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Carmina Teresa Fuss, Katharina Brohm, Max Kurlbaum, Anke Hannemann, Sabine Kendl, Martin Fassnacht, Timo Deutschbein, Stefanie Hahner, and Matthias Kroiss

Objective: Saline infusion testing (SIT) for confirmation of primary aldosteronism (PA) is based on impaired aldosterone suppression in PA compared to essential hypertension (EH). In the past, aldosterone was quantified using immunoassays (IA). Liquid chromatography tandem mass spectrometry (LC-MS/MS) is increasingly used in clinical routine. We aimed at a method-specific aldosterone threshold for the diagnosis of PA during SIT and explored diagnostic utility of steroid panel analysis.

Design: Retrospective cohort study of 187 paired SIT samples (2009-2018). Diagnosis of PA (n=103) and EH (n=84) was established based on clinical routine workup without using LC-MS/MS values.

Setting: Tertiary care center.

Methods: LC-MS/MS using a commercial steroid panel. Receiver operator characteristics analysis was used to determine method-specific cut-offs using a positive predictive value (PPV) of 90% as criterion.

Results: Aldosterone measured by IA was on average 31 ng/L higher than with LC-MS/MS. The cut-offs for PA confirmation were 54 ng/L for IA (sensitivity: 95%, 95%-CI 89.0-98.4; specificity: 87%, 95%-CI 77.8-93.3; area under the curve (AUC) 0.955, 95%-CI 0.924-0.986; PPV: 90%, 95%-CI 83.7-93.9) and 69 ng/L for LC-MS/MS (79%, 95%-CI 69.5-86.1; 89%, 95%-CI 80.6-95.0; 0.902, 95%-CI 0.857-0.947; 90%, 95%-CI 82.8-94.4). Other steroids did not improve SIT.

Conclusions: Aldosterone quantification with LC-MS/MS and IA yields comparable SIT-cut-offs. Lower AUC for LC-MS/MS is likely due to the spectrum of disease in PA and previous decision making based on IA results. Until data of a prospective trial with clinical endpoints are available, the suggested cut-off can be used in clinical routine.

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Hao Jin, Weidong Lin, Ligong Lu, and Min Cui

Objective: The complications and treatment effects of conventional thyroidectomy and thyroid thermal ablation should be compared in order to identify the best intervention for patients with benign thyroid nodules.

Methods: Patients (18-50 years old) who had benign thyroid nodules and were eligible for both thyroidectomy and thyroid thermal ablation were randomly allocated (1:1) to either conventional thyroidectomy group or thyroid thermal ablation group. Patients’ satisfaction and condition-specific quality of life were measured with the Thyroid-Specific Quality-of-Life Questionnaire Scale (QoL) at the 15th post-randomization month and were set as the co-primary outcome.

Results: A total of 450 patients were enrolled and randomized (225 patients in each group). At the 15th month after randomization, more patients in the thyroid thermal ablation group were satisfied with the treatment effects compared to those in the conventional thyroidectomy group. More patients in the thyroid thermal ablation group have a QoL score of 410 (QOL scores ranges from 0 to 410) than patients in conventional thyroidectomy. Eight (4%) of the 209 patients in conventional thyroidectomy group and 6 (3%) of the 208 patients in thyroid thermal ablation group had at least one severe postoperative complication. The time to achieve volume reduction was longer in the thermal ablation group.

Conclusion: Thyroid thermal ablation is superior to conventional thyroidectomy in terms of patients satisfaction, postoperative quality of life, and shorter hospital stay, but takes longer to achieve BTNs volume reduction. The complication rates between the two groups were similar.

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A B Hansen, D Wøjdemann, C H Renault, At Pedersen, K M Main, L L Raket, Rikke Beck Jensen, and A Juul

This review aims to cover the subject of sex steroid action in adolescence. It will include situations with too little sex steroid action, as seen in e.g Turners syndrome and androgen insensitivity issues, too much sex steroid action as seen in adolescent PCOS, CAH and gynecomastia, too late sex steroid action as seen in constitutional delay of growth and puberty and too early sex steroid action as seen in precocious puberty.

This review will cover the etiology, the signs and symptoms which the clinician should be attentive to, important differential diagnoses to know and be able to distinguish, long-term health and social consequences of these hormonal disorders and the course of action with regards to medical treatment in the pediatric endocrinological department and for the general practitioner.

This review also covers situations with exogenous sex steroid application for therapeutic purposes in the adolescent and young adult. This includes gender-affirming therapy in the transgender child and hormone treatment of tall statured children. It gives some background information of the cause of treatment, the patient’s motivation for medicating (or self-medicating), long-term consequences of exogenous sex steroid treatment and clinical outcome of this treatment.

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Mototsugu Nagao, Izumi Fukuda, Akira Asai, Jonathan L.s. Esguerra, Naomi Hizuka, Lena Eliasson, and Hitoshi Sugihara

Objective: In insulin-like growth factor II (IGF-II) producing non-islet cell tumor hypoglycemia (NICTH), high molecular weight forms of IGF-II (big IGF-II) are produced as a cause of spontaneous hypoglycemia. MicroRNA (miRNA)-483 family, encoded in an intron lesion of IGF2 gene, is suggested to be co-expressed with IGF-II. Here, we tested whether serum miR-483-5p and -3p levels are associated with the presence of big IGF-II in NICTH.

Design: Serum samples from patients who were suspected to have IGF-II producing NICTH (n=42) were tested. MiR-483-5p and -3p levels were evaluated using quantitative PCR. IGF-II level was analyzed using ELISA. The presence of big IGF-II was identified by Western blotting.

Results: Big IGF-II was detected in the sera of 32 patients. MiR-483-5p (P=0.0015) and -3p (P=0.027) levels were significantly higher in sera with big IGF-II (n=32) than in those without (n=10), whereas serum IGF-II level (P=0.055) was not significantly different between the groups. The median serum concentration of miR-483-5p was ~10 times higher than that of miR-483-3p. Although a strong correlation was observed between the two miRNAs (r=0.844, P<0.0001), but neither of which was correlated with serum IGF-II level. The areas under the receiver operating characteristic curves of miR-483-5p (0.853) and -3p (0.722) were higher than that of IGF-II (0.694) for detecting the presence of big IGF-II.

Conclusion: The associations of serum miR-483-5p and -3p levels with the presence of big IGF-II suggest the diagnostic potential of these miRNAs for IGF-II producing NICTH.

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Kara L Marlatt, Dragana Lovre, Robbie A Beyl, Chandra R Tate, Evelyn K Hayes, Charles F Burant, Eric Ravussin, and Franck Mauvais-Jarvis


Combining conjugated estrogens (CE) with the selective estrogen receptor modulator bazedoxifene (BZA) is a novel, orally administered menopausal therapy. We investigated the effect of CE/BZA on insulin sensitivity, energy metabolism, and serum metabolome in postmenopausal women with obesity.


Randomized, double-blind, crossover pilot trial with washout was conducted at Pennington Biomedical Research Center. Eight postmenopausal women (age 50–60 years, BMI 30–40 kg/m2) were randomized to 8 weeks CE/BZA or placebo. Primary outcome was insulin sensitivity (hyperinsulinemic-euglycemic clamp). Secondary outcomes included body composition (DXA); resting metabolic rate (RMR); substrate oxidation (indirect calorimetry); ectopic lipids (1H-MRS); fat cell size, adipose and skeletal muscle gene expression (biopsies); serum inflammatory markers; and serum metabolome (LC/MS).


CE/BZA treatment produced no detectable effect on insulin sensitivity, body composition, ectopic fat, fat cell size, or substrate oxidation, but resulted in a non-significant increase in RMR (basal: P = 0.06; high-dose clamp: P = 0.08) compared to placebo. CE/BZA increased serum high-density lipoprotein (HDL)-cholesterol. CE/BZA also increased serum diacylglycerol (DAG) and triacylglycerol (TAG) species containing long-chain saturated, mono- and polyunsaturated fatty acids (FAs) and decreased long-chain acylcarnitines, possibly reflecting increased hepatic de novo FA synthesis and esterification into TAGs for export into very low-density lipoproteins, as well as decreased FA oxidation, respectively (P < 0.05). CE/BZA increased serum phosphatidylcholines, phosphatidylethanolamines, ceramides, and sphingomyelins, possibly reflecting the increase in serum lipoproteins (P < 0.05).


A short treatment of obese postmenopausal women with CE/BZA does not alter insulin action or ectopic fat but increases serum markers of hepatic de novo lipogenesis and TAG production.

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Pantea Nazeri, Mamak Shariat, and Fereidoun Azizi


Objective: The current systematic review aimed to provide comprehensive data on the effects of iodine supplementation in pregnancy and investigate its potential benefits on infant growth parameters and neurocognitive development using meta-analysis.

Methods: A systematic review was conducted on trials published from January 1989 to December 2019 by searching MEDLINE, Web of Science, the Cochrane Library, Scopus, and Google Scholar. For most maternal and neonatal outcomes, a narrative synthesis of the data was performed. For birth anthropometric measurements and infant neurocognitive outcomes, the pooled standardized mean differences (SMDs) with 95% confidence intervals (CIs) were estimated using fixed/random effect models.

Results: Fourteen trials were eligible for inclusion in the systematic review, of which five trials were included in the meta-analysis. Although the findings of different thyroid parameters are inconclusive, more consistent evidence showed that iodine supplementation could prevent the increase in thyroglobulin concentration during pregnancy. In the meta-analysis, no differences were found in weight (-0.11 [95% CI -0.23–0.01]), length (-0.06 [95% CI -0.21–0.09]), and head circumference (0.26 [95% CI -0.35–0.88]) at birth, or in cognitive (0.07 [95% CI -0.07–0.20]), language (0.06 [95% CI -0.22–0.35]), and motor (0.07 [95% CI -0.06–0.21]) development during the first two years of life in infants between the iodine-supplemented and control groups.

Conclusion: Iodine supplementation during pregnancy can improve the iodine status in pregnant women and their offspring; however, according to our meta-analysis, there was no evidence of improved growth or neurodevelopmental outcomes in infants of iodine-supplemented mothers.

Free access

Magalie Haissaguerre, Marie Puerto, Marie-Laure Nunes, and Antoine Tabarin

Open access

Davide Calebiro

G protein-coupled receptors (GPCRs) are the largest family of membrane receptors and major drug targets. They play a fundamental role in the endocrine system, where they mediate the effects of several hormones and neurotransmitters. As a result, alterations of GPCR signalling are a major cause of endocrine disorders such as congenital hypothyroidism or Cushing’s syndrome. My group develops innovative optical methods such as fluorescence resonance energy transfer (FRET) and single-molecule microscopy, which allow us to investigate GPCR signalling in living cells with unprecedented spatiotemporal resolution. Using this innovative approach, we have contributed to elucidate some long debated questions about the mechanisms of GPCR signalling and their involvement in human disease. Among other findings, these studies have led to the unexpected discovery that GPCRs are not only signalling at the cell surface, as previously assumed, but also at various intracellular sites. This has important implications to understand how hormones and neurotransmitters produce specific responses in our cells and might pave the way to innovative treatments for common diseases like diabetes or heart failure.

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Alexander A Leung, Janice L Pasieka, Martin D Hyrcza, Danièle Pacaud, Yuan Dong, Jessica M Boyd, Hossein Sadrzadeh, and Gregory A Kline

Objective: Despite the significant morbidity and mortality associated with pheochromocytoma and paraganglioma, little is known about their epidemiology. The primary objective was to determine the incidence of pheochromocytoma and paraganglioma in an ethnically diverse population. A secondary objective was to develop and validate algorithms for case detection using laboratory and administrative data.

Design: Population-based cohort study in Alberta, Canada from 2012 to 2019.

Methods: Patients with pheochromocytoma or paraganglioma were identified using linked administrative databases and clinical records. Annual incidence rates per 100,000 people were calculated and stratified according to age and sex. Algorithms to identify pheochromocytoma and paraganglioma, based on laboratory and administrative data, were evaluated.

Results: A total of 239 patients with pheochromocytoma or paraganglioma (collectively with 251 tumors) were identified from a population of 5,196,368 people over a period of 7 years. The overall incidence of pheochromocytoma or paraganglioma was 0.66 cases per 100,000 people per year. The frequency of pheochromocytoma and paraganglioma increased with age and was highest in individuals aged 60 to 79 years (8.85 and 14.68 cases per 100,000 people per year for males and females, respectively). An algorithm based on laboratory data (metanephrine >2-fold or normetanephrine >3-fold higher than the upper limit of normal) closely approximated the true frequency of pheochromocytoma and paraganglioma with an estimated incidence of 0.54 cases per 100,000 people per year.

Conclusion: The incidence of pheochromocytoma and paraganglioma in an unselected population of western Canada was unexpectedly higher than rates reported from other areas of the world.

Free access

Stephanie A Roberts and Ursula B Kaiser

Pubertal timing is regulated by the complex interplay of genetic, environmental, nutritional and epigenetic factors. Criteria for determining normal pubertal timing, and thus the definition of precocious puberty, have evolved based on published population studies. The significance of the genetic influence on pubertal timing is supported by familial pubertal timing and twin studies. In contrast to the many monogenic causes associated with hypogonadotropic hypogonadism, only four monogenic causes of central precocious puberty (CPP) have been described. Loss-of-function mutations in Makorin Ring Finger Protein 3(MKRN3), a maternally imprinted gene on chromosome 15 within the Prader–Willi syndrome locus, are the most common identified genetic cause of CPP. More recently, several mutations in a second maternally imprinted gene, Delta-like noncanonical Notch ligand 1 (DLK1), have also been associated with CPP. Polymorphisms in both genes have also been associated with the age of menarche in genome-wide association studies. Mutations in the genes encoding kisspeptin (KISS1) and its receptor (KISS1R), potent activators of GnRH secretion, have also been described in association with CPP, but remain rare monogenic causes. CPP has both short- and long-term health implications for children, highlighting the importance of understanding the mechanisms contributing to early puberty. Additionally, given the role of mutations in the imprinted genes MKRN3 and DLK1 in pubertal timing, other imprinted candidate genes should be considered for a role in puberty initiation.