Effects of testosterone on Type 2 diabetes and components of the metabolic syndrome
T. Hugh JONES
Academic Unit of Diabetes, Endocrinology & Metabolism, School of Medicine and Biomedical Sciences, University of Sheffield, Sheffield, and Robert Hague Centre for Diabetes & Endocrinology, Barnsley Hospital NHS Foundation Trust, Barnsley, UK
T. Hugh Jones, Robert Hague Centre for Diabetes & Endocrinology, Barnsley Hospital NHS Foundation Trust, Barnsley, S75 2EP, UK. Tel: +44 1226 432147 Fax: +44 1226 434404 Email: firstname.lastname@example.org
Observations from clinical studies suggest that low serum levels of testosterone in men are often associated with obesity, insulin resistance, and metabolic compromise. Indeed, the clinical symptoms of late-onset hypogonadism are markedly similar to those of Type 2 diabetes mellitus (T2DM) and metabolic syndrome, and may share a similar pathophysiology. Observational and experimental data suggest that testosterone treatment improves a number of hallmark features of T2DM and metabolic syndrome, namely insulin resistance, obesity, dyslipidemia, and sexual dysfunction. Consequently, clinical studies have been undertaken to assess the impact of testosterone-replacement therapy in this patient group. The present article reviews the observational clinical data suggesting an association between low serum testosterone and metabolic impairment, the clinical data relating to the effects of testosterone treatment on components of the metabolic syndrome, and the randomized clinical trails that have formally investigated whether testosterone-replacement therapy provides clinical benefit to hypogonadal men with T2DM and/or metabolic syndrome.
Because of the increasing incidence of Type 2 diabetes mellitus (T2DM) and metabolic syndrome, the burden on healthcare provision worldwide is also growing. Numerous new therapeutic strategies for the treatment of T2DM have emerged over the past decade and there is growing emphasis on the need to prevent rather than cure metabolic disease. Modification of calorific dietary intake and improvement of a sedentary lifestyle are central to such an approach, but are acknowledged to be difficult to achieve for a variety of different reasons. New treatment options are therefore required.
T2DM and metabolic syndrome are interconnected conditions, often coexisting and with the diagnosis of metabolic syndrome often pre-empting the development of T2DM. The hallmark feature of T2DM is insulin resistance, which is diagnosed by either increased fasting blood glucose (FBG), impaired glucose tolerance (IGT), or a random blood glucose (RBG) 11 mmol/L and is the consequence of impaired pancreatic function resulting from the long-term attempt to lower glucose from an adversely elevated level. There are two main definitions of metabolic syndrome (Fig. 1), one from the National Cholesterol Education Programme–Adult Treatment Panel III (NCEP-ATP III)1 and the other from the International Diabetes Federation (IDF).2 Both definitions are similar, focusing on the key features of insulin resistance, hyperglycemia, visceral obesity, dyslipidemia [hypertriglyceridemia and lowered high-density lipoprotein–cholesterol (HDL-C)], and elevated blood pressure. The IDF definition places abdominal obesity as the central clinical feature of the syndrome, whereas the NCEP-ATP III definition places equal weighting on all characteristics (Fig. 1).
Hypogonadism is an underrecognised and underdiagnosed clinical condition that is especially prevalent in men with metabolic syndrome and/or T2DM. Hypogonadism is defined as a clinical syndrome associated with symptoms plus signs, as well biochemical evidence, of testosterone deficiency. Clinical hypogonadism shares a number of the characteristics with metabolic syndrome, including reduced insulin sensitivity, dyslipidemia and increased body fat. In a recent cross-sectional study of 355 men with T2DM, Kapoor et al.3 demonstrated that overt hypogonadism [defined as the presence of clinical symptoms of hypogonadism and total testosterone (TT) <8 nmol/L and/or bioavailable testosterone (BT) <2.5 nmol/L] was present in 17% of individuals. Borderline hypogonadism (defined as the presence of symptoms and a TT of 8–12 nmol/L or BT of 2.5–4 nmol/L) was found in 25% of individuals.3 This latter definition of TT between 8 and 12 nmol/L in conjunction with symptoms of hypogonadism is similar to the recommendations for the diagnosis of late-onset hypogonadism (LOH) made recently by the International Society of Andrology (ISA), International Society for the Study of Aging Male (ISSAM), European Association of Urology (EAU), European Academy of Andrology (EAA), and the American Society of Andrology (ASA).4 Furthermore, a number of cross-sectional studies have indicated that low serum testosterone is associated with a number of the clinical characteristics of metabolic syndrome and that testosterone treatment has a positive influence on a number of the components of metabolic syndrome. These are summarized below:
Association between low testosterone and T2DM or components of metabolic syndrome
Evidence suggests that a decline in testosterone may be linked to the development of a number of the clinical characteristics associated with T2DM and metabolic syndrome: total testosterone is inversely related to insulin concentration and insulin resistance in men,5,6 a number of cross-sectional epidemiological studies have reported an association between low testosterone and T2DM,3,7,8 and a number of studies have suggested that low levels of testosterone are a precursory factor for the incidence of insulin resistance and T2DM in healthy men.9–11 Furthermore young men with T2DM were found to have lower testosterone than an age-matched group with Type 1 diabetes that was correlated with the degree of obesity.12
Evidence also suggests that a close inverse relationship exists between serum levels of testosterone and the degree of obesity in men.13,14 Specifically, abdominal or central obesity has been inversely related to total and free testosterone15–17 and Abate et al.18 reported that subcutaneous fat accumulation in the truncal area is highly predictive of low plasma concentrations of free testosterone. Hypogonadal men exhibit a reduced lean body mass and an increased fat mass, as observed in a study of 57 men aged between 70 and 80 years, in which Vermeulen et al.19 reported that testosterone levels were negatively correlated with percentage body fat, abdominal fat and insulin levels. Another study found a strong inverse relationship between subcutaneous fat mass and free and total testosterone in men with T2DM.20
The hypogonadal obesity cycle hypothesis21 suggests an explanation for these inverse associations between testosterone and obesity and insulin resistance. Briefly, testosterone is metabolized to 17β-estradiol by aromatase located in excess adipocytes; the lower testosterone levels then allow for increased lipoprotein lipase activity, resulting in increased fatty acid uptake and triglyceride storage in adipocytes. This, in turn, results in an increase in fat mass, which correlates with increased insulin resistance and greater breakdown of testosterone. Testosterone is known to promote the development of pluripotent stem cells into myocytes and to inhibit adipogenesis, whereas testosterone deficiency facilitates adipocyte proliferation.22 The hypogonadal obesity adipocytokine hypothesis23 proposes that 17β-estradiol and the adipocytokines interleukin (IL)-6, tumor necrosis factor (TNF)-α and leptin inhibit the hypothalamic–pituitary–testicular response to hypotestosteronemia. This impaired homeo-static response explains why some men with obesity have a state of hypogonadotrophic hypogonadism with low or normal gonadotrophin levels in the presence of low serum testosterone. Furthermore, insulin resistance is associated with reduced testosterone secretion by the Leydig cells of the testis.24 This finding is supported by animal data, which demonstrate that the neuronal insulin receptor-knockout (NIRKO) mouse has hypogonadotrophic hypogonadism.25
Other studies have considered the link between hypotestosteronemia and other components of metabolic syndrome. A positive correlation between testosterone and HDL-C levels has been reported in healthy and diabetic men, with individuals measured at the highest quartile of testosterone consistently registering the highest levels of HDL-C.26,27 Similarly, low plasma testosterone has been associated with hypertension28–30 and, recently, an inverse relationship between testosterone and diastolic blood pressure (DBP) was observed in patients with erectile dysfunction and heart failure.31 Dyslipidemia is also associated with T2DM, with increases in total and low-density lipoprotein–cholesterol (LDL-C) commonplace. Many cross-sectional studies have also reported that endogenous serum levels of testosterone are negatively correlated with serum levels of total and LDL-C (for a review, see Jones and Saad32).
Effects of testosterone treatment on components of the metabolic syndrome
Insulin resistance and obesity
Many studies have shown that testosterone therapy has beneficial effects on insulin sensitivity and markers of obesity; these are summarized in Table 1. Similarly, the acute withdrawal of sex steroid therapy from young, otherwise healthy men with idiopathic hypogonadotropic hypogonadism (IHH) resulted in significant increases in fasting insulin and homeostasis model assessment of insulin resistance (HOMA-IR), which occurred just 2 weeks after the suspension of treatment.33
Table 1. Effects of testosterone treatment on obesity and insulin resistance in non-diabetic men
A number of potential hypotheses have been derived to explain these observations. Studies on the direct effects of testosterone on cultured adipocytes and adipose tissue suggest that androgen treatment may decrease adipogenesis and increase lipolysis34 by a number of different mechanisms. Testosterone has been reported to inhibit lipid uptake and lipoprotein lipase activity in adipocytes, along with stimulating lipolysis through an increased in the number of β-adrenergic receptors, and also inhibiting the differentiation of precursor adipocytes.35 Further evidence for the negative effect of testosterone on adipocyte differentiation was provided by Singh et al.,36 who reported that the treatment of isolated stem cells with testosterone promoted the development of myocytes rather than adipocytes and that testosterone deficiency favored the development of adipocytes over cells of myocyte lineage. Consequently, testosterone treatment may directly reduce visceral fat mass and increase muscle mass, resulting in the observed decrease in waist circumference, which, in turn, has a direct effect on circulating fatty acids and insulin resistance.
Another potential mechanism for the bene-ficial effect of testosterone in diabetic men may be to increase the metabolic rate and promote the acquisition of energy from fat stores. Pitteloud et al.37 describe an inverse relationship between testosterone levels and mitochondrial function, with low testosterone levels being associated with reduced muscle mitochondrial oxidative phosphorylation. Consequently, testosterone may increase the metabolic rate and promote the acquisition of energy from fat stores. In addition, inflammatory adipocytokines, including TNF-α and IL-6, are known to interfere with insulin signal transduction, leading to reduced insulin receptor sensitivity.38
Hypertriglyceridemia and lowered HDL-C
Many studies have reported on the effects of testosterone treatment on atherogenic lipid markers in a number of different patient populations (Table 2). The effect of testosterone therapy on HDL-C levels has been investigated in several studies, with differing results. These conflicting results may be explained by differences in the deposition site of adipose fat (abdominal versus gynoid), levels of insulin sensitivity among patient groups, or by the mode of testosterone administration (physiological versus supraphysiological). Overall, most of the studies show no adverse effect of testosterone treatment on HDL-C and some even reported a significant rise in levels. The studies that have found small falls in HDL-C are mainly in healthy men with chemically induced hypogonadism given testosterone replacement. Rises in HDL-C with testosterone therapy tend to occur if there is replacement to high normal or supraphysiological levels.39 Only one study using the testosterone undecanoate has reported a fall in triglyceride levels (Table 2).
Table 2. Effects of testosterone treatment on high-density lipoprotein–cholesterol and triglycerides in non-diabetic men
TU (1000 mg, i.m., at weeks 0 and 6 and thereafter every 12 weeks) or TT gel (50 mg/day), both for 9 months
Reductions in TC, LDL-C, and TG
The role of testosterone therapy on blood pressure is not clear, with most published studies showing no effect although a few have found small falls in DBP. Anabolic steroid abuse is known to be associated with an increased risk of hypertension.40–42 Only three studies have found testosterone-replacement therapy to lower blood pressure: Marin et al.43 were the first to report that transdermal testosterone produced a small but significant reduction in DBP; in an open-label study, men treated with testosterone for osteoporosis had significant falls in both systolic blood pressure (SBP) and DBP;44 and a recent study investigating the effects of testosterone undecanoate depot therapy in hypogonadal men45 demonstrated a decrease in both resting SBP and DBP.
Although not constituting a formal diagnostic criterion for metabolic syndrome, as well as T2DM per se are recognized as proinflammatory states, with a number of cytokines and adipokines having been proposed to be involved in the pathophysiology of insulin resistance. Furthermore, proinflammatory cytokines are intimately involved in the atherosclerotic process, and both T2DM and the metabolic syndrome are strong risk factors for, and often co-exist with, coronary heart disease. Several clinical studies have reported that testosterone-replacement therapy in hypogonadal individuals results in a reduction in the ex vivo production46 or the circulating concentration47,48 of a number of proinflammatory cytokines. Testosterone has also been used as a treatment prior to intracoronary stenting procedures and was shown to reduce the levels of IL-6, C-reactive protein (CRP), and other inflammatory factors that can cause post-surgical restenosis.49 Testosterone treatment of men with T2DM did not result in any significant immunomodulatory effect; however, baseline levels of both IL-6 and CRP, but not TNF-α, were significantly inversely correlated with total and bioavailable amounts of circulating testosterone, confirming that low testosterone is associated with inflammation.50,51
Total and LDL-C
Total cholesterol and LDL-C are not features of metabolic syndrome, but are important as cardiovascular risk factors. In most studies, testosterone therapy usually results in small reductions in one or both of these parameters (Table 2). Elevated total and LDL-C levels are common in T2DM and the management of this hyperlipidemia in T2DM is vital for the prevention of cardiovascular events. A number of studies have reported the effects of testosterone treatment on atherogenic lipid markers, in a number of different patient populations. Two meta-analyses of clinical trials in hypogonadal men report that significant reductions in both total cholesterol and LDL-C are associated with testosterone-replacement therapy.39,52 The key individual studies are summarized in Table 2.
Studies of testosterone-replacement therapy in patients with T2DM and metabolic syndrome
The observational data described above suggest that low levels of testosterone in men commonly coexist with, and that testosterone treatment has beneficial effects on, components of the metabolic syndrome and the clinical characteristics of T2DM. Such data suggest that testosterone-replacement therapy may be a valid therapeutic option for hypogonadal man with T2DM. A few studies have been conducted specifically to determine whether testosterone treatment has any quantifiable clinical benefit to this group of patients and these studies are summarized in Table 3.
Table 3. Effects of testosterone treatment in men with Type 2 diabetes mellitus
The first study to investigate the effects of testosterone treatment in men with T2DM was that of Boyanov et al. in 2003.53 Boyanov et al.53 recruited 48 men aged between 45 and 65 years (mean age 57.5 years) with a clinical diagnosis of T2DM, serum levels of total testosterone below 15.1 nmol/L, and either erectile dysfunction or symptoms of the andropause. This study was an open-label randomized non-treatment controlled study conducted over 3 months. Patients received oral testosterone undecanoate at a daily oral dose of 120 mg, in divided doses of 80 mg at breakfast and 40 mg at the evening meal (n = 24), or no treatment (n = 24). The main outcome measures were weight, body mass index (BMI), waist:hip ratio (WHR), body composition (as assessed by bioelectrical impedance), blood chemistry [HbA1c, FBG, postprandial blood glucose (PPBG), total cholesterol, LDL-C, HDL-C, and triglycerides], and symptoms of androgen deficiency [as assessed by the ADAM (Androgen Deficiency of the Aging Male) questionnaire]. Compared with the untreated group, testosterone treatment resulted in significant reductions in weight, WHR, and percentage body fat. Both FBG and PPBG were significantly reduced, and HbA1c fell by 1.8% (P < 0.05). No significant effects on lipid parameters were observed. Testosterone treatment also produced improvement in symptom scores of androgen deficiency and erectile dysfunction. The limitations of this study were that there was no placebo group and that more intensive clinic visits alone during the trial would have been likely to have had some beneficial effect on glycemic control. However, this study provided the first evidence that testosterone treatment may offer clinical benefit to men with T2DM.
The first randomized double-blind placebo-controlled study of testosterone therapy in men with T2DM was published 3 years later by Kapoor et al.54 In contrast with the study of Boyanov et al.,53 Kapoor et al. enrolled 24 patients with T2DM (having an HbA1c <9.5%) with a clinical diagnosis of hypogonadism, defined as having a total testosterone <12 nmol/L on two separate occasions and also having a positive ADAM questionnaire score. The study was of a double-blind placebo-controlled cross-over design, with patients randomized to treatment with either testosterone first or placebo first by a computer-generated system, each treatment phase being of 3 months duration separated by a 1-month washout period. Testosterone treatment was with 200 mg testosterone esters (24 mg testosterone propionate/48 mg testosterone phenypropionate/48 mg testosterone isocaproate/80 mg testosterone decanoate) administered as a deep intramuscular injection once every 2 weeks, such that each patient received a total of six injections. The final assessment of clinical parameters was made 12–14 days after the final injection. Equal volumes of saline were administered in an identical manner as a placebo. The primary outcomes were changes in insulin resistance, as measured by HOMA-IR, FBG and HbA1c, with changes in fasting lipids, blood pressure, waist circumference, WHR, BMI, and body fat assessed as secondary endpoints. Testosterone treatment resulted in a significant improvement in the HOMA-IR index in those patients not receiving insulin therapy (n = 14) and resulted in a reduction in insulin dose by an average of 7 units/day in those patients on insulin therapy (n = 10). In the entire patient population, significant reductions in both FBG (−1.58 mmol/L) and fasting insulin were observed, with HbA1c falling by 0.4% (P = 0.03). In addition to improvements in blood glucose parameters, testosterone treatment also resulted in significant improvements in waist circumference, WHR, and total cholesterol (−0.4 mmol/L), although no significant effect was observed on HDL-C, LDL-C, triglycerides, or blood pressure. Symptoms of hypogonadism improved, as shown by a significant reduction in the ADAM score.
The third study investigating the effects of testosterone-replacement therapy in men with T2DM is that of Heufelder et al.55 This study built on that of Kapoor et al.54 by being conducted over a 52-week treatment period, therefore representing the first longer-term investigation. The study of Heufelder et al.55 had similar recruitment criteria to that of Kapoor et al.,54 enrolling 32 hypogonadal men (defined as having a morning plasma testosterone concentration <12 nmol/L on two separate occasions) with newly diagnosed, treatment-naïve T2DM [fasting plasma glucose (FPG) >7.0 mmol/L and/or RBG >11.1 mmol/L after a 2-h oral glucose tolerance test and an elevated HbA1c], but with the additional criterion of also having metabolic syndrome (as defined by IDF criteria). Therefore, all patients were abdominally obese in addition to having hypogonadism and T2DM. The study was of a single (clinician) blind randomized design, with patients either receiving diet and exercise alone or diet and exercise in conjunction with 50 mg testosterone gel once daily. Compared with diet and exercise alone, testosterone treatment resulted in a significant improvement in HbA1c of −0.8% (P < 0.001), with all patients attaining an HbA1c of <7.0% and 87.5% of patients attaining an HbA1c <6.5%, significantly more than in the diet and exercise alone arm. This was combined with a significant reduction in the HOMA-IR index, although the observed treatment-mediated reduction in FPG (−0.3 mmol/L) narrowly failed to achieve statistical significance (P = 0.06). In addition, a significant improvement in waist circumference was observed. Finally, and in contrast with the previous studies, testosterone treatment was associated with a significant reduction in serum triglyceride levels and a significant increase in serum HDL-C levels.
These preliminary studies all suggest that testosterone-replacement therapy offers marked clinical improvements for hypogonadal men. Consequently, a large multicenter randomized double-blind placebo-controlled study was recently undertaken in eight European countries, providing suitable statistical power to test this hypothesis formally. The TIMES2 (Testosterone replacement In hypogonadal men with Metabolic Syndrome and/or Type 2 Diabetes) study 56 recruited 220 hypogonadal men (aged ≥40 years) diagnosed with either T2DM (∼25%), metabolic syndrome (defined according to the IDF criteria; ∼45%), or both (∼40%), who also had either total serum testosterone <11 nmol/L or calculated free serum testosterone <255 pmol/L, and/or at least two symptoms of hypogonadism with no testosterone-replacement therapy within the previous 6 months. Patients were stratified according to disease status (T2DM and/or metabolic syndrome) and were randomized to receive testosterone-replacement therapy initially as a 60 mg/day transdermal gel, which was subsequently dose adjusted to 20–80 mg/day to achieve serum testosterone levels within the physiological range. Patients randomized to placebo received an identical transdermal placebo gel with dummy dose adjustment. The primary endpoint was the change in HOMA-IR after 6 and 12 months, with secondary endpoints being changes in the components of metabolic syndrome (body composition, lipid profile, blood pressure, and glycemic control), symptoms of hypogonadism [the Aging Male Symptoms (AMS) questionnaire score, and the International Index of Erectile Function (IIEF) questionnaire score], and cardiovascular events, safety, and tolerability. Changes in diabetes and lipid-lowering medications were prohibited for the first 6 months of the study (unless necessary for appropriate clinical management). Patients receiving physiological testosterone-replacement therapy exhibited significant reductions in HOMA-IR compared with those on placebo [ratio: 0.836; 95% confidence interval (CI) 0.735, 0.950; P = 0.006], which was accompanied by significant reductions in HbA1c of −0.446% (95% CI −0.859, −0.032) in those patients with T2DM (62% of the intention-to-treat population). Testosterone-replacement therapy was also associated with significant reductions in body fat, waist circumference, total cholesterol, LDL-C, and lipoprotein A. Lipoprotein A is a highly atherogenic agent with no other treatment apart from testosterone known to have any suppressive effect. There were no significant effects on HDL-C. Importantly, testosterone-replacement improved symptoms of sexual function, including libido.
The results of the above observational and randomized controlled clinical studies strongly suggest that hypogonadal men with T2DM and metabolic syndrome attain clinical benefit from physiological testosterone-replacement therapy. The symptomatic clinical benefits offered by testosterone-replacement therapy to hypogonadal men are well known, and similar positive effects on androgen deficiency and erectile function questionnaire scores (ADAM, AMS, and IIEF) were also observed in these metabolically compromised men. Of note is the consistency of the findings of the four randomized controlled clinical trials of testosterone-replacement therapy in hypogonadal men with T2DM and metabolic syndrome. Despite being undertaken by different research groups and using different modalities for the replacement of serum levels of testosterone to within the physiological range, all the studies reported an improvement in insulin resistance and HbA1c, coupled with reductions in visceral obesity and improvements in body composition. In addition, beneficial effects on lipids and blood pressure have been reported in some, but not all, studies following testosterone treatment. Consequently testosterone-replacement therapy may constitute a valid therapeutic option for men with T2DM who present with symptoms of low serum testosterone, which may constitute a significant proportion of the male T2DM population. If testosterone-replacement therapy is considered, it is important that diagnostic criteria for hypogonadism are confirmed, prostate carcinoma is excluded, no contraindication to testosterone therapy exists, and treatment is carefully monitored as per international guidelines.
In addition to offering a solution for the decreased quality of life experienced by hypogonadal men, testosterone-replacement therapy may also have a positive impact on the insulin resistance and impaired glucose control inherent to individuals with T2DM. The potential impact of improvements in insulin resistance and glycemic control on reducing microvascular and macrovascular complications, which are the major causes of morbidity and mortality in this patient group, are well known.