Androgen Deficiency, Associations and Survival of Men With Stage 4 and 5 Chronic Kidney Disease: A Cohort Study.

OBJECTIVES: Anaemia is a key cause of morbidity in chronic kidney disease (CKD). Androgen deficiency (AD) in males can contribute to anaemia of all causes, including in CKD. We sought to examine the prevalence of AD in men with CKD, the extent to which it contributed to anaemia and whether it was independently associated with long-term survival. METHODS: This cross-sectional observational study was conducted among males aged 18 years and over with CKD stages 4 and 5. The study analysed morning blood samples with regard to their full blood count, urea and electrolytes, albumin, lipids, testosterone (T) and sex hormone binding globulin, with calculation of free testosterone by mass action equation. Mortality data were obtained 15 years later for survival analysis. RESULTS: Among 322 patients with a mean age of 63 years, the overall prevalence of AD was 68.9%. There was a statistically significant negative correlation between erythropoiesis stimulating agent (ESA) dose and testosterone concentrations (Pearson correlation -0.193, p = 0.05). There was a positive correlation between haemoglobin (Hb) and free testosterone level among patients not on ESA therapy (Pearson correlation 0.331, p < 0.001). Kaplan-Meier plots showed p < 0.001 on log-rank analysis, indicating that AD was significantly associated with worse survival. However, in Cox regression analysis, free testosterone was not associated with survival (95% CI for free testosterone 0.997-1.000). CONCLUSIONS: AD is highly prevalent among this population, and increases further with older age and more severe CKD warranting haemodialysis. Association of lower Hb and higher ESA dose with lower T concentration might be causative, which has important pharmaco-economic as well as clinical implications. Lower survival in men with low T, more likely reflects overall poor health rather than causation. A properly constituted randomised controlled study evaluating the effect of native T replacement is warranted in men with CKD and AD.

Cardiovascular disease and testosterone therapy in male hypogonadism.

This review assesses the evidence of the physiological effects of testosterone on cardiovascular health, the association between male hypogonadism and cardiovascular health, and the effects of testosterone therapy on cardiovascular health in male hypogonadism. Preclinical studies suggest complex effects of testosterone on cardiovascular risk by acting on skeletal muscle, cardiomyocytes, vasculature, adipocytes, insulin action, and erythropoiesis. Furthermore, low testosterone has a bi-directional association with cardiometabolic risk. Observational studies have reported worse metabolic profiles in men with organic hypogonadism. However, a consistent association between major cardiovascular events and male hypogonadism has not been established. Hematocrit increases with testosterone therapy; however, most studies do not report an increase in venous thromboembolism risk. Although some observational studies and a small randomized controlled study reported an increased risk of cardiovascular disease, recent data confirm the medium-term cardiovascular safety of testosterone therapy in middle-aged and older men with low testosterone.

The effects and safety of testosterone replacement therapy for men with hypogonadism: the TestES evidence synthesis and economic evaluation.

Background: Low levels of testosterone cause male hypogonadism, which is associated with sexual dysfunction, tiredness and reduced muscle strength and quality of life. Testosterone replacement therapy is commonly used for ameliorating symptoms of male hypogonadism, but there is uncertainty about the magnitude of its effects and its cardiovascular and cerebrovascular safety. Aims of the research: The primary aim was to evaluate the safety of testosterone replacement therapy. We also assessed the clinical and cost-effectiveness of testosterone replacement therapy for men with male hypogonadism, and the existing qualitative evidence on men's experience and acceptability of testosterone replacement therapy. Design: Evidence synthesis and individual participant data meta-analysis of effectiveness and safety, qualitative evidence synthesis and model-based cost-utility analysis. Data sources: Major electronic databases were searched from 1992 to February 2021 and were restricted to English-language publications. Methods: We conducted a systematic review with meta-analysis of individual participant data according to current methodological standards. Evidence was considered from placebo-controlled randomised controlled trials assessing the effects of any formulation of testosterone replacement therapy in men with male hypogonadism. Primary outcomes were mortality and cardiovascular and cerebrovascular events. Data were extracted by one reviewer and cross-checked by a second reviewer. The risk of bias was assessed using the Cochrane Risk of Bias tool. We performed one-stage meta-analyses using the acquired individual participant data and two-stage meta-analyses to integrate the individual participant data with data extracted from eligible studies that did not provide individual participant data. A decision-analytic Markov model was developed to evaluate the cost per quality-adjusted life-years of the use of testosterone replacement therapy in cohorts of patients of different starting ages. Results: We identified 35 trials (5601 randomised participants). Of these, 17 trials (3431 participants) provided individual participant data. There were too few deaths to assess mortality. There was no difference between the testosterone replacement therapy group (120/1601, 7.5%) and placebo group (110/1519, 7.2%) in the incidence of cardiovascular and/or cerebrovascular events (13 studies, odds ratio 1.07, 95% confidence interval 0.81 to 1.42; p = 0.62). Testosterone replacement therapy improved quality of life and sexual function in almost all patient subgroups. In the testosterone replacement therapy group, serum testosterone was higher while serum cholesterol, triglycerides, haemoglobin and haematocrit were all lower. We identified several themes from five qualitative studies showing how symptoms of low testosterone affect men's lives and their experience of treatment. The cost-effectiveness of testosterone replacement therapy was dependent on whether uncertain effects on all-cause mortality were included in the model, and on the approach used to estimate the health state utility increment associated with testosterone replacement therapy, which might have been driven by improvements in symptoms such as sexual dysfunction and low mood. Limitations: A meaningful evaluation of mortality was hampered by the limited number of defined events. Definition and reporting of cardiovascular and cerebrovascular events and methods for testosterone measurement varied across trials. Conclusions: Our findings do not support a relationship between testosterone replacement therapy and cardiovascular/cerebrovascular events in the short-to-medium term. Testosterone replacement therapy improves sexual function and quality of life without adverse effects on blood pressure, serum lipids or glycaemic markers. Future work: Rigorous long-term evidence assessing the safety of testosterone replacement therapy and subgroups most benefiting from treatment is needed. Study registration: The study is registered as PROSPERO CRD42018111005. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 17/68/01) and is published in full in Health Technology Assessment; Vol. 28, No. 43. See the NIHR Funding and Awards website for further award information.

Testosterone is a hormone which is vital for sexual activity, bone growth and muscle development in men. Men with low testosterone levels may experience problems with erections and may suffer from brittle bones (osteoporosis), weakness, feeling down (low mood) and tiredness. The manifestations of low testosterone can be treated with testosterone replacement therapy. However, there is current uncertainty about the positive effects of testosterone replacement therapy and its safety. We brought together results from all available medical studies that looked at the use of testosterone replacement therapy in men with low testosterone and contacted the doctors who led these studies to gather further information on their participants. We found 35 studies (5601 participants) conducted in different countries, 17 of which provided additional information on their participants. We did not find any evidence to show that testosterone replacement therapy increases the risk of heart problems, or any evidence to show that some men who take testosterone replacement therapy benefit more than others. Men with low testosterone reported having low mood, poor concentration and lack of energy; however, medical studies often failed to prove that these manifestations improved with testosterone replacement therapy. Most medical studies were conducted among white men in North America using questionnaires designed specifically for them; therefore, the results may not reflect the experiences of men in other countries and from more diverse ethnic backgrounds. There is too much uncertainty about the benefits of testosterone replacement therapy to accurately estimate its value for money for the NHS. We think our findings offer some reassurance to doctors and patients that testosterone replacement therapy does not increase the risk of heart problems. New studies are needed to find out whether some groups of men (such as older or younger men) are more likely to benefit from testosterone replacement therapy more than others. It is also important to develop tools which better reflect the experience of men from a diverse range of social and ethnic backgrounds. To inform men with low testosterone about our findings, we are creating a website with dedicated YouTube video clips.

Male hypogonadism: pathogenesis, diagnosis, and management.

Organic male hypogonadism due to irreversible hypothalamic-pituitary-testicular (HPT) pathology is easily diagnosed and treated with testosterone-replacement therapy. However, controversy surrounds the global practice of prescribing testosterone to symptomatic men with low testosterone and non-gonadal factors reducing health status, such as obesity, type 2 diabetes, and ageing (ie, functional hypogonadism), but without identifiable HPT axis pathology. Health optimisation remains the gold-standard management strategy. Nevertheless, in the last decade large clinical trials and an individual patient data meta-analysis of smaller clinical trials confirmed that testosterone therapy induces modest, yet statistically significant, improvements in sexual function without increasing short-term to medium-term cardiovascular or prostate cancer risks in men with functional hypogonadism. Although testosterone improves bone mineral density and insulin sensitivity in these men, trials from the last decade suggest insufficient evidence to determine the safety and effectiveness of use of this hormone for the prevention of fractures or type 2 diabetes. This Review discusses the pathogenesis and diagnosis of male hypogonadism and appraises the evidence underpinning the management of this condition.

Society for endocrinology guideline for understanding, diagnosing and treating female hypogonadism.

Female hypogonadism (FH) is a relatively common endocrine disorder in women of premenopausal age, but there are significant uncertainties and wide variation in its management. Most current guidelines are monospecialty and only address premature ovarian insufficiency (POI); some allude to management in very brief and general terms, and most rely upon the extrapolation of evidence from the studies relating to physiological estrogen deficiency in postmenopausal women. The Society for Endocrinology commissioned new guidance to provide all care providers with a multidisciplinary perspective on managing patients with all forms of FH. It has been compiled using expertise from Endocrinology, Primary Care, Gynaecology and Reproductive Health practices, with contributions from expert patients and a patient support group, to help clinicians best manage FH resulting from both POI and hypothalamo-pituitary disorders, whether organic or functional.

Androgen abuse: Risks and adverse effects in men.

Androgens, formerly known as anabolic-androgenic steroids, mimic the effects of testosterone and are being increasingly abused for nonmedical purposes such as body and performance enhancement. Androgen abuse is associated with increased mortality, and multisystem adverse effects have been reported, including cardiovascular toxicity, infertility, hypogonadism, hepatotoxicity, and mental health disorders. Men may present with the negative health consequences of androgen abuse even despite cessation for a number of years. There is frequently a reluctance to disclose androgen abuse, and substances are often sourced from the black market, which is not regulated and where the products sold may be counterfeit. All men should be encouraged to stop androgen abuse. Managing associated adverse effects will be organ-specific and is complex due to physical and neuropsychiatric symptoms, substance dependence, and high rates of relapse. Given the broad reach and prolonged adverse effects of androgen abuse, clinicians across medical specialties should have an awareness of androgen abuse, its increasing prevalence, and the harms it poses to men and their families. This narrative review aims to summarize the adverse effects and risks associated with androgen abuse.

Metabolic and cardiovascular risks of hormone treatment for transgender individuals.

Identifying metabolic and cardiovascular risks of gender-affirming hormone therapy (GAHT) is challenging due to other confounding variables that affect patient outcomes and the diversity of treatment regimes. Masculinising hormone therapy produces atherogenic lipid profiles, while effects on other metabolic parameters are not consistent. There is insufficient evidence to conclude if cardiovascular disease risk among transmen is increased. The effects of feminising hormone therapy on metabolic parameters do not demonstrate a consistent pattern in the available literature. However, the risk of venous thromboembolism is greater in transwomen than in cis-gender men and women with a possible increase in cardiovascular disease risk. It is recommended to discuss the potential effects of GAHT on cardiovascular health and encourage patients seeking GAHT to adopt a healthy lifestyle. Performing baseline and periodic assessments of cardiovascular risk factors would enable early identification and interventions. In high-risk individuals, the cardiovascular effects of hormonal regimes might impact the treatment decision.

Cost-effectiveness of testosterone treatment utilising individual patient data from randomised controlled trials in men with low testosterone levels.

BACKGROUND: Testosterone is safe and highly effective in men with organic hypogonadism, but worldwide testosterone prescribing has recently shifted towards middle-aged and older men, mostly with low testosterone related to age, diabetes and obesity, for whom there is less established evidence of clinical safety and benefit. The value of testosterone treatment in middle-aged and older men with low testosterone is yet to be determined. We therefore evaluated the cost-effectiveness of testosterone treatment in such men with low testosterone compared with no treatment. METHODS: A cost-utility analysis comparing testosterone with no treatment was conducted following best practices in decision modelling. A cohort Markov model incorporating relevant care pathways for individuals with hypogonadism was developed for a 10-year-time horizon. Clinical outcomes were obtained from an individual patient meta-analysis of placebo-controlled, double-blind randomised studies. Three starting age categories were defined: 40, 60 and 75 years. Cost utility (quality-adjusted life years) accrued and costs of testosterone treatment, monitoring and cardiovascular complications were compared to estimate incremental cost-effectiveness ratios and cost-effectiveness acceptability curves for selected scenarios. RESULTS: Ten-year excess treatment costs for testosterone compared with non-treatment ranged between £2306 and £3269 per patient. Quality-adjusted life years results depended on the instruments used to measure health utilities. Using Beck depression index-derived quality-adjusted life years data, testosterone was cost-effective (incremental cost-effectiveness ratio <£20,000) for men aged <75 years, regardless of morbidity and mortality sensitivity analyses. Testosterone was not cost-effective in men aged >75 years in models assuming increased morbidity and/or mortality. CONCLUSIONS AND FUTURE RESEARCH: Our data suggest that testosterone is cost-effective in men <75 years when Beck depression index-derived quality-adjusted life years data are considered; cost-effectiveness in men >75 years is dependent on cardiovascular safety. However, more robust and longer-term cost-utility data are needed to verify our conclusion.

Global Barriers to Accessing Off-Patent Endocrine Therapies: A Renaissance of the Orphan Disease?

CONTEXT: Clinical endocrinology encompasses many diseases requiring long-term drug therapy. Prohibitive pricing of some endocrine drugs classified as essential by the World Health Organization has created suboptimal care of patients with endocrine disorders. EVIDENCE ACQUISITION: This review is based on evidence obtained from several databases and search engines including PubMed, Google, and Google Scholar; reference searches; manual searching for web pages of international regulatory bodies; and the authors' experience from different healthcare settings. EVIDENCE SYNTHESIS: After the expiry of a patent, generic versions with the opportunity for increased availability and a price reduction are expected. There are access barriers worldwide for many off-patent endocrine drugs. The high price is the main issue for several medicines including insulin, hydrocortisone, testosterone, and gonadotropins. This is caused by several factors including the market monopoly due to the lack of registered generics or suppliers limiting the benefit of competition and a complex supply chain. Additionally, the lack of some medicines has been concerning due to market factors such as the relatively small number of patients, making it less attractive for the manufacturers. Commissioning of nonprofit manufacturers and state manufacturing as well as strict price control measures could alleviate this situation. CONCLUSION: Lack of availability and disproportionate price inflation affecting essential off-patent endocrine therapies is common due to several interrelated factors. Global collaboration among healthcare organizations with the support of policymaking bodies might be needed to mitigate this.

Improvements in Sperm Motility Following Low- or High-Intensity Dietary Interventions in Men With Obesity.

INTRODUCTION: Obesity increases risks of male infertility, but bariatric surgery does not improve semen quality. Recent uncontrolled studies suggest that a low-energy diet (LED) improves semen quality. Further evaluation within a randomized, controlled setting is warranted. METHODS: Men with obesity (18-60 years) with normal sperm concentration (normal count) (n = 24) or oligozoospermia (n = 43) were randomized 1:1 to either 800 kcal/day LED for 16 weeks or control, brief dietary intervention (BDI) with 16 weeks' observation. Semen parameters were compared at baseline and 16 weeks. RESULTS: Mean age of men with normal count was 39.4 ± 6.4 in BDI and 40.2 ± 9.6 years in the LED group. Mean age of men with oligozoospermia was 39.5 ± 7.5 in BDI and 37.7 ± 6.6 years in the LED group. LED caused more weight loss than BDI in men with normal count (14.4 vs 6.3 kg; P < .001) and men with oligozoospermia (17.6 vs 1.8 kg; P < .001). Compared with baseline, in men with normal count total motility (TM) increased 48 ± 17% to 60 ± 10% (P < .05) after LED, and 52 ± 8% to 61 ± 6% (P < .0001) after BDI; progressive motility (PM) increased 41 ± 16% to 53 ± 10% (P < .05) after LED, and 45 ± 8% to 54 ± 65% (P < .001) after BDI. In men with oligozoospermia compared with baseline, TM increased 35% [26] to 52% [16] (P < .05) after LED, and 43% [28] to 50% [23] (P = .0587) after BDI; PM increased 29% [23] to 46% [18] (P < .05) after LED, and 33% [25] to 44% [25] (P < .05) after BDI. No differences in postintervention TM or PM were observed between LED and BDI groups in men with normal count or oligozoospermia. CONCLUSION: LED or BDI may be sufficient to improve sperm motility in men with obesity. The effects of paternal dietary intervention on fertility outcomes requires investigation.

Effect of oestrogen modulation on semen parameters in men with secondary hypogonadism: Systematic review and meta-analysis.

BACKGROUND: Selective oestrogen receptor modulators and aromatase inhibitors stimulate endogenous gonadotrophins and testosterone in men with hypogonadism. There are no systematic reviews/meta-analyses assessing the effects of selective oestrogen receptor modulators/aromatase inhibitors on semen parameters in men with secondary hypogonadism. OBJECTIVES: To assess the effect of monotherapy or a combination of selective oestrogen receptor modulators/aromatase inhibitors on sperm parameters and/or fertility in men with secondary hypogonadism. MATERIALS AND METHODS: A systematic search was conducted in PubMed, MEDLINE, Cochrane Library and ClinicalTrials.gov. Study selection and data extraction were performed by two reviewers independently. Randomised controlled trials and non-randomised studies of interventions reporting effects of selective oestrogen receptor modulators and/or aromatase inhibitors on semen parameters or fertility in men with low testosterone with low/normal gonadotrophins were selected. The risk of bias was assessed using ROB-2 and ROBINS-I tools. The results of randomised controlled trials were summarised using vote counting while summarising effect estimates where available. Non-randomised studies of intervention meta-analysis were conducted using the random-effect model. The certainty of evidence was assessed using GRADE. RESULTS: Five non-randomised studies of interventions (n = 105) of selective oestrogen receptor modulators showed an increase in sperm concentration (pooled mean difference 6.64 million/mL; 95% confidence interval 1.54, 11.74, I2  = 0%) and three non-randomised studies of interventions (n = 83) of selective oestrogen receptor modulators showed an increase in total motile sperm count (pooled mean difference 10.52; 95% confidence interval 1.46-19.59, I2  = 0%), with very low certainty of evidence. The mean body mass index of participants was >30 kg/m2 . Four randomised controlled trials (n = 591) comparing selective oestrogen receptor modulators to placebo showed a heterogeneous effect on sperm concentration. Three included men with overweight or obesity. The results were of very low certainty of evidence. Limited pregnancy or live birth data were available. No studies comparing aromatase inhibitors with placebo or testosterone were found. DISCUSSION AND CONCLUSION: Current studies are of limited size and quality but suggest that selective oestrogen receptor modulators may improve semen parameters in those patients, particularly when associated with obesity.

Factors predicting normalization of reproductive hormones after cessation of anabolic-androgenic steroids in men: a single center retrospective study.

OBJECTIVE: Symptomatic hypogonadism discourages men from stopping anabolic-androgenic steroids (AAS). Some men illicitly take drugs temporarily stimulating endogenous testosterone following AAS cessation (post-cycle therapy; PCT) to lessen hypogonadal symptoms. We investigated whether prior PCT use was associated with the normalization of reproductive hormones following AAS cessation. METHODS: Retrospective analysis of 641 men attending a clinic between 2015-2022 for a single, nonfasting, random blood test <36 months following AAS cessation, with or without PCT. Normalized reproductive hormones (ie, a combination of reference range serum luteinizing hormone, follicle-stimulating hormone, and total testosterone levels) were the surrogate marker of biochemical recovery. RESULTS: Normalization of reproductive hormones was achieved in 48.2% of men. PCT use was associated with faster biochemical recovery (13.0 (IQR8.0-19.0) weeks, PCT; 26.0 (IQR10.5-52) weeks, no-PCT; P < .001). Odds of biochemical recovery during multivariable analysis were: (1) higher with PCT (OR3.80) vs no-PCT (P = .001), in men stopping AAS ≤3 months previously; (2) reduced when 2 (OR0.55), 3 (OR0.46), or 4 (OR0.25) AAS were administered vs 1 drug (P = .009); (3) lower with AAS >6 vs ≤3 months previously (OR0.34, P = .01); (4) higher with last reported AAS >3 months (OR 5.68) vs ≤3 months (P = .001). PCT use was not associated with biochemical recovery in men stopping AAS >3 months previously. CONCLUSION: Without evidence-based withdrawal protocols, men commonly try avoiding post-AAS hypogonadism with PCT, which is illicit, ill-defined, and not recommended. Only half of men had complete biochemical testicular recovery after stopping AAS. The surprising association of self-reported PCT use with short-term biochemical recovery from AAS-induced hypogonadism warrants further investigation.

The use of post-cycle therapy is associated with reduced withdrawal symptoms from anabolic-androgenic steroid use: a survey of 470 men.

BACKGROUND: Anabolic-androgenic steroids (AAS) mimic the effects of testosterone and may include testosterone itself; they are used for body enhancement within the general population. AAS use has been linked with increased mortality, cardiovascular disease, mental health disorders, and infertility. AAS-induced hypogonadism can persist for an uncertain time period despite cessation, during which men may report physical and neuropsychiatric symptoms. In an attempt to mitigate these symptoms and expedite testicular recovery, many men self-administer post-cycle-therapy (PCT), typically involving human chorionic gonadotrophin (hCG) and selective oestrogen receptor modulators (SERMs), which are known to potently stimulate testicular function. However, this practice has no objective evidence of effectiveness to lessen the severity or duration of hypogonadal symptoms. METHODS: An anonymous survey of four-hundred-and-seventy men using AAS explored the symptoms they experienced when ceasing AAS use; the effect of PCT on relieving their symptoms, and their perceived role for health service support. RESULTS: The majority of respondents were white, aged 18-30 years old, and working in skilled manual work. 51.7% (n = 243) reported no issues with AAS use, but 35.3% reported increased aggression. 65.1% (n = 306) of respondents had attempted AAS cessation and 95.1% of these experienced at least one symptom upon AAS cessation. Low mood, tiredness and reduced libido were reported in 72.9%, 58.5% and 57.0% of men stopping AAS use, respectively, with only 4.9% reporting no symptoms. PCT had been used by 56.5% of respondents with AAS cessation and mitigated cravings to restart AAS use, withdrawal symptoms and suicidal thoughts by 60%, 60% and 50%, respectively. The effect of stopping AAS on body composition and recovery of testosterone or fertility was a concern in 60.5% and 52.4%, respectively. Most respondents felt PCT should be prescribed under medical supervision in the community. CONCLUSIONS: Our survey suggests that the majority of men stopping AAS use are using some form of PCT. Some self-reported symptoms of AAS-induced hypogonadism such as cravings to restart AAS use reduce by 60% and suicidal thoughts reduce by 50%. These individuals are concerned about the negative effect of AAS use and cessation. This study provides crucial information for planning future research to evaluate the effects of PCT on symptoms when men stop AAS use.

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.

Does Testicular Sperm Improve Intracytoplasmic Sperm Injection Outcomes for Nonazoospermic Infertile Men with Elevated Sperm DNA Fragmentation? A Systematic Review and Meta-analysis.

CONTEXT: For nonazoospermic infertile men with elevated sperm DNA fragmentation (SDF), it is unclear whether the use of testicular sperm for intracytoplasmic sperm injection (ICSI) may offer advantages over ejaculated sperm. OBJECTIVE: To determine whether ICSI outcomes (fertilisation rate, pregnancy rate, miscarriage rate, and live birth rate) are better with testicular sperm than with ejaculated sperm for men with elevated SDF. EVIDENCE ACQUISITION: We searched the Cochrane Central, EMBASE, MEDLINE, Web of Science, and Scopus databases (1946-2023) in February 2023 for relevant human comparative studies according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. EVIDENCE SYNTHESIS: Out of 2032 records, nine studies (more than 536 participants, mean age range 33-40.5 yr for males and 30.1-37.9 yr for females) were included in the systematic review and meta-analysis. Pooled estimates demonstrated that the pregnancy rate was significantly higher with testicular than with ejaculated sperm according to a sperm chromatin structure assay (SCSA)/sperm chromatin integrity test (SCIT) (odds ratio [OR] 2.51; p = 0.001) and terminal deoxynucleotidyl transferase dUTP nick-end labelling (TUNEL) assays (OR 3.65; p = 0.005). The live birth rate was significantly higher according to SCSA/SCIT (OR 2.59; p = 0.005). There were no significant differences in the fertilisation rate or miscarriage rate. CONCLUSIONS: Although significant improvements in pregnancy and live birth rates were observed with testicular sperm, the strength of findings is limited by availability and quality of evidence, both of which undermine recommendations for clinical practice. Standardised randomised controlled trials are needed to definitively determine whether the use of testicular sperm improves ISCI outcomes for men with high SDF. Until such evidence exists, ICSI after testicular sperm extraction or aspiration should not be routinely performed. PATIENT SUMMARY: Our review showed that for infertile men with a high level of DNA damage in their sperm, use of sperm extracted from the testicles may give better results than ejaculated sperm for a particular IVF (in vitro fertilisation) technique. However, there is a lack of high-quality data.

A review of recent evidence on androgen abuse from interviews with users.

PURPOSE OF REVIEW: Androgens (also known as anabolic-androgenic steroids; AAS) are increasingly being abused worldwide to enhance body physique or athletic performance. Qualitative studies including interviews provide a wider understanding of androgen abuse and focus specific support needs to this group. This narrative review summarizes recent studies (2021-2023) using interviews with individuals abusing androgens. RECENT FINDINGS: Motivations for androgen abuse in men include desires to achieve certain physicality, enhance self-confidence and improve libido. The risks of androgen abuse are justified to achieve these outcomes and men may use other illicit substances as postcycle-therapy to lessen the risks. Some adverse effects may be more pronounced with certain substances. The therapeutic relationship with healthcare professionals is often described negatively by androgen abusers due to stigma and a perceived lack of knowledge. Both healthcare professionals and androgen abusers agree that development of guidelines are needed. Androgen abuse in women is rare however body dissatisfaction and desires for improve appearance and strength are motivators. SUMMARY: Recent qualitative studies have helped further our understanding of men and women who abuse androgens, however the small number of recently published studies confirms there is still a paucity of evidence in the literature. Further research is needed to develop specific harm minimization strategies in those abusing androgens.

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.

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.

Clinical characteristics of functioning gonadotroph adenoma in women presenting with ovarian hyperstimulation: Audit of UK pituitary centres.

OBJECTIVE: Functioning gonadotroph adenomas (FGAs) are rare pituitary tumours stimulating ovarian function with potential life-threatening consequences in women. However, a lack of aggregated clinical experience of FGAs impairs management in affected women. The aim of this study is to present the clinical course of FGA-induced ovarian hyperstimulation syndrome (OHSS) cases as identified by some of the largest UK pituitary endocrine tertiary centres with a view to increasing awareness and improving diagnosis and management of women with FGA. DESIGN: A retrospective observational study; audit of eight UK regional pituitary centres for cases of FGAs. SETTING: Specialist neuroendocrine centres in the United Kingdom. PATIENTS AND MEASUREMENTS: Women diagnosed with FGA-induced OHSS. Description of their clinical course. RESULTS: Seven cases of FGA were identified in women, all causing OHSS. Mean age was 33.4 years at diagnosis. Abdominal pain, irregular periods, headache, and visual disturbances were reported at presentation by 100%, 71%, 57% and 43% of women, respectively. Three of seven women underwent ovarian surgery before FGA diagnosis. Six women underwent transsphenoidal surgery (TSS) with incomplete tumour resection in five of those, but all showed improvement or resolution in symptoms and biochemistry postoperatively. CONCLUSION: FGA is a rare cause of spontaneous OHSS. TSS improves clinical and biochemical features of ovarian hyperstimulation in FGAs. Improved awareness of FGA will prevent inappropriate emergency ovarian surgery.

The role of seminal reactive oxygen species assessment in the setting of infertility and early pregnancy loss.

The male contribution to a couple suffering with adverse early pregnancy outcomes is being increasingly investigated. Seminal oxidative stress is considered to cause sperm DNA damage, thus affecting the functional capacity of the sperm. Multiple lines of evidence support an association between elevated seminal reactive oxygen species (ROS) and infertility. In the setting of assisted reproduction various factors in the in vitro environment, differing from the in vivo environment, may exacerbate oxidative stress. Furthermore, seminal ROS levels have been found to be higher in the male partners of couple's affected by both spontaneous and recurrent pregnancy loss. There are several methods by which to assess ROS levels however they are costly, inconsistent and their incorporation into clinical practice is unclear. The value of ROS assessment lies in the ability to plan targeted therapies to improve pregnancy and live birth rates. As such, further robust study is required before firm conclusions can be made to inform clinical practice. We aim to review the available evidence regarding the role of seminal ROS in infertility and pregnancy loss.