Anthony Garnier, Marie Piketty, Martin Bidlingmaier, Anya Rothenbuhler, Agnès Linglart, Claire Carette, Philippe Chaumet-Riffaud, Peter Kamenický
Objectives: X-linked hypophosphatemia (XLH) is characterized by increased concentrations of circulating fibroblast growth factor 23 (FGF-23) resulting in phosphate wasting, hypophosphatemia, atypical growth plate and bone matrix mineralization. Epidemiologic studies suggest a relationship between FGF-23, obesity, and metabolic dysfunction. The prevalence of overweight and obesity is high in children with XLH. We aimed to evaluate the prevalence of obesity and metabolic complications in adults with XLH.
Methods: We conducted a prospective cohort study in adult XLH patients from a single tertiary referral center. The proportion of patients with a BMI >25 kg/m2 was the main outcome measure. Body fat mass percentage (FM%) and adipose tissue surfaces were secondary outcome measures. Glucose homeostasis (plasma glucose and insulin concentrations after fasting and 2 hours after an oral glucose tolerance test) was explored in a subgroup of patients and compared with age-, sex-, and BMI-matched healthy controls.
Results: Among 113 evaluated patients, 85 (75%) were female and 110 (97%) carried a PHEX mutation. Sixty-three (56%) patients were overweight or obese, with a median BMI of 25.3 [IQR, 22.7; 29.2] kg/m2. BMI was correlated with FM%, abdominal and thigh subcutaneous and intra-abdominal adipose tissue surfaces. The prevalence of impaired fasting glucose, impaired glucose tolerance, and diabetes was not different between XLH patients and matched controls.
Conclusion: The prevalence of overweight and obesity is high among XLH patients and is associated with excess fat mass. However, the prevalence of glucose homeostasis abnormalities is not increased in patients compared to healthy controls, suggesting that metabolically healthy overweight or obesity predominates.
{"title":"Metabolically healthy obesity in adults with X-linked hypophosphatemia.","authors":"Anne-Lise Lecoq, Katharina Schilbach, Laurence Rocher, Séverine Trabado, Karine Briot, Julia Herrou, Aurélie Forbes, Anthony Garnier, Marie Piketty, Martin Bidlingmaier, Anya Rothenbuhler, Agnès Linglart, Claire Carette, Philippe Chaumet-Riffaud, Peter Kamenický","doi":"10.1093/ejendo/lvae089","DOIUrl":"https://doi.org/10.1093/ejendo/lvae089","url":null,"abstract":"<p><strong>Objectives: </strong>X-linked hypophosphatemia (XLH) is characterized by increased concentrations of circulating fibroblast growth factor 23 (FGF-23) resulting in phosphate wasting, hypophosphatemia, atypical growth plate and bone matrix mineralization. Epidemiologic studies suggest a relationship between FGF-23, obesity, and metabolic dysfunction. The prevalence of overweight and obesity is high in children with XLH. We aimed to evaluate the prevalence of obesity and metabolic complications in adults with XLH.</p><p><strong>Methods: </strong>We conducted a prospective cohort study in adult XLH patients from a single tertiary referral center. The proportion of patients with a BMI >25 kg/m2 was the main outcome measure. Body fat mass percentage (FM%) and adipose tissue surfaces were secondary outcome measures. Glucose homeostasis (plasma glucose and insulin concentrations after fasting and 2 hours after an oral glucose tolerance test) was explored in a subgroup of patients and compared with age-, sex-, and BMI-matched healthy controls.</p><p><strong>Results: </strong>Among 113 evaluated patients, 85 (75%) were female and 110 (97%) carried a PHEX mutation. Sixty-three (56%) patients were overweight or obese, with a median BMI of 25.3 [IQR, 22.7; 29.2] kg/m2. BMI was correlated with FM%, abdominal and thigh subcutaneous and intra-abdominal adipose tissue surfaces. The prevalence of impaired fasting glucose, impaired glucose tolerance, and diabetes was not different between XLH patients and matched controls.</p><p><strong>Conclusion: </strong>The prevalence of overweight and obesity is high among XLH patients and is associated with excess fat mass. However, the prevalence of glucose homeostasis abnormalities is not increased in patients compared to healthy controls, suggesting that metabolically healthy overweight or obesity predominates.</p>","PeriodicalId":11884,"journal":{"name":"European Journal of Endocrinology","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141906257","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Eliane Dias da Silva, Raquel Camara Riveri, Poli Mara Spritzer, Tayane Muniz Fighera
Objectives: Despite regular gender-affirming hormone therapy (GAHT), the presence of uterine bleeding can occur occasionally and cause profound discomfort. This study aimed to evaluate the histologic features and immunohistochemical expression of estrogen (ER), progesterone (PR), and androgen receptors (AR) in the endometrium and myometrium of transgender men receiving testosterone therapy and relate them to clinical and hormonal characteristics.
Design: Retrospective cross-sectional study.
Methods: Thirty-four transgender men undergoing gender-affirming surgery were included. Clinical, sociodemographic, and laboratory data as well as anatomopathological and immunohistochemical findings were evaluated.
Results: The participants' mean age was 42.35 (SD, 10.00) years, and body mass index was 28.16 (SD, 5.52) kg/m2. The mean GAHT duration before surgery was 5.36 (SD, 3.24) years. The mean testosterone levels were 814.98 (SD, 407.13) ng/dL, and estradiol levels were 55.22 (SD, 25.27) pg/mL. The endometrium was atrophic in 61.8%, proliferative in 17.6%, and secretory in 20.6%. Immunohistochemical receptor analysis revealed that endometrial epithelial cells expressed ER (90%) and PR (80%), with a lower expression of AR (30%). In stromal tissue, the median ER, PR, and AR expression was lower than that in the epithelium (60%, 70%, and 25%, respectively). The myometrium showed high expression of PR (90%) and ER (70%), with the highest expression of AR (65%) being localized to this region.
Conclusions: In the present study, GAHT induced an atrophic condition of the endometrium in two-thirds of the transgender men, with a limited AR expression in the endometrial region. The present results suggest that testosterone-based GAHT for a mean of 5 years is safe in transgender men achieving amenorrhea.
目的:尽管定期接受性别确认激素治疗(GAHT),子宫出血仍会偶尔发生,并引起严重不适。本研究旨在评估接受睾酮治疗的变性男性子宫内膜和子宫肌层中雌激素(ER)、孕激素(PR)和雄激素(AR)受体的组织学特征和免疫组化表达,并将其与临床和激素特征联系起来:设计:回顾性横断面研究:方法:纳入 34 名接受 GAS 治疗的变性男性。对临床、社会人口学、实验室数据以及解剖病理学和免疫组化结果进行了评估:结果:参与者的平均年龄为 42.35(SD,10.00)岁,体重指数为 28.16(SD,5.52)kg/m2。手术前的平均GAHT持续时间为5.36(SD,3.24)年。平均睾酮水平为 814.98 (SD,407.13) ng/dL,雌二醇水平为 55.22 (SD,25.27) pg/mL。子宫内膜萎缩占 61.8%,增生占 17.6%,分泌占 20.6%。免疫组化受体分析显示,子宫内膜上皮细胞表达ER(90%)和PR(80%),AR表达较低(30%)。在基质组织中,ER、PR 和 AR 表达的中位数低于上皮细胞(分别为 60%、70% 和 25%)。子宫肌层显示出 PR(90%)和 ER(70%)的高表达,AR 的最高表达(65%)位于该区域:结论:在本研究中,GAHT 导致三分之二的变性男性出现子宫内膜萎缩,子宫内膜区域的 AR 表达有限。本研究结果表明,对实现闭经的变性男性而言,基于睾酮的GAHT治疗平均持续5年是安全的。
{"title":"Uterine changes in transgender men receiving testosterone therapy.","authors":"Eliane Dias da Silva, Raquel Camara Riveri, Poli Mara Spritzer, Tayane Muniz Fighera","doi":"10.1093/ejendo/lvae096","DOIUrl":"10.1093/ejendo/lvae096","url":null,"abstract":"<p><strong>Objectives: </strong>Despite regular gender-affirming hormone therapy (GAHT), the presence of uterine bleeding can occur occasionally and cause profound discomfort. This study aimed to evaluate the histologic features and immunohistochemical expression of estrogen (ER), progesterone (PR), and androgen receptors (AR) in the endometrium and myometrium of transgender men receiving testosterone therapy and relate them to clinical and hormonal characteristics.</p><p><strong>Design: </strong>Retrospective cross-sectional study.</p><p><strong>Methods: </strong>Thirty-four transgender men undergoing gender-affirming surgery were included. Clinical, sociodemographic, and laboratory data as well as anatomopathological and immunohistochemical findings were evaluated.</p><p><strong>Results: </strong>The participants' mean age was 42.35 (SD, 10.00) years, and body mass index was 28.16 (SD, 5.52) kg/m2. The mean GAHT duration before surgery was 5.36 (SD, 3.24) years. The mean testosterone levels were 814.98 (SD, 407.13) ng/dL, and estradiol levels were 55.22 (SD, 25.27) pg/mL. The endometrium was atrophic in 61.8%, proliferative in 17.6%, and secretory in 20.6%. Immunohistochemical receptor analysis revealed that endometrial epithelial cells expressed ER (90%) and PR (80%), with a lower expression of AR (30%). In stromal tissue, the median ER, PR, and AR expression was lower than that in the epithelium (60%, 70%, and 25%, respectively). The myometrium showed high expression of PR (90%) and ER (70%), with the highest expression of AR (65%) being localized to this region.</p><p><strong>Conclusions: </strong>In the present study, GAHT induced an atrophic condition of the endometrium in two-thirds of the transgender men, with a limited AR expression in the endometrial region. The present results suggest that testosterone-based GAHT for a mean of 5 years is safe in transgender men achieving amenorrhea.</p>","PeriodicalId":11884,"journal":{"name":"European Journal of Endocrinology","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141757896","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Demi J Trueba-Timmermans, Lionne N Grootjen, Gerthe F Kerkhof, Edmond H H M Rings, Anita C S Hokken-Koelega
Context: Several endocrine abnormalities were reported in children with Prader-Willi syndrome (PWS), including hypothyroidism. Growth hormone (GH) treatment may impact the thyroid hormone axis by direct inhibition of T4 or TSH secretion or by increased peripheral conversion of free T4 (FT4) to T3.
Objective: The objective of this study is to evaluate thyroid function during GH treatment in a large group of children with PWS.
Methods: Serum FT4, T3, and TSH are measured in a 2-year randomized controlled GH trial (RCT) and 10-year longitudinal GH study (GH treatment with 1.0 mg/m²/day [∼0.035 mg/kg/day]).
Results: Forty-nine children with PWS were included in the 2-year RCT (median [interquartile range, IQR] age: GH group 7.44 [5.47-11.80] years, control group 6.04 [4.56-7.39] years). During the first 6 months, median (IQR) FT4 standard deviation score (SDS) decreased in the GH group from -0.84 (-1.07 to -0.62) to -1.32 (-1.57 to -1.08) (P < .001) and T3 SDS increased from 0.31 (-0.01-0.63) to 0.56 (0.32-0.79) (P = .08), while in the control group, FT4 and T3 SDS remained unchanged. In our 10-year GH study, 240 children with PWS (median [IQR] age: 1.27 (0.54-4.17) years] were included. Between 2 and 10 years, median (IQR) FT4 SDS remained unchanged, being -0.87 (-0.98 to -0.77) after 2 years and -0.88 (-1.03 to -0.74) after 10 years (P = .13). TSH SDS decreased from -0.35 (-0.50 to -0.21) after 2 years to -0.68 (-0.84 to -0.53) after 10 years (P < .001).
Conclusions: Our findings suggest that GH treatment decreases FT4 levels, due to increased peripheral conversion of FT4 to T3 in the first months of treatment, but thereafter, FT4 and T3 normalize and remain stable during long-term GH treatment in almost all children and adolescents with PWS.
{"title":"Thyroid hormone levels in children with Prader-Willi syndrome: a randomized controlled growth hormone trial and 10-year growth hormone study.","authors":"Demi J Trueba-Timmermans, Lionne N Grootjen, Gerthe F Kerkhof, Edmond H H M Rings, Anita C S Hokken-Koelega","doi":"10.1093/ejendo/lvae088","DOIUrl":"10.1093/ejendo/lvae088","url":null,"abstract":"<p><strong>Context: </strong>Several endocrine abnormalities were reported in children with Prader-Willi syndrome (PWS), including hypothyroidism. Growth hormone (GH) treatment may impact the thyroid hormone axis by direct inhibition of T4 or TSH secretion or by increased peripheral conversion of free T4 (FT4) to T3.</p><p><strong>Objective: </strong>The objective of this study is to evaluate thyroid function during GH treatment in a large group of children with PWS.</p><p><strong>Methods: </strong>Serum FT4, T3, and TSH are measured in a 2-year randomized controlled GH trial (RCT) and 10-year longitudinal GH study (GH treatment with 1.0 mg/m²/day [∼0.035 mg/kg/day]).</p><p><strong>Results: </strong>Forty-nine children with PWS were included in the 2-year RCT (median [interquartile range, IQR] age: GH group 7.44 [5.47-11.80] years, control group 6.04 [4.56-7.39] years). During the first 6 months, median (IQR) FT4 standard deviation score (SDS) decreased in the GH group from -0.84 (-1.07 to -0.62) to -1.32 (-1.57 to -1.08) (P < .001) and T3 SDS increased from 0.31 (-0.01-0.63) to 0.56 (0.32-0.79) (P = .08), while in the control group, FT4 and T3 SDS remained unchanged. In our 10-year GH study, 240 children with PWS (median [IQR] age: 1.27 (0.54-4.17) years] were included. Between 2 and 10 years, median (IQR) FT4 SDS remained unchanged, being -0.87 (-0.98 to -0.77) after 2 years and -0.88 (-1.03 to -0.74) after 10 years (P = .13). TSH SDS decreased from -0.35 (-0.50 to -0.21) after 2 years to -0.68 (-0.84 to -0.53) after 10 years (P < .001).</p><p><strong>Conclusions: </strong>Our findings suggest that GH treatment decreases FT4 levels, due to increased peripheral conversion of FT4 to T3 in the first months of treatment, but thereafter, FT4 and T3 normalize and remain stable during long-term GH treatment in almost all children and adolescents with PWS.</p>","PeriodicalId":11884,"journal":{"name":"European Journal of Endocrinology","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141757853","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Laura S Hansen, Lærke S Gasbjerg, Andreas Brønden, Niels B Dalsgaard, Emilie Bahne, Signe Stensen, Pernille H Hellmann, Jens F Rehfeld, Bolette Hartmann, Nicolai J Wewer Albrechtsen, Jens J Holst, Tina Vilsbøll, Filip K Knop
Aims: Although metformin is widely used for treatment of type 2 diabetes (T2D), its glucose-lowering mechanism remains unclear. Using the glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) antagonist exendin(9-39)NH2, we tested the hypothesis that postprandial GLP-1-mediated effects contribute to the glucose-lowering potential of metformin in T2D.
Methods: In a randomized, placebo-controlled, double-blind, crossover study, 15 individuals with T2D (median HbA1c 50 mmol/mol [6.7%], body mass index 30.1 kg/m2, age 71 years) underwent, in randomized order, 14 days of metformin and placebo treatment, respectively. Each treatment period was preceded by 14 days without any glucose-lowering medicine and concluded by two 4 h mixed meal tests performed in randomized order and separated by >24 h with either continuous intravenous exendin(9-39)NH2 or saline infusion.
Results: Compared to placebo, metformin treatment lowered fasting plasma glucose (mean of differences [MD] 1.4 mmol/L × min [95% CI 0.8-2.0]) as well as postprandial plasma glucose excursions during both saline infusion (MD 186 mmol/L × min [95% CI 64-307]) and exendin(9-39)NH2 infusion (MD 268 mmol/L × min [95% CI 108-427]). The metformin-induced improvement in postprandial glucose tolerance was unaffected by GLP-1R antagonization (MD 82 mmol/L × min [95% CI -6564-170]). Metformin treatment increased fasting plasma GLP-1 (MD 1.7 pmol/L × min [95% CI 0.39-2.9]) but did not affect postprandial GLP-1 responses (MD 820 pmol/L × min [95% CI -1750-111]).
Conclusions: Using GLP-1R antagonization, we could not detect GLP-1-mediated postprandial glucose-lowering effect of metformin in individuals with T2D. We show that 2 weeks of metformin treatment increases fasting plasma GLP-1, which may contribute to metformin's beneficial effect on fasting plasma glucose in T2D. Trial registration: Clinicaltrials.gov NCT03246451.
{"title":"The role of glucagon-like peptide 1 in the postprandial effects of metformin in type 2 diabetes: a randomized crossover trial.","authors":"Laura S Hansen, Lærke S Gasbjerg, Andreas Brønden, Niels B Dalsgaard, Emilie Bahne, Signe Stensen, Pernille H Hellmann, Jens F Rehfeld, Bolette Hartmann, Nicolai J Wewer Albrechtsen, Jens J Holst, Tina Vilsbøll, Filip K Knop","doi":"10.1093/ejendo/lvae095","DOIUrl":"10.1093/ejendo/lvae095","url":null,"abstract":"<p><strong>Aims: </strong>Although metformin is widely used for treatment of type 2 diabetes (T2D), its glucose-lowering mechanism remains unclear. Using the glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) antagonist exendin(9-39)NH2, we tested the hypothesis that postprandial GLP-1-mediated effects contribute to the glucose-lowering potential of metformin in T2D.</p><p><strong>Methods: </strong>In a randomized, placebo-controlled, double-blind, crossover study, 15 individuals with T2D (median HbA1c 50 mmol/mol [6.7%], body mass index 30.1 kg/m2, age 71 years) underwent, in randomized order, 14 days of metformin and placebo treatment, respectively. Each treatment period was preceded by 14 days without any glucose-lowering medicine and concluded by two 4 h mixed meal tests performed in randomized order and separated by >24 h with either continuous intravenous exendin(9-39)NH2 or saline infusion.</p><p><strong>Results: </strong>Compared to placebo, metformin treatment lowered fasting plasma glucose (mean of differences [MD] 1.4 mmol/L × min [95% CI 0.8-2.0]) as well as postprandial plasma glucose excursions during both saline infusion (MD 186 mmol/L × min [95% CI 64-307]) and exendin(9-39)NH2 infusion (MD 268 mmol/L × min [95% CI 108-427]). The metformin-induced improvement in postprandial glucose tolerance was unaffected by GLP-1R antagonization (MD 82 mmol/L × min [95% CI -6564-170]). Metformin treatment increased fasting plasma GLP-1 (MD 1.7 pmol/L × min [95% CI 0.39-2.9]) but did not affect postprandial GLP-1 responses (MD 820 pmol/L × min [95% CI -1750-111]).</p><p><strong>Conclusions: </strong>Using GLP-1R antagonization, we could not detect GLP-1-mediated postprandial glucose-lowering effect of metformin in individuals with T2D. We show that 2 weeks of metformin treatment increases fasting plasma GLP-1, which may contribute to metformin's beneficial effect on fasting plasma glucose in T2D. Trial registration: Clinicaltrials.gov NCT03246451.</p>","PeriodicalId":11884,"journal":{"name":"European Journal of Endocrinology","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141757852","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cécile Brachet, Alexander Laemmle, Martine Cools, Kay-Sara Sauter, Elfride De Baere, Arnaud Vanlander, Amit V Pandey, Therina du Toit, Clarissa D Voegel, Claudine Heinrichs, Hannah Verdin, Christa E Flück
Objective: Adrenal cortisol production occurs through a biosynthetic pathway which depend on NADH and NADPH for energy supply. The mitochondrial respiratory chain and the reactive oxygen species (ROS) detoxification system are therefore important for steroidogenesis. Mitochondrial dysfunction leading to oxidative stress has been implicated in the pathogenesis of several adrenal conditions. Nonetheless, only very few patients with variants in one gene of the ROS detoxification system, Thioredoxin Reductase 2 (TXNRD2), have been described with variable phenotypes.
Design: Clinical, genetic, structural, and functional characterization of a novel, biallelic TXNRD2 splice variant.
Methods: On human biomaterial, we performed whole exome sequencing to identify and RNA analysis to characterize the specific TXNRD2 splice variant. Amino acid conservation analysis and protein structure modeling were performed in silico. Using patient's fibroblast-derived human induced pluripotent stem cells, we generated adrenal-like cells (iALC) to study the impact of wild-type (WT) and mutant TXNRD2 on adrenal steroidogenesis and ROS production.
Results: The patient had a complex phenotype of primary adrenal insufficiency (PAI), combined with genital, ophthalmological, and neurological features. He carried a homozygous splice variant c.1348-1G > T in TXNRD2 which leads to a shorter protein lacking the C-terminus and thereby affecting homodimerization and flavin adenine dinucleotide binding. Patient-derived iALC showed a loss of cortisol production with overall diminished adrenal steroidogenesis, while ROS production was significantly increased.
Conclusion: Lack of TXNRD2 activity for mitochondrial ROS detoxification affects adrenal steroidogenesis and predominantly cortisol production.
{"title":"Insight into the role of TXNRD2 in steroidogenesis through a novel homozygous TXNRD2 splice variant.","authors":"Cécile Brachet, Alexander Laemmle, Martine Cools, Kay-Sara Sauter, Elfride De Baere, Arnaud Vanlander, Amit V Pandey, Therina du Toit, Clarissa D Voegel, Claudine Heinrichs, Hannah Verdin, Christa E Flück","doi":"10.1093/ejendo/lvae090","DOIUrl":"10.1093/ejendo/lvae090","url":null,"abstract":"<p><strong>Objective: </strong>Adrenal cortisol production occurs through a biosynthetic pathway which depend on NADH and NADPH for energy supply. The mitochondrial respiratory chain and the reactive oxygen species (ROS) detoxification system are therefore important for steroidogenesis. Mitochondrial dysfunction leading to oxidative stress has been implicated in the pathogenesis of several adrenal conditions. Nonetheless, only very few patients with variants in one gene of the ROS detoxification system, Thioredoxin Reductase 2 (TXNRD2), have been described with variable phenotypes.</p><p><strong>Design: </strong>Clinical, genetic, structural, and functional characterization of a novel, biallelic TXNRD2 splice variant.</p><p><strong>Methods: </strong>On human biomaterial, we performed whole exome sequencing to identify and RNA analysis to characterize the specific TXNRD2 splice variant. Amino acid conservation analysis and protein structure modeling were performed in silico. Using patient's fibroblast-derived human induced pluripotent stem cells, we generated adrenal-like cells (iALC) to study the impact of wild-type (WT) and mutant TXNRD2 on adrenal steroidogenesis and ROS production.</p><p><strong>Results: </strong>The patient had a complex phenotype of primary adrenal insufficiency (PAI), combined with genital, ophthalmological, and neurological features. He carried a homozygous splice variant c.1348-1G > T in TXNRD2 which leads to a shorter protein lacking the C-terminus and thereby affecting homodimerization and flavin adenine dinucleotide binding. Patient-derived iALC showed a loss of cortisol production with overall diminished adrenal steroidogenesis, while ROS production was significantly increased.</p><p><strong>Conclusion: </strong>Lack of TXNRD2 activity for mitochondrial ROS detoxification affects adrenal steroidogenesis and predominantly cortisol production.</p>","PeriodicalId":11884,"journal":{"name":"European Journal of Endocrinology","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141888838","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}