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

COVID-19 has changed the nature of medical consultations, emphasizing virtual patient counseling, 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 the postoperative syndrome of inappropriate antidiuresis (SIAD). They should know hyponatraemia symptoms. The prevalence of hyponatraemia in patients with pneumonia due to COVID-19 is not yet known, but seems to be low. In contrast, hypernatraemia may develop in COVID-19 patients in ICU, 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.

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Kristien Boelaert, W Edward Visser, Peter Nicholas Taylor, Carla Moran, Juliane Léger, and Luca Persani

This manuscript provides guidance on the management of thyroid dysfunction during the COVID-19 pandemic. Autoimmune thyroid diseases are not linked to increased risks of COVID-19. Uncontrolled thyrotoxicosis may result in more severe complications from SARS-CoV-2 infection, including thyroid storm. The management of patients with a new diagnosis of hyperthyroidism is best undertaken with a block-and-replace regimen due to limited biochemical testing availability. Antithyroid drug (ATD)-induced neutropenia may favour the progression of COVID-19 and symptoms of infection may be confused with SARS-CoV-2 infection. The withdrawal of ATDs and urgent measurement of neutrophils should be considered in case of flu-like manifestations occurring in the initial months of treatment. Urgent surgery or 131-I may be undertaken in selected cases of uncontrolled thyrotoxicosis. Patients with COVID-19 infection may present with conjunctivitis, which could cause diagnostic difficulties in patients with new or existing Graves’ ophthalmopathy. Patients who are on replacement treatment with thyroid hormones should ensure they have sufficient supply of medication. The usual advice to increase dosage of levothyroxine during pregnancy should be adhered to. Many newly presenting and previously diagnosed patients with thyroid dysfunction can be managed through virtual telephone or video clinics supported by a dedicated nurse-led service, depending on available facilities.

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Maria Fleseriu, Olaf M Dekkers, and Niki Karavitaki

Patients with pituitary tumours, ensuing hormonal abnormalities and mass effects are usually followed in multidisciplinary pituitary clinics and can represent a management challenge even during the times of non-pandemic. The COVID-19 pandemic has put on hold routine medical care for hundreds of millions of patients around the globe, while many pituitary patients’ evaluations cannot be delayed for too long. Furthermore, the majority of patients with pituitary tumours have co-morbidities potentially impacting the course and management of COVID-19 (e.g. hypopituitarism, diabetes mellitus, hypertension, obesity and cardiovascular disease). Here, we summarize some of the diagnostic and management dilemmas encountered, and provide guidance on safe and as effective as possible delivery of care in the COVID-19 era. We also attempt to address how pituitary services should be remodelled in the event of similar crises, while maintaining or even improving patient outcomes. Regular review of these recommendations and further adjustments are needed, depending on the evolution of the COVID-19 pandemic status. We consider that the utilization of successful models of pituitary multidisciplinary care implemented during the COVID-19 pandemic should continue after the crisis is over by using the valuable and exceptional experience gained during these challenging times.

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Alexis Vrachimis, Ioannis Iakovou, Evanthia Giannoula, and Luca Giovanella

Most patients with thyroid nodules and thyroid cancer (TC) referred for diagnostic work-up and treatment are not considered at higher risk of infection from SARS-CoV-2 compared to the general population. On the other hand, healthcare resources should be spared to the maximum extent possible during a pandemic. Indeed, while thyroid nodules are very common, only a small percentage are cancerous and, in turn, most thyroid cancers are indolent in nature. Accordingly, diagnostic work-up of thyroid nodules, thyroid surgery for either benign or malignant thyroid nodules and radioiodine treatment for differentiated thyroid cancers may be safely postponed during SARS-CoV-2 pandemic. Appropriate patient counselling, however, is mandatory and red flags should be carefully identified prompting immediate evaluation and treatment as appropriate. For these selected cases diagnostic work-up (e.g. ultrasound, scintigraphy, fine-needle aspiration), surgery and radioiodine therapy may proceed despite the threat of SARS-CoV-2 infection and COVID-19, after an individual risk-benefit analysis.

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Yunglin Gazes, Minghao Liu, Melissa Sum, Elaine Cong, Jennifer Kuo, James A Lee, Shonni Silverberg, Yaakov Stern, and Marcella Walker

Objective

The neurophysiological mechanisms underlying cognitive dysfunction in primary hyperparathyroidism (PHPT) and the brain regions affected are not clear. We assessed neural activation during cognitive testing (matrix reasoning, paired associates, and logical memory) using functional MRI (fMRI) in 23 patients with PHPT and 23 healthy controls. A subset with PHPT was re-assessed 6 months post-parathyroidectomy (PTX).

Design

This is an observational study comparing neural activation by fMRI in patients with PHPT to normative controls. Postmenopausal women were studied at a tertiary referral center.

Results

There were no between-group differences in cognitive task performance. Patients with PHPT had lower neural activation vs controls (max Z = 4.02, all P < 0.01) during matrix reasoning in brain regions involved in executive function (left frontal lobe (k = 57) and right medial frontal gyrus (k = 72)) and motor function (right precentral gyrus (k = 51)). During paired associates (verbal memory), those with PHPT had greater activation in the right inferior parietal lobule (language/mathematical operations; k = 65, P < 0.01). Greater activation in this region bilaterally correlated with higher PTH (k = 96, P < 0.01). Post-PTX, activation decreased during matrix reasoning, but in different regions than those affected pre-PTX.

Conclusions

PHPT is associated with differences in task-related neural activation patterns, but no difference in cognitive performance. While this may indicate compensation to maintain the same cognitive function, there was no clear improvement in neural activation after PTX. Larger, longitudinal studies that include PHPT patients followed without surgery are needed to determine if PTX could prevent worsening of altered neural activation patterns in PHPT.

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Alexander S Busch, Casper P Hagen, and Anders Juul

Objective

Pubertal timing is highly heritable. Observational studies were inconclusive concerning a potential sex-specific difference in the parental contribution, while genome-wide association studies highlighted a heterogeneity in the genetic architecture of pubertal timing between sexes. Our objectives were to evaluate the association of timing of pubertal milestones in offspring with parental pubertal timing and to identify the genetic basis of the heterogeneity.

Design

(1.) Population-based mixed cross-sectional/longitudinal cohort (2006–2014, COPENHAGEN Puberty Study) comprising 1381 healthy Danish children including their parents. (2.) UK Biobank-based summary statistics of genetic data on timing of menarche (n = 188 644), voice-break (n = 154 459) and facial hair (n = 161 470).

Methods

(1.) Participants underwent clinical examination(s) including blood sampling. Parental pubertal timing was obtained by questionnaire. Timing of milestones were analyzed using SAS-lifereg. (2.) Genetic correlations between pubertal outcomes were estimated using LD Score regression. Genetic heterogeneity was analyzed using METAL.

Results

We observed significant associations of relative parental pubertal timing with timing of pubertal milestones in offspring of concordant sex, that is, fathers/sons (e.g. testicular enlargement: P = 0.004, β = 0.34 years per relative category) and mothers/daughters (e.g. thelarche: P < 0.001, β = 0.45 years per relative category). Fewer milestones were associated with relative parental pubertal timing in offspring of discordant sex compared to concordant sex. Large-scale genetic data highlight both moderate to strong genetic correlations between timing of menarche, voice-break and facial hair. Out of 434 lead single-nucleotide polymorphisms significantly associated with at least one outcome, 39 exhibited a significant genetic heterogeneity between sexes (P < 1.15 × 10−4).

Conclusion

Our results highlight a distinct genetic heterogeneity of pubertal timing between sexes.

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Marta Fichna, Piotr P Małecki, Mirela Młodzikowska, Bolesław Gębarski, Marek Ruchała, and Piotr Fichna

Objective

Autoimmune conditions tend to cluster in subjects with Addison’s disease (AD) and probably also among their relatives. The aim of the study was to estimate the frequency of the endocrine gland-specific autoantibodies in first-degree relatives of patients with AD.

Methods

Autoantibodies were investigated in 113 family members using RIA and ELISA assays. The control group comprised 143 age-matched volunteers.

Results

Autoimmune diseases were diagnosed in 38.1% relatives. Hashimoto’s thyroiditis was found in 20.3%, Graves’ disease in 8.0%, vitiligo and type 1 diabetes in 3.5%, whereas AD, rheumatoid arthritis and atrophic gastritis with pernicious anaemia in 2.7% each.

All studied antibodies except for islet antigen-2 (P = 0.085) were significantly more frequent in AD relatives than in controls (P < 0.05). Antibodies to 21-hydroxylase were detected in 6.2% relatives, thyroid peroxidase in 28.3%, thyroglobulin in 19.5%, glutamic acid decarboxylase in 8.0%, and zinc transporter-8 in 7.1%. Two and more autoantibodies were detected in 18.6% subjects. Significant gender difference was revealed only for aTPO, more common in female relatives (P = 0.014; OR: 3.16; 95% CI: 1.23–8.12). Circulating autoantibodies were found more frequently in the relatives of affected males (P = 0.008; OR: 3.31; 95% CI: 1.33–8.23), and in family members of patients with polyendocrine autoimmunity (P = 0.009; OR: 3.55; 95% CI: 1.31–9.57).

Conclusions

This study provides evidence of increased susceptibility for the endocrine autoimmunity, especially thyroid disease, in close relatives of patients with AD. Relatives of the male AD patients and of those with autoimmune polyendocrine syndrome are at particular risk and should undergo periodic screening for autoimmune endocrine disorders.

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Dimitrios Chantzichristos, Björn Eliasson, and Gudmundur Johannsson

Concurrent type 1 diabetes (T1D) and Addison’s disease (AD) is a rare combination of diseases and, in approximately one third of these patients, it is also combined with an autoimmune thyroid disease. Recently, it was shown that patients with both T1D and AD have a higher risk of premature death compared to patients with T1D alone, the most common causes of death being due to diabetic complications and cardiovascular disease. These patients receiving replacement therapies with both insulin and glucocorticoids face an increased risk of hypo- and hyperglycemia and diabetic ketoacidosis and have a higher risk of adrenal crisis than patients with AD alone. Treatment challenges include the opposing effects of insulin and glucocorticoids on glucose homeostasis and the need to balance and synchronize these two treatments. The rarity of this disease combination may explain the paucity of data on outcome and specific treatment strategies in this patient group. Based on this review, we suggest management strategies for their insulin and glucocorticoid replacement therapies and indicate future areas of research.

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Brigette Marie Clarke, Andrew D Vincent, Sean Martin, Robert Adams, Sarah Appleton, Andrew Vakulin, David Jesudason, and Gary Allen Wittert

Objective

Obstructive sleep apnea (OSA) is generally considered to lower serum testosterone concentration in men, although data supporting this as a direct effect are limited. The aim of this study was to determine the relationship between the presence and severity of OSA and testosterone in a community-based cohort of men aged over 40 years.

Design and methods

Anthropometry, polysomnography and biomedical information were collected from enrolled, consenting men from the prospective, longitudinal MAILES study cohort. Fasting morning blood samples (n = 1869) were drawn between 2010 and 2012 for measurement of testosterone using liquid chromatography mass spectrometry. Home polysomnography was completed in 861 men between 2010 and 2012. The final analysis sample consisted of 623 men aged 41–86 years. The effect of OSA on testosterone were analyzed using linear regression models controlling for potential confounders (age, BMI and sex hormone binding globulin (SHBG)).

Results

The mean (s.d.) cohort characteristics were: age 59.0 (10.2) years, testosterone 16.8 (5.3) nmol/L, SHBG 32.9 (13.1) nmol/L, BMI 28.6 (4.2) kg/m2 and apnoea hypopnoea index (AHI) 14.9 (13.7). OSA was present in 51.5%. There was an inverse relationship between AHI and testosterone (P = 0.01), which was lost after covariate adjustment.

Conclusions

These data suggest that obesity, rather than OSA per se, determine testosterone concentration. This accords with the graded effect of weight loss, but limited effect of continuous positive airway pressure to increase testosterone, and highlights the importance of managing obesity in men with low testosterone concentration, particularly in the context of OSA.

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Shirui Wang, Yuelun Zhang, Shubin Lei, Huijuan Zhu, Jianqiang Li, Qing Wang, Jijiang Yang, Shi Chen, and Hui Pan

Objective

Automatic diabetic retinopathy screening system based on neural networks has been used to detect diabetic retinopathy (DR). However, there is no quantitative synthesis of performance of these methods. We aimed to estimate the sensitivity and specificity of neural networks in DR grading.

Methods

Medline, Embase, IEEE Xplore, and Cochrane Library were searched up to 23 July 2019. Studies that evaluated performance of neural networks in detection of moderate or worse DR or diabetic macular edema using retinal fundus images with ophthalmologists’ judgment as reference standard were included. Two reviewers extracted data independently. Risk of bias of eligible studies was assessed using QUDAS-2 tool.

Results

Twenty-four studies involving 235 235 subjects were included. Quantitative random-effects meta-analysis using the Rutter and Gatsonis hierarchical summary receiver operating characteristics (HSROC) model revealed a pooled sensitivity of 91.9% (95% CI: 89.6% to 94.3%) and specificity of 91.3% (95% CI: 89.0% to 93.5%). Subgroup analyses and meta-regression did not provide any statistically significant findings for the heterogeneous diagnostic accuracy in studies with different image resolutions, sample sizes of training sets, architecture of convolutional neural networks, or diagnostic criteria.

Conclusions

State-of-the-art neural networks could effectively detect clinical significant DR. To further improve diagnostic accuracy of neural networks, researchers might need to develop new algorithms rather than simply enlarge sample sizes of training sets or optimize image quality.