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Adina F Turcu, Lili Zhao, Xuan Chen, Rebecca Yang, Juilee Rege, William E Rainey, Johannes D Veldhuis, and Richard J Auchus

Background

Many hormones display distinct circadian rhythms, driven by central regulators, hormonal bioavailability, and half-life. A set of 11-oxygenated C19 steroids (11-oxyandrogens) and pregnenolone sulfate (PregS) are elevated in congenital adrenal hyperplasia and other disorders, but their circadian patterns have not been characterized.

Participants and methods

Peripheral blood was collected every 2 h over 24 h from healthy volunteer men (10 young, 18–30 years, and 10 older, 60–80 years). We used mass spectrometry to quantify 15 steroids, including androstenedione (A4), testosterone (T), 11β-hydroxy- and 11-ketotestosterone (11OHT, 11KT),11β-hydroxy- and 11-ketoandrostenedione (11OHA4, 11KA4), and 4 ∆5-steroid sulfates. Diurnal models including mesor (rhythm adjusted median), peak, and nadir concentrations, acrophase, and amplitude were computed.

Results

11OHA4 followed a rhythm similar to cortisol: acrophase 8:00 h, nadir 21:00 h and were similar in young and old men. 11KT had similar diurnal patterns, but the peak was lower in older than in young men, as was the case for A4. All four steroid sulfates were higher in young vs older men. PregS and 17-hydroxypregnenolone sulfate (17OHPregS) showed sustained elevations between 8:00 and 18:00 h, and nadirs around midnight, while DHEAS and AdiolS displayed minimal diurnal variations. All 4 11-oxyandrogens correlated tightly with cortisol (r from 0.54 for 11OHT to 0.81 for 11OHA4, P  < 0.0001 for all), but very weakly with T, supporting their adrenal origin and ACTH governance.

Conclusions

11-Oxyandrogens, PregS, and 17OHPregS display distinct circadian and age variations, which should be accounted for when used as clinical biomarkers.

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Annika M A Berends, Edward Buitenwerf, Ineke J Riphagen, Jacques W M Lenders, Henri J L M Timmers, Schelto Kruijff, Thera P Links, Anouk N A van der Horst-Schrivers, Coen A Stegeman, Elisabeth M W Eekhoff, Richard A Feelders, Eleonora P M Corssmit, Ronald Groote Veldman, Harm R Haak, Anneke C Muller Kobold, and Michiel N Kerstens

Background

Despite adequate presurgical management, blood pressure fluctuations are common during resection of pheochromocytoma or sympathetic paraganglioma (PPGL). To a large extent, the variability in blood pressure control during PPGL resection remains unexplained. Adrenomedullin and B-type natriuretic peptide, measured as MR-proADM and NT-proBNP, respectively, are circulating biomarkers of cardiovascular dysfunction. We investigated whether plasma levels of MR-proADM and NT-proBNP are associated with blood pressure fluctuations during PPGL resection.

Methods

Study subjects participated in PRESCRIPT, a randomized controlled trial in patients undergoing PPGL resection. MR-proADM and NT-proBNP were determined in a single plasma sample drawn before surgery. Multivariable linear and logistic regression analyses were used to explore associations between these biomarkers and blood pressure fluctuations, use of vasoconstrictive agents during surgery as well as the occurrence of perioperative cardiovascular events.

Results

A total of 126 PPGL patients were included. Median plasma concentrations of MR-proADM and NT-proBNP were 0.51 (0.41–0.63) nmol/L and 68.7 (27.9–150.4) ng/L, respectively. Neither MR-proADM nor NT-proBNP were associated with blood pressure fluctuations. There was a positive correlation between MR-proADM concentration and the cumulative dose of vasoconstrictive agents (03B2 0.44, P =0.001). Both MR-proADM and NT-proBNP were significantly associated with perioperative cardiovascular events (OR: 5.46, P =0.013 and OR: 1.54, P =0.017, respectively).

Conclusions

plasma MR-proADM or NT-proBNP should not be considered as biomarkers for the presurgical risk assessment of blood pressure fluctuations during PPGL resection. Future studies are needed to explore the potential influence of these biomarkers on the intraoperative requirement of vasoconstrictive agents and the perioperative cardiovascular risk.

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Idoia Martínez de LaPiscina, Nancy Portillo Najera, Itxaso Rica, Sonia Gaztambide, Susan M Webb, Alicia Santos, Maria Dolores Moure, Miguel Paja Fano, Maria Isabel Hernandez, Maria Jesús Chueca-Guindelain, Laura Cristina Hernández-Ramírez, Alfonso Soto, Nuria Valdés, and Luis Castaño

Objective

Pituitary adenomas (PA) are rare in young patients, and additional studies are needed to fully understand their pathogenesis in this population. We describe the clinical and genetic characteristics of apparently sporadic PA in a cohort of young patients.

Design

Clinical and molecular analysis of 235 patients (age ≤ 30 years) with PA. Clinicians from several Spanish and Chilean hospitals provided data.

Methods

Genetic screening was performed via next-generation sequencing and comparative genomic hybridization array. Clinical variables were compared among paediatric, adolescent (<19 years) and young adults’ (≥19–30 years) cohorts and types of adenomas. Phenotype–genotype associations were examined.

Results

Among the total cohort, mean age was 17.3 years. Local mass effect symptoms were present in 22.0%, and prolactinomas were the most frequent (44.7%). Disease-causing germline variants were identified in 22 individuals (9.3%), more exactly in 13.1 and 4.7% of the populations aged between 0–19 and 19–30 years, respectively; genetically positive patients were younger at diagnosis and had larger tumour size. Healthy family carriers were also identified.

Conclusions

Variants in genes associated with syndromic forms of PAs were detected in a large cohort of apparently sporadic pituitary tumours. We have identified novel variants in well-known genes and set the possibility of incomplete disease penetrance in carriers of MEN1 alterations or a limited clinical expression of the syndrome. Despite the low penetrance observed, screening of AIP and MEN1 variants in young patients and relatives is of clinical value.

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Yumeng Huang, Jinyang Zhen, Tengli Liu, Jianyu Wang, Na Li, Jing Yang, Rui Liang, Shusen Wang, and Ming Liu

Objective

Progressive beta-cell dysfunction is a hallmark of type 2 diabetes (T2D). Increasing evidence indicates that over-stimulating proinsulin synthesis causes proinsulin misfolding and impairs insulin maturation and storage in db/db mice. However, defective insulin maturation in patients with T2D remains unknown.

Methods

We examined intra-islet and intra-cellular distributions of proinsulin and insulin and proinsulin to insulin ratio in the islets of patients with T2D. The expression of transcription factor NKX6.1 and dedifferentiation marker ALDH1A3, as well as glucagon, were detected by immunofluorescence.

Results

We identified a novel subgroup of beta cells expressing only proinsulin but not insulin. Importantly, significantly increased proinsulin positive and insulin negative (PI+/INS) cells were evident in T2D, and this increase was strongly correlated with levels of hemoglobin A1C (HbA1c) in T2D and prediabetes. The percentages of beta cells expressing prohormone convertase 1/3 and carboxypeptidase E were not reduced. Indeed, while proinsulin displayed a higher degree of co-localization with the golgi markers GM130/TGN46 in control beta cells, it appeared to be more diffused within the cytoplasm and less co-localized with GM130/TGN46 in PI+/INS cells. Furthermore, the key functional transcription factor NKX6.1 markedly decreased in the islets of T2D, especially in the cells with PI+/INS. The decreased NKX6.1+/PI+/INS+ was strongly correlated with levels of HbA1c in T2D. Almost all PI+/INS cells showed absence of NKX6.1. Moreover, the percentages of PI+/INS cells expressing ALDH1A3 were elevated along with an increased acquisition of glucagon immunostaining.

Conclusion

Our data demonstrate defective insulin maturation in patients with T2D.

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Laura Potasso, Julie Refardt, Christian Meier, and Mirjam Christ-Crain

Objective: Hyponatremia is associated with increased risk of bone fragility and fractures. Many studies suggest that hyponatremia stimulates osteoclast activation, whereas other studies rather reveal a possible role of acute hyponatremia in impairing osteoblast function. We aimed to assess whether and how correction of hyponatremia in hospitalized patients with syndrome of inappropriate antidiuresis (SIAD) has an impact on bone metabolism.

Design and Methods: This was a pre-defined secondary analysis of 88 hospitalized patients with SIAD undergoing a randomized treatment with SGLT-2 inhibitors or placebo for 4 days. Biochemical markers of bone resorption (CTX) and bone formation (PINP) were collected in serum at baseline and after the intervention (day 5). Bone formation index (defined as PINP/CTX) and its difference between day 5 and baseline were calculated. Patients with steroid therapy (n=6), fractures (n=10), or whose data were missing (n=4) were excluded from the analysis.

Results: Out of 68 patients, 27(39.7%) were normonatremic at day 5. These patients showed an increase in serum PINP (p=0.04), whereas persistent hyponatremic patients did not (p=0.38), with a relevant difference between these two subgroups (p=0.005). Serum CTX increased similarly in the two groups (p=0.43). This produced a 47.9 points higher PINP/CTX difference between discharge and admission in normonatremic patients (95%CI 17.0-78.7, p=0.003) compared to patients with persistent hyponatremia, independent of age, sex, BMI, smoking habits, randomization arm, and baseline cortisol levels.

Conclusions: Our predefined post-hoc analysis shows that correction of hyponatremia in hospitalized patients with SIAD might have a positive impact on osteoblast function.

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Nicholas Russell, Rudolf Hoermann, Ada S Cheung, Jeffrey D Zajac, David J Handelsman, and Mathis Grossmann

Objective: Indirect evidence suggests that the effects of testosterone on fat mass in men are dependent on aromatisation to estradiol. However, no controlled study has assessed the effects of estradiol in the absence of testosterone.

Design: 6-month randomised, placebo-controlled trial with the hypothesis that men randomised to estradiol would reduce their fat mass.

Methods: 78 participants receiving androgen deprivation therapy for prostate cancer were randomised to 0.9 mg of 0.1% estradiol gel per day, or matched placebo. Dual x-ray absorptiometry body composition was measured at baseline, month 3 and month 6. The primary outcome was total fat mass.

Results: Serum estradiol increased in the estradiol group over 6 months compared to placebo, mean adjusted difference (MAD) 207 pmol/L (95% CI 123 – 292), p<0.001. Estradiol treatment changed total fat mass, MAD 1007g (95% CI 124-1891), but not significantly so, p=0.09. There were other consistent non-significant trends towards increased proportional fat mass, MAD 0.8% (95% CI 0.0-1.6), p=0.15; gynoid fat, MAD 147g (95% CI 2-293), p=0.08; visceral fat, 53g (95% CI 1-105) p=0.13; and subcutaneous fat, MAD 65g (95% CI 5-125), p=0.11. Android fat increased, MAD 164 g (95% CI 41-286), p=0.04.

Conclusion: Contrary to our hypothesis, we provide suggestive evidence that E2 acting in the absence of T, may increase total and regional fat mass in men. Given the premature closure of trials due to the COVID pandemic, this potentially important observation should encourage additional studies to confirm or refute whether estradiol promotes fat expansion in the absence of T.

Open access

Mirjam Christ-Crain, Ewout J Hoorn, Mark Sherlock, Chris J Thompson, and John Wass

COVID-19 has changed the nature of medical consultations, emphasizing virtual patient counselling, with relevance for patients with diabetes insipidus (DI) or hyponatraemia. The main complication of desmopressin treatment in DI is dilutional hyponatraemia. Since plasma sodium monitoring is not always possible in times of COVID-19, we recommend to delay the desmopressin dose once a week until aquaresis occurs allowing excess retained water to be excreted. Patients should measure their body weight daily. Patients with DI admitted to the hospital with COVID-19 have a high risk for mortality due to volume depletion. Specialists must supervise fluid replacement and dosing of desmopressin. Patients after pituitary surgery should drink to thirst and measure their body weight daily to early recognize the development of postoperative SIAD. They should know hyponatraemia symptoms. Hyponatraemia in COVID-19 is common with a prevalence of 20–30% and is mostly due to SIAD or hypovolaemia. It mirrors disease severity and is an early predictor of mortality. Hypernatraemia may also develop in COVID-19 patients, with a prevalence of 3–5%, especially in ICU, and derives from different multifactorial reasons, for example, due to insensible water losses from pyrexia, increased respiration rate and use of diuretics. Hypernatraemic dehydration may contribute to the high risk of acute kidney injury in COVID-19. IV fluid replacement should be administered with caution in severe cases of COVID-19 because of the risk of pulmonary oedema.

Open access

Barend W Florijn, Jacques M G J Duijs, Maartje Klaver, Eline N Kuipers, Sander Kooijman, Jurrien Prins, Huayu Zhang, Hetty C M Sips, Wendy Stam, Maaike Hanegraaf, Ronald W A L Limpens, Rienk Nieuwland, Bas B van Rijn, Ton J Rabelink, Patrick C N Rensen, Martin den Heijer, Roel Bijkerk, and Anton Jan van Zonneveld

Objective

Sex steroid hormones like estrogens have a key role in the regulation of energy homeostasis and metabolism. In transwomen, gender-affirming hormone therapy like estradiol (in combination with antiandrogenic compounds) could affect metabolism as well. Given that the underlying pathophysiological mechanisms are not fully understood, this study assessed circulating estradiol-driven microRNAs (miRs) in transwomen and their regulation of genes involved in metabolism in mice.

Methods

Following plasma miR-sequencing (seq) in a transwomen discovery (n = 20) and validation cohort (n = 30), we identified miR-224 and miR-452. Subsequent systemic silencing of these miRs in male C57Bl/6 J mice (n = 10) was followed by RNA-seq-based gene expression analysis of brown and white adipose tissue in conjunction with mechanistic studies in cultured adipocytes.

Results

Estradiol in transwomen lowered plasma miR-224 and -452 carried in extracellular vesicles (EVs) while their systemic silencing in mice and cultured adipocytes increased lipogenesis (white adipose) but reduced glucose uptake and mitochondrial respiration (brown adipose). In white and brown adipose tissue, differentially expressed (miR target) genes are associated with lipogenesis (white adipose) and mitochondrial respiration and glucose uptake (brown adipose).

Conclusion

This study identified an estradiol-drive post-transcriptional network that could potentially offer a mechanistic understanding of metabolism following gender-affirming estradiol therapy.

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Wei-De Lin, Chi-Fung Cheng, Chung-Hsing Wang, Wen-Miin Liang, Chien-Hsiun Chen, Ai-Ru Hsieh, Mu-Lin Chiu, Ting-Hsu Lin, Chiu-Chu Liao, Shao-Mei Huang, Chang-Hai Tsai, Cherry Yin-Yi Chang, Ying-Ju Lin, and Fuu-Jen Tsai

Objective,

To investigate the genetic characteristics of idiopathic central precocious puberty (ICPP) and validate its polygenic risk for early puberty.

Design and methods

A bootstrap subsampling and genome-wide association study were performed on Taiwanese Han Chinese girls comprising 321 ICPP patients and 148 controls. Using previous GWAS data on pubertal timing, a replication study was performed. A validation group was also investigated for the weighted polygenic risk score (wPRS) of the risk of early puberty.

Results

A total of 105 SNPs for the risk of ICPP were identified, of which 22 yielded an area under the receiver operating characteristic curve of 0.713 for the risk of early puberty in the validation group. A replication study showed that 33 SNPs from previous GWAS data of pubertal timing were associated with the risk of ICPP (training group: P-value < 0.05). In the validation group, a cumulative effect was observed between the wPRS and the risk of early puberty in a dose-dependent manner (validation group: Cochran–Armitage trend test: P-value < 1.00E−04; wPRS quartile 2 (Q2) (odds ratio (OR) = 5.00, 95% CI: 1.55–16.16), and wPRS Q3 (OR = 11.67, 95% CI: 2.44–55.83)).

Conclusions

This study reveals the ICPP genetic characteristics with 22 independent and 33 reported SNPs in the Han Chinese population from Taiwan. This study may contribute to understand the genetic features and underlying biological pathways that control pubertal timing and pathogenesis of ICPP and also to the identification of individuals with a potential genetic risk of early puberty.