Emerging evidence indicates that testosterone, which can increase muscle mass and strength, stimulates erythropoiesis, promotes competitive behaviour, and enhances the physical performance of women. Indeed, the levels of testosterone within the normal female range are related to muscle mass and athletic performance in female athletes. Furthermore, among these athletes, the prevalence of hyperandrogenic conditions, including both polycystic ovary syndrome and rare differences/disorders of sex development (DSD), which may greatly increase testosterone production, are elevated. Thus, if the androgen receptors of an individual with XY DSD are functional, her muscle mass will develop like that of a man. These findings have led to the proposal that essential hyperandrogenism is beneficial for athletic performance and plays a role in the choice by women to compete in athletic activities. Moreover, a recent randomized controlled trial demonstrated a significant increase in the lean mass and aerobic performance by young exercising women when their testosterone levels were enhanced moderately. Circulating testosterone is considered the strongest factor to explain the male advantage in sport performance, ranging between 10 and 20%. It appears to be unfair to allow female athletes with endogenous testosterone levels in the male range (i.e. 10–20 times higher than normal) to compete against those with normal female androgen levels. In 2012, this consideration led international organizations to establish eligibility regulations for the female classification in order to ensure fair and meaningful competition, but the regulations are controversial and have been challenged in court.
Angelica Lindén Hirschberg
Jie Shi, Zhen Yang, Yixin Niu, Weiwei Zhang, Ning Lin, Xiaoyong Li, Hongmei Zhang, Hongxia Gu, Jie Wen, Guang Ning, Li Qin, and Qing Su
A small thigh circumference is associated with an increased risk of diabetes, cardiovascular diseases, and total mortality. The purpose of this study was to evaluate the association between thigh circumference and hypertension in the middle-aged and elderly population.
A total of 9520 individuals aged 40 years and older with measurement of thigh circumference were available for analysis. The measurement of thigh circumference was performed directly below the gluteal fold of the thigh. The association of thigh circumference with hypertension was tested in logistic regression analyses and reported as odds ratio (OR) with 95% CI.
Thigh circumference was negatively correlated with systolic blood pressure, diastolic blood pressure, fasting glucose, and total cholesterol. Compared with the lowest thigh circumference tertile group, the risk of hypertension was significantly lower in the highest tertile group, both in overweight individuals (OR 0.68; 95% CI 0.59–0.79, P < 0.001) and obese individuals (OR 0.51; 95% CI 0.38–0.70, P < 0.001).
In the present study, large thigh circumference is associated with lower risk of hypertension in overweight and obese Chinese individuals.
Julia Modesto Vicente, Junia Carolina Santos-Silva, Caio Jordão Teixeira, Dailson Nogueira de Souza, Jean Franciesco Vettorazzi, Fabiola Sales Furtuoso, Isabel Gouveia Adabo, Fabio Takeo Sato, Marco Aurélio Ramirez Vinolo, Everardo Magalhães Carneiro, Silvana Bordin, and Gabriel Forato Anhê
Observational studies show that longer breastfeeding periods reduce maternal risk of type 2 diabetes mellitus. However, it is currently unknown if the long-term benefits of breastfeeding for maternal glucose homeostasis are linked to changes in the endocrine pancreas.
We presently evaluated functional, morphological and molecular aspects of the endocrine pancreas of mice subjected to two sequential cycles of pregnancy and lactation (L21). Age-matched mice not allowed to breastfeed (L0) and virgin mice were used as controls.
L21 mice exhibited increased tolerance and increased glucose-stimulated insulin secretion (GSIS) by isolated islets. Pancreatic islets of L21 mice did not present evident morphological changes to justify the increased GSIS. On the other hand, islets of L21 mice exhibited a reduction in Cavb3 and Kir6.2 expression with concordant increased intracellular Ca2+ levels after challenge with glucose.
Altogether, the present findings show the breastfeeding exerts long-term benefits for maternal endocrine pancreas by increasing intracellular Ca2+ levels and GSIS.
Hongyan Wang, Bin Wu, Zichuan Yao, Xianqing Zhu, Yunzhong Jiang, and Song Bai
Although resection is the primary treatment strategy for pheochromocytoma, surgery is associated with a high risk of morbidity. At present, there is no nomogram for prediction of severe morbidity after pheochromocytoma surgery, thus the aim of the present study was to develop and validate a nomogram for prediction of severe morbidity after pheochromocytoma surgery.
The development cohort consisted of 262 patients who underwent unilateral laparoscopic or open pheochromocytoma surgery at our center between 1 January 2007 and 31 December 2016. The patients’ clinicopathological characters were recorded. The least absolute shrinkage and selection operator (LASSO) binary logistic regression model was used for data dimension reduction and feature selection, then multivariable logistic regression analysis was used to develop the predictive model. An independent validation cohort consisted of 128 consecutive patients from 1 January 2017 and 31 December 2018. The performance of the predictive model was assessed in regards to discrimination, calibration, and clinical usefulness.
Predictors of this model included sex, BMI, coronary heart disease, arrhythmia, tumor size, intraoperative hemodynamic instability, and surgical duration. For the validation cohort, the model showed good discrimination with an AUROC of 0.818 (95% CI, 0.745, 0.891) and good calibration (Unreliability test, P = 0.440). Decision curve analysis demonstrated that the model was also clinically useful.
A nomogram was developed to facilitate the individualized prediction of severe morbidity after pheochromocytoma surgery and may help to improve the perioperative strategy and treatment outcome.
Petar Milovanovic and Björn Busse
An increasing number of patients worldwide suffer from bone fractures that occur after low intensity trauma. Such fragility fractures are usually associated with advanced age and osteoporosis but also with long-term immobilization, corticosteroid therapy, diabetes mellitus, and other endocrine disorders. It is important to understand the skeletal origins of increased bone fragility in these conditions for preventive and therapeutic strategies to combat one of the most common health problems of the aged population. This review summarizes current knowledge pertaining to the phenomenon of micropetrosis (osteocyte lacunar mineralization). As an indicator of former osteocyte death, micropetrosis is more common in aged bone and osteoporotic bone. Considering that the number of mineralized osteocyte lacunae per bone area can distinguish healthy, untreated osteoporotic and bisphosphonate-treated osteoporotic patients, it could be regarded as a novel structural marker of impaired bone quality. Further research is needed to clarify the mechanism of lacunar mineralization and to explore whether it could be an additional target for preventing or treating bone fragility related to aging and various endocrine diseases.
Wentao Zhou, Tiantao Kuang, Xu Han, Wenqi Chen, Xuefeng Xu, Wenhui Lou, and Dansong Wang
Systemic inflammation markers have been demonstrated to be associated with prognosis in various tumors. In this study, we aimed to assess the value of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio, lymphocyte-to-monocyte ratio (LMR), systemic immune-inflammation index and the counts of lymphocyte, monocyte and neutrophil in predicting prognosis among patients with resected pancreatic neuroendocrine neoplasms (pNENs).
A total of 174 patients were included in the study. Univariate and multivariate analyses were performed to evaluate the predictive roles of inflammation markers for relapse-free survival (RFS) and overall survival (OS) in pNEN patients.
The optimal cut-off values of NLR, LMR and lymphocyte count were 1.9, 5.0 and 1.4 × 109/L, respectively, determined by the X-tile software. RFS was found to be significantly longer in patients with NLR ≤1.9 (P = 0.041), LMR >5.0 (P < 0.001) and lymphocyte count >1.4 × 109/L (P = 0.002) in comparison to those with NLR >1.9, LMR ≤5.0 and lymphocyte count ≤1.4 × 109/L, respectively. Multivariate analysis revealed that LMR (hazard ratio 0.30, 95% CI 0.11–0.85, P = 0.023) was an independent predictor for RFS, but not NLR or lymphocyte count. For long-term survival analysis, patients with NLR ≤1.9 (P = 0.016) were found to be associated with favorable OS, but NLR was not an independent factor validated by multivariate analysis.
Preoperative LMR is an independent systemic inflammation marker to predict relapses in pNEN patients who underwent curative resections, whose clinical value needs to be verified in further large sample-based prospective studies.
Filippo Ceccato, Diego Cecchin, Michele Gregianin, Giacomo Ricci, Cristina Campi, Filippo Crimì, Marta Bergamo, Annibale Versari, Carmelo Lacognata, Federico Rea, Mattia Barbot, and Carla Scaroni
Introduction and aim
Ectopic ACTH secretion (EAS) is mostly secondary to thoracic/abdominal neuroendocrine tumours (NETs) or small cell-lung carcinoma (SCLC). We studied the diagnostic accuracy of CT with 68Ga-Dota derivatives (68Ga-SSTR) PET in localizing ACTH-secreting tumor in patients with EAS.
Materials and methods
68Ga-SSTR-PET/CT was performed and compared with the nearest enhanced CT in 18 cases (16 primary and 2 recurrent neoplasms). Unspecific, indeterminate and false-positive uptakes were assessed using conventional imaging, follow-up or histology.
We diagnosed 13 thoracic (9 primary and 2 recurrent bronchial carcinoids, 2 SCLCs) and 1 abdominal (pancreatic NET) tumors. Eight ACTH-secreting tumors were promptly identified at EAS diagnosis (’overt’, four pulmonary carcinoids with two recurrences and two SCLC); six EAS have been discovered during the subsequent follow-up (’covert’, five bronchial carcinoids and one pancreatic NET). At the time of EAS diagnosis, imaging was able to correctly detect the ACTH-secreting tumour in 8/18 cases (6 new diagnosis and 2 recurrences). During the follow-up, six out of initially ten ‘occult’ cases became ‘covert’. At last available follow-up, CT and 68Ga-SSTR-PET/CT were able to diagnose 11/18 and 12/18 ACTH-secreting tumours, respectively (11/14 and 12/14 considering only overt and covert cases, respectively). Four cases have never been localized by conventional or nuclear imaging (’occult EAS’), despite an average follow-up of 5 years.
The 68Ga-SSTR-PET/CT is useful in localizing EAS, especially to enhance positive prediction of the suggestive CT lesions and to detect occult neoplasms.
Kim K B Clemmensen, Jonas S Quist, Dorte Vistisen, Daniel R Witte, Anna Jonsson, Oluf Pedersen, Torben Hansen, Jens J Holst, Torsten Lauritzen, Marit E Jørgensen, Signe Torekov, and Kristine Færch
Fasting duration has been associated with lower fasting blood glucose levels, but higher 2-h post-load levels, and research has indicated an adverse effect of ‘weekend behavior’ on human metabolism. We investigated associations of fasting duration and weekday of examination with glucose, insulin, glucagon and incretin responses to an oral glucose tolerance test (OGTT). This cross-sectional study is based on data from the ADDITION-PRO study, where 2082 individuals attended a health examination including an OGTT. Linear regression analysis was applied to study the associations of overnight fasting duration and day of the week with glucose, insulin, glucagon, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) responses to an OGTT. We found that a 1 h longer fasting duration was associated with 1.7% (95% CI: 0.8,2.5) higher 2-h glucose levels, as well as a 3.0% (95% CI: 1.3,4.7) higher GIP and 2.3% (95% CI: 0.3,4.4) higher GLP-1 response. Fasting insulin levels were 20.6% (95% CI: 11.2,30.7) higher on Mondays compared to the other weekdays, with similar fasting glucose levels (1.7%, 95% CI: 0.0,3.4). In this study, longer overnight fasting duration was associated with a worsening of glucose tolerance and increased incretin response to oral glucose. We found higher fasting insulin levels on Mondays compared to the other days of the week, potentially indicating a worsened glucose regulation after the weekend.
Florian Schederecker, Alexander Cecil, Cornelia Prehn, Jana Nano, Wolfgang Koenig, Jerzy Adamski, Tanja Zeller, Annette Peters, and Barbara Thorand
Sex hormone-binding globulin (SHBG) and androgens have been associated with mortality in women and men, but controversy still exists. Our objective was to investigate associations of SHBG and androgens with all-cause and cause-specific mortality in men and women.
1006 men and 709 peri- and postmenopausal women (age range: 45–82 years) from the German population-based KORA F4 cohort study were followed-up for a median of 8.7 years.
SHBG was measured with an immunoassay, total testosterone (TT) and dihydrotestosterone (DHT) with mass-spectrometry in serum samples and we calculated free testosterone (cFT). To assess associations between SHBG and androgen levels and mortality, we calculated hazard ratios (HRs) with 95% CIs using Cox proportional-hazards models.
In the cohort, 128 men (12.7%) and 70 women (9.9%) died. In women, we observed positive associations of SHBG with all-cause (HR: 1.54, 95% CI: 1.16–2.04) and with other disease-related mortality (HR: 1.86, 95% CI: 1.08–3.20) and for DHT with all-cause mortality (HR: 1.32, 95% CI: 1.00–1.73). In men, we found a positive association of SHBG (HR: 1.24 95% CI: 1.00–1.54) and inverse associations of TT (HR: 0.87, 95% CI: 0.77–0.97) and cFT (HR: 0.84, 95% CI: 0.73–0.97) with all-cause mortality. No other associations were found for cause-specific mortality.
Higher SHBG levels were associated with increased risk of all-cause mortality in men and women. Lower TT and cFT levels in men and higher DHT levels in women were associated with increased risk of all-cause mortality. Future, well-powered population-based studies should further investigate cause-specific mortality risk.
Anna Olsson-Brown, Rosemary Lord, Joseph Sacco, Jonathan Wagg, Mark Coles, and Munir Pirmohamed
Immune checkpoint inhibitors can lead to thyroid dysfunction. However, the understanding of the clinical phenotype of ICI-induced thyroid dysfunction in the real-world population is limited. The purpose of this study was to characterise the clinical patterns of dysfunction and evaluate the demographic, biochemical and immunological features associated with this patient cohort.
Materials and methods
To characterise the longitudinal clinical course of thyroid dysfunction in patients from a single, UK regional cancer centre, a retrospective review of patients was conducted. Inclusion criteria included all patients treated with antiPD-1 checkpoint inhibitors (ICI), either as monotherapy (pembrolizumab/nivolumab) or in combination with a CTLA-4 inhibitor (ipilimumab). Patterns of toxicity were evaluated together with assessment of antibody titres.
Over 16 months, thyroid dysfunction was seen in 13/90 and 3/13 patients treated with anti-PD1 monotherapy and in combination with ipilimumab, respectively. Patients either developed hyperthyroidism followed by hypothyroidism (12/16) or de novo hypothyroidism (4/16). Most patients were female (n = 11). All patients required thyroid replacement therapy. There was no relationship between clinical pattern of dysfunction and the presence of thyroid autoantibodies.
There are two distinct patterns of thyroid dysfunction in ICI-treated patients. Patients with thyroiditis develop subsequent hypothyroidism in the vast majority of cases. The potential benefit from steroids or other therapy to manage the hyperthyroid phase remains unclear. Early detection of these patients through appropriate monitoring will improve clinical management and early hormone replacement, reducing the symptomatic burden of hypothyroidism.