Matthias K Auer, Duygu Büyükerzurmulu, Christian Lottspeich, Martin Bidlingmaier, Eva Rieger, Hanna Nowotny, Lea Tschaidse, Richard J Auchus, Nicole Reisch
Background: Subfertility is prevalent in men with classic 21-hydroxylase deficiency (21OHD). We sought to characterize the long-term evolution of their gonadal function.
Methods: Retrospective longitudinal single-center study in 27 men (11 with testicular adrenal rest tissue (TART)); median observation period 12 years; testosterone (T), 11-oxygenated androgens, gonadotropins and inhibin B measurement at each timepoint.
Results: T concentrations were below the normal range (n.s.) in 43.2% (no TART) and 54.6% (TART) per patient. After accounting for BMI, sex hormone-binding globulin, and age, men with TART exhibited higher T (14.0 ± 0.80 nmol/l) than those without (11.9 ± 0.71 nmol/l). During the observation period, T levels rose in both groups but more in men with TART (from 10.1 ± 1.1 to 17.3 ± 1.9 nmol/l vs. 10.3 ± 1.0 to 12.8± 1.9 nmol/l); this was accompanied by rising luteinizing hormone and diminishing hydrocortisone equivalent dosages (TART: from 38.1± 3.2 to 35.1 ± 1.8 mg/d; vs. no TART: 28.8 ± 2.7 to 28.1 ± 1.6 mg/d) without correlation with any markers of adrenal androgen control. Inhibin B declined in men with large TART over time while TART status remained stable.
Conclusion: T levels below the normal range are frequent in men with 21OHD, regardless of TART, but change little over time. Besides adrenal androgen control gonadal axis suppression from supraphysiological glucocorticoid dosages needs to be considered. While our results do not endorse regular screening for alterations in TART status among adults, Sertoli cell function should be monitored in men with large TART.
{"title":"Prevalence of adrenal rest tumors and course of gonadal dysfunction in a clinical sample of men with congenital adrenal hyperplasia - a longitudinal analysis over 10 years.","authors":"Matthias K Auer, Duygu Büyükerzurmulu, Christian Lottspeich, Martin Bidlingmaier, Eva Rieger, Hanna Nowotny, Lea Tschaidse, Richard J Auchus, Nicole Reisch","doi":"10.1093/ejendo/lvae112","DOIUrl":"https://doi.org/10.1093/ejendo/lvae112","url":null,"abstract":"<p><strong>Background: </strong>Subfertility is prevalent in men with classic 21-hydroxylase deficiency (21OHD). We sought to characterize the long-term evolution of their gonadal function.</p><p><strong>Methods: </strong>Retrospective longitudinal single-center study in 27 men (11 with testicular adrenal rest tissue (TART)); median observation period 12 years; testosterone (T), 11-oxygenated androgens, gonadotropins and inhibin B measurement at each timepoint.</p><p><strong>Results: </strong>T concentrations were below the normal range (n.s.) in 43.2% (no TART) and 54.6% (TART) per patient. After accounting for BMI, sex hormone-binding globulin, and age, men with TART exhibited higher T (14.0 ± 0.80 nmol/l) than those without (11.9 ± 0.71 nmol/l). During the observation period, T levels rose in both groups but more in men with TART (from 10.1 ± 1.1 to 17.3 ± 1.9 nmol/l vs. 10.3 ± 1.0 to 12.8± 1.9 nmol/l); this was accompanied by rising luteinizing hormone and diminishing hydrocortisone equivalent dosages (TART: from 38.1± 3.2 to 35.1 ± 1.8 mg/d; vs. no TART: 28.8 ± 2.7 to 28.1 ± 1.6 mg/d) without correlation with any markers of adrenal androgen control. Inhibin B declined in men with large TART over time while TART status remained stable.</p><p><strong>Conclusion: </strong>T levels below the normal range are frequent in men with 21OHD, regardless of TART, but change little over time. Besides adrenal androgen control gonadal axis suppression from supraphysiological glucocorticoid dosages needs to be considered. While our results do not endorse regular screening for alterations in TART status among adults, Sertoli cell function should be monitored in men with large TART.</p>","PeriodicalId":11884,"journal":{"name":"European Journal of Endocrinology","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142282363","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}
Susan Richter, Karel Pacak, Henricus Kunst, Andrzej Januszewicz, Svenja Nölting, Hanna Remde, Mercedes Robledo, Graeme Eisenhofer, Henri J Timmers, Christina Pamporaki
Objective: Head-neck paragangliomas (HNPGLs) are rare tumors with approximately half arising due to germline pathogenic variants (PVs) in succinate dehydrogenase genes (SDHx). Patients with HNPGL have heterogenous propensity to recur and metastasize. Thus, we aim to assess prevalence and predictors of recurrent (RD) and/or metastatic disease in patients with and without SDHx-related HNPGLs.
Design and methods: This cross-sectional study used retrospective data of 214 patients enrolled in six referral centers. Data included sex, age, primary tumor treatment, location, and size, biochemical phenotype, germline PVs, presence of RD (locoregional or new tumor), and/or metastasis.
Results: Patients with and without SDHx-related HNPGLs showed 74% and 40% prevalence of RD, respectively. Patients without SDHx-related HNPGLs presented with recurrent tumors only in head-neck regions. The only independent predictor for RD in the entire cohort was presence of SDHx PVs. Metastatic prevalence reached 9-13%. For patients with SDHx-related HNPGLs, large tumor size (>2.3cm, OR:50.0, CI:2.6-977.6), young age at initial diagnosis (<42years, OR:27.3, CI:1.8-407.2), and presence of SDHB PV (OR:15.6; CI:1.5-164.8) were independent predictors of metastasis. For patients without SDHx-related HNPGLs, only carotid-body location was an independent predictor of metastasis (OR:18.9, CI:2.0-182.5).
Conclusions: Patients without SDHx-related HNPGLs require long-term follow-up due to high prevalence of RD with imaging largely restricted to head-neck regions. As carotid-body HNPGLs have the highest metastatic risk among sporadic tumors, radical treatment with frequent follow-up is suggested until population-based data are available. Importantly, patients with SDHx-related HNPGLs might benefit from early radical treatment when tumors are still small to reduce metastatic risk.
{"title":"Management and follow-up strategies for patients with head and neck paraganglioma.","authors":"Susan Richter, Karel Pacak, Henricus Kunst, Andrzej Januszewicz, Svenja Nölting, Hanna Remde, Mercedes Robledo, Graeme Eisenhofer, Henri J Timmers, Christina Pamporaki","doi":"10.1093/ejendo/lvae113","DOIUrl":"https://doi.org/10.1093/ejendo/lvae113","url":null,"abstract":"<p><strong>Objective: </strong>Head-neck paragangliomas (HNPGLs) are rare tumors with approximately half arising due to germline pathogenic variants (PVs) in succinate dehydrogenase genes (SDHx). Patients with HNPGL have heterogenous propensity to recur and metastasize. Thus, we aim to assess prevalence and predictors of recurrent (RD) and/or metastatic disease in patients with and without SDHx-related HNPGLs.</p><p><strong>Design and methods: </strong>This cross-sectional study used retrospective data of 214 patients enrolled in six referral centers. Data included sex, age, primary tumor treatment, location, and size, biochemical phenotype, germline PVs, presence of RD (locoregional or new tumor), and/or metastasis.</p><p><strong>Results: </strong>Patients with and without SDHx-related HNPGLs showed 74% and 40% prevalence of RD, respectively. Patients without SDHx-related HNPGLs presented with recurrent tumors only in head-neck regions. The only independent predictor for RD in the entire cohort was presence of SDHx PVs. Metastatic prevalence reached 9-13%. For patients with SDHx-related HNPGLs, large tumor size (>2.3cm, OR:50.0, CI:2.6-977.6), young age at initial diagnosis (<42years, OR:27.3, CI:1.8-407.2), and presence of SDHB PV (OR:15.6; CI:1.5-164.8) were independent predictors of metastasis. For patients without SDHx-related HNPGLs, only carotid-body location was an independent predictor of metastasis (OR:18.9, CI:2.0-182.5).</p><p><strong>Conclusions: </strong>Patients without SDHx-related HNPGLs require long-term follow-up due to high prevalence of RD with imaging largely restricted to head-neck regions. As carotid-body HNPGLs have the highest metastatic risk among sporadic tumors, radical treatment with frequent follow-up is suggested until population-based data are available. Importantly, patients with SDHx-related HNPGLs might benefit from early radical treatment when tumors are still small to reduce metastatic risk.</p>","PeriodicalId":11884,"journal":{"name":"European Journal of Endocrinology","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142282362","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}
OBJECTIVEAge at pubertal onset has decreased over the recent decades. Early maturing girls have longer puberty duration, and higher peak height velocity (PHV) than late maturing girls. To what extent this is generated by increased insulin-like growth factor-I (IGF-I), fat mass or fasting insulin levels is currently unknown.DESIGN, SETTING, PARTICIPANTSA population-based study - part of the COPENHAGEN puberty study - longitudinal part. Eighty-one girls evaluated biannually for a median of 10 (2-15) visits for a total of 815 evaluations.METHODSPubertal staging, anthropometric measures, PHV, skin fold thickness (SFT) and IGF-I and fasting Insulin levels were measured.RESULTSEarly maturing girls achieved similar final height compared to late maturing girls (166.1 vs 167.1 cm, p = 0.36). Early pubertal onset was associated with significantly greater PHV (8.7 vs. 7.4 cm/year, p < 0.001) and a longer puberty duration (age at onset of breast development to age at PHV [1.8 vs. 1.1 years, p < 0.001]) compared with late maturation. After correcting for age at pubertal onset, neither BMI, SFT nor IGF-I levels differed between early versus late maturing girls. By contrast, fasting insulin levels were significantly higher in early compared with late maturing girls 1.5, 2.0 and 3.0 years after pubertal onset (all p = 0.039).CONCLUSIONGrowth velocity was higher and more prolonged in early compared with late maturing girls and associated with higher insulin levels. Thus, the higher insulin levels may compensate for the shorter total growth period by intensifying the pubertal growth period.
目的 近几十年来,青春期开始的年龄有所下降。与晚熟女孩相比,早熟女孩的青春期持续时间更长,身高峰值速度(PHV)更高。目前尚不清楚胰岛素样生长因子-I(IGF-I)、脂肪量或空腹胰岛素水平的增加在多大程度上导致了这种情况。结果早熟女孩的最终身高与晚熟女孩相似(166.1 vs 167.1 厘米,P = 0.36)。与晚熟女孩相比,早熟女孩的 PHV 明显更高(8.7 厘米/年 vs. 7.4 厘米/年,p < 0.001),青春期持续时间更长(乳房开始发育年龄与 PHV 年龄之比 [1.8 年 vs. 1.1 年,p < 0.001])。在对青春期开始年龄进行校正后,早熟和晚熟女孩的体重指数、SFT 和 IGF-I 水平均无差异。相比之下,在青春期开始后 1.5 年、2.0 年和 3.0 年,早熟女孩的空腹胰岛素水平明显高于晚熟女孩(所有 p = 0.039)。因此,较高的胰岛素水平可能会通过强化青春发育期来补偿较短的总生长期。
{"title":"Higher Peak Height Velocity in Early Maturing Girls Depends on Insulin rather than Fat Mass or IGF-I.","authors":"Kaspar Sørensen,Casper P Hagen,Anders Juul","doi":"10.1093/ejendo/lvae115","DOIUrl":"https://doi.org/10.1093/ejendo/lvae115","url":null,"abstract":"OBJECTIVEAge at pubertal onset has decreased over the recent decades. Early maturing girls have longer puberty duration, and higher peak height velocity (PHV) than late maturing girls. To what extent this is generated by increased insulin-like growth factor-I (IGF-I), fat mass or fasting insulin levels is currently unknown.DESIGN, SETTING, PARTICIPANTSA population-based study - part of the COPENHAGEN puberty study - longitudinal part. Eighty-one girls evaluated biannually for a median of 10 (2-15) visits for a total of 815 evaluations.METHODSPubertal staging, anthropometric measures, PHV, skin fold thickness (SFT) and IGF-I and fasting Insulin levels were measured.RESULTSEarly maturing girls achieved similar final height compared to late maturing girls (166.1 vs 167.1 cm, p = 0.36). Early pubertal onset was associated with significantly greater PHV (8.7 vs. 7.4 cm/year, p < 0.001) and a longer puberty duration (age at onset of breast development to age at PHV [1.8 vs. 1.1 years, p < 0.001]) compared with late maturation. After correcting for age at pubertal onset, neither BMI, SFT nor IGF-I levels differed between early versus late maturing girls. By contrast, fasting insulin levels were significantly higher in early compared with late maturing girls 1.5, 2.0 and 3.0 years after pubertal onset (all p = 0.039).CONCLUSIONGrowth velocity was higher and more prolonged in early compared with late maturing girls and associated with higher insulin levels. Thus, the higher insulin levels may compensate for the shorter total growth period by intensifying the pubertal growth period.","PeriodicalId":11884,"journal":{"name":"European Journal of Endocrinology","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142255206","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}
Cameron Padilla,Constantine A Stratakis,Christina Tatsi
OBJECTIVECushing syndrome (CS) often presents with obesity that is not as severe in children as it is in adults. The role of obesity in the severity of metabolic syndrome in children with CS has not been studied. This study evaluates whether pediatric patients with CS have obesity-specific differences in their demographic, biochemical and presenting findings.DESIGNCohort study.METHODSWe analyzed 273 patients with young onset of CS at ≤ 18 years old and classified as patients with or without obesity based on their BMI z-scores.RESULTSPatients without obesity (n=84, 31%) were more frequently females with an older age of onset compared to patients with obesity (n=189, 69%). Consistent with their older age, patients without obesity were also more likely to have advanced Tanner stages. Patients with and without obesity had similar duration of disease, but patients with obesity showed higher markers of hypercortisolemia (urinary free cortisol). A higher prevalence of hypertension and insulin resistance was seen in patients with obesity than those without obesity, adjusting for urinary free cortisol (UFC) (p < .05 for all comparisons). While fatty liver disease was not statistically different among the entire cohort, elevated alanine transaminase (ALT) and metabolic dysfunction-associated steatotic liver disease (MASLD) scores were more common in ACTH-dependent CS patients with obesity (p < .05).CONCLUSIONSWeight gain appears to mediate some but not all the cortisol-associated complications in pediatric CS. Therefore, obesity may be a modifiable risk factor among these patients.
{"title":"The phenotype of the pediatric patient with Cushing syndrome but without obesity.","authors":"Cameron Padilla,Constantine A Stratakis,Christina Tatsi","doi":"10.1093/ejendo/lvae114","DOIUrl":"https://doi.org/10.1093/ejendo/lvae114","url":null,"abstract":"OBJECTIVECushing syndrome (CS) often presents with obesity that is not as severe in children as it is in adults. The role of obesity in the severity of metabolic syndrome in children with CS has not been studied. This study evaluates whether pediatric patients with CS have obesity-specific differences in their demographic, biochemical and presenting findings.DESIGNCohort study.METHODSWe analyzed 273 patients with young onset of CS at ≤ 18 years old and classified as patients with or without obesity based on their BMI z-scores.RESULTSPatients without obesity (n=84, 31%) were more frequently females with an older age of onset compared to patients with obesity (n=189, 69%). Consistent with their older age, patients without obesity were also more likely to have advanced Tanner stages. Patients with and without obesity had similar duration of disease, but patients with obesity showed higher markers of hypercortisolemia (urinary free cortisol). A higher prevalence of hypertension and insulin resistance was seen in patients with obesity than those without obesity, adjusting for urinary free cortisol (UFC) (p < .05 for all comparisons). While fatty liver disease was not statistically different among the entire cohort, elevated alanine transaminase (ALT) and metabolic dysfunction-associated steatotic liver disease (MASLD) scores were more common in ACTH-dependent CS patients with obesity (p < .05).CONCLUSIONSWeight gain appears to mediate some but not all the cortisol-associated complications in pediatric CS. Therefore, obesity may be a modifiable risk factor among these patients.","PeriodicalId":11884,"journal":{"name":"European Journal of Endocrinology","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142269092","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: Renal function and the skeleton are classic target organs in primary hyperparathyroidism (PHPT), affected by the chronic course of the disease. Most patients diagnosed today exhibit mild PHPT, characterized by slight hypercalcemia and no or unspecific symptoms. Concerns have been raised that PHPT could promote deteriorating kidney function and increase cardiovascular risk directly. To examine the effect of parathyroidectomy (PTX) on mild PHPT on renal function and markers for bone turnover, cardiovascular disease (CVD), and vascular inflammation.
Participants: From 1998 to 2005, 191 patients with mild PHPT were included in Sweden, Norway, and Denmark. Of these 150 were included in the present analyses.
Intervention: Seventy patients were randomized to PTX and 80 to observation without intervention (OBS).
Measures: e-GFR was calculated based on creatinine and cystatin C. Markers of CVD and systemic inflammation: osteoprotegerin, vascular cell adhesion molecule 1, soluble CD40 ligand, interleukin-1 receptor antagonist, von Willebrand factor. Bone turnover markers: C-terminal telopeptide of type 1 collagen (CTX-1) and serum Procollagen type 1 N-terminal propeptide.
Results: No differences in the development of renal function or vascular and systemic inflammation were detected. CTX-1 was lower in PTX after 10 years.
Limitations: Secondary analyses of a randomized controlled trial.
Conclusion: PTX does not appear to affect renal function or markers of CVD and vascular inflammation in mild PHPT in a ten-year perspective.
{"title":"No effect of surgery on kidney and cardiovascular risk factors in mild primary hyperparathyroidism: secondary analyses from a 10-year randomized controlled trial.","authors":"Ansgar Heck, Mikkel Pretorius, Karolina Lundstam, Kristin Godang, Mikael Hellström, Thor Ueland, Jens Bollerslev","doi":"10.1093/ejendo/lvae109","DOIUrl":"10.1093/ejendo/lvae109","url":null,"abstract":"<p><strong>Objective: </strong>Renal function and the skeleton are classic target organs in primary hyperparathyroidism (PHPT), affected by the chronic course of the disease. Most patients diagnosed today exhibit mild PHPT, characterized by slight hypercalcemia and no or unspecific symptoms. Concerns have been raised that PHPT could promote deteriorating kidney function and increase cardiovascular risk directly. To examine the effect of parathyroidectomy (PTX) on mild PHPT on renal function and markers for bone turnover, cardiovascular disease (CVD), and vascular inflammation.</p><p><strong>Design: </strong>Prospective randomized controlled trial. ClinicalTrials.gov: NCT00522028.</p><p><strong>Setting: </strong>Eight Scandinavian referral centers.</p><p><strong>Participants: </strong>From 1998 to 2005, 191 patients with mild PHPT were included in Sweden, Norway, and Denmark. Of these 150 were included in the present analyses.</p><p><strong>Intervention: </strong>Seventy patients were randomized to PTX and 80 to observation without intervention (OBS).</p><p><strong>Measures: </strong>e-GFR was calculated based on creatinine and cystatin C. Markers of CVD and systemic inflammation: osteoprotegerin, vascular cell adhesion molecule 1, soluble CD40 ligand, interleukin-1 receptor antagonist, von Willebrand factor. Bone turnover markers: C-terminal telopeptide of type 1 collagen (CTX-1) and serum Procollagen type 1 N-terminal propeptide.</p><p><strong>Results: </strong>No differences in the development of renal function or vascular and systemic inflammation were detected. CTX-1 was lower in PTX after 10 years.</p><p><strong>Limitations: </strong>Secondary analyses of a randomized controlled trial.</p><p><strong>Conclusion: </strong>PTX does not appear to affect renal function or markers of CVD and vascular inflammation in mild PHPT in a ten-year perspective.</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":"142072369","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}
Jie Zheng, Yifu Wang, Jinghang Jiang, Tingwei Jin, Yixuan Liu, Yi Guo, Zhongyuan Chen, Cheng Su, Honghong Wang, Juanjuan Xie, Bingqian Guo, Yufang Lv, Yajie Guo, Yuanliang Xie, Mingli Li, Shengzhu Huang, Jingling Liao, Yu Ye, Linjian Mo, Zhenyuan Yu, Lin Huang, Yonghua Jiang, Zengnan Mo
Background: Adrenal-origin and peripheral tissue-transformed 11-oxygenated androgens are recognized as significant androgens. However, our current understanding of the synthesis of 11-oxygenated androgens, including the organs and cell types involved, remains limited.
Methods: We performed comprehensive analyses on an extensive dataset of normal human tissues, which included bulk RNA data from 30 tissues, single-cell RNA sequencing (scRNA) data from 16 tissues and proteomics data from 29 tissues, to characterize the expression profiles of enzyme-encoding genes. To validate the findings, immunohistochemical and liquid chromatography-tandem mass spectrometry (LC-MS/MS) techniques were employed.
Results: Our investigation revealed that the gene expression levels of the enzymes HSD11B2 and AKR1C3 were notably elevated in the kidney and intestines. Intriguingly, within these organs, we observed an increasing trend in enzyme expression with age in women, while a decreasing trend was apparent in men. scRNA analysis revealed that HSD11B2 was predominantly expressed in collecting duct principal cells in the kidney, while AKR1C3 was primarily expressed in the proximal tubules. Intriguingly, nearly all epithelial cells in the intestine expressed these key enzymes. Further analysis using LC-MS/MS revealed that the kidney exhibited the highest levels of 11-ketoandrostenedione (11KA4) and 11-ketotestosterone (11KT) among the seven tissues examined, and substantial synthesis of 11KA4 and 11KT was also observed in the intestine. Finally, we developed the TransMap website (http://gxmujyzmolab.cn:16245/TransMap/) to provide comprehensive visualization of all currently available transcriptome data.
Conclusion: This study offers an overarching perspective on tracing the synthesis of 11-oxygenated androgens in peripheral tissues, thereby providing valuable insights into the potential role of these androgens in humans.
{"title":"Decoding 11-oxygenated androgen synthesis: insights from enzyme gene expression and LC-MS/MS quantification.","authors":"Jie Zheng, Yifu Wang, Jinghang Jiang, Tingwei Jin, Yixuan Liu, Yi Guo, Zhongyuan Chen, Cheng Su, Honghong Wang, Juanjuan Xie, Bingqian Guo, Yufang Lv, Yajie Guo, Yuanliang Xie, Mingli Li, Shengzhu Huang, Jingling Liao, Yu Ye, Linjian Mo, Zhenyuan Yu, Lin Huang, Yonghua Jiang, Zengnan Mo","doi":"10.1093/ejendo/lvae104","DOIUrl":"10.1093/ejendo/lvae104","url":null,"abstract":"<p><strong>Background: </strong>Adrenal-origin and peripheral tissue-transformed 11-oxygenated androgens are recognized as significant androgens. However, our current understanding of the synthesis of 11-oxygenated androgens, including the organs and cell types involved, remains limited.</p><p><strong>Methods: </strong>We performed comprehensive analyses on an extensive dataset of normal human tissues, which included bulk RNA data from 30 tissues, single-cell RNA sequencing (scRNA) data from 16 tissues and proteomics data from 29 tissues, to characterize the expression profiles of enzyme-encoding genes. To validate the findings, immunohistochemical and liquid chromatography-tandem mass spectrometry (LC-MS/MS) techniques were employed.</p><p><strong>Results: </strong>Our investigation revealed that the gene expression levels of the enzymes HSD11B2 and AKR1C3 were notably elevated in the kidney and intestines. Intriguingly, within these organs, we observed an increasing trend in enzyme expression with age in women, while a decreasing trend was apparent in men. scRNA analysis revealed that HSD11B2 was predominantly expressed in collecting duct principal cells in the kidney, while AKR1C3 was primarily expressed in the proximal tubules. Intriguingly, nearly all epithelial cells in the intestine expressed these key enzymes. Further analysis using LC-MS/MS revealed that the kidney exhibited the highest levels of 11-ketoandrostenedione (11KA4) and 11-ketotestosterone (11KT) among the seven tissues examined, and substantial synthesis of 11KA4 and 11KT was also observed in the intestine. Finally, we developed the TransMap website (http://gxmujyzmolab.cn:16245/TransMap/) to provide comprehensive visualization of all currently available transcriptome data.</p><p><strong>Conclusion: </strong>This study offers an overarching perspective on tracing the synthesis of 11-oxygenated androgens in peripheral tissues, thereby providing valuable insights into the potential role of these androgens in humans.</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":"142105630","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}
Valentina Guarnotta, Claudia Di Stefano, Laura Tomasello, Laura Maniscalco, Giuseppe Pizzolanti, Giorgio Arnaldi, Carla Giordano
Objective: Adrenal insufficiency (AI) is characterized by increased mortality compared to general population, mainly due to cardiovascular disease. Conventional glucocorticoid (GC) replacement therapy has a role in determining the increased mortality risk. Primary outcome of the current study was to evaluate the impact of 10 years of conventional GCs and DR-HC on body weight changes in treatment-naive patients with AI. Secondary outcomes were changes from baseline to 5 and 10 years in anthropometric and metabolic profile, insulin sensitivity, cardiovascular, and bone parameters.
Design and methods: We prospectively randomized 42 patients to conventional GCs (cortisone acetate or hydrocortisone) and 44 to DR-HC (1:1). Anthropometric, metabolic, cardiovascular, and bone parameters were evaluated at baseline and after 5 and 10 years of follow-up. This trial is registered at ClinicalTrials.gov NCT06260462.
Results: At 10 years of follow-up, patients with conventional GCs had significantly higher values of BMI (P = .031), waist circumference (P = .047), systolic blood pressure (P = .039), total and LDL cholesterol (P = .041 and P = .042), HbA1c (P = .040), HOMA-IR (P = .006), AUC2h of glucose (P < .001), thickness of the interventricular septum in diastole and of the posterior wall (both P < .001) and significantly lower values of oral disposition index (P = .001) and ISI-Matsuda (P < .001), lumbar spine T score (P = .036), and femoral neck Z score (P = .026), compared to patients treated with DR-HC.
Conclusions: In patients with treatment-naive AI, 10 years of conventional GC treatment is associated with a worsening of metabolic, insulin-sensitivity, cardiac, and bone outcomes, while DR-HC had no impact on them achieving a lower risk of developing comorbidities.
{"title":"Conventional steroids vs. dual-release hydrocortisone on metabolic, cardiovascular, and bone outcomes in adrenal insufficiency: a 10-year study.","authors":"Valentina Guarnotta, Claudia Di Stefano, Laura Tomasello, Laura Maniscalco, Giuseppe Pizzolanti, Giorgio Arnaldi, Carla Giordano","doi":"10.1093/ejendo/lvae107","DOIUrl":"10.1093/ejendo/lvae107","url":null,"abstract":"<p><strong>Objective: </strong>Adrenal insufficiency (AI) is characterized by increased mortality compared to general population, mainly due to cardiovascular disease. Conventional glucocorticoid (GC) replacement therapy has a role in determining the increased mortality risk. Primary outcome of the current study was to evaluate the impact of 10 years of conventional GCs and DR-HC on body weight changes in treatment-naive patients with AI. Secondary outcomes were changes from baseline to 5 and 10 years in anthropometric and metabolic profile, insulin sensitivity, cardiovascular, and bone parameters.</p><p><strong>Design and methods: </strong>We prospectively randomized 42 patients to conventional GCs (cortisone acetate or hydrocortisone) and 44 to DR-HC (1:1). Anthropometric, metabolic, cardiovascular, and bone parameters were evaluated at baseline and after 5 and 10 years of follow-up. This trial is registered at ClinicalTrials.gov NCT06260462.</p><p><strong>Results: </strong>At 10 years of follow-up, patients with conventional GCs had significantly higher values of BMI (P = .031), waist circumference (P = .047), systolic blood pressure (P = .039), total and LDL cholesterol (P = .041 and P = .042), HbA1c (P = .040), HOMA-IR (P = .006), AUC2h of glucose (P < .001), thickness of the interventricular septum in diastole and of the posterior wall (both P < .001) and significantly lower values of oral disposition index (P = .001) and ISI-Matsuda (P < .001), lumbar spine T score (P = .036), and femoral neck Z score (P = .026), compared to patients treated with DR-HC.</p><p><strong>Conclusions: </strong>In patients with treatment-naive AI, 10 years of conventional GC treatment is associated with a worsening of metabolic, insulin-sensitivity, cardiac, and bone outcomes, while DR-HC had no impact on them achieving a lower risk of developing comorbidities.</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":"142016801","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}
Kyoung Jin Kim,Seong Hee Ahn,So Young Park,Jimi Choi,Gi Hwan Bae,Ha-Young Kim,Kyoung Min Kim,
IMPORTANCEOsteoporosis-related fractures are associated with increased mortality risk among postmenopausal women, yet the impact of antiosteoporotic medications on mortality is not fully understood.OBJECTIVEThis study evaluates the effect of antiresorptive agents (ARs) on mortality risk in postmenopausal women with osteoporosis.DESIGNThis is a nationwide cohort study using data from the National Screening Program for Transitional Ages (2008-2017).SETTINGData were derived from a national cohort of postmenopausal women in South Korea.PARTICIPANTSThis study included 117 871 postmenopausal women diagnosed with osteoporosis. Of them, 15 895 patients who used ARs, such as bisphosphonates or selective estrogen receptor modulators, for at least 1 year were matched 1:1 with nonusers using propensity scores.EXPOSURESExposure to ARs for at least 1 year was compared with no AR use.MAIN OUTCOMES AND MEASUREMortality outcomes were assessed using multivariable Cox proportional hazard regression models, focusing on all-cause mortality and cause-specific mortality, particularly cardiovascular disease (CVD) and injury-/fracture-related deaths.RESULTSIn AR users, there were 102 deaths (mortality rate 1.41 per 1000 person-years), compared with 221 deaths in non-users (mortality rate 3.14 per 1000 person-years), yielding a hazard ratio (HR) of 0.43 (95% CI, 0.34-0.54). Antiresorptive agent users showed a 52% reduction in CVD mortality risk (HR, 0.48; 95% CI, 0.34-0.69) and a 54% reduction in injury-/fracture-related mortality risk (HR, 0.46; 95% CI, 0.27-0.76). The analysis indicated a consistent decrease in all-cause and CVD mortality risks with longer durations of AR use.CONCLUSIONS AND RELEVANCEThe use of ARs in postmenopausal women with osteoporosis is associated with significantly lower risks of all-cause mortality, especially from cardiovascular events and fractures. The mortality reduction benefits appear to be enhanced with prolonged AR therapy, highlighting the potential importance of sustained treatment in this population.
{"title":"Impact of antiresorptive agents on mortality risk in postmenopausal women with osteoporosis: insights from a nationwide cohort study.","authors":"Kyoung Jin Kim,Seong Hee Ahn,So Young Park,Jimi Choi,Gi Hwan Bae,Ha-Young Kim,Kyoung Min Kim,","doi":"10.1093/ejendo/lvae111","DOIUrl":"https://doi.org/10.1093/ejendo/lvae111","url":null,"abstract":"IMPORTANCEOsteoporosis-related fractures are associated with increased mortality risk among postmenopausal women, yet the impact of antiosteoporotic medications on mortality is not fully understood.OBJECTIVEThis study evaluates the effect of antiresorptive agents (ARs) on mortality risk in postmenopausal women with osteoporosis.DESIGNThis is a nationwide cohort study using data from the National Screening Program for Transitional Ages (2008-2017).SETTINGData were derived from a national cohort of postmenopausal women in South Korea.PARTICIPANTSThis study included 117 871 postmenopausal women diagnosed with osteoporosis. Of them, 15 895 patients who used ARs, such as bisphosphonates or selective estrogen receptor modulators, for at least 1 year were matched 1:1 with nonusers using propensity scores.EXPOSURESExposure to ARs for at least 1 year was compared with no AR use.MAIN OUTCOMES AND MEASUREMortality outcomes were assessed using multivariable Cox proportional hazard regression models, focusing on all-cause mortality and cause-specific mortality, particularly cardiovascular disease (CVD) and injury-/fracture-related deaths.RESULTSIn AR users, there were 102 deaths (mortality rate 1.41 per 1000 person-years), compared with 221 deaths in non-users (mortality rate 3.14 per 1000 person-years), yielding a hazard ratio (HR) of 0.43 (95% CI, 0.34-0.54). Antiresorptive agent users showed a 52% reduction in CVD mortality risk (HR, 0.48; 95% CI, 0.34-0.69) and a 54% reduction in injury-/fracture-related mortality risk (HR, 0.46; 95% CI, 0.27-0.76). The analysis indicated a consistent decrease in all-cause and CVD mortality risks with longer durations of AR use.CONCLUSIONS AND RELEVANCEThe use of ARs in postmenopausal women with osteoporosis is associated with significantly lower risks of all-cause mortality, especially from cardiovascular events and fractures. The mortality reduction benefits appear to be enhanced with prolonged AR therapy, highlighting the potential importance of sustained treatment in this population.","PeriodicalId":11884,"journal":{"name":"European Journal of Endocrinology","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142255231","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}
Nidhi Agrawal,Sandrine A Urwyler,Sonal Mehta,Niki Karavitaki,Richard A Feelders
The first-line treatment for Cushing's disease is transsphenoidal adenomectomy, which can be curative in a significant number of patients. The second-line options in cases of failed primary pituitary surgery include repeat surgery, medical therapy, and radiation. The role for medical therapy has expanded in the last decade, and options include pituitary-targeting drugs, steroid synthesis inhibitors, and glucocorticoid receptor antagonists. Bilateral adrenalectomy is a more aggressive approach, which may be necessary in cases of persistent hypercortisolism despite surgery, medical treatment, or radiation or when rapid normalization of cortisol is needed. We review the available treatment options for Cushing's disease, focusing on the second-line treatment options to consider after failed primary pituitary surgery.
{"title":"How to manage Cushing's disease after failed primary pituitary surgery.","authors":"Nidhi Agrawal,Sandrine A Urwyler,Sonal Mehta,Niki Karavitaki,Richard A Feelders","doi":"10.1093/ejendo/lvae110","DOIUrl":"https://doi.org/10.1093/ejendo/lvae110","url":null,"abstract":"The first-line treatment for Cushing's disease is transsphenoidal adenomectomy, which can be curative in a significant number of patients. The second-line options in cases of failed primary pituitary surgery include repeat surgery, medical therapy, and radiation. The role for medical therapy has expanded in the last decade, and options include pituitary-targeting drugs, steroid synthesis inhibitors, and glucocorticoid receptor antagonists. Bilateral adrenalectomy is a more aggressive approach, which may be necessary in cases of persistent hypercortisolism despite surgery, medical treatment, or radiation or when rapid normalization of cortisol is needed. We review the available treatment options for Cushing's disease, focusing on the second-line treatment options to consider after failed primary pituitary surgery.","PeriodicalId":11884,"journal":{"name":"European Journal of Endocrinology","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142255232","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}
Kai Xu, Johan F Langenhuijsen, Charlotte L Viëtor, Richard A Feelders, Tessa M van Ginhoven, Yasir S Elhassan, Fabio Bioletto, Mirko Parasiliti-Caprino, Wouter T Zandee, Schelto Kruijff, Samuel Backman, Tobias Åkerström, Christina Pamporaki, Nicole Bechmann, Charlotte Lussey-Lepoutre, Letizia Canu, Rebecca V Steenaard, Natacha Driessens, Marieke Velema, Koen M A Dreijerink, Anton F Engelsman, Henri J L M Timmers, Joanne M de Laat
Objective: Hereditary pheochromocytoma (hPCC) commonly develops bilaterally, causing adrenal insufficiency when standard treatment, radical adrenalectomy (RA), is performed. Partial adrenalectomy (PA) aims to preserve adrenal function, but with higher recurrence rates. This study compares outcomes of PA versus RA in hPCC.
Methods: Patients with hPCC due to pathogenic variants in RET, VHL, NF1, MAX, and TMEM127 from 12 European centers (1974-2023) were studied retrospectively. Stratified analysis based on surgery type and initial presentation was conducted. The main outcomes included recurrence, adrenal insufficiency, metastasis, and mortality.
Results: The study included 256 patients (223 RA, 33 PA). Ipsilateral recurrence rates were 9/223 (4%) after RA versus 5/33 (15%) after PA (P = 0.02). Metastasis and mortality did not differ between groups. Overall, 103 patients (40%) underwent bilateral adrenalectomy either synchronously or metachronously (75 RA, 28 PA). Of these, 46% developed adrenal insufficiency after PA.In total, 191 patients presented with initial unilateral disease, of whom 50 (26%) developed metachronous contralateral disease, most commonly in RET, VHL, and MAX. In patients with metachronous bilateral disease, adrenal insufficiency developed in 3/4 (75%) when PA was performed as the first operation followed by RA, compared to 1/7 (14%) when PA was performed as the second operation after prior RA (P = 0.09).
Conclusion: In patients with hPCC undergoing PA, local recurrence rates are higher than after RA, but metastasis and disease-specific mortality are similar. Therefore, PA seems a safe method to preserve adrenal function in patients with hPCC, in cases of both synchronous and metachronous bilateral disease, when performed as a second operation.
目的:遗传性嗜铬细胞瘤(hPCC)通常为双侧发病,在进行标准治疗,即根治性肾上腺切除术(RA)时,会导致肾上腺功能不全。肾上腺部分切除术(PA)旨在保留肾上腺功能,但复发率较高。本研究比较了 PA 与 RA 对 hPCC 的治疗效果:回顾性研究了来自 12 个欧洲中心(1974-2023 年)的因 RET、VHL、NF1、MAX 和 TMEM127 的致病变异而导致的 hPCC 患者。根据手术类型和初始表现进行了分层分析。主要结果包括复发、肾上腺功能不全、转移和死亡率:研究共纳入 256 例患者(223 例 RA,33 例 PA)。RA术后同侧复发率为9/223(4%),PA术后同侧复发率为5/33(15%)(P=0.02)。两组的转移率和死亡率没有差异。总体而言,103 名患者(40%)同步或同步接受了双侧肾上腺切除术(75 例 RA,28 例 PA)。其中,46%的患者在PA术后发展为肾上腺功能不全。总共有191名患者最初为单侧疾病,其中50人(26%)发展为并发对侧疾病,最常见的是RET、VHL和MAX。在患有双侧并发症的患者中,3/4(75%)的患者在首次进行PA手术后又进行了RA手术,而1/7(14%)的患者在首次进行PA手术后又进行了RA手术(P=0.09):结论:在接受 PA 的 hPCC 患者中,局部复发率高于 RA 后,但转移率和疾病特异性死亡率相似。因此,无论是同步还是近同步双侧疾病,PA似乎都是保留hPCC患者肾上腺功能的一种安全方法。
{"title":"PRAP study-partial versus radical adrenalectomy in hereditary pheochromocytomas.","authors":"Kai Xu, Johan F Langenhuijsen, Charlotte L Viëtor, Richard A Feelders, Tessa M van Ginhoven, Yasir S Elhassan, Fabio Bioletto, Mirko Parasiliti-Caprino, Wouter T Zandee, Schelto Kruijff, Samuel Backman, Tobias Åkerström, Christina Pamporaki, Nicole Bechmann, Charlotte Lussey-Lepoutre, Letizia Canu, Rebecca V Steenaard, Natacha Driessens, Marieke Velema, Koen M A Dreijerink, Anton F Engelsman, Henri J L M Timmers, Joanne M de Laat","doi":"10.1093/ejendo/lvae108","DOIUrl":"10.1093/ejendo/lvae108","url":null,"abstract":"<p><strong>Objective: </strong>Hereditary pheochromocytoma (hPCC) commonly develops bilaterally, causing adrenal insufficiency when standard treatment, radical adrenalectomy (RA), is performed. Partial adrenalectomy (PA) aims to preserve adrenal function, but with higher recurrence rates. This study compares outcomes of PA versus RA in hPCC.</p><p><strong>Methods: </strong>Patients with hPCC due to pathogenic variants in RET, VHL, NF1, MAX, and TMEM127 from 12 European centers (1974-2023) were studied retrospectively. Stratified analysis based on surgery type and initial presentation was conducted. The main outcomes included recurrence, adrenal insufficiency, metastasis, and mortality.</p><p><strong>Results: </strong>The study included 256 patients (223 RA, 33 PA). Ipsilateral recurrence rates were 9/223 (4%) after RA versus 5/33 (15%) after PA (P = 0.02). Metastasis and mortality did not differ between groups. Overall, 103 patients (40%) underwent bilateral adrenalectomy either synchronously or metachronously (75 RA, 28 PA). Of these, 46% developed adrenal insufficiency after PA.In total, 191 patients presented with initial unilateral disease, of whom 50 (26%) developed metachronous contralateral disease, most commonly in RET, VHL, and MAX. In patients with metachronous bilateral disease, adrenal insufficiency developed in 3/4 (75%) when PA was performed as the first operation followed by RA, compared to 1/7 (14%) when PA was performed as the second operation after prior RA (P = 0.09).</p><p><strong>Conclusion: </strong>In patients with hPCC undergoing PA, local recurrence rates are higher than after RA, but metastasis and disease-specific mortality are similar. Therefore, PA seems a safe method to preserve adrenal function in patients with hPCC, in cases of both synchronous and metachronous bilateral disease, when performed as a second operation.</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":"142016803","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}