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.
Decio Armanini, Chiara Sabbadin, Luigi De Marco, and Luciana Bordin
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.
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
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.
A placebo-controlled randomized, proof-of-concept study.
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.
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.
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.
Usman Javaid, David Kennedy, Caroline Addison, Vasileios Tsatlidis, and Salman Razvi
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.
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.
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.
Davide Giordano, Cecilia Botti, Simonetta Piana, Andrea Castellucci, Andrea Frasoldati, Michele Zini, Martina Fornaciari, Francesco Maria Crocetta, and Angelo Ghidini
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.
Single-institution retrospective observational study.
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.
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.
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.
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
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.
We report for the first time two male siblings with homozygous INHAmutations.
The medical files were examined for clinical, biochemical, and imaging data. Genetic analysis was performed using next-generation and Sanger sequencing methods.
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.
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.
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
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.
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).
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.
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.
Clement N Kufe, Lisa K Micklesfield, Maphoko Masemola, Tinashe Chikowore, Andre P Kengne, Fredrik Karpe, Shane A Norris, Nigel J Crowther, Tommy Olsson, and Julia H Goedecke
Despite a higher prevalence of overweight/obesity in Black South African women compared to men, the prevalence of type 2 diabetes (T2D) does not differ. We explored if this could be due to sex differences in insulin sensitivity, clearance and/or beta-cell function and also sex-specific associations with total and regional adiposity.
This cross-sectional study included 804 Black South African men (n = 388) and women (n = 416). Dual-energy X-ray absorptiometry was used to measure total and regional adiposity. Insulin sensitivity (Matsuda index), secretion (C-peptide index) and clearance (C-peptide/insulin ratio) were estimated from an oral glucose tolerance test.
After adjusting for sex differences in the fat mass index, men were less insulin sensitive and had lower beta-cell function than women (P < 0.001), with the strength of the associations with measures of total and central adiposity being greater in men than women (P < 0.001 for interactions). Further, the association between total adiposity and T2D risk was also greater in men than women (relative risk ratio (95% CI): 2.05 (1.42–2.96), P < 0.001 vs 1.38 (1.03–1.85), P = 0.031).
With increasing adiposity, particularly increased centralisation of body fat linked to decreased insulin sensitivity and beta-cell function, Black African men are at greater risk for T2D than their female counterparts.
Christina Wenzek, Anita Boelen, Astrid M Westendorf, Daniel R Engel, Lars C Moeller, and Dagmar Führer
Over the past few years, growing evidence suggests direct crosstalk between thyroid hormones (THs) and the immune system. Components of the immune system were proposed to interfere with the central regulation of systemic TH levels. Conversely, THs regulate innate and adaptive immune responses as immune cells are direct target cells of THs. Accordingly, they express different components of local TH action, such as TH transporters or receptors, but our picture of the interplay between THs and the immune system is still incomplete. This review provides a critical overview of current knowledge regarding the interaction of THs and the immune system with the main focus on local TH action within major innate and adaptive immune cell subsets. Thereby, this review aims to highlight open issues which might help to infer the clinical relevance of THs in host defence in the context of different types of diseases such as infection, ischemic organ injury or cancer.
Christopher Rohde, Nanna Brix Finnerup, Norbert Schmitz, Troels Staehelin Jensen, Reimar Wernich Thomsen, and Søren Dinesen Østergaard
It is largely unknown whether individuals with diabetic neuropathy face an increased risk of developing mental illness. Therefore, in a population-based cohort study, we aimed to examine whether individuals with diabetic neuropathy are at elevated risk of being diagnosed with a mental disorder compared to diabetes-duration-matched individuals without diabetic neuropathy.
We used the nationwide Danish registers to identify all individuals diagnosed with diabetic neuropathy between January 1, 1996, and January 1, 2019. For each of these individuals, we identified up to five individuals with diabetes, matched on the duration of illness, who were not diagnosed with diabetic neuropathy. We then compared incidence rates of mental disorders between individuals with diabetic neuropathy and the diabetes-duration-matched individuals using a Cox proportional-hazards model.
Individuals with diabetic neuropathy had a substantial and statistically significant increased risk of being diagnosed with any mental disorder (age- and sex-adjusted hazard rate ratio: 1.40, 95% CI: 1.31–1.48) as well as all specific mental disorders (psychotic disorder, bipolar disorder, unipolar depression, and/or anxiety disorder) compared with diabetes-duration-matched individuals without diabetic neuropathy.
Diabetic neuropathy appears to be associated with a substantially increased risk of developing a mental disorder. Knowledge of the potential mechanisms underlying this association could inform prevention and treatment and should therefore be pursued further.