Number of CAG repeats and mortality in middle aged and older men.

DESIGN: The androgen receptor (AR) mediates peripheral effects of testosterone. Previous data suggests an association between the number of CAG repeats in exon-1 of the AR gene and AR transcriptional activity. The aim of this analysis was to determine the association between the number of AR CAG repeats and all-cause mortality in men and the influence of testosterone level on the association. PATIENTS AND MEASUREMENTS: Follow-up data to 27 January 2018 were available for men aged 40-79 years recruited across six countries of the European Male Aging Study between 2003 and 2005. Cox proportional hazards modelling was used to determine the association between CAG repeat number/mortality. Results were expressed as hazard ratios (HR)/95% confidence intervals (CI). RESULTS: One thousand nine hundred and seventy-seven men were followed up. Mean baseline age was 60 ± 11.1 years. Mean duration of follow-up was 12.2 years. At follow up 25.1% of men had died. CAG repeat length ranged from 6 to 39, with the highest proportion of CAG repeat number at 21 repeats (16.4%). In a multivariable model, compared to men with 22-23 AR CAG repeats: for men with <22 and >23 AR CAG HR, 95% CI for mortality were, <22 CAG repeats 1.17 (0.93-1.49) and >23 CAG repeats 1.14 (0.88-1.47). In a post-hoc analysis, the association was significant for men in the lowest tertile of baseline testosterone (<14.2 nmol/L) with >23 CAG repeats: in the adjusted model for <22 and >23 CAG repeats, respectively, 1.49 (0.97-2.27) and 1.68 (1.06-2.67) versus 22-23 repeats. CONCLUSIONS: Our European-wide cohort data overall found no association of androgen receptor CAG repeat number and mortality in men. However, post hoc analysis suggested that an association might be present in men with lower baseline testosterone concentrations, which merits further investigation.

Standardising the biochemical confirmation of adult male hypogonadism: A joint position statement by the Society for Endocrinology and Association of Clinical Biochemistry and Laboratory Medicine.

BACKGROUND: Inter-assay variation between different immunoassays and different mass spectrometry methods hampers the biochemical confirmation of male hypogonadism. Furthermore, some laboratories utilise assay manufacturer reference ranges that do not necessarily mirror assay performance characteristics, with the lower limit of normality ranging from 4.9 nmol/L to 11 nmol/L. The quality of the normative data underlying commercial immunoassay reference ranges is uncertain. DESIGN: A working group reviewed published evidence and agreed upon standardised reporting guidance to augment total testosterone reports. RESULTS: Evidence-based guidance on appropriate blood sampling, clinical action limits, and other major factors likely to affect the interpretation of results are provided. CONCLUSIONS: This article aims to improve the quality of the interpretation of testosterone results by non-specialist clinicians. It also discusses approaches for assay harmonisation which have been successful in some but not all healthcare systems.

The number of androgen receptor CAG repeats and mortality in men.

INTRODUCTION: The androgen receptor (AR) mediates peripheral effects of testosterone. Evidence suggests that the number of CAG repeats in exon-1 of the AR gene negatively correlates with AR transcriptional activity. The aim of this analysis was to determine the association between CAG repeat number and mortality in men. METHODS: Men aged 40-79 years were recruited from primary care for participation in the UK arm of the European Male Aging Study between 2003 and 2005. Cox proportional hazards modelling was used to determine the association between CAG repeat number/mortality. Results were expressed as hazard ratios(HR)/95% confidence intervals (CI). RESULTS: 312 men were followed up. The mean baseline age was 59.5 years. At follow up, 85/312(27%) men had died. CAG repeat length ranged from 14 to 39, with the highest proportion of CAG repeat number at 21 repeats(16.4%). In a multivariable model, using men with CAG repeat numbers of 22-23 as the reference, men with a lower number of CAG repeats(<22) showed a trend for a higher mortality in the follow-up period (HR 1.46 (0.75, 2.81)) as did men with higher number of repeats (>23) (1.37 (0.65, 2.91)). CONCLUSION: Our data suggest that CAG repeat number may partially influence the risk of mortality in men. Further larger studies are required to quantify the effect.

Lessons learnt from the variation across 6741 family/general practices in England in the use of treatments for hypogonadism.

INTRODUCTION: We have previously reported rates of diagnosis of male hypogonadism in United Kingdom (UK) general practices. We aimed to identify factors associated with testosterone prescribing in UK general practice. METHODS: We determined for 6741 general practices in England, the level of testosterone prescribing in men and the relation between volume of testosterone prescribing and (1) demographic characteristics of the practice, (2) % patients with specific comorbidities and (3) national GP patient survey results. RESULTS: The largest volume (by prescribing volume) agents were injectable preparations at a total cost in the 12-month period 2018/19 of £8,172,519 with gel preparations in second place: total cost £4,795,057. Transdermal patches, once the only alternative to testosterone injections or implants, were little prescribed: total cost £222,022. The analysis accounted for 0.27 of the variance in testosterone prescribing between general practices. Thus, most of this variance was not accounted for by the analysis. There was a strong univariant relation (r = .95, P < .001) between PDE5-I prescribing and testosterone prescribing. Other multivariant factors independently linked with more testosterone prescribing were as follows: HIGHER proportion of men with type 2 diabetes(T2DM) on target control (HbA1c ≤ 58 mmol/mol) and HIGHER overall practice rating on the National Patient Survey for good experience, while non-white ethnicity and socio-economic deprivation were associated with less testosterone prescribing. There were a number of comorbidity factors associated with less prescribing of testosterone (such as T2DM, hypertension and stroke/TIA). CONCLUSION: Our analysis has indicated that variation between general practices in testosterone prescribing in a well developed health economy is only related to small degree (r2  = 0.27) to factors that we can define. This suggests that variation in amount of testosterone prescribed is largely related to general practitioner choice/other factors not studied and may be amenable to measures to increase knowledge/awareness of male hypogonadism, with implications for men's health.

Important lessons about testosterone therapy- weight loss vs. testosterone therapy for symptom resolution, classical vs. functional hypogonadism, and shortterm vs. lifelong testosterone therapy.

In this commentary, we highlight important findings from a notable RCT by Ng Tang Fui et al. 2016 which investigated the effects of testosterone treatment in dieting obese men. First, a myopic focus on weight loss can detract from important improvements in body composition. Second, while weight loss in obese men may increase testosterone levels, this increase is commonly not enough to result in an improvement in symptoms associated with testosterone deficiency. Third, the RCT by Ng Tang Fui et al. adds evidence to the growing number of clinical trials showing that testosterone therapy should not be restricted to men with classical hypogonadism. Finally, the beneficial effects of testosterone therapy are not maintained after cessation of treatment. Currently, the British Society for Sexual Medicine guidelines are the only clinical guidelines which acknowledge that weight loss per se does not automatically translate to resolution of hypogonadal symptoms, that testosterone therapy can greatly benefit men with testosterone deficiency who do not have classical hypogonadism, and that cessation of testosterone therapy causes reappearance of symptoms and reversal of benefits. Lifelong testosterone therapy is therefore recommended for persistent health benefits in most men with testosterone deficiency. Physicians and patients need to be informed of this.

An audit of the measurement and reporting of male testosterone levels in UK clinical biochemistry laboratories.

INTRODUCTION: A number of guidance documents have been published in recent years for the diagnosis and management of hypogonadism (HG). Laboratory practice has a major role in supporting guidelines with accurate and precise serum total testosterone (TT) methods and standardised pre- and post-analytical protocols. Our study investigated whether laboratory practice currently supports the management guidelines for HG. METHODS: An internet-based questionnaire survey of senior laboratory biochemists (UK/Republic of Ireland) was conducted (April-May 2018). Questions reflected sampling, laboratory practice, reference ranges and reporting of results. The results were analysed in conjunction with data obtained from the UK National External Quality Assurance Service (UK NEQAS) on testosterone assay performance. RESULTS: Analyses of 96 laboratory surveys returned the following: 74 laboratories stated that the optimal sampling time was communicated to users; 81 laboratories used immunoassays; 76 laboratories included reference ranges for adult men (31 had dual/multiple age-related intervals). Wide variability in lower/upper limits was evident in the common immunoassays; the majority of reference ranges were from manufacturers (50.0%) or historical (18.8%). Action limits based on TT levels were used by 64 laboratories, but 63 did not report a borderline range as suggested by the guidelines. Protocols for cascading tests based on TT were evident in 58 laboratories, with 50 laboratories offering estimated free testosterone; interpretative comments were provided by 67 laboratories, but no references were made to the management guidelines. Data from UK NEQAS demonstrated considerable variation in testosterone assay performance. CONCLUSIONS: Our survey has highlighted inconsistencies that could lead to HG (and other conditions requiring measurement of TT) not being managed appropriately. The results from this survey and from UK NEQAS reinforce the requirement for action to be considered regarding the standardisation of testosterone assays and harmonisation of laboratory practice.

The treatment rate of erectile dysfunction (ED) in younger men with type 2 diabetes is up to four times higher than the equivalent non-diabetes population.

INTRODUCTION: Erectile dysfunction (ED) is common in older age and in diabetes mellitus (DM). Phosphodiesterase type 5-inhibitors (PDE5-is) are the first-line for ED. We investigated how the type of diabetes and age of males affect the PDE5-i use in the primary care setting. METHODS: From 2018 to 2019, the general practice level quantity of all PDE5-i agents was taken from the general practice (GP) Prescribing Dataset in England. The variation in outcomes across practices was examined across one year, and for the same practice against the previous year. RESULTS: We included 5761 larger practices supporting 25.8 million men of whom 4.2 million ≥65 years old. Of these, 1.4 million had T2DM, with 0.8 million of these >65. About 137 000 people had T1DM. About 28.8 million tablets of PDE5-i were prescribed within the 12 months (2018-2019) period in 3.7 million prescriptions (7.7 tablets/prescription), at total costs of £15.8 million (£0.55/tablet). The NHS ED limit of one tablet/user/wk suggests that 540 000 males are being prescribed a PDE5-i at a cost of £29/y each. With approximately 30 000 GPs practising, this is equivalent to one GP providing 2.5 prescriptions/wk to overall 18 males. There was a 3x variation between the highest decile of practices (2.6 tablets/male/y) and lowest decile (0.96 tablets/male/y). The statistical model captured 14% of this variation and showed that T1DM males were the largest users, while men age <65 with T2DM were being prescribed four times as much as non-DM. Those T2DM >65 were prescribed 80% of the non-DM amount. CONCLUSION: There is a wide variation in the use of PDE5-is. With only 14% variance capture, other factors including wide variation in patient awareness, prescribing rules of local health providers, and recognition of the importance of male sexual health by GP prescribers might have a significant impact.

British Society for Sexual Medicine Guidelines on the Management of Erectile Dysfunction in Men-2017.

BACKGROUND: This is an update of the 2008 British Society for Sexual Medicine (BSSM) guidelines. AIM: To provide up-to-date guidance for U.K. (and international) health care professionals managing male sexual dysfunction. METHODS: Source information was obtained from peer-reviewed articles, meetings, and presentations. A search of Embase, MEDLINE, and Cochrane Reviews was performed, covering the search terms "hypogonadism," "eugonadal or hypogonadism or hypogonadal or gonadal," and "low or lower testosterone," starting from 2009 with a cut-off date of September 2017. OUTCOMES: We offer evidence-based statements and recommendations for clinicians. RESULTS: Expert guidance for health care professionals managing male sexual dysfunction is included. CLINICAL TRANSLATION: Current U.K. management has been largely influenced by non-evidence guidance from National Health Service departments, largely based on providing access to care limited by resources. The 2008 BSSM guidelines to date have been widely quoted in U.K. policy decision making. CONCLUSIONS: There is now overwhelming evidence that erectile dysfunction is strongly associated with cardiovascular disease, such that newly presenting patients should be thoroughly evaluated for cardiovascular and endocrine risk factors, which should be managed accordingly. Measurement of fasting serum glucose, lipid profile, and morning total testosterone should be considered mandatory in all newly presenting patients. Patients attending their primary care physician with chronic cardiovascular disease should be asked about erectile problems. There can no longer be an excuse for avoiding discussions about sexual activity due to embarrassment. Hackett G, Kirby M, Wylie K, et al. British Society for Sexual Medicine Guidelines on the Management of Erectile Dysfunction in Men-2017. J Sex Med 2018;15:430-457.

The 2018 Revision to the Process of Care Model for Management of Erectile Dysfunction.

INTRODUCTION: Erectile dysfunction (ED) is a common condition the treatment of which over the years has expanded from specialty care settings to various other clinical settings. A Process of Care Model was developed in 1999 to provide primary care physicians with guidance in the diagnosis and management of ED. AIM: This update to the Process of Care Model aims to reflect current ED management practices, because the study of ED has changed since 1999. METHODS: Updates to the Process of Care Model were developed during a meeting of international experts from diverse disciplines. The updated model is data-driven, evidence-based, and relevant to a wide range of healthcare providers. MAIN OUTCOME MEASURES: This article summarizes the results of the expert meeting and focuses on ED management. The evaluation of ED is discussed in a separate article. RESULTS: The updated model presents modification of risk factors and correction of comorbidities frequently associated with ED as critical parts of patient management. Patients should be encouraged to make positive lifestyle changes such as improving diet and increasing physical exercise. Lifestyle changes may be accompanied by the first-line medical therapies of sexual counseling and therapy, which takes into consideration patient sexual dynamics and pharmacotherapy with phosphodiesterase 5 inhibitors (PDE5Is). CLINICAL IMPLICATIONS: The updated model provides guidance regarding risk factors associated with ED, their modification, sexual counseling, and PDE5I selection, dosing, and patient education. STRENGTHS AND LIMITATIONS: This update leverages the extensive clinical expertise and experience of the authors to provide updated, comprehensive guidance for ED management. The model reflects the views and experiences of a limited number of contributors; however, these authors draw upon a diverse array of clinical specialties and are regarded as experts in their fields. Additionally, no meta-analyses were performed to further support the ED evaluation guidelines presented. CONCLUSION: Effective management of ED may be achieved through a combination of patient risk factor modification and first-line therapy, taking into consideration any patient comorbidities known to be associated with ED. Treatment goals should be individualized to restore sexual satisfaction to the patient and/or couple and improve quality of life based on the patient's expressed needs and desires. Mulhall JP, Giraldi A, Hackett G, et al. The 2018 Revision to the Process of Care Model for Management of Erectile Dysfunction. J Sex Med 2018;15:1434-1445.

The 2018 Revision to the Process of Care Model for Evaluation of Erectile Dysfunction.

BACKGROUND: Erectile dysfunction (ED) is a common condition that may affect men of all ages; in 1999, a Process of Care Model was developed to provide clinicians with recommendations regarding the evaluation and management of ED. AIM: To reflect the evolution of the study of ED since 1999, this update to the process of care model presents health care providers with a tool kit to facilitate patient interactions, comprehensive evaluation, and counseling for ED. METHODS: A cross-disciplinary panel of international experts met to propose updates to the 1999 process of care model from a global perspective. The updated model was designed to be evidence-based, data-driven, and accessible to a wide range of health care providers. OUTCOMES: This article summarizes the resulting discussion of the expert meeting and focuses on ED evaluation. The management of ED is discussed in an article by Muhall et al (J Sex Med 2018;15:1280-1292). RESULTS: A comprehensive approach to the evaluation of ED is warranted because ED may involve both psychological and organic components. The updated process of care model for evaluation was divided into core and optional components and now focuses on the combination of first-line pharmacotherapy and counseling in consideration of patient sexual dynamics. CLINICAL IMPLICATIONS: Patient evaluation for ED should encompass a variety of aspects, including medical history, sexual history, physical examination, psychological evaluation, laboratory testing, and possibly adjunctive testing. STRENGTHS & LIMITATIONS: This update draws on author expertise and experience to provide multi-faceted guidance for the evaluation of ED in a modern context. Although a limited number of contributors provided input on the update, these experts represent diverse fields that encounter patients with ED. Additionally, no meta-analyses were performed to further support the ED evaluation guidelines presented. CONCLUSION: Comprehensive evaluation of ED affords health care providers an opportunity to address medical, psychological/psycho-social, and sexual issues associated with ED, with the ultimate goal being effective management and possibly resolution of ED. While some or all techniques described in the updated model may be needed for each patient, evaluation should in all cases be thorough. Mulhall JP, Giraldi A, Hackett G, et al. The 2018 Revision to the Process of Care Model for Evaluation of Erectile Dysfunction. J Sex Med 2018;15:1280-1292.

British Society for Sexual Medicine Guidelines on Adult Testosterone Deficiency, With Statements for UK Practice.

BACKGROUND: Testosterone deficiency (TD) is an increasingly common problem with significant health implications, but its diagnosis and management can be challenging. AIM: To review the available literature on TD and provide evidence-based statements for UK clinical practice. METHODS: Evidence was derived from Medline, EMBASE, and Cochrane searches on hypogonadism, testosterone (T) therapy, and cardiovascular safety from May 2005 to May 2015. Further searches continued until May 2017. OUTCOMES: To provide a guideline on diagnosing and managing TD, with levels of evidence and grades of recommendation, based on a critical review of the literature and consensus of the British Society of Sexual Medicine panel. RESULTS: 25 statements are provided, relating to 5 key areas: screening, diagnosis, initiating T therapy, benefits and risks of T therapy, and follow-up. 7 statements are supported by level 1, 8 by level 2, 5 by level 3, and 5 by level 4 evidence. CLINICAL IMPLICATIONS: To help guide UK practitioners on effectively diagnosing and managing primary and age-related TD. STRENGTHS AND LIMITATIONS: A large amount of literature was carefully sourced and reviewed, presenting the best evidence available at the time. However, some statements provided are based on poor-quality evidence. This is a rapidly evolving area of research and recommendations are subject to change. Guidelines can never replace clinical expertise when making treatment decisions for individual patients, but rather help to focus decisions and take personal values and preferences and individual circumstances into account. Many issues remain controversial, but in the meantime, clinicians need to manage patient needs and clinical expectations armed with the best clinical evidence and the multidisciplinary expert opinion available. CONCLUSION: Improving the diagnosis and management of TD in adult men should provide somatic, sexual, and psychological benefits and subsequent improvements in quality of life. Hackett G, Kirby M, Edwards D, et al. British Society for Sexual Medicine Guidelines on Adult Testosterone Deficiency, With Statements for UK Practice. J Sex Med 2017;14:1504-1523.

Quality of Life and Sexual Function Benefits of Long-Term Testosterone Treatment: Longitudinal Results From the Registry of Hypogonadism in Men (RHYME).

BACKGROUND: The benefits and risks of long-term testosterone administration have been a topic of much scientific and regulatory interest in recent years. AIM: To assess long-term quality of life (QOL) and sexual function benefits of testosterone replacement therapy (TRT) prospectively in a diverse, multinational cohort of men with hypogonadism. METHODS: A multinational patient registry was used to assess long-term changes associated with TRT in middle-age and older men with hypogonadism. Comprehensive evaluations were conducted at 6, 12, 24, and 36 months after enrollment into the registry. OUTCOMES: QOL and sexual function were evaluated by validated measures, including the Aging Males' Symptom (AMS) Scale and the International Index of Erectile Function (IIEF). RESULTS: A total of 999 previously untreated men with hypogonadism were enrolled at 25 European centers, 750 of whom received TRT at at least one visit during the period of observation. Patients on TRT reported rapid and sustained improvements in QOL, with fewer sexual, psychological, and somatic symptoms. Modest improvements in QOL and sexual function, including erectile function, also were noted in RHYME patients not on TRT, although treated patients showed consistently greater benefit over time in all symptom domains compared with untreated patients. AMS total scores for patients on TRT were 32.8 (95% confidence interval = 31.3-34.4) compared with 36.6 (95% confidence interval = 34.8-38.5) for untreated patients (P < .001). Small but significant improvements in IIEF scores over time also were noted with TRT. Approximately 25% of treated and untreated men also used phosphodiesterase type 5 inhibitors, with notable differences in the frequency of phosphodiesterase type 5 inhibitor prescription use according to physician specialty and geographic site location. CLINICAL IMPLICATIONS: TRT-related benefits in QOL and sexual function are well maintained for up to 36 months after initiation of treatment. STRENGTHS AND LIMITATIONS: The major strengths are the large, diverse patient population being treated in multidisciplinary clinical settings. The major limitation is the frequency of switching from one formulation to another. CONCLUSION: Overall, we confirmed the broad and sustained benefits of TRT across major QOL dimensions, including sexual, somatic, and psychological health, which were sustained over 36 months in our treatment cohort. Rosen RC, Wu F, Behre H, et al. Quality of Life and Sexual Function Benefits Effects of Long-Term Testosterone Treatment: Longitudinal Results From the Registry of Hypogonadism in Men (RHYME). J Sex Med 2017;14:1104-1115.

Cancer, Benign Gynecology, and Sexual Function--Issues and Answers.

INTRODUCTION: The diagnosis, treatment, and survivorship of cancer have a profound effect on the quality of life and psychological well-being of men and women. Indeed, the perturbation of sexual function because of neoplasm has far-reaching implications. AIMS: To explore the prevalence, pathophysiology, and treatment of sexual issues in persons with cancer and offer evidence-based recommendations regarding optimal prevention and treatment strategies. METHODS: A committee of multidisciplinary specialists was formed as part of the larger International Sexual Medicine Consultation working with urologic and sexual medicine societies over a 1-year period to review the result of chronic-illness management on sexual function and satisfaction. The aims, goals, data collection techniques, and report format were defined by a central committee. MAIN OUTCOMES MEASURES: Expert consensus was based on evidence-based medical and psychosocial literature review, extensive group discussion, and an open presentation with a substantial discussion period. RESULTS: This summary evaluates contemporary literature concerning the prevalence, pathophysiology, and psychological impact of cancer diagnosis and treatment on sexual dysfunction. Evidence-based recommendations and guidelines for evaluation and management are presented. CONCLUSION: The diagnosis and treatment of cancer have a significant negative impact on sexual function and satisfaction. Comprehension of baseline sexual function, role of psychological supports, and available treatment options could attenuate the heavy burden of decreased sexual function.

Coronary Heart Disease, Diabetes, and Sexuality in Men.

Erectile dysfunction (ED) has been well recognized as a marker of increased cardiovascular risk for more than 15 years, especially in younger men. Early detection of ED represents an opportunity to intervene to decrease the risk of future cardiovascular events and limit the progression of ED severity. Evidence suggests there is a window of opportunity of 3 to 5 years from the onset of ED to subsequent cardiovascular events. This opportunity is usually missed if the onus is placed on the patient to seek care for his sexual problems. Unfortunately, these clear messages have not been incorporated into routine cardiovascular care. The reasons for these disparities within specialties are discussed in this article, in addition to management algorithms. Lifestyle modification is usually recommended as the first-line treatment to correct ED and lessen cardiovascular risk, but evidence suggests that this might be effective only in men without established cardiovascular comorbidities. In men with type 2 diabetes mellitus and established cardiovascular disease, lifestyle modification alone is unlikely to be effective. Cardiovascular medications are often associated with sexual dysfunction but changes in medication are more likely to be beneficial in men with milder recent-onset ED. A balanced view must be taken related to medication adverse events, taking into account optimal management of established cardiovascular disease. Testosterone deficiency has been associated with different metabolic disorders, especially metabolic syndrome and type 2 diabetes mellitus. Testosterone deficiency syndrome has been associated with an independent burden on sexual function globally and increased cardiovascular and all-cause mortality. Testosterone replacement therapy has been shown to improve multiple aspects of sexual function and, in some studies, has been associated with a decrease in mortality, especially in men with type 2 diabetes mellitus. Recent studies have suggested that phosphodiesterase type 5 inhibitors, the first-line medications to treat ED, could decrease cardiovascular and all-cause mortality, through multiple mechanisms, predominantly related to improved endothelial function.

Testosterone supplementation and sexual function: a meta-analysis study.

INTRODUCTION: The role of testosterone supplementation (TS) as a treatment for male sexual dysfunction remains questionable. AIM: The aim of this study was to attempt a meta-analysis on the effect of TS on male sexual function and its synergism with the use of phosphodiesterase type 5 inhibitor (PDE5i). METHODS: An extensive Medline, Embase, and Cochrane search was performed. MAIN OUTCOME MEASURES: All randomized controlled trials (RCTs) comparing the effect of TS vs. placebo or the effect of TS as add on to PDE5is on sexual function were included. Data extraction was performed independently by two of the authors (A. M. Isidori and G. Corona), and conflicts resolved by the third investigator (M. Maggi). RESULTS: Out of 1,702 retrieved articles, 41 were included in the study. In particular, 29 compared TS vs. placebo, whereas 12 trials evaluated the effect of TS as add on to PDE5is. TS is able to significantly ameliorate erectile function and to improve other aspects of male sexual response in hypogonadal patients. However, the presence of possible publication bias was detected. After applying "trim and fill" method, the positive effect of TS on erectile function and libido components retained significance only in RCTs partially or completely supported by pharmaceutical companies (confidence interval [0.04-0.53] and [0.12; 0.52], respectively). In addition, we also report that TS could be associated with an improvement in PDE5i outcome. These results were not confirmed in placebo-controlled studies. The majority of studies, however, included mixed eugonadal/hypogonadal subjects, thus imparting uncertainty to the statistical analyses. CONCLUSIONS: TS plays positive effects on male sexual function in hypogonadal subjects. The role of TS is uncertain in men who are not clearly hypogonadal. The apparent difference between industry-supported and independent studies could depend on trial design more than on publication bias. New RCTs exploring the effect of TS in selected cases of PDE5i failure that persistently retain low testosterone levels are advisable.

Diagnosis and treatment of erectile dysfunction for reduction of cardiovascular risk.

PURPOSE: We established erectile dysfunction as an often neglected but valuable marker of cardiovascular risk, particularly in younger men and men with diabetes. We also reviewed evidence that lifestyle change, combined with informed prescribing of pharmacotherapies used to mitigate cardiovascular risk, can improve overall vascular health and sexual functioning in men with erectile dysfunction. MATERIALS AND METHODS: We performed a PubMed® search for articles and guidelines pertinent to relationships between erectile dysfunction and cardiovascular disease, cardiovascular and all cause mortality, and pharmacotherapies for dyslipidemia and hypertension. The clinical guidance presented incorporates the current literature and the expertise of the multispecialty investigator group. RESULTS: Numerous cardiovascular risk assessment tools exist but risk stratification remains challenging, particularly in patients at low or intermediate short-term risk. Erectile dysfunction has a predictive value for cardiovascular events that is comparable to or better than that of traditional risk factors. Interventional studies support lifestyle changes as a means of improving overall vascular health as well as sexual functioning. Statins, diuretics, ß-blockers and renin-angiotensin system modifiers may positively or negatively affect erectile function. Furthermore, the phosphodiesterase type 5 inhibitors used to treat erectile dysfunction may have systemic vascular benefits. CONCLUSIONS: Erectile dysfunction treatment should be considered secondary to decreasing cardiovascular risk. However, informed prescribing may prevent worsening sexual function in men receiving pharmacotherapy for dyslipidemia and hypertension. As the first point of medical contact for men with erectile dysfunction symptoms, the primary care physician or urologist has a unique opportunity to identify those who require early intervention to prevent cardiovascular disease.

Standardising the biochemical confirmation of adult male hypogonadism; a joint position statement by the Society for Endocrinology and Association of Clinical Biochemistry and Laboratory Medicine.

Background: Inter-assay variation between different immunoassays and different mass spectrometry methods hampers the biochemical confirmation of male hypogonadism. Furthermore, some laboratories utilis eassay manufacturer reference ranges that do not necessarily mirror assay performance characteristics, with the lower limit of normality ranging from 4.9 nmol/L to 11 nmol/L. The quality of the normative data underlying commercial immunoassay reference ranges is uncertain.Design: A working group reviewed published evidence and agreed upon standardised reporting guidance to augment total testosterone reports. Results: Evidence-based guidance on appropriate blood sampling, clinical action limits, and other major factors likely to affect the interpretation of results are provided. Conclusions: This article aims to improve the quality of the interpretation of testosterone results by non-specialist clinicians. It also discusses approaches for assay harmonisation which have been successful in some but not all healthcare systems.

Symptomatic benefits of testosterone treatment in patient subgroups: a systematic review, individual participant data meta-analysis, and aggregate data meta-analysis.

BACKGROUND: Testosterone replacement therapy is known to improve sexual function in men younger than 40 years with pathological hypogonadism. However, the extent to which testosterone alleviates sexual dysfunction in older men and men with obesity is unclear, despite the fact that testosterone is being increasingly prescribed to these patient populations. We aimed to evaluate whether subgroups of men with low testosterone derive any symptomatic benefit from testosterone treatment. METHODS: We did a systematic review and meta-analysis to evaluate characteristics associated with symptomatic benefit of testosterone treatment versus placebo in men aged 18 years and older with a baseline serum total testosterone concentration of less than 12 nmol/L. We searched major electronic databases (MEDLINE, Embase, Science Citation Index, and the Cochrane Central Register of Controlled Trials) and clinical trial registries for reports published in English between Jan 1, 1992, and Aug 27, 2018. Anonymised individual participant data were requested from the investigators of all identified trials. Primary (cardiovascular) outcomes from this analysis have been published previously. In this report, we present the secondary outcomes of sexual function, quality of life, and psychological outcomes at 12 months. We did a one-stage individual participant data meta-analysis with a random-effects linear regression model, and a two-stage meta-analysis integrating individual participant data with aggregated data from studies that did not provide individual participant data. This study is registered with PROSPERO, CRD42018111005. FINDINGS: 9871 citations were identified through database searches. After exclusion of duplicates and publications not meeting inclusion criteria, 225 full texts were assessed for inclusion, of which 109 publications reporting 35 primary studies (with a total 5601 participants) were included. Of these, 17 trials provided individual participant data (3431 participants; median age 67 years [IQR 60-72]; 3281 [97%] of 3380 aged ≥40 years) Compared with placebo, testosterone treatment increased 15-item International Index of Erectile Function (IIEF-15) total score (mean difference 5·52 [95% CI 3·95-7·10]; τ2=1·17; n=1412) and IIEF-15 erectile function subscore (2·14 [1·40-2·89]; τ2=0·64; n=1436), reaching the minimal clinically important difference for mild erectile dysfunction. These effects were not found to be dependent on participant age, obesity, presence of diabetes, or baseline serum total testosterone. However, absolute IIEF-15 scores reached during testosterone treatment were subject to thresholds in patient age and baseline serum total testosterone. Testosterone significantly improved Aging Males' Symptoms score, and some 12-item or 36-item Short Form Survey quality of life subscores compared with placebo, but it did not significantly improve psychological symptoms (measured by Beck Depression Inventory). INTERPRETATION: In men aged 40 years or older with baseline serum testosterone of less than 12 nmol/L, short-to-medium-term testosterone treatment could provide clinically meaningful treatment for mild erectile dysfunction, irrespective of patient age, obesity, or degree of low testosterone. However, due to more severe baseline symptoms, the absolute level of sexual function reached during testosterone treatment might be lower in older men and men with obesity. FUNDING: National Institute for Health and Care Research Health Technology Assessment Programme.

A randomized open-label trial with a crossover comparison of sexual self-confidence and other treatment outcomes following tadalafil once a day vs. tadalafil or sildenafil on-demand in men with erectile dysfunction.

AIM: To compare Sexual Self-Confidence and other treatment outcomes following 8 weeks of treatment with tadalafil 5 mg once a day (OaD) vs. tadalafil 20 mg or sildenafil 100 mg as needed (pro re nata [PRN]) in patients with erectile dysfunction (ED). METHODS: A randomized, open-label, crossover study in men ≥18 years of age with history of ED and satisfactory response to current oral phosphodiesterase 5 (PDE5) inhibitor PRN. Data were analyzed with a mixed effects model for crossover design. MAIN OUTCOME MEASURES: The primary outcome measure was the Sexual Self-Confidence domain of the Psychological and Interpersonal Relationship Scales (PAIRS) between tadalafil OaD and sildenafil PRN. SECONDARY OUTCOMES INCLUDED: Time Concerns and Spontaneity domains of PAIRS, and the Self-Esteem and Relationship (SEAR) scale. RESULTS: Men naive to tadalafil OaD were enrolled (N = 378), with 61-69% prior PDE5 inhibitor use. There were improvements in all PAIRS domains from baseline when comparing tadalafil OaD and PRN with sildenafil PRN (P < 0.001). The Sexual Self-Confidence domain improved from baseline and was 0.50 ± 0.78 following tadalafil OaD, 0.5 ± 0.72 for tadalafil PRN, and 0.39 ± 0.67 for sildenafil PRN. The difference in least-squares mean was 0.12 ± 0.04 (confidence interval [CI] = 0.04, 0.19; P = 0.001) between tadalafil OaD and sildenafil PRN and 0.01 ± 0.04 (CI = -0.06, 0.08; P = 0.872) between tadalafil OaD and tadalafil PRN. The Time Concerns domain score was lower with tadalafil OaD than tadalafil PRN (P < 0.001). There were no differences in SEAR scores between treatments. CONCLUSIONS: Tadalafil OaD and tadalafil PRN compared with sildenafil PRN demonstrated greater improvements in Sexual Self-Confidence, Time Concerns, and Spontaneity. There was no significant difference in Sexual Self-Confidence between tadalafil OaD and tadalafil PRN. Changes in SEAR, the erectile function domain of the International Index of Erectile Function, and the Erectile Dysfunction Inventory of Treatment Satisfaction scores from baseline to end point were similar.