Testosterone therapy over 60 months improves aging male symptoms scores in all men with adult-onset testosterone deficiency.

OBJECTIVE: We evaluated change (Δ) in AMSS in men with adult-onset testosterone deficiency (TD) on/not on testosterone undecanoate (TU) by analysing a registry of men with adult-onset TD. METHODS: Analyses were performed using non-parametric statistics to determine ΔAMSS at 6-12 monthly intervals in men on/not on TU and movement in AMSS. Factors predicting ΔAMSS were established via linear/multiple regression. RESULTS: TU was significantly associated with lower AMSS values compared with that at baseline/prior assessment during the initial 42 months treatment; 259 of the 260 men showed improvement. In the 361 men not on TU, AMSS values increased during 60 months of follow-up compared with that at baseline/prior assessment; improvement after 60 months was evident in 1 man, whilst AMSS remained the same or worsened in 213 and 147 men, respectively. In men on TU, baseline AMSS was inversely associated with ΔAMSS (R2 = 0.97), with no other factors reaching significance. Baseline AMSS, age, serum total testosterone (TT), waist circumference (WC), and diastolic blood pressure (BP) were associated with ΔAMSS in men not on TU. DISCUSSION: We show that TU was associated with lower AMSS in men with adult-onset TD whilst non-treatment led to increased values. Baseline AMSS values inversely predicted ΔAMSS in both groups.

Testosterone Replacement Therapy: Effects on Blood Pressure in Hypogonadal Men.

PURPOSE: While testosterone therapy can improve the various pathologies associated with adult-onset testosterone deficiency (TD), Summary of Product Characteristics (SPC) of five testosterone preparations caution that treatment may be associated with hypertension. This paper evaluates the impact of testosterone undecanoate (TU) on blood pressure (BP) in men with adult-onset TD. MATERIALS AND METHODS: Of 737 men with adult-onset TD in an on-going, observational, prospective, cumulative registry, we studied changes in BP using non-parametric sign-rank tests at final assessment and fixed time points. We used multiple regression analysis to establish factors (baseline BP, age, change/baseline waist circumference [WC] and hematocrit [HCT] and follow-up) potentially associated with BP change in men on TU. RESULTS: TU was associated with significant reductions in systolic, diastolic BP and pulse pressure, regardless of antihypertensive therapy (at baseline or during follow-up), larger reductions were seen with concurrent antihypertensive therapy. In men never on antihypertensive agents, median changes (interquartile range [IQR]) in systolic BP, diastolic BP and pulse pressure were -12.5 (-19.0, -8.0), -8.0 (-14.0, -3.0), and -6.0 (-10.0, -1.0) mmHg, respectively at final assessment, with only baseline BP values inversely associated with these changes (HCT and WC were not significantly associated). In men not on TU, systolic BP, diastolic BP, and pulse pressure significantly increased. In the TU treated men only 1 of the 152 men (not on antihypertensive agents at baseline) were started on antihypertensives during follow-up. In contrast 33 of the 202 men on antihypertensives (at baseline or follow-up) had the antihypertensive agent discontinued by the end of the follow-up. CONCLUSIONS: TU was associated with lowering of BP during follow-up irrespective of antihypertensive therapy, with greater reductions in men with higher baseline BP. In the context of SPC warnings, our long-term data provide reassurance on the effect of TU on BP.

Testosterone therapy reduces insulin resistance in men with adult-onset testosterone deficiency and metabolic syndrome. Results from the Moscow Study, a randomized controlled trial with an open-label phase.

AIMS: To describe changes in homeostasis model assessment of insulin resistance index (HOMA-IR) following testosterone therapy in men with hypogonadism and metabolic syndrome (MetS). MATERIALS AND METHODS: A randomized, placebo-controlled, double-blind randomized controlled trial (RCT) comprising 184 men with MetS and hypogonadism (testosterone undecanoate [TU]: 113 men, placebo: 71 men) was conducted. This was followed by an open-label phase in which all men were given TU. We focused on men who were not receiving antiglycaemic agents (TU: 81 men; placebo: 54 men) as these could affect HOMA-IR. Inter-group comparison of HOMA-IR was restricted to the RCT (30 weeks), whilst intra-group comparison was carried out on men provided TU during the RCT and open-label phases (study cohort) and men given placebo during the RCT and then switched to TU during the open-label phase (confirmatory cohort). Regression analysis was performed to identify factors associated with change in HOMA-IR (∆HOMA-IR). RESULTS: The median HOMA-IR was significantly reduced at almost every time point (after 18 weeks) compared to baseline in men receiving TU in both the study and confirmatory cohorts. There was a significant decrease in median values of fasting glucose (30 weeks: -2.1%; 138 weeks: -4.9%) and insulin (30 weeks: -10.5%; 138 weeks: -35.5%) after TU treatment. Placebo was not associated with significant ∆HOMA-IR. The only consistent predictor of HOMA-IR decrease following TU treatment was baseline HOMA-IR (r2 ≥ 0.64). CONCLUSIONS: Baseline HOMA-IR predicted ΔHOMA-IR, with a greater percentage change in insulin than in fasting glucose. In men with MetS/type 2 diabetes (T2DM) not on antiglycaemic therapy, improvements in HOMA-IR may be greater than suggested by change in fasting glucose. Our results suggest that hypogonadism screening be included in the management of men with MetS/T2DM.

Testosterone replacement therapy: association with mortality in high-risk patient subgroups.

OBJECTIVES: We describe studies determining the association between testosterone therapy (TTh) and mortality. MATERIALS & METHODS: We used a registry database of 737 men with adult-onset testosterone deficiency defined as presenting with low serum total testosterone (TT) levels ≤12.1 nmol/L and associated symptoms over a near 10-year follow-up. We compared associations between testosterone undecanoate (TU), cardio-metabolic risk factors and mortality using non-parametric statistics followed by separate Cox regression models to determine if any association between TU and morality was independent of age and cardio-metabolic risk factors. Finally, the association between TU and mortality was studied in men stratified by cardio-metabolic risk. RESULTS: During a median follow-up interquartile range (IQR) of 114 (84-132) months, 94 of the 737 men died. TU (ref: non-treatment) was associated with mortality; hazard ratio = 0.23, 95% confidence intervals = 0.14-0.40. Cox's regression models showed the above association to be independent of baseline age, waist circumference, hemoglobin A1c, lipids, blood pressure, smoking, and type 2 diabetes. These variables remained associated with mortality. We finally stratified the men by the high-risk baseline variables and established that the association between mortality and TU was only evident in men at higher risk. A possible explanation could lie with the "law of initial value," where greater improvements are evident following treatment in patients with worse baseline values. CONCLUSIONS: This study with long follow-up confirms that TTh is associated with lower mortality in men with adult-onset TD. This association was evident only in men with greater cardio-metabolic risk factors who demonstrated greater benefit.

Age and the Residual Risk of Cardiovascular Disease following Low Density Lipoprotein-Cholesterol Exposure.

We believe that there is sufficient evidence from basic science, longitudinal cohort studies and randomised controlled trials which validates the low-density lipoprotein cholesterol (LDL-C) or lipid hypothesis. It is important that we can communicate details of the cardiovascular disease (CVD) risk reduction that the average patient could expect depending on the scale of LDL-C decrease following lipid lowering therapy. It is also essential that residual risk (ResR) of CVD be highlighted. To achieve this aim by using existing trial evidence, we developed mathematical models initially for relative risk reduction (RRR) and absolute risk (AR) reduction and then showed that despite optimising LDL-C levels, a considerable degree of ResR remains that is dependent on AR. Age is significantly associated with AR (odds ratio: 1.02, 95% confidence intervals: 1.01-1.04) as was previously demonstrated by analysing the Whickham study cohort using a logistic regression model (age remaining significant even when all the other significant risk factors such as sex, smoking, systolic blood pressure, diabetes and family history were included in the regression model). A discussion of a paper by Ference et al. provided detailed evidence of the relationship between age and AR, based on lifetime LDL-C exposure. Finally, we discussed non-traditional CVD risk factors that may contribute to ResR based on randomised controlled trials investigating drugs improving inflammation, thrombosis, metabolic and endothelial status.

The association of peak systolic velocity in the carotid artery with coronary heart disease: A study based on portable ultrasound.

Cardiovascular disease (CVD) is the highest cause of death globally with more people dying annually from it than from any other cause. CVD is associated with modifiable risk factors (dyslipidaemia, hypertension and diabetes) and treating each of these factors lowers the risk of CVD. It is impossible to estimate the benefit of risk factor modification in the individual patient and extrapolating data from multiple trials is difficult. It would be useful to have a marker of risk that accurately estimates real time risk by measuring blood flow factors associated with the pathogenesis of atheroma. The aim of this preliminary study was to validate a low-cost measurement technique for obtaining blood flow velocity profiles and assess whether any of the measured and calculated factors, based on computational fluid dynamics (CFD) simulation, known to be associated with atheroma was associated with coronary heart disease (CHD), thus establishing its feasibility and acceptability as a clinical tool and suggesting areas for future research. Our study identified (i) that mean peak systolic (PS) velocity being associated with CHD; individuals without CHD: mean (SD) = 62.8 (16.1) cm/s, with CHD: mean (SD) = 53.6 (17.3) cm/s, p = 0.042; and (ii) that low-cost, portable ultrasound, which is routinely available in general practice, is a suitable assessment tool.

Testosterone Therapy: An Assessment of the Clinical Consequences of Changes in Hematocrit and Blood Flow Characteristics.

INTRODUCTION: Clinical guidelines indicate that hematocrit should be monitored during testosterone replacement therapy (TTh), with action taken if a level of 0.54 is exceeded. AIM: To consider the extent of changes in hematocrit and putative effects on viscosity, blood flow, and mortality rates after TTh. METHODS: We focused on literature describing benefits and possible pitfalls of TTh, including increased hematocrit. We used data from the BLAST RCT to determine change in hematocrit after 30 weeks of TTh and describe a clinical case showing the need for monitoring. We consider the validity of the current hematocrit cutoff value at which TTh may be modified. Ways in which hematocrit alters blood flow in the micro- and macro-vasculature are also considered. MAIN OUTCOME MEASURES: The following measures were assessed: (i) change in hematocrit, (ii) corresponding actions taken in clinical practice, and (iii) possible blood flow changes following change in hematocrit. RESULTS: Analysis of data from the BLAST RCT showed a significant increase in mean hematocrit of 0.01, the increase greater in men with lower baseline values. Although 0 of 61 men given TTh breached the suggested cutoff of 0.54 after 30 weeks, a clinical case demonstrates the need to monitor hematocrit. An association between hematocrit and morbidity and mortality appears likely but not proven and may be evident only in patient subgroups. The consequences of an increased hematocrit may be mediated by alterations in blood viscosity, oxygen delivery, and flow. Their relative impact may vary in different vascular beds. CONCLUSIONS: TTh can effect an increased hematocrit via poorly understood mechanisms and may have harmful effects on blood flow that differ in patient subgroups. At present, there appears no scientific basis for using a hematocrit of 0.54 to modify TTh; other values may be more appropriate in particular patient groups. König CS, Balabani S, Hackett GI, et al. Testosterone Therapy: An Assessment of the Clinical Consequences of Changes in Hematocrit and Blood Flow Characteristics. Sex Med Rev 2019;7:650-660.

Modelling the glycocalyx-endothelium-erythrocyte interaction in the microcirculation: a computational study.

A novel, coarse-grained, single-framework 'Eulerian' model for blood flow in the microvascular circulation is presented and used to estimate the variations in flow properties that accrue from all of the following: (i) wall position variation, associated with the endothelial cells' (ECs) shape, (ii) glycocalyx layer (GL) effects and (iii) the particulate nature of blood. We stress that our new model is fully coupled and uses only a single Eulerian computational framework to recover complex effects, dispensing altogether with the need for, e.g. re-meshing and advected sets of Lagrangian points. Physically, blood is modelled as a two-component, incompressible fluid - the plasma and corpuscular elements dispersed in it. The latter are modelled as deformable liquid droplets of increased viscosity. Interfacial membrane effects are present to mimic key blood properties and to avoid droplets' coalescence. The model is encapsulated within a multi-component lattice Boltzmann method that uses a sub-lattice 'wavy wall' closure to represent the ECs. Between this boundary and the flow domain, the model incorporates a coarse-grained representation of the endothelial GL, which is known to cover microvessel walls. The endothelial glycocalyx is modelled as a medium of variable and adaptive porosity, with approaching droplets being subject to a repulsive elastic force. Numerical simulations are presented to show the combined and simultaneous influence on fundamental flow properties of the EC wall undulation, the glycocalyx compression and repulsion and the particulate nature of blood. Several characteristic hemodynamical features of microvessel flow are successfully reproduced, including the deformability of particulates and the Fahraeus-Lindqvist effect. Moreover, the importance of modelling the GL is manifest in the magnitude of and the temporal variations in the flow rate and wall shear stresses.

Improved g-level calculations for coil planet centrifuges.

Calculation of the g-level is often used to compare CCC centrifuges, either against each other or to allow for comparison with other centrifugal techniques. This study shows the limitations of calculating the g-level in the traditional way. Traditional g-level calculations produce a constant value which does not accurately reflect the dynamics of the coil planet centrifuge. This work has led to a new equation which can be used to determine the improved non-dimensional values. The new equations describe the fluctuating radial and tangential g-level associated with CCC centrifuges and the mean radial g-level value. The latter has been found to be significantly different than that determined by the traditional equation. This new equation will give a better understanding of forces experienced by sample components and allows for more accurate comparison between centrifuges. Although the new equation is far better than the traditional equation for comparing different types of centrifuges, other factors such as the mixing regime may need to be considered to improve the comparison further.

Modelling wall shear stress in small arteries using the Lattice Boltzmann method: influence of the endothelial wall profile.

In order to address the problem of blood flow over the endothelium in small arteries, the near-endothelial region is here studied in more detail. The method used is a finite-volume discretisation of a Lattice Boltzmann equation over unstructured grids, named unstructured Lattice Boltzmann equation (ULBE). It is a new scheme based on the idea of placing the unknown fields at the nodes of the mesh and evolving them based on the fluxes crossing the surfaces of the corresponding control volumes. The study shows a significant variation and a high sensitivity of wall shear stress to the height of the endothelium corrugation and the presence of erythrocytes. The latter were modelled as deformable, viscous particles within a fluid continuum.

Study of the collateral capacity of the circle of Willis of patients with severe carotid artery stenosis by 3D computational modeling.

This numerical study aims to investigate the capacity of the circle of Wills (CoW) to provide collateral blood supply for patients with unilateral carotid arterial stenosis. The basic 3D geometry of the CoW was reconstructed based on a magnetic resonance angiogram of a normal human subject. A total of 52 computational fluid dynamics simulations were performed for four geometry configurations of the CoW with an artificially inserted axisymmetric stenosis of different luminal area reductions in an internal carotid artery (ICA) under a variety of boundary conditions. The CoW geometric configurations included (a) a normal CoW with all communicating arteries; (b) as model (a) but with enlarged communicating arterial diameters; (c) as (a) but with the ipsilateral posterior communicating artery missing, and (d) as (c) but with enlarged communicating arteries. It is found that the blood perfusion pressure drop between the ipsilateral ICA and the middle cerebral artery (MCA) only becomes significant when the degree of stenosis is greater than 86%. The cerebral autoregulation range varied significantly between the different CoW configurations for the severe stenosis cases. Without causing the flow rates to decrease at the efferent arterial ends, the mean perfusion pressure in the ipsilateral ICA can drop from 100 to 73, 67, 92 and 84 mmHg for the CoW models (a)-(d) with 96% luminal area reduction stenosis, respectively. The additional pathways are able to raise the ipsilateral MCA pressure significantly without reducing the total flow perfusion. Cerebral autoregulation effects were not directly included in the study. Therefore, the findings in the study should be interpreted with cautions when comes to the biological and clinical significance.

Coupled modeling of blood perfusion in intravascular, interstitial spaces in tumor microvasculature.

The coupling of intravascular and interstitial flow is a distinct feature of tumor microcirculation, due to the high vessel permeability, the low osmotic pressure gradient as well as the absence of functional lymphatic system inside tumors. In this paper, a coupled mathematical model of tumor microcirculation is developed, which provides the link between microvasculature and interstitial space perfusion through the matrices determining a neighbor point belonging to either connected vessel (matrix B) or interstitial space (matrix A), and combines the intravascular and interstitial flow by vascular leaky terms. In addition, the compliance of tumor vessels, blood rheology with hematocritic distribution at branches is also considered. The microvascular network, on which the microcirculation calculation is carried out, is generated from our two-dimensional 9-point (2D9P) model of tumor angiogenesis, improved from the previous 2D5P one. A specific coupling procedure is developed in the study to couple the intravascular and interstitial flow. It is based on the iteratively numerical simulation techniques, including local iterations at individual parameter level and one global loop to provide coupling and simulation convergence. The simulation results not only present the basic features and characteristics of tumor microcirculation, which agree with the corresponding experimental observations reported, but also predict an intimate relationship between the tumor intravascular and interstitial flow quantitatively. Among the parameters, the vascular leakiness is a key to govern the systemic flowing pattern, influence the tumor internal environment and contribute to the metastasis of tumor cells, which could not be presented by the previous uncoupled models.