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

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

Recommendations on the diagnosis, treatment and monitoring of testosterone deficiency in men.

The relative proportional increase of the elderly population within many countries will become one of the most significant social transformations of the twenty-first century and, for the first time in history, persons aged 65 or above outnumbered children under five years of age globally. One in four persons living in Europe and Northern America will be aged 65 or over. One of the goals of ISSAM is to raise awareness of the special health needs of older men. Since a significant number of aging men will eventually become testosterone deficient, the Hypogonadism panel of ISSAM updates its guidelines.

Recommendations on the diagnosis, treatment and monitoring of hypogonadism in men.

Hypogonadism or Testosterone Deficiency (TD) in adult men as defined by low levels of serum testosterone accompanied by characteristic symptoms and/or signs as detailed further on can be found in long-recognized clinical entities such as Klinefelter syndrome, Kallmann syndrome, pituitary or testicular disorders, as well as in men with idiopathic, metabolic or iatrogenic conditions that result in testosterone deficiency. These recommendations do not encompass the full range of pathologies leading to hypogonadism (testosterone deficiency), but instead focus on the clinical spectrum of hypogonadism related to metabolic and idiopathic disorders that contribute to the majority of cases that occur in adult men.

Testosterone and metabolic syndrome: a meta-analysis study.

INTRODUCTION: Metabolic syndrome (MetS) is often associated with male hypogonadism. Despite the well-known link, the role of testosterone replacement therapy (TRT) in MetS has not been completely clarified. AIM: To systematically analyse the relationship between androgen levels and MetS we performed a review and meta-analyses of available prospective and cross-sectional studies. In addition, a specific meta-analysis on the metabolic effects of TRT in available randomized clinical trials (RCTs) was also performed. METHODS: An extensive Medline search was performed including the following words "testosterone,""metabolic syndrome," and "males". MAIN OUTCOME MEASURES: Out of 323 retrieved articles, 302 articles were excluded for different reasons. Among the 20 published studies included, 13, 3, and 4 were cross-sectional, longitudinal, and RCTs, respectively. Another unpublished RCT was retrieved on http://www.clinicaltrials.gov. RESULTS: MetS patients showed significantly lower T plasma levels, as compared with healthy individuals. Similar results were obtained when MetS subjects with and without erectile dysfunction were analyzed separately or when NCEP-ATPIII MetS criteria were compared with other definitions. Meta-regression analysis demonstrated that type 2 diabetes (T2DM) increased the MetS-associated T fall. In a multiple regression model, after adjusting for age and BMI, both T2DM and MetS independently predicted low testosterone (adj. r = -0.752; P < 0.001 and -0.271; P < 0.05, respectively). Analysis of longitudinal studies demonstrated that baseline testosterone was significantly lower among patients with incident MetS in comparison with controls (2.17 [-2.41;-1.94] nmol/L; P < 0.0001). Combining the results of RCTs, TRT was associated with a significant reduction of fasting plasma glucose, homeostatic model assessment index, triglycerides, and waist circumference. In addition, an increase of high-density lipoprotein cholesterol was also observed. CONCLUSIONS: The meta-analysis of the available cross-sectional data suggests that MetS can be considered an independent association of male hypogonadism. Although only few RCTs have been reported, TRT seems to improve metabolic control, as well as central obesity.

Effects of testosterone supplementation on markers of the metabolic syndrome and inflammation in hypogonadal men with the metabolic syndrome: the double-blinded placebo-controlled Moscow study.

OBJECTIVE: Men with the metabolic syndrome (MetS) have low plasma testosterone (T) levels. The aim of this study was to establish whether the normalization of plasma T improves the features of the MetS. DESIGN: A randomized, placebo-controlled, double-blinded, phase III trial of 184 men suffering from both the MetS and hypogonadism. PATIENTS: One hundred and eighty-four men, aged 35-70, with the MetS and hypogonadism (baseline total T level <12·0 nm or calculated free T level <225 pm.), recruited in the outpatient andrology and urology clinic, Research Center for Endocrinology in Moscow, Russia. INTERVENTION: Treatment for 30 weeks with either parenteral T undecanoate (n = 113; TU; 1000 mg IM) or placebo (n = 71), administered at baseline, and after 6 and 18 weeks. One hundred and five (92·9%) men receiving TU and 65 (91·5%) receiving placebo completed the trial. MEASUREMENTS: Body weight, body mass index (BMI), waist circumference (WC), hip circumference, waist-to-hip ratio, insulin, leptin, glucose, cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, C-reactive protein (CRP), interleukin-1-beta (IL-1ß), interleukin-6 (IL-6), interleukin-10 (IL-10) and tumour necrosis factor-alpha (TNF-α). RESULTS: There were significant decreases in weight, BMI and WC in the TU vs placebo group. Levels of leptin and insulin also decreased, but there were no changes in serum glucose or lipid profile. Of the inflammatory markers, IL-1ß, TNF-α and CRP decreased, while IL-6 and IL-10 did not change significantly. CONCLUSIONS: Thirty weeks of T administration normalizing plasma T in hypogonadal men with the MetS improved some components of the MetS and a number of inflammatory markers.

Effects of testosterone supplementation on depressive symptoms and sexual dysfunction in hypogonadal men with the metabolic syndrome.

INTRODUCTION: Low testosterone levels in men are associated with the metabolic syndrome (MetS) as well as with depressive symptoms, low vitality, and sexual dysfunction. AIM: To assess the effects of testosterone administration on these subjective symptoms, which have not extensively been studied in hypogonadal men with the MetS. MAIN OUTCOME MEASURES: The Beck Depression Inventory (BDI-IA), Aging Males' Symptoms (AMS) scale, and International Index of Erectile Function 5-item (IIEF-5) scale at baseline, 18 and 30 weeks were analysed using multilevel analysis. METHODS: In a randomized, placebo-controlled, double-blind, phase III trial (ClinicalTrials.gov identifier: NCT00696748), 184 men suffering from both the MetS and hypogonadism were included. They were treated for 30 weeks with either parenteral testosterone undecanoate (TU; 1,000 mg IM TU, at baseline, and after 6 and 18 weeks; Nebido or placebo injections, 105 (92.9%) men receiving TU and 65 (91.5%) receiving placebo completed the 30-week trial. RESULTS: The 184 men were aged mean 52.1 years old (standard deviation [SD] 9.6; range 35-69), with a mean body mass index of 35.5 kg/m(2) (SD 6.7; range 25.1-54.8), and a mean total testosterone level of 8.0 nmol/L (SD 4.0). There were significant improvements in BDI-IA (mean difference vs. placebo after 30 weeks: -2.5 points; 95% confidence interval [CI]: -0.9; -4.1; P = 0.003), AMS (-7.4 points; 95% CI: -4.3; -10.5; P < 0.001), and IIEF-5 (+3.1 points; 95% CI: +1.8; +4.4; P < 0.001). The effects on the BDI-IA, AMS, and IIEF-5 were strongest in men with baseline total testosterone levels <7.7 mmol/L (i.e., median value). CONCLUSIONS: TU administration may improve depressive symptoms, aging male symptoms and sexual dysfunction in hypogonadal men with the MetS. The beneficial effects of testosterone were most evident in men with the lowest baseline total testosterone levels.

Breaking the vicious circle of obesity: the metabolic syndrome and low testosterone by administration of testosterone to a young man with morbid obesity / Quebrando o círculo vicioso da obesidade: síndrome metabólica e baixos níveis de testosterona pela administração de testosterona a um homem jovem com obesidade mórbida

OBJECTIVE: The metabolic syndrome (MS) is associated with low serum testosterone levels. Conversely, low testosterone levels induce MS. These operational mechanisms reinforce one another and induce a vicious cycle. This is a report on a morbid obesity 42 year-old man with the MS and serum testosterone of 5.0 nmol/L (N: 12.0-33.0), who was resistant to treatment with diet and exercise. He was treated with testosterone undecanoate for 16 months. METHODS: Anthropological and laboratory variables were measured before and during testosterone administration. Also the Aging Male Symptom Scale (AMS), the International Index of Erectile Function (IIEF) and Beck's Depression Inventory were assessed. RESULTS: After 16 months, there was a weight loss of 50 kg and a decrease in waist circumference of 36.5 cm. Blood pressure normalized and laboratory variables returned to the normal range. The patient did not meet the criteria for the MS anymore. There were improvements on the AMS, the IIEF and Beck's Depression Inventory. CONCLUSIONS: Normalizing testosterone in men with morbid obesity in combination with diet and exercise, with the MS and low testosterone levels, may rescue them from the MS, improving their mood and their stamina to follow a diet and to exercise.

OBJETIVO: A síndrome metabólica (SM) está associada a baixos níveis séricos de testosterona. Inversamente, baixos níveis de testosterona induzem a SM. Esses mecanismos operacionais se reforçam mutuamente e levam a um círculo vicioso. Este é o relato de um homem de 42 anos, obesidade mórbida com SM e testosterona sérica de 5,0 nmol/L (N: 12,0-33,5), resistente ao tratamento com dieta e exercícios. Ele foi tratado com undecanoato de testosterona por 16 meses. MÉTODOS: Variáveis antropológicas e laboratoriais foram medidas antes e durante a administração de testosterona. Também foram avaliados a Escala de Envelhecimento Masculino (AMS), o Índice Internacional de Função Erétil (IIEF) e a Escala de Beck para Depressão. RESULTADOS: Após 16 meses, houve uma perda de peso de 50 kg e diminuição de 36,5 cm da circunferência abdominal. A pressão arterial foi normalizada e as variáveis laboratoriais também retornaram para os limites de normalidade. O paciente não preenchia mais os critérios para SM. Houve melhoras da AMS, do IIEF e da Escala de Beck para Depressão. CONCLUSÕES: A normalização da testosterona em homens com obesidade mórbida, combinada à dieta e a exercícios, com SM e baixos níveis de testosterona, pode livrá-los da SM, melhorando o humor e o vigor para seguir uma dieta e exercícios.

Breaking the vicious circle of obesity: the metabolic syndrome and low testosterone by administration of testosterone to a young man with morbid obesity.

OBJECTIVE: The metabolic syndrome (MS) is associated with low serum testosterone levels. Conversely, low testosterone levels induce MS. These operational mechanisms reinforce one another and induce a vicious cycle. This is a report on a morbid obesity 42 year-old man with the MS and serum testosterone of 5.0 nmol/L (N: 12.0-33.0), who was resistant to treatment with diet and exercise. He was treated with testosterone undecanoate for 16 months. METHODS: Anthropological and laboratory variables were measured before and during testosterone administration. Also the Aging Male Symptom Scale (AMS), the International Index of Erectile Function (IIEF) and Beck's Depression Inventory were assessed. RESULTS: After 16 months, there was a weight loss of 50 kg and a decrease in waist circumference of 36.5 cm. Blood pressure normalized and laboratory variables returned to the normal range. The patient did not meet the criteria for the MS anymore. There were improvements on the AMS, the IIEF and Beck's Depression Inventory. CONCLUSIONS: Normalizing testosterone in men with morbid obesity in combination with diet and exercise, with the MS and low testosterone levels, may rescue them from the MS, improving their mood and their stamina to follow a diet and to exercise.