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.

Adverse cardiovascular events and mortality in men during testosterone treatment: an individual patient and aggregate data meta-analysis.

Background: Testosterone is the standard treatment for male hypogonadism, but there is uncertainty about its cardiovascular safety due to inconsistent findings. We aimed to provide the most extensive individual participant dataset (IPD) of testosterone trials available, to analyse subtypes of all cardiovascular events observed during treatment, and to investigate the effect of incorporating data from trials that did not provide IPD. Methods: We did a systematic review and meta-analysis of randomised controlled trials including IPD. We searched MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, MEDLINE Epub Ahead of Print, Embase, Science Citation Index, the Cochrane Controlled Trials Register, Cochrane Database of Systematic Reviews, and Database of Abstracts of Review of Effects for literature from 1992 onwards (date of search, Aug 27, 2018). The following inclusion criteria were applied: (1) men aged 18 years and older with a screening testosterone concentration of 12 nmol/L (350 ng/dL) or less; (2) the intervention of interest was treatment with any testosterone formulation, dose frequency, and route of administration, for a minimum duration of 3 months; (3) a comparator of placebo treatment; and (4) studies assessing the pre-specified primary or secondary outcomes of interest. Details of study design, interventions, participants, and outcome measures were extracted from published articles and anonymised IPD was requested from investigators of all identified trials. Primary outcomes were mortality, cardiovascular, and cerebrovascular events at any time during follow-up. The risk of bias was assessed using the Cochrane Risk of Bias tool. We did a one-stage meta-analysis using IPD, and a two-stage meta-analysis integrating IPD with data from studies not providing IPD. The study is registered with PROSPERO, CRD42018111005. Findings: 9871 citations were identified through database searches and after exclusion of duplicates and of irrelevant citations, 225 study reports were retrieved for full-text screening. 116 studies were subsequently excluded for not meeting the inclusion criteria in terms of study design and characteristics of intervention, and 35 primary studies (5601 participants, mean age 65 years, [SD 11]) reported in 109 peer-reviewed publications were deemed suitable for inclusion. Of these, 17 studies (49%) provided IPD (3431 participants, mean duration 9·5 months) from nine different countries while 18 did not provide IPD data. Risk of bias was judged to be low in most IPD studies (71%). Fewer deaths occurred with testosterone treatment (six [0·4%] of 1621) than placebo (12 [0·8%] of 1537) without significant differences between groups (odds ratio [OR] 0·46 [95% CI 0·17-1·24]; p=0·13). Cardiovascular risk was similar during testosterone treatment (120 [7·5%] of 1601 events) and placebo treatment (110 [7·2%] of 1519 events; OR 1·07 [95% CI 0·81-1·42]; p=0·62). Frequently occurring cardiovascular events included arrhythmia (52 of 166 vs 47 of 176), coronary heart disease (33 of 166 vs 33 of 176), heart failure (22 of 166 vs 28 of 176), and myocardial infarction (10 of 166 vs 16 of 176). Overall, patient age (interaction 0·97 [99% CI 0·92-1·03]; p=0·17), baseline testosterone (interaction 0·97 [0·82-1·15]; p=0·69), smoking status (interaction 1·68 [0·41-6·88]; p=0.35), or diabetes status (interaction 2·08 [0·89-4·82; p=0·025) were not associated with cardiovascular risk. Interpretation: We found no evidence that testosterone increased short-term to medium-term cardiovascular risks in men with hypogonadism, but there is a paucity of data evaluating its long-term safety. Long-term data are needed to fully evaluate the safety of testosterone. Funding: National Institute for Health Research Health Technology Assessment Programme.

Society for Endocrinology guidelines for testosterone replacement therapy in male hypogonadism.

Male hypogonadism (MH) is a common endocrine disorder. However, uncertainties and variations in its diagnosis and management exist. There are several current guidelines on testosterone replacement therapy that have been driven predominantly by single disciplines. The Society for Endocrinology commissioned this new guideline to provide all care providers with a multidisciplinary approach to treating patients with MH. This guideline has been compiled using expertise from endocrine (medical and nursing), primary care, clinical biochemistry, urology and reproductive medicine practices. These guidelines also provide a patient perspective to help clinicians best manage MH.

Nonandrogenic Anabolic Hormones Predict Risk of Frailty: European Male Ageing Study Prospective Data.

Context: Low levels of nonandrogenic anabolic hormones have been linked with frailty, but evidence is conflicting and prospective data are largely lacking. Objective: To determine associations between nonandrogenic anabolic hormones and prospective changes in frailty status. Design/Setting: A 4.3-year prospective observational study of community-dwelling men participating in the European Male Ageing Study. Participants: Men (n = 3369) aged 40 to 79 years from eight European centers. Main Outcome Measures: Frailty status was determined using frailty phenotype (FP; n = 2114) and frailty index (FI; n = 2444). Analysis: Regression models assessed relationships between baseline levels of insulinlike growth factor 1 (IGF-1), its binding protein 3 (IGFBP-3), dehydroepiandrosterone sulfate (DHEA-S), 25-hydroxyvitamin D (25OHD), and parathyroid hormone (PTH), with changes in frailty status (worsening or improving frailty). Results: The risk of worsening FP and FI decreased with 1 standard deviation higher IGF-1, IGFBP-3, and 25OHD in models adjusted for age, body mass index, center, and baseline frailty [IGF-1: odds ratio (OR) for worsening FP, 0.82 (0.73, 0.93), percentage change in FI, -3.7% (-6.0, -1.5); IGFBP-3: 0.84 (0.75, 0.95), -4.2% (-6.4, -2.0); 25OHD: 0.84 (0.75, 0.95); -4.4%, (-6.7, -2.0)]. Relationships between IGF-1 and FI were attenuated after adjusting for IGFBP-3. Higher DHEA-S was associated with a lower risk of worsening FP only in men >70 years old [OR, 0.57 (0.35, 0.92)]. PTH was unrelated to change in frailty status. Conclusions: These longitudinal data confirm the associations between nonandrogenic anabolic hormones and the changes in frailty status. Interventional studies are needed to establish causality and determine therapeutic implications.

Evaluation of cognitive subdomains, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D in the European Male Ageing Study.

PURPOSE: Although lower levels of vitamin D have been related to poor cognitive functioning and dementia in older adults, evidence from longitudinal investigations is inconsistent. The objective of this study was to determine whether 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)2D] levels are associated with specified measures of cognitive decline in ageing men. METHODS: The European Male Ageing Study (EMAS) followed 3369 men aged 40-79 over 4.4 years. 25(OH)D levels at baseline were measured by radioimmunoassay, and 1,25(OH)2D levels were obtained with liquid chromatography-tandem mass spectrometry. Visuoconstructional abilities, visual memory, and processing speed at baseline and follow-up were assessed using the Rey-Osterrieth Complex Figure Test (ROCF), Camden Topographical Recognition Memory (CTRM), and the Digit Symbol Substitution Test (DSST). RESULTS: Following attritions, a total of 2430 men with a mean (SD) age of 59.0 (10.6) were included in the analyses. At baseline, the mean 25(OH)D concentration was 64.6 (31.5) nmol/l, and mean 1,25(OH)2D level was 59.6 (16.6) pmol/l. In age-adjusted linear regression models, high 25(OH)D concentrations were associated with a smaller decline in the DSST (ß = 0.007, p = 0.020). Men with low 25(OH)D levels (<50 nmol/l) showed a greater decline in the CTRM compared to men with higher (≥75 nmol/l) levels (ß = -0.41, p = 0.035). However, these associations disappeared after adjusting for confounders such as depressive symptoms, BMI, and comorbidities. There was no indication of a relationship between 1,25(OH)2D and decline in cognitive subdomains. CONCLUSION: We found no evidence for an independent association between 25(OH)D or 1,25(OH)2D levels and visuoconstructional abilities, visual memory, or processing speed over on average 4.4 years in this sample of middle-aged and elderly European men.

Socioeconomic conditions across life related to multiple measures of the endocrine system in older adults: Longitudinal findings from a British birth cohort study.

BACKGROUND: Little is known about how socioeconomic position (SEP) across life impacts on different axes of the endocrine system which are thought to underlie the ageing process and its adverse consequences. We examined how indicators of SEP across life related to multiple markers of the endocrine system in late midlife, and hypothesized that lower SEP across life would be associated with an adverse hormone profile across multiple axes. METHODS: Data were from a British cohort study of 875 men and 905 women followed since their birth in March 1946 with circulating free testosterone and insulin-like growth factor-I (IGF-I) measured at both 53 and 60-64 years, and evening cortisol at 60-64 years. Indicators of SEP were ascertained prospectively across life-paternal occupational class at 4, highest educational attainment at 26, household occupational class at 53, and household income at 60-64 years. Associations between SEP and hormones were investigated using multiple regression and logistic regression models. RESULTS: Lower SEP was associated with lower free testosterone among men, higher free testosterone among women, and lower IGF-I and higher evening cortisol in both sexes. For example, the mean standardised difference in IGF-I comparing the lowest with the highest educational attainment at 26 years (slope index of inequality) was -0.4 in men (95% CI -0.7 to -0.2) and -0.4 in women (-0.6 to -0.2). Associations with each hormone differed by SEP indicator used and sex, and were particularly pronounced when using a composite adverse hormone score. For example, the odds of having 1 additional adverse hormone concentration in the lowest compared with highest education level were 3.7 (95% CI: 2.1, 6.3) among men, and 1.6 (1.0, 2.7) among women (P (sex interaction) = 0.02). We found no evidence that SEP was related to apparent age-related declines in free testosterone or IGF-I. CONCLUSIONS: Lower SEP was associated with an adverse hormone profile across multiple endocrine axes. SEP differences in endocrine function may partly underlie inequalities in health and function in later life, and may reflect variations in biological rates of ageing. Further studies are required to assess the likely functional relevance of these associations.

Clinical practice patterns in the assessment and management of low testosterone in men: an international survey of endocrinologists.

OBJECTIVE: To document current practices in the approach to low testosterone in older men. Given that recommendations are based on low-level evidence, we hypothesized that there would be a wide variability in clinical practice patterns. DESIGN: Members of all major endocrine and andrological societies were invited to participate in a Web-based survey of the diagnostic work-up and management of a hypothetical index case of a 61-year old overweight man presenting with symptoms suggestive of androgen deficiency, without evidence of hypothalamic-pituitary-gonadal (HPT) axis disease. RESULTS: Nine hundred and forty-three respondents (91·2% adult endocrinologists) from Northern America (63·7%), Europe (12·7%), Oceania (8·2%), Latin America and Caribbean (7·6%), and the Middle East, Asia, or Africa (7·8%) completed the survey. Response rates among participating societies ranged from 4·1-20·0%. There was a wide variability in clinical practice patterns, especially regarding biochemical diagnosis of androgen deficiency, exclusion of HPT axis pathology, and monitoring for prostate cancer. In a man with suggestive symptoms, 42·4% of participants would offer testosterone treatment below a serum total testosterone of 10·4 nmol/l (300 ng/dl). A total of 46·0% of participants were, over the last five years, 'less inclined' to prescribe testosterone to men with nonspecific symptoms and borderline testosterone levels, compared to 'no change' (29·3%) or 'more inclined' (24·7%), P < 0·001. CONCLUSIONS: This large-scale international survey shows a wide variability in the management of lowered testosterone in older men, with deviations from current clinical practice guidelines, and a temporal trend towards increasing reluctance to prescribe testosterone to men without classical hypogonadism. These findings highlight the need for better evidence to guide clinicians regarding testosterone therapy.

Assessment of sexual health in aging men in Europe: development and validation of the European Male Ageing Study sexual function questionnaire.

INTRODUCTION: Assessment of male sexual dysfunction has been the focus of substantial scientific effort. Less research has focused on the development of instruments for the measurement of sexual functioning in aging men. AIMS: The aims of this study were: (i) to characterize the psychometric properties of a new brief, reliable, and valid measure of male sexual functioning for use in a large population survey of middle-aged and elderly European men; and (ii) specifically, to determine whether the new instrument, the European Male Ageing Study-sexual function questionnaire (EMAS-SFQ), discriminates between men with high and low levels of circulating testosterone (T) (total T, free T, and bioavailable T). METHOD: One thousand six hundred men aged 40-79 years completed the self-administered EMAS-SFQ, the Beck depression inventory, and provided a blood sample for assessment of sex hormones. Eighty-five men aged 35-74 years completed the EMAS-SFQ twice, 2 weeks apart to examine the test-retest reliability of the instrument. MAIN OUTCOME MEASURES: Scores on the EMAS-SFQ in relation to age and T levels. RESULTS: Principal component analysis showed that the EMAS-SFQ had four distinct domains (overall sexual functioning [OSF], masturbation, sexual functioning-related distress, and change in sexual functioning). The instrument demonstrated excellent internal and test-retest reliability, as well as convergent, divergent, and discriminant validity. Men with the lowest levels of total, free, and bioavailable T reported lower OSF scores compared to men with the highest T levels. CONCLUSIONS: The EMAS-SFQ is a valid and reproducible instrument, sensitive to age and T levels. It should be suitable for the assessment of sexual health in population samples of men in epidemiological studies of aging.

Determinants of the rate and extent of spermatogenic suppression during hormonal male contraception: an integrated analysis.

CONTEXT: Male hormonal contraceptive methods require effective suppression of sperm output. OBJECTIVE: The objective of the study was to define the covariables that influence the rate and extent of suppression of spermatogenesis to a level shown in previous World Health Organization-sponsored studies to be sufficient for contraceptive purposes (< or =1 million/ml). DESIGN: This was an integrated analysis of all published male hormonal contraceptive studies of at least 3 months' treatment duration. SETTING: Deidentified individual subject data were provided by investigators of 30 studies published between 1990 and 2006. PARTICIPANTS: A total of 1756 healthy men (by physical, blood, and semen exam) aged 18-51 yr of predominantly Caucasian (two thirds) or Asian (one third) descent were studied. This represents about 85% of all the published data. INTERVENTION(S): Men were treated with different preparations of testosterone, with or without various progestins. MAIN OUTCOME MEASURE: Semen analysis was the main measure. RESULTS: Progestin coadministration increased both the rate and extent of suppression. Caucasian men suppressed sperm output faster initially but ultimately to a less complete extent than did non-Caucasians. Younger age and lower initial blood testosterone or sperm concentration were also associated with faster suppression, but the independent effect sizes for age and baseline testicular function were relatively small. CONCLUSION: Male hormonal contraceptives can be practically applied to a wide range of men but require coadministration of an androgen with a second agent (i.e. progestin) for earlier and more complete suppression of sperm output. Whereas considerable progress has been made toward defining clinically effective combinations, further optimization of androgen-progestin treatment regimens is still required.