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Open access

Veronica Mericq, Isabel Huang-Doran, Dhekra Al-Naqeb, Javiera Basaure, Claudia Castiglioni, Christiaan de Bruin, Yvonne Hendriks, Enrico Bertini, Fowzan S Alkuraya, Monique Losekoot, Khalid Al-Rubeaan, Robert K Semple, and Jan M Wit

Objective

To describe clinical, laboratory, and genetic characteristics of three unrelated cases from Chile, Portugal, and Saudi Arabia with severe insulin resistance, SOFT syndrome, and biallelic pathogenic POC1A variants.

Design

Observational study.

Methods

Probands’ phenotypes, including short stature, dysmorphism, and insulin resistance, were compared with previous reports.

Results

Cases 1 (female) and 3 (male) were homozygous for known pathogenic POC1A variants: c.649C>T, p.(Arg217Trp) and c.241C>T, p.(Arg81*), respectively. Case 2 (male) was compound heterozygous for p.(Arg217Trp) variant and the rare missense variant c.370G>A, p.(Asp124Asn). All three cases exhibited severe insulin resistance, acanthosis nigricans, elevated serum triglycerides and decreased HDL, and fatty liver, resembling three previously reported cases. All three also reported severe muscle cramps. Aggregate analysis of the six known cases with biallelic POC1A variants and insulin resistance showed decreased birth weight and length mean (s.d.): −2.8 (0.9) and −3.7 (0.9) SDS, respectively), severe short stature mean (s.d.) height: −4.9 (1.7) SDS) and moderate microcephaly (mean occipitofrontal circumference −3.0 (range: −4.7 to −1.2)). These findings were similar to those reported for patients with SOFT syndrome without insulin resistance. Muscle biopsy in Case 3 showed features of muscle involvement secondary to a neuropathic process.

Conclusions

Patients with SOFT syndrome can develop severe dyslipidaemic insulin resistance, independent of the exonic position of the POC1A variant. They also can develop severe muscle cramps. After diagnosis, patients should be regularly screened for insulin resistance and muscle complaints.

Free access

Decio Armanini, Chiara Sabbadin, Luigi De Marco, and Luciana Bordin

In a recent paper, Subramanian and collaborators reported a 52% increased risk of COVID-19 infection in women with polycystic ovary syndrome (PCOS) and an incidence nearly twice that of women without PCOS. The authors focused, as important factors of the increased prevalence of infection, both the inflammatory characteristic of PCOS and the increase in androgens that facilitate the entry of the virus into the cells of the target organs. We asked 200 consecutive, unvaccinated women with PCOS who had been followed with spironolactone for more than 4 months, about COVID-19 infection and found only four patients who were infected. None of the infected patients were hospitalized and only one had fever and other manifestations of the syndrome, but these symptoms resolved in a few days. The other three reported only mild or minimal symptoms. This observation needs confirmation with specific studies, considering the possibility that many other patients may have been infected by being asymptomatic and not swabbing for COVID-19. Spironolactone can increase the circulating angiotensin-converting enzyme 2 and antagonize the androgen receptor, preventing activation of transmembrane protease serine 2 in cells of the respiratory tract and other tissues. Drug also has potent anti-inflammatory and antithrombotic actions by antagonizing the mineralocorticoid receptor in target tissues and inflammatory cells. From Subramanian's study and reported observations, a proper evaluation of the use of spironolactone in COVID-19 in both PCOS and the general population is urged.

Free access

Frederic Castinetti, Jean-Baptiste De Freminville, Carole Guerin, Erika Cornu, Gabrielle Sarlon, and Laurence Amar

The question of systematic use of a pharmacological treatment before surgery in patients diagnosed with pheochromocytoma and paraganglioma (PPGL) remains highly controversial. While recent guidelines suggest that this should be used in all patients, some experienced teams consider it unnecessary in some cases, provided the surgery is performed in a dedicated center that has expert endocrinologists, cardiologists, surgeons, and anesthetists. This controversy is aimed at shedding light on the potential benefits and risks of such a treatment, focusing specifically on alpha blockers which are considered as the first-line medical treatments in patients with PPGL. After discussing the rationale for alpha blockers, hemodynamic instability, tolerance, and acute cardiac complications will then be discussed in the first part of the manuscript, defending a systematic use. The second section will focus on blood pressure control, tolerance of alpha blockers, and also the management of normotensive PPGL, examining the daily risks of PPGL and arguing against the systematic use of a preoperative pharmacological treatment before surgery. Finally, we will discuss the concept of expert centers and define the patients in whom the risk/benefit profile would favor the use of this preoperative treatment.

Restricted access

Marie Lindhardt Ljubicic, Alexander S Busch, Emmie N Upners, Margit Bistrup Fischer, Katharina M Main, Anna-Maria Andersson, Trine Holm Johannsen, Casper P. Hagen, and Anders Juul

Objective: Little is known about the ratio between luteinizing hormone (LH) and follicle-stimulating hormone (FSH) during infancy. This study aimed to evaluate serum and urinary LH/FSH as a marker of sex with age-specific cutoffs in healthy infants.

Design: A prospective, longitudinal cohort study of healthy infants aged 0-1.2 years.

Methods: In total, 236 healthy infants (122 boys, 114 girls) from The COPENHAGEN Minipuberty Study (ClinicalTrials.gov ID: NCT02784184), with 567 serum and 603 urine samples, were included. Measures of diagnostic accuracy, including sensitivity and specificity, were used to assess the ability of LH/FSH to detect sex in healthy infants.

Results: In both serum and urine, LH/FSH was highest in males with minimal overlap between the sexes. In contrast to isolated LH and FSH concentrations, LH/FSH ratios in both serum and urine were excellent markers of sex from 0-1.2 years with median sensitivities and specificities ranging from 93-100% with correspondingly narrow 95% confidence intervals.

Conclusions: Serum and urinary LH/FSH ratios are excellent discriminators of sex in healthy infants during the entire first year of life. The clinical role and application of the ratio remains to be elucidated.

Restricted access

Benjamin Burggraaf, Nadine M C Pouw, Salvador Fernández Arroyo, Leonie C van Vark-van der Zee, Gert-Jan M van de Geijn, Erwin Birnie, Jeannine Huisbrink, Ellen M van der Zwan, Wouter W de Herder, Monique T Mulder, Patrick C N Rensen, and Manuel Castro Cabezas

Objectives

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) modulate lipid metabolism and improve cardiovascular morbidity and mortality in patients with type 2 diabetes mellitus (T2DM). The exact cardioprotective mechanism of SGLT2i is unclear. We evaluated the effects of SGLT2i on postprandial lipids, lipoprotein concentrations, glucose and fatty acids.

Design

A placebo-controlled randomized, proof-of-concept study.

Methods

Fourteen male patients with T2DM on intensive insulin regimen were randomly and double-blind allocated to 12 weeks dapagliflozin (10 mg) or placebo. Postprandial effects were assessed with an 8-h standardized oral fat loading test.

Results

Mean glycated A1c did not change by dapagliflozin, but the mean daily insulin dose was significantly reduced. Although dapagliflozin did not affect fasting or postprandial levels of glucose and insulin, it increased the postprandial levels of glucagon. While fasting levels of free fatty acids and beta-hydroxybutyrate (bHBA) were unchanged, dapagliflozin significantly increased the postprandial bHBA response. This was seen in the context of increased postprandial glucagon levels by dapagliflozin, without influencing postprandial insulin or glucose levels. Dapagliflozin did not affect fasting or postprandial plasma cholesterol and triglycerides nor postprandial inflammatory markers. Fasting apolipoprotein B48 was decreased without affecting the postprandial response. Markers of inflammation and vascular function did not change.

Conclusion

Treatment with dapagliflozin of patients with T2DM led to a reduction of fasting chylomicron remnants and increased postprandial ketone bodies compared to placebo suggesting enhanced hepatic fatty acid oxidation. The latter may have been caused by decreasing the insulin–glucagon ratio. The beneficial clinical effects seen in the trials using dapagliflozin most likely are not due to effects on postprandial inflammation nor postprandial lipemia.

Restricted access

Usman Javaid, David Kennedy, Caroline Addison, Vasileios Tsatlidis, and Salman Razvi

Objective

To assess the rationale and frequency of thyroid function testing and to analyse factors that influence serum thyrotropin (TSH) levels.

Patients, design and main outcome measures

Serum TSH levels were evaluated in a hospital laboratory serving a population of 604 000 in 2018. Patients on medications or with conditions affecting thyroid function were excluded. Frequency of thyroid function testing by age and sex was assessed and the relationship between serum TSH with potential predictor variables was analysed using ordinary least square regression analysis allowing for potential non-linearity.

Results

Twenty-eight percent of the local population had their thyroid function tested at least once in 2018 with significant differences by sex (28.2% women vs 23.4% men) and by age groups, with less than 2% of <16-year-old people and more than 50% of >80-year-old people being tested. Most of the symptoms commonly attributed to thyroid dysfunction were not higher in the thyroid dysfunction groups. Serum TSH levels were higher in older people particularly after the age of 60 years, in women (by 0.1 mIU/L), during the early hours of the morning, and in winter and spring seasons. There was remarkable uniformity in the frequency of subclinical thyroid dysfunction, as well as substantial cost savings, if TSH reference intervals were recalculated across sexes, age groups, time-periods and seasons.

Conclusions

Serum TSH is frequently tested in the population but is not a good discriminant of symptoms attributed to thyroid dysfunction. Furthermore, considering the influence of factors on TSH reference limits could significantly impact patient care and resource utilisation.

Restricted access

Davide Giordano, Cecilia Botti, Simonetta Piana, Andrea Castellucci, Andrea Frasoldati, Michele Zini, Martina Fornaciari, Francesco Maria Crocetta, and Angelo Ghidini

Objective

The aim of this study was to report the rationale and selection criteria for hemithyroidectomy and ipsilateral central neck dissection in patients with selected papillary thyroid cancer and to report the surgical and oncological outcomes.

Design

Single-institution retrospective observational study.

Methods

The clinical records of patients with a histopathological diagnosis of low-risk pT1 papillary thyroid cancer who underwent hemithyroidectomy with or without ipsilateral central neck dissection between March 2000 and April 2018 at a tertiary referral center were retrospectively reviewed. Demographic, clinical, and histopathological data were collected.

Results

During the study period, 176 patients underwent hemithyroidectomy for PTC. Thirteen patients (13/176, 7.39%) were lost to follow-up and 74 patients (74/163 45.40%) underwent completion thyroidectomy within 1 month because they were classified intermediate ATA initial risk based on definitive pathology. The final study group was composed of 89 patients, who had a median follow-up of 5.3 years. The mean follow-up was 6.3 years (range: 36–207 months). Eighty-four patients (94.38%) did not experience recurrence in the follow-up period. A total of 5/89 patients (5.62%) underwent delayed completion thyroidectomy with or without neck dissection for recurrent malignancy in the residual lobe (3/5) or regional lymph nodes (2/5). The median time from surgery to recurrence was 24.8 months (range: 6–60). The follicular variant was an independent risk factor for recurrence.

Conclusions

Hemithyroidectomy with or without prophylactic ipsilateral central neck dissection is a valuable treatment option in selected low-risk papillary thyroid cancers and ensures a low risk of recurrence. Prophylactic ipsilateral central compartment dissection could have a role in improving cancer staging, and accurate ultrasonographic follow-up is essential to identify local recurrence.

Open access

Bu B Yeap, Ross J Marriott, Laurens Manning, Girish Dwivedi, Graeme J Hankey, Frederick C. W. Wu, Jeremy K Nicholson, and Kevin Murray

Objective

Men are at greater risk from COVID-19 than women. Older, overweight men, and those with type 2 diabetes, have lower testosterone concentrations, and poorer COVID-19-related outcomes. We analysed associations of premorbid serum testosterone concentrations, not confounded by effects of acute SARS-CoV-2 infection, with COVID-19-related mortality risk in men.

Design

UK Biobank prospective cohort study of community-dwelling men aged 40-69 years.

Methods

Serum total testosterone and sex hormone-binding globulin (SHBG) were measured at baseline (2006-2010). Free testosterone values were calculated (cFT). Incidence of SARS-CoV-2 infections and deaths related to COVID-19 were ascertained from 16 March 2020-31 January 2021, and modelled using time-stratified Cox regression.

Results

In 159,964 men there were 5,558 SARS-CoV-2 infections and 438 COVID-19 deaths. Younger age, higher body mass index, non-white ethnicity, lower educational attainment, and socio-economic deprivation were associated with incidence of SARS-CoV-2 infections, but total testosterone, SHBG, and cFT were not. Adjusting for potential confounders, higher total testosterone was associated with COVID-19-related mortality risk (overall trend P=0.008; hazard ratios, HR [95% confidence intervals] quintile 1, Q1 vs Q5 [reference]: 0.84 [0.65-1.12], Q2:Q5 0.82 [0.63-1.10], Q3:Q5 0.80 [0.66-1.00], Q4:Q5 0.82 [0.75-0.93]). Higher SHBG was also associated with COVID-19 mortality risk (P=0.008), but cFT was not (P=0.248).

Conclusions

Middle-aged to older men with the highest premorbid serum total testosterone and SHBG concentrations are at greater risk of COVID-19-related mortality. Men could be advised that having relatively high serum testosterone concentrations does not protect against future COVID-19-related mortality. Further investigation of causality and potential underlying mechanisms is warranted.

Open access

Esra Arslan Ates, Mehmet Eltan, Bahadir Sahin, Busra Gurpinar Tosun, Tuba Seven Menevse, Bilgen Bilge Geckinli, Andy Greenfield, Serap Turan, Abdullah Bereket, and Tulay Guran

Background

The human INHA gene encodes the inhibin subunit alpha protein, which is common to both inhibin A and B. The functional importance of inhibins in male sex development, sexual function, and reproduction remain largely unknown.

Objective

We report for the first time two male siblings with homozygous INHAmutations.

Methods

The medical files were examined for clinical, biochemical, and imaging data. Genetic analysis was performed using next-generation and Sanger sequencing methods.

Results

Two brothers complained of gynecomastia, testicular pain, and had a history of hypospadias. Biochemistry revealed low serum testosterone, high gonadotropin and anti-Mullerian hormone, and very low/undetectable inhibin concentrations, where available. Both patients had azoospermia in the spermiogram. We have identified a homozygous 2 bp deletion (c.208_209delAG, R70Gfs*3) variant, which leads to a truncated INHA protein in both patients, and confirmed heterozygosity in the parents. The external genital development, pubertal onset and progression, reproductive functions, serum gonadotropins, and sex hormones of mother and father, who were heterozygous carriers of the identified mutation, were normal.

Conclusion

Homozygosity for INHA mutations causes decreased prenatal and postnatal testosterone production and infertility in males, while the heterozygous female and male carriers of INHA mutations do not have any abnormality in sex development and reproduction.

Restricted access

Charlotte Brøns, Anne Cathrine Baun Thuesen, Line Ohrt Elingaard-Larsen, Louise Justesen, Rasmus Tanderup Jensen, Nicolai Stevns Henriksen, Helene Bæk Juel, Joachim Størling, Mathias Ried-Larsen, Lauren M Sparks, Gerrit van Hall, Else Rubæk Danielsen, Torben Hansen, and Allan Vaag

Objective

Ectopic liver fat deposition, resulting from impaired subcutaneous adipose tissue expandability, may represent an age-dependent key feature linking low birth weight (LBW) with increased risk of type 2 diabetes (T2D). We examined whether presumably healthy early middle-aged, non-obese LBW subjects exhibit increased liver fat content, whether increased liver fat in LBW is associated with the severity of dysmetabolic traits and finally whether such associations may be confounded by genetic factors.

Methods

Using 1H magnetic resonance spectroscopy, we measured hepatic fat content in 26 early middle-aged, non-obese LBW and 22 BMI-matched normal birth weight (NBW) males. Endogenous glucose production was measured by stable isotopes, and a range of plasma adipokine and gut hormone analytes were measured by multiplex ELISA. Genetic risk scores were calculated from genome-wide association study (GWAS) data for birth weight, height, T2D, plasma cholesterol and risk genotypes for non-alcoholic fatty liver disease (NAFLD).

Results

The LBW subjects had significantly increased hepatic fat content compared with NBW controls (P= 0.014), and 20% of LBW vs no controls had overt NAFLD. LBW subjects with NAFLD displayed widespread metabolic changes compared with NBW and LBW individuals without NAFLD, including hepatic insulin resistance, plasma adipokine and gut hormone perturbations as well as dyslipidemia. As an exception, plasma adiponectin levels were lower in LBW subjects both with and without NAFLD as compared to NBW controls. Genetic risk for selected differential traits did not differ between groups.

Conclusion

Increased liver fat content including overt NAFLD may be on the critical path linking LBW with increased risk of developing T2D in a non-genetic manner.