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• W4241905734 abstract "Low testosterone in older men can result in symptoms of hypogonadism including decreased muscle strength, lethargy and reduced libido. It is also associated with poor cardiovascular (CV) outcomes, possibly mediated through effects on insulin resistance, visceral obesity and dyslipidaemia. Testosterone replacement is licensed to treat the symptoms of hypogonadism. There is evidence that it has an effect on markers of cardiovascular disease (CVD), but the long-term benefits are unknown. Symptoms of hypogonadism and risk of CVD are both prevalent in diabetes. Figure 1 outlines the synthesis and physiological action of testosterone. It is mainly produced in the Leydig cells of the testes under the control of luteinising hormone. Levels peak at puberty and decline after middle age. Testosterone acts locally within the testes and peripherally on testosterone sensitive tissues. It can act directly or by conversion to an active metabolite, dihydrotestosterone. These molecules bind to androgen receptors within the nuclei of target cells, thereby regulating transcription of androgen responsive genes. Effects include promoting spermatogenesis within the testes, regulation of sexual behaviour and protein synthesis in muscle. Testosterone replacement by different routes aims to mimic the actions of endogenous testosterone and return serum levels to within the normal physiological range. Oral preparations are rapidly metabolised by the liver and have a very short half-life. Alternative routes of administration include IM injections (short- and long-acting), topical gels, buccal tablets, cutaneous patches and implants. The choice of replacement will be determined by patient circumstances and preference. The synthesis and physiological action of testosterone In a double-blind, randomised, placebo-controlled trial of 237 healthy men with hypogonadism, the effect of testosterone on body composition and CV risk factors was assessed. Participants aged 60–80 years were randomised to receive either oral testosterone undecanoate 80mg twice-daily or placebo for six months. Testosterone was associated with a significant reduction in insulin resistance (using HOMA-IR) and fasting glucose compared with placebo (0 vs 0.6, p=0.02, and 0 vs 0.2, p=0.007, respectively). Reductions in total cholesterol and HDL were observed in the treatment group (0.2mmol/L vs 0.1mmol/L, p=0.03, and 0.2mmol/L vs 0.0mmol/L, p<0.001, respectively). No significant change in LDL or triglycerides was observed. Testosterone was associated with a reduction in total body fat (–1kg vs -0.1kg, p<0.001( and a gain in lean body mass (1.01kg vs 0.3kg, p<0.001). No significant change in BMI, waist circumference or intra-abdominal fat mass was observed. There was no significant difference in the number or type of adverse effects between groups.1 The Testosterone in Older Men (TOM) trial aimed to assess the role of testosterone vs placebo to improve muscle strength and mobility in 209 hypogonadal men aged 65 and over. Participants were randomised to receive a transdermal testosterone gel or placebo gel applied once-daily for six months. This trial was prematurely terminated due to concerns about the number of CV-related adverse events reported for the treatment group: 23 vs five in the placebo group. The difference in CV events between groups persisted over the three-month observation period following the intervention period.2 In a double-blind, placebo-controlled, crossover study of 24 hypogonadal men aged over 30 with type 2 diabetes, participants received IM injections of testosterone 200mg or placebo bi-weekly for three months, with a washout period of one month between each treatment phase. Testosterone was associated with a significant reduction in HbA1c (–0.37±0.17%, p=0.03) and fasting blood glucose (–1.58±0.68mmol/L, p=0.03). For the 14 participants not using insulin, fasting insulin resistance (HOMA-IR) was reduced on testosterone therapy (–1.73±0.67, p=0.02), although there was no change in fasting insulin levels in this group (p=0.1). Testosterone was associated with a small but significant reduction in total cholesterol (–0.4±0.17mmol/L, p=0.03) but no change to HDL, LDL or triglyceride levels. Reductions in waist circumference (–1.63±0.71cm, p=0.03) and waist/hip ratio (–0.03±0.01, p=0.01) were associated with testosterone, but there was no significant change in BMI or percentage body fat. IM testosterone was well tolerated with no adverse effects documented.3 The TIMES2 study is a multicentre, double-blind, placebo-controlled trial of 220 hypogonadal men aged 40 and above.4 The population were randomised in a 1:1 ratio to use either a transdermal testosterone gel or matching placebo once-daily for 12 months; 62% had type 2 diabetes and 80% had metabolic syndrome. Type 2 diabetes and metabolic syndrome were both present in 44% and 40% of the testosterone replacement and placebo groups, respectively. The study was divided into two six-month phases: during Phase 1 no alterations to diabetes, lipid-lowering or antihypertensive medications were allowed, and during Phase 2 adjustments were allowed. Testosterone reduced insulin resistance (HOMA-IR) in the overall population significantly at six and 12 months as compared to placebo (15.2%, p=0.018, and 16.4%, p=0.006, respectively). In the diabetic population, insulin resistance was reduced at six months (16%, p=0.049), and 12 months (p=0.01). There was no significant change in insulin resistance in patients with metabolic syndrome at six or 12 months. The mean change in HbA1c between placebo and testosterone was statistically significant only at nine months, but is of uncertain clinical significance due to the modification of other medications permitted in Phase 2. In the metabolic syndrome subgroup, testosterone was associated with significant reductions in plasma levels of total cholesterol (–0.336mmol/L, p=0.003), LDL (–0.210mmol/L, p=0.012) and lipoprotein A (–0.31μmol/L, p=0.008). Testosterone was associated with a significant reduction in HDL in the total population (–0.049mmol/L, p=0.032), and in the diabetes and metabolic syndrome subgroups (–0.062mmol/L, p=0.043, and –0.058mmol/L, p=0.016, respectively). There was no significant change in triglycerides, percent body fat, BMI or waist circumference. Levels of adverse effects were similar across both treatment groups, with erythema and pruritus the most common events. There is evidence that low levels of testosterone are associated with increased CV morbidity and mortality. When administered to hypogonadal men, testosterone replacement therapy may favourably influence CV risk factors such as insulin resistance, dyslipidaemia and visceral obesity. However, there are no endpoint data to show a reduction in CV outcomes. In addition, a recent trial was stopped early because of concerns about an increase in CV events associated with testosterone therapy. Current findings are based on trials with modest follow-up periods and population sizes. In addition, comparability between trials is limited due to varying baseline characteristics and different routes of testosterone administration. The authors of the TOM trial acknowledge that the testosterone doses and serum levels in their trial are possibly higher than those used in other clinical trials and in clinical practice. Further research is required to explore the relationship between testosterone therapy and its impact on CV morbidity and mortality. There are no conflicts of interest declared. References are available online at www.practical.diabetes.com. Hypogonadism is prevalent in the aging male population, particularly in diabetes Testosterone is an effective treatment for the symptoms of hypogonadism Testosterone replacement has favourable effects on insulin resistance, dyslipidaemia and visceral obesity The effect of testosterone use on cardiovascular morbidity and mortality has not been established" @default.
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• W4241905734 date "2012-06-01" @default.
• W4241905734 modified "2023-09-25" @default.
• W4241905734 title "Testosterone" @default.
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• W4241905734 doi "https://doi.org/10.1002/pdi.1692" @default.
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