Mean Adjusted Difference Research Articles

Continuous home terlipressin infusion increases handgrip strength and reduces ascites-A prospective randomized crossover study.

Observational studies suggest a beneficial effect of continuous terlipressin infusion (CTI) on ascites and sarcopenia in decompensated cirrhosis with portal hypertension. This single-center, prospective, cross-over study randomized 30 patients with cirrhosis, ascites, and sarcopenia to commence on 12 weeks of home CTI or 12 weeks of observation prior to cross-over. The co-primary outcomes were change in handgrip strength and paracentesis volume. Secondary outcomes included quality of life, sarcopenia measures, renal function, safety, and hospitalization. The median age of participants was 62 years (IQR: 57-64), the median Model for End-Stage Liver Disease-Sodium was 16 (12.3-20.8), and 22 (73%) were male. Handgrip strength increased by a mean adjusted difference (MAD) of 3.09 kg (95% CI: 1.11-5.08 kg) between CTI and observation ( p =0.006); an 11.8% increase from baseline. The total volume of ascites drained decreased by a MAD of 11.39L (2.99-19.85, p =0.01), with 1.75 fewer episodes of paracentesis (0.925-2.59, p <0.001) on CTI. Serum creatinine decreased, urinary sodium excretion increased, and quality of life was significantly higher on CTI (all p <0.001), with an increase in Chronic Liver Disease Questionnaire score of 0.41 points (0.23-0.59). There were 7 minor line-related complications but no cardiac events or pulmonary edema. This novel study demonstrates a significant increase in handgrip strength, reduction in paracentesis volume, and improved quality of life in patients with decompensated cirrhosis treated with continuous terlipressin infusion. These findings provide a strong rationale for the use of ambulatory CTI in appropriately selected patients with cirrhosis.

Effect of Radioiodine Treatment on Quality of Life in Patients with Subclinical Hyperthyroidism: A Prospective Controlled Study.

Study aim was to evaluate thyroid-related QoL in patients with subclinical hyperthyroidism mostly due to toxic nodular goitre undergoing RIT, compared to a control group of euthyroid subjects. Study design was monocentric, prospective, controlled. Fifty control subjects were enrolled and 51 RIT patients. Most subjects were examined at least twice at an interval of 6 months, with visits immediately before and 6 months after treatment in the RIT group. QoL was estimated with the ThyPRO questionnaire, using its composite scale as primary outcome. Treatment effect was the mean adjusted difference (MAD) between groups over time, using repeated? measures mixed? effects models. TSH concentrations were lower in the RIT group prior to treatment and recovered thereafter slightly above the level of the control group. Correspondingly, QoL improved significantly after 6 months from a worse level in the RIT group, compared to controls (MAD -10.3 [95% CI -14.9, -5.7], p<0.001). QoL improvements were strong for general items, but less pronounced for the hyperthyroid domain. Compared to controls, thyroid volume, thyroid functional capacity (SPINA-GT) and deiodinase activity (SPINA-GD) were significantly reduced in the RIT group. Patients with subclinical hyperthyroidism improve both biochemically and in their QoL after RIT, compared to controls. QoL assessment should have a wider role in clinical practice to complement biochemical tests and help with treatment decisions.

Effects of aromatase inhibitor therapy on adiposity and cardiometabolic health in postmenopausal women: a controlled cohort extension study.

We previously demonstrated that 12 months of aromatase inhibitor (AI) treatment was not associated with a difference in body composition or other markers of cardiometabolic health when compared to controls. Here we report on the pre-planned extension of the study. The pre-specified primary hypothesis was that AI therapy for 24 months would lead to increased visceral adipose tissue (VAT) area when compared to controls. We completed a 12-month extension to our prospective 12-month cohort study of 52 women commencing AI treatment (median age 64.5 years) and 52 women with breast pathology not requiring endocrine therapy (63.5 years). Our primary outcome of interest was VAT area. Secondary and exploratory outcomes included other measures of body composition, hepatic steatosis, measures of atherosclerosis and vascular reactivity. Using mixed models and the addition of a fourth time point, we increased the number of study observations by 79 and were able to rigorously determine the treatment effect. Among study completers (AI = 39, controls = 40), VAT area was comparable between groups over 24 months, the mean-adjusted difference was -1.54 cm2 (95% CI: -14.9; 11.9, P = 0.79). Both groups demonstrated parallel and continuous increases in VAT area over the observation period that did not diverge or change between groups. No statistically significant difference in our secondary and exploratory outcomes was observed between groups. While these findings provide reassurance that short-to-medium-term exposure to AI therapy is not associated with metabolically adverse changes when compared to controls, risk evolution should be less focussed on the AI-associated effect and more on the general development of cardiovascular risk over time.

Effects of estradiol on bone in men undergoing androgen deprivation therapy: a randomized placebo-controlled trial.

In men, many effects of testosterone (T) on the skeleton are thought to be mediated by estradiol (E2), but trial evidence is largely lacking. This study aimed to determine the effects of E2 on bone health in men in the absence of endogenous T. This study is a 6-month randomized, placebo-controlled trial with the hypothesis that E2 would slow the decline of volumetric bone mineral density (vBMD) and bone microstructure, maintain areal bone mineral density (aBMD), and reduce bone remodelling. 78 participants receiving androgen deprivation therapy for prostate cancer were randomized to 0.9 mg of 0.1% E2 gel daily or matched placebo. The outcome measures were vBMD and microarchitecture at the distal tibia and distal radius by high-resolution peripheral quantitative CT, aBMD at the spine and hip by dual-energy x-ray absorptiometry, and serum bone remodelling markers. For the primary endpoint, total vBMD at the distal tibia, there was no significant difference between groups, mean adjusted difference (MAD) 2.0 mgHA/cm3 (95% CI: -0.8 to 4.8), P = 0.17. Cortical vBMD at the distal radius increased in the E2 group relative to placebo, MAD 14.8 mgHA/cm3 (95% CI: 4.5 to 25.0), P = 0.005. Relative to placebo, E2 increased estimated failure load at tibia, MAD 250 N (95% CI: 36 to 465), P = 0.02, and radius, MAD 193 N (95% CI: 65 to 320), P = 0.003. Relative to placebo, E2 increased aBMD at the lumbar spine, MAD 0.02 g/cm2 (95% CI: 0.01 to 0.03), P = 0.01, and ultra-distal radius, MAD 0.01 g/cm2 (95% CI: 0.00 to 0.02), P = 0.01, and reduced serum bone remodelling markers. Relative to placebo, E2 treatment increases some measures of bone density and bone strength in men and reduces bone remodelling, effects that occur in the absence of endogenous T.

Randomised clinical trial: effect of adding branched chain amino acids to exercise and standard-of-care on muscle mass in cirrhotic patients with sarcopenia.

BackgroundThe role of branched-chain amino acids (BCAA) in improving muscle mass in cirrhosis is presently debatable.AimsTo evaluate the role of BCAA in improving muscle mass in a double-blind randomized placebo-controlled trial in patients with cirrhosis having sarcopenia.MethodsConsecutive patients with cirrhosis with Child–Pugh score < 10 and sarcopenia were randomized to receive either 12 g/day of BCAA orally or a placebo (1:1) for 6 months in addition to a home-based exercise program (30 min/day), dietary counselling and standard medical therapy. Sarcopenia was defined according to gender-specific axial skeletal muscle index (SMI) cut-offs. The primary endpoint was a change in muscle mass based on CT scan (SMI) after 6 months of supplementation.ResultsSixty patients [mean age 41.6 ± 9.9 years; males (66.6%) of predominantly viral (40%) and alcohol-related (31.7%) cirrhosis] were randomized. Baseline clinical and demographic characters were similar except MELD score (10.2 ± 2.8 vs. 12.2 ± 3.5, p = 0.02) and calorie intake (1838.1 kcal ± 631.5 vs. 2217.5 kcal ± 707.3, p = 0.03), both being higher in the placebo arm. After adjusting for both baseline confounders, baseline SMI and protein intake, the change in SMI at 6 months was similar in both groups [mean adjusted difference (MAD) + 0.84, CI − 2.9; + 1.2, p = 0.42] by intention-to-treat analysis. The secondary outcomes including change in handgrip strength (p = 0.65), 6-m gait speed (p = 0.20), 6-min walk distance (p = 0.39) were similar in both arms. Four patients had minor adverse events in each arm.ConclusionAddition of BCAA to exercise, dietary counselling and standard medical therapy did not improve muscle mass in patients with cirrhosis having sarcopenia. (CTRI/2019/05/019269).Trial registration numberCTRI/2019/05/019269 (Clinical Trials Registry of India).Supplementary InformationThe online version contains supplementary material available at 10.1007/s12072-022-10334-7.

Effect of estradiol on cognition in men undergoing androgen deprivation therapy: A randomized placebo-controlled trial.

Roles for estradiol in modulating cognition in men remain uncertain. We assessed the isolated effects of estradiol on cognition in men in the absence of testosterone. Randomized trial of transdermal estradiol 0.9 mg daily, or matched placebo, for 6 months, hypothesizing that estradiol would improve verbal learning, verbal memory, and spatial problem solving over time. Men receiving androgen deprivation therapy (ADT) for prostate cancer. Cognition was assessed by a tablet-based cognitive battery (Cogstate) at baseline, Month 1, Month 3, and Month 6. Anxiety and depression symptoms were assessed using the Hospital Anxiety and Depression Scale. Seventy-eight participants were randomized. Baseline mean scores were 21.0 (standard deviation [SD] 4.1) for the International Shopping List test (ISL), assessing verbal learning and memory (higher scores better), and 60.4 (SD 19.5) for the Groton Maze Learning test (GML), assessing spatial problem solving (lower scores better). There was no significant difference in performance over time for the estradiol group versus the placebo group for the ISL, mean adjusted difference (MAD) 0.7 (95% confidence interval [CI] -1.2 to 2.5), p = .36, or the GML, MAD -3.2 (95% CI -12.0 to 5.6), p = 0.53. There was no significant difference between groups over time in performance in any other cognitive domain, or on depression or anxiety scores. We found no major effects of estradiol on cognition in men with castrate testosterone concentrations. Although the cognitive effects of ADT are debated, this study suggests that any such effects are unlikely to be prevented by the administration of estradiol.

Effects of estradiol on fat in men undergoing androgen deprivation therapy: a randomized trial.

Indirect evidence suggests that the effects of testosterone on fat mass in men are dependent on aromatization to estradiol (E2). However, no controlled study has assessed the effects of E2 in the absence of testosterone. Six-month randomized, placebo-controlled trial with the hypothesis that men randomized to E2 would reduce their fat mass. Seventy-eight participants receiving androgen deprivation therapy for prostate cancer were randomized to 0.9 mg of 0.1% E2 gel per day, or matched placebo. Dual x-ray absorptiometry body composition was measured at baseline, month 3, and month 6. The primary outcome was total fat mass. Serum E2 increased in the estradiol group over 6 months compared to placebo, and mean-adjusted difference (MAD) was 207 pmol/L (95% CI: 123-292), P < 0.001. E2 treatment changed total fat mass, MAD 1007 g (95% CI: 124-1891), but not significantly, so P = 0.09. There were other consistent non-significant trends toward increased proportional fat mass, MAD 0.8% (95% CI: 0.0-1.6), P= 0.15; gynoid fat, MAD 147 g (95% CI: 2-293), P = 0.08; visceral fat, 53 g (95% CI: 1-105) P = 0.13; and subcutaneous fat, MAD 65 g (95% CI: 5-125), P = 0.11. Android fat increased, MAD 164 g (95% CI: 41-286), P = 0.04. Contrary to our hypothesis, we provide suggestive evidence that E2 acting in the absence of testosterone, may increase total and regional fat mass in men. Given the premature closure of clinical trials due to the COVID pandemic, this potentially important observation should encourage additional studies to confirm or refute whether E2 promotes fat expansion in the absence of testosterone.

Hybrid closed-loop glucose control with faster insulin aspart compared with standard insulin aspart in adults with type 1 diabetes: A double-blind, multicentre, multinational, randomized, crossover study.

To evaluate the use of hybrid closed-loop glucose control with faster-acting insulin aspart (Fiasp) in adults with type 1 diabetes (T1D). In a double-blind, multinational, randomized, crossover study, 25 adults with T1D using insulin pump therapy (mean ± SD, age 38 ± 9 years, HbA1c 7.4% ± 0.8% [57 ± 8 mmol/mol]) underwent two 8-week periods of unrestricted living comparing hybrid closed-loop with Fiasp and hybrid closed-loop with standard insulin aspart in random order. During both interventions the CamAPS FX closed-loop system incorporating the Cambridge model predictive control algorithm was used. In an intention-to-treat analysis, the proportion of time sensor glucose was in the target range (3.9-10.0 mmol/L; primary endpoint) was not different between interventions (75% ± 8% vs. 75% ± 8% for hybrid closed-loop with Fiasp vs. hybrid closed-loop with standard insulin aspart; mean-adjusted difference -0.6% [95% CI -1.8% to 0.7%]; p < .001 for non-inferiority [non-inferiority margin 5%]). The proportion of time with sensor glucose less than 3.9 mmol/L (median [IQR] 2.4% [1.2%-3.2%] vs. 2.9% [1.7%-4.0%]; p = .01) and less than 3.0 mmol/L (median [IQR] 0.4% [0.2%-0.7%] vs. 0.7% [0.2%-0.9%]; p = .03) was reduced with Fiasp versus standard insulin aspart. There was no difference in mean glucose (8.1 ± 0.8 vs. 8.0 ± 0.8 mmol/L; p = .13) or glucose variability (SD of sensor glucose 2.9 ± 0.5 vs. 2.9 ± 0.5 mmol/L; p = .90). Total daily insulin requirements did not differ (49 ± 15 vs. 49 ± 15 units/day; p = .45). No severe hypoglycaemia or ketoacidosis occurred. The use of Fiasp in the CamAPS FX closed-loop system may reduce hypoglycaemia without compromising glucose control compared with standard insulin aspart in adults with T1D.

100-LB: Closed-Loop Control Reduces Hypoglycemia without Increased Hyperglycemia in Subjects with Increased Prestudy Hypoglycemia: Results from the iDCL DCLP3 Randomized Trial

Closed Loop Control (CLC) has the ability to reduce both hypoglycemia and hyperglycemia. We conducted a post-hoc analysis of data from the iDCL DCLP3 randomized trial comparing CLC with Control-IQ versus sensor augmented pump therapy (SAP) for 6 months in participants who had baseline CGM below 70mg/dL ≥4.0% of the time (N= 41 CLC, 14 SAP, mean±SD age of 33±16yrs, 49% female). CLC use led to a greater reduction in time below 70mg/dL (least square mean change from baseline of -4.6% in CLC vs. -3.1% in SAP, mean-adjusted treatment difference -1.5% or 22 min/d, 95% CI -2.2% to -0.9%, P&amp;lt;0.0001), increased time in range 70-180 mg/dL (mean-adjusted difference +10.4% or 2.5 hr/d, P&amp;lt;0.0001), decreased time above 180mg/dL (mean-adjusted difference -8.5% or 2.0 hr/d, P=0.0001), decreased mean glucose (mean-adjusted difference -10.4 mg/dL, P=0.005), and lower HbA1C (mean-adjusted difference -0.28%, P=0.06). CLC improves HbA1C and reduces both hypoglycemia and hyperglycemia in people with T1D with elevated levels of hypoglycemia prior to starting CLC. Disclosure C.J. Levy: Consultant; Self; Dexcom, Inc. Employee; Spouse/Partner; Allergan plc. Research Support; Self; Abbott, Dexcom, Inc., Insulet Corporation. G. O’Malley: Research Support; Self; Abbott, Dexcom, Inc. S.A. Brown: Research Support; Self; Dexcom, Inc., Insulet Corporation, Roche Diabetes Care, Tandem Diabetes Care, Tolerion, Inc. G.P. Forlenza: Advisory Panel; Self; Medtronic. Consultant; Self; Dexcom, Inc., Insulet Corporation, Tandem Diabetes Care. Research Support; Self; Abbott, Dexcom, Inc., Insulet Corporation, Medtronic, Tandem Diabetes Care. Y.C. Kudva: Research Support; Self; Dexcom, Inc., Roche Diabetes Care. Other Relationship; Self; Abbott. R. Beck: None. C. Kollman: Other Relationship; Self; Dexcom, Inc., Tandem Diabetes Care. J. Lum: None. D. Raghinaru: None. B. Kovatchev: Advisory Panel; Self; Dexcom, Inc. Research Support; Self; Dexcom, Inc., Tandem Diabetes Care. Speaker’s Bureau; Self; Dexcom, Inc., Sanofi, Tandem Diabetes Care. Other Relationship; Self; Dexcom, Inc., Johnson &amp; Johnson, Sanofi. Funding National Institute of Diabetes and Digestive and Kidney Diseases (UC4108483); University of Virginia Strategic Investment Fund (Project 88); Tandem Diabetes Care

Biomechanical Leg Muscle Function During Stair Ambulation in Men Receiving Androgen Deprivation Therapy.

The role of testosterone in maintaining functional performance in older men remains uncertain. We conducted a 12-month prospective, observational case-control study including 34 men newly commencing androgen deprivation therapy for prostate cancer and 29 age-matched prostate cancer controls. Video-based motion capture and ground reaction force data combined with computational musculoskeletal modeling, and data were analyzed with a linear mixed model. Compared with controls over 12 months, men receiving androgen deprivation therapy had a mean reduction in circulating testosterone from 14.1 nmol/L to 0.4 nmol/L, associated with reductions in peak knee extension torque, mean adjusted difference (MAD) -0.07 Nm/kg (95% confidence interval [CI]: -0.18, 0.04), p = .009, with a corresponding more marked decrease in quadriceps force MAD -0.11 × body weight (BW) [-0.27, 0.06], p = .045 (equating to a 9 kg force reduction for the mean body weight of 85 kg), and decreased maximal contribution of quadriceps to upward propulsion, MAD -0.47 m/s2 [-0.95, 0.02], p = .009. We observed between-group differences in several other parameters, including increased gluteus maximus force in men receiving androgen deprivation therapy, MAD 0.11 × BW [0.02, 0.20], p = .043, which may be compensatory. Severe testosterone deprivation over 12 months is associated with selective deficits in lower-limb function evident with an important task of daily living.

Selective Loss of Levator Ani and Leg Muscle Volumes in Men Undergoing Androgen Deprivation Therapy.

Androgen deprivation therapy (ADT) for prostate cancer (PCa) leads to a selective loss of leg muscle function during walking. Rodent models of ADT have demonstrated that the levator ani is exquisitely androgen sensitive. To determine whether the high androgen responsiveness of the levator ani muscle documented in rodents is evolutionarily conserved and ADT is associated with a selective loss in leg muscle volume. Prospective longitudinal case-control study. Tertiary referral hospital. Thirty-four men newly beginning ADT and 29 age-matched controls with PCa. The muscle volumes in liters of the levator ani and primary muscles involved in walking (iliopsoas, quadriceps, gluteus maximus, gluteus medius, calf). Compared with controls, during a 12-month period, men receiving ADT experienced a mean reduction in total testosterone from 14.1 to 0.4 nmol/L and demonstrated greater decreases in levator ani [mean adjusted difference (MAD), -0.005 L; 95% CI, -0.007 to -0.002; P = 0.002; -16% of initial median value], gluteus maximus (MAD, -0.032 L; 95% CI, -0.063 to -0.002; P = 0.017; -5% of initial median value), iliopsoas (MAD, -0.005 L; 95% CI, -0.001 to 0.000; P = 0.013; -5% of initial median value), and quadriceps (MAD, -0.050 L; 95% CI, -0.088 to -0.012; P = 0.031; -3% of initial median value). No substantial differences were observed in the gluteus medius and calf muscles. The androgen responsiveness of the levator ani appears to be evolutionarily conserved in humans. ADT selectively decreases the volume of muscles that support body weight. Interventional strategies to reduce ADT-related sarcopenia and sexual dysfunction should assess whether targeting these muscle groups, including the pelvic floor, will improve clinical outcomes.

Effects of androgen deprivation therapy on telomere length.

Recent evidence suggests that androgens either directly or via aromatisation to oestradiol may regulate telomere length, hence providing a mechanism whereby reproductive steroids are linked to biological ageing in men. Using men with prostate cancer initiating androgen deprivation therapy (ADT), we tested the hypothesis that severe sex steroid deprivation would accelerate telomere shortening. We conducted a secondary analysis of a 2-year prospective controlled study among 65 men with nonmetastatic prostate cancer newly commencing adjuvant ADT (n=40) and age- and radiotherapy-matched prostate cancer controls (n=25). We measured leucocyte telomere length (LTL) expressed as telomeric/single copy control gene (T/S) ratio at baseline, 6, 12 and 24months. Generalized linear models determined the mean adjusted difference (MAD) (95% confidence interval) between groups during follow-up. Compared to controls over 24months, men receiving ADT had no change in LTL, MAD for T/S ratio (0.105 [-0.004; 0.213], P=.235). Using men with prostate cancer receiving ADT as a model we found no evidence that prolonged and profound sex steroid deprivation is associated with accelerated telomere shortening. Larger studies will be required to confirm or refute these findings.

Effect of Testosterone Treatment on Adipokines and Gut Hormones in Obese Men on a Hypocaloric Diet.

Context:In obese men with lowered testosterone levels, testosterone treatment augments diet-associated loss of body fat.Objective:We hypothesized that testosterone treatment modulates circulating concentrations of hormonal mediators of fat mass and energy homeostasis in obese men undergoing a weight loss program.Design:Prespecified secondary analysis of a randomized, double-blind, placebo-controlled trial.Setting:Tertiary referral center.Participants:Obese men (body mass index ≥30 kg/m2) with a repeated total testosterone level ≤12 nmol/L.Intervention:One hundred participants mean age 53 years (interquartile range 47 to 60 years) receiving 10 weeks of a very low–energy diet followed by 46 weeks of weight maintenance were randomly assigned at baseline to 56 weeks of intramuscular testosterone undecanoate (cases, n = 49) or matching placebo (controls, n = 51). Eighty-two men completed the study.Main outcomes:Between-group differences in leptin, adiponectin, ghrelin, glucagon like peptide-1, gastric inhibitory polypeptide, peptide YY, pancreatic polypeptide, and amylin levels.Results:At study end, compared with controls, cases had greater reductions in leptin [mean adjusted difference (MAD), −3.6 ng/mL (95% CI, −5.3 to −1.9); P < 0.001]. The change in leptin levels between cases and controls was dependent on baseline fat mass, as the between-group difference progressively increased with increasing fat mass [MAD, −0.26 ng/mL (95% CI, −0.31 to −0.26); P = 0.001 per 1 kg of baseline fat mass]. Weight loss–associated changes in other hormones persisted during the weight maintenance phase but were not modified by testosterone treatment.Conclusions:Testosterone treatment led to reductions in leptin beyond those achieved by diet-associated weight loss. Testosterone treatment may reduce leptin resistance in obese men.

Symptomatic response to testosterone treatment in dieting obese men with low testosterone levels in a randomized, placebo-controlled clinical trial.

Obese men commonly have reductions in circulating testosterone and report symptoms consistent with androgen deficiency. We hypothesized that testosterone treatment improves constitutional and sexual symptoms over and above the effects of weight loss alone. We conducted a pre-specified analysis of a randomized double-blind, placebo-controlled trial at a tertiary referral center. About 100 obese men (body mass index (BMI)⩾30 kg m-2) with a repeated total testosterone level ⩽12 nmol l-1 and a median age of 53 years (interquartile range 47-60) receiving 10 weeks of a very-low-energy diet (VLED) followed by 46 weeks of weight maintenance were randomly assigned at baseline to 56 weeks of intramuscular testosterone undecanoate (n=49, cases) or matching placebo (n=51, controls). Pre-specified outcomes were the between-group differences in Aging Male Symptoms scale (AMS) and international index of erectile function (IIEF-5) questionnaires. Eighty-two men completed the study. At study end, cases showed significant symptomatic improvement in AMS score, compared with controls, and improvement was more marked in men with more severe baseline symptoms (mean adjusted difference (MAD) per unit of change in AMS score -0.34 (95% confidence interval (CI) -0.65, -0.02), P=0.04). This corresponds to improvements of 11% and 20% from baseline scores of 40 and 60, respectively, with higher scores denoting more severe symptoms. Men with erectile dysfunction (IIEF-5⩽20) had improved erectile function with testosterone treatment. Cases and controls lost the same weight after VLED (testosterone -12.0 kg; placebo -13.5 kg, P=0.40) and maintained this at study end (testosterone -11.4 kg; placebo -10.9 kg, P=0.80). The improvement in AMS following VLED was not different between the groups (-0.05 (95% CI -0.28, 0.17), P=0.65). In otherwise healthy obese men with mild to moderate symptoms and modest reductions in testosterone levels, testosterone treatment improved androgen deficiency symptoms over and above the improvement associated with weight loss alone, and more severely symptomatic men achieved a greater benefit.

Quality of life decrements in men with prostate cancer undergoing androgen deprivation therapy.

While androgen deprivation therapy (ADT) has been associated with decreased quality of life (QoL), controlled prospective studies are lacking. We aimed to assess QoL during ADT using two validated questionnaires and determine contributing factors. Prospective controlled study. Sixty-three men with nonmetastatic prostate cancer newly commencing ADT (n=34) and age- and radiotherapy-matched prostate cancer controls (n=29). QoL was measured by Short-Form 12 version 2 survey (SF-12) and Aging Males' Symptoms (AMS) score at 0, 6 and 12months. Generalized linear models determined the mean adjusted difference (MAD) (95% confidence interval) between groups during follow-up. Compared to controls over 12months, men receiving ADT had decreased SF-12 physical component score [MAD -3·61 (-6·94, -0·29), P=0·013] reflecting worsening QoL but no change in the mental component (P=0·74). Total AMS score increased [MAD 9·35 (5·65, 13·07), P<0·001], reflecting worse QoL. Both SF-12 and AMS changes were greater than reported minimum clinically important differences. AMS sub-domains showed increased somatic [MAD 3·96 (1·94, 5·99), P<0·001] and sexual [MAD 3·80 (2·16, 5·44), P<0·001] components but not psychological (P=0·19). Decrements were related to an increase in hot flushes (P=0·016) but not haemoglobin decrease (P=0·46). Within 12months, ADT is associated with clinically significant decreased QoL, particularly physical and sexual aspects, independent of the confounding effects of a cancer diagnosis or radiotherapy. As QoL is a crucial aspect of prostate cancer treatment, addressing hot flushes, sexual dysfunction and exercise may potentially improve outcomes for men undergoing ADT.

Testosterone therapy increases muscle mass in men with cirrhosis and low testosterone: A randomised controlled trial

Low testosterone and sarcopenia are common in men with cirrhosis and both are associated with increased mortality. Whether testosterone therapy in cirrhosis improves muscle mass and other outcomes is unknown. We conducted a 12-month, double-blinded, placebo-controlled trial of intramuscular testosterone undecanoate in 101 men with established cirrhosis and low serum testosterone (total testosterone <12nmol/L or free testosterone <230pmol/L) in a single tertiary centre. Body composition was assessed using dual-energy X-ray absorptiometry at baseline, 6 and 12months. At study completion, appendicular lean mass was significant higher in testosterone-treated subjects, with a mean adjusted difference (MAD) of +1.69kg, (CI +0.40; +2.97kg, p=0.021). Secondary outcomes included a substantially higher total lean mass in the active group (MAD +4.74kg, CI +1.75; +7.74kg, p=0.008), matched by reduced fat mass (MAD -4.34kg, CI -6.65; -2.04, p<0.001). Total bone mass increased (MAD +0.08kg, CI +0.01; +0.15kg, p=0.009) as did bone mineral density at the femoral neck (MAD +0.287points, CI +0.140; +0.434, p<0.001). Haemoglobin was higher with testosterone therapy (MAD +10.2g/L, CI +1.50; +18.9g/L, p=0.041) and percentage glycosylated haemoglobin (HbA1c) lower (MAD -0.35%, CI -0.05; -0.54, p=0.028). Mortality was non-significantly lower in testosterone-treated patients (16% vs. 25.5%, p=0.352). There was no increase in adverse events in testosterone-treated subjects. Testosterone therapy in men with cirrhosis and low serum testosterone safely increases muscle mass, bone mass and haemoglobin, and reduces fat mass and HbA1c. This is the first evidence-based therapy for sarcopenia in cirrhosis and thus requires larger-scale investigation into its potential impact on mortality. Both low testosterone and muscle wasting are associated with increased risk of death in men with severe liver disease. Administering testosterone to men with liver disease who have low testosterone levels significantly increases their muscle mass. In addition, testosterone has non-muscle beneficial effects which may be able to increase survival in this population. Australian New Zealand Clinical Trials Registry trial number ACTRN 12614000526673.

Effect of testosterone treatment on cardiac biomarkers in a randomized controlled trial of men with type 2 diabetes.

To assess the effect of testosterone treatment on cardiac biomarkers in men with type 2 diabetes (T2D). Randomized double-blind, parallel, placebo-controlled trial. Men aged 35-70 years with T2D and a total testosterone level ≤12·0 nmol/l (346 ng/dl) at high risk of cardiovascular events, median 10-year United Kingdom Prospective Diabetes Study (UKPDS) coronary heart disease (CHD) risk 21% (IQR 16%, 27%). Eighty-eight participants were randomly assigned to 40 weeks of intramuscular testosterone undecanoate (n = 45) or matching placebo (n = 43). N-terminal pro B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT). Testosterone treatment reduced NT-proBNP (mean adjusted difference (MAD) in change over 40 weeks across the testosterone and placebo groups, -17·9 ng/l [95% CI -32·4, -3·5], P = 0·047), but did not change hs-cTnT (MAD, 0·41 ng/l (95% CI -0·56, 1·39), P = 0·62). Six men, three in each group experienced an adverse cardiac event, displaying already higher baseline NT-proBNP (P < 0·01) and hs-cTnT levels (P = 0·01). At baseline, 10-year UKPDS CHD risk was associated positively with NT-proBNP (τ = 0·21, P = 0·004) and hs-cTnT (τ = 0·23, P = 0·003) and inversely with testosterone (total testosterone τ = -0·18, P = 0·02, calculated free testosterone τ = -0·19, P = 0·01), but there was no significant association between testosterone and cardiac biomarkers (P > 0·05). In this trial of men with T2D and high cardiovascular risk, testosterone treatment reduced NT-proBNP and did not change hs-cTnT. Further studies should determine whether men with increased cardiac biomarkers prior to testosterone therapy are at higher risk of testosterone treatment-associated adverse cardiac events.

Effect of testosterone treatment on constitutional and sexual symptoms in men with type 2 diabetes in a randomized, placebo-controlled clinical trial.

The objective of the study was to assess the effect of T treatment on constitutional and sexual symptoms in men with type 2 diabetes (T2D). This was a randomized double-blind, parallel, placebo-controlled trial. The study was conducted at a tertiary referral center. Men aged 35-70 years with T2D, a hemoglobin A1c less than 8.5%, and a total T level less than 12.0 nmol/L (346 ng/dL) with mild to moderate aging male symptoms and erectile dysfunction. Eighty-eight participants were randomly assigned to 40 weeks of im T undecanoate (n = 45) or matching placebo (n = 43). Constitutional symptoms using the aging male symptoms (AMS) score, sexual desire (question 17 AMS score), and erectile function (International Index of Erectile Function-5). T treatment did not substantially improve aging male symptoms [mean adjusted difference (MAD) in change over 40 weeks across the T and placebo groups in AMS total score, -0.9 (95% confidence interval [CI] -4.1, 2.2), P = .67] or sexual desire [MAD in question 17 AMS, -0.3 (95% CI -0.8, 0.2), P = .17]. Although compared with placebo, erectile function in men assigned to T was reduced [MAD in International Index of Erectile Function abridged version 5, -2.0 (95% CI -3.4, -0.6), P < .02], there was no significant difference between baseline and 40-week International Index of Erectile Function abridged version 5 scores if both groups were analyzed separately. At baseline, symptoms were worse in men with depression and microvascular complications but did not correlate with T levels. In this trial, T treatment did not substantially improve constitutional or sexual symptoms in obese, aging men with T2D with mild to moderate symptoms and modest reduction in T levels typical for the vast majority of such men.