Department of Urology, Good Hope Hospital, Heart of England Foundation Trust and University of Aston, Birmingham, UK.

A third of men with type 2 diabetes (T2DM) have hypogonadotrophic hypogonadism (HH) and associated increased risk of cardiovascular and all-cause mortality. Men with HH are at increased risk of developing incident T2DM. We conducted MEDLINE, EMBASE, and COCHRANE reviews on T2DM, HH, testosterone deficiency, cardiovascular and all-cause mortality from May 2005 to October 2017, yielding 1,714 articles, 52 clinical trials and 32 randomized controlled trials (RCT). Studies with testosterone therapy suggest significant benefits in sexual function, quality of life, glycaemic control, anaemia, bone density, fat, and lean muscle mass. Meta-analyses of RCT, rather than providing clarification, have further confused the issue by including under-powered studies of inadequate duration, multiple regimes, some discontinued, and inbuilt bias in terms of studies included or excluded from analysis.

Type 2 diabetes (T2DM) is a major health and economic concern for the Western World. In the UK in 2017, 26% of the population over 65 years are diagnosed, and 56% of these are men. The prevalence is 6 times greater in men of South East Asian origin and 3 times greater in men of Afro-Caribbean background [1]. In the USA, two-thirds of men over 65 years have T2DM [2].

Obesity is the most potent risk factor for T2DM. It accounts for 80% to 85% of the overall risk of developing T2DM and underlies the current global spread of the condition [1]. Other risk factors are lack of exercise, family history, and gestational diabetes. In men, there is now strong evidence linking low testosterone to obesity, T2DM and components of the metabolic syndrome [1]. Several studies have shown high levels of hypogonadism (HG) in men with T2DM with around 20% being overtly hypogonadal with total testosterone (TT) below 8 nmol/L and around 50% falling below the 12 nmol/L level for mild HG [3]. In 2015, the American Association of Clinical Endocrinologists recommended that all men with T2DM should be screened for HG along with all men with body mass index (BMI) >30 kg/m2 or waist circumference over 104 cm [4]. The 2018 Endocrine Society guidelines, in contrast, continues to advise against any form of testosterone screening. Recent re-classification of HG by the Endocrine Society refers to T2DM related HG as ‘functional’ and some endocrine guidelines [5] suggest that only ‘classical’ HG be treated, despite no published studies demonstrating that this group responds better. On the contrary, evidence suggests that men classified as ‘functional HG’ form the majority of patients showing benefit from clinical trials [6].

The link between T2DM and HG is considered bidirectional and conventional management has recovered around lifestyle strategies of weight and exercise which are clearly failing as the prevalence continues to increase [7]. The evidence suggests that low testosterone leads to new onset T2DM and contributes to worsening comorbidities [8,9,10].

In a study of 1,413 men, those in the first (lowest) tertile of low free testosterone (FT) and TT were four times more likely to have diabetes than those in the third tertile of low TT and FT [8]. Furthermore, low FT and sex hormone binding globulin (SHBG) have been shown to predict the onset of diabetes in men in up to 10 years of follow-up (odds ratio [OR], 1.58 for a decrease of 4 ng/dL FT and OR, 1.89 for a decrease of 16 nmol/L SHBG) [9]. A meta-analysis of prospective studies, showed men with TT levels above 15.5 nmol/L had a 42% lower risk of incident diabetes (relative risk, 0.58; 95% confidence interval [CI], 0.39 to 0.87) compared with men with a TT of no greater than 15.5 nmol/L [11]. In a 2011 meta-analysis Corona et al's study [11], found baseline TT was 2.08 nmol/L (95% CI, 3.57 to 0.59) lower in men who developed incident T2DM compared with those who did not. A major reason for this diminished relationship in some studies was adjustment for central fat by waist circumference. In addition, individual studies lacked power because only of the low rates of incident diabetes.

Several longitudinal studies have shown that low levels of TT and FT independently predict the later development of T2DM or metabolic syndrome [12,13,14,15,16,17,18].

In the largest study to date, Holmboe et al [19] reported on 5,250 men from the Danish population followed-up for 29 years and showed that low TT and low SHBG were strongly associated with incident T2DM. There were 35/599 (lowest quartile of TT) vs. 13/599 (highest quartile of TT) (p=0.13) in the non-smokers, corresponding values were 48/660 vs. 17/658 (p=0.034). As there was no effect of luteinizing hormone, the authors concluded that ‘primary hypogonadism’ was not a risk ‘factor’ for T2DM but that low TT should be considered a risk ‘marker’ for T2DM. As there were no data on testosterone therapy reported by Holmboe et al [19], a causal relationship could not be established.

Numerous long-term studies, and various reviews and meta-analyses, have provided evidence to support the association between testosterone deficiency (TD) and increased cardiovascular (CV) and all-cause mortality [20,21,22,23,24,25], although evidence for a pathogenic link is lacking [26,27].

A systematic review and meta-analysis evaluating the association between endogenous testosterone and mortality concluded that low levels of endogenous testosterone are associated with an increased risk of all-cause and CV death in community-based studies of men, with a reduction of 2.1 standard deviations in TT being associated with a 25% increase in mortality. However, most of the studies had issues with cohort selection and choice [20,21].

Two systematic reviews and meta-analyses evaluating the association between endogenous testosterone and all-cause mortality and cardiovascular disease (CVD) mortality [20] reported a protective effect of increased TT. Research examining the data from 1,954 subjects, in terms of several statistical models, found that even after strict adjustment for comorbidities, there was a consistent link between testosterone level and mortality risk throughout, without proving causation [28].

In a prospective study involving 581 men with T2DM, patients were followed-up for a mean of 5.81 years. Low testosterone was defined as TT