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Clarisse Hochman, Justine Cristante, Aurore Geslot, Sylvie Salenave, Emmanuel Sonnet, Claire Briet, Anne Bachelot, Nicolas Chevalier, Olivier Gilly, Thierry Brue, Samy Hadjadj, Veronique Kerlan, Philippe Chanson, Delphine Vezzosi, Olivier Chabre, Delphine D Drui, and Frederic F Castinetti

Design

Hypercortisolism during pregnancy is a risk factor for prematurity. Long-term exposure to hypercortisolism may lead to permanent comorbidities, such as hypertension or diabetes, even after remission. Our aim was to determine whether women with a history of Cushing’s disease (and being eu-, hypo- or hypercortisolic at the time of pregnancy) had the same risks of comorbidities, and especially prematurity, during pregnancy.

Methods

It was a retrospective multicentric study focusing on mothers with a history of Cushing’s disease or diagnosed during pregnancy, followed in French tertiary referral centers. We compared the outcomes of pregnancies depending on the cortisolic status at the time of pregnancy.

Results

A total of 60 patients (78 pregnancies including 21 with hypercortisolism, 32 with hypocortisolism and 25 in eucortisolism in 25) were evaluated. The overall rate of preterm birth was 24.3%, with a peak in women diagnosed during pregnancy (62.5%), a high risk in hypercortisolic (33%) and hypocortisolic (19.3%), and a low risk (8%) in eucortisolic women Gestational diabetes and hypertension were observed in 21% and 10.4% of the whole cohort, with a higher risk in hypercortisolic women. Cesarean delivery was performed in 33.7% of the cohort.

Conclusions

Being non-eucortisolic at the time of pregnancy increases the risk of prematurity and comorbidities compared to the general population. Women with a history of Cushing’s disease should thus be carefully monitored during pregnancy. The high rate of cesarean delivery emphasizes the fact that these pregnancies should always be considered at risk.

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Hassina Benlarbi, Dominique Simon, Jonathan Rosenblatt, Cecile Dumeine, Nicolas Deroux, Didier Chevenne, Caroline Storey, Amelie Poidvin, Laetitia Martinerie, Jean-Claude Carel, and Juliane Leger

Objective: Neonatal hyperthyroidism may be caused by a permanent non-autoimmune genetic disorder or, more frequently, by maternally transmitted high serum TRAb levels. Variable thyroid dysfunction may be observed in this second context. We aimed to evaluate the prevalence of neonatal non-autoimmune hyperthyroidism and of the different types of thyroid function in neonates with a high risk of hyperthyroidism due to maternal Graves’ disease (GD).

Design and Methods: This observational cohort study included all neonates identified in the database of a single academic pediatric care center, over a period of 13 years, as having non-autoimmune hyperthyroidism or an autoimmune disorder with high TRAb levels (above 6 IU/L) transmitted by their mothers. Patients were classified as having neonatal hyperthyroidism, hypothyroidism, or euthyroidism with a permanent or transient disorder.

Results: Two of the 34 consecutive neonates selected (6%) had permanent non-autoimmune hyperthyroidism due to germline (n=1) or somatic (n=1) mutations of the TSH receptor gene. The patients with high serum TRAb levels at birth had transient hyperthyroidism (n=23), hypothyroidism (primary n=2, central n=3) or persistent euthyroidism (n=4).

Conclusion: These original findings highlight the need for careful and appropriate monitoring of thyroid function in the long term, not only for the rare patients with non-autoimmune neonatal hyperthyroidism, but also for repeat monitoring during the first month of life in neonates with maternally transmitted high TRAb levels, to ensure the early identification of thyrotoxicosis in more than two thirds of cases and to detect primary or central hypothyroidism, thereby potentially decreasing associated morbidity.  

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Cihan Atila, Clara O Sailer, Stefano Bassetti, Sarah Tschudin-Sutter, Roland Bingisser, Martin Siegemund, Stefan Osswald, Katharina Rentsch, Marco Rüegg, Sabrina Schaerli, Gabriela M. Kuster, Raphael Twerenbold, and Mirjam Christ-Crain

Objective: The pandemic of coronavirus disease (COVID-19) has rapidly spread globally and infected millions of people. The prevalence and prognostic impact of dysnatremia in COVID-19 is inconclusive. Therefore, we investigated the prevalence and outcome of dysnatremia in COVID-19.

Design: The prospective, observational, cohort study included consecutive patients with clinical suspicion of COVID-19 triaged to a Swiss Emergency Department between March and July 2020.

Methods: Collected data included clinical, laboratory and disease severity scoring parameters on admission. COVID-19 cases were identified based on a positive nasopharyngeal swab test for SARS-CoV-2, patients with a negative swab test served as controls. The primary analysis was to assess the prognostic impact of dysnatremia on 30-day mortality using a cox proportional hazard model.

Results: 172 (17%) cases with COVID-19 and 849 (83%) controls were included. Patients with COVID-19 showed a higher prevalence of hyponatremia compared to controls (28.1% vs. 17.5%, p<0.001); while comparable for hypernatremia (2.9% vs 2.1%, p=0.34). In COVID-19 but not in controls, hyponatremia was associated with a higher 30-day mortality (HR 1.4, 95%-CI 1.10-16.62, p=0.05). In both groups, hypernatremia on admission was associated with higher 30-day mortality (COVID-19: HR 11.5, 95%-CI 5.00-26.43, p<0.001; controls: HR 5.3, 95%-CI 1.60-17.64, p=0.006). In both groups, hyponatremia and hypernatremia were significantly associated with adverse outcome, e.g. intensive care unit admission, longer hospitalization, and mechanical ventilation.

Conclusion: Our results underline the importance of dysnatremia as predictive marker in COVID-19. Treating physicians should be aware and appropriate treatment measures taken in patients with COVID-19 and dysnatremia.

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Claire L Wood, Kieren G Hollingsworth, Eric Hughes, Sadhanandham Punniyakodi, Robert Muni-Lofra, Anna Mayhew, Rod T Mitchell, Michela Guglieri, Timothy D Cheetham, and Volker Straub

Background

Pharmacological doses of glucocorticoids (GC) reduce inflammation and preserve muscle function in boys with Duchenne muscular dystrophy (DMD). Delayed puberty and bone fragility are consequences of GC treatment. The aim of this study was to determine the acceptability of a 2-year pubertal induction regimen using 4-weekly testosterone injections and examine changes in physique, bone integrity, muscle pathology (assessed by MRI) and muscle function.

Methods

Fifteen prepubertal males with DMD, aged 12–17 years and receiving GC, were treated with an incremental testosterone regimen for 2 years. Participants completed a Treatment Satisfaction Questionnaire (TSQM). Data on BMI, bone density, muscle pathology and function were collected at baseline and 2 years later.

Results

Testosterone injections were well tolerated, with high TSQM scores. Baseline BMI z-score was 2.16 (0.90) and 1.64 (1.35) 2 years later. Median testosterone levels were 9.7 nmol/L (IQR: 5.7–11.1) 6–9 months after the last injection with an associated increase in testicular volume. Lumbar spine z-score was 0.22 (s.d. 2.21) at baseline and 0.35 (s.d. 2.21) after 2 years. Upper and lower limb muscle contractile cross-sectional area increased in all participants during the trial (P = 0.05 and P < 0.01, respectively). There was a reduction in T2 relaxation times in most muscle groups with stable upper limb muscle function.

Conclusion

Incremental monthly testosterone injections were well tolerated, promoted endogenous testosterone production and had a positive impact on the skeleton and contractile muscle bulk with evidence suggesting a beneficial impact on the underlying disease process.

Open access

Anuradhaa Subramanian, Jan Idkowiak, Konstantinos A Toulis, Shakila Thangaratinam, Wiebke Arlt, and Krishnarajah Nirantharakumar

Context

The incidence of gestational diabetes mellitus (GDM) has been on the rise, driven by maternal obesity. In parallel, pubertal tempo has increased in the general population, driven by childhood obesity.

Objective

To evaluate the available evidence on pubertal timing of boys and girls born to mothers with GDM.

Data sources

We searched MEDLINE, EMBASE, CINAHL Plus, Cochrane library and grey literature for observational studies up to October 2019.

Study selection and extraction

Two reviewers independently selected studies, collected data and appraised the studies for risk of bias. Results were tabulated and narratively described as reported in the primary studies.

Results

Seven articles (six for girls and four for boys) were included. Study quality score was mostly moderate (ranging from 4 to 10 out of 11). In girls born to mothers with GDM, estimates suggest earlier timing of pubarche, thelarche and menarche although for each of these outcomes only one study each showed a statistically significant association. In boys, there was some association between maternal GDM and earlier pubarche, but inconsistency in the direction of shift of age at onset of genital and testicular development and first ejaculation. Only a single study analysed growth patterns in children of mothers with GDM, describing a 3-month advancement in the age of attainment of peak height velocity and a slight increase in pubertal tempo.

Conclusions

Pubertal timing may be influenced by the presence of maternal GDM, though current evidence is sparse and of limited quality. Prospective cohort studies should be conducted, ideally coupled with objective biochemical tests.

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Niels B Dalsgaard, Lærke S Gasbjerg, Laura S Hansen, Nina L Hansen, Signe Stensen, Bolette Hartmann, Jens F Rehfeld, Jens J Holst, TIna Vilsbøll, and Filip K Knop

Aims: The alpha-glucosidase inhibitor acarbose is believed to reduce plasma glucose by delaying hydrolysis of carbohydrates. Acarbose-induced transfer of carbohydrates to the distal parts of the intestine increases circulating glucagon-like peptide 1 (GLP-1). Using the GLP-1 receptor antagonist exendin(9-39)NH2, we investigated the effect of acarbose-induced GLP-1 secretion on postprandial glucose metabolism in patients with type 2 diabetes.

Methods: In a double-blinded, placebo-controlled, randomised, crossover study, 15 participants with metformin-treated type 2 diabetes (Age 57-85 years, HbA1c 40-74 mmol/mol) were subjected to two 14-day treatment periods with acarbose or placebo, respectively, separated by a six-week wash-out period. At the end of each period, two randomised 4-hour liquid mixed meal tests with concomitant infusion of exendin(9-39)NH2 and saline, respectively, were performed.

Results: Compared to placebo, acarbose increased postprandial GLP-1 concentrations and decreased postprandial glucose. We observed no absolute difference in the exendin(9-39)NH2-induced increase in postprandial glucose excursions between placebo and acarbose periods, but relatively, postprandial glucose was increased by 119 ± 116% (mean ± SD) during exendin(9-39)NH2 infusion in the acarbose period vs. a 39 ± 27% increase during the placebo period (p = 0.0163).

Conclusions: We confirm that acarbose treatment stimulates postprandial GLP-1 secretion in patients with type 2 diabetes. Using exendin(9-39)NH2, we did not see an impact of acarbose-induced GLP-1 secretion on absolute measures of postprandial glucose tolerance, but relatively, the effect of exendin(9-39)NH2 was most pronounced during acarbose treatment.

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Anna Sjöström, Inga Bartuseviciene, and Charlotte Höybye

Objective

The challenge of finding patients with the rare conditon of diabetes insipidus in need of vasopressin treatment is demanding. The guidelines for performing the fluid deprivation test and interpreting the results are abundant. We evaluated the discriminative capacity of the fluid deprivation test in patients with polyuria to define a cut off for a more effective discrimination between diabetes insipidus and other polyuria syndromes.

Research design and methods

Retrospective review and data collection of all ambulatory fluid deprivation tests, of patients with mild polyuria and polydipsia (< 3 L/day), performed between 2000 and 2018. Serum osmolality, urine osmolality, urine volumes and clinical information of diagnosis were retrieved from the patient’s medical records.

Results

The study group consisted of 153 patients, 123 were diagnosed with non-diabetes insipidus and 30 with diabetes insipidus. After 12 h fasting (baseline) median duration of the fluid deprivation test was 5 h (fasting range: 12–21 h). At baseline, there was a significant difference between median serum and urine osmolality between the groups (P < 0.05). The best cut-off for the diagnosis of diabetes insipidus, was the combination of < 400 mosmol/kg in urine and > 302 mosmol/kg in serum. With this cut-off a sensitivity of 90% and specificity of 98% was achieved.

Conclusion

After 12 h fasting our proposed cut off clearly differentiated between diabetes insipidus, and non-diabetes insipidus suggesting a possibility to considerably reduce the duration of the fluid deprivation test.

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Frédéric Illouz, Philippe Chanson, Emmanuel Sonnet, Thierry Brue, Amandine Ferriere, Marie-Laure Raffin Sanson, Marie-Christine Vantyghem, Gérald Raverot, Mathilde Munier, Patrice Rodien, and Claire Briet

Objective

Somatostatin receptor ligands (SRL) are useful to control central hyperthyroidism in patients with thyrotropin-secreting pituitary adenoma (TSH pituitary adenoma). The aim of this study was to describe the frequency of thyrotropin deficiency (TSH deficiency) in patients with TSH pituitary adenoma treated by SRL.

Design

Retrospective study.

Methods

Patients with central hyperthyroidism due to TSH pituitary adenoma treated by short or long-acting SRL were retrospectively included. TSH deficiency was defined by a low FT4 associated with non-elevated TSH concentrations during SRL therapy. We analysed the frequency of TSH deficiency and the characteristics of patients with or without TSH deficiency.

Results

Forty-six patients were included. SRL were used as the first-line therapy in 21 of 46 patients (46%). Central hyperthyroidism was controlled in 36 of 46 patients (78%). TSH deficiency appeared in 7 of 46 patients (15%) after a median time of 4 weeks (4–7) and for a median duration of 3 months (2.5–3). The TSH deficiency occurred after one to three injections of long-acting SRL used as first-line therapy in 6/7 cases. There were no differences in terms of clinical and hormonal features, size of adenomas or doses of SRL between patients with or without TSH deficiency.

Conclusions

SRL can induce TSH deficiency in patients with central hyperthyroidism due to TSH pituitary adenoma. Thyrotropic function should be assessed before the first three injections of SRL in order to track TSH deficiency and reduce the frequency of injections when control of thyrotoxicosis rather than tumour reduction is the aim of the treatment.

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Marco Mezzullo, Alessandra Gambineri, Guido Di Dalmazi, Alessia Fazzini, Matteo Magagnoli, Margherita Baccini, Valentina Vicennati, Carla Pelusi, Uberto Pagotto, and Flaminia Fanelli

Objective. To investigate the impact of age, obesity and metabolic parameters on thirteen circulating steroids in reproductive and menopausal age. To define reference intervals (RI).

Design. Cross-sectional.

Methods. 325 drug-free, healthy and eumenorrheic women were selected from the general population. Independent relationships of LC-MS/MS-determined steroid levels with age, body mass index (BMI) and metabolic parameters were estimated. Reference sub-cohorts were defined for calculating upper and lower limits in reproductive age, menstrual phases and menopause, and these were compared with limits in dysmetabolic sub-cohorts.

Results. Lower androgens, pro-androgens and estrogens, but higher cortisol and metabolites were found in menopausal compared to reproductive age women. Androgens and precursors decreased during reproductive age (P<0.001–P=0.002) but not after menopause. 17OH-progesterone decreased with BMI (P=0.006) and glucocorticoids with waist circumference (P<0.001–P=0.002) in reproductive age, but increased with triglycerides (P=0.011-P=0.038) after menopause. Inverse associations of dihydrotestosterone with BMI (P=0.004) and HDL-cholesterol (P=0.010), estrone with total cholesterol (P=0.033) and estradiol with triglycerides (P=0.011) were found in reproductive age. After menopause, estrone increased with waist circumference (P<0.001) and decreased with insulin resistance (P=0.012). Ovarian steroid RI were estimated in menstrual phases and menopause. Age- and reproductive status-specific RI were generated for androgens, precursors and corticosteroids. Lower limits for reproductive age cortisol (P=0.020) and menopausal 11-deoxycortisol (P=0.003) in dysmetabolic sub-cohorts were reduced and increased, respectively, compared to reference limits.

Conclusions: Obesity and dysmetabolism differently influence circulating steroids in reproductive and menopausal status. Age, menstrual and menopausal status-specific RI were provided by LC-MS/MS for a broad steroid panel.

Free access

Poupak Fallahi, Silvia Martina Ferrari, Giusy Elia, Francesca Ragusa, Sabrina Rosaria Paparo, Stefania Camastra, Valeria Mazzi, Mario Miccoli, Salvatore Benvenga, and Alessandro Antonelli

Tyrosine kinase inhibitors (TKIs) are emerging as potentially effective options in the treatment of cancer, acting on the pathways involved in growth, avoidance of apoptosis, invasiveness, angiogenesis, and local and distant spread. TKIs induce significant adverse effects, that can negatively affect patients’ quality of life. The most common adverse events (AEs) include fatigue, hand–foot skin reaction, decreased appetite, nausea, diarrhea, hypertension, vomiting, weight loss, endocrinopaties and metabolic disorders. Patients in therapy with TKIs can develop endocrine-metabolic disorders, including dyslipidemia (~50%), diabetes (~15–40%), and dysthyroidism (~20%). In some cases, patients show an improved glycemia or hypoglycemia. The effects of TKIs on adrenal or gonadal function are still not completely known. It was shown a higher prevalence of subclinical hypocortisolism in patients treated with imatinib, while an increase of cortisol was reported in patients receiving vandetanib. Long-term treatment with imatinib could impact significantly the ovarian reserve and embryo developmental capacity. It is important to evaluate patients, measure glucose levels, and manage hyperglycemia. Mild treatment-related hyperglycemia can be controlled modifying the diet and with exercise, while grade 3 and 4 hyperglycemia can lead to dose reductions and/or oral antihyperglycemic therapy. Regarding thyroid dysfunctions, it is recommendable to measure the thyroid-stimulating hormone (TSH)/free thyroxine (FT4) levels before starting the therapy, and every 3–4 weeks during the first 6 months as changes in FT4 levels precede the changes in TSH by 3–6 weeks. Additional studies are necessary to definitely clarify the mechanism of TKIs-induced endocrine-metabolic effects.