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Effects of long-term treatment with testosterone on weight and waist size in 411 hypogonadal men with obesity classes I-III: observational data from two registry studies

Effects of long-term treatment with testosterone on weight and waist size in 411 hypogonadal men... International Journal of Obesity (2016) 40, 162 –170 OPEN © 2016 Macmillan Publishers Limited All rights reserved 0307-0565/16 www.nature.com/ijo ORIGINAL ARTICLE Effects of long-term treatment with testosterone on weight and waist size in 411 hypogonadal men with obesity classes I-III: observational data from two registry studies 1,2 2,3,4 5 6 F Saad , A Yassin , G Doros and A Haider BACKGROUND/OBJECTIVES: Long-term testosterone replacement therapy (TRT) up to 5 years has been shown to produce progressive and sustainable weight loss (WL) in hypogonadal men. This study investigated effects of long-term TRT up to 8 years in hypogonadal men with different obesity classes. SUBJECTS/METHODS: From two independent observational registries we identified a total of 411 obese, hypogonadal men receiving TRT in urological clinics. The effects of TRT on anthropometric as well as metabolic parameters were studied for a maximum duration of 8 years, mean follow-up: 6 years. All men received long-acting injections of testosterone undecanoate in 3-monthly intervals. RESULTS: In all three classes of obesity, T therapy produced significant WL, decrease in waist circumference (WC) and body mass index (BMI). In patients with class I obesity, mean weight decreased from 102.6 ± 6.4 to 84.1 ± 4.9 kg, change from baseline: − 17.4 ± 0.5 kg and − 16.8 ± 0.4%. WC in this group of patients decreased from 106.8 ± 7.4 to 95.1 ± 5.3 cm, change from baseline: − 2 − 10.6 ± 0.3 cm. BMI decreased from 32.69 ± 1.4 to 27.07 ± 1.57, change from baseline: − 5.52 ± 0.15 kg m . In patients with class II obesity, weight decreased from 116.8 ± 6.9 to 91.3 ± 6.3 kg, change from baseline: − 25.3 ± 0.5 kg and − 21.5 ± 0.4%. WC decreased from 113.5 ± 7.5 to 100.0 ± 5.4 cm, change from baseline: − 13.9 ± 0.4 cm. BMI decreased from 37.32 ± 1.45 to 29.49 ± 1.71, change − 2 from baseline: − 8.15 ± 0.17 kg m . In patients with class III obesity, weight decreased from 129.0 ± 5.6 to 98.9 ± 4.8 kg, change from baseline: − 30.5 ± 0.7 kg and − 23.6 ± 0.5%. WC decreased from 118.5 ± 5.6 to 103.8 ± 4.9 cm, change from baseline: − 14.3 ± 0.4 cm. − 2 BMI decreased from 41.93 ± 1.48 to 32.46 ± 1.59, change from baseline − 9.96 ± 0.29 kg m . CONCLUSIONS: Testosterone therapy appears to be an effective approach to achieve sustained WL in obese hypogonadal men irrespective of severity of obesity. Based on these findings we suggest that T therapy offers safe and effective treatment strategy of obesity in hypogonadal men. International Journal of Obesity (2016) 40, 162–170; doi:10.1038/ijo.2015.139 INTRODUCTION and cardiovascular disease (CVD) has led to the termination of the Look AHEAD Trial, suggesting that lifestyle changes alone are Obesity is a major public health threat that has an enormous insufficient and medical intervention is deemed necessary. New economic burden on society, with an estimated economic impact strategies are urgently needed to combat and manage obesity. of greater than $2 trillion. In the USA ~ 35.5% of adult men and − 2 2,3 Although attempts to manage obesity with lifestyle changes and 35.8% of adult women are obese (BMI X30 kg m ). Obesity therapeutic interventions have been made frequently and are increases risks for atherosclerosis, diabetes, metabolic syndrome, successful to some extent, weight regain remains a major nonalcoholic fatty liver disease, heart disease among other problem. A proactive approach is necessary for the treatment comorbidities and reduces life expectancy. Obesity contributes of obesity in order to reduce the onset or complications of other to pathophysiological conditions such as hemodynamic, arrhythmic comorbidities such as type 2 diabetes mellitus (T2DM) and CVD. and anatomical modifications in the cardiovascular system. A wealth of evidence exists demonstrating that WL improves Contrary to the previously held views, obesity is a chronic health outcomes and reduces healthcare costs. WL is associated disease necessitating medical intervention. If left untreated, with reduction in the incidence of hypertension and high obesity contributes significantly to a host of adverse effects on triglycerides, concomitant with reduction in cardiovascular the cardiovascular system. Thus, significant weight loss (WL) at any 4 8 time during adult life may result in cardiovascular benefit. It is mortality. Although pharmacological approaches in the treat- becoming clear that simple behavioral and lifestyle approaches, ment of obesity are met with mixed success, employment of such as diet and exercise alone, while considered a first step in surgical approaches has taken hold. Bariatric surgery has been management of obesity, are inadequate and for the most part shown to be successful in selected patients and has proven useful in the management of excessively obese patients. Gastric by-pass unsuccessful for treatment of obesity, especially in the long run. The limited success of diet and lifestyle in the treatment of obesity surgery reduced mortality by ~ 29% and decreased deaths from 1 2 3 Global Medical Affairs Andrology, Bayer Pharma, Berlin, Germany; Department of Urology, Gulf Medical University, Ajman, UAE; Institute for Urology and Andrology, 4 5 Segeberger Kliniken, Norderstedt, Germany; Department of Preventive Medicine, Men's Health Program, Dresden International University, Dresden, Germany; Department for Epidemiology and Statistics, Boston University School of Public Health, Boston, MA, USA and Private Urology Practice, Bremerhaven, Germany. Correspondence: Professor F Saad, Global Medical Affairs Andrology, Bayer Pharma AG, Muellerstr. 178, Berlin 13353, Germany. E-mail: [email protected] Received 24 April 2015; revised 23 June 2015; accepted 2 July 2015; accepted article preview online 29 July 2015; advance online publication, 25 August2015 Effects of long-term treatment with testosterone F Saad et al 9 − 2 CVD. T2DM was significantly reduced by surgical intervention and years) and class III (BMI ⩾ 40 kg m ; n = 47, mean age: 60.51 ± 5.52 years). 10–12 13 All men were treated with testosterone undecanoate injections (TU; other approaches of WL. Arterburn et al. demonstrated Nebido, Bayer Pharma, Berlin, Germany) for up to 8 years. Men were reduced rates of mortality and decreased deaths from CVD in entered into the registry once they had received 1 year of treatment. patients who underwent bariatric surgery. The benefitofWLon Therefore, registry participants had been in the registry for different diabetes was demonstrated in the Look AHEAD Trial. In the 9 durations of time, and declining numbers do not reflect drop-out rates. Swedish Obese Subjects study, CVD was reduced by WL. It should Inclusion criteria were two separate morning measures of total be emphasized, however, that bariatric surgery is not available to − 1 testosterone ⩽ 12.1 nmol l and the presence of hypogonadal symptoms all obese patients and not without risks. measured by the Aging Males’ symptoms scale (AMS). Current strategies for treatments for obesity include diets, Exclusion criteria for testosterone administration included previous exercise, behavioral lifestyle changes, pharmaco-therapeutic treatment with androgens, prostate cancer or any suspicion thereof, such 16–18 − 1 agents and bariatric surgery. Treatment of obesity with as prostate-specific antigen levels 44ng ml or abnormal findings upon incretin, glucagon-like peptide-1 (GLP-1) receptor agonists, digital rectal examination, International Prostate Symptom Score (IPSS) 419 points, breast cancer, a history of congestive heart failure or recent enzyme inhibitors, angiopoietin-like proteins has been investi- angina, or severe untreated sleep apnea. gated. Many of these approaches have yielded modest but not fully sustainable WL. In contrast, bariatric surgery has provided promising results. Assessment and follow-up Obesity contributes to the decline of testosterone (T) and the During this period, we evaluated the effects of long-term T therapy on the prevalence of hypogonadism is greater than 70% in men with following parameters: total plasma T levels, weight, waist circumference excessive obesity. T therapy in men with T deficiency (TD) (WC), BMI, hemoglobin, hematocrit, fasting glucose levels and hemoglobin A (HbA ), systolic blood pressure (SBP) and diastolic blood pressure reduces fat mass, increases lean body mass with concomitant WL, 1c 1c (DBP), lipid profile (total cholesterol, low-density lipoprotein (LDL) reduction in waist circumference (WC) and body mass index 21–43 cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides), (BMI). T therapy in hypogonadal obese men has been 44,45 C-reactive protein (CRP) and liver transaminases. We also assessed the suggested as a novel approach for the treatment of obesity. effects of T therapy on prostate volume, prostate-specific antigen and Long-term T therapy in men with TD reported significant and questionnaires IPSS, AMS and the International Index of Erectile Function, 35–40 sustained WL, reduced BMI and WC. The potential implication Erectile Function domain (IIEF-EF). Measures were taken between two and of T therapy in management of obesity in men with TD needs to four times per year and annual average was calculated. One patient with be explored. T therapy produced sustained WL without obesity class I dropped out after 39 months of treatment as a result of 35,36,38 recidivism. It is possible that T therapy in obese men with moving to a different geographical location. TD may prove useful in treatment of the underlying patho- Ethical guidelines as formulated by the German ‘Ärztekammer’ (the physiological conditions of obesity. In this report, we summarize German Medical Association) for observational studies in patients receiving standard treatment were followed. After receiving an explanation our findings on long-term T therapy in men with TD with varying regarding the nature and the purpose of the study, all subjects consented classes of obesity. The data presented suggest significant to be included in the research of their treatment protocol. improvement in WL, reduction in WC and BMI. We propose use The data from these 411 obese, hypogonadal men were included in this of T treatment as a novel therapeutic strategy for managing analysis. Statistical methodology was described previously. overweight and obesity in hypogonadal men with TD. RESULTS PATIENTS AND METHODS Baseline characteristics Patients Table 1 provides baseline characteristics of obese patients From two prospective, cumulative registry studies of 622 hypogonadal stratified to various classes of obesity based on BMI. In class I men, we identified all 411 obese hypogonadal men (66.1% of all patients) (n = 214), 33.2% had prediabetes, defined by HbA of 5.7 to 6.4%, with varying classes of obesity (class I (BMI 30–34.9; n = 214, mean age: 1c 58.61 ± 8.04 years), class II (BMI 35–39.9; n = 150, mean age: 60.35 ± 5.73 32.7% had T2DM and 6.1% had type 1 diabetes mellitus (T1DM). Table 1. Baseline characteristics and comorbidities in 411 obese hypogonadal men according to obesity class All Classes (n=411) Class I (n=214) Class II (n=150) Class III (n=47) age (years (minimum; maximum)) 59.46±7.05 (33;84) 58.61±8.04 (33;84) 60.35±5.73 (44;74) 60.51±5.52 (43;70) mean follow-up (years) 6.06±1.91 (1;8) 5.91±1.92 (1;8) 6.09±1.94 (1;8) 6.66±1.67 (2;8) Anthropometry weight (kg (minimum; maximum)) 110.8±11.3 (86;141) 102.6±6.4 (86;129) 116.8±6.9 (95;133) 129.0±5.6 (119;141) BMI (kg/m (minimum; maximum)) 35.43±3.48 (30.1;46.51) 32.69±1.4 (30.1;34.99) 37.32±1.45 (35.01; 39.95) 41.93±1.48 (40.08;46.51) waist circumference (cm (minimum; maximum)) 110.6±8.4 (89;148) 106.8±7.4 (89;133) 113.5±7.5 (97;148) 118.5±5.6 (105;132) Glycaemic control fasting glucose (mmol/L (minimum; maximum)) 6.12±1.54 (3.77;12.93) 5.97±1.65 (3.77;12.93) 6.24±1.43 (3.77;12.82) 6.40±1.31 (4.94;11.99) HbA (% (minimum;maximum)) 7.07±1.35 (4.5;11.6) 6.67±1.25 (4.6;9.7) 7.5±1.32 (4.9;11.6) 7.56±1.37 (4.5;9.4) 1c Metabolic diseases Prediabetes 103 (25.1%) 71 (33.2%) 29 (19.3%) 3 (6.4%) Diabetes mellitus type 2 173 (42.1%) 70 (32.7%) 77 (51.3%) 26 (55.3%) Diabetes mellitus type 1 23 (5.6%) 13 (6.1%) 8 (5.3%) 2 (4.3%) total metabolic diseases 299 (72.7%) 154 (72.0%) 114 (76.0%) 31 (66.0%) Cardiovascular diseases history of myocardial infarction 35 (8.5%) 6 (2.8%) 15 (11.5%) 11 (23.4%) history of stroke 7 (1.7%) 2 (0.9%) 4 (3.1%) 1 (2.1%) previous diagnosis of coronary artery disease 46 (11.2%) 23 (10.7%) 19 (14.5%) 18 (38.3%) total cardiovascular diseases 88 (21.4%) 31 (14.5%) 38 (29%) 30 (65.0%) © 2016 Macmillan Publishers Limited International Journal of Obesity (2016) 162 – 170 Effects of long-term treatment with testosterone F Saad et al History of myocardial infarction was 2.8% and history of stroke of myocardial infarction was 23.4% and history of stroke was 0.9%. In class II (n = 150), 19.3% had prediabetes, 51.3% had was 2.1%. T2DM and 5.3% had T1DM. History of myocardial infarction was 11.5% and history of stroke was 3.1%. In class III (n = 47), 6.3% Effects of long-term T therapy on circulating total T levels in men had prediabetes, 55.3% had T2DM and 4.3% had T1DM. History with various classes of obesity Figure 1 shows that irrespective of the class of obesity, TU treatment of obese patients restored total T levels within the physiological range during the first year and these levels were maintained in the physiological range over 8 years of follow-up. Effects of long-term T therapy on the anthropometric parameters in men with various classes of obesity As shown in Figures 2a–d and Table 2, in all three classes of obesity, T therapy produced significant WL, decrease in WC and BMI. In patients with class I obesity, mean weight decreased from 102.6 ± 6.4 to 84.1 ± 4.9 kg; the changes in weight were statistically significant for all 8 years vs previous year. The change from baseline was − 17.4 ± 0.5 kg and the percent change from baseline − 16.8 ± 0.4%. WC in this group of patients decreased from 106.8 ± 7.4 to 95.1 ± 5.3 cm. The changes were statistically significant for 6 years vs previous year. Mean change from baseline was − 10.6 ± 0.3 cm. BMI decreased from 32.69 ± 1.4 to −2 27.07 ± 1.57, mean change from baseline − 5.52 ± 0.15 kg m . Figure 1. Trough levels of total testosterone (mean ± s.e.) in 411 hypogonadal men in obesity classes I, II, and III receiving long-term With regard to WL, in class I, 200 patients (93.5%) lost ⩾ 5% of testosterone treatment. their baseline weight, 144 (67.3%) ⩾ 10%, 85 (39.7%) ⩾ 15%, 35 Reduction of waist circumference. Reduction of body weight. Weight change. Reduction of BMI. Figure 2. Reductions of waist circumference (a), body weight (b), BMI (c) and weight change (d) in 411 hypogonadal men receiving long-term testosterone treatment. All values are shown as mean± s.e. International Journal of Obesity (2016) 162 – 170 © 2016 Macmillan Publishers Limited Effects of long-term treatment with testosterone F Saad et al © 2016 Macmillan Publishers Limited International Journal of Obesity (2016) 162 – 170 Table 2. Changes in metabolic, prostate, and quality of life parameters at baseline and following long-term treatment with testosterone in obese hypogonadalmen Class I (n=214) Class II (n=150) Class III (n=47) Baseline age (years) 58.61±8.04 (33;84) 60.35±5.73 (44;74) 60.51±5.52 (43;70) baseline (±s.d.) 8 years (±s.d.) change (± s.e.) baseline (±s.d.) 8 years (±s.d.) change (±s.e.) baseline (±s.d.) 8 years (±s.d.) change (±s.e.) Testosterone Testosterone (nmol/L) 8.74±1.89 17.02±2.3 8.16±0.33* 9.3±1.92 16.86±2.32 7.29±0.31* 9.34±1.89 15.99±1.02 6.41±0.45* Prostate parameters prostate volume (ml) 28±10.03 30.2±11.38 4.77±0.28* 33.25±8.37 36.77±9.44 3.73±0.25* 34.77±8.04 38.33±8.08 2.58±0.41* PSA (ng/ml) 1.23±0.85 1.51±0.81 0.36±0.03* 1.63±0.85 1.9±0.74 0.35±0.03* 1.99±0.75 2.3±0.81 0.22±0.05* IPSS 8.39±4.78 3.12±2.31 −4.33±0.23* 9.69±4.5 3.54±2.65 −6.38±0.25* 9.74±4.34 2.97±2.09 −6.93±0.33* Erectile function IIEF-EF 13.87±7.23 24.83±3.53 9.13±0.39* 15.57±7.45 24.25±4.64 7.56±0.41* 17.09±7.8 25.36±3.5 6.86±0.56* Quality of life AMS 53.3±10.05 19.74±4.21 −32.48± 0.7* 52.59±9.43 19.43±3.97 −33.39±0.7* 57±9.88 17.78±2.1 −38.24±1.16* Glycaemic control fasting glucose (mmol/L) 5.97±1.65 4.95±0.47 −0.86±0.10* 6.24±1.43 5.08±0.46 −1.15±0.12* 6.40±1.31 5.18±0.32 −1.19±0.16* HbA (%) 6.67±1.25 5.37±0.4 −1.15±0.06* 7.5±1.32 5.78±0.56 −1.79±0.08* 7.56±1.37 5.68±0.44 −1.87±0.13* 1c Lipids total cholesterol (mmol/L) 7.01±1.12 4.73±0.28 −2.21±0.09* 7.60±1.04 4.78±0.25 −2.80±0.10* 7.94±1.10 4.81±0.23 −3.07±0.15* HDL (mmol/L) 1.21±0.41 1.67±0.37 0.54±0.03* 1.45±0.50 1.99±0.48 0.57±0.03* 1.60±0.51 2.18±0.41 0.57±0.05* LDL (mmol/L) 4.14±0.84 2.48±0.79 −1.31±0.06* 4.53±0.72 2.89±0.73 −1.46±0.07* 4.95±0.94 3.13±0.64 −1.71±0.11* triglycerides (mmol/L) 2.98±0.68 2.04±0.23 −0.90±0.05* 3.32±0.66 2.10±0.16 −1.21±0.05* 3.72±0.68 2.15±0.12 −1.56±0.09* total cholesterol : HDL ratio 6.45±2.44 2.96±0.59 −3.68±0.17* 6.07±2.87 2.55±0.62 −3.51±0.17* 5.66±2.88 2.29±0.47 −3.06±0.21* Erythropoiesis/Blood count haemoglobin (g/dl) 14.49±0.95 15.08±0.47 0.59±2.68* 14.5±0.86 14.74±1.13 0.27±0.08 14.36±0.72 15.03±0.41 0.7±0.09* haematocrit (%) 43.32±3.49 48.14±1.78 4.38±0.33* 43.64±3.49 48.26±1.59 4.54±0.34* 43.3±2.81 48.25±1.33 4.8±0.47* 9 § leukocytes (10 /L) 6.67±1.39 6.39±0.51 −0.17± 0.14 7.18±1.93 6.2±0.54 −1.01±0.17* 6.99±1.5 6.53±0.3 −0.45±0.21 Liver transaminases AST (U/L) 29.97±10.37 18.17±5.25 −10.47±1* 36.84±14.32 17.65±5.74 −20.06±1.22* 42.28±17.68 15.26±3.58 −27.95±2.21* ALT (U/L) 32.96±15.09 18.31±7.83 −11.99±1.39* 38.78±18.01 17.05±5.83 −22.84±1.54* 43.38±20.53 15.15±4.27 −29.44±2.77* Inflammation CRP (mg/dl) 2.15±2.23 0.34±0.34 −1.81±0.14* 3.23±4.39 0.41±0.65 −3.39±0.28* 3.73±4.28 0.29±0.31 −3.99±0.42* Blood pressure systolic (mm Hg) 144.3±14.59 125.91±8.37 −21.57±0.83* 157.39±15 129.15±8.13 −31.11±1.01* 161.3±14.25 132.7±8.12 −33.15±1.44* diastolic (mm Hg) 85.2±10.38 74.18±4.69 −12.52±0.73* 93.54±12.03 74.33±5.44 −20.62±1.41* 97.06±10.79 75.97±5.43 −23.51±1.35* Abbreviations: ALT, alanine transaminase; AMS, Aging Males’ Symptom scale; AST, aspartate aminotransferase; CRP, C-reactive protein; HDL, high-density lipoprotein; IIEF-EF, international index of erectile # § function, erectile function; IPSS, International Prostate Symptom Score; LDL, low-density lipoprotein; PSA, prostate-specific antigen. *Po0.0001 vs baseline; P=0.0014; P=0.0319. Effects of long-term treatment with testosterone F Saad et al Table 3. Changes in weight and waist circumference from baseline to last observation (A and B); proportion of patients in categories of waist circumference at baseline and end point (C); proportion of patients in categories of BMI at last observation (D) Class I (n = 214) Class II (n = 150) Class III (n = 47) n % n % n % A. Weight change Unchanged 1 0.5 0 0 0 0 Gained 3 1.4 0 0 0 0 Any weight loss 210 98.1 150 100 47 100 Weight loss ⩾ 5% 200 93.5 147 98 47 100 Weight loss ⩾ 10% 144 67.3 134 89.3 45 95.7 Weight loss ⩾ 15% 85 39.7 108 72 42 89.4 Weight loss ⩾ 20% 35 16.4 65 43.3 28 59.6 Weight loss ⩾ 25% 6 2.8 19 12.7 11 23.4 Weight loss ⩾ 30% 0 0 3 2 0 0 B. Waist circumference change Unchanged 1 0.5 0 0 0 0 Gained 1 0.5 0 0 0 0 Any reduction in waist circumference 212 99.1 150 100 47 100 Reduction ⩾ 5 cm 192 89.7 144 96 47 100 Reduction ⩾ 10 cm 101 47.2 110 73.3 42 89.4 Reduction ⩾ 15 cm 27 12.6 51 34 15 31.9 Reduction ⩾ 20 cm 6 2.8 12 8 2 4.3 Reduction ⩾ 25 cm 1 0.5 3 2 1 2.1 C. Proportion of patients in categories of waist circumference Baseline waist circumference ⩾ 94 cm 212 99.1 150 100 47 100 Baseline waist circumference ⩾ 102 cm 165 77.1 148 98.7 47 100 End waist circumference ⩾ 94 cm 166 77.6 142 94.7 47 100 End waist circumference ⩾ 102 cm 34 15.9 58 38.7 37 72.3 End waist circumference o94 cm 48 22.4 8 5.3 0 0 End waist circumference o102 cm 180 84.1 92 6.1 10 21.3 D. Proportion of patients in categories of BMI at last observation Normal weight 9 4.2 0 0 0 0 Overweight 155 72.4 67 44.7 3 6.4 Obesity class I 49 22.9 76 50.7 35 74.5 Obesity class II 1 0.5 7 4.7 9 19.1 Obesity class III 0 0 0 0 0 0 (16.4%) ⩾ 20%, 6 (2.8%) ⩾ 25% and 3 patients (1.4%) gained In class III obesity, all 47 patients lost ⩾ 5% of their baseline weight (Table 3). weight, 45 (95.7%) ⩾ 10%, 42 (89.4%) ⩾ 15%, 28 (59.6%) ⩾ 20%, In patients with class II obesity, weight decreased from 11 (23.4%) ⩾ 25% and no patient gained weight (Table 3). 116.8 ± 6.9 to 91.3 ± 6.3 kg. The changes in weight were statisti- cally significant for all 8 years vs previous year. The change from Effects of long-term T therapy on the metabolic parameters in baseline was − 25.3 ± 0.5 kg, percent change from baseline men with various classes of obesity − 21.6 ± 0.4%. WC decreased from 113.5 ± 7.5 to 100.0 ± 5.4 cm. Table 2 summarizes the findings of this study with regard to the The observed changes were statistically significant for the first changes in metabolic parameters and improvement in quality of 6 years vs previous year. The mean change from baseline was life in men with varying classes of obesity. In men with class I − 13.9 ± 0.4 cm. BMI decreased from 37.32 ± 1.45 to 29.49 ± 1.71, − 12 obesity, long-term T therapy resulted in decreased fasting mean change from baseline − 8.15 ± 0.17 kg m (Figures 2a–d; − 1 blood glucose from 5.97 ± 1.65 to 4.95 ± 0.47 mmol l . The Table 2). − 1 change from baseline was − 0.86 ± 0.10 mmol l . A reduction in Examining WL in patients in class II, 147 patients (98%) lost HbA was recorded from 6.67 ± 1.25 to 5.37 ± 0.4%, and a 1c ⩾ 5% of their baseline weight, 134 (89.3%) ⩾ 10%, 108 (72%) change from baseline of − 1.15 ± 0.06%. Total cholesterol ⩾ 15%, 65 (43.3%) ⩾ 20%, 19 (12.7%) ⩾ 25%, 3 men (2%) ⩾ 30% − 1 (TC; mmol l ) decreased from 7.01 ± 1.12 to 4.73 ± 0.28, LDL and no patient gained weight (Table 3). − 1 (mmol l ) from 4.14 ± 0.84 to 2.48 ± 0.79, triglycerides (TG; In patients with class III obesity, weight decreased from − 1 − 1 mmol l ) from 2.98 ± 0.68 to 2.04 ± 0.23. HDL (mmol l ) 129.0 ± 5.6 to 98.9 ± 4.8 kg. The changes were statistically increased from 1.21 ± 0.41 to 1.67 ± 0.37. The TC/HDL ratio declined significant for all 8 years vs previous year (Figures 2a–d; from 6.45 ± 2.44 to 2.96 ± 0.59. SBP (mm Hg) decreased from Table2). Thechangefrombaselinewas − 30.5 ± 0.7 kg 144.3 ± 14.59 to 125.91 ± 8.37, DBP from 85.2 ± 10.38 to 74.18 ± 4.69. and the percent change from baseline − 23.6 ± 0.5%. WC − 1 CRP (mg dl ) declined from 2.15 ± 2.23 to 0.34 ± 0.34 (Po0.0001 decreased from 118.45 ± 5.64 to 103.75 ± 4.86 cm. Changes for all). were statistically significant for the first 6 years vs previous In men with class II obesity, long-term T therapy reduced fasting year. The mean change from baseline was − 14.3 ± 0.4 cm. − 1 BMI decreased from 41.93 ± 1.48 to 32.46 ± 1.59, mean glucose from 6.24 ± 1.43 to 5.08 ± 0.46 mmol l . The change from −2 − 1 change from baseline − 9.96 ± 0.29 kg m (Figures 2a–d; baseline was − 2.80 ± 0.10 mmol l . HbA levels were reduced 1c Table 2). from 7.5 ± 1.32 to 5.78 ± 0.56%. The change from baseline was International Journal of Obesity (2016) 162 – 170 © 2016 Macmillan Publishers Limited Effects of long-term treatment with testosterone F Saad et al − 1.79 ± 0.08%. Concentrations of TC decreased from 7.60 ± 1.04 to significant reduction in alanine and aspartate transaminases 4.78 ± 0.25, LDL from 4.53 ± 0.72 to 2.89 ± 0.73, TG from 3.32 ± 0.66 suggesting reduced fat content in the liver and improvement in to 2.10 ± 0.16 and HDL increased from 1.45 ± 0.50 to 1.99 ± 0.48. liver function. The marked and significant improvements in The TC/HDL ratio declined from 6.07 ± 2.87 to 2.55 ± 0.62. SBP various metabolic parameters clearly indicate improvement in (mm Hg) decreased from 157.39 ± 15 to 129.15 ± 8.13, DBP from metabolic function, as reflected by decrease in inflammatory − 1 93.54 ± 12.03 to 74.33 ± 5.44. CRP (mg dl ) declined from biomarkers and improved liver function. These findings combined 3.23 ± 4.39 to 0.41 ± 0.65 (Po0.0001 for all). with the improvement in lipid profiles, blood sugar, blood Similarly, in men with class III obesity, T therapy produced pressure and urogenital function support the reported improve- marked reduction in fasting glucose, which decreased from ment in quality of life assessed by the AMS questionnaire and the − 1 6.40 ± 1.31 to 5.18 ± 0.32 mmol l . The change from baseline improvement in lower urinary tract symptoms assessed by the − 1 IPSS questionnaire. Equally important is the improvement was − 1.19 ± 0.16 mmol l . T therapy resulted in reduction in observed in erectile function, assessed by the IIEF (EF) scale. The HbA from 7.56 ± 1.37 to 5.68 ± 0.44%, and a change from 1c data from subgroup analyses in patients ⩽ 65 years old or 465 baseline of − 1.87 ± 0.13%. Significant reductions occurred in TC years old demonstrated that T therapy is equally effective in from 7.94 ± 1.10 to 4.81 ± 0.23, LDL from 4.95 ± 0.94 to 3.13 ± 0.64 improving the anthropometric parameters as well as the and TG from 3.72 ± 0.68 to 2.15 ± 0.12. We observed an increase in metabolic functions in both subgroups, irrespective of age, as HDL from 1.60 ± 0.51 to 2.18 ± 0.41. The TC/HDL ratio declined suggested previously. Therefore we emphasize that long-term from 5.66 ± 2.88 to 2.29 ± 0.47. SBP (mm Hg) decreased from T therapy is effective in younger as well as older patients, contrary 161.3 ± 14.25 to 132.7 ± 8.12, DBP from 97.06 ± 10.79 to 75.97 ± 5.43. − 1 to some previous claims. This is an important finding that CRP (mg dl ) declined from 3.73 ± 4.28 to 0.29 ± 0.31 (Po0.0001 indicates benefits of T therapy are not limited by age. for all) (Table 2). The improvements in the cardio-metabolic risk factors are, in part, attributed to improved metabolism, mitochondrial function, Effects of long-term T therapy on the quality of life parameters in increased energy utilization, reduced inflammation, increased men with various classes of obesity motivation and vigor resulting in improved cardio-metabolic As shown in Table 2, T therapy resulted in significant improvement function and enhanced physical activity. The improved motiva- in quality of life as assessed by the marked and significant tion, vigor, energy and reduced fatigue associated with long-term reduction in the AMS (32-point reduction in class I; 33-point T therapy is likely to have contributed, in part, to the observed WL 23,25,26,31,34,36–38,47,48 reduction in class II and 38-point reduction in class III) (Table 2). in obese men. The significance of our findings Similarly, a significant reduction was recorded in IPSS in all classes is that long-term T therapy in hypogonadal men with varying of obesity, indicating that T therapy improves lower urinary tract classes of obesity may represent a novel effective and safe symptoms in obese men and also improves urinary flow. More intervention strategy in management of obesity in hypogonadal importantly, a higher score was recorded for the International men. Index of Erectile Function (IIEF-EF) suggesting that T therapy As obesity is a chronic disease, necessitating medical interven- improves erectile function in obese men, irrespective of the class tion and long-term therapy, it is imperative to develop new of obesity (Table 2). approaches to the management of obesity. Recently, treatment with liraglutide coupled with a diet and exercise resulted in Effects of long-term T therapy in men with various classes of sustained and significant WL. This treatment also reduced obesity according to age cardiovascular risk in obese nondiabetic adults. Treatment with liraglutide produced reductions in SBP and fasting blood glucose, We have performed subgroup analyses to assess the effectiveness HbA and reductions in CRP concentrations. 1c of T therapy in patients ⩽ 65 years old (n = 323) and in patients One of the recent advances in management of obesity is 465 years old (n = 88). As shown in Table 4, T therapy appears to bariatric surgery. This approach has produced substantial and be equally effective in WL, reduction in WC and BMI in both sustained WL and ameliorated several obesity-related subgroups, as in all other parameters, irrespective of age. comorbidities. Bariatric surgery produces improvements in the CVD risk-factor profile, including metabolic syndrome, a lower risk Effects of long-term T therapy on the safety parameters in men of ischemic heart disease and mortality. Bariatric surgery also with various classes of obesity prevents new cases of diabetes compared with lifestyle treatment. T therapy in obese men increased hemoglobin concentrations and A robust finding in many studies, independent of bariatric hematocrit but the levels remained within physiological ranges procedure, has been the improvement or remission of T2DM, (Tables 2 and 4). There were no reported major adverse before any significant WL. On the basis of several studies it is cardiovascular events. T therapy in men in all three classes of suggested that bariatric surgery serves as an alternative approach obesity increased prostate volume. However, no case of urinary to intervention in obesity and this strategy may represent an retention was reported. In fact, lower urinary tract symptoms effective treatment with concomitant reduction in T2DM, obesity- decreased, as assessed by the IPSS scale (Tables 2 and 4). As related comorbidities and reduced mortality. Bariatric surgery expected, serum prostate-specific antigen increased in all men in increases levels of total T and free T concomitant with reduction in the three classes of obesity but the increase was not deemed weight, BMI and WC. Also fasting blood glucose and fasting insulin clinically meaningful. Eight patients were diagnosed with low- levels were significantly reduced. These findings strongly suggest grade prostate cancer while on T treatment. that weight reduction via bariatric surgery is associated with normalization of hormonal profiles in obese men. It should be emphasized that only carefully selected patients can be subjected DISCUSSION to bariatric surgery and patients need to be followed-up very In this study, we report that in men with various classes of obesity closely and carefully. More research is needed to understand the and TD, long-term T therapy produced significant and sustained long-term consequences of bariatric procedures in obese WL, together with marked reductions in WC and BMI. Furthermore, patients. we demonstrate that long-term T therapy in men with various Current strategies for the treatments for obesity include diets, classes of obesity reduced blood glucose, HbA , SBP and DBP, exercise, behavioral lifestyle changes, pharmaco-therapeutic 1c 53,54 CRP and improved lipid profiles. We also note that long-term agents and bariatric surgery. T therapy is another novel T therapy in men with various classes of obesity resulted in approach to treatment of obesity, as it reduces fat mass and © 2016 Macmillan Publishers Limited International Journal of Obesity (2016) 162 – 170 Effects of long-term treatment with testosterone F Saad et al Table 4. Changes of anthropometric, metabolic, prostate and quality of life parameters in obese hypogonadal men receiving testosterone treatment according to age group Baseline age (years) Class I (n = 214) Class II (n = 150) Class III (n = 47) ⩽ 65 (n = 163) 465 (n = 51) ⩽ 65 (n = 120) 465 (n = 30) ⩽ 65 (n = 40) 465 (n =7) Anthropometry Change ± s.e. Change ± s.e. Change ± s.e. Change ± s.e. Change ± s.e. Change ± s.e. Weight (kg) − 17.5± 0.5* − 16.7± 1.1* − 25.7± 0.6* − 24.2± 1.1* − 30.4± 0.7* − 31.4± 2.4* − 2 BMI (kg m ) − 5.55± 0.16* − 5.34± 0.36* − 8.26± 0.19* − 7.76± 0.35* − 9.94± 0.31* − 10.18± 0.72* Weight loss (%) − 16.9± 0.46* − 16.16± 1.01* − 21.92± 0.46* − 20.58± 0.94* − 23.55± 0.53* − 23.97± 1.6* Waist circumference (cm) − 10.3± 0.3* − 11.7± 0.8* − 14.1± 0.4* − 13.0± 0.7* − 14.4± 0.4* − 14.3± 1.2* Testosterone − 1 Testosterone (nmol l)8± 0.36* 8.66± 0.8* 7.06± 0.35* 8.09± 0.68* 6.26± 0.48* 7.42± 1.29* Prostate parameters Prostate volume (ml) 5.08± 0.31* 3.41± 0.66* 3.81± 0.3* 3.51± 0.41* 2.79± 0.34* 1.05± 2.26 − 1 # PSA (ng ml ) 0.39± 0.03* 0.27± 0.08 0.33± 0.04* 0.44± 0.07* 0.29± 0.04* − 0.18± 0.24 IPSS − 3.89± 0.25* − 6.09± 0.51* − 6.35± 0.3* − 6.52± 0.43* − 6.75± 0.35* − 8.01± 0.82* Erectile function IIEF-EF 8.83± 0.42* 10.26± 1.02* 7.71± 0.48* 6.95± 0.74* 7.26± 0.61* 4.06± 1.35** Quality of life AMS − 32.58± 0.78* − 32.15± 1.6* − 32.85± 0.79* − 35.42± 1.52* − 38.62± 1.18* − 36.04± 4.37* Glycaemic control − 1 § ## Fasting glucose (mmol l ) − 0.74± 0.09* − 1.25± 0.32 − 0.95± 0.12* − 1.81± 0.28* − 1.03± 0.13* − 2.14± 0.87 HbA (%) − 1.12± 0.07* − 1.25± 0.16* − 1.74± 0.09* − 2.03± 0.14* − 1.84± 0.14* − 2.02± 0.36* 1c Lipids − 1 Total cholesterol (mmol l ) − 2.14± 0.10* − 2.47± 0.23* − 2.76± 0.11* − 2.98± 0.23* − 3.10± 0.15* − 2.77± 0.57* − 1 HDL (mmol l ) 0.57± 0.03* 0.42± 0.08* 0.60± 0.04* 0.45± 0.06" 0.55± 0.05* 0.71± 0.14* − 1 §§ LDL (mmol l ) − 1.30± 0.07* − 1.43± 0.12* − 1.43± 0.08* − 1.60± 0.17* − 1.78± 0.10* − 1.27± 0.43 − 1 Triglycerides (mmol l ) − 0.86± 0.06* − 1.07± 0.14* − 1.14± 0.06* − 1.48± 0.12* − 1.51± 0.09* − 1.79± 0.28* Total cholesterol:HDL ratio − 3.77± 0.19* − 3.28± 0.34* − 3.59± 0.19* − 3.2± 0.33* − 3 ± 0.23* − 3.44± 0.59* Erythropoiesis/blood count − 1 $ ‡ $$ Haemoglobin (g dl ) 0.49± 3.39 0.66± 0.22 0.26± 0.09 0.3± 0.21 0.62± 0.09* 1.18± 0.31 Haematocrit (%) 4.22± 0.36* 5.03± 0.79* 4.74± 0.36* 3.89± 0.85* 4.54± 0.5* 6.49± 1.38* 9 − 1 Leukocytes (10 l ) − 0.29± 0.16 0.21± 0.32 − 0.85± 0.2* − 1.6± 0.38* − 0.38± 0.22 − 0.87± 0.64 Liver transaminases − 1 § †† AST (U l ) − 10.9± 1.1* − 9.46± 2.4 − 20.6± 1.41* − 18.32± 2.47* − 27.5± 2.23* − 30.35± 8.59 − 1 † ‡‡ ALT (U l ) − 12.22± 1.47* − 11.79± 3.7 − 22.67± 1.68* − 23.26± 3.69* − 27.93± 2.82* − 38.42± 10.31 Inflammation − 1 CRP (mg dl ) − 1.91± 0.16* − 1.47± 0.24* − 3.29± 0.32* − 3.74± 0.55* − 3.91± 0.47* − 4.53± 0.93* Blood pressure Systolic (mm Hg) − 19.68± 0.83* − 28.91± 2.36* − 32.25± 1.17* − 26.93± 1.88* − 33.05± 1.57* − 33.51± 3.43* Diastolic (mm Hg) − 11.6± 0.77* − 15.88± 1.86* − 20.34± 1.78* − 21.51± 1.41* − 22.84± 1.51* − 27.84±2.7* Abbreviations: ALT, alanine transaminase; AMS, Aging Males’ Symptom scale; AST, aspartate aminotransferase; BMI, body mass index; CRP, C-reactive protein; HDL, high-density lipoprotein; IIEF-EF, international index of erectile function, erectile function; IPSS, International Prostate Symptom Score; LDL, low-density # § $ † ‡ ** ## lipoprotein; PSA, prostate-specific antigen. *Po0.0001 vs baseline; P= 0.0008; P= 0.0001; P= 0.0031; P= 0.0016; P= 0.0037; P= 0.0048; P= 0.0185; §§ $$ †† ‡‡ P= 0.0057; P= 0.0005; P= 0.0012; P= 0.0007. improves lean body mass. This is of critical importance, as balance safety concerns, (c) patients would adhere to the therapy and in the body composition relates to metabolic function. We remain compliant. One most noted observation is that with believe that T therapy represents a novel pharmaco-therapeutic nonsurgical WL interventions including pharmacotherapy, most approach in the treatment of underlying patho-physiological WL occurs in the first 6 months after which there is a weight conditions of obesity. We should also point out that treatment plateau, or a small degree of WL or gain when followed-up for adherence is a major concern in managing chronic diseases such longer term. Thus, T therapy for treatment of obesity meets the as obesity. We report that adherence and compliance to T therapy aforementioned criteria. Simply, T therapy produces WL, is well with TU 3-monthly injections was remarkable in previous studies. -tolerated and safe, and no weight regain, and patient compliance In this study, only one patient was dropped out in 8 years, due to is very high. Most importantly, this therapy improves mood, moving to a new geographical location. energy, vigor and overall quality of life. Pharmaco-therapeutics used to treat obesity must meet several It should be pointed out that labels of testosterone preparations important criteria, including (a) long-term WL and weight list weight increase as a potential adverse effect of T therapy. maintenance, (b) should be well tolerated and exhibit no major An initial weight gain in response to T therapy may be a result of International Journal of Obesity (2016) 162 – 170 © 2016 Macmillan Publishers Limited Effects of long-term treatment with testosterone F Saad et al water retention, which is transient. Indeed, we measured a CONFLICT OF INTEREST moderate weight gain in some of our patients after 3–6 months of FS is a full-time employee of Bayer Pharma; AY and AH have received partial T therapy, which, however, was a transient phenomenon. Only compensation for data entry from Bayer Pharma; GD has received payment for three men (o1%) had gained weight at the end of the statistical analyses from Bayer Pharma. observation time. It is, however, important that T therapy in hypogonadal men will not result in rapid WL. The US Food and REFERENCES Drug Administration (FDA) used to require a quick effect of 1 Dobbs R, Sawers C, Thompson F, Manyika J, Woetzel J, Child P et al. Overcoming weight-loss drugs, although more recently it was acknowledged obesity: an initial economic analysis executive summary. McKinsey Global Institute that long-term effects over 1–2 years should be proven. 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Shifting the paradigm of testosterone and prostate 683515. cancer: the saturation model and the limits of androgen-dependent growth. Eur 37 Haider A, Saad F, Doros G, Gooren L. Hypogonadal obese men with and without Urol 2009; 55:310–320. diabetes mellitus type 2 lose weight and show improvement in cardiovascular risk 60 Morgentaler A, Miner MM, Caliber M, Guay AT, Khera M, Traish AM. Testosterone factors when treated with testosterone: An observational study. Obes Res Clin therapy and cardiovascular risk: advances and controversies. Mayo Clin Proc 2015; Pract 2014; 8: e339–e349. 90:224–251. 38 Yassin A, Doros G. Testosterone therapy in hypogonadal men results in sustained and clinically meaningful weight loss. Clin Obes 2013; 3:73–83. 39 Hackett G, Cole N, Bhartia M, Kennedy D, Raju J, Wilkinson P et al. Testosterone This work is licensed under a Creative Commons Attribution 4.0 replacement therapy improves metabolic parameters in hypogonadal men with International License. The images or other third party material in this type 2 diabetes but not in men with coexisting depression: The BLAST Study. J Sex article are included in the article’s Creative Commons license, unless indicated Med 2014; 11: 840–856. otherwise in the credit line; if the material is not included under the Creative Commons 40 Hackett G, Cole N, Bhartia M, Kennedy D, Raju J, Wilkinson P et al. The response to license, users will need to obtain permission from the license holder to reproduce the testosterone undecanoate in men with type 2 diabetes is dependent on achieving material. To view a copy of this license, visit http://creativecommons.org/licenses/ threshold serum levels (the BLAST study). Int J Clin Pract 2014; 68:203–215. by/4.0/ International Journal of Obesity (2016) 162 – 170 © 2016 Macmillan Publishers Limited http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png International Journal of Obesity Springer Journals

Effects of long-term treatment with testosterone on weight and waist size in 411 hypogonadal men with obesity classes I-III: observational data from two registry studies

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Medicine & Public Health; Medicine/Public Health, general; Public Health; Epidemiology; Internal Medicine; Metabolic Diseases; Health Promotion and Disease Prevention
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10.1038/ijo.2015.139
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International Journal of Obesity (2016) 40, 162 –170 OPEN © 2016 Macmillan Publishers Limited All rights reserved 0307-0565/16 www.nature.com/ijo ORIGINAL ARTICLE Effects of long-term treatment with testosterone on weight and waist size in 411 hypogonadal men with obesity classes I-III: observational data from two registry studies 1,2 2,3,4 5 6 F Saad , A Yassin , G Doros and A Haider BACKGROUND/OBJECTIVES: Long-term testosterone replacement therapy (TRT) up to 5 years has been shown to produce progressive and sustainable weight loss (WL) in hypogonadal men. This study investigated effects of long-term TRT up to 8 years in hypogonadal men with different obesity classes. SUBJECTS/METHODS: From two independent observational registries we identified a total of 411 obese, hypogonadal men receiving TRT in urological clinics. The effects of TRT on anthropometric as well as metabolic parameters were studied for a maximum duration of 8 years, mean follow-up: 6 years. All men received long-acting injections of testosterone undecanoate in 3-monthly intervals. RESULTS: In all three classes of obesity, T therapy produced significant WL, decrease in waist circumference (WC) and body mass index (BMI). In patients with class I obesity, mean weight decreased from 102.6 ± 6.4 to 84.1 ± 4.9 kg, change from baseline: − 17.4 ± 0.5 kg and − 16.8 ± 0.4%. WC in this group of patients decreased from 106.8 ± 7.4 to 95.1 ± 5.3 cm, change from baseline: − 2 − 10.6 ± 0.3 cm. BMI decreased from 32.69 ± 1.4 to 27.07 ± 1.57, change from baseline: − 5.52 ± 0.15 kg m . In patients with class II obesity, weight decreased from 116.8 ± 6.9 to 91.3 ± 6.3 kg, change from baseline: − 25.3 ± 0.5 kg and − 21.5 ± 0.4%. WC decreased from 113.5 ± 7.5 to 100.0 ± 5.4 cm, change from baseline: − 13.9 ± 0.4 cm. BMI decreased from 37.32 ± 1.45 to 29.49 ± 1.71, change − 2 from baseline: − 8.15 ± 0.17 kg m . In patients with class III obesity, weight decreased from 129.0 ± 5.6 to 98.9 ± 4.8 kg, change from baseline: − 30.5 ± 0.7 kg and − 23.6 ± 0.5%. WC decreased from 118.5 ± 5.6 to 103.8 ± 4.9 cm, change from baseline: − 14.3 ± 0.4 cm. − 2 BMI decreased from 41.93 ± 1.48 to 32.46 ± 1.59, change from baseline − 9.96 ± 0.29 kg m . CONCLUSIONS: Testosterone therapy appears to be an effective approach to achieve sustained WL in obese hypogonadal men irrespective of severity of obesity. Based on these findings we suggest that T therapy offers safe and effective treatment strategy of obesity in hypogonadal men. International Journal of Obesity (2016) 40, 162–170; doi:10.1038/ijo.2015.139 INTRODUCTION and cardiovascular disease (CVD) has led to the termination of the Look AHEAD Trial, suggesting that lifestyle changes alone are Obesity is a major public health threat that has an enormous insufficient and medical intervention is deemed necessary. New economic burden on society, with an estimated economic impact strategies are urgently needed to combat and manage obesity. of greater than $2 trillion. In the USA ~ 35.5% of adult men and − 2 2,3 Although attempts to manage obesity with lifestyle changes and 35.8% of adult women are obese (BMI X30 kg m ). Obesity therapeutic interventions have been made frequently and are increases risks for atherosclerosis, diabetes, metabolic syndrome, successful to some extent, weight regain remains a major nonalcoholic fatty liver disease, heart disease among other problem. A proactive approach is necessary for the treatment comorbidities and reduces life expectancy. Obesity contributes of obesity in order to reduce the onset or complications of other to pathophysiological conditions such as hemodynamic, arrhythmic comorbidities such as type 2 diabetes mellitus (T2DM) and CVD. and anatomical modifications in the cardiovascular system. A wealth of evidence exists demonstrating that WL improves Contrary to the previously held views, obesity is a chronic health outcomes and reduces healthcare costs. WL is associated disease necessitating medical intervention. If left untreated, with reduction in the incidence of hypertension and high obesity contributes significantly to a host of adverse effects on triglycerides, concomitant with reduction in cardiovascular the cardiovascular system. Thus, significant weight loss (WL) at any 4 8 time during adult life may result in cardiovascular benefit. It is mortality. Although pharmacological approaches in the treat- becoming clear that simple behavioral and lifestyle approaches, ment of obesity are met with mixed success, employment of such as diet and exercise alone, while considered a first step in surgical approaches has taken hold. Bariatric surgery has been management of obesity, are inadequate and for the most part shown to be successful in selected patients and has proven useful in the management of excessively obese patients. Gastric by-pass unsuccessful for treatment of obesity, especially in the long run. The limited success of diet and lifestyle in the treatment of obesity surgery reduced mortality by ~ 29% and decreased deaths from 1 2 3 Global Medical Affairs Andrology, Bayer Pharma, Berlin, Germany; Department of Urology, Gulf Medical University, Ajman, UAE; Institute for Urology and Andrology, 4 5 Segeberger Kliniken, Norderstedt, Germany; Department of Preventive Medicine, Men's Health Program, Dresden International University, Dresden, Germany; Department for Epidemiology and Statistics, Boston University School of Public Health, Boston, MA, USA and Private Urology Practice, Bremerhaven, Germany. Correspondence: Professor F Saad, Global Medical Affairs Andrology, Bayer Pharma AG, Muellerstr. 178, Berlin 13353, Germany. E-mail: [email protected] Received 24 April 2015; revised 23 June 2015; accepted 2 July 2015; accepted article preview online 29 July 2015; advance online publication, 25 August2015 Effects of long-term treatment with testosterone F Saad et al 9 − 2 CVD. T2DM was significantly reduced by surgical intervention and years) and class III (BMI ⩾ 40 kg m ; n = 47, mean age: 60.51 ± 5.52 years). 10–12 13 All men were treated with testosterone undecanoate injections (TU; other approaches of WL. Arterburn et al. demonstrated Nebido, Bayer Pharma, Berlin, Germany) for up to 8 years. Men were reduced rates of mortality and decreased deaths from CVD in entered into the registry once they had received 1 year of treatment. patients who underwent bariatric surgery. The benefitofWLon Therefore, registry participants had been in the registry for different diabetes was demonstrated in the Look AHEAD Trial. In the 9 durations of time, and declining numbers do not reflect drop-out rates. Swedish Obese Subjects study, CVD was reduced by WL. It should Inclusion criteria were two separate morning measures of total be emphasized, however, that bariatric surgery is not available to − 1 testosterone ⩽ 12.1 nmol l and the presence of hypogonadal symptoms all obese patients and not without risks. measured by the Aging Males’ symptoms scale (AMS). Current strategies for treatments for obesity include diets, Exclusion criteria for testosterone administration included previous exercise, behavioral lifestyle changes, pharmaco-therapeutic treatment with androgens, prostate cancer or any suspicion thereof, such 16–18 − 1 agents and bariatric surgery. Treatment of obesity with as prostate-specific antigen levels 44ng ml or abnormal findings upon incretin, glucagon-like peptide-1 (GLP-1) receptor agonists, digital rectal examination, International Prostate Symptom Score (IPSS) 419 points, breast cancer, a history of congestive heart failure or recent enzyme inhibitors, angiopoietin-like proteins has been investi- angina, or severe untreated sleep apnea. gated. Many of these approaches have yielded modest but not fully sustainable WL. In contrast, bariatric surgery has provided promising results. Assessment and follow-up Obesity contributes to the decline of testosterone (T) and the During this period, we evaluated the effects of long-term T therapy on the prevalence of hypogonadism is greater than 70% in men with following parameters: total plasma T levels, weight, waist circumference excessive obesity. T therapy in men with T deficiency (TD) (WC), BMI, hemoglobin, hematocrit, fasting glucose levels and hemoglobin A (HbA ), systolic blood pressure (SBP) and diastolic blood pressure reduces fat mass, increases lean body mass with concomitant WL, 1c 1c (DBP), lipid profile (total cholesterol, low-density lipoprotein (LDL) reduction in waist circumference (WC) and body mass index 21–43 cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides), (BMI). T therapy in hypogonadal obese men has been 44,45 C-reactive protein (CRP) and liver transaminases. We also assessed the suggested as a novel approach for the treatment of obesity. effects of T therapy on prostate volume, prostate-specific antigen and Long-term T therapy in men with TD reported significant and questionnaires IPSS, AMS and the International Index of Erectile Function, 35–40 sustained WL, reduced BMI and WC. The potential implication Erectile Function domain (IIEF-EF). Measures were taken between two and of T therapy in management of obesity in men with TD needs to four times per year and annual average was calculated. One patient with be explored. T therapy produced sustained WL without obesity class I dropped out after 39 months of treatment as a result of 35,36,38 recidivism. It is possible that T therapy in obese men with moving to a different geographical location. TD may prove useful in treatment of the underlying patho- Ethical guidelines as formulated by the German ‘Ärztekammer’ (the physiological conditions of obesity. In this report, we summarize German Medical Association) for observational studies in patients receiving standard treatment were followed. After receiving an explanation our findings on long-term T therapy in men with TD with varying regarding the nature and the purpose of the study, all subjects consented classes of obesity. The data presented suggest significant to be included in the research of their treatment protocol. improvement in WL, reduction in WC and BMI. We propose use The data from these 411 obese, hypogonadal men were included in this of T treatment as a novel therapeutic strategy for managing analysis. Statistical methodology was described previously. overweight and obesity in hypogonadal men with TD. RESULTS PATIENTS AND METHODS Baseline characteristics Patients Table 1 provides baseline characteristics of obese patients From two prospective, cumulative registry studies of 622 hypogonadal stratified to various classes of obesity based on BMI. In class I men, we identified all 411 obese hypogonadal men (66.1% of all patients) (n = 214), 33.2% had prediabetes, defined by HbA of 5.7 to 6.4%, with varying classes of obesity (class I (BMI 30–34.9; n = 214, mean age: 1c 58.61 ± 8.04 years), class II (BMI 35–39.9; n = 150, mean age: 60.35 ± 5.73 32.7% had T2DM and 6.1% had type 1 diabetes mellitus (T1DM). Table 1. Baseline characteristics and comorbidities in 411 obese hypogonadal men according to obesity class All Classes (n=411) Class I (n=214) Class II (n=150) Class III (n=47) age (years (minimum; maximum)) 59.46±7.05 (33;84) 58.61±8.04 (33;84) 60.35±5.73 (44;74) 60.51±5.52 (43;70) mean follow-up (years) 6.06±1.91 (1;8) 5.91±1.92 (1;8) 6.09±1.94 (1;8) 6.66±1.67 (2;8) Anthropometry weight (kg (minimum; maximum)) 110.8±11.3 (86;141) 102.6±6.4 (86;129) 116.8±6.9 (95;133) 129.0±5.6 (119;141) BMI (kg/m (minimum; maximum)) 35.43±3.48 (30.1;46.51) 32.69±1.4 (30.1;34.99) 37.32±1.45 (35.01; 39.95) 41.93±1.48 (40.08;46.51) waist circumference (cm (minimum; maximum)) 110.6±8.4 (89;148) 106.8±7.4 (89;133) 113.5±7.5 (97;148) 118.5±5.6 (105;132) Glycaemic control fasting glucose (mmol/L (minimum; maximum)) 6.12±1.54 (3.77;12.93) 5.97±1.65 (3.77;12.93) 6.24±1.43 (3.77;12.82) 6.40±1.31 (4.94;11.99) HbA (% (minimum;maximum)) 7.07±1.35 (4.5;11.6) 6.67±1.25 (4.6;9.7) 7.5±1.32 (4.9;11.6) 7.56±1.37 (4.5;9.4) 1c Metabolic diseases Prediabetes 103 (25.1%) 71 (33.2%) 29 (19.3%) 3 (6.4%) Diabetes mellitus type 2 173 (42.1%) 70 (32.7%) 77 (51.3%) 26 (55.3%) Diabetes mellitus type 1 23 (5.6%) 13 (6.1%) 8 (5.3%) 2 (4.3%) total metabolic diseases 299 (72.7%) 154 (72.0%) 114 (76.0%) 31 (66.0%) Cardiovascular diseases history of myocardial infarction 35 (8.5%) 6 (2.8%) 15 (11.5%) 11 (23.4%) history of stroke 7 (1.7%) 2 (0.9%) 4 (3.1%) 1 (2.1%) previous diagnosis of coronary artery disease 46 (11.2%) 23 (10.7%) 19 (14.5%) 18 (38.3%) total cardiovascular diseases 88 (21.4%) 31 (14.5%) 38 (29%) 30 (65.0%) © 2016 Macmillan Publishers Limited International Journal of Obesity (2016) 162 – 170 Effects of long-term treatment with testosterone F Saad et al History of myocardial infarction was 2.8% and history of stroke of myocardial infarction was 23.4% and history of stroke was 0.9%. In class II (n = 150), 19.3% had prediabetes, 51.3% had was 2.1%. T2DM and 5.3% had T1DM. History of myocardial infarction was 11.5% and history of stroke was 3.1%. In class III (n = 47), 6.3% Effects of long-term T therapy on circulating total T levels in men had prediabetes, 55.3% had T2DM and 4.3% had T1DM. History with various classes of obesity Figure 1 shows that irrespective of the class of obesity, TU treatment of obese patients restored total T levels within the physiological range during the first year and these levels were maintained in the physiological range over 8 years of follow-up. Effects of long-term T therapy on the anthropometric parameters in men with various classes of obesity As shown in Figures 2a–d and Table 2, in all three classes of obesity, T therapy produced significant WL, decrease in WC and BMI. In patients with class I obesity, mean weight decreased from 102.6 ± 6.4 to 84.1 ± 4.9 kg; the changes in weight were statistically significant for all 8 years vs previous year. The change from baseline was − 17.4 ± 0.5 kg and the percent change from baseline − 16.8 ± 0.4%. WC in this group of patients decreased from 106.8 ± 7.4 to 95.1 ± 5.3 cm. The changes were statistically significant for 6 years vs previous year. Mean change from baseline was − 10.6 ± 0.3 cm. BMI decreased from 32.69 ± 1.4 to −2 27.07 ± 1.57, mean change from baseline − 5.52 ± 0.15 kg m . Figure 1. Trough levels of total testosterone (mean ± s.e.) in 411 hypogonadal men in obesity classes I, II, and III receiving long-term With regard to WL, in class I, 200 patients (93.5%) lost ⩾ 5% of testosterone treatment. their baseline weight, 144 (67.3%) ⩾ 10%, 85 (39.7%) ⩾ 15%, 35 Reduction of waist circumference. Reduction of body weight. Weight change. Reduction of BMI. Figure 2. Reductions of waist circumference (a), body weight (b), BMI (c) and weight change (d) in 411 hypogonadal men receiving long-term testosterone treatment. All values are shown as mean± s.e. International Journal of Obesity (2016) 162 – 170 © 2016 Macmillan Publishers Limited Effects of long-term treatment with testosterone F Saad et al © 2016 Macmillan Publishers Limited International Journal of Obesity (2016) 162 – 170 Table 2. Changes in metabolic, prostate, and quality of life parameters at baseline and following long-term treatment with testosterone in obese hypogonadalmen Class I (n=214) Class II (n=150) Class III (n=47) Baseline age (years) 58.61±8.04 (33;84) 60.35±5.73 (44;74) 60.51±5.52 (43;70) baseline (±s.d.) 8 years (±s.d.) change (± s.e.) baseline (±s.d.) 8 years (±s.d.) change (±s.e.) baseline (±s.d.) 8 years (±s.d.) change (±s.e.) Testosterone Testosterone (nmol/L) 8.74±1.89 17.02±2.3 8.16±0.33* 9.3±1.92 16.86±2.32 7.29±0.31* 9.34±1.89 15.99±1.02 6.41±0.45* Prostate parameters prostate volume (ml) 28±10.03 30.2±11.38 4.77±0.28* 33.25±8.37 36.77±9.44 3.73±0.25* 34.77±8.04 38.33±8.08 2.58±0.41* PSA (ng/ml) 1.23±0.85 1.51±0.81 0.36±0.03* 1.63±0.85 1.9±0.74 0.35±0.03* 1.99±0.75 2.3±0.81 0.22±0.05* IPSS 8.39±4.78 3.12±2.31 −4.33±0.23* 9.69±4.5 3.54±2.65 −6.38±0.25* 9.74±4.34 2.97±2.09 −6.93±0.33* Erectile function IIEF-EF 13.87±7.23 24.83±3.53 9.13±0.39* 15.57±7.45 24.25±4.64 7.56±0.41* 17.09±7.8 25.36±3.5 6.86±0.56* Quality of life AMS 53.3±10.05 19.74±4.21 −32.48± 0.7* 52.59±9.43 19.43±3.97 −33.39±0.7* 57±9.88 17.78±2.1 −38.24±1.16* Glycaemic control fasting glucose (mmol/L) 5.97±1.65 4.95±0.47 −0.86±0.10* 6.24±1.43 5.08±0.46 −1.15±0.12* 6.40±1.31 5.18±0.32 −1.19±0.16* HbA (%) 6.67±1.25 5.37±0.4 −1.15±0.06* 7.5±1.32 5.78±0.56 −1.79±0.08* 7.56±1.37 5.68±0.44 −1.87±0.13* 1c Lipids total cholesterol (mmol/L) 7.01±1.12 4.73±0.28 −2.21±0.09* 7.60±1.04 4.78±0.25 −2.80±0.10* 7.94±1.10 4.81±0.23 −3.07±0.15* HDL (mmol/L) 1.21±0.41 1.67±0.37 0.54±0.03* 1.45±0.50 1.99±0.48 0.57±0.03* 1.60±0.51 2.18±0.41 0.57±0.05* LDL (mmol/L) 4.14±0.84 2.48±0.79 −1.31±0.06* 4.53±0.72 2.89±0.73 −1.46±0.07* 4.95±0.94 3.13±0.64 −1.71±0.11* triglycerides (mmol/L) 2.98±0.68 2.04±0.23 −0.90±0.05* 3.32±0.66 2.10±0.16 −1.21±0.05* 3.72±0.68 2.15±0.12 −1.56±0.09* total cholesterol : HDL ratio 6.45±2.44 2.96±0.59 −3.68±0.17* 6.07±2.87 2.55±0.62 −3.51±0.17* 5.66±2.88 2.29±0.47 −3.06±0.21* Erythropoiesis/Blood count haemoglobin (g/dl) 14.49±0.95 15.08±0.47 0.59±2.68* 14.5±0.86 14.74±1.13 0.27±0.08 14.36±0.72 15.03±0.41 0.7±0.09* haematocrit (%) 43.32±3.49 48.14±1.78 4.38±0.33* 43.64±3.49 48.26±1.59 4.54±0.34* 43.3±2.81 48.25±1.33 4.8±0.47* 9 § leukocytes (10 /L) 6.67±1.39 6.39±0.51 −0.17± 0.14 7.18±1.93 6.2±0.54 −1.01±0.17* 6.99±1.5 6.53±0.3 −0.45±0.21 Liver transaminases AST (U/L) 29.97±10.37 18.17±5.25 −10.47±1* 36.84±14.32 17.65±5.74 −20.06±1.22* 42.28±17.68 15.26±3.58 −27.95±2.21* ALT (U/L) 32.96±15.09 18.31±7.83 −11.99±1.39* 38.78±18.01 17.05±5.83 −22.84±1.54* 43.38±20.53 15.15±4.27 −29.44±2.77* Inflammation CRP (mg/dl) 2.15±2.23 0.34±0.34 −1.81±0.14* 3.23±4.39 0.41±0.65 −3.39±0.28* 3.73±4.28 0.29±0.31 −3.99±0.42* Blood pressure systolic (mm Hg) 144.3±14.59 125.91±8.37 −21.57±0.83* 157.39±15 129.15±8.13 −31.11±1.01* 161.3±14.25 132.7±8.12 −33.15±1.44* diastolic (mm Hg) 85.2±10.38 74.18±4.69 −12.52±0.73* 93.54±12.03 74.33±5.44 −20.62±1.41* 97.06±10.79 75.97±5.43 −23.51±1.35* Abbreviations: ALT, alanine transaminase; AMS, Aging Males’ Symptom scale; AST, aspartate aminotransferase; CRP, C-reactive protein; HDL, high-density lipoprotein; IIEF-EF, international index of erectile # § function, erectile function; IPSS, International Prostate Symptom Score; LDL, low-density lipoprotein; PSA, prostate-specific antigen. *Po0.0001 vs baseline; P=0.0014; P=0.0319. Effects of long-term treatment with testosterone F Saad et al Table 3. Changes in weight and waist circumference from baseline to last observation (A and B); proportion of patients in categories of waist circumference at baseline and end point (C); proportion of patients in categories of BMI at last observation (D) Class I (n = 214) Class II (n = 150) Class III (n = 47) n % n % n % A. Weight change Unchanged 1 0.5 0 0 0 0 Gained 3 1.4 0 0 0 0 Any weight loss 210 98.1 150 100 47 100 Weight loss ⩾ 5% 200 93.5 147 98 47 100 Weight loss ⩾ 10% 144 67.3 134 89.3 45 95.7 Weight loss ⩾ 15% 85 39.7 108 72 42 89.4 Weight loss ⩾ 20% 35 16.4 65 43.3 28 59.6 Weight loss ⩾ 25% 6 2.8 19 12.7 11 23.4 Weight loss ⩾ 30% 0 0 3 2 0 0 B. Waist circumference change Unchanged 1 0.5 0 0 0 0 Gained 1 0.5 0 0 0 0 Any reduction in waist circumference 212 99.1 150 100 47 100 Reduction ⩾ 5 cm 192 89.7 144 96 47 100 Reduction ⩾ 10 cm 101 47.2 110 73.3 42 89.4 Reduction ⩾ 15 cm 27 12.6 51 34 15 31.9 Reduction ⩾ 20 cm 6 2.8 12 8 2 4.3 Reduction ⩾ 25 cm 1 0.5 3 2 1 2.1 C. Proportion of patients in categories of waist circumference Baseline waist circumference ⩾ 94 cm 212 99.1 150 100 47 100 Baseline waist circumference ⩾ 102 cm 165 77.1 148 98.7 47 100 End waist circumference ⩾ 94 cm 166 77.6 142 94.7 47 100 End waist circumference ⩾ 102 cm 34 15.9 58 38.7 37 72.3 End waist circumference o94 cm 48 22.4 8 5.3 0 0 End waist circumference o102 cm 180 84.1 92 6.1 10 21.3 D. Proportion of patients in categories of BMI at last observation Normal weight 9 4.2 0 0 0 0 Overweight 155 72.4 67 44.7 3 6.4 Obesity class I 49 22.9 76 50.7 35 74.5 Obesity class II 1 0.5 7 4.7 9 19.1 Obesity class III 0 0 0 0 0 0 (16.4%) ⩾ 20%, 6 (2.8%) ⩾ 25% and 3 patients (1.4%) gained In class III obesity, all 47 patients lost ⩾ 5% of their baseline weight (Table 3). weight, 45 (95.7%) ⩾ 10%, 42 (89.4%) ⩾ 15%, 28 (59.6%) ⩾ 20%, In patients with class II obesity, weight decreased from 11 (23.4%) ⩾ 25% and no patient gained weight (Table 3). 116.8 ± 6.9 to 91.3 ± 6.3 kg. The changes in weight were statisti- cally significant for all 8 years vs previous year. The change from Effects of long-term T therapy on the metabolic parameters in baseline was − 25.3 ± 0.5 kg, percent change from baseline men with various classes of obesity − 21.6 ± 0.4%. WC decreased from 113.5 ± 7.5 to 100.0 ± 5.4 cm. Table 2 summarizes the findings of this study with regard to the The observed changes were statistically significant for the first changes in metabolic parameters and improvement in quality of 6 years vs previous year. The mean change from baseline was life in men with varying classes of obesity. In men with class I − 13.9 ± 0.4 cm. BMI decreased from 37.32 ± 1.45 to 29.49 ± 1.71, − 12 obesity, long-term T therapy resulted in decreased fasting mean change from baseline − 8.15 ± 0.17 kg m (Figures 2a–d; − 1 blood glucose from 5.97 ± 1.65 to 4.95 ± 0.47 mmol l . The Table 2). − 1 change from baseline was − 0.86 ± 0.10 mmol l . A reduction in Examining WL in patients in class II, 147 patients (98%) lost HbA was recorded from 6.67 ± 1.25 to 5.37 ± 0.4%, and a 1c ⩾ 5% of their baseline weight, 134 (89.3%) ⩾ 10%, 108 (72%) change from baseline of − 1.15 ± 0.06%. Total cholesterol ⩾ 15%, 65 (43.3%) ⩾ 20%, 19 (12.7%) ⩾ 25%, 3 men (2%) ⩾ 30% − 1 (TC; mmol l ) decreased from 7.01 ± 1.12 to 4.73 ± 0.28, LDL and no patient gained weight (Table 3). − 1 (mmol l ) from 4.14 ± 0.84 to 2.48 ± 0.79, triglycerides (TG; In patients with class III obesity, weight decreased from − 1 − 1 mmol l ) from 2.98 ± 0.68 to 2.04 ± 0.23. HDL (mmol l ) 129.0 ± 5.6 to 98.9 ± 4.8 kg. The changes were statistically increased from 1.21 ± 0.41 to 1.67 ± 0.37. The TC/HDL ratio declined significant for all 8 years vs previous year (Figures 2a–d; from 6.45 ± 2.44 to 2.96 ± 0.59. SBP (mm Hg) decreased from Table2). Thechangefrombaselinewas − 30.5 ± 0.7 kg 144.3 ± 14.59 to 125.91 ± 8.37, DBP from 85.2 ± 10.38 to 74.18 ± 4.69. and the percent change from baseline − 23.6 ± 0.5%. WC − 1 CRP (mg dl ) declined from 2.15 ± 2.23 to 0.34 ± 0.34 (Po0.0001 decreased from 118.45 ± 5.64 to 103.75 ± 4.86 cm. Changes for all). were statistically significant for the first 6 years vs previous In men with class II obesity, long-term T therapy reduced fasting year. The mean change from baseline was − 14.3 ± 0.4 cm. − 1 BMI decreased from 41.93 ± 1.48 to 32.46 ± 1.59, mean glucose from 6.24 ± 1.43 to 5.08 ± 0.46 mmol l . The change from −2 − 1 change from baseline − 9.96 ± 0.29 kg m (Figures 2a–d; baseline was − 2.80 ± 0.10 mmol l . HbA levels were reduced 1c Table 2). from 7.5 ± 1.32 to 5.78 ± 0.56%. The change from baseline was International Journal of Obesity (2016) 162 – 170 © 2016 Macmillan Publishers Limited Effects of long-term treatment with testosterone F Saad et al − 1.79 ± 0.08%. Concentrations of TC decreased from 7.60 ± 1.04 to significant reduction in alanine and aspartate transaminases 4.78 ± 0.25, LDL from 4.53 ± 0.72 to 2.89 ± 0.73, TG from 3.32 ± 0.66 suggesting reduced fat content in the liver and improvement in to 2.10 ± 0.16 and HDL increased from 1.45 ± 0.50 to 1.99 ± 0.48. liver function. The marked and significant improvements in The TC/HDL ratio declined from 6.07 ± 2.87 to 2.55 ± 0.62. SBP various metabolic parameters clearly indicate improvement in (mm Hg) decreased from 157.39 ± 15 to 129.15 ± 8.13, DBP from metabolic function, as reflected by decrease in inflammatory − 1 93.54 ± 12.03 to 74.33 ± 5.44. CRP (mg dl ) declined from biomarkers and improved liver function. These findings combined 3.23 ± 4.39 to 0.41 ± 0.65 (Po0.0001 for all). with the improvement in lipid profiles, blood sugar, blood Similarly, in men with class III obesity, T therapy produced pressure and urogenital function support the reported improve- marked reduction in fasting glucose, which decreased from ment in quality of life assessed by the AMS questionnaire and the − 1 6.40 ± 1.31 to 5.18 ± 0.32 mmol l . The change from baseline improvement in lower urinary tract symptoms assessed by the − 1 IPSS questionnaire. Equally important is the improvement was − 1.19 ± 0.16 mmol l . T therapy resulted in reduction in observed in erectile function, assessed by the IIEF (EF) scale. The HbA from 7.56 ± 1.37 to 5.68 ± 0.44%, and a change from 1c data from subgroup analyses in patients ⩽ 65 years old or 465 baseline of − 1.87 ± 0.13%. Significant reductions occurred in TC years old demonstrated that T therapy is equally effective in from 7.94 ± 1.10 to 4.81 ± 0.23, LDL from 4.95 ± 0.94 to 3.13 ± 0.64 improving the anthropometric parameters as well as the and TG from 3.72 ± 0.68 to 2.15 ± 0.12. We observed an increase in metabolic functions in both subgroups, irrespective of age, as HDL from 1.60 ± 0.51 to 2.18 ± 0.41. The TC/HDL ratio declined suggested previously. Therefore we emphasize that long-term from 5.66 ± 2.88 to 2.29 ± 0.47. SBP (mm Hg) decreased from T therapy is effective in younger as well as older patients, contrary 161.3 ± 14.25 to 132.7 ± 8.12, DBP from 97.06 ± 10.79 to 75.97 ± 5.43. − 1 to some previous claims. This is an important finding that CRP (mg dl ) declined from 3.73 ± 4.28 to 0.29 ± 0.31 (Po0.0001 indicates benefits of T therapy are not limited by age. for all) (Table 2). The improvements in the cardio-metabolic risk factors are, in part, attributed to improved metabolism, mitochondrial function, Effects of long-term T therapy on the quality of life parameters in increased energy utilization, reduced inflammation, increased men with various classes of obesity motivation and vigor resulting in improved cardio-metabolic As shown in Table 2, T therapy resulted in significant improvement function and enhanced physical activity. The improved motiva- in quality of life as assessed by the marked and significant tion, vigor, energy and reduced fatigue associated with long-term reduction in the AMS (32-point reduction in class I; 33-point T therapy is likely to have contributed, in part, to the observed WL 23,25,26,31,34,36–38,47,48 reduction in class II and 38-point reduction in class III) (Table 2). in obese men. The significance of our findings Similarly, a significant reduction was recorded in IPSS in all classes is that long-term T therapy in hypogonadal men with varying of obesity, indicating that T therapy improves lower urinary tract classes of obesity may represent a novel effective and safe symptoms in obese men and also improves urinary flow. More intervention strategy in management of obesity in hypogonadal importantly, a higher score was recorded for the International men. Index of Erectile Function (IIEF-EF) suggesting that T therapy As obesity is a chronic disease, necessitating medical interven- improves erectile function in obese men, irrespective of the class tion and long-term therapy, it is imperative to develop new of obesity (Table 2). approaches to the management of obesity. Recently, treatment with liraglutide coupled with a diet and exercise resulted in Effects of long-term T therapy in men with various classes of sustained and significant WL. This treatment also reduced obesity according to age cardiovascular risk in obese nondiabetic adults. Treatment with liraglutide produced reductions in SBP and fasting blood glucose, We have performed subgroup analyses to assess the effectiveness HbA and reductions in CRP concentrations. 1c of T therapy in patients ⩽ 65 years old (n = 323) and in patients One of the recent advances in management of obesity is 465 years old (n = 88). As shown in Table 4, T therapy appears to bariatric surgery. This approach has produced substantial and be equally effective in WL, reduction in WC and BMI in both sustained WL and ameliorated several obesity-related subgroups, as in all other parameters, irrespective of age. comorbidities. Bariatric surgery produces improvements in the CVD risk-factor profile, including metabolic syndrome, a lower risk Effects of long-term T therapy on the safety parameters in men of ischemic heart disease and mortality. Bariatric surgery also with various classes of obesity prevents new cases of diabetes compared with lifestyle treatment. T therapy in obese men increased hemoglobin concentrations and A robust finding in many studies, independent of bariatric hematocrit but the levels remained within physiological ranges procedure, has been the improvement or remission of T2DM, (Tables 2 and 4). There were no reported major adverse before any significant WL. On the basis of several studies it is cardiovascular events. T therapy in men in all three classes of suggested that bariatric surgery serves as an alternative approach obesity increased prostate volume. However, no case of urinary to intervention in obesity and this strategy may represent an retention was reported. In fact, lower urinary tract symptoms effective treatment with concomitant reduction in T2DM, obesity- decreased, as assessed by the IPSS scale (Tables 2 and 4). As related comorbidities and reduced mortality. Bariatric surgery expected, serum prostate-specific antigen increased in all men in increases levels of total T and free T concomitant with reduction in the three classes of obesity but the increase was not deemed weight, BMI and WC. Also fasting blood glucose and fasting insulin clinically meaningful. Eight patients were diagnosed with low- levels were significantly reduced. These findings strongly suggest grade prostate cancer while on T treatment. that weight reduction via bariatric surgery is associated with normalization of hormonal profiles in obese men. It should be emphasized that only carefully selected patients can be subjected DISCUSSION to bariatric surgery and patients need to be followed-up very In this study, we report that in men with various classes of obesity closely and carefully. More research is needed to understand the and TD, long-term T therapy produced significant and sustained long-term consequences of bariatric procedures in obese WL, together with marked reductions in WC and BMI. Furthermore, patients. we demonstrate that long-term T therapy in men with various Current strategies for the treatments for obesity include diets, classes of obesity reduced blood glucose, HbA , SBP and DBP, exercise, behavioral lifestyle changes, pharmaco-therapeutic 1c 53,54 CRP and improved lipid profiles. We also note that long-term agents and bariatric surgery. T therapy is another novel T therapy in men with various classes of obesity resulted in approach to treatment of obesity, as it reduces fat mass and © 2016 Macmillan Publishers Limited International Journal of Obesity (2016) 162 – 170 Effects of long-term treatment with testosterone F Saad et al Table 4. Changes of anthropometric, metabolic, prostate and quality of life parameters in obese hypogonadal men receiving testosterone treatment according to age group Baseline age (years) Class I (n = 214) Class II (n = 150) Class III (n = 47) ⩽ 65 (n = 163) 465 (n = 51) ⩽ 65 (n = 120) 465 (n = 30) ⩽ 65 (n = 40) 465 (n =7) Anthropometry Change ± s.e. Change ± s.e. Change ± s.e. Change ± s.e. Change ± s.e. Change ± s.e. Weight (kg) − 17.5± 0.5* − 16.7± 1.1* − 25.7± 0.6* − 24.2± 1.1* − 30.4± 0.7* − 31.4± 2.4* − 2 BMI (kg m ) − 5.55± 0.16* − 5.34± 0.36* − 8.26± 0.19* − 7.76± 0.35* − 9.94± 0.31* − 10.18± 0.72* Weight loss (%) − 16.9± 0.46* − 16.16± 1.01* − 21.92± 0.46* − 20.58± 0.94* − 23.55± 0.53* − 23.97± 1.6* Waist circumference (cm) − 10.3± 0.3* − 11.7± 0.8* − 14.1± 0.4* − 13.0± 0.7* − 14.4± 0.4* − 14.3± 1.2* Testosterone − 1 Testosterone (nmol l)8± 0.36* 8.66± 0.8* 7.06± 0.35* 8.09± 0.68* 6.26± 0.48* 7.42± 1.29* Prostate parameters Prostate volume (ml) 5.08± 0.31* 3.41± 0.66* 3.81± 0.3* 3.51± 0.41* 2.79± 0.34* 1.05± 2.26 − 1 # PSA (ng ml ) 0.39± 0.03* 0.27± 0.08 0.33± 0.04* 0.44± 0.07* 0.29± 0.04* − 0.18± 0.24 IPSS − 3.89± 0.25* − 6.09± 0.51* − 6.35± 0.3* − 6.52± 0.43* − 6.75± 0.35* − 8.01± 0.82* Erectile function IIEF-EF 8.83± 0.42* 10.26± 1.02* 7.71± 0.48* 6.95± 0.74* 7.26± 0.61* 4.06± 1.35** Quality of life AMS − 32.58± 0.78* − 32.15± 1.6* − 32.85± 0.79* − 35.42± 1.52* − 38.62± 1.18* − 36.04± 4.37* Glycaemic control − 1 § ## Fasting glucose (mmol l ) − 0.74± 0.09* − 1.25± 0.32 − 0.95± 0.12* − 1.81± 0.28* − 1.03± 0.13* − 2.14± 0.87 HbA (%) − 1.12± 0.07* − 1.25± 0.16* − 1.74± 0.09* − 2.03± 0.14* − 1.84± 0.14* − 2.02± 0.36* 1c Lipids − 1 Total cholesterol (mmol l ) − 2.14± 0.10* − 2.47± 0.23* − 2.76± 0.11* − 2.98± 0.23* − 3.10± 0.15* − 2.77± 0.57* − 1 HDL (mmol l ) 0.57± 0.03* 0.42± 0.08* 0.60± 0.04* 0.45± 0.06" 0.55± 0.05* 0.71± 0.14* − 1 §§ LDL (mmol l ) − 1.30± 0.07* − 1.43± 0.12* − 1.43± 0.08* − 1.60± 0.17* − 1.78± 0.10* − 1.27± 0.43 − 1 Triglycerides (mmol l ) − 0.86± 0.06* − 1.07± 0.14* − 1.14± 0.06* − 1.48± 0.12* − 1.51± 0.09* − 1.79± 0.28* Total cholesterol:HDL ratio − 3.77± 0.19* − 3.28± 0.34* − 3.59± 0.19* − 3.2± 0.33* − 3 ± 0.23* − 3.44± 0.59* Erythropoiesis/blood count − 1 $ ‡ $$ Haemoglobin (g dl ) 0.49± 3.39 0.66± 0.22 0.26± 0.09 0.3± 0.21 0.62± 0.09* 1.18± 0.31 Haematocrit (%) 4.22± 0.36* 5.03± 0.79* 4.74± 0.36* 3.89± 0.85* 4.54± 0.5* 6.49± 1.38* 9 − 1 Leukocytes (10 l ) − 0.29± 0.16 0.21± 0.32 − 0.85± 0.2* − 1.6± 0.38* − 0.38± 0.22 − 0.87± 0.64 Liver transaminases − 1 § †† AST (U l ) − 10.9± 1.1* − 9.46± 2.4 − 20.6± 1.41* − 18.32± 2.47* − 27.5± 2.23* − 30.35± 8.59 − 1 † ‡‡ ALT (U l ) − 12.22± 1.47* − 11.79± 3.7 − 22.67± 1.68* − 23.26± 3.69* − 27.93± 2.82* − 38.42± 10.31 Inflammation − 1 CRP (mg dl ) − 1.91± 0.16* − 1.47± 0.24* − 3.29± 0.32* − 3.74± 0.55* − 3.91± 0.47* − 4.53± 0.93* Blood pressure Systolic (mm Hg) − 19.68± 0.83* − 28.91± 2.36* − 32.25± 1.17* − 26.93± 1.88* − 33.05± 1.57* − 33.51± 3.43* Diastolic (mm Hg) − 11.6± 0.77* − 15.88± 1.86* − 20.34± 1.78* − 21.51± 1.41* − 22.84± 1.51* − 27.84±2.7* Abbreviations: ALT, alanine transaminase; AMS, Aging Males’ Symptom scale; AST, aspartate aminotransferase; BMI, body mass index; CRP, C-reactive protein; HDL, high-density lipoprotein; IIEF-EF, international index of erectile function, erectile function; IPSS, International Prostate Symptom Score; LDL, low-density # § $ † ‡ ** ## lipoprotein; PSA, prostate-specific antigen. *Po0.0001 vs baseline; P= 0.0008; P= 0.0001; P= 0.0031; P= 0.0016; P= 0.0037; P= 0.0048; P= 0.0185; §§ $$ †† ‡‡ P= 0.0057; P= 0.0005; P= 0.0012; P= 0.0007. improves lean body mass. This is of critical importance, as balance safety concerns, (c) patients would adhere to the therapy and in the body composition relates to metabolic function. We remain compliant. One most noted observation is that with believe that T therapy represents a novel pharmaco-therapeutic nonsurgical WL interventions including pharmacotherapy, most approach in the treatment of underlying patho-physiological WL occurs in the first 6 months after which there is a weight conditions of obesity. We should also point out that treatment plateau, or a small degree of WL or gain when followed-up for adherence is a major concern in managing chronic diseases such longer term. Thus, T therapy for treatment of obesity meets the as obesity. We report that adherence and compliance to T therapy aforementioned criteria. Simply, T therapy produces WL, is well with TU 3-monthly injections was remarkable in previous studies. -tolerated and safe, and no weight regain, and patient compliance In this study, only one patient was dropped out in 8 years, due to is very high. Most importantly, this therapy improves mood, moving to a new geographical location. energy, vigor and overall quality of life. Pharmaco-therapeutics used to treat obesity must meet several It should be pointed out that labels of testosterone preparations important criteria, including (a) long-term WL and weight list weight increase as a potential adverse effect of T therapy. maintenance, (b) should be well tolerated and exhibit no major An initial weight gain in response to T therapy may be a result of International Journal of Obesity (2016) 162 – 170 © 2016 Macmillan Publishers Limited Effects of long-term treatment with testosterone F Saad et al water retention, which is transient. Indeed, we measured a CONFLICT OF INTEREST moderate weight gain in some of our patients after 3–6 months of FS is a full-time employee of Bayer Pharma; AY and AH have received partial T therapy, which, however, was a transient phenomenon. Only compensation for data entry from Bayer Pharma; GD has received payment for three men (o1%) had gained weight at the end of the statistical analyses from Bayer Pharma. observation time. It is, however, important that T therapy in hypogonadal men will not result in rapid WL. The US Food and REFERENCES Drug Administration (FDA) used to require a quick effect of 1 Dobbs R, Sawers C, Thompson F, Manyika J, Woetzel J, Child P et al. Overcoming weight-loss drugs, although more recently it was acknowledged obesity: an initial economic analysis executive summary. McKinsey Global Institute that long-term effects over 1–2 years should be proven. 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The images or other third party material in this type 2 diabetes but not in men with coexisting depression: The BLAST Study. J Sex article are included in the article’s Creative Commons license, unless indicated Med 2014; 11: 840–856. otherwise in the credit line; if the material is not included under the Creative Commons 40 Hackett G, Cole N, Bhartia M, Kennedy D, Raju J, Wilkinson P et al. The response to license, users will need to obtain permission from the license holder to reproduce the testosterone undecanoate in men with type 2 diabetes is dependent on achieving material. To view a copy of this license, visit http://creativecommons.org/licenses/ threshold serum levels (the BLAST study). Int J Clin Pract 2014; 68:203–215. by/4.0/ International Journal of Obesity (2016) 162 – 170 © 2016 Macmillan Publishers Limited

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International Journal of Obesity – Springer Journals

Published: Jul 29, 2015

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