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Maelle Le Bras, Hélène Leclerc, Olivia Rousseau, Pierre Goudet, Thomas Cuny, Frederic Castinetti, Catherine Bauters, Philippe Chanson, Antoine Tabarin, Sebastien Gaujoux, Sophie Christin-Maitre, Philippe Ruszniewski, Francoise Borson-Chazot, Isabelle Guilhem, Philippe Caron, Bernard Goichot, Albert Beckers, Brigitte Delemer, Isabelle Raingeard, Bruno Vergès, Sarra Smati, Matthieu Wargny, Bertrand Cariou, and Samy Hadjadj

Objective

Pituitary adenoma (PA) is one of the three major components of multiple endocrine neoplasia type 1 (MEN1). Recent studies have suggested that MEN1-associated PAs are less aggressive than initially estimated. We propose an analysis of the outcome of PAs with a standard of care treatment in a nationwide cohort of MEN1 patients.

Design

Retrospective observational nationwide cohort study using the MEN1 patient registry from the French Group of Endocrine Tumours (GTE).

Methods

The GTE database population consists of 1435 patients with MEN1. This analysis focused on 551 patients recruited after 2000 with at least 3 years of follow-up. The study outcome was tumour progression of PA defined by an increase in Hardy classification (HC) during follow-up according to referring physician regular reports.

Results

Among 551 MEN1 patients (index and related), 202 (36.7%) had PA, with 114 (56.4%) diagnosed by MEN1-related screening. PAs were defined according to HC as microadenoma (grade I) in 117 cases (57.9%), macroadenoma in 59 (29.2%) with 20 HC grade II and 39 HC grades III–IV and unspecified in 26 (12.8%). They were prolactinomas in 92 cases (45.5%) and non-secreting in 73 (36.1%). After a median follow-up of 3 years among the 137 patients with HC grades I–II, 4 patients (2.9%) presented tumour progression.

Conclusion

PAs in patients with MEN1 are less aggressive than previously thought. Tumour progression is rare with a standard of care monitoring and treatment, especially in related patients who mostly present non-secreting microadenoma. MRI monitoring for asymptomatic MEN1 patients should be reduced accordingly.

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Bertrand Baussart, Chiara Villa, Anne Jouinot, Marie-Laure Raffin-Sanson, Luc Foubert, Laure Cazabat, Michèle Bernier, Fideline Bonnet, Anthony Dohan, Jerome Bertherat, Guillaume Assié, and Stephan Gaillard

Objective

Microprolactinomas are currently treated with dopamine agonists. Outcome information on microprolactinoma patients treated by surgery is limited. This study reports the first large series of consecutive non-invasive microprolactinoma patients treated by pituitary surgery and evaluates the efficiency and safety of this treatment.

Design

Follow-up of a cohort of consecutive patients treated by surgery.

Methods

Between January 2008 and October 2020, 114 adult patients with pure microprolactinomas were operated on in a single tertiary expert neurosurgical department, using an endoscopic endonasal transsphenoidal approach. Eligible patients presented with a microprolactinoma with no obvious cavernous invasion on MRI. Prolactin was assayed before and after surgery. Disease-free survival was modeled using Kaplan–Meier representation. A cox regression model was used to predict remission.

Results

Median follow-up was 18.2 months (range: 2.8–155). In this cohort, 14/114 (12%) patients were not cured by surgery, including ten early surgical failures and four late relapses occurring 37.4 months (33–41.8) after surgery. From Kaplan–Meier estimates, 1-year and 5-year disease free survival was 90.9% (95% CI: 85.6–96.4%) and 81% (95% CI: 71.2–92.1%) respectively. The preoperative prolactinemia was the only significant preoperative predictive factor for remission (P < 0.05). No severe complication was reported, with no anterior pituitary deficiency after surgery, one diabetes insipidus, and one postoperative cerebrospinal fluid leakage properly treated by muscle plasty.

Conclusions

In well-selected microprolactinoma patients, pituitary surgery performed by an expert neurosurgical team is a valid first-line alternative treatment to dopamine agonists.

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George J Kahaly and Luigi Bartalena

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Carolin Girschik, Sophie-Charlotte Drogge, Bernd Kowall, Nils Lehmann, Andreas Stang, Denise Zwanziger, Raimund Erbel, Dagmar Führer, and Karl-Heinz Jöckel

Objective

Studies that evaluated the genetic influences on thyroid-stimulating hormone (TSH) concentrations were primarily performed in twin cohorts. The aim of this study was to investigate the sex-specific association of serum TSH concentrations between parents and their offspring.

Methods

We used data from the population-based Heinz Nixdorf Recall Study and the associated MultiGeneration Study, including offspring and their biological parents. In 3115 participants (including 1558 offspring from 1138 families), self-reported thyroid diseases and median TSH concentrations depending on thyroid status were assessed. Familial associations of TSH concentrations were investigated in 1485 healthy subjects using linear regression modeling in each group of the parent–offspring relationship using the parent’s TSH concentration as the exposure of interest. To account for the family effect, a mixed‐effects ordinal logistic regression model with random intercept varying at the family level was fitted, using the TSH concentration of the offspring classified into sex- and age-specific quartiles as the outcome.

Results

For every 1 mIU/L increase in the mother’s or father’s TSH concentration, the daughter’s TSH concentration increases by 0.13 mIU/L (95% CI: −0.01; 0.27) and 0.19 mIU/L (0.05; 0.33), respectively, and the son’s TSH concentration increases by 0.13 mIU/L (0.02; 0.25) and 0.20 mIU/L (0.08; 0.32), respectively. Further sensitivity analyses by expanding inclusion criteria and taking family clustering into account corroborated these results.

Conclusions

Serum TSH concentrations of parents are positively associated with those of their offspring in all sex-specific relationships.

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Danae A Delivanis, Maria D Hurtado Andrade, Tiffany Cortes, Shobana Athimulam, Aakanksha Khanna, Elizabeth Atkinson, Travis McKenzie, Naoki Takahashi, Michael R Moynagh, and Irina Bancos

Objective

Increased visceral fat and sarcopenia are cardiovascular risk factors that may explain increased cardiovascular morbidity and frailty in patients with adrenal adenomas. Our objective was to compare body composition measurement of patients with adrenal adenomas to referent subjects without adrenal disease.

Design

Cross-sectional study, 2014–2018.

Methods

Participants were adults with nonfunctioning adrenal tumor (NFAT), mild autonomous cortisol secretion (MACS), and Cushing syndrome (CS) and age, sex, and BMI 1:1 matched referent subjects without adrenal disorders. Main outcome measures were body composition measurements calculated from abdominal CT imaging. Intra-abdominal adipose tissue and muscle mass measurements were performed at the third lumbar spine level.

Results

Of 227 patients with adrenal adenomas, 20 were diagnosed with CS, 76 with MACS, and 131 with NFAT. Median age was 56 years (range: 18–89), and 67% were women. When compared to referent subjects, patients with CS, MACS, and NFAT demonstrated a higher visceral fat (odds ratio (OR): 2.2 (95% CI: 0.9–6.5), 2.0 (1.3–3.2), and 1.8 (1.2–2.7) and a lower skeletal muscle area (OR: 0.01 (95% CI: 0–0.09), 0.31 (0.18–0.49), and 0.3 (1.2–2.7)) respectively. For every 1 µg/dL cortisol increase after overnight dexamethasone, visceral fat/muscle area ratio increased by 2.3 (P = 0.02) and mean total skeletal muscle area decreased by 2.2 cm2 (P = 0.03).

Conclusion

Patients with adrenal adenomas demonstrate a lower muscle mass and a higher proportion of visceral fat when compared to referent subjects, including patients with NFAT. Even a subtle abnormality in cortisol secretion may impact health of patients with adenomas.

Open access

Wiebke Schlötelburg, Ines Ebert, Bernhard Petritsch, Andreas Max Weng, Ulrich Dischinger, Stefan Kircher, Andreas Konrad Buck, Thorsten Alexander Bley, Timo Deutschbein, and Martin Fassnacht

Objective: Reliable results of wash-out CT in the diagnostic workup of adrenal incidentalomas are scarce. Thus, we evaluated the diagnostic accuracy of delayed wash-out CT and determined thresholds to accurately differentiate adrenal masses.

Design: Retrospective, single-center cohort study including 216 patients with 252 adrenal lesions who underwent delayed wash-out CT. Definitive diagnoses based on histopathology (n=92) or comprehensive follow-up.

Methods: Size, average attenuation values of the adrenal lesions in all CT scan phases, absolute and relative percentage washout (APW/RPW) were determined by an expert radiologist blinded for clinical data. Adrenal lesions with unenhanced attenuation values >10HU built a subgroup (n=142). Diagnostic accuracy were calculated.

Results: The study group consisted of 171 adenomas, 32 other benign tumors, 11 pheochromocytomas, 9 adrenocortical carcinomas and 29 other malignant tumors. All (potentially) malignant and 46% of benign lesions showed unenhanced attenuation values >10HU. In this most relevant subgroup, the established thresholds of 60% for APW and 40% for RPW misclassified 35.9% and 35.2% of masses, respectively. When we applied optimized cutoffs (APW>83%; RPW>58%) and excluded pheochromocytomas, we missed only 1 malignant tumor by APW and none by RPW. However, only 11% and 15% of benign tumors were correctly identified.

Conclusions: Washout CT with the established thresholds for APW und RPW is insufficient to reliably diagnose adrenal masses. Using the proposed cutoff of 58% for RPW, malignant tumors will be correctly identified, but the added value is limited, namely 15% of patients with benign tumors can be prevented from additional imaging or even unnecessary surgery.

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Yu Xie, Changzhi Huang, Xingchen Zhu, Jiayu Wang, Xikang Fan, Zan Fu, Yanan Ma, and Dong Hang

Background

Insulin-like growth factor 1 (IGF1) is an important growth factor modulating development, homeostasis, and aging. However, whether and how circulating IGF1 concentrations influence early death risk in the general population remains largely unknown.

Methods

We included 380 997 participants who had serum IGF1 measurement and no history of cancer, cardiovascular disease (CVD), or diabetes at baseline from UK Biobank, a prospective cohort study initiated in 2006–2010. Restricted cubic splines and Cox proportional hazards regression models were used to assess the association between baseline IGF-1 concentrations and all-cause and cause-specific mortality.

Results

Over a median follow-up of 8.8 years, 10 753 of the participants died, including 6110 from cancer and 1949 from CVD. Dose–response analysis showed a U-shaped relationship between IGF1 levels and mortality. Compared to the fifth decile of IGF1, the lowest decile was associated with 39% (95% CI: 29–50%), 20% (95% CI: 8–34%), and 39% (95% CI: 14–68%) higher risk of all-cause, cancer, and CVD mortality, respectively, while the highest decile was associated with 17% (95% CI: 7–28%) and 38% (95% CI: 11–71%) higher risk of all-cause and CVD mortality, respectively. The results remained stable in detailed stratified and sensitivity analyses.

Conclusions

Our findings indicate that both low and high concentrations of serum IGF1 are associated with increased risk of mortality in the general population. Our study provides a basis for future interrogation of underlying mechanisms of IGF1 in early death occurrence and possible implications for mitigating the risk.

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Zhi-Hao Li, Pei-Dong Zhang, Qing Chen, Xiang Gao, Vincent C H Chung, Dong Shen, Xi-Ru Zhang, Wen-Fang Zhong, Qing-Mei Huang, Dan Liu, Pei-Liang Chen, Wei-Qi Song, Xian-Bo Wu, Virginia Byers Kraus, and Chen Mao

Objective

To examine the association of incident type 2 diabetes (T2D) risk with sleep factors, genetic risk, and their combination effects.

Design

Large prospective population-based cohort study.

Methods

This population-based prospective cohort study included 360 403 (mean (s.d.) age: 56.6 (8.0) years) participants without T2D at baseline from the UK Biobank. Genetic risk was categorised as high (highest quintile), intermediate (quintiles: 2–4), and low (lowest quintile) based on a polygenic risk score for T2D. Sleep scores, including long or short sleep duration, insomnia, snoring, late chronotype, and excessive daytime sleepiness, were categorized as an unfavourable, intermediate, or favourable sleep and circadian pattern.

Results

During a median follow-up of 9.0 years, 13 120 incident T2D cases were recorded. Among the participants with an unfavourable sleep and circadian pattern, 6.96% (95% CI: 6.68–7.24%) developed T2D vs 2.37% (95% CI: 2.28–2.46%) of participants with a favourable sleep and circadian pattern (adjusted hazard ratio (HR): 1.53, 95% CI: 1.45–1.62). Of participants with a high genetic risk, 5.53% (95% CI: 5.36–5.69%) developed T2D vs 2.01% (95% CI: 1.91–2.11%) of participants with a low genetic risk (adjusted HR: 2.89, 95% CI: 2.72–3.07). The association with sleep and circadian patterns was independent of genetic risk strata. Participants in the lowest quintile with an unfavourable sleep and circadian pattern were 3.97-fold more likely to develop T2D than those in the lowest quintile with a favourable sleep and circadian pattern.

Conclusions

Sleep and circadian patterns and genetic risk were independently associated with incident T2D. These results indicate the benefits of adhering to a healthy sleep and circadian pattern in entire populations, independent of genetic risk.

Open access

Mikiko Okazaki-Hada, Eijun Nishihara, Mako Hisakado, Takumi Kudo, Mitsuru Ito, Shuji Fukata, Mitsushige Nishikawa, Takashi Akamizu, and Akira Miyauchi

Objective: Resistance to thyroid hormone-beta (RTHβ) is an inherited syndrome caused by mutations in the thyroid hormone receptor β (THRB) gene. Patients with RTHβ typically have elevated thyroid hormone levels with non-suppressed serum TSH. We aimed to elucidate the clinical, laboratory, and imaging findings of RTHβ patients and further to explore their association with THRB gene mutations.

Design and Methods: We retrospectively reviewed the clinical charts and compared the clinical findings of 68 RTHβ patients (45 probands and 23 relatives) and 30 unaffected relatives in Kuma Hospital.

Results: Genetic testing revealed 35 heterozygous THRB gene mutations. Among all RTHβ patients, autoimmune thyroid disease (AITD) was detected in 42.1% of men and 40.9% of women, showing that the prevalence of AITD in affected males was significantly higher than in unaffected relatives (p = 0.019). During the follow-up of 44 patients, 13 patients (29.5%; eight [42.1%] with AITD and five [20%] without) temporarily showed thyroid function test results inconsistent with RTHβ. Two patients with the R383H mutation which has little dominant negative effect temporarily showed normal thyroid hormone and TSH levels without AITD.

Conclusions: The frequency of AITD in male RTHβ patients was significantly higher compared to unaffected relatives. More than 20% of RTHβ patients temporarily showed laboratory findings atypical of RTHβ during their follow-up, and patients with AITD and specific THRB mutations were prone to display such findings. Therefore, genetic testing should be performed even for patients with fluctuations in thyroid function test results to avoid misdiagnosis and inappropriate treatment.

Open access

Min Sun, Jonathan W Mueller, Lorna C Gilligan, Angela E Taylor, Fozia Shaheen, Anna Noczyńska, Guy T’Sjoen, Louise Denvir, Savitha Shenoy, Piers Fulton, Timothy D Cheetham, Helena Gleeson, Mushtaqur Rahman, Nils P Krone, Norman F Taylor, Cedric H L Shackleton, Wiebke Arlt, and Jan Idkowiak

Context

17α-Hydroxylase/17,20-lyase deficiency (17OHD) caused by mutations in the CYP17A1 gene is a rare form of congenital adrenal hyperplasia typically characterised by cortisol deficiency, mineralocorticoid excess and sex steroid deficiency.

Objective

To examine the phenotypic spectrum of 17OHD by clinical and biochemical assessment and corresponding in silico and in vitro functional analysis.

Design

Case series.

Patients and results

We assessed eight patients with 17OHD, including four with extreme 17OHD phenotypes: two siblings presented with failure to thrive in early infancy and two with isolated sex steroid deficiency and normal cortisol reserve. Diagnosis was established by mass spectrometry-based urinary steroid profiling and confirmed by genetic CYP17A1 analysis, revealing homozygous and compound heterozygous sequence variants. We found novel (p.Gly111Val, p.Ala398Glu, p.Ile371Thr) and previously described sequence variants (p.Pro409Leu, p.Arg347His, p.Gly436Arg, p.Phe53/54del, p.Tyr60IlefsLys88X). In vitro functional studies employing an overexpression system in HEK293 cells showed that 17,20-lyase activity was invariably decreased while mutant 17α-hydroxylase activity retained up to 14% of WT activity in the two patients with intact cortisol reserve. A ratio of urinary corticosterone over cortisol metabolites reflective of 17α-hydroxylase activity correlated well with clinical phenotype severity.

Conclusion

Our findings illustrate the broad phenotypic spectrum of 17OHD. Isolated sex steroid deficiency with normal stimulated cortisol has not been reported before. Attenuation of 17α-hydroxylase activity is readily detected by urinary steroid profiling and predicts phenotype severity.

Significance statement

Here we report, supported by careful phenotyping, genotyping and functional analysis, a prismatic case series of patients with congenital adrenal hyperplasia due to 17α-hydroxylase (CYP17A1) deficiency (17OHD). These range in severity from the abolition of function, presenting in early infancy, and unusually mild with isolated sex steroid deficiency but normal ACTH-stimulated cortisol in adult patients. These findings will guide improved diagnostic detection of CYP17A1 deficiency.