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.

Does a high dietary intake of resistant starch affect glycaemic control and alter the gut microbiome in women with gestational diabetes? A randomised control trial protocol.

BACKGROUND: Gestational Diabetes Mellitus (GDM) is prevalent with lasting health implications for the mother and offspring. Medical nutrition therapy is the foundation of GDM management yet achieving optimal glycaemic control often requires treatment with medications, like insulin. New dietary strategies to improve GDM management and outcomes are required. Gut dysbiosis is a feature of GDM pregnancies, therefore, dietary manipulation of the gut microbiota may offer a new avenue for management. Resistant starch is a fermentable dietary fibre known to alter the gut microbiota and enhance production of short-chain fatty acids. Evidence suggests that short-chain fatty acids improve glycaemia via multiple mechanisms, however, this has not been evaluated in GDM. METHODS: An open-label, parallel-group design study will investigate whether a high dietary resistant starch intake or resistant starch supplement improves glycaemic control and changes the gut microbiome compared with standard dietary advice in women with newly diagnosed GDM. Ninety women will be randomised to one of three groups - standard dietary treatment for GDM (Control), a high resistant starch diet or a high resistant starch diet plus a 16 g resistant starch supplement. Measurements taken at Baseline (24 to 30-weeks' gestation), Day 10 and Day 56 (approximately 36 weeks' gestation) will include fasting plasma glucose levels, microbial composition and short-chain fatty acid concentrations in stool, 3-day dietary intake records and bowel symptoms questionnaires. One-week post-natal data collection will include microbial composition and short-chain fatty acid concentrations of maternal and neonatal stools, microbial composition of breastmilk, birthweight, maternal and neonatal outcomes. Mixed model analysis of variance will assess change in glycaemia and permutation-based multivariate analysis of variance will assess changes in microbial composition within and between intervention groups. Distance-based linear modelling will identify correlation between change in stool microbiota, short-chain fatty acids and measures of glycaemia. DISCUSSION: To improve outcomes for GDM dyads, evaluation of a high dietary intake of resistant starch to improve glycaemia through the gut microbiome needs to be established. This will expand the dietary interventions available to manage GDM without medication. TRIAL REGISTRATION: Australian New Zealand Clinical Trial Registry, ACTRN12620000968976p . Registered 28 September 2020.

Effect of testosterone treatment on cardiac biomarkers in a randomized controlled trial of men with type 2 diabetes.

OBJECTIVE: To assess the effect of testosterone treatment on cardiac biomarkers in men with type 2 diabetes (T2D). DESIGN: Randomized double-blind, parallel, placebo-controlled trial. PATIENTS: Men aged 35-70 years with T2D and a total testosterone level ≤12·0 nmol/l (346 ng/dl) at high risk of cardiovascular events, median 10-year United Kingdom Prospective Diabetes Study (UKPDS) coronary heart disease (CHD) risk 21% (IQR 16%, 27%). Eighty-eight participants were randomly assigned to 40 weeks of intramuscular testosterone undecanoate (n = 45) or matching placebo (n = 43). MAIN OUTCOME MEASURES: N-terminal pro B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT). RESULT: Testosterone treatment reduced NT-proBNP (mean adjusted difference (MAD) in change over 40 weeks across the testosterone and placebo groups, -17·9 ng/l [95% CI -32·4, -3·5], P = 0·047), but did not change hs-cTnT (MAD, 0·41 ng/l (95% CI -0·56, 1·39), P = 0·62). Six men, three in each group experienced an adverse cardiac event, displaying already higher baseline NT-proBNP (P < 0·01) and hs-cTnT levels (P = 0·01). At baseline, 10-year UKPDS CHD risk was associated positively with NT-proBNP (τ = 0·21, P = 0·004) and hs-cTnT (τ = 0·23, P = 0·003) and inversely with testosterone (total testosterone τ = -0·18, P = 0·02, calculated free testosterone τ = -0·19, P = 0·01), but there was no significant association between testosterone and cardiac biomarkers (P > 0·05). CONCLUSIONS: In this trial of men with T2D and high cardiovascular risk, testosterone treatment reduced NT-proBNP and did not change hs-cTnT. Further studies should determine whether men with increased cardiac biomarkers prior to testosterone therapy are at higher risk of testosterone treatment-associated adverse cardiac events.

Effect of testosterone treatment on constitutional and sexual symptoms in men with type 2 diabetes in a randomized, placebo-controlled clinical trial.

OBJECTIVE: The objective of the study was to assess the effect of T treatment on constitutional and sexual symptoms in men with type 2 diabetes (T2D). DESIGN: This was a randomized double-blind, parallel, placebo-controlled trial. SETTING: The study was conducted at a tertiary referral center. PATIENTS: Men aged 35-70 years with T2D, a hemoglobin A1c less than 8.5%, and a total T level less than 12.0 nmol/L (346 ng/dL) with mild to moderate aging male symptoms and erectile dysfunction. INTERVENTION: Eighty-eight participants were randomly assigned to 40 weeks of im T undecanoate (n = 45) or matching placebo (n = 43). MAIN OUTCOME MEASURES: Constitutional symptoms using the aging male symptoms (AMS) score, sexual desire (question 17 AMS score), and erectile function (International Index of Erectile Function-5). RESULTS: T treatment did not substantially improve aging male symptoms [mean adjusted difference (MAD) in change over 40 weeks across the T and placebo groups in AMS total score, -0.9 (95% confidence interval [CI] -4.1, 2.2), P = .67] or sexual desire [MAD in question 17 AMS, -0.3 (95% CI -0.8, 0.2), P = .17]. Although compared with placebo, erectile function in men assigned to T was reduced [MAD in International Index of Erectile Function abridged version 5, -2.0 (95% CI -3.4, -0.6), P < .02], there was no significant difference between baseline and 40-week International Index of Erectile Function abridged version 5 scores if both groups were analyzed separately. At baseline, symptoms were worse in men with depression and microvascular complications but did not correlate with T levels. CONCLUSIONS: In this trial, T treatment did not substantially improve constitutional or sexual symptoms in obese, aging men with T2D with mild to moderate symptoms and modest reduction in T levels typical for the vast majority of such men.

Effect of testosterone treatment on glucose metabolism in men with type 2 diabetes: a randomized controlled trial.

OBJECTIVE: To determine whether testosterone therapy improves glucose metabolism in men with type 2 diabetes (T2D) and lowered testosterone. RESEARCH DESIGN AND METHODS: We conducted a randomized, double-blind, parallel, placebo-controlled trial in 88 men with T2D, aged 35-70 years with an HbA1c ≤8.5% (69 mmol/mol), and a total testosterone level, measured by immunoassay, of ≤12.0 nmol/L (346 ng/dL). Participants were randomly assigned to 40 weeks of intramuscular testosterone undecanoate (n = 45) or matching placebo (n = 43). All study subjects were included in the primary analysis. Seven men assigned to testosterone and six men receiving placebo did not complete the study. Main outcome measures were insulin resistance by homeostatic model assessment (HOMA-IR, primary outcome) and glycemic control by HbA1c (secondary outcome). RESULTS: Testosterone therapy did not improve insulin resistance (mean adjusted difference [MAD] for HOMA-IR compared with placebo -0.08 [95% CI -0.31 to 0.47; P = 0.23]) or glycemic control (MAD HbA1c 0.36% [0.0-0.7]; P = 0.05), despite a decrease in fat mass (MAD -2.38 kg [-3.10 to -1.66]; P < 0.001) and an increase in lean mass (MAD 2.08 kg [1.52-2.64]; P < 0.001). Testosterone therapy reduced subcutaneous (MAD -320 cm(3) [-477 to -163]; P < 0.001) but not visceral abdominal adipose tissue (MAD 140 cm(3) [-89 to 369]; P = 0.90). CONCLUSIONS: Testosterone therapy does not improve glucose metabolism or visceral adiposity in obese men with moderately controlled T2D and modest reductions in circulating testosterone levels typical for men with T2D.

Failure of functional imaging with gallium-68-DOTA-D-Phe1-Tyr3-octreotide positron emission tomography to localize the site of ectopic adrenocorticotropic hormone secretion: a case report.

INTRODUCTION: The diagnostic efficacy of biochemical and imaging modalities for investigating the causes of Cushing's syndrome are limited. We report a case demonstrating the limitations of these modalities, especially the inability of functional imaging to help localize the site of ectopic adrenocorticotropic hormone secretion. CASE PRESENTATION: A 37-year-old Arabian woman presented with 12 months of progressive Cushing's syndrome-like symptoms. Biochemical evaluation confirmed adrenocorticotropic hormone -dependent Cushing's syndrome. However, the anatomical site of her excess adrenocorticotropic hormone secretion was not clearly delineated by further investigations. Magnetic resonance imaging of our patient's pituitary gland failed to demonstrate the presence of an adenoma. Spiral computed tomography of her chest only revealed the presence of a non-specific 7 mm lesion in her left inferobasal lung segment. Functional imaging, including a positron emission tomography scan using 18-fluorodeoxyglucose and gallium-68-DOTA-D-Phe1-Tyr3-octreotide, also failed to show increased metabolic activity in the lung lesion or in her pituitary gland. Our patient was commenced on medical treatment with ketoconazole and metyrapone to control the clinical features associated with her excess cortisol secretion. Despite initial normalization of her urinary free cortisol excretion rate, levels began to rise eight months after commencement of medical treatment. Repeated imaging of her pituitary gland, chest and pelvis again failed to clearly localize a source of her excess adrenocorticotropic hormone secretion. The bronchial nodule was stable in size on serial imaging and repeatedly reported as having a nonspecific appearance of a small granuloma or lymph node. We re-explored the treatment options and endorsed our patient's favored choice of resection of the bronchial nodule, especially given that her symptoms of cortisol excess were difficult to control and refractory. Subsequently, our patient had the bronchial nodule resected. The histological appearance of the lesion was consistent with that of a carcinoid tumor and immunohistochemical analysis revealed that the tumor stained strongly positive for adrenocorticotropic hormone. Furthermore, removal of the lung lesion resulted in a normalization of our patient's 24-hour urinary free cortisol excretion rate and resolution of her symptoms and signs of hypercortisolemia. CONCLUSION: This case report demonstrates the complexities and challenges in diagnosing the causes of adrenocorticotropic hormone -dependent Cushing's syndrome. Functional imaging may not always localize the site of ectopic adrenocorticotropic hormone secretion.

Testosterone and type 2 diabetes.

PURPOSE OF REVIEW: To describe the relationship between testosterone levels and type 2 diabetes (T2D). RECENT FINDINGS: Multiple epidemiological studies have shown that low testosterone levels are associated with and predict the future development of T2D and the metabolic syndrome. Although this relationship is confounded by the association of total testosterone with sex hormone-binding globulin, free testosterone remains associated with measures of insulin resistance and T2D in some, but not all studies. Although the link between low testosterone levels and insulin resistance is not solely a consequence of adiposity, current studies suggest that a substantial component is mediated through its association with body fat, in particular abdominal visceral adipose tissue. This testosterone-fat relationship is bi-directional, as both weight loss and testosterone therapy increase testosterone levels, reduce fat mass, and decrease insulin resistance. SUMMARY: Low testosterone levels are very commonly found in men with T2D and are associated with aging and obesity. Whether testosterone treatment in men with T2D decreases insulin resistance above that attributable to its fat-reducing effect is currently unknown. Future studies should compare testosterone treatment with lifestyle changes (exercise and weight loss measures), and other insulin-sensitizing agents. Until further evidence is available, testosterone therapy outside clinical trials should be reserved for diabetic men with unequivocal hypogonadism.