Objective: Sociodemographic, lifestyle, and medical variables influence total testosterone (T) and sex hormone-binding globulin (SHBG) concentrations. The relationship between these factors and "free" T remains unclear. We examined 21 sociodemographic, lifestyle, and medical predictors influencing calculated free T (cFT) in community-dwelling men across ages. Design: This is a cross-sectional analysis in 20 631 participants in the Androgens in Men Study. Methods: Individual participant data (IPD) were provided by 9 cohorts. Total T was determined using mass spectrometry, SHBG using immunoassays, and cFT using the Vermeulen formula. Associations were analyzed using 2-stage random effects IPD meta-analyses. Results: Cohort median ages ranged from 40 to 76 years and median cFT concentrations from 174.3 to 422.8 pmol/L. In men aged 17-99 years, there was a linear inverse association of cFT with age (-57.2 pmol/L [95% confidence interval, -69.4, -44.9] per 1 SD increase in age). Calculated free T increased with increasing baseline body mass index (BMI) among men with BMI < 23.6 kg/m2 , but decreased among men with BMI > 23.6 kg/m2 (-24.7 pmol/L [-29.1, -20.3] per 1 SD increase in the 25.4-29.6 kg/m2 BMI range). Calculated free T was lower in younger men, who were married or in a de facto relationship (-18.4 pmol/L [-27.6, -9.3]) and in men who formerly smoked (-5.7 pmol/L [-8.9, -2.6]), were in poor general health (-14.0 pmol/L [-20.1, -7.8]), and had diabetes (-19.6 pmol/L [-23.0, -16.3]), cardiovascular disease (-5.8 pmol/L [-8.3, -3.2]), or cancer (-19.2 pmol/L [-24.4, -14.1]) Conclusions: Calculated free T was most prominently associated with age and BMI. The linear, inverse association with age, nonlinear association with BMI, and presence of diabetes, cancer, and sociodemographic factors should be considered when interpreting cFT values.

Empirical evidence for a low normal or reference interval for serum prolactin (PRL) is lacking for men, while the implications of very low PRL levels for human health have never been studied. A clinical state of “PRL deficiency” has not been defined except in relation to lactation. Using data from the European Male Ageing Study (EMAS), we analyzed the distribution of PRL in 3,369 community-dwelling European men, aged 40–80 years at phase-1 and free from acute illnesses. In total, 2,948 and 2,644 PRL samples were collected during phase-1 and phase-2 (3 to 5.7 years later). All samples were analysed in the same centre with the same assay. After excluding individuals with known pituitary diseases, PRL ≥ 35 ng/ml, and PRL-altering drugs including antipsychotic agents, selective serotonin reuptake inhibitors, or dopamine agonists, 5,086 data points (2,845 in phase-1 and 2,241 in phase-2) were available for analysis. The results showed that PRL declined minimally with age (slope = -0.02) and did not correlate with BMI. The positively skewed PRL distribution was log-transformed to a symmetrical distribution (skewness reduced from 13.3 to 0.015). Using two-sigma empirical rule (2[]SD about the mean), a threshold at 2.5

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.

BACKGROUND:Whether circulating sex hormones modulate mortality and cardiovascular disease (CVD) risk in aging men is controversial. PURPOSE:To clarify associations of sex hormones with these outcomes. DATA SOURCES:Systematic literature review to July 2019, with bridge searches to March 2024. STUDY SELECTION:Prospective cohort studies of community-dwelling men with sex steroids measured using mass spectrometry and at least 5 years of follow-up. DATA EXTRACTION:Independent variables were testosterone, sex hormone-binding globulin (SHBG), luteinizing hormone (LH), dihydrotestosterone (DHT), and estradiol concentrations. Primary outcomes were all-cause mortality, CVD death, and incident CVD events. Covariates included age, body mass index, marital status, alcohol consumption, smoking, physical activity, hypertension, diabetes, creatinine concentration, ratio of total to high-density lipoprotein cholesterol, and lipid medication use. DATA SYNTHESIS:Nine studies provided individual participant data (IPD) (255 830 participant-years). Eleven studies provided summary estimates (n = 24 109). Two-stage random-effects IPD meta-analyses found that men with baseline testosterone concentrations below 7.4 nmol/L (<213 ng/dL), LH concentrations above 10 IU/L, or estradiol concentrations below 5.1 pmol/L had higher all-cause mortality, and those with testosterone concentrations below 5.3 nmol/L (<153 ng/dL) had higher CVD mortality risk. Lower SHBG concentration was associated with lower all-cause mortality (median for quintile 1 [Q1] vs. Q5, 20.6 vs. 68.3 nmol/L; adjusted hazard ratio [HR], 0.85 [95% CI, 0.77 to 0.95]) and lower CVD mortality (adjusted HR, 0.81 [CI, 0.65 to 1.00]). Men with lower baseline DHT concentrations had higher risk for all-cause mortality (median for Q1 vs. Q5, 0.69 vs. 2.45 nmol/L; adjusted HR, 1.19 [CI, 1.08 to 1.30]) and CVD mortality (adjusted HR, 1.29 [CI, 1.03 to 1.61]), and risk also increased with DHT concentrations above 2.45 nmol/L. Men with DHT concentrations below 0.59 nmol/L had increased risk for incident CVD events. LIMITATIONS:Observational study design, heterogeneity among studies, and imputation of missing data. CONCLUSION:Men with low testosterone, high LH, or very low estradiol concentrations had increased all-cause mortality. SHBG concentration was positively associated and DHT concentration was nonlinearly associated with all-cause and CVD mortality. PRIMARY FUNDING SOURCE:Medical Research Future Fund, Government of Western Australia, and Lawley Pharmaceuticals. (PROSPERO: CRD42019139668).

Insulin-like peptide 3 (INSL3) is a circulating biomarker for Leydig cell functional capacity in men, also indicating Leydig Cell Insufficiency (LCI) and potential primary hypogonadism. Using results from large cohort studies we explore sources of biological and technical variance, and establish a reference range for adult men. It is constitutively secreted with little within-individual variation and reflects testicular capacity to produce testosterone. The main INSL3 assays available indicate good concordance with low technical variance; there is no effect of ethnicity. INSL3 declines with age from 35 years at about 15% per decade. Like low calculated free testosterone, and to a lesser extent low total testosterone, reduced INSL3 is significantly associated with increasing age-related morbidity, including lower overall sexual function, reflecting LCI. Consequently, low INSL3 (≤0.4 ng/ml; ca. <2 SD from the population mean) might serve as an additional biochemical marker in the assessment of functional hypogonadism (late-onset hypogonadism, LOH) where testosterone is in the borderline low range. Excluding individuals with low LCI (INSL3 ≤ 0.4 ng/ml) leads to an age-independent (> 35 years) reference range (serum) for INSL3 in the eugonadal population of 0.4 - 2.3 ng/ml, with low INSL3 prospectively identifying individuals at risk of increased future morbidity.

Non-surgical (reversible) male contraception methods, when approved for general clinical application, should be made available to all interested men aged 18 50 years in good general health regardless of their semen parameters. In the preliminary workup, a complete personal and family history aimed at identifying specific conditions that may potentially increase the risks for adverse effects (associated with testosterone replacement) is advisable but a general or andrological examination is not required, unless indicated by the history. Baseline body weight, blood pressure and haemoglobin should be recorded for the purpose of future monitoring. While risks and benefits of vasectomy have been well established, appropriately nuanced patient counselling and assessment are essential for ensuring a satisfactory outcome of vasectomy.

Background Previous studies have suggested an association between sleep disturbance and frailty. The mechanism is unknown, although it has been suggested that hormonal factors may play a role. Methods The aim was to determine the association between sleep duration, sleep quality and frailty, and to determine whether testosterone influenced this association. Males aged 40–79 years were recruited from eight European centres to the European Male Aging Study (EMAS). Subjects completed an interviewer-assisted questionnaire including questions regarding sleep quality and duration. Sleep quality was scored 0–20 and categorised as 0–4, 5–9, 10–14, and 15–20, with higher scores indicating poorer quality. A 39-component frailty index (FI) was constructed. Total testosterone levels were measured. The association between sleep duration, sleep quality and the FI was assessed using negative binomial regression, with adjustment for putative confounders including testosterone level. Results Two thousand three hundred ninety-three participants contributed data to the analysis. The mean age was 63.3 years and mean sleep duration was 7.01 h. The mean frailty index was 0.15. Mean testosterone levels declined with decreasing sleep quality. After adjustment, compared to those with a sleep score of 0–4, the FI was 57% (95% CI 38%, 78%) higher among those with a sleep score of 15–20. After adjustment compared to those with normal sleep duration (6–9 h) , those with a short (< 6 h) and long (≥ 9 h) sleep duration had a 16% (95% CI 6%, 28%) and 11% (95% CI 0%, 23%) higher FI, respectively. Adjustment for testosterone did not influence the strength of either association. Conclusion Frailty is associated with impaired sleep quality and sleep duration. The association cannot, however, be explained by variation in testosterone levels.

Abstract Disclosure: B.B. Yeap: None. R.J. Marriott: None. L. Antonio: None. S. Bhasin: None. A.S. Dobs: None. D.J. Handelsman: None. G.J. Hankey: None. R. Haring: None. A.M. Matsumoto: None. C. Ohlsson: None. E.S. Orwoll: None. D.M. Vanderschueren: None. G.A. Wittert: None. F.C. Wu: None. K. Murray: None. Studies examining associations of circulating sex steroids with mortality risk in men show inconsistent results for testosterone (T), with limited data for dihydrotestosterone (DHT) and estradiol (E2). We aimed to clarify associations of sex steroids, sex hormone-binding globulin (SHBG) and luteinising hormone (LH) with risks of all-cause and cardiovascular disease (CVD) mortality and incident CVD events in men, by conducting individual participant data (IPD) meta-analyses of prospective cohort studies with sex steroids measured using mass spectrometry. The Androgens In Men Study protocol was registered (PROSPERO: CRD42019139668) and published (BMJ Open 2020;10:e034777). A systematic review (completed Dec 2019) identified relevant studies (BMJ Open 2021;11:e048013). IPD were requested. Cox proportional hazards analyses related total T, SHBG, LH, DHT and E2 concentrations to risk of all-cause mortality and CVD deaths, and risk of incident CVD events. Models were adjusted for age and other sociodemographic factors, lifestyle factors, medical conditions and medications. Summary curves and hazard ratios (HRs) with 95% confidence intervals (CIs) were determined using two-stage random-effects IPD meta-analyses. Summary estimates were obtained from 11 studies (24,596 men), with median baseline age 49-76 years and 4-20 years follow-up among studies. Associations of T with all-cause and CVD mortality risk were non-linear. Risk of all-cause mortality increased for men with baseline T concentrations <8.7 nmol/L, and risk of CVD death increased for men with baseline T <5.3 nmol/L. Lower SHBG concentrations were associated with lower risk of all-cause mortality (median Quintile [Q]1 vs Q5 [Q1:Q5], 20.6 vs 68.3 nmol/L; HR=0.85, CI=0.77-0.95), and CVD death (HR=0.81, CI 0.65-1.00). Men with LH >10 IU/L or E2 <5.1 pmol/L had higher all-cause mortality, with no association of LH or E2 with CVD deaths. Associations of DHT with all-cause and CVD mortality risk were non-linear. Men with lower baseline DHT concentrations had higher risk of all-cause mortality (median Q1:Q5, 0.69 vs 2.45 nmol/L; HR=1.19, CI=1.08-1.30) and CVD deaths (HR=1.29, CI=1.03-1.61), with risk increasing for DHT >2.45 nmol/L. Men with baseline DHT concentrations <0.59 nmol/L had increased risk of incident CVD events, no other hormones were associated with this outcome. Our results suggest greater all-cause and CVD mortality risk among men with very low baseline T, higher baseline SHBG, or either lower or very high baseline DHT concentrations. There was greater risk of CVD events among men with very low baseline DHT concentrations. Potential mechanisms by which SHBG and DHT might influence mortality risk in ageing men merit further investigation. Presentation: Thursday, June 15, 2023

Objective To determine the influence of serum sodium on physical, psychologic and sexual function. Methods This is a cross-sectional survey on 3340 community-dwelling men aged 40–79 years from a prospective cohort study in eight European countries, the European Male Ageing Study (EMAS). Participants filled-out the Short Form-36 (SF-36), the Physical Activity Scale for the Elderly (PASE), and the EMAS sexual function questionnaire. For all the analyses, serum sodium corrected for glycaemia ([Na + ] G ) was used. Results The relationship between [Na + ] G and SF-36 physical function score (F = 3.99; p = 0.01), SF-36 mental health score (F = 7.69; p < 0.001), and PASE score (F = 14.95; p < 0.001) were best described by a quadratic equation, with worse scores for [Na + ] G in either the lowest or the highest ends of the range. After dividing the sample into [Na + ] G < 136 mmol/L (n = 81), 136–147 mmol/L (n = 3223) and > 147 mmol/L (n = 36), linear regression analyses with linear spline functions adjusted for confounders did not confirm these relationships. Similarly, erectile dysfunction and [Na + ] G , were in a quadratic relationship (F = 9.00; p < 0.001). After adjusting for confounders, the linear regression with spline functions denoted a significantly worsened erectile function for increases in serum [Na + ] G > 147 mmol/L (B = 0.15 [0.04;0.26], p < 0.01) but no relationship with [Na + ] G < 136 mmol/L. Likewise, the relationship of [Na + ] G with concerns about sexual dysfunction was confirmed only for men with serum [Na + ] G > 147 mmol/L. Conclusions This is the first study supporting an association between [Na + ] G and sexual function. A worsening of erection and concerns about sexual function were observed for the highest values of [Na + ] G , independently of other relevant factors.

Abstract Disclosure: R.J. Marriott: None. K. Murray: None. L. Antonio: None. S. Bhasin: None. A.S. Dobs: None. D.J. Handelsman: None. G.J. Hankey: None. R. Haring: None. A.M. Matsumoto: None. C. Ohlsson: None. E.S. Orwoll: None. D.M. Vanderschueren: None. G.A. Wittert: None. F.C. Wu: None. B.B. Yeap: None. Different factors modulate circulating testosterone in men, impacting interpretation of reference ranges. We aimed to clarify factors associated with variations in sex hormone concentrations by conducting individual participant data (IPD) meta-analyses of prospective cohort studies of adult men with total testosterone measured using mass spectrometry. The Androgens In Men Study protocol was submitted to PROSPERO (23 July 2019), registered (20 November 2019; CRD42019139668) and published (BMJ Open 2020; 10: e034777). A systematic review (14 June-31 December 2019) identified prospective cohort studies (BMJ Open 2021; 11: e048013). IPD data were requested. Cross-sectional analyses related total testosterone (measured using mass spectrometry), sex hormone binding globulin (SHBG), luteinising hormone (LH), dihydrotestosterone (DHT) and estradiol (also measured using mass spectrometry) concentrations to sociodemographic, lifestyle, and health factors. Summary curves and effect estimates with 95% confidence intervals (CIs) were obtained using two-stage random-effects IPD meta-analyses. Summary estimates were obtained from 11 studies (25,149 men). There was a non-linear association of testosterone with age, with negligible change among men aged 17-70 years (1SD increase about age 43.5, from 35.7 to 51.3 years -0.27 nmol/L, CI -0.71 to 0.18) and decreasing testosterone with age for men >70 years (1SD increase about age 84.5, from 76.7 to 92.3 years -1.55 nmol/L, CI -2.05 to -1.06). Testosterone was inversely associated with BMI (1SD increase about 27.5 kg/m2, from 25.5 to 29.6 kg/m2 -2.42 nmol/L, CI -2.70 to -2.13). Testosterone concentrations were lower for men who: were married/de facto (-0.57 nmol/L); undertook ≤75 minutes vigorous physical activity/week (-0.51 nmol/L); former smokers (-0.34 nmol/L); had hypertension (-0.53 nmol/L), cardiovascular disease (-0.35 nmol/L), cancer (-1.39 nmol/L), or diabetes (-1.43 nmol/L); all CIs excluded zero. SHBG increased with age (per SD increase in age 11.3 nmol/L, CI 9.0 to 13.6) and decreased with BMI (per SD increase in BMI -5.9 nmol/L, CI -6.9 to -5.0). There was little change in mean LH with age in men <70 years (1SD increase in age 0.10 IU/L, CI -0.08 to 0.28), but an increase in LH with age in men ≥70 years (1SD increase in age 4.14 IU/L, CI 3.71 to 4.56). DHT and estradiol were less prominently associated with these factors. Multiple factors are associated with variation in male testosterone and SHBG concentrations, with evidence of primary impairment of testicular hormone production after age 70 years. Interpretation of testosterone results in individuals needs to account for these factors, especially age >70 years, BMI, diabetes and cancer. Further research is needed to determine health impacts of declining testosterone in older men. Presentation Date: Saturday, June 17, 2023

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 center dot 52 [95% CI 3 center dot 95-7 center dot 10]; tau 2=1 center dot 17; n=1412) and IIEF-15 erectile function subscore (2 center dot 14 [1 center dot 40-2 center dot 89]; tau 2=0 center dot 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. Copyright (c) 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.

Background: Various factors modulate circulating testosterone in men, affecting interpretation of testosterone measurements. Purpose: To clarify factors associated with variations in sex hormone concentrations. Data Sources: Systematic literature searches (to July 2019). Study Selection: Prospective cohort studies of community-dwelling men with total testosterone measured using mass spectrometry. Data Extraction: Individual participant data (IPD) (9 studies; n = 21 074) and aggregate data (2 studies; n = 4075). Sociodemographic, lifestyle, and health factors and concentrations of total testosterone, sex hormone-binding globulin (SHBG), luteinizing hormone (LH), dihydrotestosterone, and estradiol were extracted. Data Synthesis: Two-stage random-effects IPD meta-analyses found a nonlinear association of testosterone with age, with negligible change among men aged 17 to 70 years (change per SD increase about the midpoint, -0.27 nmol/L [-7.8 ng/dL] [CI, -0.71 to 0.18 nmol/L {-20.5 to 5.2 ng/dL}]) and decreasing testosterone levels with age for men older than 70 years (-1.55 nmol/L [-44.7 ng/dL] [CI, -2.05 to -1.06 nmol/L {-59.1 to -30.6 ng/dL}]). Testosterone was inversely associated with body mass index (BMI) (change per SD increase, -2.42 nmol/L [-69.7 ng/dL] [CI, -2.70 to -2.13 nmol/L {-77.8 to -61.4 ng/dL}]). Testosterone concentrations were lower for men who were married (mean difference, -0.57 nmol/L [-16.4 ng/dL] [CI, -0.89 to -0.26 nmol/L {-25.6 to -7.5 ng/dL}]); undertook at most 75 minutes of vigorous physical activity per week (-0.51 nmol/L [-14.7 ng/dL] [CI, -0.90 to -0.13 nmol/L {-25.9 to -3.7 ng/dL}]); were former smokers (-0.34 nmol/L [-9.8 ng/dL] [CI, -0.55 to -0.12 nmol/L {-15.9 to -3.5 ng/dL}]); or had hypertension (-0.53 nmol/L [-15.3 ng/dL] [CI, -0.82 to -0.24 nmol/L {-23.6 to -6.9 ng/dL}]), cardiovascular disease (-0.35 nmol/L [-10.1 ng/dL] [CI, -0.55 to -0.15 nmol/L {-15.9 to -4.3 ng/dL}]), cancer (-1.39 nmol/L [-40.1 ng/dL] [CI, -1.79 to -0.99 nmol/L {-51.6 to -28.5 ng/dL}]), or diabetes (-1.43 nmol/L [-41.2 ng/dL] [CI, -1.65 to -1.22 nmol/L {-47.6 to -35.2 ng/dL}]). Sex hormone-binding globulin was directly associated with age and inversely associated with BMI. Luteinizing hormone was directly associated with age in men older than 70 years. Limitation: Cross-sectional analysis, heterogeneity between studies and in timing of blood sampling, and imputation for missing data. Conclusion: Multiple factors are associated with variation in male testosterone, SHBG, and LH concentrations. Reduced testosterone and increased LH concentrations may indicate impaired testicular function after age 70 years. Interpretation of individual testosterone measurements should account particularly for age older than 70 years, obesity, diabetes, and cancer.

Abstract Disclosure: J. Hudson: None. M. Cruickshank: None. R. Quinton: Speaker; Self; Bayer Schering Pharma, Besins. L. Aucott: None. F.C. Wu: None. M. Grossmann: None. S. Bhasin: None. P.J. Snyder: None. S. Ellenberg: None. T.G. Travison: None. G.B. Brock: None. E.J. Gianatti: None. Y.T. van der Schouw: None. M.H. Emmelot-Vonk: None. E. Giltay: None. H. Geoff: None. S. Ramachandran: None. J.B. Svartberg: None. K.L. Hildreth: None. K. Groti Antonic: None. J.S. Tenover: None. H. Tan: None. C. Ho Chee Kong: None. T. Wei Shen: None. L.S. Marks: None. R.J. Ross: None. R.S. Schwartz: None. S. Roberts: None. M. Andersen: None. L. Magnussen: None. M. Aceves-Martins: None. S. Bhattacharya: None. W.S. Dhillo: None. M. Brazzelli: None. C.N. Jayasena: Grant Recipient; Self; Logixx Pharma Ltd. Background: Testosterone treatment increases the international index of erectile function 15 (IIEF-15) in young men with pathological hypogonadism. However, testosterone is most frequently prescribed to middle-aged and older men, and men with obesity, whose sexual dysfunction may be unrelated to their low testosterone; prior studies suggest that symptomatic responses to testosterone treatment may be attenuated in older men and those with obesity. To identify subgroups of men with low testosterone experiencing the greatest symptomatic benefit during testosterone therapy, we utilised individual participant data (IPD) from the Testosterone Efficacy and Safety (TestES) Consortium. Methods: Systematic review of randomised controlled trials including IPD meta-analysis (PROSPERO CRD42018111005) identifying clinical efficacy outcomes, and subgroups associated with outcomes in RCTs comparing testosterone with placebo in men with baseline total testosterone <12nmol/L (348ng/dL). One-stage meta-analyses used IPD, and two-stage meta-analyses integrated IPD with aggregate data from studies not providing IPD. Findings: Seventeen of 35 trials provided IPD (3431/5601 participants; mean duration 9.5months; 97% men aged >40years). As expected, testosterone increased IIEF-15 compared with placebo (MD 5.52 (95% CI 3.95, 7.10; τ^2=1.17). However, no significant increment in IIEF-15 during testosterone compared with placebo was observed in smokers (interaction -9.03, 99% CI -48.90, 30.84). Increases in IIEF-15 during testosterone compared with placebo were not associated with patient age, obesity, presence of diabetes, or baseline total testosterone. However, absolute levels of sexual function achieved during testosterone treatment were subject to thresholds in patient age (mean IIEF-15: 46.8 (19.4), <52 years; 38.8 (21.9), 52-70 years; 26.8 (21.1), >70 years; P<0.001), body mass index (BMI) (mean IIEF-15: 40.0 (22.2), <30.6kg/m2; 34.4 (21.9), ≥30.6kg/m2; P<0.001), and baseline serum testosterone (mean IIEF-15: 42.2 (23.9), ≥9.8nmol/L; 30.7 (22.1), <9.8nmol/L; P<0.001). Interpretation: In men aged >40 years with serum baseline testosterone <12nmol/L, we were surprised to observe that increments in IIEF-15 during testosterone treatment are not significantly affected by age, obesity, or baseline testosterone status. However, baseline factors may influence the absolute post-treatment IIEF-15 achieved during testosterone treatment. Funding: National Institute for Health Research Health Technology Assessment programme (NIHR HTA 17/68/01). Presentation Date: Saturday, June 17, 2023

Background: Various factors modulate circulating testosterone in men, affecting interpretation of testosterone measurements. Purpose: To clarify factors associated with variations in sex hormone concentrations. Data Sources: Systematic literature searches (to July 2019). Study Selection: Prospective cohort studies of community-dwelling men with total testosterone measured using mass spectrometry. Data Extraction: Individual participant data (IPD) (9 studies; n = 21 074) and aggregate data (2 studies; n = 4075). Sociodemographic, lifestyle, and health factors and concentrations of total testosterone, sex hormone–binding globulin (SHBG), luteinizing hormone (LH), dihydrotestosterone, and estradiol were extracted. Data Synthesis: Two-stage random-effects IPD meta-analyses found a nonlinear association of testosterone with age, with negligible change among men aged 17 to 70 years (change per SD increase about the midpoint, −0.27 nmol/L [−7.8 ng/dL] [CI, −0.71 to 0.18 nmol/L {−20.5 to 5.2 ng/dL}]) and decreasing testosterone levels with age for men older than 70 years (−1.55 nmol/L [−44.7 ng/dL] [CI, −2.05 to −1.06 nmol/L {−59.1 to −30.6 ng/dL}]). Testosterone was inversely associated with body mass index (BMI) (change per SD increase, −2.42 nmol/L [−69.7 ng/dL] [CI, −2.70 to −2.13 nmol/L {−77.8 to −61.4 ng/dL}]). Testosterone concentrations were lower for men who were married (mean difference, −0.57 nmol/L [−16.4 ng/dL] [CI, −0.89 to −0.26 nmol/L {−25.6 to −7.5 ng/dL}]); undertook at most 75 minutes of vigorous physical activity per week (−0.51 nmol/L [−14.7 ng/dL] [CI, −0.90 to −0.13 nmol/L {−25.9 to −3.7 ng/dL}]); were former smokers (−0.34 nmol/L [−9.8 ng/dL] [CI, −0.55 to −0.12 nmol/L {−15.9 to −3.5 ng/dL}]); or had hypertension (−0.53 nmol/L [−15.3 ng/dL] [CI, −0.82 to −0.24 nmol/L {−23.6 to −6.9 ng/dL}]), cardiovascular disease (−0.35 nmol/L [−10.1 ng/dL] [CI, −0.55 to −0.15 nmol/L {−15.9 to −4.3 ng/dL}]), cancer (−1.39 nmol/L [−40.1 ng/dL] [CI, −1.79 to −0.99 nmol/L {−51.6 to −28.5 ng/dL}]), or diabetes (−1.43 nmol/L [−41.2 ng/dL] [CI, −1.65 to −1.22 nmol/L {−47.6 to −35.2 ng/dL}]). Sex hormone–binding globulin was directly associated with age and inversely associated with BMI. Luteinizing hormone was directly associated with age in men older than 70 years. Limitation: Cross-sectional analysis, heterogeneity between studies and in timing of blood sampling, and imputation for missing data. Conclusion: Multiple factors are associated with variation in male testosterone, SHBG, and LH concentrations. Reduced testosterone and increased LH concentrations may indicate impaired testicular function after age 70 years. Interpretation of individual testosterone measurements should account particularly for age older than 70 years, obesity, diabetes, and cancer. Primary Funding Source: Medical Research Future Fund, Government of Western Australia, and Lawley Pharmaceuticals. (PROSPERO: CRD42019139668)

Abstract Objectives Testosterone (T) circulates bound to sex hormone-binding globulin (SHBG). Although it is commonly deemed that only the amount of T not linked to proteins (free T) is biologically active, evidence supporting this hypothesis is lacking. To investigate the predictors and clinical consequences of developing or maintaining increased SHBG levels in ageing men from European general population. Methods 3369 men from the general population of eight European countries were recruited in the longitudinal population-based study “European Male Ageing Study”. Subjects completed questionnaires, underwent physical examination, physical and cognitive functional tests and blood sampling during two visits (one baseline and one after a median of 4.3 years of follow-up). Results Among a series of putative candidate predictors for new occurred-stable high SHBG, older men, reporting physical inactivity, with liver diseases and with higher T and LH at baseline were more predisposed to maintain or develop high SHBG; conversely, obesity, higher LDL and IGF1 were protective towards the occurrence of SHBG. Concerning the clinical consequences, men who develop or maintain high SHBG levels reported the new occurrence or worsening of erectile dysfunction, impaired morning erections and low sexual desire. Moreover, they had new or worsened feelings of sadness, worse physical functioning, vitality, mental and social well-being. This was confirmed by worse scoring in physical performance and memory tests, as well as by higher scores on the Beck Depression Inventory. Conclusions The development or maintenance of high SHBG levels is associated with symptoms of hypogonadism, independently of total T levels. Besides sexual symptoms, also physical and depressive symptoms are present. The cognitive and physical performance is also compromised. This study demonstrates that increased SHBG favor the development or worsening of hypogonadism-related symptoms. This provides evidence for the role of SHBG in limiting the biological activity of T, thus supporting the free hormone hypothesis. Conflicts of Interest None

OBJECTIVE:Older men on an average have lower testosterone concentrations, compared with younger men, and more age-related comorbidities. Whether lower testosterone concentrations contribute to biological ageing remains unclear. Shorter telomeres are a marker for biological age. We tested the hypothesis that testosterone concentrations are associated with leucocyte telomere length (LTL), in middle- to older-aged men.DESIGN:Cross-sectional analysis of the UK Biobank study, involving community-dwelling men aged 40-69 years.METHODS:Serum testosterone and sex hormone-binding globulin (SHBG) were assayed. Free testosterone was calculated (cFT). Leucocyte telomere length was measured using polymerase chain reaction. Multivariable models were used to assess associations of hormones with standardised LTL.RESULTS:In 167 706 men, median age 58 years, adjusting for sociodemographic, lifestyle, and medical factors, total testosterone was inversely associated with standardised LTL, which was 0.09 longer (95% confidence interval [CI], 0.08-0.10, P < .001) in men with total testosterone at median of lowest quintile [Q1] vs highest [Q5]. This relationship was attenuated after additional adjustment for SHBG (0.03 longer, CI = 0.02-0.05, P = .003). The association between cFT and LTL was similar in direction but lower in magnitude. In multivariable analysis, SHBG was inversely associated with standardised LTL, which was 0.12 longer (CI = 0.10-0.13, P < .001) for SHBG at median Q1 vs Q5. Results were similar with testosterone included in the model (0.10 longer, CI = 0.08-0.12, P < .001).CONCLUSIONS:Total testosterone and SHBG were independently and inversely associated with LTL. Men with higher testosterone or SHBG had shorter telomeres, arguing against a role for testosterone to slow biological ageing in men.

BACKGROUND:Previous research suggests that sarcopenia is associated with lower cognitive functioning. Evidence on the longitudinal relationship between cognition and sarcopenia, according to the revised criteria of the European Working Group on Sarcopenia in Older People (EWGSOP2), is scarce. This study aimed to investigate both cross-sectional and longitudinal associations between sarcopenia and its defining parameters (muscle strength, muscle mass and physical performance) and cognitive performance in middle-aged and older men.METHODS:This was a secondary analysis of data from the European Male Ageing Study (EMAS), a multicentre cohort study of men aged 40-79 years, recruited from population registers in eight European centres. Cognitive functioning was assessed by using a battery of three neuropsychological tests, measuring fluid intelligence: Rey-Osterrieth Complex Figure (ROCF-Copy and ROCF-Recall), Camden Topographical Recognition Memory (CTRM) and Digit Symbol Substitution Test (DSST). Sarcopenia-defining parameters appendicular lean mass (aLM), gait speed (GS), chair stand test (CST) and handgrip strength (HGS) were measured. Sarcopenia was diagnosed according to the criteria of the EWGSOP2. All measurements were performed at baseline and after a follow-up of 4.3 years. Cross-sectional associations between cognition, sarcopenia-defining parameters and prevalent sarcopenia (EWGSOP2) were analysed. Longitudinally, the predictive value of baseline cognition on decline in sarcopenia-defining parameters, onset of new sarcopenia and vice versa was examined. Linear and logistic regression were used and adjusted for putative confounders.RESULTS:In the whole cohort (n = 3233), ROCF-Copy (β = 0.016; P < 0.05), ROCF-Recall (β = 0.010; P < 0.05), CTRM (β = 0.015; P < 0.05), DSST score (β = 0.032; P < 0.05) and fluid cognition (β = 0.036; P < 0.05) were significantly and independently associated with GS at baseline. In the Leuven + Manchester subcohorts (n = 456), ROCF-Copy (β = 1.008; P < 0.05), ROCF-Recall (β = 0.908; P < 0.05) and fluid cognition (β = 1.482; P < 0.05) were associated with HGS. ROCF-Copy (β = 0.394; P < 0.05), ROCF-Recall (β = 0.316; P < 0.05), DSST (β = 0.393; P < 0.05) and fluid cognition (β = 0.765; P < 0.05) were associated with aLM. The prevalence of sarcopenia in this population was 17.8%. No associations were detected between cognition and prevalent or incident sarcopenia. Longitudinal analysis showed that low ROCF-Copy score at baseline was associated with an increase in CST in men ≥70 years (β = -0.599; P < 0.05). In addition, a decrease in ROCF-Recall was associated with a decrease in GS, and a decrease in DSST was associated with an increase in CST (β = 0.155; P < 0.0001, β = -0.595; P < 0.001, respectively) in persons with the highest change in both cognition and muscle function.CONCLUSIONS:Sarcopenia was not associated with cognitive performance in this population, whereas several components of sarcopenia were associated with domain-specific cognitive performance. Longitudinally, baseline and change in subdomains of cognition predicted change in muscle function in specific subgroups.

BackgroundsDespite a wide spectrum of contraceptive methods for women, the unintended pregnancy rate remains high (45% in the US), with 50% resulting in abortion. Currently, 20% of global contraceptive use is male-directed, with a wide variation among countries due to limited availability and lack of efficacy. Worldwide studies indicate that >50% of men would opt to use a reversible method, and 90% of women would rely on their partner to use a contraceptive. Additional reasons for novel male contraceptive methods to be available include the increased life expectancy, sharing the reproductive risks among partners, social issues, the lack of pharma industry involvement and the lack of opinion makers advocating for male contraception.AimThe present guidelines aim to review the status regarding male contraception, the current state of the art to support the clinical practice, recommend minimal requirements for new male contraceptive development and provide and grade updated, evidence-based recommendations from the European Society of Andrology (EAA) and the American Society of Andrology (ASA).MethodsAn expert panel of academicians appointed by the EAA and the ASA generated a consensus guideline according to the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) system.ResultsSixty evidence-based and graded recommendations were produced on couple-centered communication, behaviors, barrier methods, semen analysis and contraceptive efficacy, physical agents, surgical methods, actions before initiating male contraception, hormonal methods, non-hormonal methods, vaccines, and social and ethical considerations.ConclusionAs gender roles transform and gender equity is established in relationships, the male contribution to family planning must be facilitated. Efficient and safe male-directed methods must be evaluated and introduced into clinical practice, preferably reversible, either hormonal or non-hormonal. From a future perspective, identifying new hormonal combinations, suitable testicular targets, and emerging vas occlusion methods will produce novel molecules and products for male contraception.

The diagnosis of functional hypogonadism should prompt a thorough assessment and optimization of general health, including lifestyle changes, weight reduction, care of comorbidities and cessation of offending medications, some of which can lead to meaningful gains in endogenous testosterone (T) concentrations. Having excluded or addressed reversible causes and contra-indications, patients with functional hypogonadism can be offered a trial of testosterone replacement therapy (TRT) after full discussion on the anticipated benefits and potential risks. T treatment improves libido but may be less effective for erectile dysfunction (ED). T treatment can also have modest positive effects on insulin resistance, bone strength, some measures of physical strength, and mild depressive symptoms but the clinical significance of these relatively short-term improvements remain uncertain in terms of longer-term patient-important outcomes. Initiation of TRT is a joint decision between patient and clinician since longer-term benefits and risks have not been adequately defined.

Context Low total 25-hydroxyvitamin D (25(OH)D) has been associated with mortality. Whether vitamin D in its free form or 1,25-dihydroxyvitamin D (1,25(OH)(2)D), provide any additional information is unclear. Objective To determine what level of 25(OH)D is predictive for mortality and if free 25(OH)D or 1,25(OH) (2) D concentrations have any added value. Methods This prospective cohort comprised 1915 community-dwelling men, aged 40 to 79 years. Intervention included determination of association of total and free 25(OH)D and 1,25(OH) (2) D concentrations with survival status. Vitamin D results were grouped into quintiles. For total 25(OH)D, specific cutoff values were also applied. Cox proportional hazard models were used adjusted for center, body mass index, smoking, alcohol, physical activity, season of blood sample, kidney function, and number of comorbidities. Results A total of 469 (23.5%) men died during a mean follow-up of 12.3 +/- 3.4 years. Compared to those with normal vitamin D values (> 30 mu g/L), men with a total 25(OH)D of less than 20 mu g/L had an increased mortality (hazard ratio [HR] 2.03 [95% CI, 1.39-2.96]; P < .001). Likewise, men in the lowest 3 free 25(OH)D quintiles (< 4.43 ng/L) had a higher mortality risk compared to the highest quintile (HR 2.09 [95% CI, 1.34-3.25]; P < .01). Mortality risks were similar across all 1,25(OH)(2)D and vitamin D binding protein quintiles. Conclusion Aging men with vitamin D deficiency have a 2-fold increased mortality risk. Determinations of either the free fractions of vitamin D or measurement of its active form offer no additional information on mortality risks.