Androgen Society Position Paper on Cardiovascular Risk With Testosterone Therapy.

The Androgen Society is an international, multidisciplinary medical organization committed to advancing research and education in the field of testosterone deficiency and testosterone therapy (TTh). This position paper is written in response to results of the TRAVERSE study, published in June 2023, which reported no increased risk of major adverse cardiovascular events (MACE) in men who received TTh compared with placebo. In 2013-2014, 2 observational studies reported increased cardiovascular (CV) risks with TTh and received wide media attention. Despite strong criticism of those 2 studies, in 2015, the Food and Drug Administration added a CV warning to testosterone product labels and required pharmaceutical companies to perform a CV safety study, which became the TRAVERSE trial. TRAVERSE enrolled 5246 men at high risk for MACE based on existing heart disease or multiple risk factors. Participants were randomized to daily testosterone gel or placebo gel, with a mean follow-up of 33 months. Results revealed no greater risk of MACE (myocardial infarction, stroke, or CV death) or venothrombotic events in men who received TTh compared with placebo. Review of the prior literature reveals near uniformity of studies reporting no increased MACE with TTh. This includes 2 additional large randomized controlled trials, multiple smaller randomized controlled trials, several large observational studies, and 19 meta-analyses. In view of these findings, it is the position of the Androgen Society that it has now been conclusively determined that TTh is not associated with increased risks of heart attack, stroke, or CV death.

European Association of Urology Guidelines on Penile Size Abnormalities and Dysmorphophobia: Summary of the 2023 Guidelines.

CONTEXT: Recommendations regarding the management of penile size abnormalities and dysmorphophobia are important in guiding evidence-based clinical practice. OBJECTIVE: To present a summary of the 2023 European Association of Urology sexual and reproductive health evidence-based recommendations for the management of penile size abnormalities and dysmorphophobia. EVIDENCE ACQUISITION: A broad and comprehensive scoping exercise covering all areas of the guidelines was performed. Databases searched included Medline, EMBASE, and the Cochrane Libraries. A level of evidence and a strength of recommendation were assigned for each recommendation according to the evidence identified. The evidence cutoff date for the 2023 guidelines is June 1, 2022. EVIDENCE SYNTHESIS: Well-structured studies reporting high level of evidence, with standardized PROMS were deficient on penile size abnormalities and dysmorphohobia. A shared definition for short penis/micropenis was also lacking. Categorisation of penile abnormalities according to congenital, acquired, and dysmorphophobic aetiology is deemed compulsory. A detailed medical and psychosexual history and precise measurements of penile size are essential in the diagnostic pathway. Patients with normal penile size who are seeking penile augmentation should be referred for psychological evaluation for potential dysmorphophobic disorders. Penile length and girth enhancements can be achieved via a multitude of treatments, but a personalised management plan is crucial for satisfactory results. Endocrinological therapies, when indicated, are effective in the prepubertal setting only. Vacuum therapy has a limited evidence base in treatment protocols, although acceptable outcomes have been reported for penile traction therapy. Surgical techniques to enhance penile length and girth have limited evidence and should only be proposed after extensive patient counselling. CONCLUSIONS: Management of penile abnormalities and dysmorphophobia is a complex issue with considerable ethical concerns. The adoption of a structured diagnostic and therapeutic pathway is crucial, as recommended in the guidelines. PATIENT SUMMARY: Requests for medical/surgical treatments to increase penis size have increased dramatically worldwide. Several conservative and surgical treatments are available. However, few patients receive clear information on the benefits and possible harms of these treatments. These guidelines aim to provide a structured path to guide both physicians and patients in the selection of appropriate treatment(s) to increase penis size.

Leflutrozole in male obesity-associated hypogonadotropic hypogonadism: Ph 2b double-blind randomised controlled trial.

OBJECTIVE: Assessment of the efficacy and safety/tolerability of the aromatase inhibitor leflutrozole to normalise testosterone in Obesity-associated Hypogonadotropic Hypogonadism (OHH). DESIGN: Placebo-controlled, double-blind, RCT, in 70 sites in Europe/USA. METHODS: Patient inclusion criteria: men with BMI of 30-50 kg/m2, morning total testosterone (TT) < 10.41 nmol/L, and two androgen deficiency symptoms (at least one of sexual dysfunction). Patients randomised to weekly leflutrozole (0.1/0.3/1.0 mg) or placebo for 24 weeks. Primary endpoint: normalisation of TT levels in ≥75% of patients after 24 weeks. Secondary endpoints (included): time to TT normalisation and change in LH/FSH. Safety was assessed through adverse events and laboratory monitoring. RESULTS AND CONCLUSIONS: Of 2103 screened, 271 were randomised, 81 discontinued. Demographic characteristics were similar across groups. Mean BMI was 38.1 kg/m2 and TT 7.97 nmol/L. The primary endpoint was achieved in all leflutrozole-treated groups by 24 weeks with a dose-tiered response; mean TT 15.89; 17.78; 20.35 nmol/L, for leflutrozole 0.1 mg, 0.3 mg, and 1.0 mg groups respectively, vs 8.04 nmol/L for placebo. LH/FSH significantly increased in leflutrozole vs placebo groups. No improvements in body composition or sexual dysfunction were observed. Semen volume/total motile sperm count improved with leflutrozole vs placebo. Treatment-emergent adverse events, more common in leflutrozole-treated groups included, raised haematocrit, hypertension, increased PSA, and headache. Some reduction in lumbar bone density was observed with leflutrozole (mean -1.24%, -1.30%, -2.09%) and 0.66% for 0.1 mg, 0.3 mg, 1.0 mg, and placebo, respectively, without change at the hip. This RCT of leflutrozole in OHH demonstrated normalisation of TT in obese men. FSH/LH and semen parameter changes support that leflutrozole may preserve/improve testicular function. CLINICAL TRIAL REGISTRATION NUMBER: NCT02730169.

The British Society for Sexual Medicine Guidelines on Male Adult Testosterone Deficiency, with Statements for Practice.

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.

European Association of Urology Guidelines on Sexual and Reproductive Health-2021 Update: Male Sexual Dysfunction.

CONTEXT: The present summary of the European Association of Urology (EAU) guidelines is based on the latest guidelines on male sexual health published in March 2021, with a last comprehensive update in January 2021. OBJECTIVE: To present a summary of the 2021 version of the EAU guidelines on sexual and reproductive health. EVIDENCE ACQUISITION: A literature review was performed up to January 2021. The guidelines were updated, and a strength rating for each recommendation was included based on either a systematic review of the evidence or a consensus opinion from the expert panel. EVIDENCE SYNTHESIS: Late-onset hypogonadism is a clinical condition in the ageing male combining low levels of circulating testosterone and specific symptoms associated with impaired hormone production and/or action. A comprehensive diagnostic and therapeutic work-up, along with screening recommendations and contraindications, is provided. Erectile dysfunction (ED) is the persistent inability to attain and maintain an erection sufficient to permit satisfactory sexual performance. Along with a detailed basic and advanced diagnostic approach, a novel decision-making algorithm for treating ED in order to better tailor therapy to individual patients is provided. The EAU guidelines have adopted the definition of premature ejaculation (PE), which has been developed by the International Society for Sexual Medicine. After the subtype of PE has been defined, patient's expectations should be discussed thoroughly and pharmacotherapy must be considered as the first-line treatment for patients with lifelong PE, whereas treating the underlying cause must be the initial goal for patients with acquired PE. Haemospermia is defined as the appearance of blood in the ejaculate. Several reasons of haemospermia have been acknowledged; the primary goal over the management work-up is to exclude malignant conditions and treat any other underlying cause. CONCLUSIONS: The 2021 guidelines on sexual and reproductive health summarise the most recent findings, and advise in terms of diagnosis and treatment of male hypogonadism and sexual dysfunction for their use in clinical practice. These guidelines reflect the multidisciplinary nature of their management. PATIENT SUMMARY: Updated European Association of Urology guidelines on sexual and reproductive health are presented, addressing the diagnosis and treatment of the most prevalent conditions in men. Patients must be fully informed of all relevant diagnostic and therapeutic options and, together with their treating physicians, decide on optimal personalised management strategies.

Testosterone stimulates cholesterol clearance from human macrophages by activating LXRα.

AIMS: Low testosterone in men is associated with increased cardiovascular events and mortality. Testosterone has beneficial effects on several cardiovascular risk factors including cholesterol, endothelial dysfunction and inflammation as key mediators of atherosclerosis. Although evidence suggests testosterone is anti-atherogenic, its mechanism of action is unknown. The present study investigates whether testosterone exerts anti-atherogenic effects by stimulating cholesterol clearance from macrophages via activation of liver X receptor (LXRα), a nuclear master regulator of cellular cholesterol homeostasis, lipid regulation, and inflammation. MAIN METHODS: Using human monocyte THP-1 cells differentiated into macrophages, the effect of testosterone (1-10 nM) treatment (24-72 h) on the expression of LXRα and LXR- targets apolipoprotein E (APOE), ATP-binding cassette transporter A1 (ABCA1), sterol regulatory element-binding transcription factor 1 (SREBF1) and fatty acid synthase (FAS), was investigated via qPCR and western blotting, with or without androgen receptor blockade with flutamide or LXR antagonism with CPPSS-50. Cholesterol clearance was measured by monitoring fluorescent dehydroergosterol (DHE) cellular clearance and ABCA1 cellular translocation was observed via immunocytochemistry in testosterone treated macrophages. KEY FINDINGS: Testosterone increased mRNA and protein expression of LXRα, APOE, ABCA1, SREBF1 and FAS. These effects were blocked by flutamide and independently by LXR antagonism with CPPSS-50. Furthermore testosterone stimulated cholesterol clearance from the macrophages and promoted the translocation of ABCA1 toward the cell membrane. SIGNIFICANCE: Testosterone acts via androgen receptor-dependent pathways to stimulate LXRα and downstream targets to induce cholesterol clearance in human macrophages. This may, in part, explain the anti-atherogenic effects of testosterone frequently seen clinically.

Male hypogonadism: 14-year prospective outcome in 550 men with type 2 diabetes.

INTRODUCTION: Hypogonadism is more prevalent in men with type 2 diabetes (T2DM) (25%-40%) than in men without T2DM. Hypogonadism has been associated with poorer glycaemic outcomes and increased cardiovascular morbidity/mortality. We report a 14-year follow-up study to evaluate the influence of baseline testosterone level on T2DM outcomes. RESEARCH DESIGN AND METHODS: A total of 550 men with T2DM underwent baseline total testosterone and dihydrotestosterone measurement by tandem mass spectrometry. Mean age of the men was 59.7 ± 12 (mean ± SD) years. Sex hormone-binding globulin (SHBG) was measured and free testosterone estimated. Patients were followed up between 2002 and 2016. Mean follow-up period was 12.2 ± 4 years using the Salford (UK) Integrated Health Records system. RESULTS: Mean baseline total testosterone was 13.7 ± 5.8 nmol/L, and mean free testosterone was 245.7 ± 88.0 pmol/L. Mean for low total testosterone (<10 nmol/L) was 7.6 ± 2.0 nmol/L (n = 154) and 142 men had a free testosterone <190 pmol/L. During the 14-year duration follow-up, 22% of men experienced a myocardial infarction, 18% experienced a stroke, 11% developed angina, 14% underwent coronary revascularization. About 38% of the men initially recruited died. A lower total testosterone was associated with a higher body mass index (kg/m2) at follow-up: regression coefficient -0.30 (95% CI -0.445 to -0.157), P = 0.0001. The mortality rate was higher in patients with lower total testosterone compared to normal baseline total testosterone (5.0% vs 2.8% per year, P < 0.0001). A similar phenomenon was seen for dihydrotestosterone (4.3% vs 2.9% per year, P = 0.002) for normal vs low dihydrotestosterone) and for lower SHBG. Over the whole follow-up period 36.1% (143/396), men with normal baseline testosterone died vs 55.8% (86/154) of hypogonadal men at baseline. In Cox regression, the age-adjusted hazard ratio (HR) for higher mortality associated with low total testosterone was 1.54 (95% CI: 1.2-2.0, P < 0.002), corresponding to a 3.2 year reduced life expectancy for hypogonadal T2DM men. CONCLUSION: Low testosterone and dihydrotestosterone levels are associated with higher all-cause mortality in T2DM men. Hypogonadal men with T2DM should be considered as very high risk for cardiovascular events/death.

Diagnosis and Treatment of Testosterone Deficiency: Updated Recommendations From the Lisbon 2018 International Consultation for Sexual Medicine.

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.

Assessment and Management of Anti-Insulin Autoantibodies in Varying Presentations of Insulin Autoimmune Syndrome.

Context: Insulin autoimmune syndrome (IAS), spontaneous hyperinsulinemic hypoglycemia due to insulin-binding autoantibodies, may be difficult to distinguish from tumoral or other forms of hyperinsulinemic hypoglycemia, including surreptitious insulin administration. No standardized treatment regimen exists. Objectives: To evaluate an analytic approach to IAS and responses to different treatments. Design and Setting: Observational study in the UK Severe Insulin Resistance Service. Patients: Six patients with hyperinsulinemic hypoglycemia and detectable circulating anti-insulin antibody (IA). Main Outcome Measures: Glycemia, plasma insulin, and C-peptide concentrations by immunoassay or mass spectrometry (MS). Immunoreactive insulin was determined in the context of polyethylene glycol (PEG) precipitation and gel filtration chromatography (GFC). IA quantification using ELISA and RIA, and IA were further characterized using radioligand binding studies. Results: All patients were diagnosed with IAS (five IgG, one IgA) based on a high insulin/C-peptide ratio, low insulin recovery after PEG precipitation, and GFC evidence of antibody-bound insulin. Neither ELISA nor RIA result proved diagnostic for every case. MS provided a more robust quantification of insulin in the context of IA. One patient was managed conservatively, four were treated with diazoxide without sustained benefit, and four were treated with immunosuppression with highly variable responses. IA affinity did not appear to influence presentation or prognosis. Conclusions: IAS should be considered in patients with hyperinsulinemic hypoglycemia and a high insulin/C-peptide ratio. Low insulin recovery on PEG precipitation supports the presence of insulin-binding antibodies, with GFC providing definitive confirmation. Immunomodulatory therapy should be customized according to individual needs and clinical response.

Metabolic phenotype of male obesity-related secondary hypogonadism pre-replacement and post-replacement therapy with intra-muscular testosterone undecanoate therapy.

AIM: To explore the metabolic phenotype of obesity-related secondary hypogonadism (SH) in men pre-replacement and post-replacement therapy with long-acting intramuscular (IM) testosterone undecanoate (TU). METHODS: A prospective observational pilot study on metabolic effects of TU IM in male obesity-related SH (hypogonadal [HG] group, n = 13), including baseline comparisons with controls (eugonadal [EG] group, n = 15). Half the subjects (n = 7 in each group) had type 2 diabetes mellitus (T2D). Baseline metabolic assessment on Human Metabolism Research Unit: fasting blood samples; BodPod (body composition), and; whole-body indirect calorimetry. The HG group was treated with TU IM therapy for 6-29 months (mean 14.8-months [SD 8.7]), and assessment at the Human Metabolism Research Unit repeated. T-test comparisons were performed between baseline and follow-up data (HG group), and between baseline data (HG and EG groups). Data reported as mean (SD). RESULTS: Overall, TU IM therapy resulted in a statistically significant improvement in HbA1C (9 mmol/mol, P = 0.03), with 52% improvement in HOMA%B. Improvement in glycaemic control was driven by the HG subgroup with T2D, with 18 mmol/mol [P = 0.02] improvement in HbA1C. Following TU IM therapy, there was a statistically significant reduction in fat mass (3.5 Kg, P = 0.03) and increase in lean body mass (2.9 kg, P = 0.03). Lipid profiles and energy expenditure were unchanged following TU IM therapy. Comparisons between baseline data for HG and EG groups were equivalent apart from differences in testosterone, SHBG and basal metabolic rate (BMR). CONCLUSION: In men with obesity-related SH (including a subgroup with T2D), TU IM therapy improved glycaemic control, beta cell function, and body composition.

Randomized controlled trials - mechanistic studies of testosterone and the cardiovascular system.

Testosterone deficiency is common in men with cardiovascular disease (CVD), and randomized placebo-controlled trials (RCTs) have reported beneficial effects of testosterone therapy on exercise-induced cardiac ischemia in chronic stable angina, functional exercise capacity, maximum oxygen consumption during exercise (VO2max) and muscle strength in chronic heart failure (CHF), shortening of the Q-T interval, and improvement of some cardiovascular risk factors. Testosterone deficiency is associated with an adverse CV risk profile and mortality. Clinical and scientific studies have provided mechanistic evidence to support and explain the findings of the RCTs. Testosterone is a rapid-onset arterial vasodilator within the coronary circulation and other vascular beds including the pulmonary vasculature and can reduce the overall peripheral systemic vascular resistance. Evidence has demonstrated that testosterone mediates this effect on vascular reactivity through calcium channel blockade (L-calcium channel) and stimulates potassium channel opening by direct nongenomic mechanisms. Testosterone also stimulates repolarization of cardiac myocytes by stimulating the ultra-rapid potassium channel-operated current. Testosterone improves cardiac output, functional exercise capacity, VO2maxand vagally mediated arterial baroreceptor cardiac reflex sensitivity in CHF, and other mechanisms. Independent of the benefit of testosterone on cardiac function, testosterone substitution may also increase skeletal muscle glucose metabolism and enhance muscular strength, both factors that could contribute to the improvement in functional exercise capacity may include improved glucose metabolism and muscle strength. Testosterone improves metabolic CV risk factors including body composition, insulin resistance, and hypercholesterolemia by improving both glucose utilization and lipid metabolism by a combination of genomic and nongenomic actions of glucose uptake and utilization expression of the insulin receptor, glucose transporters, and expression on regulatory enzymes of key metabolic pathways. The effect on high-density lipoprotein-cholesterol (HDL-C) differs between studies in that it has been found to fall, rise, or have no change in levels. Testosterone replacement can suppress the levels of circulating pro-inflammatory cytokines and stimulate the production of interleukin-10 (IL-10) which has anti-inflammatory and anti-atherogenic actions in men with CVD. No effect on C-reactive protein has been detected. No adverse effects on clotting factors have been detected. RCTs have not clearly demonstrated any significant evidence that testosterone improves or adversely affects the surrogate markers of atherosclerosis such as reduction in carotid intima thickness or coronary calcium deposition. Any effect of testosterone on prevention or amelioration of atherosclerosis is likely to occur over years as shown in statin therapy trials and not months as used in testosterone RCTs. The weight of evidence from long-term epidemiological studies supports a protective effect as evidenced by a reduction in major adverse CV events (MACEs) and mortality in studies which have treated men with testosterone deficiency. No RCT where testosterone has been replaced to the normal healthy range has reported a significant benefit or adverse effect on MACE nor has any recent meta-analysis.

UK policy statements on testosterone deficiency.

To address widespread media and scientific concerns over the appropriate treatment of TDS with Testosterone Therapy (T Therapy), the Executive Committee of the British Society for Sexual Medicine developed eight consensus statements, based on current scientific evidence to address these controversial issues. These statements were in no-way designed to replace the published evidence-based guidelines on the subject developed by various professional organisations, but to provide specific answers to several current controversial issues. This review examined evidence from Medline, EMBASE and Cochrane searches on HG, T Therapy and cardiovascular safety from May 2005 to May 2015, which revealed 1714 articles, with 52 clinical trials and 32 placebo-controlled randomised controlled trials. The task force developed the following eight key statements.

Testosterone differentially regulates targets of lipid and glucose metabolism in liver, muscle and adipose tissues of the testicular feminised mouse.

Testosterone deficiency is commonly associated with obesity, metabolic syndrome, type 2 diabetes and their clinical consequences-hepatic steatosis and atherosclerosis. The testicular feminised mouse (non-functional androgen receptor and low testosterone) develops fatty liver and aortic lipid streaks on a high-fat diet, whereas androgen-replete XY littermate controls do not. Testosterone treatment ameliorates these effects, although the underlying mechanisms remain unknown. We compared the influence of testosterone on the expression of regulatory targets of glucose, cholesterol and lipid metabolism in muscle, liver, abdominal subcutaneous and visceral adipose tissue. Testicular feminised mice displayed significantly reduced GLUT4 in muscle and glycolytic enzymes in muscle, liver and abdominal subcutaneous but not visceral adipose tissue. Lipoprotein lipase required for fatty acid uptake was only reduced in subcutaneous adipose tissue; enzymes of fatty acid synthesis were increased in liver and subcutaneous tissue. Stearoyl-CoA desaturase-1 that catalyses oleic acid synthesis and is associated with insulin resistance was increased in visceral adipose tissue and cholesterol efflux components (ABCA1, apoE) were decreased in subcutaneous and liver tissue. Master regulator nuclear receptors involved in metabolism-Liver X receptor expression was suppressed in all tissues except visceral adipose tissue, whereas PPARγ was lower in abdominal subcutaneous and visceral adipose tissue and PPARα only in abdominal subcutaneous. Testosterone treatment improved the expression (androgen receptor independent) of some targets but not all. These exploratory data suggest that androgen deficiency may reduce the buffering capability for glucose uptake and utilisation in abdominal subcutaneous and muscle and fatty acids in abdominal subcutaneous. This would lead to an overspill and uptake of excess glucose and triglycerides into visceral adipose tissue, liver and arterial walls.

Fundamental Concepts Regarding Testosterone Deficiency and Treatment: International Expert Consensus Resolutions.

To address widespread concerns regarding the medical condition of testosterone (T) deficiency (TD) (male hypogonadism) and its treatment with T therapy, an international expert consensus conference was convened in Prague, Czech Republic, on October 1, 2015. Experts included a broad range of medical specialties including urology, endocrinology, diabetology, internal medicine, and basic science research. A representative from the European Medicines Agency participated in a nonvoting capacity. Nine resolutions were debated, with unanimous approval: (1) TD is a well-established, clinically significant medical condition that negatively affects male sexuality, reproduction, general health, and quality of life; (2) symptoms and signs of TD occur as a result of low levels of T and may benefit from treatment regardless of whether there is an identified underlying etiology; (3) TD is a global public health concern; (4) T therapy for men with TD is effective, rational, and evidence based; (5) there is no T concentration threshold that reliably distinguishes those who will respond to treatment from those who will not; (6) there is no scientific basis for any age-specific recommendations against the use of T therapy in men; (7) the evidence does not support increased risks of cardiovascular events with T therapy; (8) the evidence does not support increased risk of prostate cancer with T therapy; and (9) the evidence supports a major research initiative to explore possible benefits of T therapy for cardiometabolic disease, including diabetes. These resolutions may be considered points of agreement by a broad range of experts based on the best available scientific evidence.

Testosterone and mortality.

Epidemiological studies have found that men with low or low normal endogenous testosterone are at an increased risk of mortality than those with higher levels. Cardiovascular disease accounts for the greater proportion of deaths in those with low testosterone. Cancer and respiratory deaths in some of the studies are also significantly more prevalent. Disease-specific studies have identified that there are higher mortality rates in men with cardiovascular, respiratory and renal diseases, type 2 diabetes and cancer with low testosterone. Obesity, metabolic syndrome, type 2 diabetes, cardiovascular disease and inflammatory disorders are all associated with an increased prevalence of testosterone deficiency. Two major questions that arise from these findings are (1) is testosterone deficiency directly involved in the pathogenesis of these conditions and/or a contributory factor impairing the body's natural defences or is it merely a biomarker of ill health and the severity of underlying disease process? (2) Does testosterone replacement therapy retard disease progression and ultimately enhance the clinical prognosis and survival? This review will discuss the current state of knowledge and discuss whether or not there are any answers to either of these questions. There is convincing evidence that low testosterone is a biomarker for disease severity and mortality. Testosterone deficiency is associated with adverse effects on certain cardiovascular risk factors that when combined could potentially promote atherosclerosis. The issue of whether or not testosterone replacement therapy improves outcomes is controversial. Two retrospective studies in men with diagnosed hypogonadism with or without type 2 diabetes have reported significantly improved survival.

Testosterone suppresses the expression of regulatory enzymes of fatty acid synthesis and protects against hepatic steatosis in cholesterol-fed androgen deficient mice.

AIMS: Non-alcoholic fatty liver disease and its precursor hepatic steatosis is common in obesity and type-2 diabetes and is associated with cardiovascular disease (CVD). Men with type-2 diabetes and/or CVD have a high prevalence of testosterone deficiency. Testosterone replacement improves key cardiovascular risk factors. The effects of testosterone on hepatic steatosis are not fully understood. MAIN METHODS: Testicular feminised (Tfm) mice, which have a non-functional androgen receptor (AR) and very low serum testosterone levels, were used to investigate testosterone effects on high-cholesterol diet-induced hepatic steatosis. KEY FINDINGS: Hepatic lipid deposition was increased in Tfm mice and orchidectomised wild-type littermates versus intact wild-type littermate controls with normal androgen physiology. Lipid deposition was reduced in Tfm mice receiving testosterone treatment compared to placebo. Oestrogen receptor blockade significantly, but only partially, reduced the beneficial effects of testosterone treatment on hepatic lipid accumulation. Expression of key regulatory enzymes of fatty acid synthesis, acetyl-CoA carboxylase alpha (ACACA) and fatty acid synthase (FASN) were elevated in placebo-treated Tfm mice versus placebo-treated littermates and Tfm mice receiving testosterone treatment. Tfm mice on normal diet had increased lipid accumulation compared to littermates but significantly less than cholesterol-fed Tfm mice and demonstrated increased gene expression of hormone sensitive lipase, stearyl-CoA desaturase-1 and peroxisome proliferator-activated receptor-gamma but FASN and ACACA were not altered. SIGNIFICANCE: An action of testosterone on hepatic lipid deposition which is independent of the classic AR is implicated. Testosterone may act in part via an effect on the key regulatory lipogenic enzymes to protect against hepatic steatosis.

Testosterone and cardiovascular risk in men.

Testosterone deficiency is highly prevalent in men with cardiovascular disease (CVD) and is associated with an increased mortality. Low testosterone also has an adverse effect on several cardiovascular risk factors, which include insulin resistance, diabetes, dyslipidaemia, central adiposity and endothelial dysfunction. Male gender is a well-recognised risk factor for premature CVD and mortality. The question of whether or not testosterone deficiency is a contributory factor to atherogenesis or merely a biomarker of ill health arises. Animal studies and experiments on isolated cells indicate that many of the mechanisms intimate to the atherosclerotic process are beneficially modulated by testosterone. Epidemiological studies have shown that men with endogenous testosterone levels in the mid-upper normal range have reduced cardiovascular events and mortality compared to those with low or lower range, and with high range testosterone. Testosterone replacement in men diagnosed with hypogonadism where mid-normal range levels are achieved have shown a beneficial effect on several cardiovascular risk factors, cardiac ischaemia, functional exercise capacity and improved mortality. Yet studies where patients were either undertreated or given high-dose testosterone have been associated with an increased risk of cardiovascular-related events. Clinical monitoring and titration of testosterone dose is therefore of paramount importance.

Testosterone deficiency is associated with increased risk of mortality and testosterone replacement improves survival in men with type 2 diabetes.

OBJECTIVE: Men with type 2 diabetes are known to have a high prevalence of testosterone deficiency. No long-term data are available regarding testosterone and mortality in men with type 2 diabetes or any effect of testosterone replacement therapy (TRT). We report a 6-year follow-up study to examine the effect of baseline testosterone and TRT on all-cause mortality in men with type 2 diabetes and low testosterone. RESEARCH DESIGN AND METHODS: A total of 581 men with type 2 diabetes who had testosterone levels performed between 2002 and 2005 were followed up for a mean period of 5.81.3 S.D. years. mortality rates were compared between total testosterone 10.4nmol/l (300ng/dl; n=343) and testosterone 10.4nmol/l (n=238). the effect of TRT (as per normal clinical practise: 85.9% testosterone gel and 14.1% intramuscular testosterone undecanoate) was assessed retrospectively within the low testosterone group. RESULTS: Mortality was increased in the low testosterone group (17.2%) compared with the normal testosterone group (9%; P=0.003) when controlled for covariates. In the Cox regression model, multivariate-adjusted hazard ratio (HR) for decreased survival was 2.02 (P=0.009, 95% CI 1.2-3.4). TRT (mean duration 41.6±20.7 months; n=64) was associated with a reduced mortality of 8.4% compared with 19.2% (P=0.002) in the untreated group (n=174). The multivariate-adjusted HR for decreased survival in the untreated group was 2.3 (95% CI 1.3-3.9, P=0.004). CONCLUSIONS: Low testosterone levels predict an increase in all-cause mortality during long-term follow-up. Testosterone replacement may improve survival in hypogonadal men with type 2 diabetes.