Review
Metabolic Effects of Testosterone Therapy in Men with Type 2 Diabetes and Metabolic Syndrome

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Abstract

Introduction

Up to 40% of men with type 2 diabetes (T2DM) and metabolic syndrome (MetS) have hypogonadotrophic hypogonadism (HH). Men with HH are at increased risk of cardiovascular (CV) and all-cause mortality, as well as of the development of incident T2DM.

Aim

To review the current literature on the metabolic effects of testosterone therapy (TTh) in men with T2DM and MetS.

Methods

We searched MEDLINE, Embase, and Cochrane Reviews for articles on T2DM, HH, testosterone deficiency, and CV and all-cause mortality published between May 2005 and July 2018, yielding 1817 articles, including 54 clinical trials and 32 randomized controlled trials (RCTs).

Main Outcome Measures

The main outcomes were glycemic control, insulin resistance, lipid profile, and metabolic markers associated with increased CV risk.

Results

RCTs of TTh suggest significant benefits for sexual function, quality of life, glycemic control, insulin sensitivity, anemia, bone density, and fat and lean muscle mass that might be expected to translate into reduced long-term morbidity and mortality. Several longitudinal and observational studies suggest long-term sustained improvements in metabolic parameters and a trend toward reduced CV and all-cause mortality, especially in men at increased CV risk, such as those with T2DM and MetS. The greatest benefit is seen in those men treated with TTh to target levels and for longer durations.

Conclusion

Meta-analyses of RCTs, rather than providing clarification, may have further confused the issue by including underpowered studies of inadequate duration, multiple therapy regimens, some obsolete or withdrawn, and built-in bias in terms of studies included or excluded from analysis.

Hackett G. Metabolic Effects of Testosterone Therapy in Men with Type 2 Diabetes and Metabolic Syndrome. Sex Med Rev 2019;7:476–490.

Introduction

Type 2 diabetes mellitus (T2DM) is a major health and economic concern in the Western world. In the United Kingdom in 2017, 26% of the general population age >65 years had a diagnosis of T2DM, and 56% of these were men.1 The prevalence is 6 times greater in men of Southeast Asian origin and 3-fold greater in men of Afro-Caribbean background.1 In the United States, two-thirds of men age >65 years have T2DM.2

Obesity is the most potent risk factor for T2DM, accounting for 80%–85% of the overall risk of developing T2DM, and underlies the current global spread of the condition.3 Other risk factors include lack of exercise, family history, and gestational diabetes. In men, there is now strong evidence linking low testosterone level to obesity, T2DM, and components of the metabolic syndrome (MetS).3

Low circulating total testosterone (TT) concentrations in modest obesity primarily reflect reduced concentrations of sex hormone-binding globulin (SHBG). More marked obesity can lead to genuine hypothalamic-pituitary-testicular axis suppression through the GPR54-kisspeptin pathway. Hypothalamic-pituitary-testicular axis suppression is thought to be mediated via proinflammatory cytokines and dysregulated leptin signaling aggravated by associated comorbidities, such as T2DM, hypertension, and dyslipidemia. Low circulating testosterone levels lead to greater visceral adiposity, and this bidirectional association leads to a further rise in proinflammatory cytokines and increased cardiometabolic risk.4

Several studies have shown high levels of hypogonadism (HG) in men with T2DM, with approximately 20% being overtly hypogonadal with TT <8 nmol/L and approximately 50% with TT below the 12 nmol/L level defining mild HG.3

In this review, we consider the metabolic consequences of untreated low testosterone level, as well as the impact of testosterone therapy (TTh) in men with T2DM and MetS.

Section snippets

Methods

We searched MEDLINE, Embase, and Cochrane Reviews for articles on T2DM, HG, MetS, testosterone deficiency, and cardiovascular (CV) and all-cause mortality published between May 2005 and July 2018. This search yielded 1817 articles, 54 clinical trials, and 32 randomized clinical trials (RCTs). 37 of these articles were included in this study. The articles reported 28 cross-sectional studies, 25 longitudinal studies, and 15 interventional studies. During the review process, a further 4

Recommendations from published guidelines

In 2016, the American Academy of Clinical Endocrinologists recommended screening for HG in all men with T2DM, as well as all men with a body mass index (BMI) >30 or waist circumference >104 cm.5 In contrast, the 2018 Endocrine Society guidelines continue to advise against any form of testosterone screening, but do acknowledge the high prevalence rates of HG in conditions such as T2DM. The recent reclassification of HG by the Endocrine Society refers to T2DM-related HG as “functional,” and some

Incident T2DM and low testosterone

The link between T2DM and HG is considered bidirectional, and conventional management has centered around lifestyle strategies of weight and exercise; the prevalence continues to increase, however.2, 3 Several longitudinal studies have shown that low levels of TT, free testosterone (FT), and SHBG independently predict the later development of T2DM or MetS.11, 12, 13, 14, 15, 16, 17, 18, 19, 20 Despite these studies, testosterone measurement is not included in national strategies for T2DM

Low testosterone and cv and all-cause mortality

Numerous long-term studies, and various reviews and meta-analyses, have provided evidence to support the association between low endogenous testosterone and increased CV and all-cause mortality.25, 26, 27, 28, 29, 30, 31 The likely mechanism is the heightened proinflammatory state and association with components of MetS, such as increased insulin resistance and dyslipidemia, known to be associated with increased CV risk. Unfortunately, however, direct evidence of a pathogenic link is lacking.25

TTH and metabolic effects in T2DM and METS

Low testosterone has been closely linked with components of MetS in T2DM.22 The mainstay of modern therapy for T2DM is directed at reducing CV risk. Smoking cessation, weight reduction, and exercise have been shown to improve insulin sensitivity and should always be offered in conjunction with other therapies.33 Aggressive management of dyslipidemia and hypertension led to the National Institute for Health and Clinical Excellence guideline of offering all men with T2DM metformin, a statin, and

Nonalcoholic fatty liver disease

Low testosterone levels in men with T2DM and MetS have been associated with nonalcoholic fatty liver disease,60 and in animal experiments, administration of TU significantly reduced liver enzymes and liver fat.61 Hoyos et al62 conducted an RCT of 69 obese men with obstructive sleep apnea (mean BMI, 31.3) with placebo or long-acting TU, and found increased insulin sensitivity and reduced liver fat in the TU group. In contrast, Huang et al63 studied 209 hypogonadal men (mean age, 73 years)

Lipid metabolism and biomarkers

Trials of testosterone injection therapy on lipids have repeatedly demonstrated small reductions in TC, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) levels. Meta-analyses involving variable entry criteria, routes of administration, doses, and durations of therapy have generally shown inconsistent effects.

In the T Trial,56 with 69% of 780 men age >65 receiving statin therapy, the effects of testosterone 1% gel vs placebo over 12 months were

Reviews and meta-analyses of testosterone and metabolism

Several meta-analyses have considered the impact of TTh on metabolism, but, far from clarifying the issue, in some cases they have created confusion.70 The highest level of evidence comes from RCTs, but many of these were of insufficient duration, often less than 26 weeks and sometimes only 12 weeks (mean, 33.5 weeks).71 Many involved mixed populations, making it doubtful that changes in insulin resistance or HbA1c can be achieved in men without significant insulin resistance.22, 71 These

TTH and CV and all-cause mortality in T2DM

Numerous long-term studies and various reviews and meta-analyses have provided evidence supporting the association between HG and increased CV and all-cause mortality. 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 mortality in community-based studies of men, with a reduction in TT of 2.1 SDs being associated with a 25%

Conclusion

The low testosterone level frequently seen in men with T2DM is associated with increased comorbidity and mortality. Studies with TTh suggest significant benefits in sexual function, quality of life, glycemic control, lipids, anemia, bone density, and fat and lean muscle mass. Critical evaluation of clinical trials has been complicated by the inclusion of mixed populations, often nonobese, and with the inclusion of well-controlled men with minimal insulin resistance and with variable regimens of

Statement of authorship

Category 1

  1. (a)

    Conception and Design

    • Geoffrey Hackett

  2. (b)

    Acquisition of Data

    • Geoffrey Hackett

  3. (c)

    Analysis and Interpretation of Data

    • Geoffrey Hackett

Category 2
  1. (a)

    Drafting the Article

    • Geoffrey Hackett

  2. (b)

    Revising It for Intellectual Content

    • Geoffrey Hackett

Category 3
  1. (a)

    Final Approval of the Completed Article

    • Geoffrey Hackett

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    Conflicts of interest: The author reports no conflicts of interest.

    Funding: None.

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