Circulating glucocorticoids are associated with metabolic syndrome and related cardiometabolic risk factors in non-Africans. This study investigated these associations in Africans, whose metabolic phenotype reportedly differs from Europeans. Adiposity, blood pressure, glycaemia, insulin resistance, and lipid profile, were measured in 316 African men and 788 African women living in Soweto, Johannesburg. The 2009 harmonized criteria were used to define metabolic syndrome. Serum glucocorticoids were measured using liquid chromatography-mass spectrometry. Cortisol was associated with greater odds presenting with metabolic syndrome (odds ratio (95% CI) =1.50 (1.04, 2.17) and higher systolic (beta coefficient, β (95% CI) =0.04 (0.01, 0.08)) and diastolic (0.05 (0.02, 0.09)) blood pressure, but higher HDL (0.10 (0.02, 0.19)) and lower LDL (−0.14 (−0.24, −0.03)) cholesterol concentrations, in the combined sample of men and women. In contrast, corticosterone was only associated with higher insulin sensitivity (Matsuda index; 0.22 (0.03, 0.41)), but this was not independent of BMI. Sex-specific associations were observed, such that both cortisol and corticosterone were associated with higher fasting glucose (standardized β (95% CI): 0.24 (0.12, 0.36) for cortisol and 0.12 (0.01, 0.23) for corticosterone) and HbA1c (0.13 (0.01, 0.25) for cortisol and 0.12 (0.01, 0.24) for corticosterone) in men only, but lower HbA1c (0.10 (−0.20, −0.01) for cortisol and −0.09 (−0.18, −0.03) for corticosterone) in women only. Our study reports for the first time that associations between circulating glucocorticoid concentrations and key cardiometabolic risk factors exhibit both glucocorticoid- and sex-specificity in Africans.
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Siphiwe N Dlamini, Zané Lombard, Lisa K Micklesfield, Nigel Crowther, Shane A Norris, Tracy Snyman, Andrew A Crawford, Brian R Walker, and Julia H Goedecke
Thomas Reinehr, Alberto Sánchez-Guijo, Nina Lass, and Stefan A Wudy
Little information is available on the steroid sulfates profile in obese children. Therefore, we examined whether sulfated steroids are linked with weight status and associated comorbidities in obese children.
We analyzed 66 obese children (mean age 10.5 ± 2.5 years, 57.6% female, 53.9% prepubertal, mean BMI 27.0 ± 4.6 kg/m2, 50% with BMI-SDS reduction >0.5, 50% without BMI-SDS reduction) who participated in an outpatient 1-year intervention program based on exercise, behavior and nutrition therapy. We measured intact sulfated steroids (cholesterol sulfate (CS), pregnenolone sulfate (PregS), 17αOH pregnenolone sulfate (17OH-PregS), 16αOH dehydroepiandrosterone sulfate (16OH-DHEAS), DHEAS, androstenediol-3-sulfate, androsterone sulfate and epiandrosterone sulfate) by LC–MS/MS, and insulin resistance index HOMA, lipids, blood pressure at baseline and 1 year later.
All sulfated steroids except 17OH-PregS, 16OH-DHEAS, androsterone sulfate and epiandrosterone sulfate were higher in boys compared to girls. Concentrations of CS before intervention were higher in children who lost weight. After 1 year of treatment, both groups showed increased levels of DHEAS, 16OH-DHEAS and androstenediol-3-sulfate, but PregS was only increased in children with weight loss. None of the steroid sulfates was significantly related to cardiovascular risk factors or HOMA except 17OH-PregS, which was associated with systolic blood pressure both in cross-sectional (β-coefficient: 0.09 ± 0.07, P = 0.020) and longitudinal analyses (β-coefficient: 0.06 ± 0.04, P = 0.013) in multiple linear regression analyses.
Since higher steroid sulfation capacity was associated with successful weight intervention in children disruption of sulfation may be associated with difficulties to lose weight. Future studies are necessary to prove this hypothesis.
Ananda A Santana-Ribeiro, Giulliani A Moreira-Brasileiro, Manuel H Aguiar-Oliveira, Roberto Salvatori, Vitor O Carvalho, Claudia K Alvim-Pereira, Carlos R Araújo-Daniel, Júlia G Reis-Costa, Alana L Andrade-Guimarães, Alécia A Oliveira-Santos, Edgar R Vieira, and Miburge B Gois-Junior
Walking and postural balance are extremely important to obtain food and to work. Both are critical for quality of life and ability to survive. While walking reflects musculoskeletal and cardiopulmonary systems, postural balance depends on body size, muscle tone, visual, vestibular and nervous systems. Since GH and IGF-I act on all these systems, we decided to study those parameters in a cohort of individuals with severe short stature due to untreated isolated GH deficiency (IGHD) caused by a mutation in the GHRH receptor gene. These IGHD subjects, despite reduction in muscle mass, are very active and have normal longevity.
In a cross-sectional study, we assessed walking (by a 6-min walk test), postural balance (by force platform) and fall risk (by the 'Timed Up and Go' test) in 31 IGHD and 40 matched health controls.
The percentage of the walked distance measured in relation to the predicted one was similar in groups, but higher in IGHD, when corrected by the leg length. Absolute postural balance data showed similar velocity of unipodal support in the two groups, and better values, with open and closed eyes and unipodal support, in IGHD, but these differences became non-significant when corrected for height and lower-limb length. The time in 'Timed Up and Go' test was higher in IGHD cohort, but still below the cut-off value for fall risk.
IGHD subjects exhibit satisfactory walking and postural balance, without increase in fall risk.
Anna Eremkina, Julia Krupinova, Ekaterina Dobreva, Anna Gorbacheva, Ekaterina Bibik, Margarita Samsonova, Alina Ajnetdinova, and Natalya Mokrysheva
Hypercalcemic crisis is a severe but rare complication of primary hyperparathyroidism (PHPT), and data on denosumab treatment of patients with this disease is still very limited. The aim of this paper is to investigate the hypocalcemic effect of denosumab in PHPT patients with severe hypercalcemia when surgery should be delayed or is impossible for some reasons. We performed a retrospective study of 10 patients. The analysis included the use of biochemical markers of calcium-phosphorus metabolism, which were followed after the administration of 60 mg of denosumab. The trend to calcium reduction was already determined on the 3rd day after denosumab administration. In most cases the decrease in serum calcium level to the range of 2.8 mmol/L on average or lower was observed on the 7th day (P = 0.002). In addition to a significant increase in calcium levels we confirmed a significant increase in the estimated glomerular filtration rate on 7th day (P = 0.012). After that, seven patients underwent successful parathyroidectomy and achieved eucalcemia or hypocalcemia, one patient developed the recurrence of parathyroid cancer after initial surgery, while two patients with severe cardiovascular pathology refused surgery. Our study shows that denosumab is a useful tool in PHPT-associated hypercalcemia before surgery or if surgery is contraindicated.
Sirazum Choudhury, Tricia Tan, Katharine Lazarus, and Karim Meeran
The introduction of adrenocortical extract in 1930 improved the life expectancy of hyhpoadrenal patients, with further increases seen after the introduction of cortisone acetate from 1948. Most patients are now treated with synthetic hydrocortisone, and incremental advances have been made with optimisation of daily dosing and the introduction of multidose regimens. There remains a significant mortality gap between individuals with treated hypoadrenalism and the general population. It is unclear whether this gap is a result of glucocorticoid over-replacement, under-replacement or loss of the circadian and ultradian rhythm of cortisol secretion, with the risk of detrimental excess glucocorticoid exposure at later times in the day. The way forwards will involve replacement of the diurnal cortisol rhythm with better glucocorticoid replacement regimens. The steroid profile produced by both prednisolone and dual-release hydrocortisone (Plenadren), provide a smoother glucocorticoid profile of cortisol than standard oral multidose regimens of hydrocortisone and cortisone acetate. The individualisation of prednisolone doses and lower bioavailability of Plenadren offer reductions in total steroid exposure. Although there is emerging evidence of both treatments offering better cardiometabolic outcomes than standard glucocorticoid replacement regimens, there is a paucity of evidence involving very low dose prednisolone (2–4 mg daily) compared to the larger doses (~7.5 mg) historically used. Data from upcoming clinical studies on prednisolone will therefore be of key importance in informing future practice.
Christine Rode Andreasen, Andreas Andersen, Filip Krag Knop, and Tina Vilsbøll
In recent years, glucagon-like peptide 1 receptor agonists (GLP-1RAs) have become central in the treatment of type 2 diabetes (T2D). In addition to their glucose-lowering properties with low risk of hypoglycaemia, GLP-1RAs reduce body weight and show promising results in reducing cardiovascular risk and renal complications in high-risk individuals with T2D. These findings have changed guidelines on T2D management over the last years, and GLP-1RAs are now widely used in overweight patients with T2D as well as in patients with T2D and cardiovascular disease regardless of glycaemic control. The currently available GLP-1RAs have different pharmacokinetic profiles and differ in their ability to improve glycaemia, reduce body weight and in their cardio- and renal protective potentials. Understanding how these agents work, including insights into their pleiotropic effects on T2D pathophysiology, may improve their clinical utilisation and be useful for exploring other indications such as non-alcoholic steatohepatitis and neurodegenerative disorders. In this review, we provide an overview of approved GLP-1RAs, their clinical effects and mode of action, and we offer insights into the potential of GLP-1RAs for other indications than T2D. Finally, we will discuss the emerging data and therapeutic potential of using GLP-1RAs in combinations with other receptor agonists.
Mírian Romitti, Vitor C Fabris, Patricia K Ziegelmann, Ana Luiza Maia, and Poli Mara Spritzer
Polycystic ovary syndrome (PCOS) is the most prevalent endocrine disorder affecting women of reproductive age. PCOS has been associated with distinct metabolic and cardiovascular diseases and with autoimmune conditions, predominantly autoimmune thyroid disease (AITD). AITD has been reported in 18–40% of PCOS women, depending on PCOS diagnostic criteria and ethnicity. The aim of this systematic review and meta-analysis was to summarize the available evidence regarding the likelihood of women with PCOS also having AITD in comparison to a reference group of non-PCOS women. We systematically searched EMBASE and MEDLINE for non-interventional case control, cross-sectional or cohort studies published until August 2017. The Ottawa–Newcastle Scale was used to assess the methodological quality of studies. Statistical meta-analysis was performed with R. Thirteen studies were selected for the present analysis, including 1210 women diagnosed with PCOS and 987 healthy controls. AITD was observed in 26.03 and 9.72% of PCOS and control groups respectively. A significant association was detected between PCOS and chance of AITD (OR = 3.27, 95% CI 2.32–4.63). Notably, after geographical stratification, the higher risk of AITD in PCOS women persisted for Asians (OR = 4.56, 95% CI 2.47–8.43), Europeans (OR = 3.27, 95% CI 2.07–5.15) and South Americans (OR = 1.86, 95% CI 1.05–3.29). AIDT is a frequent condition in PCOS patients and might affect thyroid function. Thus, screening for thyroid function and thyroid-specific autoantibodies should be considered in patients with PCOS even in the absence of overt symptoms. This systematic review and meta-analysis is registered in PROSPERO under number CRD42017079676.
Elena Izkhakov, Joseph Meyerovitch, Micha Barchana, Yacov Shacham, Naftali Stern, and Lital Keinan-Boker
Thyroid cancer (TC) survivors may be at risk of subsequent cardiovascular and cerebrovascular (CaV&CeV) morbidity. The 2009 American Thyroid Association (ATA) guidelines recommended less aggressive treatment for low-risk TC patients. The aim of this study was to assess the atherosclerotic CaV&CeV outcome of Israeli TC survivors compared to individuals with no thyroid disease, and the atherosclerotic CaV&CeV outcome before (2000–2008) and after (2009–2011) implementation of the 2009 ATA guidelines.
All members of the largest Israeli healthcare organization who were diagnosed with TC from 1/2000 to 12/2014 (study group) and age- and sex-matched members with no thyroid disease (controls) were included. Adjusted hazard ratios (HRs) and 95% confidence intervals (95% CIs) were calculated using Cox proportional hazards models.
The mean follow-up was 7.6 ± 4.2 and 7.8 ± 4.1 years for the study (n = 5,677, 79% women) and control (n = 23,962) groups, respectively. The former had an increased risk of new atherosclerotic CaV&CeV events (adjusted HR 1.26, 95% CI 1.15–1.39). The 5-year incidence of CaV&CeV was lower (adjusted HR 0.49, 95% CI 0.38–0.62) from 2009 to 2011 compared to 2000 to 2008, but remained higher in the study group than in the control group (adjusted HR 1.5, 95% CI 1.14–1.69).
This large Israeli population-based cohort study showed greater atherosclerotic CaV&CeV morbidity in TC survivors compared to individuals with no thyroid diseases. There was a trend toward a decreased 5-year incidence of atherosclerotic CaV&CeV events among TC survivors following the implementation of the 2009 ATA guidelines, but it remained higher compared to the general population.
T L C Wolters, C D C C van der Heijden, N van Leeuwen, B T P Hijmans-Kersten, M G Netea, J W A Smit, D H J Thijssen, A R M M Hermus, N P Riksen, and R T Netea-Maier
Acromegaly is characterized by an excess of growth hormone (GH) and insulin-like growth factor 1 (IGF1). Cardiovascular disease (CVD) risk factors are common in acromegaly and often persist after treatment. Both acute and long-lasting pro-inflammatory effects have been attributed to IGF1. Therefore, we hypothesized that inflammation persists in treated acromegaly and may contribute to CVD risk.
In this cross-sectional study, we assessed cardiovascular structure and function, and inflammatory parameters in treated acromegaly patients. Immune cell populations and inflammatory markers were assessed in peripheral blood from 71 treated acromegaly patients (with controlled or uncontrolled disease) and 41 matched controls. Whole blood (WB) was stimulated with Toll-like receptor ligands. In a subgroup of 21 controls and 33 patients with controlled disease, vascular ultrasound measurements were performed.
Leukocyte counts were lower in patients with controlled acromegaly compared to patients with uncontrolled acromegaly and controls. Circulating IL18 concentrations were lower in patients; concentrations of other inflammatory mediators were comparable with controls. In stimulated WB, cytokine production was skewed toward inflammation in patients, most pronounced in those with uncontrolled disease. Vascular measurements in controlled patients showed endothelial dysfunction as indicated by a lower flow-mediated dilatation/nitroglycerine-mediated dilatation ratio. Surprisingly, pulse wave analysis and pulse wave velocity, both markers of endothelial dysfunction, were lower in patients, whereas intima-media thickness did not differ.
Despite treatment, acromegaly patients display persistent inflammatory changes and endothelial dysfunction, which may contribute to CVD risk and development of CVD.
M A Webb, H Mani, S J Robertson, H L Waller, D R Webb, C L Edwardson, D H Bodicoat, T Yates, K Khunti, and M J Davies
Physical activity has been proposed to be an effective non-pharmacological method of reducing systemic inflammation and therefore may prove particularly efficacious for women with polycystic ovary syndrome (PCOS) who have been shown to have high levels of inflammation and an increased risk of type 2 diabetes (T2DM) and cardiovascular disease (CVD). Therefore, the aim of the present study was to assess whether modest changes in daily step count could significantly reduce levels of inflammatory markers in women with PCOS.
Subjects and Methods
Sixty-five women with PCOS were assessed at baseline and again at 6 months. All had been provided with an accelerometer and encouraged to increase activity levels. Multivariate linear regression analyses (adjusted for age, ethnicity, baseline step count, change in BMI and change in accelerometer wear-time) were used to assess changes in daily step count against clinical and research biomarkers of inflammation, CVD and T2DM.
Mean step count/day at baseline was 6337 (±270). An increase in step count (by 1000 steps) was associated with a 13% reduction in IL6 (β: −0.81 ng/L; 95% CI, −1.37, −0.25, P = 0.005) and a 13% reduction in CRP (β: −0.68 mg/L; 95% CI, −1.30, −0.06, P = 0.033). Additionally, there was a modest decrease in BMI (β: 0.20 kg/m2; 95% CI, −0.38, −0.01, P = 0.038). Clinical markers of T2DM and CVD were not affected by increased step count.
Modest increases in step count/day can reduce levels of inflammatory markers in women with PCOS, which may reduce the future risk of T2DM and CVD.