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

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

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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.

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

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Testosterone deficiency (TD) is an increasingly common problem with significant health implications, but its diagnosis and management can be challenging. A multi-disciplinary panel from BSSM reviewed the available literature on TD and provide evidence-based statements for clinical practice. Evidence was derived from Medline, EMBASE and Cochrane searches on hypogonadism, testosterone therapy (T Therapy) and cardiovascular safety from May 2017 to September 2022. This revealed 1,714 articles, including 52 clinical trials and 32 placebo-controlled randomised controlled trials. A total of twenty-five statements are provided, relating to five key areas: screening, diagnosis, initiating T Therapy, benefits and risks of T Therapy, and follow-up. Seven statements are supported by level 1 evidence, eight by level 2, five by level 3, and five by level 4. Recent studies have demonstrated that low levels of testosterone in men are associated with increased risk of incident type 2 diabetes mellitus, worse outcomes in chronic kidney disease and COVID 19 infection with increased all-cause mortality, along with significant quality of life implications. These guidelines should help practitioners to effectively diagnose and manage primary and age-related TD.

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Although not universal, many epidemiological data sources signal that a higher proportion of males than females with confirmed Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infections have adverse outcomes, such as intensive care unit (ICU) admission and death. Though likely multifactorial, the various hypotheses that have been proposed as underlying factors behind this trend are related to greater smoking prevalence among males, testosterone (T) deficiency causing an inflammatory storm, androgen-driven pathogenesis of SARS-CoV-2, a protective effect of estrogen in females, and inborn errors of cytokine immunity. This review aims at examining the evidence and at assessing the likelihood that the factors being investigated are contributory to the reported trend of male predominance of severe COVID-19 cases. Sources were obtained using the PubMed database and were selected based on their relevance to one of the primary hypotheses attempting to explain the strong male sex bias of severe SARS-CoV-2 infections. Emphasis was placed on meta-analyses and population-based studies. Sources are current through February 22, 2022. A severe COVID-19 case or outcome is defined in this review as a progression of the SARS-CoV-2 virus that results in either admission to an ICU for management of symptoms and clinical stabilization or which leads to death. Although the trend of male predominance of severe COVID-19 cases is likely multifactorial, the hypothesis of T deficiency causing an inflammatory storm has support from many studies with limited conflicting evidence. An inborn error in cytokine immunity is also well supported, but it needs more studies to add support to the hypothesis. The immunologic protective effect of estrogen is supported by multiple studies, but it also has conflicting evidence. It appears less likely that the trend is caused solely by an increased prevalence of smoking among males or an androgen-driven pathogenesis, based on the extent of conflicting evidence.

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BACKGROUND: As circulating testosterone may be suppressed in the post-prandial state, it has been recommended that measurements are carried out with the patient fasted. OBJECTIVES: In this regard, we assessed the effect of fasting/non-fasting status on total testosterone (T) levels in men. MATERIALS AND METHODS: Data was collected in a single UK Hospital in men with two serum T requests taken within a 6-month period of each other and sampled at a time of day ≤ 2 h apart. Three groups were established, with T levels compared via signed-rank test in men with both a fasting and non-fasting sample (Group 1; n = 69), and in men with paired non-fasting (Group 2; n = 126) and paired fasting (Group 3; n = 18) samples. The differences in T levels between the paired samples was compared between the three groups using the rank-sum test and also via multiple regression analysis with the groups factorised. RESULTS: Median (Interquartile Range, IQR) age did not vary significantly between Groups 1, 2 and 3 at 49 (38-56), 51.5 (42-60) and 51.5 (40-59) years, respectively. No significant difference (p = 0.89) was found between the T levels in Group 1 with non-fasting (median (IQR) T = 11.1 (9.3-13.6) nmol/L) versus fasting samples T = 10.8 (8.9-14.1) nmol/L). Paired T levels did not significantly differ in each of the other two groups (2 and 3). There was no significant association between the differences in paired T levels between the three groups, even when the model was adjusted for age and time, with Group 1 (as reference) versus Group 2 (p = 0.79) and versus Group 3 (p = 0.63). DISCUSSION: We found no significant differences between fasting and non-fasting T levels. A definitive confirmatory study is required to determine whether fasting status is necessary to diagnose hypogonadism. CONCLUSION: Non-requirement of fasting status when checking testosterone levels would remove a major hurdle in the diagnosis of hypogonadism.

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INTRODUCTION: Testosterone deficiency (TD) is an increasing problem that can affect a man's physical and psychological health, and quality of life. Testosterone replacement therapy (TRT), combined with weight reduction, lifestyle advice, and the treatment of co-morbidities, is the treatment of choice in men who are not concerned about fertility. However, there remains an unmet need in this therapeutic area, relating to factors such as inconvenient or painful administration, fluctuations in testosterone levels, supra-physiologic testosterone levels, poor tolerability, and secondary safety issues, which may be associated with the current TRT options. Advances in transdermal delivery systems have resulted in the development of a new 2% transdermal testosterone gel, that may offer some additional features over the other currently available TRTs. AREAS COVERED: We performed a comprehensive review of the published and gray literature to identify randomized studies and non-randomized studies (NRS) involving adult men receiving treatment for low testosterone levels. EXPERT OPINION: Topical gels are often the most convenient first-line treatment for testosterone deficiency, but options are important as patient preference is more important than virtually any other clinical area of medicine. The chosen therapy must be convenient to use and reach reliable therapeutic levels to effectively and consistently relieve symptoms. Testavan, a new 2% testosterone gel, goes some way to achieving these goals.

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BACKGROUND: Testosterone replacement therapy (TRT) improves health in some but not all men with type 2 diabetes (T2DM) and adult-onset testosterone deficiency (TD). Such heterogeneity is compatible with the concept of patient subgroups that respond differently to therapy. OBJECTIVES: Use baseline SHBG and age to identify putative subgroups that demonstrate different responses in variables such as waist circumference and HbA1c following TRT. MATERIALS AND METHODS: A randomized double-blind trial approach was used to recruit and randomize men with T2DM and adult-onset TD into placebo and TRT-treated groups. Multiple regression was used to study differences between groups. RESULTS: Baseline SHBG and change in SHBG (∆SHBG) were inversely related in the TRT group. Both median values of SHBG and age mediated the effect of TRT on ∆SHBG depending on whether baseline values were ≤ or>median (28.1 nmol/L, 63 years, respectively). In men with both SHBG ≤ 28.1 nmol/L and age ≤ 63 years (subgroup 1), TRT was positively associated with ∆SHBG (c = 4.67, 95%CI 1.17-8.16, P = .010) while in those with SHBG > 28.1 nmol/L and age > 63.1 years (subgroup 4) the association was inverse (c = -7.07, 95%CI -11.64 to -2.49, P = .003). The association between TRT and change (∆) in waist circumference, HbA1c and International Index of Erectile Function (IIEF) score differed between subgroups; in subgroup 4 but not subgroup 1, the therapy was significantly associated with ∆waist circumference, ∆HbA1c and ∆IIEF. DISCUSSION: Though the mechanism remains unclear, our finding of different responses to TRT in terms of change in waist circumference, HbA1c and IIEF score supports the concept of subgroups in men with T2DM and adult-onset TD. CONCLUSION: Our approach may provide a basis for identifying men who will or will not derive benefit from TRT though a larger study is required.

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Important health problems in men such as type 2 diabetes (T2DM), insulin resistance, erectile dysfunction, benign prostatic hyperplasia and depression have been shown to have to share common pathological processes, such as endothelial dysfunction and inflammation. This paper discusses the role of phosphodiesterase type 5 (PDE5) inhibitors, through beneficial effects on endothelial function and mediators of chronic inflammation and the possibility to treat or preventing these common conditions. We explore possible barriers to this approach, namely the lack of multiple product licences to treat each of these conditions and how these can be overcome by involving the patient in personalised decisions. We also discuss how opportunities are lost by patients with multiple medical conditions being referred to specialists, primarily interested in one specific problem, with little motivation to treat or prevent conditions outside their remit. We explore how these problems might be related to time and financial restraints or simply a lack of awareness of evidence published in journals related to other specialities. As specialists, we often pride ourselves on providing "personalised" or "patient centred" care, but we can only truly be doing so if we assess the specific needs of the patient across a range of conditions. As part of personalised care in T2DM, we routinely prescribe statins, angiotensin converting enzyme inhibitors and metformin, often with poor compliance. In this paper we explore whether the licensed daily PDE5 inhibitor tadalafil should be added routinely to this list as it will potentially improve and prevent bothersome symptoms and improve compliance with other medications.

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PURPOSE: To describe the 4-year metabolic follow-up results from the BLAST study. MATERIALS AND METHODS: Baseline hemoglobin A1c (HbA1c), weight, and waist circumference (WC) data were recorded in 185 men recruited for the BLAST randomised controlled trial (RCT) and erectile function (EF) scores were also available in an additional 48 men screened for the RCT. Intra/inter-group associations between these parameters and testosterone replacement therapy (TRT) were assessed at 1) end of the RCT (30 weeks), 2) open-label phase (82 weeks), and 3) final assessment via non-parametric statistics. RESULTS: Improvement in HbA1c and weight at the end of the RCT and open-label phase in men on TRT was not maintained long-term. The convergence in HbA1c could have been due to incentivised care with HbA1c targets. Interestingly those on TRT at final assessment required fewer anti-diabetic agents. The weight increase in routine care may have been due to changes in diabetes medication or an increase in lean muscle mass. WC continued to decrease in men on TRT indicating possible reduction in visceral fat. Improvement in EF scores continued with long-term TRT, this was abolished when TRT was discontinued. CONCLUSIONS: This study hints at benefits in glycaemic control, weight and WC, and long-term RCTs studying mechanisms of benefit and clinical outcomes are necessary. Our results also show that EF scores continued to improve with long-term TRT, even beyond the 6 months that we previously reported in the BLAST RCT.

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INTRODUCTION: The age-related fall in male testosterone levels can have clinical consequences. The concentration of serum-free testosterone, the putative bioactive moiety, is mediated by carrier proteins, especially SHBG. AIM: The aim of this study was to consider the nature of hormone binding to carriers with new insights into determining calculated free testosterone levels and review how SHBG and testosterone influence age-related mortality. METHODS: Where possible, we focused on recent literature describing binding of testosterone to carrier proteins or, associations among age, SHBG, testosterone, and mortality. We then used logistic regression to study the impact of SHBG and total testosterone on age-related mortality in men with type 2 diabetes mellitus (T2DM). MAIN OUTCOME MEASURES: The association between mortality and age and SHBG and/or total testosterone was determined in a cohort of 364 men with T2DM leading to a graphical display of the impact of SHBG/testosterone levels on age-related mortality. RESULTS: Low total testosterone and high SHBG are independently associated with increased all-cause mortality. Our analyses support these findings showing that men with T2DM and a combination of total testosterone <12 nmol/L and SHBG >35nmol/L (odds ratio [OR]: 3.05; 95% CI: 1.43-6.53; P = .004) demonstrated an increased risk of mortality, independent of age (OR: 1.08; 95% CI: 1.06-1.11; P < .001). We graphically demonstrated that the risk combination altered the relationship between age and mortality. CONCLUSION: Until free testosterone is precisely, accurately, and conveniently measured, calculated values may provide useful even if somewhat inaccurate estimates. We also suggest that SHBG and testosterone assays are standardized to allow establishment of diagnostic and treatment thresholds. Although it is possible that the association in men with T2DM, among the combination of SHBG and total testosterone and age-related mortality is driven by free hormone levels, it is so far, unproven. Sudarshan Ramachandran, Geoffrey I. Hackett, Richard C. Strange, et al. Sex Hormone Binding Globulin: A Review of its Interactions With Testosterone and Age, and its Impact on Mortality in Men With Type 2 Diabetes. Sex Med Rev 2019;7:669-678.

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INTRODUCTION: The International Consultation for Sexual Medicine met in Lisbon in 2018 to review updated recommendations regarding testosterone deficiency (TD) and its treatment. AIM: To provide updated clinical recommendations regarding TD and its treatment. METHODS: A Medline search was performed for testosterone (T) articles published since the 2015 International Consultation for Sexual Medicine report. Recommendations were presented at the Lisbon meeting, and feedback was incorporated into final recommendations. MAIN OUTCOME MEASURES: Selected topics for these updates included terminology, clinical diagnosis, sexual function, prostate, cardiovascular, metabolic conditions, anemia, bone health, and therapeutic options. RESULTS: The terms "testosterone deficiency" (TD) and "testosterone therapy" (TTh) were endorsed over numerous competing terms. The wide interindividual variability of sex hormone binding globulin concentrations influences the interpretation of total T concentrations. Symptoms of T deficiency more closely follow free T than total T concentrations. Symptomatic men with total T <350 ng/dL or free T <65-100 pg/mL may reasonably undergo a trial of T therapy. An empirical 6-month trial of TTh may be considered in men with strongly suggestive symptoms and values above these thresholds. Morning blood testing is indicated in men <40 years of age. Men >40 years may undergo initial afternoon testing, as long as confirmatory morning blood tests are later obtained. High-level evidence demonstrates TTh in men with TD improves sexual desire and erectile function. The weight of evidence indicates that TTh is not associated with increased risk of prostate cancer, cardiovascular events, or worsening lower urinary tract symptoms. Bone density and anemia are improved with TTh. Obesity and type 2 diabetes are associated with TD, and TTh provides consistent improvement in metabolic parameters. Multiple safe and effective therapeutic options are available to treat men with TD. CONCLUSIONS: Treatment of TD offers multiple benefits for sexual symptoms as well as for general health, without compelling evidence for increased risk of prostate cancer or cardiovascular events. Morgentaler A, Traish A, Hackett G, et al. Diagnosis and Treatment of Testosterone Deficiency: Updated Recommendations From the Lisbon 2018 International Consultation for Sexual Medicine. Sex Med Rev 2019;7:636-649.

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The development of a subnormal level of testosterone (T) is not universal in ageing men, with 75% of men retaining normal levels. However, a substantial number of men do develop T deficiency (TD), with many of them carrying a portfolio of cardiovascular (CV) risk factors, including type 2 diabetes (T2D) and the metabolic syndrome. TD increases the risk of CV disease (CVD) and the risk of developing T2D and the metabolic syndrome. The key symptoms suggesting low T are sexual in nature, including erectile dysfunction (ED), loss of night-time erections and reduced libido. Many men with heart disease, if asked, admit to ED being present; a problem that is often compounded by drugs used to treat CVD. A large number of studies and meta-analyses have provided evidence of the link between TD and an increase in CVD and total mortality. Patients with chronic heart failure (CHF) who have TD have a poor prognosis and this is associated with more frequent admissions and increased mortality compared with those who do not have TD. Conversely, in men with symptoms and documented TD, T therapy has been shown to have beneficial effects, namely improvement in exercise capacity in patients with CHF, improvement of myocardial ischaemia and coronary artery disease. Reductions in BMI and waist circumference, and improvements in glycaemic control and lipid profiles, are observed in T-deficient men receiving T therapy. These effects might be expected to translate into benefits and there are more than 100 studies showing CV benefit or improved CV risk factors with T therapy. There are flawed retrospective and prescribing data studies that have suggested increased mortality in treated men, which has led to regulatory warnings, and one placebo-controlled study demonstrating an increase in coronary artery non-calcified and total plaque volumes in men treated with T, which is open for debate. Men with ED and TD who fail to respond to phosphodiesterase type 5 (PDE5) inhibitors can be salvaged by treating the TD. There are data to suggest that T and PDE5 inhibitors may act synergistically to reduce CV risk.

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The hypothalamic-pituitary-gonadal axis is of relevance in many processes related to the development, maturation and ageing of the male. Through this axis, a cascade of coordinated activities is carried out leading to sustained testicular endocrine function, with gonadal testosterone production, as well as exocrine function, with spermatogenesis. Conditions impairing the hypothalamic-pituitary-gonadal axis during paediatric or pubertal life may result in delayed puberty. Late-onset hypogonadism is a clinical condition in the ageing male combining low concentrations of circulating testosterone and specific symptoms associated with impaired hormone production. Testosterone therapy for congenital forms of hypogonadism must be lifelong, whereas testosterone treatment of late-onset hypogonadism remains a matter of debate because of unclear indications for replacement, uncertain efficacy and potential risks. This Primer focuses on a reappraisal of the physiological role of testosterone, with emphasis on the critical interpretation of the hypogonadal conditions throughout the lifespan of the male individual, with the exception of hypogonadal states resulting from congenital disorders of sex development.

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

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INTRODUCTION: Up to 40% of men with type 2 diabetes (T2DM) and metabolic syndrome (MetS) have hypogonadotrophic hypogonadism (HH). Men with HH are at increased risk of cardiovascular (CV) and all-cause mortality, as well as of the development of incident T2DM. AIM: To review the current literature on the metabolic effects of testosterone therapy (TTh) in men with T2DM and MetS. METHODS: We searched MEDLINE, Embase, and Cochrane Reviews for articles on T2DM, HH, testosterone deficiency, and CV and all-cause mortality published between May 2005 and July 2018, yielding 1817 articles, including 54 clinical trials and 32 randomized controlled trials (RCTs). MAIN OUTCOME MEASURES: The main outcomes were glycemic control, insulin resistance, lipid profile, and metabolic markers associated with increased CV risk. RESULTS: RCTs of TTh suggest significant benefits for sexual function, quality of life, glycemic control, insulin sensitivity, anemia, bone density, and fat and lean muscle mass that might be expected to translate into reduced long-term morbidity and mortality. Several longitudinal and observational studies suggest long-term sustained improvements in metabolic parameters and a trend toward reduced CV and all-cause mortality, especially in men at increased CV risk, such as those with T2DM and MetS. The greatest benefit is seen in those men treated with TTh to target levels and for longer durations. CONCLUSION: Meta-analyses of RCTs, rather than providing clarification, may have further confused the issue by including underpowered studies of inadequate duration, multiple therapy regimens, some obsolete or withdrawn, and built-in bias in terms of studies included or excluded from analysis. Hackett G. Metabolic Effects of Testosterone Therapy in Men with Type 2 Diabetes and Metabolic Syndrome. Sex Med Rev 2019;7:476-490.

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A third of men with type 2 diabetes (T2DM) have hypogonadotrophic hypogonadism (HH) and associated increased risk of cardiovascular and all-cause mortality. Men with HH are at increased risk of developing incident T2DM. We conducted MEDLINE, EMBASE, and COCHRANE reviews on T2DM, HH, testosterone deficiency, cardiovascular and all-cause mortality from May 2005 to October 2017, yielding 1,714 articles, 52 clinical trials and 32 randomized controlled trials (RCT). Studies with testosterone therapy suggest significant benefits in sexual function, quality of life, glycaemic control, anaemia, bone density, fat, and lean muscle mass. Meta-analyses of RCT, rather than providing clarification, have further confused the issue by including under-powered studies of inadequate duration, multiple regimes, some discontinued, and inbuilt bias in terms of studies included or excluded from analysis.